2,080 research outputs found

    Protein-RNA interactions: a structural analysis

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    A detailed computational analysis of 32 protein-RNA complexes is presented. A number of physical and chemical properties of the intermolecular interfaces are calculated and compared with those observed in protein-double-stranded DNA and protein-single-stranded DNA complexes. The interface properties of the protein-RNA complexes reveal the diverse nature of the binding sites. van der Waals contacts played a more prevalent role than hydrogen bond contacts, and preferential binding to guanine and uracil was observed. The positively charged residue, arginine, and the single aromatic residues, phenylalanine and tyrosine, all played key roles in the RNA binding sites. A comparison between protein-RNA and protein-DNA complexes showed that whilst base and backbone contacts (both hydrogen bonding and van der Waals) were observed with equal frequency in the protein-RNA complexes, backbone contacts were more dominant in the protein-DNA complexes. Although similar modes of secondary structure interactions have been observed in RNA and DNA binding proteins, the current analysis emphasises the differences that exist between the two types of nucleic acid binding protein at the atomic contact level

    The impact of AlphaFold2 one year on

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    The greatly improved prediction of protein 3D structure from sequence achieved by the second version of AlphaFold in 2020 has already had a huge impact on biological research, but challenges remain; the protein folding problem cannot be considered solved. We expect fierce competition to improve the method even further and new applications of machine learning to help illuminate proteomes and their many interactions

    Transcriptional feedback in the insulin signalling pathway modulates ageing in both Caenorhabditis elegans and Drosophila melanogaster.

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    Several components have been previously identified, that modulate longevity in several species, including the target of rapamycin (TOR) and the Insulin/IGF-1 (IIS) signalling pathways. In order to infer paths and transcriptional feedback loops that are likely to modulate ageing, we manually built a comprehensive and computationally efficient signalling network model of the IIS and TOR pathways in worms. The core insulin transduction is signalling from the sole insulin receptor daf-2 to ultimately inhibit the translocation of the transcription factor daf-16 into the nucleus. Reduction in this core signalling is thought to increase longevity in several species. In addition to this core insulin signalling, we have also recorded in our worm model the transcription factors skn-1 and hif-1, those are also thought to modulate ageing in a daf-16 independent manner. Several paths that are likely to modulate ageing were inferred via a web-based service NetEffects, by utilising perturbed components (rheb-1, let-363, aak-2, daf-2;daf-16 and InR;foxo in worms and flies respectively) from freely available gene expression microarrays. These included "routes" from TOR pathway to transcription factors daf-16, skn-1, hif-1 and daf-16 independent paths via skn-1/hif-1. Paths that could be tested by experimental hypotheses, with respect to relative contribution to longevity, are also discussed. Direct comparison of the IIS and TOR pathways in both worm and fly suggest a remarkable similarity. While similarities in the paths that could modulate ageing in both organisms were noted, differences are also discussed. This approach can also be extended to other pathways and processes

    VarSite: disease variants and protein structure

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    VarSite is a web server mapping known disease-associated variants from UniProt and ClinVar, together with natural variants from gnomAD, onto protein 3D structures in the Protein Data Bank (PDB). The analyses are primarily image-based and provide both an overview for each human protein, as well as a report for any specific variant of interest. The information can be useful in assessing whether a given variant might be pathogenic or benign. The structural annotations for each position in the protein include protein secondary structure, interactions with ligand, metal, DNA/RNA, or other protein, and various measures of a given variant's possible impact on the protein's function. The 3D locations of the disease-associated variants can be viewed interactively via the 3dmol.js JavaScript viewer, as well as in RasMol and PyMOL. Users can search for specific variants, or sets of variants, by providing the DNA coordinates of the base change(s) of interest. Additionally, various agglomerative analyses are given, such as the mapping of disease and natural variants onto specific Pfam or CATH domains. The server is freely accessible to all at: https://www.ebi.ac.uk/thornton-srv/databases/VarSite. This article is protected by copyright. All rights reserved

    Using answer set programming to integrate RNA expression with signalling pathway information to infer how mutations affect ageing.

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    A challenge of systems biology is to integrate incomplete knowledge on pathways with existing experimental data sets and relate these to measured phenotypes. Research on ageing often generates such incomplete data, creating difficulties in integrating RNA expression with information about biological processes and the phenotypes of ageing, including longevity. Here, we develop a logic-based method that employs Answer Set Programming, and use it to infer signalling effects of genetic perturbations, based on a model of the insulin signalling pathway. We apply our method to RNA expression data from Drosophila mutants in the insulin pathway that alter lifespan, in a foxo dependent fashion. We use this information to deduce how the pathway influences lifespan in the mutant animals. We also develop a method for inferring the largest common sub-paths within each of our signalling predictions. Our comparisons reveal consistent homeostatic mechanisms across both long- and short-lived mutants. The transcriptional changes observed in each mutation usually provide negative feedback to signalling predicted for that mutation. We also identify an S6K-mediated feedback in two long-lived mutants that suggests a crosstalk between these pathways in mutants of the insulin pathway, in vivo. By formulating the problem as a logic-based theory in a qualitative fashion, we are able to use the efficient search facilities of Answer Set Programming, allowing us to explore larger pathways, combine molecular changes with pathways and phenotype and infer effects on signalling in in vivo, whole-organism, mutants, where direct signalling stimulation assays are difficult to perform. Our methods are available in the web-service NetEffects: http://www.ebi.ac.uk/thornton-srv/software/NetEffects

    SurvCurv database and online survival analysis platform update

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    Understanding the biology of ageing is an important and complex challenge. Survival experiments are one of the primary approaches for measuring changes in ageing. Here, we present a major update to SurvCurv, a database and online resource for survival data in animals. As well as a substantial increase in data and additions to existing graphical and statistical survival analysis features, SurvCurv now includes extended mathematical mortality modelling functions and survival density plots for more advanced representation of groups of survival cohorts

    The widespread increase in inter-individual variability of gene expression in the human brain with age

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    Aging is broadly defined as a time-dependent progressive decline in the functional and physiological integrity of organisms. Previous studies and evolutionary theories of aging suggest that aging is not a programmed process but reflects dynamic stochastic events. In this study, we test whether transcriptional noise shows an increase with age, which would be expected from stochastic theories. Using human brain transcriptome dataset, we analyzed the heterogeneity in the transcriptome for individual genes and functional pathways, employing different analysis methods and pre-processing steps. We show that unlike expression level changes, changes in heterogeneity are highly dependent on the methodology and the underlying assumptions. Although the particular set of genes that can be characterized as differentially variable is highly dependent on the methods, we observe a consistent increase in heterogeneity at every level, independent of the method. In particular, we demonstrate a weak but reproducible transcriptome-wide shift towards an increase in heterogeneity, with twice as many genes significantly increasing as opposed to decreasing their heterogeneity. Furthermore, this pattern of increasing heterogeneity is not specific but is associated with a wide range of pathways

    Longevity GWAS Using the Drosophila Genetic Reference Panel

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    We used 197 Drosophila melanogaster Genetic Reference Panel (DGRP) lines to perform a genome-wide association analysis for virgin female lifespan, using ~2M common single nucleotide polymorphisms (SNPs). We found considerable genetic variation in lifespan in the DGRP, with a broad-sense heritability of 0.413. There was little power to detect signals at a genome-wide level in single-SNP and gene-based analyses. Polygenic score analysis revealed that a small proportion of the variation in lifespan (~4.7%) was explicable in terms of additive effects of common SNPs (≥2% minor allele frequency). However, several of the top associated genes are involved in the processes previously shown to impact ageing (eg, carbohydrate-related metabolism, regulation of cell death, proteolysis). Other top-ranked genes are of unknown function and provide promising candidates for experimental examination. Genes in the target of rapamycin pathway (TOR; Chrb, slif, mipp2, dredd, RpS9, dm) contributed to the significant enrichment of this pathway among the top-ranked 100 genes (p = 4.79×10(-06)). Gene Ontology analysis suggested that genes involved in carbohydrate metabolism are important for lifespan; including the InterPro term DUF227, which has been previously associated with lifespan determination. This analysis suggests that our understanding of the genetic basis of natural variation in lifespan from induced mutations is incomplete
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