WormQTL-public archive and analysis web portal for natural variation data in Caenorhabditis spp

Here, we present WormQTL (http://www.wormqtl.org), an easily accessible database enabling search, comparative analysis and meta-analysis of all data on variation in Caenorhabditis spp. Over the past decade, Caenorhabditis elegans has become instrumental for molecular quantitative genetics and the systems biology of natural variation. These efforts have resulted in a valuable amount of phenotypic, high-throughput molecular and genotypic data across different developmental worm stages and environments in hundreds of C. elegans strains. WormQTL provides a workbench of analysis tools for genotype-phenotype linkage and association mapping based on but not limited to R/qtl (http://www.rqtl.org). All data can be uploaded and downloaded using simple delimited text or Excel formats and are accessible via a public web user interface for biologists and R statistic and web service interfaces for bioinformaticians, based on open source MOLGENIS and xQTL workbench software. WormQTL welcomes data submissions from other worm researcher

FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation

SARS-CoV-2 can cause acute respiratory distress and death in some patients1. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood2. Monocytes and macrophages are sentinel cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD), leading to inflammatory death (pyroptosis) and release of potent inflammatory mediators3. Here we show that about 6% of blood monocytes in COVID-19 patients are infected with SARS-CoV-2. Monocyte infection depends on uptake of antibody-opsonized virus by Fcγ receptors. Vaccine recipient plasma does not promote antibody-dependent monocyte infection. SARS-CoV-2 begins to replicate in monocytes, but infection is aborted, and infectious virus is not detected in infected monocyte culture supernatants. Instead, infected cells undergo inflammatory cell death (pyroptosis) mediated by activation of NLRP3 and AIM2 inflammasomes, caspase-1 and GSDMD. Moreover, tissue-resident macrophages, but not infected epithelial and endothelial cells, from COVID-19 lung autopsies have activated inflammasomes. These findings taken together suggest that antibody-mediated SARS-CoV-2 uptake by monocytes/macrophages triggers inflammatory cell death that aborts production of infectious virus but causes systemic inflammation that contributes to COVID-19 pathogenesis

Genetic Variation Shapes Protein Networks Mainly through Non-transcriptional Mechanisms

Variation in the levels of co-regulated proteins that function within networks in an outbred yeast population is not driven by variation in the corresponding transcripts

コクゴカ ガクシュウ シドウアン ヘイセイ 24ネンド ジッセン ホウコク

Complex traits, including common disease-related traits, are affected by many different genes that function in multiple pathways and networks. The apoptosis, MAPK, Notch and Wnt signalling pathways play important roles in development and disease progression. At the moment we have a poor understanding of how allelic variation affects gene expression in these pathways at the level of translation. Here we report the effect of natural genetic variation on transcript and protein abundance involved in developmental signalling pathways in Caenorhabditis elegans. We used selected reaction monitoring to analyse proteins from the abovementioned four pathways in a set of recombinant inbred lines (RILs) generated from the wild-type strains Bristol N2 and Hawaii CB4856 to enable quantitative trait loci (QTL) mapping. Variation in gene expression was greater in the RILs than in the parental lines, at the proteome as well as at the transcriptome levels. We detected a trans-QTL on the left arm of chromosome II that affected protein abundance of the phosphatidylserine receptor protein PSR-1, and two separate QTLs that influenced embryonic and ionizing radiation-induced apoptosis on chromosome IV. Our results demonstrate that natural variation in C. elegans is sufficient to cause significant changes in signalling pathways both at the gene expression (transcript and protein abundance) and phenotypic levels

Reduced human activity during COVID-19 alters avian land use across North America

Funding: Natural Sciences and Engineering Research Council of Canada Alliance COVID-19 grant ALLRP 550721-20. In-kind support was provided by Environment and Climate Change Canada and Cornell Lab of Ornithology.The COVID-19 pandemic resulted in extraordinary declines in human mobility, which, in turn, may affect wildlife. Using records of more than 4.3 million birds observed by volunteers from March to May 2017-2020 across Canada and the United States, we found that counts of 66 (80%) of 82 focal bird species changed in pandemic-altered areas, usually increasing in comparison to prepandemic abundances in urban habitat, near major roads and airports, and in counties where lockdowns were more pronounced or occurred at the same time as peak bird migration. Our results indicate that human activity affects many of North America's birds and suggest that we could make urban spaces more attractive to birds by reducing traffic and mitigating the disturbance from human transportation after we emerge from the pandemic.Publisher PDFPeer reviewe

Structure-acitivity studies and analgesic efficacy of N-(3-pyridinyl)-bridged bicyclic diamines, exceptionally potent agonists at nicotinic acetylcholine receptors

A series of exceptionally potent agonists at neuronal nicotinic acetylcholine receptors (nAChRs) has been investigated. Several N-(3-pyridinyl) derivatives of bridged bicyclic diamines exhibit double-digit-picomolar binding affinities for the alpha4beta2 subtype, placing them with epibatidine among the most potent nAChR ligands described to date. Structure-activity studies have revealed that substitutions, particularly hydrophilic groups in the pyridine 5-position, differentially modulate the agonist activity at ganglionic vs central nAChR subtypes, so that improved subtype selectivity can be demonstrated in vitro. Analgesic efficacy has been achieved across a broad range of pain states, including rodent models of acute thermal nociception, persistent pain, and neuropathic allodynia. Unfortunately, the hydrophilic pyridine substituents that were shown to enhance agonist selectivity for central nAChRs in vitro tend to limit CNS penetration in vivo, so that analgesic efficacy with an improved therapeutic window was not realized with those compounds

pQTL profiles of seven selected signalling pathway proteins.

<p>Blue curves show the significance of the pQTLs multiplied by the sign of the effect of the N2 allele (positive values of blue curve indicate higher protein abundance when the N2 allele is present, whereas negative values indicate higher protein abundance when the CB4856 allele is present). Horizontal orange and red dashed lines show 0.1 and 0.05 FDR thresholds respectively. Vertical dotted grey lines separate chromosomes I to V and X from left to right. Vertical magenta bands indicate the position of the gene in the genome. PSR-1 shows a significant pQTL on the left arm of chromosome II.</p

RILs show similar protein and transcript abundance variation for the tested 44 genes as the parental strains.

<p>Comparison of protein and transcript abundance (log₂ scaled fold changes relative to N2) for 44 signalling pathway proteins in CB4856 and four selected RILs. Horizontal and vertical dashed lines represent the fold change cut-off of 1.3 (~ 0.38 on log₂ scale). Tukey-style box plot on top and right side represents variability in protein and transcript log₂ fold changes respectively. Pearson correlation coefficient is denoted by r. Table on bottom right represents the <i>P</i>-values from the Fligner-Killeen test for homogeneity of variances between protein (column 1) and transcript (column 2) data for RILs compared with CB4856.</p