Multi‐Omics Analysis Reveals the Interaction Between The
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Hemoglobin Interaction with Gp1ba Induces Platelet Activation And
ARTICLE Platelet Biology & its Disorders Hemoglobin interaction with GP1bα induces platelet activation and apoptosis: a novel mechanism associated with intravascular hemolysis Rashi Singhal,1,2,* Gowtham K. Annarapu,1,2,* Ankita Pandey,1 Sheetal Chawla,1 Amrita Ojha,1 Avinash Gupta,1 Miguel A. Cruz,3 Tulika Seth4 and Prasenjit Guchhait1 1Disease Biology Laboratory, Regional Centre for Biotechnology, National Capital Region, Biotech Science Cluster, Faridabad, India; 2Biotechnology Department, Manipal University, Manipal, Karnataka, India; 3Thrombosis Research Division, Baylor College of Medicine, Houston, TX, USA, and 4Hematology, All India Institute of Medical Sciences, New Delhi, India *RS and GKA contributed equally to this work. ABSTRACT Intravascular hemolysis increases the risk of hypercoagulation and thrombosis in hemolytic disorders. Our study shows a novel mechanism by which extracellular hemoglobin directly affects platelet activation. The binding of Hb to glycoprotein1bα activates platelets. Lower concentrations of Hb (0.37-3 mM) significantly increase the phos- phorylation of signaling adapter proteins, such as Lyn, PI3K, AKT, and ERK, and promote platelet aggregation in vitro. Higher concentrations of Hb (3-6 mM) activate the pro-apoptotic proteins Bak, Bax, cytochrome c, caspase-9 and caspase-3, and increase platelet clot formation. Increased plasma Hb activates platelets and promotes their apoptosis, and plays a crucial role in the pathogenesis of aggregation and development of the procoagulant state in hemolytic disorders. Furthermore, we show that in patients with paroxysmal nocturnal hemoglobinuria, a chronic hemolytic disease characterized by recurrent events of intravascular thrombosis and thromboembolism, it is the elevated plasma Hb or platelet surface bound Hb that positively correlates with platelet activation. -
Common Gene Polymorphisms Associated with Thrombophilia
Chapter 5 Common Gene Polymorphisms Associated with Thrombophilia Christos Yapijakis, Zoe Serefoglou and Constantinos Voumvourakis Additional information is available at the end of the chapter http://dx.doi.org/10.5772/61859 Abstract Genetic association studies have revealed a correlation between DNA variations in genes encoding factors of the hemostatic system and thrombosis-related disease. Certain var‐ iant alleles of these genes that affect either gene expression or function of encoded protein are known to be genetic risk factors for thrombophilia. The chapter presents the current genetics and molecular biology knowledge of the most important DNA polymorphisms in thrombosis-related genes encoding coagulation factor V (FV), coagulation factor II (FII), coagulation factor XII (FXII), coagulation factor XIII A1 subunit (FXIIIA1), 5,10- methylene tetrahydrofolate reductase (MTHFR), serpine1 (SERPINE1), angiotensin I-con‐ verting enzyme (ACE), angiotensinogen (AGT), integrin A2 (ITGA2), plasma carboxypeptidase B2 (CPB2), platelet glycoprotein Ib α polypeptide (GP1BA), thrombo‐ modulin (THBD) and protein Z (PROZ). The molecular detection methods of each DNA polymorphism is presented, in addition to the current knowledge regarding its influence on thrombophilia and related thrombotic events, including stroke, myocardial infarction, deep vein thrombosis, spontaneous abortion, etc. In addition, best thrombosis prevention strategies with a combination of genetic counseling and molecular testing are discussed. Keywords: Thrombophilia, coagulation -
LRP1 Shedding in Human Brain: Roles of ADAM10 and ADAM17 Qiang Liu Washington University School of Medicine in St
Washington University School of Medicine Digital Commons@Becker ICTS Faculty Publications Institute of Clinical and Translational Sciences 2009 LRP1 shedding in human brain: roles of ADAM10 and ADAM17 Qiang Liu Washington University School of Medicine in St. Louis Juan Zhang Washington University School of Medicine in St. Louis Hien Tran Washington University School of Medicine in St. Louis Marcel M. Verbeek Radboud University Nijmegen Medical Centre Karina Reiss Christian-Albrecht University Kiel See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/icts_facpubs Part of the Medicine and Health Sciences Commons Recommended Citation Liu, Qiang; Zhang, Juan; Tran, Hien; Verbeek, Marcel M.; Reiss, Karina; Estus, Steven; and Bu, Guojun, "LRP1 shedding in human brain: roles of ADAM10 and ADAM17". Molecular Neurodegeneration, 17. 2009. Paper 85. https://digitalcommons.wustl.edu/icts_facpubs/85 This Article is brought to you for free and open access by the Institute of Clinical and Translational Sciences at Digital Commons@Becker. It has been accepted for inclusion in ICTS Faculty Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Qiang Liu, Juan Zhang, Hien Tran, Marcel M. Verbeek, Karina Reiss, Steven Estus, and Guojun Bu This article is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/icts_facpubs/85 Molecular Neurodegeneration BioMed Central Research article Open Access LRP1 shedding -
Leveraging Mouse Chromatin Data for Heritability Enrichment Informs Common Disease Architecture and Reveals Cortical Layer Contributions to Schizophrenia
Downloaded from genome.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Research Leveraging mouse chromatin data for heritability enrichment informs common disease architecture and reveals cortical layer contributions to schizophrenia Paul W. Hook1 and Andrew S. McCallion1,2,3 1McKusick-Nathans Department of Genetic Medicine, 2Department of Comparative and Molecular Pathobiology, 3Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA Genome-wide association studies have implicated thousands of noncoding variants across common human phenotypes. However, they cannot directly inform the cellular context in which disease-associated variants act. Here, we use open chro- matin profiles from discrete mouse cell populations to address this challenge. We applied stratified linkage disequilibrium score regression and evaluated heritability enrichment in 64 genome-wide association studies, emphasizing schizophrenia. We provide evidence that mouse-derived human open chromatin profiles can serve as powerful proxies for difficult to ob- tain human cell populations, facilitating the illumination of common disease heritability enrichment across an array of hu- man phenotypes. We demonstrate that signatures from discrete subpopulations of cortical excitatory and inhibitory neurons are significantly enriched for schizophrenia heritability with maximal enrichment in cortical layer V excitatory neu- rons. We also show that differences between schizophrenia and bipolar disorder are concentrated in excitatory neurons in cortical layers II-III, IV, and V, as well as the dentate gyrus. Finally, we leverage these data to fine-map variants in 177 schiz- ophrenia loci nominating variants in 104/177. We integrate these data with transcription factor binding site, chromatin in- teraction, and validated enhancer data, placing variants in the cellular context where they may modulate risk. -
047605V1.Full.Pdf
bioRxiv preprint doi: https://doi.org/10.1101/047605; this version posted April 8, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Assembly and Activation of Dynein-Dynactin by the Cargo Adaptor Protein Hook3 Courtney M. Schroeder1,2 and Ronald D. Vale1,2 1The Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California, USA 2Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA. Corresponding Author: Ronald D. Vale Dept. of Cellular and Molecular Pharmacology University of California, San Francisco Genentech Hall, MC 2200, Room N312A 600-16th Street San Francisco, CA 94158-2517 E-mail: [email protected] Phone: 415-476-6380 Fax: 415-514-4412 bioRxiv preprint doi: https://doi.org/10.1101/047605; this version posted April 8, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 2 Abstract Metazoan cytoplasmic dynein moves processively along microtubules with the aid of dynactin and an adaptor protein that joins dynein and dynactin into a stable ternary complex. Here, we have examined how Hook3, a cargo adaptor involved in Golgi and endosome transport, forms a motile dynein-dynactin complex. We show that the conserved Hook domain interacts directly with the dynein light intermediate chain 1 (LIC1). -
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. -
4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4). -
Management of Brain and Leptomeningeal Metastases from Breast Cancer
International Journal of Molecular Sciences Review Management of Brain and Leptomeningeal Metastases from Breast Cancer Alessia Pellerino 1,* , Valeria Internò 2 , Francesca Mo 1, Federica Franchino 1, Riccardo Soffietti 1 and Roberta Rudà 1,3 1 Department of Neuro-Oncology, University and City of Health and Science Hospital, 10126 Turin, Italy; [email protected] (F.M.); [email protected] (F.F.); riccardo.soffi[email protected] (R.S.); [email protected] (R.R.) 2 Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, 70121 Bari, Italy; [email protected] 3 Department of Neurology, Castelfranco Veneto and Treviso Hospital, 31100 Treviso, Italy * Correspondence: [email protected]; Tel.: +39-011-6334904 Received: 11 September 2020; Accepted: 10 November 2020; Published: 12 November 2020 Abstract: The management of breast cancer (BC) has rapidly evolved in the last 20 years. The improvement of systemic therapy allows a remarkable control of extracranial disease. However, brain (BM) and leptomeningeal metastases (LM) are frequent complications of advanced BC and represent a challenging issue for clinicians. Some prognostic scales designed for metastatic BC have been employed to select fit patients for adequate therapy and enrollment in clinical trials. Different systemic drugs, such as targeted therapies with either monoclonal antibodies or small tyrosine kinase molecules, or modified chemotherapeutic agents are under investigation. Major aims are to improve the penetration of active drugs through the blood–brain barrier (BBB) or brain–tumor barrier (BTB), and establish the best sequence and timing of radiotherapy and systemic therapy to avoid neurocognitive impairment. Moreover, pharmacologic prevention is a new concept driven by the efficacy of targeted agents on macrometastases from specific molecular subgroups. -
Endothelial LRP1 Transports Amyloid-Β1–42 Across the Blood- Brain Barrier
Endothelial LRP1 transports amyloid-β1–42 across the blood- brain barrier Steffen E. Storck, … , Thomas A. Bayer, Claus U. Pietrzik J Clin Invest. 2016;126(1):123-136. https://doi.org/10.1172/JCI81108. Research Article Neuroscience According to the neurovascular hypothesis, impairment of low-density lipoprotein receptor–related protein-1 (LRP1) in brain capillaries of the blood-brain barrier (BBB) contributes to neurotoxic amyloid-β (Aβ) brain accumulation and drives Alzheimer’s disease (AD) pathology. However, due to conflicting reports on the involvement of LRP1 in Aβ transport and the expression of LRP1 in brain endothelium, the role of LRP1 at the BBB is uncertain. As global Lrp1 deletion in mice is lethal, appropriate models to study the function of LRP1 are lacking. Moreover, the relevance of systemic Aβ clearance to AD pathology remains unclear, as no BBB-specific knockout models have been available. Here, we developed transgenic mouse strains that allow for tamoxifen-inducible deletion of Lrp1 specifically within brain endothelial cells (Slco1c1- CreERT2 Lrp1fl/fl mice) and used these mice to accurately evaluate LRP1-mediated Aβ BBB clearance in vivo. Selective 125 deletion of Lrp1 in the brain endothelium of C57BL/6 mice strongly reduced brain efflux of injected [ I] Aβ1–42. Additionally, in the 5xFAD mouse model of AD, brain endothelial–specific Lrp1 deletion reduced plasma Aβ levels and elevated soluble brain Aβ, leading to aggravated spatial learning and memory deficits, thus emphasizing the importance of systemic Aβ elimination via the BBB. Together, our results suggest that receptor-mediated Aβ BBB clearance may be a potential target for treatment and prevention of Aβ brain accumulation in AD. -
Over-Expression of Low-Density Lipoprotein Receptor-Related Protein-1 Is Associated with Poor Prognosis and Invasion in Pancreatic Ductal Adenocarcinoma
Pancreatology 19 (2019) 429e435 Contents lists available at ScienceDirect Pancreatology journal homepage: www.elsevier.com/locate/pan Over-expression of low-density lipoprotein receptor-related Protein-1 is associated with poor prognosis and invasion in pancreatic ductal adenocarcinoma Ali Gheysarzadeh a, Amir Ansari a, Mohammad Hassan Emami b, * Amirnader Emami Razavi c, Mohammad Reza Mofid a, a Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran b Gastrointestinal and Hepatobiliary Diseases Research Center, Poursina Hakim Research Institute for Health Care Development, Isfahan, Iran c Iran National Tumor Bank, Cancer Biology Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran article info abstract Article history: Background: Low-density lipoprotein receptor-Related Protein-1 (LRP-1) has been reported to involve in Received 1 December 2018 tumor development. However, its role in pancreatic cancer has not been elucidated. The present study Received in revised form was designed to evaluate the expression of LRP-1 in Pancreatic Ductal Adenocarcinoma Cancer (PDAC) as 16 February 2019 well as its association with prognosis. Accepted 23 February 2019 Methods: Here, 478 pancreatic cancers were screened for suitable primary PDAC tumors. The samples Available online 14 March 2019 were analyzed using qRT-PCR, western blotting, and Immunohistochemistry (IHC) staining as well as LRP-1 expression in association with clinicopathological features. Keywords: PDAC Results: The relative LRP-1 mRNA expression was up-regulated in 82.3% (42/51) of the PDAC tumors and ± fi ± LRP-1 its expression (3.72 1.25) was signi cantly higher than that in pancreatic normal margins (1.0 0.23, Prognosis P < 0.05). -
Therapeutic Antibody-Like Immunoconjugates Against Tissue Factor with the Potential to Treat Angiogenesis-Dependent As Well As Macrophage-Associated Human Diseases
antibodies Review Therapeutic Antibody-Like Immunoconjugates against Tissue Factor with the Potential to Treat Angiogenesis-Dependent as Well as Macrophage-Associated Human Diseases Zhiwei Hu ID Department of Surgery Division of Surgical Oncology, The James Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA; [email protected]; Tel.: +1-614-685-4606 Received: 10 October 2017; Accepted: 18 January 2018; Published: 23 January 2018 Abstract: Accumulating evidence suggests that tissue factor (TF) is selectively expressed in pathological angiogenesis-dependent as well as macrophage-associated human diseases. Pathological angiogenesis, the formation of neovasculature, is involved in many clinically significant human diseases, notably cancer, age-related macular degeneration (AMD), endometriosis and rheumatoid arthritis (RA). Macrophage is involved in the progression of a variety of human diseases, such as atherosclerosis and viral infections (human immunodeficiency virus, HIV and Ebola). It is well documented that TF is selectively expressed on angiogenic vascular endothelial cells (VECs) in these pathological angiogenesis-dependent human diseases and on disease-associated macrophages. Under physiology condition, TF is not expressed by quiescent VECs and monocytes but is solely restricted on some cells (such as pericytes) that are located outside of blood circulation and the inner layer of blood vessel walls. Here, we summarize TF expression on angiogenic VECs, macrophages and other diseased cell types in these human diseases. In cancer, for example, the cancer cells also overexpress TF in solid cancers and leukemia. Moreover, our group recently reported that TF is also expressed by cancer-initiating stem cells (CSCs) and can serve as a novel oncotarget for eradication of CSCs without drug resistance. -
Alternatively Spliced Tissue Factor Induces Angiogenesis Through Integrin Ligation
Alternatively spliced tissue factor induces angiogenesis through integrin ligation Y. W. van den Berga, L. G. van den Hengela, H. R. Myersa, O. Ayachia, E. Jordanovab, W. Rufc, C. A. Spekd, P. H. Reitsmaa, V. Y. Bogdanove, and H. H. Versteega,1 aThe Einthoven Laboratory for Experimental Vascular Medicine and bDepartment of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands; cDepartment of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037; dCenter for Experimental and Molecular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; and eDivision of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, 3125 Eden Avenue, Cincinnati, OH 45267 Edited by Charles T. Esmon, Oklahoma Medical Research Foundation, Oklahoma City, OK, and approved September 25, 2009 (received for review May 15, 2009) The initiator of coagulation, full-length tissue factor (flTF), in complex pancreatic cancer cells transfected to express asTF produce more with factor VIIa, influences angiogenesis through PAR-2. Recently, an blood vessels (20), but it remained mechanistically unclear if and alternatively spliced variant of TF (asTF) was discovered, in which part how angiogenesis is regulated by asTF. One possibility is that asTF of the TF extracellular domain, the transmembrane, and cytoplasmic stimulates cancer cells to produce angiogenic factors, but it is also domains are replaced by a unique C terminus. Subcutaneous tumors plausible that asTF enhances angiogenesis via paracrine stimulation produced by asTF-secreting cells revealed increased angiogenesis, but of endothelial cells. Moreover, the role of VIIa, PAR-2 activation it remained unclear if and how angiogenesis is regulated by asTF.