In silico approach to screen compounds active against parasitic nematodes of major socio-economic importance

Infections due to parasitic nematodes are common causes of morbidity and fatality around the world especially in developing nations. At present however, there are only three major classes of drugs for treating human nematode infections. Additionally the scientific knowledge on the mechanism of action and the reason for the resistance to these drugs is poorly understood. Commercial incentives to design drugs that are endemic to developing countries are limited therefore, virtual screening in academic settings can play a vital role is discovering novel drugs useful against neglected diseases. In this study we propose to build robust machine learning model to classify and screen compounds active against parasitic nematodes.A set of compounds active against parasitic nematodes were collated from various literature sources including PubChem while the inactive set was derived from DrugBank database. The support vector machine (SVM) algorithm was used for model development, and stratified ten-fold cross validation was used to evaluate the performance of each classifier. The best results were obtained using the radial basis function kernel. The SVM method achieved an accuracy of 81.79% on an independent test set. Using the model developed above, we were able to indentify novel compounds with potential anthelmintic activity.In this study, we successfully present the SVM approach for predicting compounds active against parasitic nematodes which suggests the effectiveness of computational approaches for antiparasitic drug discovery. Although, the accuracy obtained is lower than the previously reported in a similar study but we believe that our model is more robust because we intentionally employed stringent criteria to select inactive dataset thus making it difficult for the model to classify compounds. The method presents an alternative approach to the existing traditional methods and may be useful for predicting hitherto novel anthelmintic compounds.12 page(s

Changing expression of vertebrate immunity genes in an anthropogenic environment: a controlled experiment

Background: The effect of anthropogenic environments on the function of the vertebrate immune system is a problem of general importance. For example, it relates to the increasing rates of immunologically-based disease in modern human populations and to the desirability of identifying optimal immune function in domesticated animals. Despite this importance, our present understanding is compromised by a deficit of experimental studies that make adequately matched comparisons between wild and captive vertebrates. Results: We transferred post-larval fishes (three-spined sticklebacks), collected in the wild, to an anthropogenic (captive) environment. We then monitored, over 11 months, how the systemic expression of immunity genes changed in comparison to cohort-matched wild individuals in the originator population (total n = 299). We found that a range of innate (lyz, defbl2, il1r-like, tbk1)and adaptive (cd8a, igmh) immunity genes were up-regulated in captivity, accompanied by an increase in expression of the antioxidant enzyme, gpx4a. For some genes previously known to show seasonality in the wild, this appeared to be reduced in captive fishes. Captive fishes tended to express immunity genes, including igzh, foxp3b, lyz, defbl2, and il1r-like, more variably. Furthermore, although gene co-expression patterns (analyzed through gene-by-gene correlations and mutual information theory based networks) shared common structure in wild and captive fishes, there was also significant divergence. For one gene in particular, defbl2, high expression was associated with adverse health outcomes in captive fishes. Conclusion: Taken together, these results demonstrate widespread regulatory changes in the immune system in captive populations, and that the expression of immunity genes is more constrained in the wild. An increase in constitutive systemic immune activity, such as we observed here, may alter the risk of immunopathology and contribute to variance in health in vertebrate populations exposed to anthropogenic environments

Gravitational Wave Detection by Interferometry (Ground and Space)

Significant progress has been made in recent years on the development of gravitational wave detectors. Sources such as coalescing compact binary systems, neutron stars in low-mass X-ray binaries, stellar collapses and pulsars are all possible candidates for detection. The most promising design of gravitational wave detector uses test masses a long distance apart and freely suspended as pendulums on Earth or in drag-free craft in space. The main theme of this review is a discussion of the mechanical and optical principles used in the various long baseline systems in operation around the world - LIGO (USA), Virgo (Italy/France), TAMA300 and LCGT (Japan), and GEO600 (Germany/U.K.) - and in LISA, a proposed space-borne interferometer. A review of recent science runs from the current generation of ground-based detectors will be discussed, in addition to highlighting the astrophysical results gained thus far. Looking to the future, the major upgrades to LIGO (Advanced LIGO), Virgo (Advanced Virgo), LCGT and GEO600 (GEO-HF) will be completed over the coming years, which will create a network of detectors with significantly improved sensitivity required to detect gravitational waves. Beyond this, the concept and design of possible future "third generation" gravitational wave detectors, such as the Einstein Telescope (ET), will be discussed.Comment: Published in Living Reviews in Relativit

Social policy.

Contents: Part I: Theory. Some History Leading to Design Criteria for Bayesian Prediction; A.C. Atkinson, V.V. Fedorov. Optimal Designs for the Evaluation of an Extremum Point; R.C.H. Cheng, et al. On Regression Experiment Design in the Presence of Systematic Error; S.M. Ermakov. Gröbner Basis Methods in Mixture Experiments and Generalisations; B. Giglio, et al. Efficient Designs for Paired Comparisons with a Polynomial Factor; H. Großmann, et al. On Generating and Classifying All qn-m Regular Designs for Square-Free q; P.J. Laycock, P.J. Rowley. Second-Order Optimal Sequential Tests; M.B. Malyutov, I.I. Tsitovich. Variational Calculus in the Space of Measures and Optimal Design; I. Molchanov, S. Zuyev. On the Efficiency of Generally Balanced Designs Analysed by Restricted Maximum Likelihood; H. Monod. Concentration Sets, Elfving Sets and Norms in Optimum Design; A. Pázman. Sequential Construction of an Experimental Design from an I.I.D. Sequence of Experiments without Replacement; L. Pronzato. Optimal Characteristic Designs for Polynomial Models; J.M. Rodríguez-Díaz, J. López-Fidalgo. A Note on Optimal Bounded Designs; M. Sahm, R. Schwabe. Construction of Constrained Optimal Designs; B. Torsney, S. Mandal. Part II: Applications. Pharmaceutical Applications of a Multi-Stage Group Testing Method; B. Bond, et al. Block Designs for Comparison of Two Test Treatments with a Control; S.M. Bortnick, et al. Optimal Sampling Design with Random Size Clusters for a Mixed Model with Measurement Errors; A. Giovagnoli, L. Martino. Optimizing a Unimodal Response Function for Binary Variables; J. Hardwick, Q.F. Stout. An Optimizing Up-And-Down Design; E.E. Kpamegan, N. Flournoy. Further Results on Optimal and Efficient Designs for Constrained Mixture Experiments; R.J. Martin, et al. Coffee-House Designs; W.G. Müller. (D,t, C)-Optimal Run Orders; L. Tack, M. Vandebroek. Optimal Design in Flexible Models, including Feed-Forward Networks and Nonparametric Regression; D.M. Titterington. On Optimal Designs for High Dimensional Binary Regression Models; B. Torsney, N. Gunduz. Planning Herbicide Dose-Response Bioassays Using the Bootstrap; S.S. Zocchi, C.G. Borges Demétrio. Photo Gallery. Optimum Design 2000: List of Participants

Timed Action of IL-27 Protects from Immunopathology while Preserving Defense in Influenza

Infection with influenza virus can result in massive pulmonary infiltration and potentially fatal immunopathology. Understanding the endogenous mechanisms that control immunopathology could provide a key to novel adjunct therapies for this disease. Here we show that the cytokine IL-27 plays a crucial role in protection from exaggerated inflammation during influenza virus infection. Using Il-27ra−/− mice, IL-27 was found to limit immunopathology, neutrophil accumulation, and dampened TH1 or TH17 responses via IL-10–dependent and -independent pathways. Accordingly, the absence of IL-27 signals resulted in a more severe disease course and in diminished survival without impacting viral loads. Consistent with the delayed expression of endogenous Il-27p28 during influenza, systemic treatment with recombinant IL-27 starting at the peak of virus load resulted in a major amelioration of lung pathology, strongly reduced leukocyte infiltration and improved survival without affecting viral clearance. In contrast, early application of IL-27 impaired virus clearance and worsened disease. These findings demonstrate the importance of IL-27 for the physiological control of immunopathology and the potential value of well-timed IL-27 application to treat life-threatening inflammation during lung infection