Comparative genomics and understanding of microbial biology.

The sequences of close to 30 microbial genomes have been completed during the past 5 years, and the sequences of more than 100 genomes should be completed in the next 2 to 4 years. Soon, completed microbial genome sequences will represent a collection of >200,000 predicted coding sequences. While analysis of a single genome provides tremendous biological insights on any given organism, comparative analysis of multiple genomes provides substantially more information on the physiology and evolution of microbial species and expands our ability to better assign putative function to predicted coding sequences

Plan U: Universal access to scientific and medical research via funder preprint mandates

Preprint servers such as arXiv and bioRxiv represent a highly successful and relatively low cost mechanism for providing free access to research findings. By decoupling the dissemination of manuscripts from the much slower process of evaluation and certification by journals, preprints also significantly accelerate the pace of research itself by allowing other researchers to begin building on new results immediately. If all funding agencies were to mandate posting of preprints by grantees-an approach we term Plan U (for "universal")-free access to the world's scientific output for everyone would be achieved with minimal effort. Moreover, the existence of all articles as preprints would create a fertile environment for experimentation with new peer review and research evaluation initiatives, which would benefit from a reduced barrier to entry because hosting and archiving costs were already covered

The assessment of science: the relative merits of post- publication review, the impact factor, and the number of citations

The assessment of scientific publications is an integral part of the scientific process. Here we investigate three methods of assessing the merit of a scientific paper: subjective post-publication peer review, the number of citations gained by a paper, and the impact factor of the journal in which the article was published. We investigate these methods using two datasets in which subjective post-publication assessments of scientific publications have been made by experts. We find that there are moderate, but statistically significant, correlations between assessor scores, when two assessors have rated the same paper, and between assessor score and the number of citations a paper accrues. However, we show that assessor score depends strongly on the journal in which the paper is published, and that assessors tend to over-rate papers published in journals with high impact factors. If we control for this bias, we find that the correlation between assessor scores and between assessor score and the number of citations is weak, suggesting that scientists have little ability to judge either the intrinsic merit of a paper or its likely impact. We also show that the number of citations a paper receives is an extremely error-prone measure of scientific merit. Finally, we argue that the impact factor is likely to be a poor measure of merit, since it depends on subjective assessment. We conclude that the three measures of scientific merit considered here are poor; in particular subjective assessments are an error-prone, biased, and expensive method by which to assess merit. We argue that the impact factor may be the most satisfactory of the methods we have considered, since it is a form of pre-publication review. However, we emphasise that it is likely to be a very error-prone measure of merit that is qualitative, not quantitative

The NBD-NBD interface is not the sole determinant for transport in ABC transporters

International audienceOne of the most exciting scientific challenges in functional genomics concerns the discovery of biologically relevant patterns from gene expression data. For instance, it is extremely useful to provide putative synexpression groups or transcription modules to molecular biologists. We propose a methodology that has been proved useful in real cases. It is described as a prototypical KDD scenario which starts from raw expression data selection until useful patterns are delivered. Our conceptual contribution is (a) to emphasize how to take the most from recent progress in constraint-based mining of set patterns, and (b) to propose a generic approach for gene expression data enrichment. The methodology has been validated on real data sets

Gene Function Classification Using Bayesian Models with Hierarchy-Based Priors

We investigate the application of hierarchical classification schemes to the annotation of gene function based on several characteristics of protein sequences including phylogenic descriptors, sequence based attributes, and predicted secondary structure. We discuss three Bayesian models and compare their performance in terms of predictive accuracy. These models are the ordinary multinomial logit (MNL) model, a hierarchical model based on a set of nested MNL models, and a MNL model with a prior that introduces correlations between the parameters for classes that are nearby in the hierarchy. We also provide a new scheme for combining different sources of information. We use these models to predict the functional class of Open Reading Frames (ORFs) from the E. coli genome. The results from all three models show substantial improvement over previous methods, which were based on the C5 algorithm. The MNL model using a prior based on the hierarchy outperforms both the non-hierarchical MNL model and the nested MNL model. In contrast to previous attempts at combining these sources of information, our approach results in a higher accuracy rate when compared to models that use each data source alone. Together, these results show that gene function can be predicted with higher accuracy than previously achieved, using Bayesian models that incorporate suitable prior information

α-Synuclein-112 impairs synaptic vesicle recycling consistent with its enhanced membrane binding properties

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Soll, L. G., Eisen, J. N., Vargas, K. J., Medeiros, A. T., Hammar, K. M., & Morgan, J. R. α-Synuclein-112 impairs synaptic vesicle recycling consistent with its enhanced membrane binding properties. Frontiers in Cell and Developmental Biology, 8, (2020): 405, doi:10.3389/fcell.2020.00405.Synucleinopathies are neurological disorders associated with α-synuclein overexpression and aggregation. While it is well-established that overexpression of wild type α-synuclein (α-syn-140) leads to cellular toxicity and neurodegeneration, much less is known about other naturally occurring α-synuclein splice isoforms. In this study we provide the first detailed examination of the synaptic effects caused by one of these splice isoforms, α-synuclein-112 (α-syn-112). α-Syn-112 is produced by an in-frame excision of exon 5, resulting in deletion of amino acids 103–130 in the C-terminal region. α-Syn-112 is upregulated in the substantia nigra, frontal cortex, and cerebellum of parkinsonian brains and higher expression levels are correlated with susceptibility to Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple systems atrophy (MSA). We report here that α-syn-112 binds strongly to anionic phospholipids when presented in highly curved liposomes, similar to α-syn-140. However, α-syn-112 bound significantly stronger to all phospholipids tested, including the phosphoinositides. α-Syn-112 also dimerized and trimerized on isolated synaptic membranes, while α-syn-140 remained largely monomeric. When introduced acutely to lamprey synapses, α-syn-112 robustly inhibited synaptic vesicle recycling. Interestingly, α-syn-112 produced effects on the plasma membrane and clathrin-mediated synaptic vesicle endocytosis that were phenotypically intermediate between those caused by monomeric and dimeric α-syn-140. These findings indicate that α-syn-112 exhibits enhanced phospholipid binding and oligomerization in vitro and consequently interferes with synaptic vesicle recycling in vivo in ways that are consistent with its biochemical properties. This study provides additional evidence suggesting that impaired vesicle endocytosis is a cellular target of excess α-synuclein and advances our understanding of potential mechanisms underlying disease pathogenesis in the synucleinopathies.This study was supported by a research grant from the National Institutes of Health (NIH NINDS/NIA R01 NS078165 to JM), as well as research funds from the Marine Biological Laboratory (to JM)

Limited polymorphism in Plasmodium falciparum ookinete surface antigen, von Willebrand factor A domain-related protein from clinical isolates

BACKGROUND: As malaria becomes increasingly drug resistant and more costly to treat, there is increasing urgency to develop effective vaccines. In comparison to other stages of the malaria lifecycle, sexual stage antigens are under less immune selection pressure and hence are likely to have limited antigenic diversity. METHODS: Clinical isolates from a wide range of geographical regions were collected. Direct sequencing of PCR products was then used to determine the extent of polymorphisms for the novel Plasmodium falciparum sexual stage antigen von Willebrand Factor A domain-related Protein (PfWARP). These isolates were also used to confirm the extent of diversity of sexual stage antigen Pfs28. RESULTS: PfWARP was shown to have non-synonymous substitutions at 3 positions and Pfs28 was confirmed to have a single non-synonymous substitution as previously described. CONCLUSION: This study demonstrates the limited antigenic diversity of two prospective P. falciparum sexual stage antigens, PfWARP and Pfs28. This provides further encouragement for the proceeding with vaccine trials based on these antigens