Discovery of GlyT1 inhibitors with improved pharmacokinetic properties

Glycine transporter 1 (GlyT1) represents a novel target for the treatment of schizophrenia via the potentiation of glutamatergic NMDA receptors. The discovery of 4,4-disubstituted piperidine inhibitors of GlyT1 which exhibit improved pharmacokinetic properties, including oral bioavailability, is discussed.     

Enrichment of sequencing targets from the human genome by solution hybridization

Background

Genome sequences, now available for most pathogens, hold promise for the rational design of new therapies. However, biological resources for genome-scale identification of gene function (notably genes involved in pathogenesis) and/or genes essential for cell viability, which are necessary to achieve this goal, are often sorely lacking. This holds true for Neisseria meningitidis, one of the most feared human bacterial pathogens that causes meningitis and septicemia.

Results

By determining and manually annotating the complete genome sequence of a serogroup C clinical isolate of N. meningitidis (strain 8013) and assembling a library of defined mutants in up to 60% of its non-essential genes, we have created NeMeSys, a biological resource for Neisseria meningitidis systematic functional analysis. To further enhance the versatility of this toolbox, we have manually (re)annotated eight publicly available Neisseria genome sequences and stored all these data in a publicly accessible online database. The potential of NeMeSys for narrowing the gap between sequence and function is illustrated in several ways, notably by performing a functional genomics analysis of the biogenesis of type IV pili, one of the most widespread virulence factors in bacteria, and by identifying through comparative genomics a complete biochemical pathway (for sulfur metabolism) that may potentially be important for nasopharyngeal colonization.

Conclusions

By improving our capacity to understand gene function in an important human pathogen, NeMeSys is expected to contribute to the ongoing efforts aimed at understanding a prokaryotic cell comprehensively and eventually to the design of new therapies.     

The low abundance of clonally expanded mitochondrial DNA point mutations in aged substantia nigra neurons

Clonally expanded mitochondrial DNA (mtDNA) deletions accumulate with age in human substantia nigra (SN) and high levels cause respiratory chain deficiency. In other human tissues, mtDNA point mutations clonally expand with age. Here, the abundance of mtDNA point mutations within single SN neurons from aged controls was investigated. From 31 single cytochrome c oxidase normal SN neurons, only one clonally expanded mtDNA point mutation was identified, suggesting in these neurons mtDNA point mutations occur rarely, whereas mtDNA deletions are frequently observed. This contrasts observations in mitotic tissues and suggests that different forms of mtDNA maintenance may exist in these two cell types.     

Synthesis and SAR of GlyT1 inhibitors derived from a series of N-((4-(morpholine-4-carbonyl)-1-(propylsulfonyl)piperidin-4-yl)methyl)benzamides

This Letter describes the synthesis and SAR, developed through an iterative analog library approach, of potent and selective non-sarcosine-derived GlyT1 inhibitors.     

Bias Due to Changes in Specified Outcomes during the Systematic Review Process

Background

Adding, omitting or changing outcomes after a systematic review protocol is published can result in bias because it increases the potential for unacknowledged or post hoc revisions of the planned analyses. The main objective of this study was to look for discrepancies between primary outcomes listed in protocols and in the subsequent completed reviews published on the Cochrane Library. A secondary objective was to quantify the risk of bias in a set of meta-analyses where discrepancies between outcome specifications in protocols and reviews were found.

Methods and Findings

New reviews from three consecutive issues of the Cochrane Library were assessed. For each review, the primary outcome(s) listed in the review protocol and the review itself were identified and review authors were contacted to provide reasons for any discrepancies. Over a fifth (64/288, 22%) of protocol/review pairings were found to contain a discrepancy in at least one outcome measure, of which 48 (75%) were attributable to changes in the primary outcome measure. Where lead authors could recall a reason for the discrepancy in the primary outcome, there was found to be potential bias in nearly a third (8/28, 29%) of these reviews, with changes being made after knowledge of the results from individual trials. Only 4(6%) of the 64 reviews with an outcome discrepancy described the reason for the change in the review, with no acknowledgment of the change in any of the eight reviews containing potentially biased discrepancies. Outcomes that were promoted in the review were more likely to be significant than if there was no discrepancy (relative risk 1.66 95% CI (1.10, 2.49), p = 0.02).

Conclusion

In a review, making changes after seeing the results for included studies can lead to biased and misleading interpretation if the importance of the outcome (primary or secondary) is changed on the basis of those results. Our assessment showed that reasons for discrepancies with the protocol are not reported in the review, demonstrating an under-recognition of the problem. Complete transparency in the reporting of changes in outcome specification is vital; systematic reviewers should ensure that any legitimate changes to outcome specification are reported with reason in the review.     

Ecological tracers reveal resource convergence among prey fish species in a large lake ecosystem

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Comparing Dirichlet normal surface energy of tooth crowns, a new technique of molar shape quantification for dietary inference, with previous methods in isolation and in combination

Inferred dietary preference is a major component of paleoecologies of extinct primates. Molar occlusal shape correlates with diet in living mammals, so teeth are a potentially useful structure from which to reconstruct diet in extinct taxa. We assess the efficacy of Dirichlet normal energy (DNE) calculated for molar tooth surfaces for reflecting diet. We evaluate DNE, which uses changes in normal vectors to characterize curvature, by directly comparing this metric to metrics previously used in dietary inference. We also test whether combining methods improves diet reconstructions. The study sample consisted of 146 lower (mandibular) second molars belonging to 24 euarchontan taxa. Five shape quantification metrics were calculated on each molar: DNE, shearing quotient, shearing ratio, relief index, and orientation patch count rotated (OPCR). Statistical analyses were completed for each variable to assess effects of taxon and diet. Discriminant function analysis was used to assess ability of combinations of variables to predict diet. Values differ significantly by diets for all variables, although shearing ratios and OPCR do not distinguish statistically between insectivores and folivores or omnivores and frugivores. Combined analyses were much more effective at predicting diet than any metric alone. Alone, relief index and DNE were most effective at predicting diet. OPCR was the least effective alone but is still valuable as the only quantitative measure of surface complexity. Of all methods considered, DNE was the least methodologically sensitive, and its effectiveness suggests it will be a valuable tool for dietary reconstruction.     

Structural-functional role of chloride in photosystem II

Chloride binding in photosystem II (PSII) is essential for photosynthetic water oxidation. However, the functional roles of chloride and possible binding sites, during oxygen evolution, remain controversial. This paper examines the functions of chloride based on its binding site revealed in the X-ray crystal structure of PSII at 1.9 ? resolution. We find that chloride depletion induces formation of a salt bridge between D2-K317 and D1-D61 that could suppress the transfer of protons to the lumen.