663 research outputs found
Coagulation factor V is a T-cell inhibitor expressed by leukocytes in COVID-19
No full textThis work was supported by the NIHR BioResource, the NIHR Cambridge Biomedical Research Centre and the NIHR Cambridge Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts and staff for their contribution. FV plasma assays were performed by the NIHR Cambridge Biochemical Assay Laboratory. The Cambridge University Hospitals Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre. FV constructs were prepared and expressed by Peak Proteins. Neutrophil proteins were characterized at the Mass Spectrometry Facility at the University of Dundee and the QMRI flow cytometry and cell sorting facility. Sequencing was supported by Paul Coupland from the CRUK Cambridge Institute Genomics Core. The graphical abstract was produced using Biorender (https://biorender.com/). The work was funded by awards from NIHR to the NIHR BioResource and the NIHR Cambridge Biomedical Research Centre, Evelyn Trust, Addenbrooke's Charitable Trust, UKRI/NIHR funding through the UK Coronavirus Immunology Consortium (UK-CIC) and a CSO award (COV/DUN/20/01). KGCS holds a Wellcome Trust Investigator award. BG holds an award from the Aging Biology Foundation Europe to BG. RKG holds a Wellcome Senior Fellowship (WT108082AIA). PK is supported by the Australian and New Zealand Society of Nephrology and the Royal Australasian College of Physicians. SRW holds a Wellcome Trust Senior Clinical Fellowship (209220). ERW holds a Wellcome Clinical Training Fellowship award (108717/Z/15/Z). NM was supported by a DFG Research Fellowship. PFC is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z), and a NIHR Senior Investigator, and receives support from the Medical Research Council (MRC) Mitochondrial Biology Unit, the MRC International Centre for Genomic Medicine in Neuromuscular Disease, the Leverhulme Trust, an MRC research grant, and an Alzheimer's Society Project Grant. JAN holds a Wellcome Trust Senior Research Fellowship (215477/Z/19/Z).Peer reviewe
IBD BioResource: an open-access platform of 25 000 patients to accelerate research in Crohn's and Colitis.
No full textAn alliance of clinicians, academics, research nurses, funders, coordinators, programmers and, most importantly, patients has come together in the UK to deliver a powerful new platform to accelerate Crohn’s and colitis research – the Inflammatory Bowel Disease (IBD) BioResource. As part of the NIHR BioResource for translational research, 25,000 patients in over 90 hospitals UK-wide have signed up since we launched in January 2016 (Fig 1). All have detailed phenotypes databased including Montreal classification1, treatment response history (updated annually), surgical history and comorbidities (IBD BioResource panel descriptive, Clinical data collection sheet and Health and Lifestyle questionnaire). Serum, plasma and DNA samples are banked; and genome-wide genetic profiling undertaken. Participants’ data and samples can be studied, and they themselves surveyed or recalled for resampling or downstream studies (see Fig 2). Critically such studies can be lead by any UK or overseas investigator whether from the worlds of clinical research, pharmacovigilance, science or industry
Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans
No full textBACKGROUND: The genetic cause of primary immunodeficiency disease (PID) carries prognostic information. OBJECTIVE: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource-Rare Diseases cohort. METHODS: In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses. RESULTS: Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21low B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases. CONCLUSION: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells
Practicing engagement:Participation in the UK BioResource
No full textThe National Institute for Health Research (NIHR), the research arm of the UK National Health Service, is investing in research infrastructures. One such infrastructure, the NIHR BioResource, on the surface appears to be a typical biobank - it stores biological samples and the derived data for research purposes. However, there is at least one crucial difference, the banked resource is not the samples and data but the potential, stratified, research participants. BioResource staff recruit those with and without health problems as volunteers for future research studies. These volunteers provide biological samples containing genetic information which is sequenced and, along with clinical data, databased. Researchers from academia and commercial pharmaceutical industries can then apply to the BioResource for volunteers that meet specific genotypic or phenotypic criteria and invite them to take part in research. As such, the BioResource offers a case study of a novel form of biobank participation which is, in part, dependent on the successful recruitment of volunteers and the development and nurturing of a relationship between bank and these individuals. Using participant observation and semi-structured interviews with those involved in the engagement process, this paper explores how notions of future (bio)value and social responsibility along with the creation of a volunteers "community" intertwine in the processes of planning and practicing BioResource engagement for different publics. This paper contributes to extant STS literature by providing an insight into a different configuration of biosocial participation and its implications for the future of personalised medicine
Light enhanced the accumulation of total fatty acids (TFA) and docosahexaenoic acid (DHA) in a newly isolated heterotrophic microalga Crypthecodinium sp SUN
No full textIn the present study, light illumination was found to be efficient in elevating the total fatty acid content in a newly isolated heterotrophic microalga, Crypthecodinium sp. SUN. Under light illumination, the highest total fatty acid and DHA contents were achieved at 96 h as 24.9% of dry weight and 82.8 mg g (1) dry weight, respectively, which were equivalent to 1.46-fold and 1.68-fold of those under the dark conditions. The elevation of total fatty acid content was mainly contributed by an increase of neutral lipids at the expense of starches. Moreover, light was found to alter the cell metabolism and led to a higher specific growth rate, higher glucose consumption rate and lower non-motile cell percentage. This is the first report that light can promote the total fatty acids accumulation in Crypthecodinium without growth inhibition. (C) 2016 Elsevier Ltd. All rights reserved.National Research Foundation (NRF); Prime Minister's Office, Singapore under its Campus for Research Excellence and Technological Enterprise (CREATE) Programme [R-182-000-205-592]; 985 Project of Peking University; National Natural Science Foundation of China [31471717]SCI(E)ARTICLE227-23422
Investigating genotype-phenotype relationship of extreme neuropathic pain disorders in a UK national cohort
No full textThe aims of our study were to use whole genome sequencing in a cross-sectional cohort of patients to identify new variants in genes implicated in neuropathic pain, to determine the prevalence of known pathogenic variants and to understand the relationship between pathogenic variants and clinical presentation. Patients with extreme neuropathic pain phenotypes (both sensory loss and gain) were recruited from secondary care clinics in the UK and underwent whole genome sequencing as part of the National Institute for Health and Care Research Bioresource Rare Diseases project. A multidisciplinary team assessed the pathogenicity of rare variants in genes previously known to cause neuropathic pain disorders and exploratory analysis of research candidate genes was completed. Association testing for genes carrying rare variants was completed using the gene-wise approach of the combined burden and variance-component test SKAT-O. Patch clamp analysis was performed on transfected HEK293T cells for research candidate variants of genes encoding ion channels. The results include the following: (i) Medically actionable variants were found in 12% of study participants (205 recruited), including known pathogenic variants: SCN9A(ENST00000409672.1): c.2544T>C, p.Ile848Thr that causes inherited erythromelalgia, and SPTLC1(ENST00000262554.2):c.340T>G, p.Cys133Tr variant that causes hereditary sensory neuropathy type-1. (ii) Clinically relevant variants were most common in voltage-gated sodium channels (Nav). (iii) SCN9A(ENST00000409672.1):c.554G>A, pArg185His variant was more common in non-freezing cold injury participants than controls and causes a gain of function of NaV1.7 after cooling (the environmental trigger for non-freezing cold injury). (iv) Rare variant association testing showed a significant difference in distribution for genes NGF, KIF1A, SCN8A, TRPM8, KIF1A, TRPA1 and the regulatory regions of genes SCN11A, FLVCR1, KIF1A and SCN9A between European participants with neuropathic pain and controls. (v) The TRPA1(ENST00000262209.4):c.515C>T, p.Ala172Val variant identified in participants with episodic somatic pain disorder demonstrated gain-of-channel function to agonist stimulation. Whole genome sequencing identified clinically relevant variants in over 10% of participants with extreme neuropathic pain phenotypes. The majority of these variants were found in ion channels. Combining genetic analysis with functional validation can lead to a better understanding as to how rare variants in ion channels lead to sensory neuron hyper-excitability, and how cold, as an environmental trigger, interacts with the gain-of-function NaV1.7 p.Arg185His variant. Our findings highlight the role of ion channel variants in the pathogenesis of extreme neuropathic pain disorders, likely mediated through changes in sensory neuron excitability and interaction with environmental triggers
sj-pdf-1-tag-10.1177_17562848231193211 – Supplemental material for Planning to conceive within a year is associated with better pregnancy-specific disease-related patient knowledge and better medication adherence in women of childbearing age with inflammatory bowel disease
No full textSupplemental material, sj-pdf-1-tag-10.1177_17562848231193211 for Planning to conceive within a year is associated with better pregnancy-specific disease-related patient knowledge and better medication adherence in women of childbearing age with inflammatory bowel disease by Christian P. Selinger, Robyn Laube, Helen Steed, Matthew Brookes, NIHR BioResource and Rupert W. L. Leong in Therapeutic Advances in Gastroenterology</p
Simultaneous production of triacylglycerol and high-value carotenoids by the astaxanthin-producing oleaginous green microalga Chlorella zofingiensis
No full textThe production of lipids and astaxanthin, a high-value carotenoid, by Chlorella zofingiensis was investigated under different culture conditions. Comparative analysis revealed a good correlation between triacylglycerol (TAG) and astaxanthin accumulation in C. zofingiensis. Stress conditions promoted cell size and weight and induced the accumulation of neutral lipids, especially TAG and astaxanthin, with a concomitant decrease in membrane lipids. The highest contents of TAG and astaxanthin achieved were 387 and 4.89 mg g(-1) dry weight, respectively. A semi-continuous culture strategy was developed to optimize the TAG and astaxanthin productivities, which reached 297 and 3.3 mg L-1 day(-1), respectively. Additionally, astaxanthin accumulation was enhanced by inhibiting de novo fatty acid biosynthesis. In summary, our study represents a pioneering work of utilizing Chlorella for the integrated production of lipids and high-value products and C. zofingiensis has great potential to be a promising production strain and serve as an emerging oleaginous model alga. (C) 2016 Elsevier Ltd. All rights reserved.National Natural Science Foundation of China [31571807]; start-up grant from National Youth Thousand Talents Program; 985 Project of Peking UniversitySCI(E)[email protected]
Predicting the Occurrence of Variants in RAG1 and RAG2
No full textWhile widespread genome sequencing ushers in a new era of preventive medicine, the tools for predictive genomics are still lacking. Time and resource limitations mean that human diseases remain uncharacterized because of an inability to predict clinically relevant genetic variants. A strategy of targeting highly conserved protein regions is used commonly in functional studies. However, this benefit is lost for rare diseases where the attributable genes are mostly conserved. An immunological disorder exemplifying this challenge occurs through damaging mutations in RAG1 and RAG2 which presents at an early age with a distinct phenotype of life-threatening immunodeficiency or autoimmunity. Many tools exist for variant pathogenicity prediction, but these cannot account for the probability of variant occurrence. Here, we present a method that predicts the likelihood of mutation for every amino acid residue in the RAG1 and RAG2 proteins. Population genetics data from approximately 146,000 individuals was used for rare variant analysis. Forty-four known pathogenic variants reported in patients and recombination activity measurements from 110 RAG1/2 mutants were used to validate calculated scores. Probabilities were compared with 98 currently known human cases of disease. A genome sequence dataset of 558 patients who have primary immunodeficiency but that are negative for RAG deficiency were also used as validation controls. We compared the difference between mutation likelihood and pathogenicity prediction. Our method builds a map of most probable mutations allowing pre-emptive functional analysis. This method may be applied to other diseases with hopes of improving preparedness for clinical diagnosis
Effects of pulsed electric field treatment on enhancing lipid recovery from the microalga, Scenedesmus
No full textabstract: Chloroform and methanol are superior solvents for lipid extraction from photosynthetic microorganisms, because they can overcome the resistance offered by the cell walls and membranes, but they are too toxic and expensive to use for large-scale fuel production. Biomass from the photosynthetic microalga Scenedesmus, subjected to a commercially available pre-treatment technology called Focused-Pulsed® (FP), yielded 3.1-fold more crude lipid and fatty acid methyl ester (FAME) after extraction with a range of solvents. FP treatment increased the FAME-to-crude-lipid ratio for all solvents, which means that the extraction of non-lipid materials was minimized, while the FAME profile itself was unchanged compared to the control. FP treatment also made it possible to use only a small proportion of chloroform and methanol, along with isopropanol, to obtain equivalent yields of lipid and FAME as with 100% chloroform plus methanol.NOTICE: this is the author's version of a work that was accepted for publication in BIORESOURCE TECHNOLOGY. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in BIORESOURCE TECHNOLOGY, 173, 457-461. DOI: 10.1016/j.biortech.2014.09.12
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