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Sources of mesenchymal stem cells.
Mesenchymal stem cells are heterogenous adult multipotent stromal cells that can be isolated from various sources including: bone marrow, peripheral blood, umbilical cord blood, dental pulp, and adipose tissue. They have certain immunomodulatory, immunosuppressive, and antimicrobial properties that enable them to have several therapeutic and clinical applications including: treatment of autoimmune disorders, role in hematopoietic stem cell transplantation and regenerative medicine, as well as treatment of various infections and their associated complications such as septic shock and acute respiratory distress syndrome. Although more success has been achieved in preclinical trials on the use of mesenchymal stem cells in animal models than in human clinical trials, particularly in septic shock and Chagas disease, more progress has been made in both disorders after the recent use of specific sources and certain doses of mesenchymal stem cells. Nevertheless, the utilization of this type of stem cells has shown remarkable progress in the treatment of few infections such as tuberculosis. The clinical application of mesenchymal stem cells in the treatment of several diseases still faces real challenges that need to be resolved. The following book chapter will be an updated review on the role of mesenchymal stem cells in various infections and their complications.
- mesenchymal stem cells
- host immunity
- antimicrobial properties
- septic shock
- Mycobacterium tuberculosis
- Chagas disease
- human immunodeficiency virus
1. Introduction to mesenchymal stem cells
Mesenchymal stem cells (MSCs), which were first described by Alexander Fridenstein in the 1960s, are heterogeneous, non-hematopoietic, adult multipotent stromal progenitor cells that are capable of self-renewal as well as differentiation into multiple lineages and various cell types [1, 2, 3, 4, 5, 6, 7, 8]. They can be isolated from several sources including bone marrow (BM), peripheral blood (PB), umbilical cord blood (UCB), amniotic fluid, placenta, adipose tissue (AT), and dental pulp as shown in Table 1 [1, 2, 3, 4, 5, 6, 7, 8]. Although the BM is the main source of MSCs, these stromal cells constitute only a small fraction of the total number of cells populating the BM [2, 4, 5, 6].
|3||Umbilical cord blood: Wharton’s jelly|
|4||Placenta: chorionic villi of placenta|
|7||Fallopian tubes and cervical tissue|
|9||Adipose tissues: fat|
|10||Dental pulp, periodontal ligaments, and exfoliated deciduous teeth|
|13||Skeletal muscle tissues|
|15||Lung tissues and alveolar epithelium|
|16||Liver tissues: fetal liver|
|17||Synovial membrane and fluid|
MSCs have the following distinguishing features: (1) ability to adhere to the plastic vessel under optimal culture conditions; (2) capability to differentiate into osteoblasts, adipocytes, and chondrocytes; and (3) having characteristic immunophenotypic profile on flow cytometry [1, 2, 3, 5, 6, 8, 9]. MSCs are characteristically positive for: CD 105, CD 73, and CD 90 and characteristically negative for the following surface markers: CD 45, CD 34, CD 11b, CD 14, CD 19, CD 79a, and HLA-DR. However, certain types of MSCs can occasionally show positivity or negativity for specific surface markers as shown in Table 2 [1, 2, 3, 5, 6, 8, 9, 10, 11, 12, 13, 14]. Also, MSCs can differentiate into other cell types including: myocytes, cardiomyocytes, and neurons .
|Characteristic surface markers|
|Other surface markers that may/may not be expressed||CD 117|
Several studies have shown that MSCs obtained from BM, AT, and other sources do express CD 34 surface markers [4, 15, 16, 17, 18]. MSCs can be seen in abundant numbers in the circulation under the following circumstances: stem cell mobilization with growth factors, tissue injuries, stroke, hypoxia, and inflammatory conditions [4, 19, 20, 21, 22, 23, 24]. Despite the efforts displayed over the last five decades including identification of nine transcriptional factors, little is known about the molecular basis underlying the stemness of MSCs and it is still unclear whether these recently discovered genes regulate stemness or only differentiation of MSCs .
2. Functions, properties, and therapeutic indications of MSCs
MSCs have immunomodulatory and immunosuppressive properties that enable them to have several therapeutic and clinical applications including: hematopoietic stem cell transplantation (HSCT), autoimmune disorders, regenerative medicine and tissue repair, neurological diseases, bone and cartilage disorders, as well as treatment of several infections and acute respiratory distress syndrome (ARDS). Details are shown in Table 3 [1, 2, 6, 8, 25, 26, 27, 28, 29]. MSCs are major constituents of the BM microenvironment and the HSC niche and apparently they are the masters of survival and clonality [30, 31, 32]. The main functions of MSCs include: formation of hematopoietic microenvironment, modulation of the activity of the immune system, and regulating cell trafficking .
3. Role of MSCs in host defense and infections
The putative roles of BM-MSCs during infection are: (1) detection of pathogens, (2) activation of host immune responses, (3) elimination of pathogens, (4) induction of proinflammatory gradients, and (5) modulation of proinflammatory host immune response due to having specific immunoregulatory properties of MSCs including: inhibition of differentiation of monocytes to dendritic cells (DCs), alteration of cytokine profile of DCs, induction of tolerant phenotypes of naïve and effector T-cells, inhibition of antibody production by B-cells, and suppression of natural killer (NK) cell proliferation and NK-mediated cytotoxicity [1, 2, 28, 34]. BM-MSCs may augment antimicrobial responses, abridge proinflammatory and damage responses, and ameliorate associated tissue injury and they appear to function as a critical fulcrum providing balance by promoting pathogen clearance during the initial inflammatory response, and suppressing inflammation to preserve integrity of the host and facilitate tissue repair [1, 2, 34].
The immunomodulatory properties of MSCs are mediated by cell-to-cell interaction and the secreted cytokines [35, 36, 37]. MSCs could potentially be involved at multiple levels in host defense by mobilizing immune effector cells and modulation of proinflammatory immune responses to minimize tissue damage [1, 37]. BM-MSCs may protect against infectious challenge by direct effects on the pathogens or through indirect effects on the host . However, placenta-derived MSCs and fetal membrane-derived MSCs are highly susceptible to herpes viruses including varicella zoster virus (VZV) [2, 38]. Several types of stem cells including BM-MSCs and neural stem cells can cross the blood brain barrier and reach not only brain tumors but also ischemic and injured tissues caused by certain infections in the brain and engraft there. Consequently, MSCs can be utilized as means of cellular carriers to deliver therapeutic agents to sites of brain injury in order to exert their therapeutic and tissue regenerative effects in the brain [39, 40, 41, 42, 43].
4. Antimicrobial properties of MSCs
MSCs have been shown to exhibit the following antimicrobial properties: (1) capacity to enhance antibacterial activity by interaction with the host innate immune system in order to increase antibiotic sensitivity, increase bacterial killing, and slow bacterial growth; (2) capacity to enhance bacterial clearance in preclinical models of sepsis, cystic fibrosis, and ARDS; and (3) secretion of antimicrobial peptides such as: interleukin (IL)-17, indoleamine 2,3-dioxygenase (IDO), β-defensins, lipocalin-2, and cathelicidin LL-37 [44, 45, 46]. Members of the chemokine family have been found to have antimicrobial peptide activity although the role of chemokines in immunity during infection is rather complicated .
5. MSCs in sepsis, ARDS, and chronic bacterial infections
5.1 MSCs in sepsis syndrome and septic shock
Sepsis syndrome and septic shock represent major health problems worldwide and they are leading causes of death in hospitalized patients due to their association with high rates of morbidity and mortality in the absence of effective therapy [48, 49, 50, 51]. Sepsis is a potentially lethal syndrome that can develop following an infection in which a breakdown in the immune homeostasis results in both proinflammatory and anti-inflammatory mechanisms that become uncoupled from normal regulation . The inflammatory-driven maladaptive response induces disruption of endothelial and epithelial barriers, thus resulting in organ dysfunction. However, the host responds to sepsis by stimulating the proliferation of HSCs in the BM or by activating emergency hematopoiesis in an attempt to counteract the effects of sepsis on the function of multiple body organs . Septic shock is a devastating complication of uncontrolled bacterial infection that carries a mortality rate of 20–50% [50, 52]. Currently, there is no specific treatment for septic shock and the management of this devastating complication of serious infections remains supportive. However, the following measures should be taken into consideration: early identification, fluid resuscitation, prompt institution of antibiotic therapy, control of the source of infection, circulatory support, and lung protection by mechanical ventilation [48, 49, 52, 53].
Based on numerous preclinical studies, cell-based therapies are potentially beneficial in the treatment of septic shock and ARDS. However, various types of stem cells including embryonic stem cells, MSCs, and induced pluripotent stem cells have been used in the treatment of sepsis and ARDS, but MSCs are the most commonly used stem cells in septic shock . In patients with septic shock complicated by acute lung injury (ALI) and ARDS, the paracrine factors secreted by MSCs can: mediate endothelial and epithelial permeability, and increase alveolar fluid clearance in addition to other mechanisms that reduce the complications of septic shock .
In a mouse model of sepsis, lipopolysaccharide-preconditioned MSC transplantation has been shown to: ameliorate survival rate after transplantation, protect cells from apoptosis and organ damage, and have immunomodulatory therapeutic properties . Also, transplanted MSC can secrete Toll-like receptor-4, which plays a seminal role in attenuating in vivo
Several preclinical sepsis studies have suggested that MSCs are capable of: modulating inflammation, enhancing clearance of pathogens as well as tissue repair, thus resulting in improvement in symptoms and reduction in organ damage and finally improvement in survival and reduction in mortality rates [48, 49, 50, 52]. A meta-analysis that evaluated the preclinical use of MSCs in animal models of septic shock demonstrated that MSC treatment significantly reduced mortality rates and the results of this survey supported the decision to proceed to clinical trials that test the effectiveness of MSCs in treating infections causing sepsis in humans .
In a phase I clinical trial that included patients admitted to the intensive care unit (ICU) with septic shock, infusion of freshly cultured allogeneic BM-MSCs in doses up to 3 million cells/kg into these ICU patients was shown to be safe as this dose of stem cells did not exacerbate the elevated cytokine levels in the plasma of patients with septic shock [52, 61].
5.2 MSCs in ALI and ARDS
Bacterial pneumonia and sepsis from non-pulmonary causes are the most common etiologies of ALI and ARDS that are associated with mortality rates ranging between 25 and 50% [62, 63, 64, 65]. Management of ARDS is mainly supportive with: protective ventilation, fluid conservation, and antimicrobial therapy [62, 64]. In patients with bacterial pneumonia and sepsis, MSCs can attenuate inflammatory process and enhance bacterial clearance [63, 65]. MSCs secrete paracrine factors that can regulate lung permeability and decrease inflammation and this makes MSCs a potentially attractive therapeutic modality for ALI . In patients with ARDS, MSCs can exert beneficial effects by secreting paracrine factors, microvesicles, and transfer of mitochondria. These secretory products have: (1) anti-inflammatory properties that participate in resolving injuries to lung endothelium and alveolar epithelium; (2) regulatory effects on alveolar fluid clearance, thus reducing lung edema; (3) antimicrobial effects mediated by release of antimicrobial factors; and (4) upregulation of monocyte/macrophage phagocytosis . In
In patients with bacterial pneumonia causing ALI and ARDS, MSCs could become a promising novel therapeutic modality and an ideal candidate for future cellular therapy due to the following reasons: (1) MSCs are able to differentiate into various cell types, (2) MSCs can secrete multiple bioactive molecules that are capable of stimulating recovery of injured cells and inhibiting inflammation, (3) MSCs lack immunogenicity, and (4) MSCs can perform immunomodulatory functions [62, 63, 65, 67]. In a phase I clinical trial, Jennifer Wilson et al. showed safety of allogeneic BM-MSCs administered to patients with ARDS [56, 68]. However, the role of MSCs in ARDS patients should be carefully evaluated by well-designed multicenter randomized clinical trials .
5.3 MSCs in severe and chronic infections
Chronic implant and wound infections that are characterized by biofilm formation are often difficult to treat and they usually require continuous antibiotic therapy for weeks to months. However, alternative therapies for chronically infected wounds include: use of antibiotic impregnated implant materials or biological scaffolds, administration of biofilm disrupting agents, and combining cellular immunotherapy with antibiotics .
In patients with very severe aplastic anemia (VSAA), prolonged neutropenia results in refractory and overwhelming bacterial infections as well as invasive fungal infections that are associated with significant morbidity and mortality in these severely immunocompromised individuals . In patients with VSAA lacking human leukocyte antigen identical sibling donors and having refractory infections, co-transplantation of haploidentical HSCs and allogeneic BM-MSCs has been shown to be a safe and a promising therapeutic modality .
Studies have shown that: (1) secretion of cathelicidin LL-37 by MSCs could enhance bacterial products indicating that MSCs can upregulate antimicrobial activity in the presence of infection and (2) activated MSCs, when administered intravenously and in combination with conventional antibiotics, can potentially suppress and eradicate chronic
5.4 MSCs in bone, joint, and dental infections
The multidirectional differentiation potential of BM-MSCs is essential for tissue repair after local injury of bones, joints, and medullary adipose tissue. Additionally, the regulation of multiple differentiation potentials of MSCs by various antimicrobial agents affects the recovery from bone and joint infectious diseases . Minocycline induces the following favorable changes in MSCs: migratory capacity, proliferation, gene expression, and growth factor release, ultimately resulting in enhancement of angiogenesis. Also, the triple antimicrobial-loaded hydrogels reduce bacterial bioburden and preserve viability of MSCs in the presence of bacteria .
Gingival MSCs encapsulated in silver lactate-containing alginate hydrogel have successfully differentiated into osteogenic tissue and have shown promise for bone tissue engineering with antimicrobial properties against peri-implantitis caused by gram negative bacterial infections . Synthesized antibiotic-containing scaffolds have been shown to possess significantly lower effects on proliferation and viability of human dental pulp stem cells when compared to the saturated ciprofloxacin/metronidazole solution .
6. MSCs in viral infections
Studies have shown that: (1) MSCs are susceptible to infection by members of the herpes group of viruses such as: cytomegalovirus, Epstein-Barr virus, herpes simplex virus (HSV) type 1, HSV-2, and VZV, and MSCs become functionally defective following infection with herpes viruses; (2) AT-MSCs can differentiate into functional hepatocyte-like cells but AT-MSCs undergoing hepatic differentiation are not susceptible to infection by hepatitis B virus in vitro; (3) human MSCs are permissive to the highly pathogenic avian influenza A/H5N1 infection and infection of MSCs can cause apoptosis and loss of their immunomodulatory activity; and (4) MSCs can significantly reduce the impairment of alveolar fluid clearance induced by influenza A/H5N1 infection in vitro and prevent or reduce influenza A/H5N1-associated ALI in vivo [28, 34, 74]. The extracellular vesicles (ECVs) secreted by MSCs have anti-inflammatory and anti-influenza properties. Hence, they can be used as cell-free therapy for influenza in humans . Infection of MSCs by respiratory syncytial virus (RSV) alters their immunoregulatory functions by upregulating interferon (IFN)-β and IDO, thus accounting for the lack of protective RSV immunity and for the chronicity of RSV-associated lung diseases such as bronchial asthma and chronic obstructive airway disease . In mice models, treatment with MSCs alleviates inflammation and mortality associated with Japanese encephalitis virus, which is a leading cause of viral encephalitis in Asia . Zika virus infection of human MSCs promotes differential expression of proteins that are linked to several neurological disorders such as Alzheimer’s disease, Parkinson’s disease, autism, and amyotrophic lateral sclerosis .
MSCs exhibit immunomodulatory, anti-inflammatory, and pro-angiogenic properties, and therefore have the potential to improve the outcome of allogeneic HSCT in patients with AA. In a multicenter study that included 75 patients with AA, the combination of HSCs obtained from BM and PB sources as well as MSCs has resulted in amelioration of acute graft versus host disease (GVHD) and viremia resulting ultimately in an improved survival benefit .
6.1 MSCs in HIV infection and AIDS
Acquired immunodeficiency syndrome (AIDS), which is caused by human immunodeficiency virus (HIV), poses a real threat to human life . Despite the advent of highly active antiretroviral therapy (HAART) that suppresses plasma viral load but does not cure disease, HIV-1 persists in latent tissue reservoirs, mainly in macrophages and T-helper lymphocytes, and this poses significant challenge to long-term cure [2, 80, 81, 82]. HIV-1 predominantly infects HSCs such as macrophages, monocytes, and T-helper lymphocytes . Non-immune responders (NIRs) do respond to HAART, which effectively suppresses HIV replication, but do not show any improvement in their immune status as reflected by an increase in CD4+ T-cell counts . More than 20% of HAART-treated HIV-infected individuals exhibit NIR phenotype and these individuals are at risk of opportunistic infections, cancer, and reduced life expectancy .
Coexposure to MSC-conditioned media can enhance the latency-reactivation efficacy of the approved latency reversing drugs vorinostat and panobinostat . Undifferentiated AT resident MSCs are not permissive to HIV-1 infection despite that HIV-1 exposure may increase the expression of some hematopoietic lineage related genes . It has been reported that transfusions of UCB-MSC or more specifically WJ are well tolerated and can efficiently improve immune reconstitution in HIV-infected individuals who are NIRs [83, 84]. Memory CD4 T cells are the key cells organizing all immune actions against HIV while being the targets of HIV infection . MSCs can express receptors that permit their infection by HIV-1. Additionally, human T-lymphotropic virus (HTLV)-1 could infect and replicate in human BM-MSCs possibly by involvement or infiltration of CD4+ lymphocytes [2, 86, 87].
7. MSCs in parasitic infections
Recently, MSCs have been introduced to treat parasitic infections associated with tissue damage in the form of granuloma formation or organ fibrosis such as: schistosomiasis, malaria, and Chagas disease [88, 89]. Studies have shown that MSCs can: (1) ameliorate liver injury and hepatic fibrosis induced by Schistosoma japonicum, particularly when combined with conventional therapies such as praziquantel and (2) play an important role in improving host protective immune responses against malaria by modulating regulatory T cells [88, 89].
7.1 MSCs in Chagas disease
Chagas disease, which is caused by the protozoan
The available and future therapies of Chagas disease include: treatment of arrhythmias and heart failure, antiparasitic therapy, resynchronization treatment, heart transplantation, and stem cell therapies [2, 90, 91, 93, 95]. In patients with chronic Chagas CMP and cardiac failure, conventional pharmacologic therapies are limited by being not always effective, thus rendering the disease incurable [90, 91, 96]. Heart transplantation may occasionally be needed but the procedure has a number of problems including: shortage of donors, high costs, and complications of long-term immunosuppressive therapies administered to recipients of heart transplants [90, 95].
Different stem cell types and delivery approaches have been used in both preclinical models as well as clinical trials with the aim of improving cardiac function and reversing complications . In animal models, stem cell therapies have shown reductions in: right ventricular dilatation, and inflammatory infiltrates as well as fibrosis [91, 93]. Stem cell therapy with BM-MSCs has emerged as a novel therapeutic option for Chagas CMP and heart failure [91, 93]. In a murine model of Chagas disease, cotransplantation of autologous BM-MSCs and skeletal myoblasts has been shown to be effective in reversing ventricular dysfunction . Also, in an animal model of chronic Chagas disease, genetic modification of MSCs mobilized by granulocyte colony stimulating factor has increased the immunomodulatory actions and paracrine functions of MSCs by recruitment of suppressor cells such as regulatory T-cells and myeloid-derived suppressor cells .
Transplantation of MSCs has shown clinical efficacy in animal or mouse models but studies in humans have not shown equivalent success due to a number of challenges that need to be overcome [2, 91, 93, 95, 98]. In animal models of chronic Chagas CMP, cardiac MSCs have been shown to exert protective effects by decreasing the degrees of fibrosis and inflammatory infiltrates in the affected myocardium . The beneficial effects of MSC therapy in Chagas mice models may be an indirect action of the cells on the heart rather than a direct action of the large numbers of transplanted MSCs on the myocardium [91, 96]. Tracking of infused BM-MSCs in animal models has shown migration of these cells to the heart and their participation in tissue repair or regeneration [91, 92, 93]. Although an early clinical trial of intracoronary injection of autologous BM-cells in patients with chronic Chagas CMP and heart failure showed safety and feasibility, a large multicenter, randomized double-blind, placebo-controlled trial using intracoronary infusion of BM-mononuclear cells showed no improvement in cardiac function or in quality of life in patients with chronic Chagas CMP [2, 99, 100].
8. MSCs in tuberculosis
Despite the strong host immune response in humans, MTB organisms are capable of persisting or staying dormant for prolonged periods of time, thus resulting in latent infection [104, 105, 106]. Hypoxia or hypoxemic microenvironment may favor dormancy of MTB and subsequent evolution of drug resistance . MSCs play a crucial role in the ability of MTB to evade the potent host immune responses and cause TB. Hence, targeting MSCs or nitrous oxide (NO) seems a plausible therapeutic intervention for the design of new effective preventive strategies against TB . Studies have shown that MSCs are recruited into the tuberculous granulomas and they position themselves between the harbored pathogen and the effector T-cells [107, 108, 109]. CD271+ BM-MSCs can provide an antimicrobial protective intracellular niche in the host in which dormant MTB can reside for prolonged periods of time [106, 109, 110, 111]. MTB infects and persists in a dormant form inside BM-MSCs even after successful antimicrobial therapy . Virulent mycobacteria can manipulate Toll-like receptors and certain signaling pathways including nuclear factor kappa-light-chain-enhancer of activated B cells in order to survive inside the BM stem cells . MSCs can increase NO production in
9. MSCs in fungal infections
Administration of human MSCs does not have negative impact on host response against Aspergillus fumigatus [118, 119]. Also, Aspergillus fumigatus does not stimulate MSCs to secrete cytokines that play a major role in the pathogenesis of GVHD indicating that Aspergillus fumigatus is not involved in the pathogenesis of GVHD following HSCT. In an animal model, infusion of BM-MSCs into mice infected with Paracoccidioides brasiliensis failed to induce any antimicrobial effects.
10. Conclusions and future directions
Since their first description in the 1960s, the history of MSCs has witnessed steady progress that ultimately resulted in their clinical application in the treatment of many disorders including several infectious diseases. Although the success has not been uniform with regard to various infections and despite the gap between the achievements in animal studies and results of clinical trials in humans, plenty of efforts have been made to resolve the remaining challenges in the clinical applications of MSCs in several diseases.
Some of the remaining challenges facing the utilization of MSCs in the clinical arena include: (1) encountering failure of treatment or resistance to therapy; (2) the need to have quality control and safety measures; (3) implementation of guidelines and design of specific protocols for: preparation and manufacture, banking and cryopreservation of MSC products, administration and therapeutic use of each type and source of MSCs, and finally tracing of infused MSCs; and (4) performing large prospective multicenter clinical trials on the use of specific MSCs in certain diseases in order to test their uniform efficacy and verify their long-term safety.
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Dong HJ, Li G, Meng HP, Shang CZ, Luo Y, Wen G, et al. How can mesenchymal stem cells penetrate the blood brain barrier? Turkish Neurosurgery. 2018; 28(6):1013-1014. DOI: 10.5137/1019-5149.JTN.22639-18.1
Conaty P, Sherman LS, Naaldijk Y, Ulrich H, Stolzing A, Rameshwar P. Methods of mesenchymal stem cell homing to the blood-brain barrier. Methods in Molecular Biology. 1842; 2018:81-91. DOI: 10.1007/978-1-4939-8697-2_6
Liu L, Eckert MA, Riazifar H, Kang DK, Agalliu D, Zhao W. From blood to the brain: can systemically transplanted mesenchymal stem cells cross the blood-brain barrier? Stem Cells International. 2013; 2013:435093. DOI: 10.1155/2013/435093 [Epub: 12 August 2013]
Christodoulou I, Goulielmaki M, Devetzi M, Panagiotidis M, Koliakos G, Zoumpourlis V. Mesenchymal stem cells in preclinical cancer cytotherapy: A systematic review. Stem Cell Research and Therapy. 2018; 9(1):336. DOI: 10.1186/s13287-018-1078-8
Johnson V, Webb T, Norman A, Coy J, Kurihara J, Regan D, et al. Activated mesenchymal stem cells interact with antibiotics and host innate immune responses to control chronic bacterial infections. Scientific Reports. 2017; 7(1):9575. DOI: 10.1038/s41598-017-08311-4
Alcayaga-Miranda F, Cuenca J, Khoury M. Antimicrobial activity of mesenchymal stem cells: Current status and new perspectives of antimicrobial peptide-based therapies. Frontiers in Immunology. 2017; 8:339. DOI: 10.3389/fimmu.2017.00339 [eCollection 2017]
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Valdivia-Silva J, Medina-Tamayo J, Garcia-Zepeda EA. Chemokine-derived peptides: Novel antimicrobial and antineoplasic agents. International Journal of Molecular Sciences. 2015; 16(6):12958-12985. DOI: 10.3390/ijms160612958
Laroye C, Gibot S, Reppel L, Bensoussan D. Concise review: Mesenchymal stromal/stem cells: A new treatment for sepsis and septic shock? Stem Cells. 2017; 35(12):2331-2339. DOI: 10.1002/stem.2695 [Epub: 16 September 2017]
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Johnson CL, Soeder Y, Dahlke MH. Concise review: Mesenchymal stromal cell-based approaches for the treatment of acute respiratory distress and sepsis syndromes. Stem Cells Translational Medicine. 2017; 6(4):1141-1151. DOI: 10.1002/sctm.16-0415 [Epub: 9 January 2017]
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Guillamat-Prats R, Camprubí-Rimblas M, Bringué J, Tantinyà N, Artigas A. Cell therapy for the treatment of sepsis and acute respiratory distress syndrome. Annals of Translational Medicine. 2017; 5(22):446. DOI: 10.21037/atm.2017.08.28
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Kamocki K, Nör JE, Bottino MC. Dental pulp stem cell responses to novel antibiotic-containing scaffolds for regenerative endodontics. International Endodontic Journal. 2015; 48(12):1147-1156. DOI: 10.1111/iej.12414 [Epub: 24 December 2014]
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Khatri M, Richardson LA, Meulia T. Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model. Stem Cell Research & Therapy. 2018; 9(1):17. DOI: 10.1186/s13287-018-0774-8
Cheung MB, Sampayo-Escobar V, Green R, Moore ML, Mohapatra S, Mohapatra SS. Respiratory syncytial virus-infected mesenchymal stem cells regulate immunity via interferon beta and indoleamine-2,3-dioxygenase. PLoS One. 2016; 11(10):e0163709. DOI: 10.1371/journal.pone.0163709 [eCollection 2016]
Bian P, Ye C, Zheng X, Yang J, Ye W, Wang Y, et al. Mesenchymal stem cells alleviate Japanese encephalitis virus-induced neuroinflammation and mortality. Stem Cell Research & Therapy. 2017; 8(1):38. DOI: 10.1186/s13287-017-0486-5
Beys-da-Silva WO, Rosa RL, Santi L, Berger M, Park SK, Campos AR, et al. Zika virus infection of human mesenchymal stem cells promotes differential expression of proteins linked to several neurological diseases. Molecular Neurobiology. 2019; 56(7):4708-4717. DOI: 10.1007/s12035-018-1417-x [Epub: 30 October 2018]
Chen M, Zheng Z, Hu J, Yang T. Co-transplantation of mesenchymal stem cells can ameliorates acute GVHD and viremia after allo-HSCT for aplastic anemia: A multi-center retrospective study of 75 patients. HemaSphere. 2019; 3:710. Poster Session II: Stem cell transplantation—Clinical. PS1537. DOI: 10.1097/01.HS9.0000564408.36600.07
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Allam O, Samarani S, Ahmad A. Mesenchymal stem cell therapy in HIV-infected HAART-treated nonimmune responders restores immune competence. AIDS. 2013; 27(8):1349-1352. DOI: 10.1097/QAD.0b013e32836010f7
Zhang Z, Fu J, Xu X, Wang S, Xu R, Zhao M, et al. Safety and immunological responses to human mesenchymal stem cell therapy in difficult-to-treat HIV-1-infected patients. AIDS. 2013; 27(8):1283-1293. DOI: 10.1097/QAD.0b013e32835fab77
Zhang J, Crumpacker C. Eradication of HIV and cure of AIDS, now and how? Frontiers in Immunology. 2013; 4:337. DOI: 10.3389/fimmu.2013.00337
Cotter EJ, Chew N, Powderly WG, Doran PP. HIV type 1 alters mesenchymal stem cell differentiation potential and cell phenotype ex vivo. AIDS Research and Human Retroviruses. 2011; 27(2):187-199. DOI: 10.1089/aid.2010.0114 [Epub: 7 October 2010]
Rodrigues ES, de Macedo MD, Pinto MT, Orellana MD, Rocha Junior MC, de Magalhães DA, et al. HTLV-1 infects human mesenchymal stromal cell in vitro and modifies their phenotypic characteristics. Virology. 2014; 449:190-199. DOI: 10.1016/j.virol.2013.11.022 [Epub: 6 December 2013]
Zhang Y, Mi JY, Rui YJ, Xu YL, Wang W. Stem cell therapy for the treatment of parasitic infections: Is it far away? Parasitology Research. 2014; 113(2):607-612. DOI: 10.1007/s00436-013-3689-4 [Epub: 26 November 2013]
Xu H, Qian H, Zhu W, Zhang X, Yan Y, Mao F, et al. Mesenchymal stem cells relieve fibrosis of Schistosoma japonicum-induced mouse liver injury. Experimental Biology and Medicine (Maywood, NJ). 2012;(5):237, 585-592. DOI: 10.1258/ebm.2012.011362
de Carvalho AC, Carvalho AB. Stem cell-based therapies in Chagasic cardiomyopathy. Biomed Research International. 2015; 2015:436314. DOI: 10.1155/2015/436314 [Epub: 15 June 2015]
Jasmin, Jelicks LA, Koba W, Tanowitz HB, Mendez-Otero R, et al. Mesenchymal bone marrow cell therapy in a mouse model of chagas disease. Where do the cells go? PLoS Neglected Tropical Diseases. 2012; 6(12):e1971. DOI: 10.1371/journal.pntd.0001971
Souza BS, Azevedo CM, d Lima RS, Kaneto CM, Vasconcelos JF, Guimarães ET, et al. Bone marrow cells migrate to the heart and skeletal muscle and participate in tissue repair after Trypanosoma cruziinfection in mice. International Journal of Experimental Pathology. 2014; 95(5):321-329. DOI: 10.1111/iep.12089 [Epub: 30 June 2014]
Irion CI, Paredes BD, Brasil GV, Cunha STD, Paula LF, Carvalho AR, et al. Bone marrow cell migration to the heart in a chimeric mouse model of acute Chagasic disease. Memórias do Instituto Oswaldo Cruz. 2017; 112(8):551-560. DOI: 10.1590/0074-02760160526
Guarita-Souza LC, Carvalho KA, Woitowicz V, Rebelatto C, Senegaglia A, Hansen P, et al. Simultaneous autologous transplantation of cocultured mesenchymal stem cells and skeletal myoblasts improves ventricular function in a murine model of Chagas disease. Circulation. 2006; 114(1 Suppl):I120-I1124. DOI: 10.1161/CIRCULATIONAHA.105.000646
de Carvalho KA, Abdelwahid E, Ferreira RJ, Irioda AC, Guarita-Souza LC. Preclinical stem cell therapy in Chagas disease: Perspectives for future research. World Journal of Transplantation. 2013; 3(4):119-126. DOI: 10.5500/wjt.v3.i4.119
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Vilas-Boas F, Feitosa GS, Soares MB, Mota A, Pinho-Filho JA, Almeida AJ, et al. Early results of bone marrow cell transplantation to the myocardium of patients with heart failure due to Chagas disease. Arquivos Brasileiros de Cardiologia. 2006; 87(2):159-166. DOI: 10.1590/s0066-782x2006001500014
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domain: literature


On Wednesday, November 19, 2014, all roads led to Quilox Nite Club, the new venue of Industry Nite. The occasion was the album release party of Yoruba rapper Olamide.
The venue was packed as hundreds of fans, and celebrities came out to support the King of Nigerian rap. As usual DJ Spinall and Jimmie held down the deejaying and hosting duties.
Celebrities at the event included Eniola Badamus, Mr. Songz, CDQ, Adunni Ade, DJ Humility, Moet Abebe, Stephanie Coker, Ehiz of MTV Base, Sound Sultan, Baba Dee, DJ Lambo, and others.
The event started proper when YBNL act Viktoh came out to perform his new single ‘All My Ladies’. Next up was YQ who performed his new song ‘Tear Rubber’. Lil’ Kesh stepped on stage after YQ, and killed the show with his hit track ‘Shoki’. He also performed ‘Lyrical’, and ‘Last Card’.
Star Nation artist OmoAkin also was on stage as he sang ‘Ijo Oloti’ with Uche Sensei and Tosin Igho supporting him on stage.
Olamide stepped on stage after midnight. He was ushered in by Dotun of Cool FM who is his hypeman. The first song he performed was ‘Hood Rap’ off his latest album. He continued by performing more songs from ‘Street OT’.
He was later joined by Phyno. Together they performed their latest collaborative effort ‘In My Circle’. They also went on to rap their other hit singles ‘Dope Money’ and ‘Ghost Mode’.
Reminisce was in the building also. The Alaga Ibile is a frequent collaborator of Olamide. On this new album they worked on ‘Hustle, Loyalty, Respect’, which they performed for the crowd.
Viktoh came back on stage and performed alongside his boss on ‘Up In The Club’. Olamide wrapped up his set with his two hit singles off Street OT, ‘Goons Mi’, and ‘Story For The Gods’ with many of his fans bum rushing the stage.Check out some pictures below!


text:
South Hill Park is looking for community actors to take part in Great Expectations by Charles Dickens which is being directed by Joe Malyan (Private Peaceful, 2018 and Romeo and Juliet, 2018). The performances run from Wed 23 Oct – Sun 27 Oct 2019.
The set will be design by Victoria Spearing, the costumes by Anne Thomson and the lighting by Alan Valentine.
Mr Phillip Pippip, ‘Pip’ – Leading role. Male. Age 16-25.
Joe Gargery/Mr Jaggers – Lead supporting role. Male. Age 28-40.
Mrs Joe/Biddy/Wemmick – Lead supporting role. Female. Age 28-40.
Miss Havisham – Lead supporting role. Female. Age 40-60.
Estella – Lead supporting role. Female. Age 16-25.
Mr Pumblechook/Sarah Pocket – Lead supporting role. Male. Age 35-60.
Herbert Pocket/Compeyson/Mr Wopsle – Lead supporting role. Male. Age 16-30.
A Sergeant/Bentley Drummle – Supporting role. Male. Age 25-35.
Abel Magwitch – Lead supporting role. Male. Age 35-45.
*Sundays and Thursday evenings from 20th June – 28th July and then from the 1st September – 17th October.
PLEASE NOTE THAT THERE ARE SOME MATINEE WEEKDAY PERFORMANCES and a DAY TIME TECHNICAL REHEARSAL SO PLEASE DO NOT AUDITION IF YOU ARE UNABLE TO COMMIT TO THESE TIMES/DAYS
Auditions are by appointment, each lasting 15 minutes.
Please arrive 15 minutes prior to your allocated audition time, which will be given to you once you have emailed the contact below.
Please specify which role you would like to audition for when emailing.
What to prepare:
- Script section for your chosen character. This will be sent to you once you’ve informed us which role you’d like to audition for.
- One monologue from any other classic play. Around 1-2 minutes long.
Audition Date – Saturday 18th May from 10am-1pm or Sunday 19th May from 1.30pm-4pm. The Recital Room at South Hill Park.
Production Week Sunday 20th October – TECH PM
Monday 21st October – TECH ALL DAY
Tuesday 22nd October – DRESS PM
PLEASE DO NOT AUDITION IF YOU CANNOT COMMIT TO THE ENTIRE REHEARSAL AND PRODUCTION PERIOD. CANDIDATES WHO AUDITION WHO CAN THEN NOT MAKE ALL DATES MAY NOT BE CONSIDERED.
If you are interested in taking part, please email email@example.com

domain: artistic


HOUSTON – It's fair to say this weekend's MLS Cup 2011 rematch has lost a bit of luster.
With the LA Galaxy – who currently sit in last place in the Western Conference – limping into Houston Saturday to face the Dynamo (2:30pm ET, NBCSN, live chat on MLSsoccer.com), there does not seem to be the excitement you would expect around the match. But while LA’s position in the table may suggest they are ripe for the picking, Houston are not falling into the trap of overlooking a talented opponent.
NBCSN Preview: HOU - LA
“I’m a little bit surprised because in preseason everyone was picking them to do pretty [well],” Dynamo head coach Dominic Kinnear said. “But they still have enough quality. It does raise some eyebrows with the way they’ve started.”
While it may not be what people expected from LA, the star-laden club comes into the weekend clash on a six-match winless streak, having lost four of their last five. Knowing that it only takes a slight nudge to put a team back on the right course, Houston’s goal this weekend is to keep the Galaxy’s woes going.
“We have to be careful that they don’t change their momentum on us,” Brian Ching said. “So we have to stay on top of them and continue to make things difficult.”
While LA will be coming to Houston without two of their big stars – Robbie Keane and Landon Donovan are both away on international duty – the third member of their trio of Designated Players, David Beckham, will be making the trip. The midfielder had a big influence on the Galaxy’s 1-0 MLS Cup win last November, and the man tasked with stopping him knows what he has to do to keep the English icon from putting his imprint on this match.
“For him you have to deny service because you see the balls he can play,” said midfielder Adam Moffat. “You have to get tight with him and make sure he doesn’t get much time or space. It’s going to be a big challenge.”
With Houston and LA set to kick off at early in the afternoon, there is enough time for the Dynamo to settle in for Saturday’s US national team match against Scotland that evening. And yes, many of the Dynamo’s eyes will be on teammate Geoff Cameron, but there will be some interest in Scotland’s fortunes as well.
“I’d love to [break into the team] if the opportunity came my way,” said Glasgow-born Scottish hopeful Moffat. “It’s a great honor to play for your country but I’ll just keep plugging away here and hopefully they notice me. We’ve struggled as a nation of late, but it’s going to be good to see some guys I used to play with and I’ll definitely be watching.”
Darrell Lovell covers the Houston Dynamo for MLSsoccer.com.


text:
On December 31, Valencians toasted semi-confined to leave 2020 behind, the most disastrous year of their lives.. The jump to 2021 had a psychological component, as if the next morning the coronavirus would be a bad memory. The arrival of the vaccine uncorked optimism. The new year has been a cold shower, and January, which ends today, has turned the most tragic month of the whole pandemic in the Valencian Community.. Hospitals are collapsed, the number of infections is around ten thousand per day and one out of four deaths in Spain is in the Comunitat Valenciana. In spring, the collective gestures pulled the cart. There was hope. Today, the weariness has settled in thousands of homes at a time when mental fortitude is essential.. Depression is gaining ground and is emerging as the main sequel to the coronavirus.
January has been the month of bad news. Experts said the holiday relaxation would pay off, but perhaps no one expected the catastrophe to be gigantic. More than half of the total coronavirus infections in the Comunitat have occurred in the last month. The latest update of the Ministry of Health reports 306,379 positive Valencians – consolidated data at 14 hours on 29 January, of which 157,582 have been diagnosed since January 1.
The Comunitat Valenciana went through the first wave of the coronavirus and the autumn crisis with some strength with respect to the rest of autonomies. On the last day of 2020 the contagion curve was 7.7% of the total in Spain.. In less than a month, that percentage has risen to 10.9%, which leads to the Valencian region to be at this moment the one with the worst numbers of the pandemic in Europe. The incidence exceeds 1,400 cases per 100,000 inhabitants, making it the worst nationally.
The spectacular increase in cases, which has not been able to stop with the measures of the Consell, has put the Valencian hospitals to the limit. The coronavirus has a three-week course: infection, admission and death. Today’s Covid-19 positives will be hospitalized in ten days and the deceased in twenty. A manual process and that leads experts to not yet set the turning point of a curve of positives that has become a wall, as said the president of the College of Physicians, Mercedes Hurtado.
January has been disastrous. The Minister of Health, Ana Barceló, acknowledged in the tribune of Les Corts that the transmission was “out of control” in the Comunitat. A limit situation that has broken the seams of the management of the Generalitat and that has bared the real shortcomings of the Botanicwith the field hospital evacuated by the wind as a symbol of the chaos. Moreover, the partners of the Consell have been more concerned with blaming each other for the situation than with joining forces to overcome the biggest crisis of the coronavirus -Twitter is the new parliamentary hemicycle-.
In January, the Ministry of Health has reported 7,482 deaths from coronavirus in Spain. Of these, 1,789 have occurred in the Comunitat Valenciana, so almost one – 22% – of every four deaths in 2021 has death stamp in the Valencian autonomy. With the latest official data published, the average number of deaths in January is 60 Valencians a day, a devastating figure.
In the last week, the reported deaths have not fallen below ninety a day, and almost a third are counted in nursing homes. The request to bury or cremate those who have died of the virus within 24 hours of their death is the X-ray of the chaos that is lived from the hospital doors inwards. The aim is not to accumulate bodies.
The latest update of the Daily Mortality Monitoring System (MoMo) reported an excess of deaths in the Comunitat since December 1 of 35.6% -2,746 deaths more than estimated-. In less than two months, the excess of deaths has been the same as from March to November.
The Valencian Community leads the incidence of positives in Spain. If during the last days of 2020 the 2,000 cases per day were an earthquake, in recent weeks ranging between 7,000 and 10,000, figures that have led to the Comunitat the closest thing to a full-blown humanitarian catastrophe. There are countries with a larger population that report fewer daily cases. 20% of the positives in Spain in January has been given in the Comunitat Valenciana.
The drama of the deaths recorded is the result of an overwhelmed hospital situation. There have been days that have been admitted through the doors of hospitals in Valencia more than 400 people. Non-Covid patients have been transferred to private hospitals while the public enabled corridors, chapels and cafeterias to cover the flood of admitted patients. For now, the almost 16 million euros spent on the field hospitals have not given the desired coverage to the Valencian health system. The bet for the open-air tents are an obvious failure.
In one month, have been admitted to hospitals in the Comunitat 8,802 people, according to government data, and about 14% have died. During the last few days the pressure on the floor has given some respite, without losing sight of the British strain, but the ICU does not stop adding units. In intensive care, 63% of patients is by Covid when on 31 December the percentage was 29%. The pressure on the ground zero of hospitals has doubled.
On Friday, at the same time that the beaches of the Comunitat lived outside the pandemic, the department led by the Councillor Ana Barceló reported 98 deaths. Yesterday, the same tone. The curve does not end to bend and the data do not point to an improvement in the short term. In the last 24 hours, the curve of infections must be added 7,990 new positive. In addition, 97 deaths were reported to bring the total number of deaths to 4,707 people since the beginning of the pandemic.
The truce is given in the admissions in plant, which continues to fall although at a moderate speed. There are now 4,338 people affected by Sars-CoV-2 when earlier this week they hovered around 4,800. Hospital care during this month of January has been limit, with 8,802 people entering the hospitals and with waits of more than ten hours for patients to occupy a bed. The number of floors with Covid patients multiplied week after week.
Half of the positive cases for Covid – 51% – in the Comunitat have been reported in the month of January. In ten months have been reported fewer cases than in thirty days, a comparison that reflects the stressful situation that exists in the Valencian region. The cumulative incidence per 100,000 inhabitants in the last two weeks is 1,431 positive -on December 31 was 390 cases-. Of the 592 municipalities, 375 have an incidence above 500 cases, the limit recommended by the European Union to shield a territory.
By provinces, Alicante, which has 66% of its ICUs occupied by Covid patients, is more worrying than any other. In addition, according to the latest update from the Ministry, the cumulative incidence in the last two weeks is more than 1,700 cases.
One of the keys is the positivity rate. The Comunitat maintains a value of very high risk in this section with three positive tests out of every ten that are performed. The World Health Organization states that the ideal situation is below 5% and the Valencian autonomy multiplies it by six. While the positivity rate does not fall, it will be difficult to bend the curve.

domain: news


text:
During the hot summer of 2004--the year of the 2004 Summer Olympics in Athens--somewhere in a small Cretan village, Andipas, a spirited twelve-year-old boy, dreams of becoming a runner. However, without a coach on his side and no real training routine, the determined boy has no other choice but to turn the whole village into his running track. Now, even the smallest of errands are a reason for a battle against the clock--but, when everything goes wrong all at once on the big day of the 200m final--a frenzied race against Andipas' friends, the villagers, and ultimately, the clock, will be on. But, will he make it in time to watch the event on TV?
Did You Know?
The movie was shot in Fre, a village located in Chania of Crete, Greece. As of 2011, it is a part of the municipality of Apokoronou, with a total population of 1.117 according to the 2001 census. See more

domain: geography


The popularity of flash drives has made USB storage ubiquitous. Thumb drives have effectively killed off the floppy, and perhaps before long, they'll push optical media out of the picture, too. Despite its convenience, the USB interface doesn't offer all that much bandwidth. Version 2.0 of the specification calls for transfer rates up to 60MB/s. In the real world, though, you're looking at less than 40MB/s. That may be much quicker than a floppy, but it's relatively slow for a modern PC. And slow transfer rates only get more annoying as storage capacities expand, encouraging users to transfer more and more data.
Help lurks just over the horizon in the form of a new USB 3.0 specification that promises to increase transfer rates up to 600MB/s. However, USB's third iteration isn't expected to be integrated into all-important Intel chipsets until 2011. There's no word on when it'll be included in core-logic chipsets from AMD or Nvidia, either, leaving would-be users to purchase add-in cards or one of a handful of new motherboards that offer USB 3.0 connectivity via third-party silicon.
So what about external Serial ATA? eSATA ports have slowly become common on even mid-range motherboards, and they've even popped up in a few laptops. The interface is plenty quick, too, offering transfer rates up to 300MB/s. But eSATA is just a data pipe, so it can't provide connected drives with power. That has to come from an external source, which has typically involved bulky power adapters for eSATA enclosures that plug into wall sockets. Auxiliary cables are cumbersome at best, and they're certainly not appropriate for pocket-sized flash drives.
Fortunately, a better solution exists. A hybrid eSATA/USB connector has been developed that elegantly melds USB and external Serial ATA plugs.
If you think about it, the two interfaces are really a perfect match. A single USB port can already power the wealth of thumb drives on the market, and it can even handle most external 2.5" mechanical hard drives. eSATA brings ample bandwidth to the table, and with recent SATA controllers supporting hot-swapping, there's no need to restart your system to connect a drive.
You don't have to wait for hybrid eSATA/USB, either. Ports can already be found on several new P55-based motherboards from Gigabyte and MSI. Drives that use the technology are available, too. The first one we've seen is a Kanguru e-Flash thumb drive that comes with both USB and hybrid interfaces. It's currently selling in 32 and 64GB flavors for $114 and $190, respectively. That sounds expensive, but it's actually quite reasonable considering the prices of other high-capacity flash drives. And this one's a heck of a lot faster.
I plugged the e-Flash into USB and hybrid ports on a Gigabyte GA-P55M-UD4 motherboard and ran HD Tach's full disk test to get an idea of the drive's performance under Windows 7. When plugged into the USB port, the e-Flash achieved burst speeds of 37MB/s, sustained 36MB/s reads and 24MB/s writes, and consumed just 4% of the system's CPU time. On the hybrid connector, burst rates jumped to 84MB/s, sustained reads climbed to 67MB/s, writes increased to 32MB/s, and CPU utilization remained at 4%.
While the e-Flash doesn't come close to the peak theoretical bandwidth offered by the hybrid connector's eSATA component, the drive still offers double the read speeds and 33% faster writes than a typical thumb driveand with seemingly zero penalty. I didn't even need to run the hot-swap application that comes loaded on the drive. Windows 7 handled the e-Flash much like a standard USB device.
With the exception of a slightly longer casing to make room for a second plug, the e-Flash is really no larger than your average thumb drive. It's a featherweight at just 22 grams, and measures an easily pocketable 89 x 24 x 7 mm (3.5" x 0.94" x 0.28"). The drive may not look terribly exciting, but it does have a thin-wall aluminum housing with a matte finish that doesn't attract fingerprints or smudges. The drive feels surprisingly solid for something so light, and the caps for both plugs fit nice and snugly. My only complaint about the casing is that it doesn't have an anchor that can be used to attach the drive to a keychain.
Of course, there's also the issue of whether your system has a hybrid eSATA/USB port that can take advantage of the drive's performance. Kanguru thought of that, though. The e-Flash comes with a PCI back plate adapter and the necessary cables to transform any internal Serial ATA port to an external hybrid connector. Power comes from a four-pin Molex plug, so you don't have to give up a USB port. Kanguru even throws in an extension cable to bring the hybrid connector out from behind the back of the system.
The adapter kit is a perfect addition to the package, making it easy to recommend the e-Flash to anyone looking for a faster flash drive than existing USB-based products. This little thumb drive also has me quite bullish on the future of the hybrid connector. The interface is perfect for high-performance thumb drives and even better for external 2.5" hard drive enclosures. With ports easily added to existing systems, hybrid eSATA/USB looks to be the best external storage interface to tide us over until USB 3.0 sees widespread adoption.


On 4th of June 2021, the Japanese multinational conglomerate Fujifilm released a statement confirming that they had suffered a ransomware attack on the 1st of June which disrupted business operations.
The ransomware attack was discovered when FujiFilm started an investigation into an incident of unauthorized access that had occurred in the late evening of the 1st of June. When they concluded the attack was ransomware, the company was forced to shut down parts of its global network to reduce the spread and impact of the ransomware.
The shutdown impacted the running of business as the shutdown had prevented access to email, the billing system, and a reporting system. Therefore, Fujifilm added notices to their websites warning customers that it is currently experiencing problems affecting all forms of communications, including emails and incoming calls.
Even though FujiFilm has not disclosed what ransomware gang was behind the attack, it is believed to be the REvil ransomware group who are behind the attack as there is evidence that Fujifilm had recently been infected by the Qbot banking trojan, which is known to have been partnered with the REvil ransomware group at the time of the attack, to help provide the threat actors with remote access that is used to laterally move through victims’ networks.


text: 5-stars Hotels in Lake Tahoe (California) 4-stars Hotels in Lake Tahoe (California) 3-stars Hotels in Lake Tahoe (California) By Hotel Brand. Top Searches Holiday Gifts. There are South Lake Tahoe ski resorts for every style of skier or boarder. Northstar is also known for its excellent protection from the wind and its lively base village. Lake Tahoe (California) Ski-In / Ski-Out Hotels; Casinos in Lake Tahoe (California) By Hotel Class. We have three signature styles of map depending on what you’re looking for: “Minimalist” - This map has the title and a faint hillshade in the background as well as hydrology. 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327-331 East Houston Street
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Halpern Real Estate Ventures
This 78-apartment rental project is located on a L-shaped site fronting Houston and Ridge Streets in the Lower East Side. The ground floor includes the residential lobby, a lounge, and apartments in the rear of the building which have access to outdoor space. A large skylight brings natural light to the gym in the cellar, and stairs provide access to recreational outdoor space in the rear yard. A mix of studios, one, and two-bedroom apartments make up the bulk of the building. The top floor includes a three-bedroom apartment with a balcony. The rooftop is designed as an amenity space for the building, complete with deck seating, projector screen, bar, and outdoor shower.
The interior design was inspired by the raw nature of materials in the Lower East Side, such as exposed concrete and blackened steel, and includes touches of color such as the graffiti tiled accent wall in the lobby.


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text:
For more than 160 years, the name Hood® has been synonymous with fresh, quality dairy products that taste great. Founded in 1846 in Charlestown, Massachusetts by Harvey Perley Hood, the company has since extended its New England roots, and today Hood is a national company distributing dairy products throughout the United States. In fact, HP Hood LLC is now one of the country’s largest branded dairy operators with 15 manufacturing plants throughout the United States. The company also maintains its own research and development operation, which supports the superior product quality and innovation that Hood customers have come to expect.
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Hood branded lines of milk, cream, ice cream, cottage cheese and sour cream regularly rank among the top branded dairy products in New England. The Hood family of products also includes Simply Smart® Milks, and Calorie Countdown® low calorie dairy beverages. For more information about Hood’s portfolio of regional brands and product offerings, please visit our Family of Brands page. Hood also has national and super-regional franchise rights to process and sell extended-shelf-life products including LACTAID®, Fiber One™ Cottage Cheese, HERSHEY®'S Milk & Milkshakes and Almond Breeze® Almondmilk.

domain: food


text:
The Information Literacy Toolkit is an excellent resource to share with faculty and use in enhancing and guiding collaboration. It contains assignments, tutorials, and assessment tools for incorporating information literacy skills into any course.
The Assignment Design Rubric for Research Assignments can help faculty identify and reflect on how their assignments are supporting student learning of effective research methods. This is a great tool for generating discussion and collaboration
This work is licensed under a Creative Commons Attribution-NonCommercial 2.0 Generic License.

domain: library


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PER: 2009 Volume 12 No 1
26 March 2009
- Monitoring, interception and Big Boss in the workplace: is the devil in the details? / Pistorius, T
- A commentary on the positive discrimination policy of India / Deane, T
- A very long engagement: The Children's Act 38 of 2005 and the 1993 Hague Convention on the Protection of Children and Cooperation in Respect of Intercountry Adoption / Couzens, M
- Reflections on the Biowatch Dispute – Reviewing the fundamental rules on costs In the light of the needs of constitutional and/or public interest litigation / Humby, T
- "The show must go on!" Beserings van dramastudente tydens opleiding / Snyman, R & Deacon, J
In this issue the nexus between labour relations and electronic privacy, affirmative action in India, intercountry adoption of children, the award of costs in public interest litigation and the legal uncertainties surrounding liability for injuries of student actors are the themes of the contributions.
Tania Pistorius of UNISA suggests that an employer that knows the relevant links and clicks can avoid the difficulties created by the emergence of e-communication technology regarding the manner in which employees are expected to perform their duties in the workplace.
Tameshnie Deane of UNISA argues, with reference to the case of India, that affirmative action is required for equality to be achieved, but if affirmative action measures are not properly conceived, they become burdensome and even more discriminatory.
Meda Couzens of the University of KwaZulu-Natal comprehensively assesses the impact of the incorporation of the 1993 Hague Convention on the Protection of Children and Cooperation in Respect of Intercountry Adoptions into South African legislation and concludes that the legal recognition of intercountry adoption does not offer a complete response to all of the legal and social problems associated therewith, but that it may ensure that adoptions are performed in the best interests of the child.
Tracy-Lynn Humby of the University of the Witwaters-rand argues that the current South African rules regarding cost orders in public interest and constitutional litigation are not satisfactory as regards access to justice, equal protection and benefit of the law, proportionality, and the accountability of the judiciary and she makes some suggestions for the reform of those rules.
Rika Snyman and Jaco Deacon of the University of the Free State engage the question where the liability lies for injuries suffered by a university student participating in practical drama training, finding that clear answers are not to be found either in labour legislation, nor in legislation concerning occupational health and safety.
Editor: Professor Francois Venter / Edition editor: Christa Rautenbach
(2009)This article emphasises the uncertainty in the relationship between a student undergoing practical training and his/her lecturer or university, if the student should be injured and wants to claim compensation. One must ...
Reflections on the Biowatch Dispute – Reviewing the fundamental rules on costs In the light of the needs of constitutional and/or public interest litigation (2009)Using as a case study the recent decision on costs in the Biowatch matter, this article critically examines the traditional fundamental rules on costs in the light of the needs of constitutional and a fortiori public ...
A very long engagement: The Children's Act 38 of 2005 and the 1993 Hague Convention on the Protection of Children and Cooperation in Respect of Intercountry Adoption (2009)This article analyses the intercountry adoptions provisions contained in Chapter 16 of the Children’s Act 38 of 2005, against the standards of the Hague Convention on the Protection of Children and Cooperation in Respect ...
(2009)Affirmative action and discriminatory measures are complex and controversial issues. The goal of affirmative action is to speed up the creation of a representative and equitable workforce and to assist those who were ...
(2009)This article discusses the opposing dynamics in the modern workplace environment, specifically employees’ expectations of e-privacy and employers’ interception and monitoring of electronic communications. In terms of the ...


text:
|"Duncan, I know Wallace Fennel...and you are no Wallace|
1) While there is some lip service given to there being a done-in-one plot, this is really Diane Ruggiero setting up a whole slew of threads for the second act of this season’s mystery. And it’s to her credit that some of these thread set ups are very, very subtle.
2) And that done-in-one is a Trojan Horse that advances Duncan’s subplot while foreshadowing the reintroduction of Alona Tal’s Meg, and her ultimate role as this season’s Lilly Kane stand-in. And, quite frankly, the final reveal is truly shocking.
3) This may be the only time that Michael Muhney’s Sheriff Lamb acts like a human being. After a healthy dollop of comic relief, Lamb actually acts like a sheriff when confronted with what Veronica and Duncan discover. It’s a rare moment that gives this otherwise one dimensional character a little nuance.
4) While I understand that at this phase of the Kendall Casablancas’ character arc, she’s serving as the lead up to the Fitzpatrick subplot (more on this in later episodes), but too much is spent on her striving to stay a woman of leisure in light of her husband’s disappearance. Now maybe some of this is my feeling that a little Charisma Carpenter goes a long way, but I could really do without her taking up so much running time. On top of that, there’s that weird little grace note that seems designed to throw doubt into the Veronica/Duncan storyline that I don’t recall going anywhere.
|This scene is the one that almost makes|
5) Boy, Krysten Ritter is a touch broad at this phase in her career. I gather that Gia is supposed to be a spoiled rich girl trying to hard to fit in and become part of the Cool Clique, but her forced cherriness and cluelessness seems too forced. Even though she gets much, much better in the years following her one year tenure here but at this moment...Yikes!
6) I am still amazed at how subtle some of the clues as to the solution of the season mystery is. There’s a single line of dialogue from the person who turns out to be the villain, and its not until you’ve seen the mystery play out that you realize he’s trying to escape the scene of the crime.
7) It strikes me that there’s what I assume to be a conscious parallel between a scene with Steve Guttenberg’s Wally Goodman an his son and the scene in season one where Logan enters The Belt Room. What it says about Goodman speaks volumes once we realize the skeleton in his closet.
8) This is the beginning of the Dr. Thomas Griffith subplot. Maybe it’s because Rick Peters isn’t that great of an actor; maybe it’s because I know how this storyline goes nowhere...but it turns out to be really, really awful.
|Not the picture I would draw of Kristen Bell, to be honest.|
9) You know, I would not have known that was supposed to be Amanda Noret’s Madison Sinclair at Gia’s pajama party landing zings against Veronica if it wasn't for the closing credits. Given how massive an influence Madison has in Veronica Mars mythology (so much so that the movie goes out of its way to give us a scene of Veronica slugging her), making her appearance in this episode so generic is puzzling.
10) In this episode, there is an attempt to make Duncan into a Wallace Manque....and Teddy Dunn thoroughly fails to live up to the task. His lameness in Watsoning Veronica only makes one yearn for Percy Daggs all the more.
Overall...the final third almost makes up for the scattershot nature of the rest of the episode, as the episode tries too much to cover all its bases.


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Super User is a question and answer site for computer enthusiasts and power users. E-mail this to: Enter the e-mail address of the recipient Add your own personal message: 0 of 1, characters Submit cancel. Yes No. Unfortionatly Csr bluecore bluetooth dongle broke the blutooth device to it so I bought a new generic one thinking it should work to connect with that.
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Bluetooth Wireless Forum
My computer can't find the Bluetooth device I am trying to connect to. Refer to the manual of that device to find out how.
Posted 09 September - PM On the other computer where the dongle works fine, are they Windows 10 and if yes do they have both Bluetooth Services? Posted 09 September - PM The other pc is windows 10 and it gets bluetooth if I plug in the dongle. Posted 09 September - PM If the new dongle does not work then there is some kind csr bluecore bluetooth dongle borkage going on with Windows It's called DeviceCleanupCmd.
CSR v Bluetooth Dongle does not work on my Windows 10 computer - Microsoft Community
Turn on Bluetooth Windows Services Open windows services run services. Uninstall the bluetooth driver that comes with the device When you connect the device, the driver gets installed automatically.
Edit: Something that may work but do at your own risk. Install the Toshiba Bluetooth stack in Windows Posted 11 September - AM.
Can´t connect my wireless keyboard with a generic bluetooth device.
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- Windows 7 - How to pair with bluetooth speaker using USB bluetooth dongle? - Super User
- CSR v4.0 Bluetooth Dongle does not work on my Windows 10 computer
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In that case this tutorial will help you: tomsguide. Frustrated I headed to Amazon and set out to find a new Bluetooth 4.
Windows 7 - How to pair with bluetooth speaker using USB bluetooth dongle? - Super User
Installing the CSR 4. Log in.
Category 1 Category 2 Category 3 Category 4.Hi there This CSR dongle doesn't work on my computer. My computer runs windows 10 and all drivers across the whole computer were Need to enable Bluetooth stack on my desktop system. This guide will detail how to make a CSR USB bluetooth adapter work with a computer. Will also work with most other brands that use the same csr bluecore bluetooth dongle.


text:
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