National Human Genome Research Institute (NHGRI)’s Post

PE lipid as ligand for orphan receptor...

RECEPTOR "ORPHAN" FINDS PARENT at Science Magazine #Immunology | #Lipid Ligand for #RORγt Controls #Th17 Cell Differentiation | #metabolism | #immunity | #inflammation | #autoimmunedisease | #infection | #Tcells | Lipid metabolic pathways and the transcription factor RORγt are known to control the differentiation of pro-inflammatory Th17 cells, but direct links between cellular metabolism and the activity of RORγt have not been fully elucidated. Using a combination of gene knockouts and lipidomics, Endo et al. identified a specific lipid metabolite, along with five enzymes required for its biosynthesis, that maintained the Th17 gene expression program. The lipid, called 1-Oleoyl-lysophosphatidylethanolamine, could bind to RORγt directly, and knockout of an orphan phospholipase A2 (PLA2) isoform required for its biosynthesis inhibited the differentiation of murine Th17 cells and protected against pathology driven by Th17 cells in a mouse model of autoimmune encephalomyelitis. This study develops understanding of how metabolic pathways influence T cell differentiation. Celentyx Ltd #drugdiscovery #platforms www.celentyx.com Professor Nicholas Barnes PhD, FBPhS Omar Qureshi Catherine Brady

1-Oleoyl-lysophosphatidylethanolamine stimulates RORγt activity in T(H)17 cells. ABSTRACT: Metabolic fluxes involving fatty acid biosynthesis play essential roles in controlling the differentiation of T helper 17 (T(H)17) cells. However, the exact enzymes and lipid metabolites involved, as well as their link to promoting the core gene transcriptional signature required for the differentiation of T(H)17 cells, remain largely unknown. From a pooled CRISPR-based screen and unbiased #lipidomics analyses, we identified that 1-oleoyl-lysophosphatidylethanolamine could act as a lipid modulator of retinoid-related orphan receptor gamma t (RORgammat) activity in T(H)17 cells. In addition, we specified five enzymes, including Gpam, Gpat3, Lplat1, Pla2g12a, and Scd2, suggestive of the requirement of glycerophospholipids with monounsaturated fatty acids being required for the transcription of Il17a. 1-Oleoyl-lysophosphatidylethanolamine was reduced in Pla2g12a-deficient T(H)17 cells, leading to the abolition of interleukin-17 (IL-17) production and disruption to the core transcriptional program required for the differentiation of T(H)17 cells. Furthermore, mice with T cell-specific deficiency of Pla2g12a failed to develop disease in an experimental autoimmune encephalomyelitis model of multiple sclerosis. Thus, our data indicate that 1-oleoyl-lysophosphatidylethanolamine is a lipid metabolite that promotes RORgammat-induced T(H)17 cell differentiation and the pathogenicity of T(H)17 cells. Source: Sci Immunol https://lnkd.in/ewUBpMbe

#splicingfactor #neuroprotection #serine #arginine Serine and arginine rich splicing factor 1: a potential target for neuroprotection and other diseases https://lnkd.in/gQMZ9hKy The University of Sheffield Alternative splicing is the process of producing variably spliced mRNAs by choosing distinct combinations of splice sites within a messenger RNA precursor. This splicing enables mRNA from a single gene to synthesize different proteins, which have different cellular properties and functions and yet arise from the same single gene. A family of splicing factors, Serine-arginine rich proteins, are needed to initiate the assembly and activation of the spliceosome. Serine and arginine rich splicing factor 1, part of the arginine/serine-rich splicing factor protein family, can either activate or inhibit the splicing of mRNAs, depending on the phosphorylation status of the protein and its interaction partners. Considering that serine and arginine rich splicing factor 1 is either an activator or an inhibitor, this protein has been studied widely to identify its various roles in different diseases. Research has found that serine and arginine rich splicing factor 1 is a key target for neuroprotection, showing its promising potential use in therapeutics for neurodegenerative disorders. Furthermore, serine and arginine rich splicing factor 1 might be used to regulate cancer development and autoimmune diseases. In this review, we highlight how serine and arginine rich splicing factor 1 has been studied concerning neuroprotection. In addition, we draw attention to how serine and arginine rich splicing factor 1 is being studied in cancer and immunological disorders, as well as how serine and arginine rich splicing factor 1 acts outside the central or peripheral nervous system.

Olink Proteomics profiling reveals the systemic #inflammatory signature of paradoxical #eczema occurring as an adverse event of biologic #therapy in patients with #psoriasis! The paradoxical eczema systemic #inflammatory proteome trends toward atopic #dermatitis (AD) at a gene-set level and is detectable before onset of the phenotype. This signature may be mediated genetically by functional SNPs associated with these gene sets. The journal of allergy and clinical immunology, Nov 2023 Title: "Integrated #proteomics and #genomics analysis of paradoxical #eczema in #psoriasis patients treated with biologics" This study used the #Olink Target 96 #Inflammation panel on 256 serum samples from 71 patients with psoriasis and paradoxical eczema, and 75 controls with psoriasis to identify differentially expressed proteins and enriched gene sets. Case samples from 1 or more time points (T1 prebiologic, T2 postbiologic, and T3 postparadoxical eczema) were matched 1:1 with control samples. Genes contributing to enriched gene sets were selected, and functional single nucleotide #polymorphisms (#SNP) used to create #polygenic risk scores in a genotyped cohort of 88 paradoxical eczema cases and 3124 psoriasis controls. • STAMBP expression was lower in cases at T1 than in controls; no other proteins reached statistical significance at equivalent time points. • Eleven gene sets including #cytokine and #chemokine pathways were enriched in cases at T2 and 10 at T3. • Of the 39 #proteins contributing to enriched gene sets, the majority are associated with the atopic dermatitis serum proteome. • A polygenic risk score including 38 functional single nucleotide polymorphisms linked to enriched gene sets was associated with paradoxical eczema. Further studies are needed to define risk factors, explore the role of specific pathways (such as #IL10 signaling) in paradoxical eczema, and define the #inflammatory profile in skin. #immunology #genetic #adverseevents #pathology #immune #dermatology #biomarker #omics #proteomics

📃Scientific paper: GLIS3 expression in the thyroid gland in relation to TSH signaling and regulation of gene expression Abstract: Loss of GLI-Similar 3 (GLIS3) function in mice and humans causes congenital hypothyroidism (CH). In this study, we demonstrate that GLIS3 protein is first detectable at E15.5 of murine thyroid development, a time at which GLIS3 target genes, such as Slc5a5 ( Nis ), become expressed. This, together with observations showing that ubiquitous Glis3 KO mice do not display major changes in prenatal thyroid gland morphology, indicated that CH in Glis3 KO mice is due to dyshormonogenesis rather than thyroid dysgenesis. Analysis of GLIS3 in postnatal thyroid suggested a link between GLIS3 protein expression and blood TSH levels. This was supported by data showing that treatment with TSH, cAMP, or adenylyl cyclase activators or expression of constitutively active PKA enhanced GLIS3 protein stability and transcriptional activity, indicating that GLIS3 activity is regulated at least in part by TSH/TSHR-mediated activation of PKA. The TSH-dependent increase in GLIS3 transcriptional activity would be critical for the induction of GLIS3 target gene expression, including several thyroid hormone (TH) biosynthetic genes, in thyroid follicular cells of mice fed a low iodine diet (LID) when blood TSH levels are highly elevated. Like TH biosynthetic genes, the expression of cell cycle genes is suppressed in ubiquitous Glis3 KO mice fed a LID; however, in thyroid-specific Glis3 knockout mice, the expression of cell cycle genes was not repressed, in contrast to TH biosynthetic genes. This ... Continued on ES/IODE ➡️ https://etcse.fr/9kC ------- If you find this interesting, feel free to follow, comment and share. We need your help to enhance our visibility, so that our platform continues to serve you.

We’d like to recognize this informative #diabetes research on #WorldDiabetesDay – Since diabetes can be different for everyone and cause diverse complications, recent work from the University of Helsinki examined various stages of diabetic kidney disease and identified candidate marker genes involved in cellular stress responses linked to long-term kidney function decline. These markers can be used as early non-invasive biomarkers or drug targets to help manage and treat kidney disease associated with diabetes. The team used RNA sequencing to find novel candidate genes, analyzed RNA profiles with NGS and validated the differential expression results from NGS using Taqman qPCR assays on the microfluidics-based #Biomark System. Dwivedi et al. Cell iScience 2023: https://lnkd.in/dW5VhcdM #genomics #microfluidics #kidney

Benchmarking AlphaMissense pathogenicity predictions against cystic fibrosis variants Accession Number: 38271453 PMCID: PMC10810519 DOI: 10.1371/journal.pone.0297560 https://lnkd.in/ea63B4iv https://lnkd.in/eciAHFjE Variants in the cystic fibrosis transmembrane conductance regulator gene (CFTR) result in cystic fibrosis-a lethal autosomal recessive disorder. Missense variants that alter a single amino acid in the CFTR protein are among the most common cystic fibrosis variants, yet tools for accurately predicting molecular consequences of missense variants have been limited to date. AlphaMissense (AM) is a new technology that predicts the pathogenicity of missense variants based on dual learned protein structure and evolutionary features. Here, we evaluated the ability of AM to predict the pathogenicity of CFTR missense variants. AM predicted a high pathogenicity for CFTR residues overall, resulting in a high false positive rate and fair classification performance on CF variants from the CFTR2.org database. AM pathogenicity score correlated modestly with pathogenicity metrics from persons with CF including sweat chloride level, pancreatic insufficiency rate, and Pseudomonas aeruginosa infection rate. Correlation was also modest with CFTR trafficking and folding competency in vitro. By contrast, the AM score correlated well with CFTR channel function in vitro-demonstrating the dual structure and evolutionary training approach learns important functional information despite lacking such data during training. Different performance across metrics indicated AM may determine if polymorphisms in CFTR are recessive CF variants yet cannot differentiate mechanistic effects or the nature of pathophysiology. Finally, AM predictions offered limited utility to inform on the pharmacological response of CF variants i.e., theratype. Development of new approaches to differentiate the biochemical and pharmacological properties of CFTR variants is therefore still needed to refine the targeting of emerging precision CF therapeutics.

New Long Covid “Lipidomics”-study finds evident changes in long covid patients versus controls using lipidomic profiles. “Lipidomics signature in post-COVID patient sera and its influence on the prolonged inflammatory response” Lipidomics is defined as “the full characterization of lipid molecular species and of their biological roles with respect to expression of proteins involved in lipid metabolism and function, including gene regulation.” Key Points of this study: - The study analyzed plasma samples from 147 post-COVID conditions (PCC) patients using untargeted lipidomics and found substantial changes in various lipid subclasses, with elevated levels of lysophosphatidylglycerols (LPGs) and phosphatidylethanolamines (PEs), and reduced levels of lysophosphatidylcholines (LPCs) identified as potential lipid biomarkers for PCC. - The lipidomic alterations were correlated with ongoing inflammation and immune response, with specific anionic lipid changes suggesting the involvement of antimicrobial peptides in inflammation. - Classification models successfully differentiated between symptomatic and asymptomatic PCC groups using lipidomic profiles, indicating the potential for personalized therapeutic strategies and novel diagnostic tools. Interestingly, there is a similar study done in post-SARS patients 12 years (!) after infection, also finding significant abnormalities in lipid metabolism: Altered Lipid Metabolism in Recovered SARS Patients Twelve Years after Infection, https://lnkd.in/eq6nvQCt #LongCovid