22 research outputs found

    Descriptive Data in the EDIT Platform for Cybertaxonomy

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    This paper describes the integration of structured descriptive data in the EDIT platform for Cybertaxonomy. The platform is composed of several software modules supporting the taxonomic workflow from data capture and storage to publication. Descriptive data play an important role within the taxonomic work process. The integration of these data via import/export modules to and from the platform and the publication as natural language output or as keys are explained

    Comparative Epigenomics Reveals that RNA Polymerase II Pausing and Chromatin Domain Organization Control Nematode piRNA Biogenesis.

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    Piwi-interacting RNAs (piRNAs) are important for genome regulation across metazoans, but their biogenesis evolves rapidly. In Caenorhabditis elegans, piRNA loci are clustered within two 3-Mb regions on chromosome IV. Each piRNA locus possesses an upstream motif that recruits RNA polymerase II to produce an ∼28 nt primary transcript. We used comparative epigenomics across nematodes to gain insight into the origin, evolution, and mechanism of nematode piRNA biogenesis. We show that the piRNA upstream motif is derived from core promoter elements controlling snRNA transcription. We describe two alternative modes of piRNA organization in nematodes: in C. elegans and closely related nematodes, piRNAs are clustered within repressive H3K27me3 chromatin, while in other species, typified by Pristionchus pacificus, piRNAs are found within introns of active genes. Additionally, we discover that piRNA production depends on sequence signals associated with RNA polymerase II pausing. We show that pausing signals synergize with chromatin to control piRNA transcription.Work in the Sarkies laboratory is funded by a grant from the Medical Research Council MC-A652-5PY80. P.S. was funded by an Imperial College Research Fellowship. L.S. was funded by a Bailie-Gifford PhD studentship. We thank the London Institute of Medical Sciences Genomics Facility for sequencing. Some sequencing was carried out at Edinburgh Genomics, which has core support from the NERC Biomolecular Analysis Facility award UKSBS PR18037. Work in the Martínez-Pérez laboratory was funded by a grant from the Medical Research Council MC-A652-5PY60. G.S. was funded by a Newton International Fellowship (Royal Society). J.A. was funded by a Wellcome Senior Research Fellowship (101863). T.Y.B. was funded by a Genetics Society Summer Studentship to the Sarkies lab

    <i>GRIN2A</i>-related disorders:genotype and functional consequence predict phenotype

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    Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10-6) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a+/- cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and misATD+LBD of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of misTMD+Linker (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders

    A bow-tie genetic architecture for morphogenesis suggested by a genome-wide RNAi screen in Caenorhabditis elegans.

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    During animal development, cellular morphogenesis plays a fundamental role in determining the shape and function of tissues and organs. Identifying the components that regulate and drive morphogenesis is thus a major goal of developmental biology. The four-celled tip of the Caenorhabditis elegans male tail is a simple but powerful model for studying the mechanism of morphogenesis and its spatiotemporal regulation. Here, through a genome-wide post-embryonic RNAi-feeding screen, we identified 212 components that regulate or participate in male tail tip morphogenesis. We constructed a working hypothesis for a gene regulatory network of tail tip morphogenesis. We found regulatory roles for the posterior Hox genes nob-1 and php-3, the TGF-β pathway, nuclear hormone receptors (e.g. nhr-25), the heterochronic gene blmp-1, and the GATA transcription factors egl-18 and elt-6. The majority of the pathways converge at dmd-3 and mab-3. In addition, nhr-25 and dmd-3/mab-3 regulate each others' expression, thus placing these three genes at the center of a complex regulatory network. We also show that dmd-3 and mab-3 negatively regulate other signaling pathways and affect downstream cellular processes such as vesicular trafficking (e.g. arl-1, rme-8) and rearrangement of the cytoskeleton (e.g. cdc-42, nmy-1, and nmy-2). Based on these data, we suggest that male tail tip morphogenesis is governed by a gene regulatory network with a bow-tie architecture

    The skin transcriptome in hidradenitis suppurativa uncovers an antimicrobial and sweat gland gene signature which has distinct overlap with wounded skin.

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    Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease resulting in non-healing wounds affecting body areas of high hair follicle and sweat gland density. The pathogenesis of HS is not well understood but appears to involve dysbiosis-driven aberrant activation of the innate immune system leading to excessive inflammation. Marked dysregulation of antimicrobial peptides and proteins (AMPs) in HS is observed, which may contribute to this sustained inflammation. Here, we analyzed HS skin transcriptomes from previously published studies and integrated these findings through a comparative analysis with a published wound healing data set and with immunofluorescence and qPCR analysis from new HS patient samples. Among the top differently expressed genes between lesional and non-lesional HS skin were members of the S100 family as well as dermcidin, the latter known as a sweat gland-associated AMP and one of the most downregulated genes in HS lesions. Interestingly, many genes associated with sweat gland function, such as secretoglobins and aquaporin 5, were decreased in HS lesional skin and we discovered that these genes demonstrated opposite expression profiles in healing skin. Conversely, HS lesional and wounded skin shared a common gene signature including genes encoding for S100 proteins, defensins, and genes encoding antiviral proteins. Overall, our results suggest that the pathogenesis of HS may be driven by changes in AMP expression and altered sweat gland function, and may share a similar pathology with chronic wounds

    Is intravenously administered, subdissociative-dose KETAmine non-inferior to MORPHine for prehospital analgesia (the KETAMORPH study): study protocol for a randomized controlled trial

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    Abstract Background Acute pain is a common condition among prehospital patients and prompt management is pivotal. Opioids are the most frequently analgesics used in the prehospital setting. However, opioids are highly addictive, and some patients may develop opioid dependence, even when they are exposed to brief opioid treatments. Therefore, alternative non-opioid analgesia should be developed to manage pain in the prehospital setting. Used at subdissociative doses, ketamine, a noncompetitive N-methyl-D-aspartate and glutamate receptor antagonist, provides analgesic effects accompanied by preservation of protective airway reflexes. In this context, we will carry out a randomized controlled, open-label, multicenter trial to compare a subdissociative dose of ketamine to morphine to provide pain relief in the prehospital setting, in patients with traumatic and non-traumatic pain. Methods/design This will be a multicenter, single-blind, randomized controlled trial. Consecutive adults will be enrolled in the prehospital setting if they experience moderate to severe, acute, non-traumatic and traumatic pain, defined as a numeric rating scale score greater or equal to 5. Patients will be randomized to receive ketamine or morphine by intravenous push. The primary outcome will be the between-group difference in mean change in numeric rating scale pain scores measured from the time before administration of the study medication to 30 min later. Discussion This upcoming randomized clinical trial was design to assess the efficacy and safety of ketamine, an alternative non-opiate analgesia, to manage non-traumatic and traumatic pain in the prehospital setting. We aim to provide evidence to change prescribing practices to reduce exposition to opioids and the subsequent risk of addiction. Trial registration ClinicalTrials.gov, ID: NCT03236805. Registered on 2 August 2017

    DataSheet_1_Defining genetic diversity of rhesus macaque Fcγ receptors with long-read RNA sequencing.pdf

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    Fcγ receptors (FcγRs) are membrane-bound glycoproteins that bind to the fragment crystallizable (Fc) constant regions of IgG antibodies. Interactions between IgG immune complexes and FcγRs can initiate signal transduction that mediates important components of the immune response including activation of immune cells for clearance of opsonized pathogens or infected host cells. In humans, many studies have identified associations between FcγR gene polymorphisms and risk of infection, or progression of disease, suggesting a gene-level impact on FcγR-dependent immune responses. Rhesus macaques are an important translational model for most human health interventions, yet little is known about the breadth of rhesus macaque FcγR genetic diversity. This lack of knowledge prevents evaluation of the impact of FcγR polymorphisms on outcomes of preclinical studies performed in rhesus macaques. In this study we used long-read RNA sequencing to define the genetic diversity of FcγRs in 206 Indian-origin Rhesus macaques, Macaca mulatta. We describe the frequency of single nucleotide polymorphisms, insertions, deletions, frame-shift mutations, and isoforms. We also index the identified diversity using predicted and known rhesus macaque FcγR and Fc-FcγR structures. Future studies that define the functional significance of this genetic diversity will facilitate a better understanding of the correlation between human and macaque FcγR biology that is needed for effective translation of studies with antibody-mediated outcomes performed in rhesus macaques.</p
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