Evaluation of machine-learning methods for ligand-based virtual screening

Machine-learning methods can be used for virtual screening by analysing the structural characteristics of molecules of known (in)activity, and we here discuss the use of kernel discrimination and naive Bayesian classifier (NBC) methods for this purpose. We report a kernel method that allows the processing of molecules represented by binary, integer and real-valued descriptors, and show that it is little different in screening performance from a previously described kernel that had been developed specifically for the analysis of binary fingerprint representations of molecular structure. We then evaluate the performance of an NBC when the training-set contains only a very few active molecules. In such cases, a simpler approach based on group fusion would appear to provide superior screening performance, especially when structurally heterogeneous datasets are to be processed

Sex differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress

Depression and anxiety disorders are more prevalent in females, but the majority of research in animal models, the first step in finding new treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depression-associated behaviors in female mice, whereas males are resilient as they do not develop these behavioral abnormalities. In concert with these different behavioral responses, transcriptional analysis of nucleus accumbens (NAc), a major brain reward region, by use of RNA sequencing (RNA-seq) revealed markedly different patterns of stress regulation of gene expression between the sexes. Among the genes displaying sex differences was DNA methyltransferase 3a (Dnmt3a), which shows a greater induction in females after SCVS. Interestingly, Dnmt3a expression levels were increased in the NAc of depressed humans, an effect seen in both males and females. Local overexpression of Dnmt3a in NAc rendered male mice more susceptible to SCVS, whereas Dnmt3a knock-out in this region rendered females more resilient, directly implicating this gene in stress responses. Associated with this enhanced resilience of female mice upon NAc knock-out of Dnmt3a was a partial shift of the NAc female transcriptome toward the male pattern after SCVS. These data indicate that males and females undergo different patterns of transcriptional regulation in response to stress and that a DNA methyltransferase in NAc contributes to sex differences in stress vulnerability

Artificial Intelligence

Contains research objectives and reports on five research projects.Computation Center, M.I.T

Artificial Intelligence

Contains research objectives and reports on eight research projects.Computation Center, M.I.T

Differences in pregnancy outcomes in donor egg frozen embryo transfer (FET) cycles following preimplantation genetic screening (PGS): a single center retrospective study

PURPOSE: This study aims to test the hypothesis, in a single-center retrospective analysis, that live birth rates are significantly different when utilizing preimplantation genetic screening (PGS) compared to not utilizing PGS in frozen–thawed embryo transfers in our patients that use eggs from young, anonymous donors. The question therefore arises of whether PGS is an appropriate intervention for donor egg cycles. METHODS: Live birth rates per cycle and live birth rates per embryo transferred after 398 frozen embryo transfer (FET) cycles were examined from patients who elected to have PGS compared to those who did not. Blastocysts derived from donor eggs underwent trophectoderm biopsy and were tested for aneuploidy using array comparative genomic hybridization (aCGH) or next-generation sequencing (NGS), then vitrified for future use (test) or were vitrified untested (control). Embryos were subsequently warmed and transferred into a recipient or gestational carrier uterus. Data was analyzed separately for single embryo transfer (SET), double embryo transfer (DET), and for own recipient uterus and gestational carrier (GC) uterus recipients. RESULTS: Rates of implantation of embryos leading to a live birth were significantly higher in the PGS groups transferring two embryos (DET) compared to the no PGS group (GC, 72 vs. 56 %; own uterus, 60 vs. 36 %). The live birth implantation rate in the own uterus group for SET was higher in the PGS group compared to the control (58 vs. 36 %), and this almost reached significance but the live birth implantation rate for the SET GC group remained the same for both tested and untested embryos. Live births per cycle were nominally higher in the PGS GC DET and own uterus SET and DET groups compared to the non-PGS embryo transfers. These differences almost reached significance. The live birth rate per cycle in the SET GC group was almost identical. CONCLUSIONS: Significant differences were noted only for DET; however, benefits need to be balanced against risks associated with multiple pregnancies. Results observed for SET need to be confirmed on larger series and with randomized cohorts

The Retardation of Enamel Dissolution Rates by Adsorbed Long-Chain Ammonium Chlorides

Dissolution rate studies were conducted with hydroxyapatite and enamel in the presence of adsorbed surfactants. In general, the ability of the surfactant to retard the dissolution rate was directly related to its ability to adsorb onto apatite. Cetylpyridinium chloride adsorbed poorly onto apatite, and its influence on the dissolution rate was marginal. The long-chain protonated amines were much more effective as rate retarding agents, sometimes of the order of 1,000-, to 10,000-fold. These compounds were also found to adsorb much more strongly. A systematic dependence of the dissolution rate on chain length was found for these amines.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68179/2/10.1177_00220345690480040301.pd

The Swift Surge of Perovskite Photovoltaics

The breakthrough early 1990s dye sensitization of mesoscopic TiO2 films along with a regenerative iodide redox couple led to the explosive growth of dye-sensitized solar cell (DSC) research. The pioneering work of Grätzel and colleagues also made it possible to develop a solid-state DSSC with spiro-oMETAD as the hole conductor and thus replace the liquid electrolyte in the cell. Research efforts of Konenkamp and others further initiated the search for the “extremely thin absorber” (ETA) nanostructured solar cell, using TiO2 as the electron conductor, an inorganic absorber, and a hole conductor. Another major research thrust was by Weller, Kamat, Zaban, Nozik, Hodes, and others, who employed inorganic quantum dots (e.g., CdS and CdSe) as sensitizers. While discussing developments in sensitized solar cells, it is important to note the contributions of early visionaries like Gerischer, Sutin, and Bard, who were first to establish the concepts of sensitization using dye molecules and semiconductor nanostructures

Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions.

Inflammatory cytokines are commonly elevated in acute depression and are associated with resistance to monoaminergic treatment. To examine the potential role of cytokines in the pathogenesis and treatment of depression, we carried out a systematic review and meta-analysis of antidepressant activity of anti-cytokine treatment using clinical trials of chronic inflammatory conditions where depressive symptoms were measured as a secondary outcome. Systematic search of the PubMed, EMBASE, PsycINFO and Cochrane databases, search of reference lists and conference abstracts, followed by study selection process yielded 20 clinical trials. Random effect meta-analysis of seven randomised controlled trials (RCTs) involving 2370 participants showed a significant antidepressant effect of anti-cytokine treatment compared with placebo (standardised mean difference (SMD)=0.40, 95% confidence interval (CI), 0.22-0.59). Anti-tumour necrosis factor drugs were most commonly studied (five RCTs); SMD=0.33 (95% CI; 0.06-0.60). Separate meta-analyses of two RCTs of adjunctive treatment with anti-cytokine therapy and eight non-randomised and/or non-placebo studies yielded similar small-to-medium effect estimates favouring anti-cytokine therapy; SMD=0.19 (95% CI, 0.00-0.37) and 0.51 (95% CI, 0.34-0.67), respectively. Adalimumab, etanercept, infliximab and tocilizumab all showed statistically significant improvements in depressive symptoms. Meta-regression exploring predictors of response found that the antidepressant effect was associated with baseline symptom severity (P=0.018) but not with improvement in primary physical illness, sex, age or study duration. The findings indicate a potentially causal role for cytokines in depression and that cytokine modulators may be novel drugs for depression in chronically inflamed subjects. The field now requires RCTs of cytokine modulators using depression as the primary outcome in subjects with high inflammation who are free of other physical illnesses.GMK is supported by a Clinical Lecturer Starter Grant from the Academy of Medical Sciences, UK (grant no. 80354) and a Gosling Fellowship from the Royal College of Psychiatrists, UK (2015). GMK also received funding support from the Wellcome Trust 094790/Z/10/Z). PBJ acknowledges grant sup port from the Wellcome Trust (095844/Z/11/Z & 088869/Z/09/Z) and NIHR (RP-PG-0606-1335, Cambridge Biomedical Research Centre and CLAHRC East of England). RD has received grants from the National Institute of Neurological Diseases and Stroke of the National Institutes of Health (grants R01 NS073939; R01 NS074999).This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/mp.2016.16