Shape: automatic conformation prediction of carbohydrates using a genetic algorithm

<p>Abstract</p> <p>Background</p> <p>Detailed experimental three dimensional structures of carbohydrates are often difficult to acquire. Molecular modelling and computational conformation prediction are therefore commonly used tools for three dimensional structure studies. Modelling procedures generally require significant training and computing resources, which is often impractical for most experimental chemists and biologists. <monospace>Shape</monospace> has been developed to improve the availability of modelling in this field.</p> <p>Results</p> <p>The <monospace>Shape</monospace> software package has been developed for simplicity of use and conformation prediction performance. A trivial user interface coupled to an efficient genetic algorithm conformation search makes it a powerful tool for automated modelling. Carbohydrates up to a few hundred atoms in size can be investigated on common computer hardware. It has been shown to perform well for the prediction of over four hundred bioactive oligosaccharides, as well as compare favourably with previously published studies on carbohydrate conformation prediction.</p> <p>Conclusion</p> <p>The <monospace>Shape</monospace> fully automated conformation prediction can be used by scientists who lack significant modelling training, and performs well on computing hardware such as laptops and desktops. It can also be deployed on computer clusters for increased capacity. The prediction accuracy under the default settings is good, as it agrees well with experimental data and previously published conformation prediction studies. This software is available both as open source and under commercial licenses.</p

Neuroimaging in Dementia

Dementia is a common illness with an incidence that is rising as the aged population increases. There are a number of neurodegenerative diseases that cause dementia, including Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia, which is subdivided into the behavioral variant, the semantic variant, and nonfluent variant. Numerous other neurodegenerative illnesses have an associated dementia, including corticobasal degeneration, Creutzfeldt–Jakob disease, Huntington’s disease, progressive supranuclear palsy, multiple system atrophy, Parkinson’s disease dementia, and amyotrophic lateral sclerosis. Vascular dementia and AIDS dementia are secondary dementias. Diagnostic criteria have relied on a constellation of symptoms, but the definite diagnosis remains a pathologic one. As treatments become available and target specific molecular abnormalities, differentiating amongst the various primary dementias early on becomes essential. The role of imaging in dementia has traditionally been directed at ruling out treatable and reversible etiologies and not to use imaging to better understand the pathophysiology of the different dementias. Different brain imaging techniques allow the examination of the structure, biochemistry, metabolic state, and functional capacity of the brain. All of the major neurodegenerative disorders have relatively specific imaging findings that can be identified. New imaging techniques carry the hope of revolutionizing the diagnosis of neurodegenerative disease so as to obtain a complete molecular, structural, and metabolic characterization, which could be used to improve diagnosis and to stage each patient and follow disease progression and response to treatment. Structural and functional imaging modalities contribute to the diagnosis and understanding of the different dementias

Health Policy and Systems Research in Twelve Eastern Mediterranean Countries: a stocktaking of production and gaps (2000-2008)

<p>Abstract</p> <p>Background</p> <p>The objectives of this study are to: (1) profile the production of Health Policy and Systems Research (HPSR) published between 2000 and 2008 in 12 countries in the Eastern Mediterranean Region (EMR): Bahrain, Egypt, Jordan, Lebanon, Libya, Morocco, Oman, Palestine, Sudan, Syria, Tunisia, and Yemen; (2) identify gaps; and (3) assess the extent to which existing HPSR produced in the region addresses regional priorities pertaining to Health Financing, Human Resources for Health and the Role of the Non-State Sector. This is the first stocktaking paper of HPSR production and gaps in the EMR.</p> <p>Methods</p> <p>Articles indexed on Medline between years 2000 and 2008 for the 12 study countries were selected. A MeSH term based search was conducted using country names. Articles were assessed using a coding sheet adapted for the region which included themes on: Governance Arrangements, Financial Arrangements, Delivery Arrangements, and Implementation Strategies. Identified articles were matched against regional research priorities to assess the extent to which research production aligns with priorities.</p> <p>Results</p> <p>A total of 1,487 articles (11.94%) fit the criteria in the coding sheet. Results showed an increase in HPSR production which peaked after 2005. Most identified articles focused on Delivery Arrangements (68.1%), and Implementation Strategies (24.4%). Most HPSR addressed priorities in Human Resources for Health (39%<b>)</b>, and some articles focused on Health Financing (12%) and Role of the Non-State Sector (6.1%).</p> <p>Conclusions</p> <p>Despite global calls for producing and translating HPSR into policy, there are still significant gaps in the EMR. More efforts are needed to produce HPSR and align production and translation with the demand for evidence by policymakers. Findings can help inform and direct future plans and activities for the Evidence Informed Policy Network- EMR, World Health Organization- EMR, and the Middle East and North Africa Health Policy Forum, in addition to being useful for countries that host or are planning to host KT platforms in the region.</p

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Ethical Issues in Engineering Models: An Operations Researcher’s Reflections

This article starts with an overview of the author’s personal involvement—as an Operations Research consultant—in several engineering case-studies that may raise ethical questions; e.g., case-studies on nuclear waste, water management, sustainable ecology, military tactics, and animal welfare. All these case studies employ computer simulation models. In general, models are meant to solve practical problems, which may have ethical implications for the various stakeholders; namely, the modelers, the clients, and the public at large. The article further presents an overview of codes of ethics in a variety of disciples. It discusses the role of mathematical models, focusing on the validation of these models’ assumptions. Documentation of these model assumptions needs special attention. Some ethical norms and values may be quantified through the model’s multiple performance measures, which might be optimized. The uncertainty about the validity of the model leads to risk or uncertainty analysis and to a search for robust models. Ethical questions may be pressing in military models, including war games. However, computer games and the related experimental economics may also provide a special tool to study ethical issues. Finally, the article briefly discusses whistleblowing. Its many references to publications and websites enable further study of ethical issues in modeling

Rapid copper acquisition by developing murine mesothelioma: Decreasing bioavailable copper slows tumor growth, normalizes vessels and promotes T cell infiltration

Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF). Decreasing bioavailable copper has been used as an antiangiogenic and anti-cancer strategy with promising results. However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry. Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. These data imply that copper uptake may play an important role in early tumor development. Lowering bioavailable copper using the copper chelators, penicillamine, trientine or tetrathiomolybdate, slowed in vivo mesothelioma growth but did not provide any cures similar to using cisplatin chemotherapy or anti-VEGF receptor antibody therapy. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. Copper lowering was associated with reduced tumor vessel diameter, reduced endothelial cell proliferation (reduced Ki67 expression) and lower surface ICAM/CD54 expression implying reduced endothelial cell activation, in a process similar to endothelial normalization. Copper lowering was also associated with a CD4+ T cell infiltrate. In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes

Influence of serum testosterone on urinary continence and sexual activity in patients undergoing radical prostatectomy for clinically localized prostate cancer

The aim of the present study was to evaluate how serum testosterone level (T) can affect urinary continence and erectile function in patients undergoing radical prostatectomy (RP). We included 257 patients with clinically localized prostate cancer, those who had filled out preoperative quality of life questionnaires (University of California, Los Angeles Prostate Cancer Index, International Index of Erectile Function (IIEF)), and those who had T and total PSA sampled the day before surgery. We calculated correlations between T and age, body mass index (BMI), PSA, urinary function or bother (UF, UB) and sexual function or bother (SF, SB) and IIEF-5 in the whole population and in sub-populations with normal (⩾10.4 nmol l−1) and low (<10.4 ng ml−1) T using Pearson's and Spearman's correlation coefficients. We evaluated differences in these parameters between patients with low and normal T using the unpaired samples t-test and Mann–Whitney test, and finally the correlation between UF and SF, UB and SB, and between PSA and T in the overall population, and separately in patients with low and normal T using the Pearson's correlation coefficient. Mean preoperative T was 13.5 nmol l−1 and 23.7% of patients presented a low T. Mean age, mean BMI and mean preoperative total PSA at RP were 64.3 years, 25.9 kg m−2 and 9.0 ng ml−1, respectively. BMI was negatively correlated with T in the overall population (r=−0.266; P=0.02); moreover, patients with normal T presented lower BMI compared with patients with low T (25.7 vs 27.6: P=0.02). We found a significant correlation between SF scores and T in patients with normal T (r=0.1777: P=0.05). SF was significantly higher in patients with normal T compared with those with low T (74.8 vs 64.8: P=0.05). Furthermore, UF and UB were significantly correlated with SF (r=0.2544: P<0.01) and SB (r=0.2512: P=0.01), respectively, in men with normal T. Serum T was significantly correlated with PSA in men with low T (r=0.3874: P=0.0029), whereas this correlation was missed in the whole population and in men with normal T. The correlation between preoperative PSA and T in men with low T is in agreement with the ‘saturation' model proposed by Morgentaler. The correlation between basal T and preoperative erectile function and urinary continence underlines the importance of assessing T before RP

Strong mucosal immune responses in SIV infected macaques contribute to viral control and preserved CD4+ T-cell levels in blood and mucosal tissues

<p>Abstract</p> <p>Background</p> <p>Since there is still no protective HIV vaccine available, better insights into immune mechanism of persons effectively controlling HIV replication in the absence of any therapy should contribute to improve further vaccine designs. However, little is known about the mucosal immune response of this small unique group of patients. Using the SIV-macaque-model for AIDS, we had the rare opportunity to analyze 14 SIV-infected rhesus macaques durably controlling viral replication (controllers). We investigated the virological and immunological profile of blood and three different mucosal tissues and compared their data to those of uninfected and animals progressing to AIDS-like disease (progressors).</p> <p>Results</p> <p>Lymphocytes from blood, bronchoalveolar lavage (BAL), and duodenal and colonic biopsies were phenotypically characterized by polychromatic flow cytometry. In controllers, we observed higher levels of CD4+, CD4+CCR5+ and Gag-specific CD8+ T-cells as well as lower immune activation in blood and all mucosal sites compared to progressors. However, we could also demonstrate that immunological changes are distinct between these three mucosal sites.</p> <p>Intracellular cytokine staining demonstrated a significantly higher systemic and mucosal CD8+ Gag-specific cellular immune response in controllers than in progressors. Most remarkable was the polyfunctional cytokine profile of CD8+ lymphocytes in BAL of controllers, which significantly dominated over their blood response. The overall suppression of viral replication in the controllers was confirmed by almost no detectable viral RNA in blood and all mucosal tissues investigated.</p> <p>Conclusion</p> <p>A strong and complex virus-specific CD8+ T-cell response in blood and especially in mucosal tissue of SIV-infected macaques was associated with low immune activation and an efficient suppression of viral replication. This likely afforded a repopulation of CD4+ T-cells in different mucosal compartments to almost normal levels. We conclude, that a robust SIV-specific mucosal immune response seems to be essential for establishing and maintaining the controller status and consequently for long-term survival.</p