DOCSLIB.ORG

Investigation of Functional Genes at Homologous Loci Identified Based

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Investigation of Functional Genes at Homologous Loci Identified Based Journal of Atherosclerosis and Thrombosis Vol.22, No.5 455 Original Article Investigation of Functional Genes at Homologous Loci Identified Based on Genome-wide Association Studies of Blood Lipids via High-fat Diet Intervention in Rats using an in vivo Approach Koichi Akiyama, Yi-Qiang Liang, Masato Isono and Norihiro Kato Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan Aim: It is challenging to identify causal (or target) genes at individual loci detected using genome- wide association studies (GWAS). In order to follow up GWAS loci, we investigated functional genes at homologous loci identified using human lipid GWAS that responded to a high-fat, high-choles- terol diet (HFD) intervention in an animal model. Methods: The HFD intervention was carried out for four weeks in male rats of the spontaneously hypertensive rat strain. The liver and adipose tissues were subsequently excised for analyses of changes in the gene expression as compared to that observed in rats fed normal rat chow (n=8 per group). From 98 lipid-associated loci reported in previous GWAS, 280 genes with rat orthologs were initially selected as targets for the two-staged analysis involving screening with DNA microarray and validation with quantitative PCR (qPCR). Consequently, genes showing a differential expression due to HFD were examined for changes in the expression induced by atorvastatin, which was indepen- dently administered to the rats. Results: Using the HFD intervention in the rats, seven known (Abca1, Abcg5, Abcg8, Lpl, Nr1h3, Pcsk9 and Pltp) and three novel (Madd, Stac3 and Timd4) genes were identified as potential signifi- cant targets, with an additional list of 23 suggestive genes. Among these 33 genes, Stac3, Fads1 and six known genes exhibited nominally significant expression changes following treatment with atorv- astatin. Six (of 33) genes overlapped with those previously detected in the expression QTL studies. Conclusions: Our experimental in vivo approach increases the ability to identify target gene(s), when combined with other functional studies, thus improving understanding of the mechanisms by which GWAS variants act. See editorial vol. 22: 442-444 J Atheroscler Thromb, 2015; 22: 455-480. Key words: Lipid, mRNA, Gene expression, Genome-wide association study, Diet the plasma lipid concentrations1, 2). However, as most Introduction disease- and trait-associated variants lie within non- Genome-wide association studies (GWAS) have coding sequences3), it is difficult to identify causal (or succeeded in identifying a number of genomic loci target) genes at individual GWAS loci. Several lines of associated with complex diseases and traits, including evidence suggest that a substantial proportion of such variants are involved in transcriptional mechanisms, Address for correspondence: Norihiro Kato, Department of including the modulation of cis-regulatory elements Gene Diagnostics and Therapeutics, Research Institute, 3, 4) National Center for Global Health and Medicine, 1-21-1 (e.g., promoter and enhancer elements) . Toyama, Shinjuku-ku, Tokyo 162-8655, JAPAN One of the most popular approaches for finding E-mail: [email protected] associations between target genes and regulatory ele- Received: August 26, 2014 ments is to analyze SNPs. Information on SNP geno- Accepted for publication: September 30, 2014 types, which can be compared with trait phenotypes 456 Akiyama et al. using GWAS, is analyzed in conjunction with gene level. expression data for particular types of cells derived from individuals. This process enables researchers to Materials and Methods identify associations between specific genetic variants and the gene expression levels using expression quanti- Animals tative trait locus (eQTL) studies5). Therefore, disease- We used the spontaneously hypertensive rats of a and trait-associated variants have been shown to often Japanese colony (SHR/Izm, hereafter referred to as affect the expression of nearby genes (cis-eQTLs) and SHR) for the HFD intervention, as previously those located over long genetic distances (trans- reported7). SHR rats are characterized by prominent eQTLs). In general, authors are inclined to assume the hypertension with a conspicuous response to a high- enrichment of GWAS SNPs in regulatory elements lipid diet and are considered to constitute a rat model when lead SNPs (i.e., SNPs showing the strongest of metabolic syndrome. This model allowed us to association signal) lie within regulatory DNA or examine the lipid GWAS-identified gene loci in the exhibit strong LD (e.g., r2 ≥ 0.8) with SNPs in regula- context of metabolic syndrome. Male rats (n =8 each tory DNA3). That is, since eQTL studies by them- for the HFD and control groups) were weaned at 4 selves show possible relationships between disease- and weeks of age and placed on a diet of normal rat chow trait-associated variants and the gene expression levels, (SP diet, Funabashi Farm, Japan). The rats were fed further investigation is warranted to clarify the mecha- the HFD diet (28.6% fat, Funabashi Farm, Japan) nistic basis in each case4). during the intervention period, which was restricted Recent large-scale GWAS and meta-analyses have to four weeks between 12 and 16 weeks of age, and identified ＞100 genomic loci contributing to inter- thereafter again fed the normal rat chow. The control individual variation in the plasma lipid concentra- rats (n =8) were fed the normal rat chow throughout tions1, 2). However, their practical value, in particular the study period. At two points, before and after the with regard to exact genetic elements and pathogenic dietary intervention, blood samples were drawn from events underlying associations, remains a subject of the tail vein of the rats in an overnight (16-hour) fast- debate. Focusing on human tissues relevant to lipo- ing state to measure the levels of glucose, total choles- protein metabolism (liver and fat—omental and sub- terol, triglycerides and free fatty acids. cutaneous fat), a total of 54 genes located at 35 unique Furthermore, in order to obtain clues regarding loci (i.e., 37% of 95 loci reported in a previous the involvement of uncharacterized genes in various study1)) have been shown to constitute SNP-to-gene lipid regulatory functions, we used male rats of a eQTLs, with partial overlap between tissues. Sepa- stroke-prone substrain of SHR (SHRSP) for pharma- rately, as an approach to systematically follow up cological intervention with atorvastatin, a lipid-lower- GWAS loci, RNAi-based functional profiling in vitro ing drug, as previously reported8). Briefly, the male has been performed in HeLa cells among 110 genes rats (n =5) were subjected to atorvastatin administra- derived from 43 lipid-associated loci (of which 33 tion (15 mg/kg/day via the gavage method) for four overlap with the list of 95 loci1)), subsequently identi- weeks between 12 and 16 weeks of age. The control fying an additional list of 45 genes from 25 lipid-asso- rats (n =5) were fed normal rat chow throughout the ciated loci, although overlap with eQTL data remains study period, similar to the HFD intervention. While rather limited6). a substantial portion of the predisposition to cardio- vascular disease is assumed to be shared between SHR and SHRSP animals, some features are relatively pro- Aim nounced or unique to each rat strain alone. SHR rats In order to provide evidence for disease-relevant are characterized by prominent hypertension as well as functions in vivo, we designed the present study with a conspicuous response to HFD. SHRSP rats, in con- two principal aims: [1] to investigate functional genes trast, are characterized by severe hypertension and car- at homologous loci identified in human lipid GWAS diovascular complications, including stroke and renal that respond to high-fat, high-cholesterol diet (HFD) dysfunction. Hence, we chose the individual strain to intervention in a rat model of metabolic syndrome; suit the nature of the intervention; that is, SHR for and [2] to examine the degree of overlap between the the dietary intervention and SHRSP for the pharma- list of genes with a differential expression induced by cological intervention, with a particular focus on end- HFD and those detectable using eQTL studies and/or organ protective effects7, 8). RNAi-based functional profiling, thereby integrating The rats were killed under pentobarbital anesthe- biological evidence for GWAS loci at the phenotypic sia (50 mg/kg via intraperitoneal infusion), and the Functional Genes for Lipid Regulation 457 organs were excised and immediately frozen at －70℃ tions. For both analyses, the probes were initially for subsequent RNA extraction. All rats were labora- selected if the fold induction was ≥ 1.3 with a nominal tory animals and treated in compliance with institu- P-value of ＜0.1. Such generous cut-off levels were set tional regulations. in order to avoid excluding probes for the functional All animal experiments were approved by the genes that exhibited relatively modest expression Animal Care and Use Committee of the National changes induced by HFD. In the first analysis, the Center for Global Health and Medicine (NCGM) corresponding probes were subjected to validation via Research Institute (permit number: 23-C-14) and qPCR, as described below. In the second analysis, the conducted in accordance with institutional proce- datasets were used for a pathway analysis with Ingenu- dures. ity iReport (Ingenuity Systems, Inc., CA). In this study, the gene annotation reports (Pathways, Biologi- Tissue Processing and RNA Isolation cal Processes and Disease) were based on insight from One gram each of the liver and retroperitoneal the Ingenuity® Knowledge Base (http://www.ingenu- adipose tissues were homogenized with a 0.5 inch- ity.com/). DAVID (ver. 6.7, http://david.abcc.ncifcrf. diameter generator shaft at a speed of 22,000 rpm for gov/)9) and g:Profiler (http://biit.cs.ut.ee/gprofiler/)10) 60 seconds. Total RNA was extracted using the were also used for functional profiling.
Load more

Recommended publications
  • Recombinant T-Cell Immunoglobulin and Mucin Domain Containing Protein 4 (TIMD4)
    RPH854Hu01 100µg Recombinant T-Cell Immunoglobulin And Mucin Domain Containing Protein 4 (TIMD4) Organism Species: Homo sapiens (Human) Instruction manual FOR RESEARCH USE ONLY NOT FOR USE IN CLINICAL DIAGNOSTIC PROCEDURES 12th Edition (Revised in Aug, 2016) 1 / 4 [ PROPERTIES ] Source: Prokaryotic expression Host: E.coli Residues: Glu25~Gln314 Tags: N-terminal His Tag Subcellular Location: Secreted Purity: > 95% Traits: Freeze-dried powder Buffer formulation: 100mMNaHCO3, 500mMNaCl, pH8.3, containing 0.01% SKL, 5% Trehalose. Original Concentration: 100µg/mL Applications: Positive Control; Immunogen; SDS-PAGE; WB. (May be suitable for use in other assays to be determined by the end user.) Predicted isoelectric point: Predicted Molecular Mass: 35.0kDa Accurate Molecular Mass: 40kDa as determined by SDS-PAGE reducing conditions. Phenomenon explanation: The possible reasons that the actual band size differs from the predicted are as follows: 1.Splice variants: Alternative splicing may create different sized proteins from the same gene. 2. Relative charge: The composition of amino acids may affects the charge of the protein. 3. Post-translational modification: Phosphorylation, glycosylation, methylation etc. 4. Post-translation cleavage: Many proteins are synthesized as pro-proteins, and then cleaved to give the active form. 5. Polymerization of the target protein: Dimerization, multimerization etc. [ USAGE ] Reconstitute in 100mM NaHCO3, 500mM NaCl (pH8.3) to a concentration of 0.1-1.0 mg/mL. Do not vortex. 2 / 4 [ STORAGE AND STABILITY ] Storage: Avoid repeated freeze/thaw cycles. Store at 2-8ºC for one month. Aliquot and store at -80ºC for 12 months. Stability Test: The thermal stability is described by the loss rate.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Mining Public Toxicogenomic Data Reveals Insights and Challenges in Delineating Liver Steatosis Adverse Outcome Pathways
    ORIGINAL RESEARCH published: 18 October 2019 doi: 10.3389/fgene.2019.01007 Mining Public Toxicogenomic Data Reveals Insights and Challenges in Delineating Liver Steatosis Adverse Outcome Pathways Mohamed Diwan M. AbdulHameed 1,2*, Venkat R. Pannala 1,2 and Anders Wallqvist 1* 1 Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD, United States, 2 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States Edited by: Exposure to chemicals contributes to the development and progression of fatty liver, or Chris Vulpe, University of Florida, steatosis, a process characterized by abnormal accumulation of lipids within liver cells. United States However, lack of knowledge on how chemicals cause steatosis has prevented any large- Reviewed by: scale assessment of the 80,000+ chemicals in current use. To address this gap, we mined Xuefang Liang, Inner Mongolia University, a large, publicly available toxicogenomic dataset associated with 18 known steatogenic China chemicals to assess responses across assays (in vitro and in vivo) and species (i.e., Annamaria Colacci, rats and humans). We identified genes that were differentially expressed (DEGs) in rat Agenzia Regionale Prevenzione E Ambiente Della Regione Emilia- in vivo, rat in vitro, and human in vitro studies in which rats or in vitro primary cell lines Romagna, Italy were exposed to the chemicals at different doses and durations. Using these DEGs, we *Correspondence: performed pathway enrichment analysis, analyzed the molecular initiating events (MIEs) of Mohamed Diwan M. AbdulHameed [email protected] the steatosis adverse outcome pathway (AOP), and predicted metabolite changes using Anders Wallqvist metabolic network analysis.
    [Show full text]
  • Supplementary Materials
    Supplementary materials Supplementary Table S1: MGNC compound library Ingredien Molecule Caco- Mol ID MW AlogP OB (%) BBB DL FASA- HL t Name Name 2 shengdi MOL012254 campesterol 400.8 7.63 37.58 1.34 0.98 0.7 0.21 20.2 shengdi MOL000519 coniferin 314.4 3.16 31.11 0.42 -0.2 0.3 0.27 74.6 beta- shengdi MOL000359 414.8 8.08 36.91 1.32 0.99 0.8 0.23 20.2 sitosterol pachymic shengdi MOL000289 528.9 6.54 33.63 0.1 -0.6 0.8 0 9.27 acid Poricoic acid shengdi MOL000291 484.7 5.64 30.52 -0.08 -0.9 0.8 0 8.67 B Chrysanthem shengdi MOL004492 585 8.24 38.72 0.51 -1 0.6 0.3 17.5 axanthin 20- shengdi MOL011455 Hexadecano 418.6 1.91 32.7 -0.24 -0.4 0.7 0.29 104 ylingenol huanglian MOL001454 berberine 336.4 3.45 36.86 1.24 0.57 0.8 0.19 6.57 huanglian MOL013352 Obacunone 454.6 2.68 43.29 0.01 -0.4 0.8 0.31 -13 huanglian MOL002894 berberrubine 322.4 3.2 35.74 1.07 0.17 0.7 0.24 6.46 huanglian MOL002897 epiberberine 336.4 3.45 43.09 1.17 0.4 0.8 0.19 6.1 huanglian MOL002903 (R)-Canadine 339.4 3.4 55.37 1.04 0.57 0.8 0.2 6.41 huanglian MOL002904 Berlambine 351.4 2.49 36.68 0.97 0.17 0.8 0.28 7.33 Corchorosid huanglian MOL002907 404.6 1.34 105 -0.91 -1.3 0.8 0.29 6.68 e A_qt Magnogrand huanglian MOL000622 266.4 1.18 63.71 0.02 -0.2 0.2 0.3 3.17 iolide huanglian MOL000762 Palmidin A 510.5 4.52 35.36 -0.38 -1.5 0.7 0.39 33.2 huanglian MOL000785 palmatine 352.4 3.65 64.6 1.33 0.37 0.7 0.13 2.25 huanglian MOL000098 quercetin 302.3 1.5 46.43 0.05 -0.8 0.3 0.38 14.4 huanglian MOL001458 coptisine 320.3 3.25 30.67 1.21 0.32 0.9 0.26 9.33 huanglian MOL002668 Worenine
    [Show full text]
  • 1 Self-Maintaining Gut Macrophages Are Essential for Intestinal
    Self-maintaining Gut Macrophages Are Essential for Intestinal Homeostasis De Schepper Sebastiaan1*, Verheijden Simon1*†, Aguilera-Lizarraga Javi1, Viola Maria Francesca1, Boesmans Werend2, Stakenborg Nathalie1, Voytyuk Iryna3, Smidt Inga3, Boeckx Bram4,5, Dierckx de Casterlé Isabelle6, Baekelandt Veerle7, Gonzalez Dominguez Erika1, Mack Matthias8, Depoortere Inge9, De Strooper Bart3, Sprangers Ben4, Himmelreich Uwe10, Soenen Stefaan10, Guilliams Martin11, Vanden Berghe Pieter2, Jones Elizabeth12, Lambrechts Diether5,6, Boeckxstaens Guy1 1Laboratory for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, University of Leuven, Leuven, Belgium. 2Laboratory for Enteric Neuroscience, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, University of Leuven, Leuven, Belgium. 3VIB – KU Leuven Center for Brain and Disease Research, Leuven, Belgium. 4VIB Center for Cancer Biology, Leuven, Belgium. 5Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium. 6Laboratory of Experimental Transplantation, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium. 7Research Group for Neurobiology and Gene Therapy, Department of Neurosciences, University of Leuven, Leuven, Belgium. 8Department of Internal Medicine – Nephrology, University Hospital Regensburg, Regensburg, Germany. 9Gut Peptide Research Lab, Translational
    [Show full text]
  • Self-Renewing Resident Cardiac Macrophages Limit Adverse Remodeling Following Myocardial Infarction
    JOURNAL CLUB 3/19/19 SAHIL MAHAJAN ARTICLES https://doi.org/10.1038/s41590-018-0272-2 Corrected: Publisher Correction Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction Sarah A. Dick1,2,11, Jillian A. Macklin 1,2,3,4,11, Sara Nejat 1,11, Abdul Momen1, Xavier Clemente-Casares1, Marwan G. Althagafi1,4, Jinmiao Chen 5,6, Crystal Kantores 1, Siyavash Hosseinzadeh1,4, Laura Aronoff1,4, Anthony Wong 1,7, Rysa Zaman 1,7, Iulia Barbu1,7, Rickvinder Besla1,4, Kory J. Lavine8, Babak Razani8,9, Florent Ginhoux 5,6, Mansoor Husain1,2,3,4,10, Myron I. Cybulsky1,4,10, Clinton S. Robbins1,4,7,10 and Slava Epelman 1,2,3,4,7,10* Macrophages promote both injury and repair after myocardial infarction, but discriminating functions within mixed populations remains challenging. Here we used fate mapping, parabiosis and single-cell transcriptomics to demonstrate that at steady state, TIMD4+LYVE1+MHC-IIloCCR2− resident cardiac macrophages self-renew with negligible blood monocyte input. Monocytes par- tially replaced resident TIMD4–LYVE1–MHC-IIhiCCR2− macrophages and fully replaced TIMD4−LYVE1−MHC-IIhiCCR2+ macro- phages, revealing a hierarchy of monocyte contribution to functionally distinct macrophage subsets. Ischemic injury reduced TIMD4+ and TIMD4– resident macrophage abundance, whereas CCR2+ monocyte-derived macrophages adopted multiple cell fates within infarcted tissue, including those nearly indistinguishable from resident macrophages. Recruited macrophages did not express TIMD4, highlighting the ability of TIMD4 to track a subset of resident macrophages in the absence of fate map- ping. Despite this similarity, inducible depletion of resident macrophages using a Cx3cr1-based system led to impaired cardiac function and promoted adverse remodeling primarily within the peri-infarct zone, revealing a nonredundant, cardioprotective role of resident cardiac macrophages.
    [Show full text]
  • Methylation Epigenetic Landscape of Cpg DNA Defining CD4 T Cell Memory By
    The Journal of Immunology Defining CD4 T Cell Memory by the Epigenetic Landscape of CpG DNA Methylation H. Kiyomi Komori, Traver Hart, Sarah A. LaMere, Pamela V. Chew, and Daniel R. Salomon Memory T cells are primed for rapid responses to Ag; however, the molecular mechanisms responsible for priming remain incom- pletely defined. CpG methylation in promoters is an epigenetic modification, which regulates gene transcription. Using targeted bisulfite sequencing, we examined methylation of 2100 genes (56,000 CpGs) mapped by deep sequencing of T cell activation in human naive and memory CD4 T cells. Four hundred sixty-six CpGs (132 genes) displayed differential methylation between naive and memory cells. Twenty-one genes exhibited both differential methylation and gene expression before activation, linking pro- moter DNA methylation states to gene regulation; 6 of 21 genes encode proteins closely studied in T cells, whereas 15 genes represent novel targets for further study. Eighty-four genes demonstrated differential methylation between memory and naive cells that cor- related to differential gene expression following activation, of which 39 exhibited reduced methylation in memory cells coupled with increased gene expression upon activation compared with naive cells. These reveal a class of primed genes more rapidly expressed in memory compared with naive cells and putatively regulated by DNA methylation. These findings define a DNA methylation sig- nature unique to memory CD4 T cells that correlates with activation-induced gene expression. The Journal of Immunology, 2015, 194: 1565–1579. ifferentiation into fast-acting memory cells following Ag have a demethylated IL-4 gene promoter (10), do not express IFN-g, recognition is a central tenet of T cell immunology.
    [Show full text]
  • Innate and Adaptive Immune Functions of Peyer's Patch
    Innate and Adaptive Immune Functions of Peyer’s Patch Monocyte-Derived Cells Article Innate and Adaptive Immune Functions of Peyer’s Patch Monocyte-Derived Cells Johnny Bonnardel, Clément da Silva, Sandrine Henri, Samira Tamoutounour, Lionel Chasson, Frederic Montañana-Sanchis, Jean-Pierre Gorvel, Hugues Lelouard To cite this version: Johnny Bonnardel, Clément da Silva, Sandrine Henri, Samira Tamoutounour, Lionel Chasson, et al.. Innate and Adaptive Immune Functions of Peyer’s Patch Monocyte-Derived Cells Article Innate and Adaptive Immune Functions of Peyer’s Patch Monocyte-Derived Cells. Cell Reports, Elsevier Inc, 2015, pp.770-784. 10.1016/j.celrep.2015.03.067. hal-01212685 HAL Id: hal-01212685 https://hal-amu.archives-ouvertes.fr/hal-01212685 Submitted on 7 Oct 2015 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Article Innate and Adaptive Immune Functions of Peyer’s Patch Monocyte-Derived Cells Graphical Abstract Authors Johnny Bonnardel, Cle´ ment Da Silva, ..., Jean-Pierre Gorvel, Hugues Lelouard Correspondence [email protected] In Brief Bonnardel et al. provide a comprehensive analysis of the phenotype, distribution, ontogeny, lifespan, function, and transcriptional profile of Peyer’s patch (PP) mononuclear phagocyte system.
    [Show full text]
  • Timd4 Rat Monoclonal Antibody [Clone ID: RMT4-54] Product Data
    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for AM60019PU-S Timd4 Rat Monoclonal Antibody [Clone ID: RMT4-54] Product data: Product Type: Primary Antibodies Clone Name: RMT4-54 Applications: FC, IF, IHC Recommended Dilution: Flow cytometry: 1/25-1/200, use 10µl of this suggested working dilution to label 10e6 cells in 100µl. Immunofluorescence. Immunohistochemistry on Paraffin sections. Positive control: Mouse spleen. For functional assays Cat.-No. AM60019LE-N is recommended. Reactivity: Mouse Host: Rat Isotype: IgG2a Clonality: Monoclonal Immunogen: Mouse TIMD4 (amino acids 1-288), coupled with the Fc portion of mouse IgG2a Specificity: Clone RMT4-54 specifically recognises mouse Tim-4. Studies have shown that clone RMT4-54 significantly inhibits the efficient phagocytosis of apoptotic cells by PRMs (peritoneal resident Mac1+ cells), but not PEMs (peritoneal exudate Mac1+ cells) [Nakayama, 2009]. Formulation: PBS containing 0.09% Sodium azide State: Purified State: Liquid purified IgG Concentration: lot specific Purification: Affinity chromatography on Protein G Conjugation: Unconjugated Storage: Store undiluted at 2-8°C for one month or (in aliquots) at -20°C for longer. Avoid repeated freezing and thawing. Stability: Shelf life: one year from despatch. Gene Name: T cell immunoglobulin and mucin domain containing 4 This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies, Inc., 9620 Medical Center Drive, Ste 200, Rockville, MD 20850, US 1 / 2 Timd4 Rat Monoclonal Antibody [Clone ID: RMT4-54] – AM60019PU-S Database Link: Entrez Gene 276891 Mouse Q6U7R4 Background: TIMD4 / TIM-4 (T-cell immunoglobulin mucin 4), a transmembrane glycoprotein and member of the immunoglobulin superfamily, exclusively expressed by antigen-presenting cells, which acts as the natural ligand of TIM-1, involved in T-cell expansion and cytokine production.
    [Show full text]
  • TIMD4 Rs6882076 SNP Is Associated with Decreased Levels Of
    Int. J. Med. Sci. 2019, Vol. 16 864 Ivyspring International Publisher International Journal of Medical Sciences 2019; 16(6): 864-871. doi: 10.7150/ijms.31729 Research Paper TIMD4 rs6882076 SNP Is Associated with Decreased Levels of Triglycerides and the Risk of Coronary Heart Disease and Ischemic Stroke Eksavang Khounphinith1, Rui-Xing Yin1,2,3,, Xiao-Li Cao2,3,4, Feng Huang1,2,3, Jin-Zhen Wu1, Hui Li5 1. Department of Cardiology, Institute of Cardiovascular Diseases, The First Affiliated Hospital, Guangxi Medical University, 6 Shuangyong Road, Nanning 530021, Guangxi, China. 2. Guangxi Key Laboratory Base of Precision Medicine in Cardio-cerebrovascular Disease Control and Prevention, 6 Shuangyong Road, Nanning 530021, Guangxi, China. 3. Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, 6 Shuangyong Road, Nanning 530021, Guangxi, China. 4. Department of Neurology, The First Affiliated Hospital, Guangxi Medical University, 6 Shuangyong Road, Nanning 530021, Guangxi, China. 5. Clinical Laboratory of the Affiliated Cancer Hospital, Guangxi Medical University, 71 Hedi Road, Nanning 530021, Guangxi, China. Corresponding author: Rui-Xing Yin; [email protected] © Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2018.11.22; Accepted: 2019.04.03; Published: 2019.06.02 Abstract Background: The T-cell immunoglobulin and mucin domain 4 gene (TIMD4) rs6882076 single nucleotide polymorphism (SNP) has been associated with serum total cholesterol, low-density lipoprotein cholesterol and triglycerides (TG) levels, but the results are inconsistent.
    [Show full text]
  • Functionally Diverse Human T Cells Recognize Non-Microbial Antigens Presented By
    RESEARCH ARTICLE Functionally diverse human T cells recognize non-microbial antigens presented by MR1 Marco Lepore1, Artem Kalinichenko1, Salvatore Calogero1, Pavanish Kumar2, Bhairav Paleja2, Mathias Schmaler1, Vipin Narang2, Francesca Zolezzi2, Michael Poidinger2,3, Lucia Mori1,2, Gennaro De Libero1,2* 1Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland; 2Singapore Immunology Network, A*STAR, Singapore, Singapore; 3Singapore Institute for Clinical Sciences, A*STAR, Singapore, Singapore Abstract MHC class I-related molecule MR1 presents riboflavin- and folate-related metabolites to mucosal-associated invariant T cells, but it is unknown whether MR1 can present alternative antigens to other T cell lineages. In healthy individuals we identified MR1-restricted T cells (named MR1T cells) displaying diverse TCRs and reacting to MR1-expressing cells in the absence of microbial ligands. Analysis of MR1T cell clones revealed specificity for distinct cell-derived antigens and alternative transcriptional strategies for metabolic programming, cell cycle control and functional polarization following antigen stimulation. Phenotypic and functional characterization of MR1T cell clones showed multiple chemokine receptor expression profiles and secretion of diverse effector molecules, suggesting functional heterogeneity. Accordingly, MR1T cells exhibited distinct T helper-like capacities upon MR1-dependent recognition of target cells expressing physiological levels of surface MR1. These data extend the role of
    [Show full text]
  • The Genomic and Clinical Landscape of Fetal Akinesia
    © American College of Medical Genetics and Genomics ARTICLE The genomic and clinical landscape of fetal akinesia Matthias Pergande, MSc1,2, Susanne Motameny, PhD3, Özkan Özdemir, PhD1,2, Mona Kreutzer1,2, Haicui Wang, PhD1,2, Hülya-Sevcan Daimagüler, MSc1,2, Kerstin Becker, PhD1,2, Mert Karakaya, MD1,4, Harald Ehrhardt, MD5, Nursel Elcioglu, MD, Prof6,7, Slavica Ostojic, MD8, Cho-Ming Chao, MD, PhD5, Amit Kawalia, PhD3, Özgür Duman, MD, Prof9, Anne Koy, MD2, Andreas Hahn, MD, Prof10, Jens Reimann, MD11, Katharina Schoner, MD12, Anne Schänzer, MD13, Jens H. Westhoff, MD14, Eva Maria Christina Schwaibold, MD15, Mireille Cossee, MD16, Marion Imbert-Bouteille, MSc17, Harald von Pein, MD18, Göknur Haliloglu, MD, Prof19, Haluk Topaloglu, MD, Prof19, Janine Altmüller, MD1,3, Peter Nürnberg, PhD, Prof1,3, Holger Thiele, MD3, Raoul Heller, MD, PhD4,20,21 and Sebahattin Cirak, MD 1,2,21 Purpose: Fetal akinesia has multiple clinical subtypes with over Conclusion: Our analysis indicates that genetic defects leading to 160 gene associations, but the genetic etiology is not yet completely primary skeletal muscle diseases might have been underdiagnosed, understood. especially pathogenic variants in RYR1. We discuss three novel Methods: In this study, 51 patients from 47 unrelated families putative fetal akinesia genes: GCN1, IQSEC3 and RYR3. Of those, were analyzed using next-generation sequencing (NGS) techniques IQSEC3, and RYR3 had been proposed as neuromuscular aiming to decipher the genomic landscape of fetal akinesia (FA). disease–associated genes recently, and our findings endorse them Results: We have identified likely pathogenic gene variants in 37 as FA candidate genes. By combining NGS with deep clinical cases and report 41 novel variants.
    [Show full text]