The Genome Sequence of Taurine Cattle
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Pentraxin-2 Suppresses C-Jun/AP-1 Signaling to Inhibit Progressive Fibrotic Disease
Pentraxin-2 suppresses c-Jun/AP-1 signaling to inhibit progressive fibrotic disease Naoki Nakagawa, … , Sina A. Gharib, Jeremy S. Duffield JCI Insight. 2016;1(20):e87446. https://doi.org/10.1172/jci.insight.87446. Research Article Immunology Inflammation Pentraxin-2 (PTX-2), also known as serum amyloid P component (SAP/APCS), is a constitutive, antiinflammatory, innate immune plasma protein whose circulating level is decreased in chronic human fibrotic diseases. Here we show that recombinant human PTX-2 (rhPTX-2) retards progression of chronic kidney disease in Col4a3 mutant mice with Alport syndrome, reducing blood markers of kidney failure, enhancing lifespan by 20%, and improving histological signs of disease. Exogenously delivered rhPTX-2 was detected in macrophages but also in tubular epithelial cells, where it counteracted macrophage activation and was cytoprotective for the epithelium. Computational analysis of genes regulated by rhPTX-2 identified the transcriptional regulator c-Jun along with its activator protein–1 (AP-1) binding partners as a central target for the function of rhPTX-2. Accordingly, PTX-2 attenuates c-Jun and AP-1 activity, and reduces expression of AP-1–dependent inflammatory genes in both monocytes and epithelium. Our studies therefore identify rhPTX-2 as a potential therapy for chronic fibrotic disease of the kidney and an important inhibitor of pathological c-Jun signaling in this setting. Find the latest version: https://jci.me/87446/pdf RESEARCH ARTICLE Pentraxin-2 suppresses c-Jun/AP-1 signaling to inhibit progressive fibrotic disease Naoki Nakagawa,1,2,3 Luke Barron,4 Ivan G. Gomez,1,2,4 Bryce G. -
African-Centric TP53 Variant Increases Iron Accumulation and Bacterial Pathogenesis but Improves Response to Malaria Toxin
ARTICLE There are amendments to this paper https://doi.org/10.1038/s41467-019-14151-9 OPEN African-centric TP53 variant increases iron accumulation and bacterial pathogenesis but improves response to malaria toxin Kumar Sachin Singh1,8, Julia I-Ju Leu2,8, Thibaut Barnoud3,8, Prashanthi Vonteddu1, Keerthana Gnanapradeepan3,4, Cindy Lin5, Qin Liu 3, James C. Barton6, Andrew V. Kossenkov7, Donna L. George2,9*, Maureen E. Murphy3,9* & Farokh Dotiwala 1,9* 1234567890():,; A variant at amino acid 47 in human TP53 exists predominantly in individuals of African descent. P47S human and mouse cells show increased cancer risk due to defective ferrop- tosis. Here, we show that this ferroptotic defect causes iron accumulation in P47S macro- phages. This high iron content alters macrophage cytokine profiles, leads to higher arginase level and activity, and decreased nitric oxide synthase activity. This leads to more productive intracellular bacterial infections but is protective against malarial toxin hemozoin. Proteomics of macrophages reveal decreased liver X receptor (LXR) activation, inflammation and anti- bacterial defense in P47S macrophages. Both iron chelators and LXR agonists improve the response of P47S mice to bacterial infection. African Americans with elevated saturated transferrin and serum ferritin show higher prevalence of the P47S variant (OR = 1.68 (95%CI 1.07–2.65) p = 0.023), suggestive of its role in iron accumulation in humans. This altered macrophage phenotype may confer an advantage in malaria-endemic sub-Saharan Africa. 1 Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA 19104, USA. 2 Department of Genetics, The Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. -
TREM-1; Is It a Pivotal Target for Cardiovascular Diseases?
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 3 September 2018 doi:10.20944/preprints201809.0040.v1 Review TREM-1; is It a Pivotal Target for Cardiovascular Diseases? Kouassi T Kouassi 1†, Palanikumar Gunasekar 1†, Devendra. K. Agrawal 1 and Gopal Jadhav 1,* 1 Department of Clinical and Translational Sciences, School of Medicine, Creighton University; Omaha, NE 68178, USA. Emails: [email protected] (T. K.); [email protected] (K. G); [email protected] (D. K.) * Correspondence: [email protected] (G. J.); Tel.: +1-402-280-1821 † The authors contributed equally Abstract: Cardiovascular Diseases (CVDs) are still menacing and killing adults worldwide, notwithstanding the tremendous effort, to decrease their related mortality and morbidity. Lately, a growing body of evidences indicated that inflammation plays a pivotal role in the pathogenesis and complications of CVDs. A receptor of the immunoglobulin superfamily, triggering receptor expressed on myeloid cells -1 (TREM-1) was shown to induce and to amplify the inflammation in both acute and chronic diseases pathogenesis and progression and hence it is one of the important factors that complicates CVDs. Thus, studies endeavored to investigate the role played by TREM-1 in CVDs with respect to their etiologies, complications and possible therapeutics. We examined here, for the first time, the most relevant studies regarding TREM-1 involvement in CVDs. We summarized the finding after critically analyzing them and made some suggestions for furtherance of the investigations with the aim to utilize TREM-1 and its pathways for diagnostic, management and prognosis of CVDs. Overall, TREM-1 was found to be involved in the pathogenesis of acute and chronic cardiovascular conditions like Acute myocardial infraction (AMI) and atherosclerosis as well. -
Supplementary Figure 1. Network Map Associated with Upregulated Canonical Pathways Shows Interferon Alpha As a Key Regulator
Supplementary Figure 1. Network map associated with upregulated canonical pathways shows interferon alpha as a key regulator. IPA core analysis determined interferon-alpha as an upstream regulator in the significantly upregulated genes from RNAseq data from nasopharyngeal swabs of COVID-19 patients (GSE152075). Network map was generated in IPA, overlaid with the Coronavirus Replication Pathway. Supplementary Figure 2. Network map associated with Cell Cycle, Cellular Assembly and Organization, DNA Replication, Recombination, and Repair shows relationships among significant canonical pathways. Significant pathways were identified from pathway analysis of RNAseq from PBMCs of COVID-19 patients. Coronavirus Pathogenesis Pathway was also overlaid on the network map. The orange and blue colors in indicate predicted activation or predicted inhibition, respectively. Supplementary Figure 3. Significant biological processes affected in brochoalveolar lung fluid of severe COVID-19 patients. Network map was generated by IPA core analysis of differentially expressed genes for severe vs mild COVID-19 patients in bronchoalveolar lung fluid (BALF) from scRNA-seq profile of GSE145926. Orange color represents predicted activation. Red boxes highlight important cytokines involved. Supplementary Figure 4. 10X Genomics Human Immunology Panel filtered differentially expressed genes in each immune subset (NK cells, T cells, B cells, and Macrophages) of severe versus mild COVID-19 patients. Three genes (HLA-DQA2, IFIT1, and MX1) were found significantly and consistently differentially expressed. Gene expression is shown per the disease severity (mild, severe, recovered) is shown on the top row and expression across immune cell subsets are shown on the bottom row. Supplementary Figure 5. Network map shows interactions between differentially expressed genes in severe versus mild COVID-19 patients. -
Divergent Neuroinflammatory Regulation of Microglial TREM Expression and Involvement of NF-Κb
Edinburgh Research Explorer Divergent neuroinflammatory regulation of microglial TREM expression and involvement of NF-B Citation for published version: Owens, R, Grabert, K, Davies, CL, Alfieri, A, Antel, JP, Healy, LM & McColl, BW 2017, 'Divergent neuroinflammatory regulation of microglial TREM expression and involvement of NF-B', Frontiers in Cellular Neuroscience, vol. 11, 56. https://doi.org/10.3389/fncel.2017.00056 Digital Object Identifier (DOI): 10.3389/fncel.2017.00056 Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: Frontiers in Cellular Neuroscience Publisher Rights Statement: Copyright © 2017 Owens, Grabert, Davies, Alfieri, Antel, Healy and McColl. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. -
Integrated Bioinformatics Approach to Understand Immune-Related Key
Integrated bioinformatics approach to understand immune-related key genes and pathways in chronic spontaneous urticaria wenxing su Second Aliated Hospital of Soochow University biao huang First Aliated Hospital of Soochow University ying zhao Second Aliated Hospital of Soochow University xiaoyan zhang Second Aliated Hospital of Soochow University lu chen second aliated hospital of soochow university jiang ji ( [email protected] ) Second Aliated Hospital of Soochow University qingqing Jiao rst aliated hospital of soochow university Research Keywords: Chronic spontaneous urticaria, bioinformatical analysis, differentially expressed genes, immune inltration Posted Date: December 31st, 2020 DOI: https://doi.org/10.21203/rs.3.rs-137346/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/29 Abstract Background Chronic spontaneous urticaria (CSU) refers to recurrent urticaria that lasts for more than 6 weeks in the absence of an identiable trigger. Due to its recurrent wheal and severe itching, CSU seriously affects patients' life quality. There is currently no radical cure for it and its vague pathogenesis limits the development of targeted therapy. With the goal of revealing the underlying mechanism, two data sets with accession numbers GSE57178 and GSE72540 were downloaded from the Gene Expression Omnibus (GEO) database. After identifying the differentially expressed genes (DEGs) of CSU skin lesion samples and healthy controls, four kinds of analyses were performed, namely functional annotation, protein- protein interaction (PPI) network and module construction, co-expression and drug-gene interaction prediction analysis, and immune and stromal cells deconvolution analyses. Results 92 up-regulated genes and 7 down-regulated genes were selected for subsequent analyses. -
Analyses of Pig Genomes Provide
Edinburgh Research Explorer Analyses of pig genomes provide insight into porcine demography and evolution Citation for published version: Groenen, MAM, Archibald, AL, Uenishi, H, Tuggle, CK, Takeuchi, Y, Rothschild, MF, Rogel-Gaillard, C, Park, C, Milan, D, Megens, H-J, Li, S, Larkin, DM, Kim, H, Frantz, LAF, Caccamo, M, Ahn, H, Aken, BL, Anselmo, A, Anthon, C, Auvil, L, Badaoui, B, Beattie, CW, Bendixen, C, Berman, D, Blecha, F, Blomberg, J, Bolund, L, Bosse, M, Botti, S, Zhan Bujie, NV, Bystrom, M, Capitanu, B, Carvalho-Silva, D, Chardon, P, Chen, C, Cheng, R, Choi, S-H, Chow, W, Clark, RC, Clee, C, Crooijmans, RPMA, Dawson, HD, Dehais, P, De Sapio, F, Dibbits, B, Drou, N, Du, Z-Q, Eversole, K, Fadista, J, Fairley, S, Faraut, T, Faulkner, G, Fowler, KE, Fredholm, M, Fritz, E, Gilbert, JGR, Giuffra, E, Gorodkin, J, Griffin, DK, Harrow, JL, Hayward, A, Howe, K, Hu, Z-L, Humphray, SJ, Hunt, T, Hornshoj, H, Jeon, J-T, Jern, P, Jones, M, Jurka, J, Kanamori, H, Kapetanovic, R, Kim, J, Kim, J-H, Kim, K-W, Kim, T-H, Larson, G, Lee, K, Lee, K-T, Leggett, R, Lewin, HA, Li, Y, Liu, W, Loveland, JE, Lu, Y, Lunney, JK, Ma, J, Madsen, O, Mann, K, Matthews, L, McLaren, S, Morozumi, T, Murtaugh, MP, Narayan, J, Dinh Truong Nguyen, NV, Ni, P, Oh, S-J, Onteru, S, Panitz, F, Park, E-W, Park, H-S, Pascal, G, Paudel, Y, Perez-Enciso, M, Ramirez-Gonzalez, R, Reecy, JM, Rodriguez-Zas, S, Rohrer, GA, Rund, L, Sang, Y, Schachtschneider, K, Schraiber, JG, Schwartz, J, Scobie, L, Scott, C, Searle, S, Servin, B, Southey, BR, Sperber, G, Stadler, P, Sweedler, JV, Tafer, H, Thomsen, B, Wali, R, Wang, J, Wang, J, White, S, Xu, X, Yerle, M, Zhang, G, Zhang, J, Zhang, J, Zhao, S, Rogers, J, Churcher, C & Schook, LB 2012, 'Analyses of pig genomes provide insight into porcine demography and evolution', Nature, vol. -
Transepithelial Migration of Neutrophils Into the Lung Requires TREM-1 Julia Klesney-Tait University of Iowa Carver College of Medicine
Washington University School of Medicine Digital Commons@Becker Open Access Publications 2013 Transepithelial migration of neutrophils into the lung requires TREM-1 Julia Klesney-Tait University of Iowa Carver College of Medicine Kathy Keck University of Iowa Carver College of Medicine Xiaopeng Li University of Iowa Carver College of Medicine Susan Gilfillan Washington University School of Medicine in St. Louis Karel Otero Washington University School of Medicine in St. Louis See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Klesney-Tait, Julia; Keck, Kathy; Li, Xiaopeng; Gilfillan, Susan; Otero, Karel; Baruah, Sankar; Meyerholz, David K.; Varga, Steven M.; Knudson, Cory J.; Moninger, Thomas O.; Moreland, Jessica; Zabner, Joseph; and Colonna, Marco, ,"Transepithelial migration of neutrophils into the lung requires TREM-1." The ourJ nal of Clinical Investigation.123,1. 138-149. (2013). https://digitalcommons.wustl.edu/open_access_pubs/1707 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Julia Klesney-Tait, Kathy Keck, Xiaopeng Li, Susan Gilfillan, Karel Otero, Sankar Baruah, David K. Meyerholz, Steven M. Varga, Cory J. Knudson, Thomas O. Moninger, Jessica Moreland, Joseph Zabner, and Marco Colonna This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/open_access_pubs/1707 Downloaded on October 19, 2013. The Journal of Clinical Investigation. More information at www.jci.org/articles/view/64181 Research article Transepithelial migration of neutrophils into the lung requires TREM-1 Julia Klesney-Tait,1 Kathy Keck,1 Xiaopeng Li,1 Susan Gilfillan,2 Karel Otero,2 Sankar Baruah,1 David K. -
CREB-Dependent Transcription in Astrocytes: Signalling Pathways, Gene Profiles and Neuroprotective Role in Brain Injury
CREB-dependent transcription in astrocytes: signalling pathways, gene profiles and neuroprotective role in brain injury. Tesis doctoral Luis Pardo Fernández Bellaterra, Septiembre 2015 Instituto de Neurociencias Departamento de Bioquímica i Biologia Molecular Unidad de Bioquímica y Biologia Molecular Facultad de Medicina CREB-dependent transcription in astrocytes: signalling pathways, gene profiles and neuroprotective role in brain injury. Memoria del trabajo experimental para optar al grado de doctor, correspondiente al Programa de Doctorado en Neurociencias del Instituto de Neurociencias de la Universidad Autónoma de Barcelona, llevado a cabo por Luis Pardo Fernández bajo la dirección de la Dra. Elena Galea Rodríguez de Velasco y la Dra. Roser Masgrau Juanola, en el Instituto de Neurociencias de la Universidad Autónoma de Barcelona. Doctorando Directoras de tesis Luis Pardo Fernández Dra. Elena Galea Dra. Roser Masgrau In memoriam María Dolores Álvarez Durán Abuela, eres la culpable de que haya decidido recorrer el camino de la ciencia. Que estas líneas ayuden a conservar tu recuerdo. A mis padres y hermanos, A Meri INDEX I Summary 1 II Introduction 3 1 Astrocytes: physiology and pathology 5 1.1 Anatomical organization 6 1.2 Origins and heterogeneity 6 1.3 Astrocyte functions 8 1.3.1 Developmental functions 8 1.3.2 Neurovascular functions 9 1.3.3 Metabolic support 11 1.3.4 Homeostatic functions 13 1.3.5 Antioxidant functions 15 1.3.6 Signalling functions 15 1.4 Astrocytes in brain pathology 20 1.5 Reactive astrogliosis 22 2 The transcription -
Network-Based Method for Drug Target Discovery at the Isoform Level
www.nature.com/scientificreports OPEN Network-based method for drug target discovery at the isoform level Received: 20 November 2018 Jun Ma1,2, Jenny Wang2, Laleh Soltan Ghoraie2, Xin Men3, Linna Liu4 & Penggao Dai 1 Accepted: 6 September 2019 Identifcation of primary targets associated with phenotypes can facilitate exploration of the underlying Published: xx xx xxxx molecular mechanisms of compounds and optimization of the structures of promising drugs. However, the literature reports limited efort to identify the target major isoform of a single known target gene. The majority of genes generate multiple transcripts that are translated into proteins that may carry out distinct and even opposing biological functions through alternative splicing. In addition, isoform expression is dynamic and varies depending on the developmental stage and cell type. To identify target major isoforms, we integrated a breast cancer type-specifc isoform coexpression network with gene perturbation signatures in the MCF7 cell line in the Connectivity Map database using the ‘shortest path’ drug target prioritization method. We used a leukemia cancer network and diferential expression data for drugs in the HL-60 cell line to test the robustness of the detection algorithm for target major isoforms. We further analyzed the properties of target major isoforms for each multi-isoform gene using pharmacogenomic datasets, proteomic data and the principal isoforms defned by the APPRIS and STRING datasets. Then, we tested our predictions for the most promising target major protein isoforms of DNMT1, MGEA5 and P4HB4 based on expression data and topological features in the coexpression network. Interestingly, these isoforms are not annotated as principal isoforms in APPRIS. -
Genome-Wide Meta-Analysis, Fine-Mapping, and Integrative Prioritization Identify New Alzheimer's Disease Risk Genes
medRxiv preprint doi: https://doi.org/10.1101/2020.01.22.20018424; this version posted January 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Genome-wide meta-analysis, fine-mapping, and integrative prioritization identify new Alzheimer’s disease risk genes Jeremy Schwartzentruber1,2*, Sarah Cooper2,3, Jimmy Z Liu4, Inigo Barrio-Hernandez1,2, Erica Bello2,3, Natsuhiko Kumasaka3, Toby Johnson5, Karol Estrada6, Daniel J. Gaffney2,3,7, Pedro Beltrao1,2, Andrew Bassett2,3* *Corresponding: Jeremy Schwartzentruber ([email protected]) Andrew Bassett ([email protected]) Affiliations: 1. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL- EBI), Wellcome Genome Campus, Cambridge, UK 2. Open Targets, Wellcome Genome Campus, Cambridge, UK 3. Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK 4. Biogen, Cambridge, MA, 02142, USA 5. Target Sciences-R&D, GSK Medicines Research Centre, Stevenage, UK 6. BioMarin Pharmaceutical, San Rafael, CA 94901, USA 7. Genomics Plc, Oxford, OX1 1JD, UK NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.01.22.20018424; this version posted January 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . -
Vast Human-Specific Delay in Cortical Ontogenesis Associated With
Supplementary information Extension of cortical synaptic development distinguishes humans from chimpanzees and macaques Supplementary Methods Sample collection We used prefrontal cortex (PFC) and cerebellar cortex (CBC) samples from postmortem brains of 33 human (aged 0-98 years), 14 chimpanzee (aged 0-44 years) and 44 rhesus macaque individuals (aged 0-28 years) (Table S1). Human samples were obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, USA, the Netherlands Brain Bank, Amsterdam, Netherlands and the Chinese Brain Bank Center, Wuhan, China. Informed consent for use of human tissues for research was obtained in writing from all donors or their next of kin. All subjects were defined as normal by forensic pathologists at the corresponding brain bank. All subjects suffered sudden death with no prolonged agonal state. Chimpanzee samples were obtained from the Yerkes Primate Center, GA, USA, the Anthropological Institute & Museum of the University of Zürich-Irchel, Switzerland and the Biomedical Primate Research Centre, Netherlands (eight Western chimpanzees, one Central/Eastern and five of unknown origin). Rhesus macaque samples were obtained from the Suzhou Experimental Animal Center, China. All non-human primates used in this study suffered sudden deaths for reasons other than their participation in this study and without any relation to the tissue used. CBC dissections were made from the cerebellar cortex. PFC dissections were made from the frontal part of the superior frontal gyrus. All samples contained an approximately 2:1 grey matter to white matter volume ratio. RNA microarray hybridization RNA isolation, hybridization to microarrays, and data preprocessing were performed as described previously (Khaitovich et al.