The Transition from Primary Colorectal Cancer to Isolated Peritoneal
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The Role of Nuclear Lamin B1 in Cell Proliferation and Senescence
Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press The role of nuclear lamin B1 in cell proliferation and senescence Takeshi Shimi,1 Veronika Butin-Israeli,1 Stephen A. Adam,1 Robert B. Hamanaka,2 Anne E. Goldman,1 Catherine A. Lucas,1 Dale K. Shumaker,1 Steven T. Kosak,1 Navdeep S. Chandel,2 and Robert D. Goldman1,3 1Department of Cell and Molecular Biology, 2Department of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA Nuclear lamin B1 (LB1) is a major structural component of the nucleus that appears to be involved in the regulation of many nuclear functions. The results of this study demonstrate that LB1 expression in WI-38 cells decreases during cellular senescence. Premature senescence induced by oncogenic Ras also decreases LB1 expression through a retinoblastoma protein (pRb)-dependent mechanism. Silencing the expression of LB1 slows cell proliferation and induces premature senescence in WI-38 cells. The effects of LB1 silencing on proliferation require the activation of p53, but not pRb. However, the induction of premature senescence requires both p53 and pRb. The proliferation defects induced by silencing LB1 are accompanied by a p53-dependent reduction in mitochondrial reactive oxygen species (ROS), which can be rescued by growth under hypoxic conditions. In contrast to the effects of LB1 silencing, overexpression of LB1 increases the proliferation rate and delays the onset of senescence of WI-38 cells. This overexpression eventually leads to cell cycle arrest at the G1/S boundary. -
PARSANA-DISSERTATION-2020.Pdf
DECIPHERING TRANSCRIPTIONAL PATTERNS OF GENE REGULATION: A COMPUTATIONAL APPROACH by Princy Parsana A dissertation submitted to The Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland July, 2020 © 2020 Princy Parsana All rights reserved Abstract With rapid advancements in sequencing technology, we now have the ability to sequence the entire human genome, and to quantify expression of tens of thousands of genes from hundreds of individuals. This provides an extraordinary opportunity to learn phenotype relevant genomic patterns that can improve our understanding of molecular and cellular processes underlying a trait. The high dimensional nature of genomic data presents a range of computational and statistical challenges. This dissertation presents a compilation of projects that were driven by the motivation to efficiently capture gene regulatory patterns in the human transcriptome, while addressing statistical and computational challenges that accompany this data. We attempt to address two major difficulties in this domain: a) artifacts and noise in transcriptomic data, andb) limited statistical power. First, we present our work on investigating the effect of artifactual variation in gene expression data and its impact on trans-eQTL discovery. Here we performed an in-depth analysis of diverse pre-recorded covariates and latent confounders to understand their contribution to heterogeneity in gene expression measurements. Next, we discovered 673 trans-eQTLs across 16 human tissues using v6 data from the Genotype Tissue Expression (GTEx) project. Finally, we characterized two trait-associated trans-eQTLs; one in Skeletal Muscle and another in Thyroid. Second, we present a principal component based residualization method to correct gene expression measurements prior to reconstruction of co-expression networks. -
Plakins, a Versatile Family of Cytolinkers: Roles in Skin Integrity and in Human Diseases Jamal-Eddine Bouameur1,2, Bertrand Favre1 and Luca Borradori1
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector REVIEW Plakins, a Versatile Family of Cytolinkers: Roles in Skin Integrity and in Human Diseases Jamal-Eddine Bouameur1,2, Bertrand Favre1 and Luca Borradori1 The plakin family consists of giant proteins involved in in (Roper et al., 2002; Jefferson et al., 2004; Sonnenberg and the cross-linking and organization of the cytoskeleton Liem, 2007; Boyer et al., 2010; Suozzi et al., 2012). and adhesion complexes. They further modulate sev- Mammalian plakins share a similar structural organization eral fundamental biological processes, such as cell and comprise seven members: bullous pemphigoid antigen 1 adhesion, migration, and polarization or signaling (BPAG1), desmoplakin, envoplakin, epiplakin, microtubule- pathways. Inherited and acquired defects of plakins actin cross-linking factor 1 (MACF1), periplakin, and plectin in humans and in animal models potentially lead to (Figure 1) (Choi et al., 2002; Jefferson et al., 2007; Choi and dramatic manifestations in the skin, striated muscles, Weis, 2011; Ortega et al., 2011). The existence of develop- and/or nervous system. These observations unequivo- mentally regulated and tissue-specific splice variants of some cally demonstrate the key role of plakins in the plakins further increases the diversity and versatility of these proteins (Table 1; Figure 1; Leung et al., 2001; Rezniczek et al., maintenance of tissue integrity. Here we review the 2003; Lin et al., 2005; Jefferson et al., 2006; Cabral et al., 2010). characteristics of the mammalian plakin members BPAG1 (bullous pemphigoid antigen 1), desmoplakin, PLAKINS IN THE EPIDERMIS plectin, envoplakin, epiplakin, MACF1 (microtubule- Epithelial BPAG1 (BPAG1e, also called BP230) constitutes the actin cross-linking factor 1), and periplakin, highlight- epithelium-specific isoform of BPAG1 and is localized in basal ing their role in skin homeostasis and diseases. -
Systems and Chemical Biology Approaches to Study Cell Function and Response to Toxins
Dissertation submitted to the Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto-Carola University of Heidelberg, Germany for the degree of Doctor of Natural Sciences Presented by MSc. Yingying Jiang born in Shandong, China Oral-examination: Systems and chemical biology approaches to study cell function and response to toxins Referees: Prof. Dr. Rob Russell Prof. Dr. Stefan Wölfl CONTRIBUTIONS The chapter III of this thesis was submitted for publishing under the title “Drug mechanism predominates over toxicity mechanisms in drug induced gene expression” by Yingying Jiang, Tobias C. Fuchs, Kristina Erdeljan, Bojana Lazerevic, Philip Hewitt, Gordana Apic & Robert B. Russell. For chapter III, text phrases, selected tables, figures are based on this submitted manuscript that has been originally written by myself. i ABSTRACT Toxicity is one of the main causes of failure during drug discovery, and of withdrawal once drugs reached the market. Prediction of potential toxicities in the early stage of drug development has thus become of great interest to reduce such costly failures. Since toxicity results from chemical perturbation of biological systems, we combined biological and chemical strategies to help understand and ultimately predict drug toxicities. First, we proposed a systematic strategy to predict and understand the mechanistic interpretation of drug toxicities based on chemical fragments. Fragments frequently found in chemicals with certain toxicities were defined as structural alerts for use in prediction. Some of the predictions were supported with mechanistic interpretation by integrating fragment- chemical, chemical-protein, protein-protein interactions and gene expression data. Next, we systematically deciphered the mechanisms of drug actions and toxicities by analyzing the associations of drugs’ chemical features, biological features and their gene expression profiles from the TG-GATEs database. -
Structural Forms of the Human Amylase Locus and Their Relationships to Snps, Haplotypes, and Obesity
Structural Forms of the Human Amylase Locus and Their Relationships to SNPs, Haplotypes, and Obesity The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Usher, Christina Leigh. 2015. Structural Forms of the Human Amylase Locus and Their Relationships to SNPs, Haplotypes, and Obesity. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467224 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Structural forms of the human amylase locus and their relationships to SNPs, haplotypes, and obesity A dissertation presented by Christina Leigh Usher to The Division of Medical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Genetics and Genomics Harvard University Cambridge, Massachusetts March 2015 © 2015 Christina Leigh Usher All rights reserved. Dissertation Advisor: Professor Steven McCarroll Christina Leigh Usher Structural forms of the human amylase locus and their relationships to SNPs, haplotypes, and obesity Abstract Hundreds of human genes reside in structurally complex loci that elude molecular analysis and assessment in genome-wide association studies (GWAS). One such locus contains the three different amylase genes (AMY2B, AMY2A, and AMY1) responsible for digesting starch into sugar. The copy number of AMY1 is reported to be the genome’s largest influence on obesity, yet has gone undetected in GWAS. -
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. -
Differential Proteomic Analysis of the Pancreas of Diabetic Db/Db Mice Reveals the Proteins Involved in the Development of Complications of Diabetes Mellitus
Int. J. Mol. Sci. 2014, 15, 9579-9593; doi:10.3390/ijms15069579 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Article Differential Proteomic Analysis of the Pancreas of Diabetic db/db Mice Reveals the Proteins Involved in the Development of Complications of Diabetes Mellitus Victoriano Pérez-Vázquez 1,*, Juan M. Guzmán-Flores 1, Daniela Mares-Álvarez 1, Magdalena Hernández-Ortiz 2, Maciste H. Macías-Cervantes 1, Joel Ramírez-Emiliano 1 and Sergio Encarnación-Guevara 2 1 Depto. de Ciencias Médicas, División de Ciencias de la Salud, Campus León, Universidad de Guanajuato, León, Guanajuato 37320, Mexico; E-Mails: [email protected] (J.M.G.-F.); [email protected] (D.M.-A.); [email protected] (M.H.M.-C.); [email protected] (J.R.-E.) 2 Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, Morelos 62210, Mexico; E-Mails: [email protected] (M.H.-O.); [email protected] (S.E.-G.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +52-477-7143-812; Fax: +52-477-7167-623. Received: 4 April 2014; in revised form: 14 May 2014 / Accepted: 19 May 2014 / Published: 30 May 2014 Abstract: Type 2 diabetes mellitus is characterized by hyperglycemia and insulin-resistance. Diabetes results from pancreatic inability to secrete the insulin needed to overcome this resistance. We analyzed the protein profile from the pancreas of ten-week old diabetic db/db and wild type mice through proteomics. Pancreatic proteins were separated in two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and significant changes in db/db mice respect to wild type mice were observed in 27 proteins. -
Chuanxiong Rhizoma Compound on HIF-VEGF Pathway and Cerebral Ischemia-Reperfusion Injury’S Biological Network Based on Systematic Pharmacology
ORIGINAL RESEARCH published: 25 June 2021 doi: 10.3389/fphar.2021.601846 Exploring the Regulatory Mechanism of Hedysarum Multijugum Maxim.-Chuanxiong Rhizoma Compound on HIF-VEGF Pathway and Cerebral Ischemia-Reperfusion Injury’s Biological Network Based on Systematic Pharmacology Kailin Yang 1†, Liuting Zeng 1†, Anqi Ge 2†, Yi Chen 1†, Shanshan Wang 1†, Xiaofei Zhu 1,3† and Jinwen Ge 1,4* Edited by: 1 Takashi Sato, Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of 2 Tokyo University of Pharmacy and Life Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China, Galactophore Department, The First 3 Sciences, Japan Hospital of Hunan University of Chinese Medicine, Changsha, China, School of Graduate, Central South University, Changsha, China, 4Shaoyang University, Shaoyang, China Reviewed by: Hui Zhao, Capital Medical University, China Background: Clinical research found that Hedysarum Multijugum Maxim.-Chuanxiong Maria Luisa Del Moral, fi University of Jaén, Spain Rhizoma Compound (HCC) has de nite curative effect on cerebral ischemic diseases, *Correspondence: such as ischemic stroke and cerebral ischemia-reperfusion injury (CIR). However, its Jinwen Ge mechanism for treating cerebral ischemia is still not fully explained. [email protected] †These authors share first authorship Methods: The traditional Chinese medicine related database were utilized to obtain the components of HCC. The Pharmmapper were used to predict HCC’s potential targets. Specialty section: The CIR genes were obtained from Genecards and OMIM and the protein-protein This article was submitted to interaction (PPI) data of HCC’s targets and IS genes were obtained from String Ethnopharmacology, a section of the journal database. -
United States Patent (19) 11 Patent Number: 5,981,727 Baden Et Al
USOO5981727A United States Patent (19) 11 Patent Number: 5,981,727 Baden et al. (45) Date of Patent: Nov. 9, 1999 54 PLANT GROUP 2 PROMOTERS AND USES OTHER PUBLICATIONS THEREOF Oommen et al (1994) The Plant Cell 6: 1789–1803. 75 Inventors: Catherine S. Baden, Martinez, Pamela Lewin, (1985) In: Genes II, Wiley and Sons, NY, pp. Dunsmuir, Piedmont; Kathleen Y. Lee, 182-183. Oakland, all of Calif. Van Haaven et al (1991) Plant Mol Biol 17: 615-630. 73 Assignee: DNA Plant Technology Corporation, Pear et al (1989) Plant Mol Biol 13: 639-651. Oakland, Calif. Primary Examiner Elizabeth F. McElwain 21 Appl. No.: 08/761,549 Attorney, Agent, or Firm Townsend and Townsend and 22 Filed: Dec. 6, 1996 Crew Related U.S. Application Data 57 ABSTRACT This invention relates to compositions and methods useful in 63 Continuation of application No. 08/289,458, Aug. 12, 1994, the production of transgenic plants. In particular, the inven Pat. No. 5,608,144. tion relates to Group 2 (Gp2) plant promoter Sequences and 51 Int. Cl. ............................ C12N 15700;s CO7H 21/04 to expressionp cassettes containingg Gp2Op.4 planlplant ppromoter 52 U.S. Cl. ...................... 536/23.6; 536/24.1; 435/1723 Sequences. The invention also relates to vectors and trans 58 Field of Search ........................... 800/205; 435/69.1, genic plants containing Gp2 plant promoter Sequences that 435/172.3, 419, 536/24.1, 23.6 are operably linked to heterologous DNA sequences. In addition, the invention relates to methods of producing 56) References Cited transgenic plants by using vectors containing Gp2 promoter Sequences. -
Effects and Mechanisms of Eps8 on the Biological Behaviour of Malignant Tumours (Review)
824 ONCOLOGY REPORTS 45: 824-834, 2021 Effects and mechanisms of Eps8 on the biological behaviour of malignant tumours (Review) KAILI LUO1, LEI ZHANG2, YUAN LIAO1, HONGYU ZHOU1, HONGYING YANG2, MIN LUO1 and CHEN QING1 1School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500; 2Department of Gynecology, Yunnan Tumor Hospital and The Third Affiliated Hospital of Kunming Medical University; Kunming, Yunnan 650118, P.R. China Received August 29, 2020; Accepted December 9, 2020 DOI: 10.3892/or.2021.7927 Abstract. Epidermal growth factor receptor pathway substrate 8 1. Introduction (Eps8) was initially identified as the substrate for the kinase activity of EGFR, improving the responsiveness of EGF, which Malignant tumours are uncontrolled cell proliferation diseases is involved in cell mitosis, differentiation and other physiological caused by oncogenes and ultimately lead to organ and body functions. Numerous studies over the last decade have demon- dysfunction (1). In recent decades, great progress has been strated that Eps8 is overexpressed in most ubiquitous malignant made in the study of genes and signalling pathways in tumours and subsequently binds with its receptor to activate tumorigenesis. Eps8 was identified by Fazioli et al in NIH-3T3 multiple signalling pathways. Eps8 not only participates in the murine fibroblasts via an approach that allows direct cloning regulation of malignant phenotypes, such as tumour proliferation, of intracellular substrates for receptor tyrosine kinases (RTKs) invasion, metastasis and drug resistance, but is also related to that was designed to study the EGFR signalling pathway. Eps8 the clinicopathological characteristics and prognosis of patients. -
Functional Analogy in Human Metabolism: Enzymes with Different Biological Roles Or Functional Redundancy?
GBE Functional Analogy in Human Metabolism: Enzymes with Different Biological Roles or Functional Redundancy? Rafael Mina Piergiorge1, Antonio Basılio de Miranda2, Ana Carolina Guimaraes~ 1,*, and Marcos Catanho1 1Laboratorio de Genoˆ mica Funcional e Bioinformatica, Fiocruz, Instituto Oswaldo Cruz, Manguinhos, Rio de Janeiro, Brazil 2Laboratorio de Biologia Computacional e Sistemas, Fiocruz, Instituto Oswaldo Cruz, Manguinhos, Rio de Janeiro, Brazil *Corresponding author: E-mail: carolg@fiocruz.br. Accepted: July 4, 2017 Abstract Since enzymes catalyze almost all chemical reactions that occur in living organisms, it is crucial that genes encoding such activities are correctly identified and functionally characterized. Several studies suggest that the fraction of enzymatic activities in which multiple events of independent origin have taken place during evolution is substantial. However, this topic is still poorly explored, and a comprehensive investigation of the occurrence, distribution, and implications of these events has not been done so far. Fundamental questions, such as how analogous enzymes originate, why so many events of independent origin have apparently occurred during evolution, and what are the reasons for the coexistence in the same organism of distinct enzymatic forms catalyzing the same reaction, remain unanswered. Also, several isofunctional enzymes are still not recognized as nonhomologous, even with substantial evidence indicating different evolutionary histories. In this work, we begin to investigate the biological significance of the cooccur- rence of nonhomologous isofunctional enzymes in human metabolism, characterizing functional analogous enzymes identified in metabolic pathways annotated in the human genome. Our hypothesis is that the coexistence of multiple enzymatic forms might not be interpreted as functional redundancy. Instead, these enzymatic forms may be implicated in distinct (and probably relevant) biological roles. -
The Transition from Primary Colorectal Cancer to Isolated Peritoneal Malignancy
medRxiv preprint doi: https://doi.org/10.1101/2020.02.24.20027318; this version posted February 25, 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 . The transition from primary colorectal cancer to isolated peritoneal malignancy is associated with a hypermutant, hypermethylated state Sally Hallam1, Joanne Stockton1, Claire Bryer1, Celina Whalley1, Valerie Pestinger1, Haney Youssef1, Andrew D Beggs1 1 = Surgical Research Laboratory, Institute of Cancer & Genomic Science, University of Birmingham, B15 2TT. Correspondence to: Andrew Beggs, [email protected] KEYWORDS: Colorectal cancer, peritoneal metastasis ABBREVIATIONS: Colorectal cancer (CRC), Colorectal peritoneal metastasis (CPM), Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS & HIPEC), Disease free survival (DFS), Differentially methylated regions (DMR), Overall survival (OS), TableFormalin fixed paraffin embedded (FFPE), Hepatocellular carcinoma (HCC) ARTICLE CATEGORY: Research article NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 1 medRxiv preprint doi: https://doi.org/10.1101/2020.02.24.20027318; this version posted February 25, 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 . NOVELTY AND IMPACT: Colorectal peritoneal metastasis (CPM) are associated with limited and variable survival despite patient selection using known prognostic factors and optimal currently available treatments.