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FHL3 Contributes to EMT and Chemotherapy Resistance Through Inhibiting Ubiquitination of Slug and Activating Tgfβ/Smad-Independent Pathways in Gastric Cancer
FHL3 Contributes to EMT and Chemotherapy Resistance Through Inhibiting Ubiquitination of Slug and Activating TGFβ/Smad-Independent Pathways in Gastric Cancer Guodong Cao First Aliated Hospital of Anhui Medical University Pengping Li Hangzhou Xiaoshan No 1 People's Hospital Qiang Sun Xuzhou Medical University Sihan Chen First Aliated Hospital of Anhui Medical University Xin Xu First Aliated Hospital of Anhui Medical University Xiaobo He First Aliated Hospital of Anhui Medical University Zhenyu Wang Hangzhou Xiaoshan No 1 People's Hospital Peng Chen First Aliated Hospital of Anhui Medical University Maoming Xiong ( [email protected] ) First Aliated Hospital of Anhui Medical University Bo Chen First Aliated Hospital of Anhui Medical University Research Keywords: EMT, Chemotherapy resistance, FHL3, Ubiquitination, Gastric cancer Posted Date: October 9th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-87249/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. ReLoaadd iFngu l[Ml LaitchJeanxs]/ejax/output/CommonHTML/jax.js Page 1/28 Loading [MathJax]/jax/output/CommonHTML/jax.js Page 2/28 Abstract Background: Gastric cancer presents high risk of metastasis and chemotherapy resistance. Hence, the mechanistic understanding of the tumor metastasis and chemotherapy resistance is quietly important. Methods: TCGA database and clinical samples are used for exploring the role of FHL3 in disease progression and prognosis. The roles of FHL3 in metastasis and chemotherapy resistance are explored in vitro and in vivo by siRNA or shRNA treatment. Finally, we explore the FHL3-mediated EMT and chemotherapy resistance. Results: mRNA and protein level of FHL3 is signicantly up-regulated in gastric cancer tissues when compares with it in adjacent tissue. -
MYCL Promotes Ipsc-Like Colony Formation Via MYC Box 0 and 2 Domains
MYCL promotes iPSC-like colony formation via MYC Box 0 and 2 domains Chiaki Akifuji Department of Life Science Frontiers, Center for iPS cell Research and Application (CiRA), Kyoto University Mio Iwasaki Department of Life Science Frontiers, Center for iPS cell Research and Application (CiRA), Kyoto University Yuka Kawahara Department of Life Science Frontiers, Center for iPS cell Research and Application (CiRA), Kyoto University Chiho Sakurai Department of Life Science Frontiers, Center for iPS cell Research and Application (CiRA), Kyoto University Yusheng Cheng Department of Life Science Frontiers, Center for iPS cell Research and Application (CiRA), Kyoto University Takahiko Imai Department of Life Science Frontiers, Center for iPS cell Research and Application (CiRA), Kyoto University Masato Nakagawa ( [email protected] ) Department of Life Science Frontiers, Center for iPS cell Research and Application (CiRA), Kyoto University Research Article Keywords: mycl, reprogramming, ipsc, eciency, induced Posted Date: August 19th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-817686/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License 1 MYCL promotes iPSC-like colony formation via MYC Box 0 and 2 domains 2 3 Authors 4 Chiaki Akifuji1, Mio Iwasaki1, Yuka Kawahara1, Chiho Sakurai1, Yusheng Cheng1, Takahiko 5 Imai1, and Masato Nakagawa1* 6 7 Affiliation 8 1 Department of Life Science Frontiers, Center for iPS cell Research and Application (CiRA), 9 Kyoto University, Kyoto 606-8507, Japan 10 11 *Correspondence: [email protected] 12 13 Abstract 14 Induced pluripotent stem cells (iPSCs) have the potential to differentiate into any cell in 15 the body and thus have attractive regenerative medicine potential. -
In Vivo Studies Using the Classical Mouse Diversity Panel
The Mouse Diversity Panel Predicts Clinical Drug Toxicity Risk Where Classical Models Fail Alison Harrill, Ph.D The Hamner-UNC Institute for Drug Safety Sciences 0 The Importance of Predicting Clinical Adverse Drug Reactions (ADR) Figure: Cath O’Driscoll Nature Publishing 2004 Risk ID PGx Testing 1 People Respond Differently to Drugs Pharmacogenetic Markers Identified by Genome-Wide Association Drug Adverse Drug Risk Allele Reaction (ADR) Abacavir Hypersensitivity HLA-B*5701 Flucloxacillin Hepatotoxicity Allopurinol Cutaneous ADR HLA-B*5801 Carbamazepine Stevens-Johnson HLA-B*1502 Syndrome Augmentin Hepatotoxicity DRB1*1501 Ximelagatran Hepatotoxicity DRB1*0701 Ticlopidine Hepatotoxicity HLA-A*3303 Average preclinical populations and human hepatocytes lack the diversity to detect incidence of adverse events that occur only in 1/10,000 people. Current Rodent Models of Risk Assessment The Challenge “At a time of extraordinary scientific progress, methods have hardly changed in several decades ([FDA] 2004)… Toxicologists face a major challenge in the twenty-first century. They need to embrace the new “omics” techniques and ensure that they are using the most appropriate animals if their discipline is to become a more effective tool in drug development.” -Dr. Michael Festing Quantitative geneticist Toxicol Pathol. 2010;38(5):681-90 Rodent Models as a Strategy for Hazard Characterization and Pharmacogenetics Genetically defined rodent models may provide ability to: 1. Improve preclinical prediction of drugs that carry a human safety risk 2. -
Detailed Review Paper on Retinoid Pathway Signalling
1 1 Detailed Review Paper on Retinoid Pathway Signalling 2 December 2020 3 2 4 Foreword 5 1. Project 4.97 to develop a Detailed Review Paper (DRP) on the Retinoid System 6 was added to the Test Guidelines Programme work plan in 2015. The project was 7 originally proposed by Sweden and the European Commission later joined the project as 8 a co-lead. In 2019, the OECD Secretariat was added to coordinate input from expert 9 consultants. The initial objectives of the project were to: 10 draft a review of the biology of retinoid signalling pathway, 11 describe retinoid-mediated effects on various organ systems, 12 identify relevant retinoid in vitro and ex vivo assays that measure mechanistic 13 effects of chemicals for development, and 14 Identify in vivo endpoints that could be added to existing test guidelines to 15 identify chemical effects on retinoid pathway signalling. 16 2. This DRP is intended to expand the recommendations for the retinoid pathway 17 included in the OECD Detailed Review Paper on the State of the Science on Novel In 18 vitro and In vivo Screening and Testing Methods and Endpoints for Evaluating 19 Endocrine Disruptors (DRP No 178). The retinoid signalling pathway was one of seven 20 endocrine pathways considered to be susceptible to environmental endocrine disruption 21 and for which relevant endpoints could be measured in new or existing OECD Test 22 Guidelines for evaluating endocrine disruption. Due to the complexity of retinoid 23 signalling across multiple organ systems, this effort was foreseen as a multi-step process. -
Pitx3 KNOCKOUT MICE ENTRAIN to SCHEDULED FEEDING DESPITE
Pitx3 KNOCKOUT MICE ENTRAIN TO SCHEDULED FEEDING DESPITE FREE-RUNNING LIGHT ENTRAINED RHYTHMS A Thesis Presented to the Faculty of California State Polytechnic University, Pomona In Partial Fulfillment Of the Requirements for the Degree Master of Science In Biological Sciences By Lori L. Scarpa 2019 SIGNATURE PAGE THESIS: Pitx3 KNOCKOUT MICE ENTRAIN TO SCHEDULED FEEINDING DESPITE FREE-RUNNING LIGHT ENTRAINED RHYTHMS AUTHOR: Lori L. Scarpa DATE SUBMITTED: Fall 2019 Department of Biological Sciences Dr. Andrew D. Steele Thesis Committee Chair Biological Sciences Dr. Juanita Jellyman Biological Sciences Dr. Robert Talmadge Biological Sciences ii ACKNOWLEDGEMENTS Funding for this project was provided by the Whitehall Foundation and California State Polytechnic University of Pomona, California. I would like to thank the many people who assisted in the daily labors required to complete this project: Raymundo Miranda, Michael Sidikpramana, Jeffrey Falkenstein, Michael Williams, Jaskaran Dhanoa, and many other members of the Steele lab. I would like to specially recognize fellow graduate students in the Steele lab, Damien Wolfe and Andrew Villa, for their unconditional encouragement and support. I would like to thank Dr. Juanita Jellyman for her kindness and nurturing spirit. Dr. Jellyman never wavered her belief in me and it was this that kept me working harder towards my goals. Lastly, I would like thank Dr. Andrew Steele for accepting me into his lab, for being my personal mentor, and for pushing me towards success. Through him, I have grown to become a better scientist and found greater inspiration in my pursuit to further study neuroscience. Thank you, Dr. Steele, for your support and patience, and for playing a leading role in my success as a graduate student in your lab. -
Bioinformatic Analysis of Structure and Function of LIM Domains of Human Zyxin Family Proteins
International Journal of Molecular Sciences Article Bioinformatic Analysis of Structure and Function of LIM Domains of Human Zyxin Family Proteins M. Quadir Siddiqui 1,† , Maulik D. Badmalia 1,† and Trushar R. Patel 1,2,3,* 1 Alberta RNA Research and Training Institute, Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada; [email protected] (M.Q.S.); [email protected] (M.D.B.) 2 Department of Microbiology, Immunology and Infectious Disease, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive, Calgary, AB T2N 4N1, Canada 3 Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada * Correspondence: [email protected] † These authors contributed equally to the work. Abstract: Members of the human Zyxin family are LIM domain-containing proteins that perform critical cellular functions and are indispensable for cellular integrity. Despite their importance, not much is known about their structure, functions, interactions and dynamics. To provide insights into these, we used a set of in-silico tools and databases and analyzed their amino acid sequence, phylogeny, post-translational modifications, structure-dynamics, molecular interactions, and func- tions. Our analysis revealed that zyxin members are ohnologs. Presence of a conserved nuclear export signal composed of LxxLxL/LxxxLxL consensus sequence, as well as a possible nuclear localization signal, suggesting that Zyxin family members may have nuclear and cytoplasmic roles. The molecular modeling and structural analysis indicated that Zyxin family LIM domains share Citation: Siddiqui, M.Q.; Badmalia, similarities with transcriptional regulators and have positively charged electrostatic patches, which M.D.; Patel, T.R. -
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. -
Noninvasive Sleep Monitoring in Large-Scale Screening of Knock-Out Mice
bioRxiv preprint doi: https://doi.org/10.1101/517680; this version posted January 11, 2019. 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-ND 4.0 International license. Noninvasive sleep monitoring in large-scale screening of knock-out mice reveals novel sleep-related genes Shreyas S. Joshi1*, Mansi Sethi1*, Martin Striz1, Neil Cole2, James M. Denegre2, Jennifer Ryan2, Michael E. Lhamon3, Anuj Agarwal3, Steve Murray2, Robert E. Braun2, David W. Fardo4, Vivek Kumar2, Kevin D. Donohue3,5, Sridhar Sunderam6, Elissa J. Chesler2, Karen L. Svenson2, Bruce F. O'Hara1,3 1Dept. of Biology, University of Kentucky, Lexington, KY 40506, USA, 2The Jackson Laboratory, Bar Harbor, ME 04609, USA, 3Signal solutions, LLC, Lexington, KY 40503, USA, 4Dept. of Biostatistics, University of Kentucky, Lexington, KY 40536, USA, 5Dept. of Electrical and Computer Engineering, University of Kentucky, Lexington, KY 40506, USA. 6Dept. of Biomedical Engineering, University of Kentucky, Lexington, KY 40506, USA. *These authors contributed equally Address for correspondence and proofs: Shreyas S. Joshi, Ph.D. Dept. of Biology University of Kentucky 675 Rose Street 101 Morgan Building Lexington, KY 40506 U.S.A. Phone: (859) 257-2805 FAX: (859) 257-1717 Email: [email protected] Running title: Sleep changes in knockout mice bioRxiv preprint doi: https://doi.org/10.1101/517680; this version posted January 11, 2019. 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. -
An Amino-Terminal Domain of Mxil Mediates Anti-Myc Oncogenic Activity and Interacts with a Homolog of the Yeast Transcriptional Repressor SIN3
CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Cell, Vol, 80, 777-786, March 10, 1995, Copyright © 1995 by Cell Press An Amino-Terminal Domain of Mxil Mediates Anti-Myc Oncogenic Activity and Interacts with a Homolog of the Yeast Transcriptional Repressor SIN3 Nicole Schreiber-Agus,*t Lynda Chin,*tt Ken Chen,t et al., 1990), and a carboxy-terminal a-helical domain re- Richard Torres, t Govinda Rao,§ Peter Guida,t quired for dimerization with another basic region-helix- Arthur h Skoultchi,§ and Ronald A. DePinhot Ioop-helix-leucine zipper (bHLH-LZ) protein, Max (Black- "rDepartments of Microbiology and Immunology wood and Eisenman, 1991; Prendergast et al., 1991). and of Medicine Many of the biochemical and biological activities of Myc §Department of Cell Biology appear to be highly dependent upon its association with ~Division of Dermatology Max (Blackwood and Eisenman, 1991 ; Prendergast et al., Albert Einstein College of Medicine 1991; Kretzner et al., 1992; Amati et al., 1993a, 1993b). Bronx, New York 10461 In addition to its key role as an obligate partner in transacti- vation-competent Myc-Max complexes, Max may also re- press Myc-responsive genes through the formation of Summary transactivation-inert complexes that are capable of bind- ing the Myc-Max recognition sequence (Blackwood et al., Documented interactions among members of the Myc 1992; Kato et al., 1992; Kretzner et al., 1992; Makela et superfamily support a yin-yang model for the regula- al., 1992; Mukherjee et al., 1992; Prendergast et al., 1992; tion of Myc-responsive genes in which t ransactivation- Ayer et al., 1993; Zervos et al., 1993). -
Original Article MYCN-Mediated Regulation of the HES1 Promoter Enhances the Chemoresistance of Small-Cell Lung Cancer by Modulating Apoptosis
Am J Cancer Res 2019;9(9):1938-1956 www.ajcr.us /ISSN:2156-6976/ajcr0100301 Original Article MYCN-mediated regulation of the HES1 promoter enhances the chemoresistance of small-cell lung cancer by modulating apoptosis Qin Tong1,2*, Shuming Ouyang3*, Rui Chen1, Jie Huang4, Linlang Guo1 1Department of Pathology, Zhujiang Hospital, Southern Medical University, 253 Gongye Road, Guangzhou 510282, People’s Republic of China; Departments of 2Radiation Oncology, 3Reproductive Medicine, The First Affiliated Hospital of University of South China, Hengyang 421001, People’s Republic of China; 4Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, People’s Republic of China. *Equal contributors. Received June 29, 2019; Accepted August 10, 2019; Epub September 1, 2019; Published September 15, 2019 Abstract: MYCN, a member of the MYC family, is correlated with tumorigenesis, metastasis and therapy in many malig nancies; however, its role in small-cell lung cancer (SCLC) remains unclear. In this study, we sought to identify the function of MYCN in SCLC chemoresistance and found that MYCN is overexpressed in chemoresistant SCLC cells. We used MYCN gain- and loss-of- function experiments to demonstrate that MYCN promotes in vitro and in vivo chemoresistance in SCLC by inhibiting apoptosis. Mechanistic investigations showed that MYCN binds to the HES1 promoter and exhibits transcriptional activity. Furthermore, MYCN mediated SCLC chemoresistance through HES1. Accordingly, the NOTCH inhibitor FLI-60 derepressed HES1 and diminished MYCN-induced chemoresistance in SCLC. Finally, the positive correlation between HES1 and MYCN was confirmed in SCLC patients. -
Mouse Population-Guided Resequencing Reveals That Variants in CD44 Contribute to Acetaminophen-Induced Liver Injury in Humans
Downloaded from genome.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Letter Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans Alison H. Harrill,1,2,12 Paul B. Watkins,3,12 Stephen Su,6 Pamela K. Ross,2 David E. Harbourt,5 Ioannis M. Stylianou,7 Gary A. Boorman,8 Mark W. Russo,3 Richard S. Sackler,9 Stephen C. Harris,11 Philip C. Smith,5 Raymond Tennant,8 Molly Bogue,7 Kenneth Paigen,7 Christopher Harris,9,10 Tanupriya Contractor,9 Timothy Wiltshire,5 Ivan Rusyn,1,2,14 and David W. Threadgill1,4,13,14,15 1Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599, USA; 2Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, USA; 3Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina 27599, USA; 4Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA; 5School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA; 6Department of Mouse Genetics, Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA; 7The Jackson Laboratory, Bar Harbor, Maine 04609, USA; 8National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA; 9Verto Institute Research Laboratories, New Brunswick, New Jersey 08903, USA; 10Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA; 11Purdue Pharma L.P., Stamford, Connecticut 06901, USA; 12Hamner-UNC Center for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, USA; 13Department of Genetics, North Carolina State University, Raleigh, North Carolina 27695, USA Interindividual variability in response to chemicals and drugs is a common regulatory concern. -
Actin Nucleator Spire 1 Is a Regulator of Ectoplasmic Specialization in the Testis Qing Wen1,Nanli1,Xiangxiao 1,2,Wing-Yeelui3, Darren S
Wen et al. Cell Death and Disease (2018) 9:208 DOI 10.1038/s41419-017-0201-6 Cell Death & Disease ARTICLE Open Access Actin nucleator Spire 1 is a regulator of ectoplasmic specialization in the testis Qing Wen1,NanLi1,XiangXiao 1,2,Wing-yeeLui3, Darren S. Chu1, Chris K. C. Wong4, Qingquan Lian5,RenshanGe5, Will M. Lee3, Bruno Silvestrini6 and C. Yan Cheng 1 Abstract Germ cell differentiation during the epithelial cycle of spermatogenesis is accompanied by extensive remodeling at the Sertoli cell–cell and Sertoli cell–spermatid interface to accommodate the transport of preleptotene spermatocytes and developing spermatids across the blood–testis barrier (BTB) and the adluminal compartment of the seminiferous epithelium, respectively. The unique cell junction in the testis is the actin-rich ectoplasmic specialization (ES) designated basal ES at the Sertoli cell–cell interface, and the apical ES at the Sertoli–spermatid interface. Since ES dynamics (i.e., disassembly, reassembly and stabilization) are supported by actin microfilaments, which rapidly converts between their bundled and unbundled/branched configuration to confer plasticity to the ES, it is logical to speculate that actin nucleation proteins play a crucial role to ES dynamics. Herein, we reported findings that Spire 1, an actin nucleator known to polymerize actins into long stretches of linear microfilaments in cells, is an important regulator of ES dynamics. Its knockdown by RNAi in Sertoli cells cultured in vitro was found to impede the Sertoli cell tight junction (TJ)-permeability barrier through changes in the organization of F-actin across Sertoli cell cytosol. Unexpectedly, Spire 1 knockdown also perturbed microtubule (MT) organization in Sertoli cells cultured in vitro.