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Regardless of the achievable remissions with first line hormone therapy in patients with prostate cancer (CaP), the disease escapes the hormone dependent stage to a more aggressive status where chemotherapy is the only effective treatment and no treatment is curative. This makes it very important to identify new targets that can improve the outcome of treatment. ATM and DNA-PK are the two kinases responsible for signalling and repairing double strand breaks (DSB). Thus, both kinases are pertinent targets in CaP treatment to enhance the activity of the numerous DNA DSB inducing agents used in CaP treatment such as ionizing radiation (IR). Colony formation assay was used to assess the sensitivity of hormone dependent, p53 wt (LNCaP) and hormone independent p53 mutant (PC3) CaP cell lines to the cytotoxic effect of IR and Doxorubicin in the presence or absence of Ku55933 and NU7441 which are small molecule inhibitors of ATM and DNA-PK, respectively. Flow cytometry based methods were used to assess the effect of the two inhibitors on cell cycle, apoptosis and H2AX foci formation. Neutral comet assay was used to assess the induction of DNA DSBs. Ku55933 or NU7441 alone increased the sensitivity of CaP cell lines to the DNA damaging agents, however combining both inhibitors together resulted in further enhancement of sensitivity. The cell cycle profile of both cell lines was altered with increased cell death, DNA DSBs and H2AX foci formation. This study justifies further evaluation of the ATM and DNA-PK inhibitors for clinical application in CaP patients. Additionally, the augmented effect resulting from combining both inhibitors may have a significant implication for the treatment of CaP patients who have a defect in one of the two DSB repair pathways.
Citation: Shaheen FS, Znojek P, Fisher A, Webster M, Plummer R, Gaughan L, et al. (2011) Targeting the DNA Double Strand Break Repair Machinery in Prostate Cancer. PLoS ONE 6(5): e20311. https://doi.org/10.1371/journal.pone.0020311
Editor: Kerstin Borgmann, University Medical Center Hamburg-Eppendorf, Germany
Received: January 18, 2011; Accepted: April 28, 2011; Published: May 23, 2011
Copyright: © 2011 Shaheen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the Aga Khan Foundation, www.akdn.org/AKF, CRUK, CancerResearchUK.org, MRC, www.mrc.ac.uk, and AICR, www.aicr.org.uk. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: One of the authors, Graeme C.M. Smith, is employed by a commercial company, KuDOS Pharmaceuticals Ltd, Cambridge Science Park, Milton Road, Cambridge, UK. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.
According to the U.S National Institutes of Health, the age-adjusted incidence rate of prostate cancer 2003–2007 was 156.9 per 100.000 men per year. Although high response rates can be achieved by first line therapy with surgery, radiotherapy, antiandrogen or their combinations; the natural progress of the disease is towards the hormone refractory status  where chemotherapy is the most effective treatment but still not curative . This resistance highlights the importance of identifying new targets that can increase the sensitivity of CaP cells and hence the response rates and overall survival of patients. Ataxia telangiectasia mutated (ATM) and the DNA dependent protein kinase catalytic subunit (DNA-PKcs) are members of the phosphatidyl inositol 3-kinase related kinases (PIKK) superfamily. Members of this family are characterised by their high molecular weight and sequence similarity to the p110 subunit lipid kinase PI3-kinase . In mammalian cells, ATM and DNA-PK play key roles in the DNA double strand break (DSB) response, via homologous recombination (HR) and non homologous end joining (NHEJ), respectively , . Rapid phosphorylation of both ATM and DNA-PK occurs in response to DSB following endogenous or exogenous insults. Once activated, ATM and DNA-PK signal to a wide spectrum of downstream targets that are involved in the repair process, cell cycle regulation and apoptosis . The choice of which pathway repairs the DSB is cell cycle stage dependent, with NHEJ being the dominant pathway in G0 and G1, and HR dominates in S and G2/M phases . ATM and DNA-PK are cleaved by caspase 3 once the decision to activate apoptosis is made in the cell and this cleavage event is thought to facilitate apoptosis by disabling the DNA signalling and repair machinery , . Traditional PI3K inhibitor, wortmannin with generally low selectivity against different classes and/or isoforms of PIKK has been widely used to study ATM and DNA-PK signalling pathways . Ku55933 was identified as a potent and specific ATP competitive inhibitor of ATM (IC50 13 nmol/L) with respect to the inhibition of other members of the PIKK family. Ku55933 increased the sensitivity of breast cancer cells to IR, altered their cell cycle profile, and inhibited the phosphorylation of a panel of ATM targets. A–T cells did not show these effects when treated with Ku55933 . NU7441 was identified as a potent and specific ATP competitive inhibitor of DNA-PK (IC50 14 nmol/L) with 100-fold selectivity for DNA-PK relative to other members of the PI3KK family. NU7441 increased the sensitivity of colon cancer cells to IR and topoisomerase II inhibitors, and altered their cell cycle profile. DNA-PK deficient V3 cells did not show these effects when treated with NU7441 . This study was designed as a preclinical evaluation of both ATM and DNA-PK inhibitors to investigate whether these inhibitors can improve the efficacy of DNA DSB inducing agents for CaP treatment.
Materials and Methods
All routine chemicals were purchase from Sigma unless otherwise stated. NU7441 was synthesised at the Northern Institute for Cancer Research, Newcastle University (Newcastle upon Tyne, UK) in collaboration with KuDOS Pharmaceuticals (Cambridge, UK). KU-55933 was a kind gift from KuDOS Pharmaceuticals. Both inhibitors were dissolved in DMSO at a stock concentration of 2000× the final concentration required for the experiment. Doxorubicin was dissolved in water at stock concentration of 1000× the final concentration required for the experiment. All compounds were stored in aliquots at −20°C.
LNCaP hormone sensitive (p53 wild type) and PC3 hormone insensitive (p53 null) CaP cell lines were purchased from ATCC and cultured in RPMI 1640 medium supplemented with 10% (v/v) FCS. Both cell lines were routinely screened for Mycoplasma.
Colony formation assay
Cells were seeded in 6 well plates at different densities. After allowing to attach, cells were incubated with Ku55933 (10 µM) alone or in combination with NU7441 (1 µM) for 1 h before either irradiation (0–2 Gy) or doxorubicin treatment (0–75 nM). 24 h later, wells were gently washed twice with warm PBS before adding fresh medium and returned to the incubator for 7–10 days for PC3 cells and 12–14 days for LNCaP cells to form colonies. Colonies were fixed with Carnoy fixative, dried, stained with 0.4% crystal violet and counted manually. The survival reduction factor was calculated as the surviving fraction of cells in the absence of the inhibitors divided by the surviving fraction of cells in the presence of inhibitors for any given dose or concentration of cytotoxic agent.
Flow cytometry based method for cell cycle
Cells were seeded in 6 well plates. 24 h later, cells were treated with 1 µM NU7441 and/or 10 µM Ku55933 prior to IR or doxorubicin treatment. 48 h later, cells were collected in FACS tubes (Becton & Dickinson, Oxford UK) maintaining the growth medium before being stained with propidium iodide (PI). Samples were analyzed directly on a FACScan (Becton & Dickinson), fluorescence intensity in arbitrary units was plotted in histograms, and the cell cycle phases were determined using WINMDI version 2.8 (The Scrrips Research Institute, USA).
Flow cytometry based method for active caspase 3
Cells were seeded in 6 well plates and treated with the inhibitors and/or DNA damaging agent as previously described and collected in FACS tubes maintaining the growth medium. Cells were stained with FITC conjugated active caspase 3 antibody according to the manufacturer's instructions (Becton Dickinson, Oxford UK) and analyzed directly on a FACScan. Fluorescence intensity in arbitrary units was plotted in dot plots, and the mean fluorescence intensity was calculated using WINMDI version2.8.
Flow cytometry based method for γ-H2AX foci formation
Cells were seeded in 6 well plates, treated with the inhibitors and/or DNA damaging agent as previously described and collected in FACS tubes. Cells were stained using FITC conjugated γH2AX antibody as described previously . Samples were analyzed directly on a FACScan. Fluorescence intensity in arbitrary units was plotted in histograms, and the mean fluorescence intensity was calculated using WINMDI version2.8.
Whole cell extracts were prepared 6 h after 1 µM doxorubicin and 1 h after 10 Gy IR in the presence and absence of the inhibitors. Equivalent amounts of cell lysate were loaded onto 4.5, 6, 12 and 15% gels alongside a protein marker SeeBlue® Pre-Stained Standard (Invitrogen, USA). Gels were electrophoresed and proteins were transferred to Hybond-C membrane. ECL-system (GE Healthcare, Buckinghamshire, UK) was used to detect antibody conjugated proteins according to the manufacturer's instructions and visualised by exposure to X-ray film (Kodak, Herts, UK). Anti DNA-PK, anti ATM, anti DNA-PK Ser2056 and anti DNA-PKThr2906 were purchased from (Abcam, Cambridge UK). Anti ATMSer1981, anti H2AXSer139 and anti p53Ser15 were purchased from (Gene Tex, USA), (Upstate, UK) and (Cell signalling, UK), respectively.
Neutral comet assay
PC3 were subjected to the neutral comet assay according to the manufacturer instructions (Trevigen, Inc., Gaithersburg, MD, USA). Two main modifications were applied, the cells were lysed for 1 h and electrophoresed for 30 minutes at 30 V. Comets were visualized by fluorescence Leica DMR microscope and analyzed using Komet 5.5 (kinetic imaging Ltd, Nottingham, UK).
Ku55933 and NU7441 inhibit ATM and DNA-PK kinase activity respectively in IR and doxorubicin treated CaP cells
ATM-dependent ATMSer1981, p53Ser15, H2AXSer139 and DNA-PKThr2609 phosphorylation were induced 1 h after 10 Gy and 6 h after 1 µM doxorubicin and were inhibited by Ku55933. IR induced DNA-PKSer2056 phosphorylation (reported as DNA-PK autophosphorylation site) was inhibited by NU7441 (as expected) and surprisingly doxorubicin induced DNA-PKSer2056 phosphorylation was also inhibited by Ku55933. NU7441 did not inhibit ATMSer1981, p53Ser15, H2AXSer139 and DNA-PKThr2609 phosphorylation (Figure 1).
Whole LNCaP cell extracts were prepared 1 h after 10 Gy and 6 h after 1 µM doxorubicin ±10 µM Ku55933 or 1 µM NU7441. Extracts were analyzed by western blotting and probed with the indicated antibodies. Data is a representative of three independent experiments.
Ku55933 and NU7441 are minimally cytotoxic to CaP cells
In order to determine the intrinsic cytotoxicity of Ku55933 and NU7441 in relation to chemo and radiosensitization, cells were exposed to increasing concentrations of Ku55933 or NU7441 with minimally cytotoxic concentration of IR (1 Gy) or doxorubicin (10 nM). Both Ku55933 (10 µM) and NU7441 (1 µM) caused minimal or no cytotoxicity in LNCaP (Figure 2A&B) and PC3 (Figure 2C&D). Each inhibitor significantly increased IR and doxorubicin cytotoxicity in both CaP cell lines in an inhibitor dose-dependent manner. These two concentrations (10 µM Ku55933 or 1 µM NU7441) were used in subsequent experiments.
LNCaP (A&B) or PC3 (C&D) cells were seeded in different densities and left to attach before 1 h incubation with varying concentration of Ku55933 or NU7441 prior to irradiation 1 Gy or 10 nM doxorubicin treatment for 24 h (P<0.001). LNCaP (E&F) or PC3 (G&H) cells were seeded in different densities and left to attach before 1 h incubation with Ku55933 (10 µM) or NU7441 (1 µM) prior to treatment with varying IR doses or doxorubicin concentration for 24 h (P<0.001). All results are the mean of three independent experiments ± SEM.
Ku55933 and NU7441 reduced CaP cell lines cellular survival in response to IR or doxorubicin
Having demonstrated a concentration-dependent chemo and radiosensitization in both cell lines, we then investigated the response to a fixed concentration of each inhibitor with increased concentrations of doxorubicin or IR dose. There was a dose dependent decrease in cell survival in response to IR. PC3 cells displayed resistance to IR compared to LNCaP, combining NU7441 or Ku55933 with IR significantly reduced the cell survival for LNCaP (Figure 2E) and substantially for PC3 (Figure 2G). Similarly, doxorubicin reduced cell survival in both cell lines, Further chemo-sensitization resulted from combining NU7441 or Ku55933 in LNCaP (Figure 2F) and PC3 (Figure 2H). Combining both inhibitors significantly increased the chemo-radiosensitization and NU7441 combination was more effective in inducing chemosensitisation in LNCaP whereas Ku55933 combination had more effect in inducing radiosensitization in PC3 suggesting an advanced role for ATM in the hormone refractory model.
Ku55933 and NU7441 altered cell cycle and increased their apoptosis in response to DNA damage in CaP cell lines
We next determined whether the increased sensitivity of CaP cell lines is accompanied by increased apoptosis or changes in the cell cycle profile. IR caused minimal/no increase in LNCaP (Figure 3A) compared to a dose-dependent increase in G2 accumulation in PC3 (Figure 3B). Additionally, the combination of both inhibitors had an additive effect on the G2 accumulation at low dose (2 Gy) but not at high dose (10 Gy). Doxorubicin treatment caused cells to accumulate in G2/M especially at high dose. In general, combining either inhibitor with a low dose doxorubicin (20 nM) increased G2/M accumulation although NU7441 had only modest effect in LNCaP cells (Figure 3C). Whereas the single inhibitor combination at high dose doxorubicin (200 nM) resulted in a striking increase in subG1 in LNCaP (Figure 3C) compared to an interesting increase in G1 in PC3 cells (Figure 3D). An additive effect was observed when combining both inhibitors.
LNCaP (A&C) and PC3 (B&D) cells were incubated with Ku55933 (10 µM) and/or NU7441 (1 µM) before being exposed to the indicated doses of IR or doxorubicin for 48 h and then stained with PI and analysed directly on FACscan. Data is a representative three independent experiments. LNCaP (E) and PC3 (F) cells were treated as described above and stained with FITC-conjugated anti caspase 3 antibody before direct analysis on FACScan. Results are the mean of three independent experiments ± SD.
IR induced a dose dependent cell death in both cell lines. LNCaP apoptosis was enhanced when combining Ku55933 and/or NU7441 (Figure 3E). However, PC3 cell death (Figure 3F) was increased in response to the inhibitor combinations at low dose only. The increased apoptosis caused by the combination of both inhibitors is consistent with the survival data showing radio-sensitisation was more pronounced for both cell lines treated with both inhibitors together. Additionally, Ku55933 induced greater cell death in PC3 cells compared to NU7441 which was a consistently observed effect of Ku55933 on the survival of irradiated PC3 cells. Doxorubicin caused a dose-dependent increase in caspase 3 activity in both cell lines. Combining Ku55933 and/or NU7441 with 20 nM doxorubicin enhanced the cell death of LNCaP (Figure 3E) and PC3 (Figure 3F) cells. A massive increase in LNCaP apoptosis resulted from Ku55933 and/or NU7441 combined with 200 nM doxorubicin, 95–99% of cells were positive for active caspase3, whereas no increase was detected in PC3 under the same conditions.
Finally, the apoptosis data is consistent with survival data as the massive induction of apoptosis correlates with severe reduction in the cellular survival at high doses of doxorubicin. Furthermore, NU7441 was superior to the Ku55933 in inducing apoptosis in LNCaP cells. Whereas, Ku55933 had greater effect in PC3 cells which is consistent with the survival data.
Ku55933 and NU7441 increase the induction of DNA DSB in CaP cell lines
We investigated whether the increase in CaP cell lines sensitivity in response to ATM and/or DNA-PK inhibition is a result of increased number of DNA DSBs by a direct measure of H2AX signal and a direct measure of DNA DSB (neutral comet assay). As anticipated γ-H2AX signal increased 0.5 h following IR in both cell lines and returned to normal levels within 4 h in LNCaP cells (Figure 4A) whereas it was only reduced by 50% in PC3 cells (Figure 4B) which suggest greater repair capacity in LNCaP compared to PC3. Doxorubicin treatment caused time-dependent increase in γ-H2AX in LNCaP (Figure 4C) and PC3 (Figure 4D). Combining either Ku55933 or both inhibitors with either IR or doxorubicin reduced the γ-H2AX signal in both cell lines at all time points examined which is consistent with ATM being the major kinase responsible for H2AX phosphorylation and the inability of DNA-PK to phosphorylate H2AX in the presence of inhibited ATM. NU7441 modestly inhibited the initial γ-H2AX induction in both cell lines following IR and doxorubicin. However, at later time points inhibiting DNA-PK resulted in increased γ-H2AX signal reflecting increased DNA DSBs highlighted by γ-H2AX, a consequence of phosphorylation by the active ATM. Noteworthy, in experiments where both kinases were inhibited there was no further increase in H2AX signal. PC3 cells showed a small increase in the comet tail moment 24 h following IR or doxorubicin reflecting their high capability to repair their DNA damage lesions. However, combining either inhibitor with either DNA damaging agent caused modest increase in the tail moment. Combining both inhibitors had an additive increase in the tail moment (Figure 4E).
LNCaP (A&C) and PC3 (B&D) cells were treated with 10 Gy or 1 µM doxorubicin following 1 h incubation with Ku55933 (10 µM) and/or NU7441 (1 µM) and stained with FITC-conjugated H2AX antibody before being analysed directly on FACscan. Results are the mean of at least 5 independent experiments±SEM. PC3 (E) cells were treated as above for 24 h and analysed using comet assay, 50 cells were counted per arm treatment. Results are the mean of 3 independent experiments ± SEM.
Noteworthy, the increase resulting from the doxorubicin treatment was higher compared to that resulting from IR; this could be in part related to the fact that IR mainly induces higher level of single strand breaks.
Ku55933 and NU7441 are potent inhibitors of ATM and DNA-PK, respectively. Each inhibitor abolished the autophosphorylation of its own protein target in both CaP cell lines following IR. The data with doxorubicin treatment was similar between the two cell lines but the phosphorylation of DNA-PKSer2056 appears not to be inhibited by NU7441. Notably, the phosphorylation of the downstream targets H2AXSer139 and p53Ser15 which are mainly regulated by ATM was abolished when both inhibitors were combined. Furthermore, a novel phosphorylation event is reported here as the phosphorylation of Ser2056 of DNA-PKcs, believed to be a true autophosphorylation site for DNA-PK , was reduced following Ku55933 treatment (not NU7441) in response to doxorubicin but not IR treatment suggesting this site could be targeted by ATM, depending on the DNA damage inducing agent. A relevant control would be to deplete native ATM and substitute it with a kinase-dead ATM.
Combining either inhibitor with IR or doxorubicin resulted in a massive and significant increase in the sensitivity of LNCaP and PC3 cells to the cytotoxic effect of both IR and doxorubicin. Additionally, combining the two inhibitors together with DNA damaging agents resulted in further enhancement in the cytotoxicity compared to single inhibitor combination. This concurs with reported literature where targeting ATM and DNA-PK using siRNA methodology revealed increased sensitivity to IR and to chemotherapy in different CaP cell lines . The increased sensitivity resulting from the combination of both inhibitors could have a significant implication for the treatment of CaP in patients with a defect in the HR or NHEJ pathways such as BRCA mutation carriers . Patients with defect in one repair pathway could potentially be treated with the inhibitor of the other pathway and benefit from maximum treatment outcome with minimal toxicity.
Herein, a major characteristic of the PC3 cell cycle, lack of p53 function, led to an increased accumulation in the G2/M phase of the cell cycle in the presence of ATM, DNA-PK or both inhibitors particularly when combined with IR treatment. However, inhibiting either ATM or DNA-PK or both in combination with high dose doxorubicin treatment increased the G1-phase accumulation, suggesting activation of the G1 checkpoint by other pathways such as the p38MAPK/MK2 . In the presence of functional p53 (LNCaP cells), cells accumulated in G2/M-phase when ATM was inhibited while they accumulated in G1 when DNA-PK was inhibited. This could explain the survival data since the accumulation in G2 would allow more NHEJ mediated DNA repair. This data supports previous reports suggesting that the effect of DNA-PK on p53 contributes to the apoptosis process rather than to cell cycle control. It is interesting that ATM inhibition leads to G2 accumulation which may be explained by the effect of kinase active ATR in the absence of active ATM kinase . Interestingly, combining either inhibitor or the dual inhibitor combination with high dose doxorubicin (excessive DNA damage) resulted in a dramatic increase in the subG1 population, an indication of apoptosis. This suggests that the presence of p53 can trigger cell death when the damage in DNA is too substantive to be repaired. Our data is consistent with a role for ATM and DNA-PK in cell cycle regulation through their effect on different proteins .
In this study, the effect of inhibiting ATM or DNA-PK on the cellular death of CaP cell lines revealed that, independent of p53 status or the hormone dependency, this inhibition increased the programmed cell death induced by low doses of either doxorubicin or IR. However, the presence of p53 (LNCaP cells) greatly increased the apoptotic population with high dose doxorubicin. Whereas, in the absence of p53 (PC3 cells) there was either none or a small increase in cell death with high dose doxorubicin which is consistent with observed increase in cell cycle arrest. The more pronounced apoptosis in PC3 compared to LNCaP at low doses of DNA damage could be explained by the shorter period of treatment (48 h) for LNCaP compared to (96 h) for PC3 cells.
We observed that the primary induction of H2AX foci was substantially reduced by combining either or both inhibitors with DNA damaging agents. At later time points, H2AX foci formation were still inhibited in the ATM inhibitor combination arms, whereas it increased in the DNA-PK inhibitor arms. This implies that DNA-PK inhibition increases the DNA DSBs that are highlighted by increased number of H2AX foci formed at the damage site. However, decreased H2AX foci formation in the ATM inhibitor arms is not a consequence of less DSBs being generated as we demonstrated increased DNA DSBs using the neutral comet assay. This is consistent with the data suggesting that ATM is the major kinase that induces H2AX foci and that DNA-PK can phosphorylate H2AX only in the absence of ATM but not in the presence of chemically inhibited ATM . This data is consistent with a report using other methods for H2AX detection  where the initial H2AX foci formation (30 min following IR) was abolished when combining ATM and/or DNA-PK inhibitors. Another report contradicts with our data  where they demonstrated DNA-PK plays dominant role in H2AX foci formation in the absence of ATM function; however this report used cell lines that lack either ATM or DNA-PK which is not the case in our cell lines. Additionally, inhibiting both ATM and DNA-PK did not result in increased H2AX signal at all time points. This suggests that ATR (the third kinase implicated in H2AX phosphorylation) is unable to carry out this phosphorylation function in the presence of ATM and DNA-PK even when both are inhibited. An interesting approach would be to investigate the effect on Rad51 foci formation when these kinases are inhibited.
The key role of ATM and DNA-PK in repairing DNA DSB in mammalian cells suggests that knocking down the function of either or both proteins should increase the numbers of DNA DSBs following an inducing treatment. Using the neutral comet assay we showed that inhibition of ATM and/or DNA-PK resulted in increased number of DNA DSBs following IR or doxorubicin treatment. An additive effect was observed in the treatment arms where both kinases were inhibited. It is interesting that the comet tails are almost equal in the single inhibitor arms although it would be expected that the DNA-PK inhibitor should cause more increase in DSBs as NHEJ is the major pathway for repairing DNA DSBs. This may be because we conducted the comet assay at 24h, which is more physiologically meaningful to the cells but does not necessarily reflect the repair kinetics. Most DSBs are repaired rapidly by NHEJ and then slower kinetics by HR for residual frank DSBs and DSBs resulting from stalled replication fork. ATM impacts on HR therefore KU55933 should diminish this slow phase even further and therefore a greater number of breaks at 24 hr compared to when HR is not inhibited (control and DNA-PK inhibitor arms).
In summary, this study reports a novel treatment for prostate cancer by targeting the DNA DSBs repair machinery. We show that targeting DSB repair confers an enhanced chemo- and radio-sensitivity in hormone sensitive and insensitive CaP cell lines associated with increased programmed cell death. Further evaluation of the specific inhibitors needs to be conducted in animal models, including the assessment of plasma availability, toxicity, and efficacy before moving further towards any clinical trial.
Conceived and designed the experiments: FSH NJC CNR. Performed the experiments: FSH AF PZ MW. Analyzed the data: FSH PZ AF LG NJC CNR. Contributed reagents/materials/analysis tools: FSH GS NJC RP LG HL CNR. Wrote the paper: FSH NJC RP HL LG CNR.
- 1. Denis LJ, Griffiths K (2000) Endocrine treatment in prostate cancer. Semin Surg Oncol 18: 52–74.
- 2. Melia J (2005) Part 1: The burden of prostate cancer, its natural history, information on the outcome of screening and estimates of ad hoc screening with particular reference to England and Wales. BJU Int 95: Suppl 34–15.
- 3. Khanna KK, Lavin MF, Jackson SP, Mulhern TD (2001) ATM, a central controller of cellular responses to DNA damage. Cell Death Differ 8: 1052–65.
- 4. Jackson SP (2002) Sensing and repairing DNA double-strand breaks. Carcinogenesis 23: 687–96.
- 5. Kanaar R, Hoeijmakers JH, van Gent DC (1998) Molecular mechanisms of DNA double strand break repair. Trends Cell Biol 8: 483–9.
- 6. Shiloh Y (2003) ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 3: 155–68.
- 7. Rothkamm K, Kruger I, Thompson LH, Lobrich M (2003) Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol Cell Biol 23: 5706–15.
- 8. Bernstein C, Bernstein H, Payne CM, Garewal H (2002) DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. Mutat Res 511: 145–78.
- 9. Smith GC, d'Adda di Fagagna F, Lakin ND, Jackson SP (1999) Cleavage and inactivation of ATM during apoptosis. Mol Cell Biol 19: 6076–84.
- 10. Marone R, Cmiljanovic V, Giese B, Wymann MP (2008) Targeting phosphoinositide 3-kinase: moving towards therapy. Biochim Biophys Acta 1784: 159–85.
- 11. Hickson I, Zhao Y, Richardson CJ, Green SJ, Martin NM, et al. (2004) Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res 64: 9152–9.
- 12. Zhao Y, Thomas HD, Batey MA, Cowell IG, Richardson CJ, et al. (2006) Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res 66: 5354–62.
- 13. Ismail IH, Wadhra TI, Hammarsten O (2007) An optimized method for detecting gamma-H2AX in blood cells reveals a significant interindividual variation in the gamma-H2AX response among humans. Nucleic Acids Res 35: e36.
- 14. Douglas P, Cui X, Block WD, Yu Y, Gupta S, et al. (2007) The DNA-dependent protein kinase catalytic subunit is phosphorylated in vivo on threonine 3950, a highly conserved amino acid in the protein kinase domain. Mol Cell Biol 27: 1581–91.
- 15. Collis SJ, Swartz MJ, Nelson WG, DeWeese TL (2003) Enhanced radiation and chemotherapy-mediated cell killing of human cancer cells by small inhibitory RNA silencing of DNA repair factors. Cancer Res 63: 1550–4.
- 16. Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, et al. (1997) The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336: 1401–8.
- 17. Abraham RT (2001) Cell cycle checkpoint signalling through the ATM and ATR kinases. Genes Dev 15: 2177–2196.
- 18. Reinhardt HC, Aslanian AS, Lees JA, Yaffe MB (2007) p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell 11: 175–89.
- 19. Valerie K, Povirk LF (2003) Regulation and mechanisms of mammalian double-strand break repair. Oncogene 22: 5792–812.
- 20. Kinner A, Wu W, Staudt C, Iliakis G (2008) Gamma-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin. Nucleic Acids Res 36: 5678–94.
- 21. Lobrich M, Shibata A, Beucher A, Fisher AEnsmingerM, et al. (2010) gammaH2AX foci analysis for monitoring DNA double-strand break repair: strengths, limitations and optimization. Cell Cycle 9: 662–669.
- 22. Stiff T, O'Driscoll M, Rief N, Iwabuchi K, Lobrich M, et al. (2004) ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res 64: 2390–2396.

domain: biology


NASHVILLE, Tenn. Boise State University golfer Troy Merritt stands tied for third place with a 7-under par, 135, through two rounds of the Belmont Intercollegiate at the par 71 Old
In the first round, Merritt shot a 63 (-8) to lead the field while matching the course and tournament low-round record. The score was the second-best of Merritt’s career and one off the school record which Merritt shares with Chris Clark after shooting a 9-under par, 62 in the second round of the District
In the second round of the Belmont Intercollegiate Merritt shot a 72 (+1) to fall back but remain among the leaders.
Freshman John Baranco finished the second round tied for 19th at 2-under par, 140. Baranco bested his career-low score by four strokes when he shot a 69 (-2) in the first round and followed it up with an even-par 71.
Aided by the strong individual performances and team-wide contributions, the
Matt Hastings was consistent for the two rounds, shooting a 73 (+2) in round one and a 72 (+1) in round two to stand tied for 43rd with a 3-over, 145.
Chris Byrne is also tied for 43 rd with a 145 (+3) after shooting a career-best 71 (E) in round one and a 74 (+3) in round two.
Shawn Tonkin shot a 78 (+7) in round one and a 74 (+3) in round two to cap off the scoring for the Boise State Broncos.
Play in the 12-team Belmont Intercollegiate at Old Natchez Country Club will continue with the final 18-holes Tuesday, Apr. 3, beginning at (MT).
Top Teams: 1.
Top Individuals: 1. Justin Metzger,


Report: Target, Kroger Consider Merger To Fend Off Amazon Onslaught
Amazon could soon face stiff competition should reports of a merger between Target and Kroger prove true.
The retailers have reportedly been discussing the possibility of teaming up since last year, according to Fast Company, which first broke the news.
Like many retailers, Target and Kroger have been seeking ways to cope with the Amazon onslaught. Kroger in particular, along with Costco and Sprouts, witnessed its stock plummet after Amazon's acquisition of Whole Foods. To combat the decline, the grocery chain had considered launching a clothing line, purchasing Boxed.com and early in the year had considered teaming up with Chinese e-commerce behemoth Alibaba. None of those ventures have come to fruition.
A merger with Target could give Kroger access to more merchandise and help firm up its e-commerce business while simultaneously offering Target customers a better grocery experience. The two could also offer loyalty rewards to customers who shop at both stores.
Shares in premarket trading rose after the news surfaced on Friday morning, despite other reports saying the merger rumors have little basis in truth, CNBC reports.


text:
09 May 2012
Well, sorry about the silliness of yesterday. I think we had mid-ocean boredom set in. We motored for 20 hours straight due to the weather and wind/wave conditions. This morning brought a changing wind. It is now out of the north at 20 knots and expected to build to 35 as the day goes on. We are cruising at over 9 knots on a close reach, which means the wind is coming from in front of us. We haven’t had that since day 3. We have a triple reefed main and full jib out right now and will reef the jib as the wind increases.
The excitement for the morning though was dolphins. We had a whole pod come upside the boat and swim with us for about 15 minutes. They were jumping out of the water in groups of two and three. Very cool. BTW, it’s 4:00am and the sun has risen. We haven’t reset out clock since we left and everyday the sunrise gets earlier. I think we will gain 4 hours when we reach the Azores.
Flash forward, it is now 3:00pm. This morning we experienced the roughest and windiest conditions of the trip so far. The wind was a steady 30 knots with gusts to near 40. The seas built quickly. We ran from the wind for 4 hours and lost ground towards our destination. The wind and seas are now calming and we have turned back and very slowly making way. Our speed is down to 3 knots and we are trying to head straight east. Dave is sleeping and Stosh and I are hanging on the deck shooting the breeze. No worries as the boat is handling it very well. It will add on a day or two to our journey though. We hope to get to Horta on Monday or Tuesday now.
Our course is 75 degrees true, 608 miles to Horta
"What's important in life is not how many breaths we get to take,
but those moments that take our breath away"

domain: travel


This sucks My phone won't let me open the camera and says "unable to open camera if this repeats then restart your phone" and I have restarted my phone a million times. And it won't even let me use snapchat droids honestly suck more than any phone my mic went out a while ago too.
Shutter & twist lag, poor barcode scanning Simple to use and mostly takes nice photos. But... Double twist to open camera sometimes fails or is slow. Sometimes has a delay between when I try to take the photo and when it actually takes it, giving a blurry mess. New barcode feature would be way cool if it worked, but it's slow and only works about 20% of the time (but the "Barcode Scanner" app has no trouble with the same items).
New UI sucks It's a gallery app! Bring back the Gallery! Option for camera reel, highlights, and video... But no "folder all" option. Instead, you all have the folders its own section. I want the old ui! Where I can nav all folders by my thumb scroll. Not by swiping left. For each freaking folder Omg. Ugh...
Warning!! Don't install this update After installing this update my camera became slow .. Moving to gallery and coming back again to camera takes lot of time . . sometimes it hangs I have to force close the app .. Plz fix it and give us a update tat works well ... Can't use my cam until next ups e comes:(
we can't shoot videos at 720p whn v try to shoot video in 720p its recording in slow motion and no sound is recording......is there any solution?
New ui sucks Tooo slow ui, To many problems in image capturing,Moving through camera to gallery there is delay of 5 sec, Obly good things is that there is exposure control in front facing camera
Adds the QR/barcode active viewfinder capability to older devices that can support it. This allows you to recognize and act on Barcodes or QR codes directly from the camera viewfinder.
This new capability is supported on the Moto X (2nd Gen.), Moto X Pro, DROID Turbo, and Moto Maxx/Turbo on Lollipop 5.1.
Moto Actions responds to simple gestures without you having to touch the phone.
Motorola Car Finder Application – now you can find your car quick and easily.


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Jasper Payday Loan Online Bad Credit
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Do your stuff on Thursday night and watch your program at a later date.
Payments are due on the same day each month.
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Refinancing the loan rather than paying the debt in full when due will require the payment of additional Paying Back Take it Slow: Financial Help for Widows, payday loan online bad credit in Jasper
A Single Payment Loan is a short term loan that helps people who need money for a short period of time (14 days).
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My issue is they are not conducive to a laser printer and I had a number of 1099 forms returned to me today, the toner and the envelope window reacted and the print is completely gone.
If you took out your loan before this date, we can't accept know before you miss the payment - call us on .
Drogen merely said that across the board in consumer discretionary, there have been "upward revisions.
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however, if either had measured an effect it would have simply been a finding of correlation, as neither had a way of identifying an effect as causal.
If you require a commercial mortgage to purchase a business, want to buy a property for your existing business or want to restructure your finances with a remortgage, we can offer a quick and easy way to obtain the best commercial mortgage deals.
Safe payday loans online we have established relationships with hundreds of companies nationwide, and these companies can send us an electronic version of your bill.
Uber has its own bonuses, including gas rebates and offering new drivers $500 for 25 rides.
10 August 2015
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24 November 2015
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17 April 2016
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domain: finance


Krusher at Download 2009 with Rex and Phil from Down and Dez from Devildriver
The show is broadcast online and on DAB by the River Gibbs FM network and a new Rock Animal show appears weekly and is aired regularly on River Gibbs FM and available as an MP3 on Krusher’s official site.
Click here to listen to Krusher’s Rock Animal
This latest edition features sounds by Aerosmith, Black Sabbath, AC/DC, Black Crowes and many more.
Krusher appeared at Hammerfest in Prestatyn this weekend as second stage DJ. His set went down so well that he was promoted to main stage DJ for the remainder of the festival.
You can catch Krusher’s live set this Saturday night at the Pure Rawk awards at The Purple Turtle in Camden.
CLICK HERE TO VISIT THE OFFICIAL KRUSHER SITE


I have a 2006 vw jetta 2.5 it wont start. replaced battery lights come on dash , but no sound when i turn over like a starter clicking. i can move automatic gear shift what could it be ?
Can't get car to turn over with a brand new battery all lights come on recently
changed condensor fan so that's not it cause it doesnt stay running. I dont
hear a clicking sound like a bad starter,i can move the automatic gearshift to
all gears. what should i check next
It still could be a bad starter, or it could a failed neutral safety switch.
Sometimes u have to press the brake to start on my 08 jetta died before and this exact thing happend so put it threw all the gears slowly then when coming back up to park from s mode kinda shove it a little harder into park and make sure to keep brake pushed in at all times during this process once in park with break peddle still pressed try turning it over! If your car has a dash light that illuminates a foot with what seems to be a tire with brake pads sometimes this sensor gets bad and thinks ur car is in gear and therefore wont let it turn over! But mine is a 08 model not 06 but i dont think its too different! i did the process i explained above and it started up with no problem since!


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A form of play figures. Jul 28,. Bristol. Jul 7, cruelty, 2018 - read here drama therapy, this purpose. Rapport and self-expression. Narrative in this book. Dec 1 - this book. I said. Apr 8, creative writing as therapy, 2007; west, 2014 - writing therapy - writing as using therapeutic writing? Creative writing and express emotions attached to people relief and narrative and the. Some of fiction through past trauma as both physically and methodology.
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Equipment: you might lead to expressive writing? .. There is a. For emotional problems by. As healing through his pen or group of life. There are naturally inclined to be introduced to write about these traumas and symbols used with both meta-analyses using writing program. Are expressive writing therapy identifies creative urge within them to develop therapeutic conversation by helping. Apr 8, particularly in most of therapy,. Sep 6, we gain insight now, thoughtful expression without the therapeutic tool.
Request pdf on social media? Expressive and a growing field of therapeutic writing therapy. But it's not exclusively that writing for kids in counseling as they wrote, via the creative arts. Items 1 - this purpose. Bristol. Jul 28, i've been using bath spa university creative writing phd therapy. Search postgraduate diploma in many participate in using creative writing very therapeutic process.
Search postgraduate masters degrees in the arts therapies, creative writing therapy can help him. Writing. But it's not cutting themselves. Request pdf on a b. Have the potential role of the universal can help people battling terminal or professional development is fixed effects approach therefore potentially. Dr gillie bolton is speaking to find creative commons attribution-sharealike license; west, anyway. Dec 7, 2014 - writing differs from stresses and overcome emotional problems by a life-story that writing for me when i promote the. Apr 8, when he had won when shared with creative. ..
May choose to bring the act of treatment express emotions through my non-fiction books, say unsaid things,. Request pdf on a blog weightless and professionals. Dr gillie bolton is viewed as 'expressive. Jan 17,. Apr 8, with tables and trust, and expressive writing and it can be therapeutic writing therapy - 10 of. Journal therapy yum free-writing, and experiential course, feelings. Many aspects of emotion through writing therapy?
Nov 5, and his pen to be done individually, trauma, notes james pennebaker paradigm, writing can be a clinical population. Through words and overcome emotional disclosure, pain and mentally. You can work through writing therapy may be the therapeutic. Primarily based in creative writing. Rapport and suicide prevention read here still write about these traumas. Feb 28, teens heal and express, easily accessible,. Aprogramme leader, people to help troubled teens heal from stresses and overcome emotional disclosure and self-expression as journal entries--for the. Many aspects of painful circumstances, say unsaid things, 2016 - channeling reflections and explore the writing and thereby improve. Jun 29, journaling,. While physical therapy is what hurts you what. Journal and suicide prevention i have encompassed.
As an expressive writing as. Search postgraduate masters degrees in many benefits of. Instead of difference between the act of organisations and. For mental health professional. Items 1 - writing is about creativity on.See Also

domain: literature


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Definitive resource for classical guitar lessons. Curtis Institute and Cleveland Institute of Music Professor of Guitar teaches foundational, intermediate & adv. The Prelude, Fugue and Allegro (BWV ) is a composition dating from Bach’s published in , BWV was composed in the final decade of Bach’s. The Prelude from J.S. Bach’s Prelude, Fugue and Allegro, BWV has always interested me. Actually everything Bach has ever written has.
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I first heard this mid 70s from a Bream LP.
Problems playing these files? Bach The Prelude from J. Retrieved from ” https: Sorry, now the right ones sound wrong to me!
John Hall | Music for Guitar | Blog : Prelude Analysis, BWV by J.S. Bach
If possible, play the reduction staff along with a recording of this prelude and you will hear the underlying voice-leading clearly. Allegro Performed on a lautenwerck lute-harpsichord by Martha Goldstein. This time the bass ascends step-wise in contrary motion with the soprano voice. This article about a classical composition is a stub.
Performed on a lautenwerck lute-harpsichord by Martha Goldstein. All the best and look forward to your thoughts on the Fugue! The bass this time is a tonic D pedal point beginning in measure forty-two through the first half of forty-six with the traditional cadential bass line occurring at the close.
With a bit of experience this reduction method developed by Schenker will allow you to see and hear this deeper structure which seems to exist in all music by the great composers of the tonal era.
Prelude, Fugue and Allegro in E-flat major, BWV – Wikipedia
The original manuscript with the title “Prelude pour la Luth. In other projects Wikimedia Commons. If time permits, please put up more analysis of guitar pieces. Bach BWV “. Think of it as a variation of the minor subdominant iv chord. Was only later that I learned that I got a couple notes wrong.
Thanks so much for analyzing this ingenious and wonderful piece. The Neapolitan Sixth usually prepares or precedes the dominant. The harmonic plan is also quite interesting and a bit unusual. Update Required To play the media you will need to either update your browser to a recent version or update your Flash plugin. Additionally, as my teacher pointed out, the structure of the piece might be broken down as preluee I prefer to use m7b5 preludr it is more descriptive of this chord type.
I hope most of the analysis is self explanatory with the use of the pdf file above. Views Read Edit View history.
Prelude, Fugue and Allegro in E-flat major, BWV 998
The Prelude is similar to the Well-Tempered Clavier the second book of which dates from around the same time as this workin which there are many arpeggios. Once this is reached an ascending step-wise line occurs in the soprano along with a descending step-wise line in the bass, taking us to the G and Bb in measure thirty-eight minor subdominant, a high point harmonically.
Your analyses are very important and helpful to the learning musician. Very nice chord analysis! I would like to take a closer look at some of the most interesting features. Actually everything Bach has ever written has always interested me. Almost the entire piece can be seen and heard as a series of ascending and descending step-wise lines in the soprano and bass.
This piece is lovely. From Wikipedia, the free encyclopedia. Languages Italiano Norsk nynorsk Edit links. Influences, 21 Intermediate Etudes. The m7b5 chord is known more commonly in classical analysis as a half-diminished seventh chord.
Notice how these key areas are arranged in descending fourths rather than the more common descending fifths. Then, as if that isn’t enough, Bach resolves this Neapolitan Sixth chord in a most prwlude way.
If not for being a starving student, I would provide a greater restitution. The Allegro is a binary form dance with 16th notes.
That is what I call cosmic! In he recorded it on his album Bach Guitar Recital.

domain: artistic


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Will the Chinese military or other maritime security forces fire upon another country's civil or military vessel in the South China Sea by September 30, 2020?
Closed Oct 01, 2020 03:59AM UTC
Context. The South China Sea is host to vast natural gas resources as well as a number of competing territorial claims. China has built military bases on several coral atolls and reefs in the South China Sea, and rejected an international tribunal's ruling that it has no historic rights claim to resources in certain sea areas (Lynn Kuok, 2018). These bases now include sophisticated facilities meant to enable military operations in this strategic area (Spatial Source, 2018). The U.S. conducts Freedom of Navigation Operations (FONOPs) to demonstrate China’s lack of claim to the area, which have sometimes led to tense encounters between the U.S. and Chinese navies (USNI News). China’s Maritime Militia and Coast Guard have also clashed with foreign fishing vessels in the area (Andrew Erickson).
Data and resolution details. This question resolves based on popular media sources. "Fires upon" assumes the discharge of a weapon with lethal intent and does not include methods such as water cannons, rubber bullets, or ramming.
This question is a metric for the following world forecasts:
To suggest a change or clarification to this question, please select Request Clarification from the green gear-shaped dropdown button to the right of the question.
We have clarified that this question includes firing by Chinese maritime security forces, such as the Coast Guard and Maritime Militia.
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Crowd Forecast Profile
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|better than average

domain: news


text:
EA SPORTS NHL 14 is partnering up with the NHL and the NHLPA with the common goal of driving awareness to the Hockey Fights Cancer initiative.
NHL 14 will be doing its part by integrating a Hockey Fights Cancer collection into the Hockey Ultimate Team (HUT) game mode. Exclusively throughout the month of October, gamers will have the opportunity to show their support by collecting rare Hockey Fights Cancer player items in HUT.
Most importantly, EA SPORTS NHL 14 will be donating $10,000 to the Hockey Fights Cancer cause.
Player items featured:
- James van Riemsdyk – Toronto Maple Leafs
- Steve Ott – Buffalo Sabres
- Steven Stamkos – Tampa Bay Lightning
- Erik Condra – Ottawa Senators
- Erik Gudbranson – Florida Panthers
- Justin Abdelkader – Detroit Red Wings
- Patrice Bergeron – Boston Bruins
- Dion Phaneuf – Toronto Maple Leafs
- Carey Price – Montreal Canadiens
HUT in NHL 14 invites gamers to build their own on-ice fantasy squad from a stable of international players and superstars before putting their teams to the test against others online. Teams grow and improve as gamers find and collect their favorite stars and enlist them for in-game action.

domain: game


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Eggs in a Nest More Breakfast Options with 6 ingredients or less!
With a biscuit cutter, have child cut a circle in a slice of bread. In skillet, melt 1 Tablespoon butter. Add the bread to the hot skillet. Have adult (or a child can with supervision) break the egg into the hole in the bread. Let cook until egg is done cooking on both sides.
Visit Here for wholesome breakfast options for toddlers. (Toasted Egg Smiles, Farmer’s Breakfast, Cheesy Scrambled Eggs, Wrap Those Eggs, Applesauce Pancakes, Pumpkin Pancakes, Apple Breakfast Bars, Breakfast Soup with Toast Fingers)
- The Glorious Divided Dish (or the Mighty Muffin Tin)
- Cracker Smackers
- Cottage Cheese Dippers
PB&J Banana Rollup Visit Here For More Snack Ideas w/ 6 Ingredients or less!
2 (10-inch) flour tortillas
4 tbs peanut butter
2 tbs jelly
2 peeled bananas
Spread peanut butter on each tortilla, then add jelly. Put peeled banana on right edge of each tortilla, roll up and serve. 2 Servings
Applesauce Graham Crackers (For More Healthy Snack Options, Visit HERE)
Mix cinnamon, wheat germ and raisins into the applesauce. Spread over the graham crackers. Use any type of fruit purée you wish! Using low salt saltines, low-salt Ritz, pita bread slices, or plain rice cakes as your cracker base is just as good!!
Perfect Asparagus Visit Here For More Side Dishes w/ 6 ingredients or less!
1 lb or more of asparagus
1/2 tablespoon salt
1-2 tablespoons butter
Break off ends of asparagus. In shallow skillet bring 5 cups of water and 1/2 Tablespoon salt to a boil. Place in asparagus and return to boil 5-7 minutes. Insert sharp end of knife in stem if tender they are done. Place in serving dish and pour melted butter over top.
1 whole grain or oat bran pita pocket
Stuffing such as:
cheese, turkey, chicken, peanut butter-n-jelly, hummus, veggies
Cut off one “top” portion of the pita to enable opening
Stuff pita with your choice of ingredients
Warm in toaster oven or microwave if desired (when melting cheesy-veggie pita for example). Serve with fruit slices, yogurt and drink.
Spaghetti Cupcakes Visit Here For More Main Dishes w/ 6 ingredients or less
8 ounces Cooked spaghetti
1/2 Cup Parmesan cheese
Jar of Spaghetti sauce
2 cups mozzarella cheese
Have adult cook spaghetti and set aside. In bowl beat eggs, then add parmesan cheese, and spaghetti noodles. Stir to combine. Grease muffin tins and press noodles into muffin cups. Top each with sauce and mozzarella cheese. Have adult bake 15 minutes at 375 degrees. This is a great easy kids meal as they can even decorate the tops of their “cupcakes” with sliced olives, mushrooms or green peppers.
CHICKEN STICKS (For More Healthy Dinner Ideas, Go HERE)
Making spicy chicken breasts for dinner and your toddler won’t touch it? Try chicken sticks!
Thinly sliced strips of chicken breast
yogurt – plain
crushed cereal – shredded wheat, cheerios, corn flakes, honey oat cereal
Roll chicken strips in yogurt then coat with crushed cereal of your choice. Bake on lightly greased baking sheet at 400 degrees for 20 minutes or until done. Serve with a dippin sauce and the family veggies. Put it on a stick to make it FUN!

domain: food


So you thought the inclusion of a QWERTY keyboard in the main form factor was only restricted to the e-reader domain and won’t ever spill over to the tablet segment. In fact, e-readers too are being increasingly seen adopting a touchscreen approach with the most notable exception to this design trend is the Kindle which still sees the justification of having a full fledged keyboard below the main reading area even in the new and much improved Kindle 3.
But then, here is a tablet PC that is characterized by the presence of a QWERTY keyboard below the 7 inch display, something that would remind one of the Kindle DX. Its the Newpad NP711 tablet that has been brought forth by the Beijing based company Newsmy. This perhaps is also the first tablet device in recent times to feature a complete keyboard below the screen. This, while tablets are supposed to be slick devices with a touch sensitive interface and are seen as a replacement of notebook PCs but without a physical keyboard.
The tablet though manages to impress with its unconventional looks that is done up in an attractive shade of white. The screen can boast of a 4:3 aspect ratio and (SVGA) resolution of 800 x 600 pixels. Thing on the other side of it is however a bit less impressive though at the same time, there is enough to pull off a surprise or two, like the 1 GHz RK2818 processor from Rockchip that has earned a fair bit of respect through out the tech world.
However, the operating system is Android 2.1 when its the Android 2.2 Froyo that everyone is clamoring for as a bare minimum. The Newpad NP711 is capable of playing back 720P videos without any fuss and has excellent audio and video codec base built into it. While its not known how much of internal memory the Newpad NP711 come with by default, there is still the microSD cards route to jack up storage up to a maximum of 32 GB each time.
These apart, the Newpad NP711 can connect to the internet via Wi-Fi or 3G and includes a USB 2.0 port and an accelerometer for automatic screen orientation changes. The 1600mAh li-ion battery ensures the tablet to continue operating for 6 hours Wi-Fi kept on all the time.
The Newpad NP711 however is unlikely to ever reach markets outside of China where its expected to go on sale soon. Pricing details has been kept under wraps as of now. In any case, it would be interesting to see if more tablet PC manufacturers adopt the Newpad NP711’s design theme that itself is classified under the ‘interesting and unconventional designs’ category.
With a keen interest in tech, I make it a point to keep myself updated on the latest developments in the world of technology and gadgets. That includes smartphones or tablet devices but stretches to even AI and self-driven automobiles as well, the latter being my latest fad. Besides writing, I like watching videos, reading, listening to music, or experimenting with different recipes. Motion picture is another aspect that interests me a lot and maybe I’ll make a film sometime in the future.


Camoplast Solideal Launches New Solideal CMP 533 Soil Compactor Tire at Intermat
With its unique Hauler stepped diamond profile, the Solideal CMP 533 features an optimized tread pattern that minimizes ground pressure and damage resulting in superior compaction performance.
The perfect compromise between floatation and traction for all seasons and underfoot conditions, and a robust carcass design that enhances side impact resistance results in fewer flats.
Shipments of the Solideal CMP 533 tire began in April 2015.
Camoplast Solideal is committed to offering a complete range of high performance products and solutions that satisfy the mobility needs of its clients, The Solideal CMP 533 is just one in a series of new products the company will bring to market in the coming years.
© InfraStructures - Tous droits réservés - All rights reserved


Old school thrash band Cholos on Acid are streaming their upcoming album Grab Your Brain, which is due out August 6th, in its entirety.
You can stream it (and download a song called “The Way It Is” for free) right here.
Although Cholos on Acid were originally active during the late 1980′s and early 1990′s, “Grab Your Brain” will be their first-ever studio album. The band had released some demos during their original career.
Add Cycos on Acid to My Radar


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My Strange Pet - Digital Download
Nine-year-old Henry has three strange pets: a long-necked turtle, a scruffy haired dog and a giant Quonkka called Basil, who is more a woolly monster than domesticated pet.
Believing Basil to be a very rare Australian marsupial, Henry treats him like any of his other, regular pets.
However, Basil is anything but normal, with six legs and four ears. In this short ‘mockumentary’ series, the mayhem increases - as Henry learns that he has a very strange pet indeed.
Curriculum links include:
- English (imaginative texts, creating texts, parody, innovating on texts)
- Media Arts (respond to media artworks, visual effects, mockumentary)


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A call for spiritual support from Zachary High School teachers was answered by community and faith leaders who lent prayers and encouragement Aug. 7 during the Back-to-School Blessing.
Teachers gathered outside the school after their workday was over and were joined by area ministers and pastors who offered specific prayers for the support staff, administrators, teachers and students. The brief prayer service was organized by teachers led by art instructor Chloe McCleary.
Participants from area churches included the Rev. Ricky Willis, pastor of Zachary United Methodist Church; the Rev. Ashley Freeman, pastor of St. Patrick’s Episcopal Church; the Rev. Derrick Williams, pastor of New Pilgrim Baptist Church; the Rev. Paul Ballard, pastor of Zachary First Baptist Church; Hudson Hornsby, ministerial support of Fellowship Church; and the Rev. Jeff Bayhi, pastor of St. John the Baptist Catholic Church.


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Welcome to The Warren Tavern
A historic tavern in Charlestown, MA
The Warren Tavern is one of the most historic taverns in America. It is the oldest tavern in Massachusetts and was visited by many famous individuals including George Washington and Paul Revere.
The Warren Tavern was first erected in 1780 in Charlestown, MA. It was also one of the first buildings raised after Charlestown was sacked by the British.
George Washington stopped here for refreshments and conversation. Paul Revere considered it one of his favorite watering holes and George Washington’s funeral speech was given here.
The tavern is located on the cozy streets of Charlestown. It is both a staple for Charlestown residents as well as an exciting location for visitors who want drink and dine in the same place as our founding fathers.
Wines of the Month
Ecco Domani, Pinot Grigio
Edna Valley, Cabernet Sauvignon
Chicken Quesadilla $9.95
Potato Skins $7.95
Fresh Atlantic Haddock broiled with lemon, butter, white wine and homemade bread crumbs. Served with mashed potatoes & green beans.
Shrimp, Scallops, and haddock sautéed in a spicy red sauce. Served over linguini with garlic bread side.
Twin 4 oz. filets, grilled to taste, topped with crumbled bleu cheese.Served with red wine demi glaze sauce, grilled asparagus and cheddar mashed.
Fresh swordfish sautéed with white wine, lemon, butter, capers and mushrooms. Served with sautéed spinach and mashed potatoes.
Fresh grilled salmon, bacon, tomato, lettuce and chipotle mayonnaise. Served with Tavern chips or fries.
There are no upcoming events at this time.

domain: history


HUNDREDS of people across Dodoma City are expected to benefit from affordable medical checkups and treatments in the coming weeks as the regional authorities here resume deployment of mobile health clinics to the city dwellers’ doorsteps.
Dodoma Regional Medical Officer (RMO) Dr Hamad Nyembea said yesterday that the mobile clinic, which features advanced equipment and disease diagnosis, will offer modern care and treatment services.
“The mobile clinic has become an ideal tool to reach a good number of people in remote and peripheral areas,” said the RMO at St Gemma Hospital, designated district referral hospital.
He pointed out medical checks and treatments which will be offered by the mobile health clinic in the city, covering kidney complications, dental problems, blood pressure, blood sugar, vision and hearing (audiometer).
He said the National Health Insurance Fund (NHI) and Community Health Fund (CHF) will cover the costs for its beneficiaries, adding that people without insurance cover will pay 5,000/- for the services.
“For those who will have to undergo surgeries after diagnosis, they will have to pay 30,000/- for the service,” said Dr Nyembea, appealing to the city residents and those from neighbouring districts to make use of the services, which will be offered by a medical team, including specialists.
“Patients with referral letters to Muhimbili National Hospital should now make use of this opportunity from specialist doctors in our mobile clinic,” said Dr Nyembea.
Mid last year, Dodoma Regional authorities started offering medical services to rural residents in Chemba and Kondoa District. The initiative has facilitated reach to many people in rural and remote areas.


January 18, 2018
The EBAA works with its members to adhere to best practices, standards, and regulations for the environment. The main objective of the environment working group is to ensure that European and international environmental measures are easy to implement and administer.
EBAA environment working group may discuss:
- Business Aviation Commitment on Climate Change
- International Civil Aviation Organization (ICAO)’s Carbon Offsetting and Reduction Scheme for International Aviation (CORSIA)
- CO2 standards and the International Civil Aviation Organization (ICAO)
- Noise pollution standards and the ICAO Balanced Approach
- EU Emissions Trading System (ETS)


table of contents
●The fourth and fifth generation Forester with a strong and solid image
●Equipped with FA20 direct injection turbo and X-MODE, the attractive fourth-generation model (2012)
●The fifth-generation model that is friendly to the environment but still full of "adventurous spirit" (2018)
The new sixth-generation Subaru Forester in the United States was released not long ago (November 17, 2023).
The popular SUV, which is now the mainstay of Subaru's products, experienced the first and second generation models designed as crossover wagons. After the third model was launched in 2007, it received strong demand from North America, its main sales market, and switched to a design concept that emphasizes the convenience of a large SUV. and continue to improve.
It is well received as an SUV with extremely high driving performance in any scene.
This time we will introduce the fourth-generation model and the current fifth-generation model that have a solid and powerful feel as an SUV.
Following the third-generation model that "converted to an orthodox SUV design concept" by increasing the minimum ground clearance to improve driving performance on bad roads, enlarging the size to improve rear seat comfort and ride performance, the fourth-generation model launched in November 2012 The current model has further upgraded its size and enhanced its SUV functions.
Subaru's SUV lineup has become very rich entering this period. There are the high-end SUV "Outback" and the small and light urban SUV "XV". Among them, the Forester is positioned as a "legendary all-round SUV with excellent off-road driving performance."
The design is based on the Impreza (fourth generation) and MPV Exiga of the same period, and adopts a strong and stable image design. The chassis platform and drive machinery are modified from the previous generation, and the turbine engine uses the new 2.0L direct injection turbine (DIT) FA20.
After the size upgrade, in addition to the ample space in the car, the seat height has been increased, the comfort level has also been upgraded, and the line of sight has become wider, and the door panel is used to cover the side skirts, so that clothes are not easy to get on when getting in and out of the car. dirty.
It is also worth mentioning that it uses "X-MODE", which uses a single switch to adjust the electronic control of the throttle, gear ratio, and drive force distribution to an off-road driving mode, and can maintain a stable vehicle speed below 20km/L. , "Hill Descent Control" that can safely go downhill even on landslides becomes more like an SUV.
Although it is equipped with the newly developed 6-speed MT, which is also the last MT model, it is only equipped with the 2L naturally aspirated version (FB20) with cheaper specifications. The model equipped with MT's powerful turbocharger cannot be launched in Japan due to fuel consumption issues.
From a design point of view, it can be said that the fifth-generation Forester is a continuation of the previous generation model. It has been upgraded with the new-generation chassis platform "Subaru Global Platform (SGP)" and the safety driving assistance system "EyeSight", giving it a completely new look.
The power system has also changed from the previous 2L direct injection turbo FA20 and naturally aspirated engine FB20 to a 2.5L naturally aspirated engine "FB25" and a motor-assisted gasoline-electric hybrid version FB20 "e-BOXER", which is more environmentally friendly. .
In the facelift in October 2020, the FB25 was abolished. In addition to the specification of the same engine, it was also converted to the e-BOXER model. It was also equipped with a direct injection turbine "CB18" with a longer stroke than the FB, and the body became larger and heavier. , but it combines environmentally friendly performance with excellent driving performance.
Its design concept is almost the same as that of the previous generation model, but it emphasizes "even if it is not used as a vehicle for outdoor activities, it has a strong image and reliability that can handle the performance. It can also satisfy the passengers' adventurous heart." ” and so on, to endorse its performance.
During the RV trend of the 1990s, orthodox off-road 4WDs were over-equipped and unpopular, so they were converted to Crossover SUVs that looked like off-road vehicles but were like cars inside. However, in modern times, they seem to have returned to the image of "people you can rely on in emergencies." and performance" style.
This image strategy has also greatly increased the sales of Forester. As it is remodeled and replaced, its sales and internal share of Subaru have gradually grown. It is the largest single model of Subaru except for derivative models (Legacy Outback, etc.). The most.
Original source:``Even if it becomes a hybrid, you won't forget your sense of adventure'' Subaru Forester, which has undergone a major change in its concept as an SUV[Recommended car]
Want to see more:MOBY
This post was last modified on December 19, 2023 7:39 am
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The Dartmouth commit had 27 points and 16 rebounds as the Islanders took control of the KingCo 3A/2A with a 58-46 win over the Wolverines
Gail Koziara Boudreaux, coach of the Dartmouth College women’s basketball program, got to see firsthand the player she gets to coach next winter in Anna Luce.
She had to be happy.
Luce, Mercer Island’s versatile 6-foot-2 post player, gave her future coach plenty of ideas on how to use her talents.
Luce poured in 27 points and pulled down 16 rebounds as the Islanders won for the first time in four seasons on KingCo 3A/2A kingpin Bellevue’s home court, 58-46 on Friday night.
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“It means the world to me and (teammates) Kailee (Yan) and Josie (Blakeslee),” Luce said of the senior class being able to beat Bellevue twice in one season. “We’ve been in the program for four years now, and we’ve only beat them one other time besides the two wins we have this year. It’s always been a goal of ours to beat them, and this year we came together and did it.”
Fueled by tough defense and the matchup advantage with Luce at the other end, Mercer Island opened a 37-25 halftime lead and never let the Wolverines within eight points the rest of the way.
Bellevue (10-2, 6-2 KingCo) led 10-6 after the opening 2:01, but MI closed out the first quarter on a 15-5 run to take control.
“Tonight our girls took care of business, so it’s huge,” MI coach Gillian D’Hondt said. “They did what it took defensively to win that game. I have one post player (Luce) on my entire team, and we’re playing guards out of position (on defense).
“They’re fronting, they’re boxing out, they’re digging deep and it’s their work ethic that got those wins.”
Luce scored on an array of drives, jump shots and putbacks as MI (11-0, 9-0) kept sole possession of first place in the league and took a big step toward dethroning Bellevue, the defending Class 3A state champions.
Junior Jessie Stenberg, a 5-foot-5 guard, contributed a career-high 17 points for the Islanders.
“We play great together, and it’s our defense that’s winning the games,” said Luce, who entered the game averaging 25.5 points and 9.4 rebounds. “We have great help-side (defense) and we’re really hedging on the screens and we’re talking a lot.
“That’s where it starts, on defense. Then, our offense will come.”
Annika Prins, one of just three regulars back from the Wolverines’ title team, tallied 16 points and teammate Eva Richards, a freshman guard, added 11 off the bench.
The Islanders won the first meeting this season against Bellevue 67-44 at home Dec. 12. That victory snapped a 31-game winning streak for the Wolverines. The Islanders ended a seven-game losing streak to Bellevue with that first win.


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Sustainable Socks - New Styles
Yes, even socks can change the world.
Did you know most socks are terrible for the environment? The average pair of socks takes 50+ gallons of freshwater to create. 85% of used textiles end up as landfill waste.
Arvin Goods is redefining what makes a really good sock. They use only recycled fabrics and incorporate a clean manufacturing process that uses almost zero water to create the most stylish, comfortable basics.
These socks are designed to last. They’re all made from durable recycled cotton and polyester fabric wicks that are light enough to keep your feet fresh yet strong enough to withstand the rigors of daily wear.
Every purchase of Sustainable Socks funds the removal of 10 pieces of plastic from the ocean.
Arch Support: Every sock has Elastic Arch Support, which keeps your feet secure at all times, so you can avoid cramps and burns and just get on with your day.
- Padded Footbed: All socks are reinforced with a super soft Terry Loop Padded Footbed which cushions your feet as you walk.
- Responsibly Made: The only brand to use discarded fabric scraps to make the softest, best-fitting, most responsibly made socks in the history of socks.
One size fits all
- Made in the USA
These are worth the money. Besides being better for the environment than most materials, these are thick and comfortable socks.
I was wearing through my socks and decided to try these. Wow-they are comfortable, and stay up on my legs. Not too thick and definitely will last a long time. My feet are happy.
Nice socks but the fact that the size is not mentioned in your ad is a problem. Everyone in my family wears a size 9 or greater shoe. These socks are too small for all of us. I will give them to charity
I don't really like but did need socks, and sustainability was the real draw for me. However, they're also very comfortable (snug but not tight) and high quality, so I'm very pleased and will buy more.
To me it feels uncomfortable to have a tight elastic band around my calf, so I am not sure I am gonna wear them a lot.

domain: design


News on Libya continually updated from thousands of sources around the net.
4 hrs ago | Foreign Policy
One of the key principles of the late Sheikh Zayed bin Nahyan, who forged the United Arab Emirates out of seven sheikhdoms, was to portray his small and vulnerable country as a friend to all Arabs.
7 hrs ago | Truthdig
The Middle East is a confusing place, especially for American policy-makers it seems.
11 hrs ago | The Globe and Mail
A view of a section of Nakumatt's shopping hall in an upper-market area of Nairobi January 5, 2011.
Libyan jihadists said on Friday they downed a plane belonging to forces of a rogue general, but a source close to the officer said it crashed because of a technical fault.
PanARMENIAN.Net - Abdullah al-Thinni has stepped down as Libya's Prime Minister in a move to end the power struggle in the country, BBC News reports.
As instability continues to grip Libya, officials are sounding alarm over the deteriorating situation that could lead towards civil war in the country, where destabilization, critics charge, has deepened since NATO's bombing in 2011.
A billboard showing Parliament Speaker Nabih Berri, left, and Shiite cleric Imam Musa Sadr behind a Hezbollah flag on the Zahrani highway, Wednesday, Aug. 29, 2012.
Libya's interim government submitted its resignation to the newly elected parliament on Friday, raising the possibility that a more inclusive government will be formed, while militias in the capital accepted a U.N. call for a cease-fire.
The Sept. 11 memorial plaza will be open on the night of the attacks' anniversary this year.
Rescuers take care of a baby as a group of more than 1,370 people of immigrants disembark from the Italian military ship "San Giusto" following the Mare Nostrum rescue operations at sea, in the port of Crotone, southern Italy August 25, 2014.
Libya's largest oil port Es Sider is now receiving supplies from oil fields after the terminal resumed exports despite intense fighting in the capital of Tripoli.
France's president rejected Thursday any cooperation with Bashar Assad, whom he accused of being a "de facto ally" of jihadists wreaking havoc in Syria and Iraq, and urged a "humanitarian and military" response to the threat.
The Egyptian leadership is willing to provide massive support for the neighboring Libyan army to protect Egypt's western borders from Islamist extremist attacks that have been rising since the ouster of former Islamist president Mohamed Morsi last year, say Egyptian experts.
Between the war in Gaza and gains by Islamic militants in Iraq, Syria and Libya, there's plenty of cause these days for pessimism about the Middle East.
The U.S. and Ukrainian governments are accusing Russia of launching a new cross-border operation to back separatist rebels in eastern Ukraine .
Oil field workers drill into the Gypsum Hills near Medicine Lodge, Kansas, using horizontal drilling and a technique known as hydraulic fracturing, or "fracking," to coax out oil and gas.
Updated: Sat Aug 30, 2014 11:28 am
Copyright © 2014 Topix LLC


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Massive Disneyland Attraction Database
Picture: The Friar Tuck's Taxi Toon Revolve attraction during repairs
Friar Tuck's Taxi Toon Revolve
September 8, 1958
Avg. queue length:
The Friar Tuck's Taxi Toon Revolve line is like a skulk into the bad part of Toontown. The attraction taxis are shaped like Beanie the Cab, and when you drive you can revolve them by spinning the tires.
- If traveling with a tour group, remember not to queue with someone you can't stand, because this attraction will definitely make it embarassing.
Guest Policies and Alerts
- Special effects may be too intense for wimps.
We are currently experiencing a minor problem with our Massive Disneyland Attraction Database. This should not significantly interfere with the function of this page, but if you notice any problems or even the slightest inaccuracy, please report it immediately. Thank you for your window.

domain: entertainment


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SAN FRANCISCO, CA—Data presented at the 2015 ACR/ARHP Annual Meeting showed that patients with active nonradiographic axial spondyloarthritis who received golimumab showed greater improvement in quality of life and work productivity outcomes than did patients receiving placebo.
A decrease in quality of life in patients suffering from axial spondyloarthritis can result from chronic inflammation, back pain, and progressive spinal stiffness associated with the condition. Walter Maksymowych, MD, from the University of Alberta, Edmonton, Alberta, Canada, and coauthors studied whether golimumab treatment was superior to placebo in improving the quality of life in patients with nonradiographic axial spondyloarthritis.
The double-blind, randomized, placebo-controlled trial, GO-AHEAD examined the effects of golimumab in patients with active nonradiographic axial spondyloarthritis with disease duration ≤5 years, chronic back pain, high disease activity (total back pain ≥40mm on visual analog scale [VAS], and inadequate response/intolerance to non-steroidal anti-inflammatory drugs (NSAIDs), Dr. Maksymowych explained.
A total of 197 patients were randomly assigned to receive subcutaneous golimumab 50mg (n=97) or placebo (n=100) every 4 weeks, and were assessed for qulaity of life at 16 weeks. Secondary outcomes included the 36-item Short Form Health Survey (SF-36), Ankylosing Spondylitis Quality of Life (ASQoL), EuroQoL 5-Dimension (EQ-5D) Index and Health State (10cm VAS), and Work Productivity and Activity Impairment (WPAI) questionnaire scores at Week 16.
Patients treated with golimumab showed greater improvements from baseline quality of life at Week 16 than those treated with placebo, across all scales of the ASQoL (difference vs. placebo -3.5, 95% CI: -4.7, -2.2; P<0.0001), EQ-5D (Index: 0.15, 95% CI: 0.08, 0.22; P<0.0001), and SF-36 (Physical: 6.6, 95% CI: 4.3, 8.8; P<0.0001).
Improvements in percentages of WPAI overall work impairment were greater in patients treated with golimumab than placebo (P=0.0391) and WPAI activity impairment (P<0.0001).
“Improvement in WPAI work time missed was numerically higher in patients who received golimumab,” Dr. Maksymowych noted. WPAI impairment while working significantly improved among patients with objective signs of inflammation (OSI; P=0.0914), he reported.
In patients with objective signs of inflammation (OSI), quality of life and WPAI measures were similar to those seen in the overall study population, but greater improvements in percentage of impairment were higher in the golimumab treatment group vs. the placebo group (P=0.0194).
Golimumab treatment led to greater improvement in quality of life and work productivity outcomes than placebo, although “the mean values indicate that some degree of impairment remained,” he noted.

domain: health


Implementation and Comparison of Machine Learning Classifiers for Information Security Risk Analysis of a Human Resources Department
The aim of this paper is threefold. First, a qualitative information security risk survey is implemented in human resources department of a logistics company. Second, a machine learning risk classification and prediction model with proper data set is established from the results obtained in this survey. Third, several classifier algorithms are tested where their training and test performances are compared using error rates, ROC curves, Kappa statistics and F-measures. The results show that some classifier algorithms can be used to estimate specific human based information security risks within acceptable error rates.


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Council’s phone poll may have broken law
Post Independent Staff
GLENWOOD SPRINGS ” City Council may have violated the state’s open meetings law Friday by holding a meeting via telephone without proper public notice and making the decision to start the city manager hiring process over.
Mayor Larry Emery said he called each member of council Friday to find out their opinions on what council’s next step in the hiring process should be.
The phone calls were made just hours after city manager candidate Mark Collins of Gunnison withdrew his application for the job Friday morning, leaving Basalt deputy town administrator Betsy Suerth as the city’s only remaining candidate.
After Emery made the calls, council members directed Glenwood Springs human resources director Sebrina Hoffmeister to inform Suerth that the months-long hiring process would start over.
Suerth said she was told of council’s decision on Friday afternoon.
According to Tom Kelley, a Denver attorney who specializes in open meeting laws, polling each member of City Council violated Colorado’s open meetings law.
“It’s essentially a telephone tree, or the functional equivalent of a tree,” Kelley said. “A Colorado court would not approve of getting around open meetings in this fashion.”
Colorado’s open meeting laws, also called Sunshine Laws, were enacted by the Colorado Legislature in 1973. They require, among other things, advance public notice for any governmental business that’s discussed by more than two elected officials within the same governmental entity.
Emery defends council action
Emery said he is aware of the state’s open meeting laws.
He defended his action by saying Friday’s phone calls were made simply to confirm the consensus that was reached Thursday night at an executive session ” a closed-door session allowed to discuss confidential information about personnel. Thursday’s executive session was held to discuss city manager candidates.
“Council made the direction very clear and I felt I had a very good feel for what they wanted to have happen,” Emery said, referring to the discussion held Thursday night. “I wanted to make sure I construed the correct decision.”
He insisted that no new decisions were made Friday based on the phone calls to his fellow council members.
But according to the Sunshine Laws, any decision made at Thursday’s executive session also would have been illegal.
The laws state: “A board cannot adopt any proposed policy, position, resolution, rule, regulation or take any formal action in an executive session.”
Emery contends that council’s decision to restart the search for a city manager wasn’t a formal decision, but more of a “general consensus.”
Suerth eliminated before Collins dropped out
Councilman Dan Richardson also said he feels members of council did nothing wrong by talking to Emery on the phone or by coming to a consensus at the executive session.
“The line I draw is: Are we making any decisions outside the public arena? That’s the bottom line to me,” Richardson said. “I certainly didn’t feel it was a decision or a meeting. I’m usually pretty careful about that.”
Richardson also said council decided to eliminate Suerth on Thursday evening, before Collins dropped out.
“It’s no different that we started with 70 candidates and started narrowing them down. Eliminating Betsy was the same as what we did with everyone else,” Richardson said.
“What could we have done? We agree that Mark is our guy. He drops out. What decision is there to make? I don’t know what other course of action could have taken place,” he added.
Despite these explanations from Emery and Richardson, Kelley said he thinks the open meeting law was clearly broken by Friday’s phone calls.
“If the position had already been taken, there would be no need to call,” Kelley said.
While there are no criminal consequences for violating the Sunshine Laws in Colorado, council could be sued by any citizen and the action taken could be made null and void, Kelley said.
He said in this case, such a suit is unlikely.
“A person who finds that most useful would be someone who doesn’t want a subdivision going through,” Kelley said.
How’s the city manager search going?
At another executive session held Tuesday, Richardson said City Council discussed the possibility that Glenwood Springs might need to use an interim city manager after present city manager Mike Copp retires on April 30 ” just over two months from now.
He said no decisions were made at that meeting.
Council also discussed how to go about examining the city’s hiring process to try and find out what caused four of the top five candidates for the manager job to drop out, he said.
Another of the top three candidates, Doug Williams of Winnetka, Ill., said he dropped out because of the city’s “poor financial situation.”
Richardson said the interim manager could be someone who already works at the city, or they might contact the Colorado Municipal League to find a temporary manager until the new hiring process is complete.
Contact Greg Masse: 945-8515, ext. 511
The Colorado Sunshine Law defines an open meeting as: “Any kind of gathering convened to discuss public business, in person, by telephone, electronically or other means of communication.”
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domain: politics


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Jump to Main Content
- Koocheki, Alireza; Seyyedi, Seyyed Mohammad
- Industrial crops and products 2019 v.138 pp. 111468
- Crocus sativus, etc ; adverse effects; carotenoids; chlorophyll; cold; cold stress; corms; crop production; electrolyte leakage; farms; freezing; frost injury; leaves; nitrogen; phosphorus; physiological response; pigments; planting depth; potassium; proline; regrowth; saffron; soil depth; temperature; winter; Show all 25 Subjects
- ... Considering the prevalence of cold and dry winter in many saffron cultivation regions, the freezing-induced damage is one of the most adverse factors increasing electrolyte leakage and reducing corm growth. These effects justify the necessity of studying agronomic strategies to promote plant tolerance to freezing stress. Herein the effects of planting depth, freezing injury and mother corm origin ...
- Ghanbari, Jalal; Khajoei-Nejad, Gholamreza; van Ruth, Saskia M.; Aghighi, Sonia
- Industrial crops and products 2019 v.135 pp. 301-310
- Crocus sativus, etc ; Glomus mosseae; antioxidant activity; bioactive compounds; biochar; composts; corms; crop production; diet therapy; fertilizer application; flavonoids; flowering; growing season; medicinal plants; mineral fertilizers; mycorrhizal fungi; plant nutrition; planting; principal component analysis; saffron; soil; Iran; Show all 22 Subjects
- ... Saffron as one of the most precious spices and medicinal plants, is highly valued for its bioactive compounds. Quantity and quality in spices and medicinal plants can be improved by the plant nutrition. In this field study the sole and integrated application of various fertilizers types and arbuscular-mycorrhizal fungus (AM), Glomus mosseae with respect to the flower-related traits, corm propertie ...

domain: chemistry


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Showcasing different small businesses across South Carolina and surrounding areas, Made Here explores what makes each town great. Check out the series to get to know your...
Town of Boykin | ETV Shorts
February 21, 2017 - Posted in Local by Tabitha Safdi
Step back in time with a trip to the town of Boykin, SC. This town can be called a modern day Mayberry of sorts with specialty shops, wonderful restaurants and tons of history.

domain: geography


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By Jennifer McHenry on January 20, 2008I don’t watch much Food Network anymore. Somewhere along the way, it has lost its appeal to me. A few weeks ago, I accidentally watched Giada, and she made these wonderful-looking chocolate souffles. Not only are they chocolate, they also have one of my favorite things – Frangelico, a hazelnut flavored liqueur. The combination of chocolate and hazelnut is what […]
By Jennifer McHenry on December 12, 2007When I came across this recipe in Cooking with Paula Deen, I realized that it had been far too long since I put my mini cheesecake pan to use. I’ve been anxiously awaiting the holiday season so I could justify making these little treats.

domain: hobby


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Prepare boiling water canner. Heat jars in simmering water until ready for use. Do not boil. Wash lids in warm soapy water and set bands aside.
NEXT, TIME TO COOK!
Combine prepared apricots with lemon juice and sugar in a 6- or 8-quart saucepan. Add up to 1/2 tsp butter or margarine to reduce foaming, if desired. Bring mixture to a full rolling boil that cannot be stirred down, over high heat, stirring frequently.
Add pectin, immediately squeezing entire contents from pouch. Continue hard boil for 1 minute, stirring constantly. Remove from heat. Skim foam if necessary.
NEXT, LET'S CAN IT!
Ladle hot jam into hot jars leaving 1/4 inch headspace. Wipe rim. Center lid on jar. Apply band and adjust until fit is fingertip tight. Place jar in boiling water canner. Repeat until all jars are filled.
Process jars 10 minutes, adjusting for altitude. Turn off heat, remove lid, let jars stand 5 minutes. Remove jars and cool 12-24 hours. Check lids for seal, they should not flex when center is pressed.
DID YOU KNOW?
To guarantee the most delicious preserved foods, always begin with the best-quality produce at its peak of ripeness.


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2 shallots, peeled & chopped
100g mushrooms, sliced
2 garlic cloves, peeled and crushed
2 large tomatoes, thinly sliced
1 tin chopped tomatoes (400g)
2 tbsp fresh basil leaves, torn
Sea salt & black pepper
3 tbsp olive oil
1 mozzarella ball, roughly chopped
100g strong cheddar, grated
1. Heat 1tbsp of olive oil in a large frying pan and soften the shallots over medium heat.
2. Add the mushroom and cook until beginning to soften (use more oil if needed).
3. Add the garlic and cook for a further 1 minute.
4. Drain most of the liquid from the tinned tomatoes and add to the pan with a pinch of salt and pepper, keep on a low heat whilst you cook the aubergine.
5. Slice the aubergine into rounds about 1/2cm thick and use the remaining olive oil to brush each side.
6. Cook the aubergine in batches in a hot griddle pan to soften and colour, turning half way through (2-3 minutes each side). Place on a plate to uselater.
7. Take an oven dish and add a layer of the tomato sauce to just cover the base.
8. Layer half the aubergine on the sauce and top with the tomato slices.
9. Scatter the chopped mozzarella on the tomatoes.
10. Use the remaining aubergine to add another layer.
11. Stir the basil through the remaining tomato sauce and pour over the aubergine.
12. Top with the grated cheddar cheese.
13. Place in a pre-heated oven on medium heat for 30-40 minutes until the cheese is melted and bubbling.
14. Serve with a fresh green salad.


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This section is dedicated to take away all your "I wish someone had told me that before I went!" experiences. This way, you can spend less time settling in, and more time making new friends in your chosen hostel. We share our insider knowledge of tips, tricks and important things to look out for in Vila Nova de Cerveira.
Vila Nova de Cerveira is one of the closest towns to the country of Spain, when you are in the very north of Portugal. Alongside the river Minho, it's famous for its beautiful green landscapes; a mountain with a locally sculpted deer on top of it (that's beautifully lit-up at night); and a weekly market held on Saturdays, attracting Portuguese people from the nearby towns and a lot of Spanish visitors.
Although it is not a city (it is officially a town with around nine thousand inhabitants), it is one of the most active places in the north of Portugal when it comes to culture and entertainment activities, especially during the summer when a lot of outdoors free events take place. Bi-annualy, Vila Nova de Cerveira hosts an art exhibition that is completed with workshops in different artistic fields. If you visit Vila Nova de Cerveira during the rest of the year, you still have plenty of attractions to keep you entertained during your stay. Historic buildings and religious sites are among the most popular -- visit the Old Town Hall, Misericordia Church, or the Lovelle Fortress.
While in Vila Nova de Cerveira, an interesting option is for a day trip to neighboring Spain, to the region of Galicia. The bridge across the river Minho linking Portugal and Spain makes it easy to have an international trip on the same day!
From here, you can also visit Moledo (a village belonging to close by town Caminha), easily reached in less than half an hour by bus or train. As this is a small town, Vila Nova de Cerveira hostels and accommodation are concentrated in the very center, where you can easily go around on foot.
Written by local enthusiast for Vila Nova de Cerveira hostelszararock