Mouse Clptm1l Conditional Knockout Project (CRISPR/Cas9)
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Dong et al. Genome Medicine (2021) 13:110 https://doi.org/10.1186/s13073-021-00927-6 RESEARCH Open Access A global overview of genetically interpretable multimorbidities among common diseases in the UK Biobank Guiying Dong1,2, Jianfeng Feng1,2,3, Fengzhu Sun4, Jingqi Chen1,2,3* and Xing-Ming Zhao1,2,3* Abstract Background: Multimorbidities greatly increase the global health burdens, but the landscapes of their genetic risks have not been systematically investigated. Methods: We used the hospital inpatient data of 385,335 patients in the UK Biobank to investigate the multimorbid relations among 439 common diseases. Post-GWAS analyses were performed to identify multimorbidity shared genetic risks at the genomic loci, network, as well as overall genetic architecture levels. We conducted network decomposition for the networks of genetically interpretable multimorbidities to detect the hub diseases and the involved molecules and functions in each module. Results: In total, 11,285 multimorbidities among 439 common diseases were identified, and 46% of them were genetically interpretable at the loci, network, or overall genetic architecture levels. Multimorbidities affecting the same and different physiological systems displayed different patterns of the shared genetic components, with the former more likely to share loci-level genetic components while the latter more likely to share network-level genetic components. Moreover, both the loci- and network-level genetic components shared by multimorbidities converged on cell immunity, protein metabolism, and gene silencing. Furthermore, we found that the genetically interpretable multimorbidities tend to form network modules, mediated by hub diseases and featuring physiological categories. Finally, we showcased how hub diseases mediating the multimorbidity modules could help provide useful insights for the genetic contributors of multimorbidities. -
Supplemental Materials 1 SUPPLEMENTAL METHODS CSC
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) J Immunother Cancer Identification of MM immunotherapy targets by MS – Supplemental materials 1 SUPPLEMENTAL METHODS 2 CSC-technology 3 Approximately 100 million cells from each biological replicate (n=3-6) were taken 4 through the CSC-Technology workflow as previously described in detail.(1-3) Cells were 5 washed with PBS and oxidized by treatment with 1 mM sodium meta-periodate (Pierce, 6 Rockford, IL) in PBS pH 7.6 for 15 min at 4°C followed by 2.5 mg/ml biocytin hydrazide 7 (Biotium, Hayward, CA) in PBS pH 6.5 for 1 hour at 4°C. Cells were then collected and 8 homogenized in 10mM Tris pH 7.5, 0.5 mM MgCl2 and the resulting cell lysate was centrifuged 9 at 800 x g for 10 min at 4°C. The supernatant was centrifuged at 210,000 x g for 16 hours at 4°C 10 to collect the membranes. The supernatant was removed and the membrane protein pellet was 11 washed with 25 mM Na2CO3 to disrupt peripheral protein interactions. To the resulting 12 membrane pellet, 300µl 100 mM NH4HCO3, 5 mM Tris(2-carboxyethyl) phosphine (Sigma, St. 13 Louis, MO), and 0.1% (v/v) Rapigest (Waters, Milford, MA) were added and placed on a 14 Thermomixer (750 rpm) to continuously vortex. Proteins were allowed to reduce for 10 min at 15 25°C followed by alklylation with 10 mM iodoacetamide for 30 min. -
Spatial Maps of Prostate Cancer Transcriptomes Reveal an Unexplored Landscape of Heterogeneity
ARTICLE DOI: 10.1038/s41467-018-04724-5 OPEN Spatial maps of prostate cancer transcriptomes reveal an unexplored landscape of heterogeneity Emelie Berglund1, Jonas Maaskola1, Niklas Schultz2, Stefanie Friedrich3, Maja Marklund1, Joseph Bergenstråhle1, Firas Tarish2, Anna Tanoglidi4, Sanja Vickovic 1, Ludvig Larsson1, Fredrik Salmeń1, Christoph Ogris3, Karolina Wallenborg2, Jens Lagergren5, Patrik Ståhl1, Erik Sonnhammer3, Thomas Helleday2 & Joakim Lundeberg 1 1234567890():,; Intra-tumor heterogeneity is one of the biggest challenges in cancer treatment today. Here we investigate tissue-wide gene expression heterogeneity throughout a multifocal prostate cancer using the spatial transcriptomics (ST) technology. Utilizing a novel approach for deconvolution, we analyze the transcriptomes of nearly 6750 tissue regions and extract distinct expression profiles for the different tissue components, such as stroma, normal and PIN glands, immune cells and cancer. We distinguish healthy and diseased areas and thereby provide insight into gene expression changes during the progression of prostate cancer. Compared to pathologist annotations, we delineate the extent of cancer foci more accurately, interestingly without link to histological changes. We identify gene expression gradients in stroma adjacent to tumor regions that allow for re-stratification of the tumor micro- environment. The establishment of these profiles is the first step towards an unbiased view of prostate cancer and can serve as a dictionary for future studies. 1 Department of Gene Technology, School of Engineering Sciences in Chemistry, Biotechnology and Health, Royal Institute of Technology (KTH), Science for Life Laboratory, Tomtebodavägen 23, Solna 17165, Sweden. 2 Department of Oncology-Pathology, Karolinska Institutet (KI), Science for Life Laboratory, Tomtebodavägen 23, Solna 17165, Sweden. 3 Department of Biochemistry and Biophysics, Stockholm University, Science for Life Laboratory, Tomtebodavägen 23, Solna 17165, Sweden. -
Statistical Methods for Integrating Disparate Data Sources
STATISTICAL METHODS FOR INTEGRATING DISPARATE DATA SOURCES by Prosenjit Kundu A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland April, 2020 Copyright 2020 by Prosenjit Kundu All rights reserved Abstract My thesis is about developing statistical methods by integrating disparate data sources with real data applications, and identifying gene-environment interac- tions (G E) in more extensive studies using existing analytical methods. We × propose a general and novel statistical framework for combining information on multivariate regression parameters across multiple different studies which have varying level of covariate information (Chapter 2). We illustrate the method us- ing real data for developing a breast cancer risk prediction model. We propose a generalized method of moments (GMM) approach for analyzing two-phase studies where we take into account the dependent structure of the datasets across the two-phases (Chapter 3). We illustrate the method using real data on Wilm’s tumor, a common type of kidney cancer in children. We analyze the largest gene by smoking interaction study for pancreatic ductal adenocarcinoma risk conducted to date using existing statistical methods (Chapter 4). Primary Readers Nilanjan Chatterjee (Advisor) Professor Department of Biostatistics & Department of Oncology ii Bloomberg School of Public Health, School of Medicine, The Johns Hop- kins University Alison Patricia Klein Professor Department of Oncology School of Medicine, The Johns Hopkins University Mei-Cheng Wang Professor Department of Biostatistics Bloomberg School of Public Health, The Johns Hopkins University Debashree Ray Assisstant Professor Department of Epidemiology Bloomberg School of Public Health, The Johns Hopkins University Alternate Readers Elizabeth L. -
Winners Sorted by Institute-Center
FARE2020WINNERS Sorted By Institute Ji Chen Postdoctoral Fellow CC Neuroscience - General Toward a Wearable Pediatric Robotic Knee Exoskeleton for Real World Overground Gait Rehabilitation in Ambulatory Individuals Crouch gait, or excessive knee flexion, is a debilitating gait pathology in children with cerebral palsy (CP). Surgery, bracing and therapy provide only short term correction of crouch and more sustainable solutions remain a significant challenge in children with CP. One major hurdle is achieving the required dosage and intensity of gait training necessary to produce meaningful long term improvements in walking ability. Rather than replace lost or absent function, gait training in CP population aims to improve the participant’s baseline walking pattern by encouraging longer bouts of training and exercise, which is different than in those with paralysis. Wearable robotic exoskeletons, as a potential strategy, can assist individuals with CP to gradually regain knee extension over time and help maintain it for longer periods through intense task-specific gait training. We previously tested our initial prototype which produced significant improvement in knee extension comparable in magnitude to reported results from orthopedic surgery. Children continued to exert voluntary knee extensor muscle when walking with the exoskeleton which indicated the device was assisting but not controlling their gait. These positive initial results motivated us to design second prototype to expand the user population, and to enable its effective use outside of the laboratory environment. The current version has individualized control capability and device portability for home use as it implemented a multi-layered closed loop control system and a microcontroller based data acquisition system. -
WO 2015/108719 Al 23 July 2015 (23.07.2015) P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/108719 Al 23 July 2015 (23.07.2015) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, C07K 16/30 (2006.01) A61P 35/00 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, PCT/US2015/010219 MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 6 January 2015 (06.01 .2015) SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 61/927,330 14 January 2014 (14.01.2014) US TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant: THE MEDICAL COLLEGE OF WISCON¬ DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, SIN, INC. -
216141 2 En Bookbackmatter 461..490
Glossary A2BP1 ataxin 2-binding protein 1 (605104); 16p13 ABAT 4-(gamma)-aminobutyrate transferase (137150); 16p13.3 ABCA5 ATP-binding cassette, subfamily A, member 5 (612503); 17q24.3 ABCD1 ATP-binding cassette, subfamily D, member 1 (300371):Xq28 ABR active BCR-related gene (600365); 17p13.3 ACR acrosin (102480); 22q13.33 ACTB actin, beta (102630); 7p22.1 ADHD attention deficit hyperactivity disorder—three separate conditions ADD, ADHD, HD that manifest as poor focus with or without uncontrolled, inap- propriately busy behavior, diagnosed by observation and quantitative scores from parent and teacher questionnaires ADSL adenylosuccinate lyase (608222); 22q13.1 AGL amylo-1,6-glucosidase (610860); 1p21.2 AGO1 (EIF2C1), AGO3 (EIF2C3) argonaute 1 (EIF2C1, eukaryotic translation initiation factor 2C, subunit 1 (606228); 1p34.3, argonaute 3 (factor 2C, subunit 3—607355):1p34.3 AKAP8, AKAP8L A-kinase anchor protein (604692); 19p13.12, A-kinase anchor protein 8-like (609475); 19p13.12 ALG6 S. cerevisiae homologue of, mutations cause congenital disorder of glyco- sylation (604566); 1p31.3 Alopecia absence of hair ALX4 aristaless-like 4, mouse homolog of (605420); 11p11.2 As elsewhere in this book, 6-digit numbers in parentheses direct the reader to gene or disease descriptions in the Online Mendelian Disease in Man database (www.omim.org) © Springer Nature Singapore Pte Ltd. 2017 461 H.E. Wyandt et al., Human Chromosome Variation: Heteromorphism, Polymorphism and Pathogenesis, DOI 10.1007/978-981-10-3035-2 462 Glossary GRIA1 glutamate receptor, -
The TERT-CLPTM1L Locus for Lung Cancer Predisposes to Bronchial Obstruction and Emphysema
Eur Respir J 2011; 38: 924–931 DOI: 10.1183/09031936.00187110 CopyrightßERS 2011 The TERT-CLPTM1L locus for lung cancer predisposes to bronchial obstruction and emphysema E. Wauters*,#,",e, D. Smeets*,#,e, J. Coolen+, J. Verschakelen+, P. De Leyn1, M. Decramer", J. Vansteenkiste", W. Janssens" and D. Lambrechts*,# ABSTRACT: Clinical studies suggest that bronchial obstruction and emphysema increase AFFILIATIONS susceptibility to lung cancer. We assessed the possibility of a common genetic origin and *Vesalius Research Center (VRC), VIB, investigated whether the lung cancer susceptibility locus on chromosome 5p15.33 increases the #VRC, KU Leuven, and, risk for bronchial obstruction and emphysema. "Respiratory Division, and, Three variants in the 5p15.33 locus encompassing the TERT and CLPTM1L genes were Depts of +Radiology, and, 1 genotyped in 777 heavy smokers and 212 lung cancer patients. Participants underwent pulmonary Thoracic Surgery, University Hospital Gasthuisberg, KU Leuven, function tests and computed tomography of the chest, and completed questionnaires assessing Leuven, Belgium. smoking behaviour. eThese authors contributed equally to The rs31489 C-allele correlated with reduced forced expiratory volume in 1 s (p50.006). this work. Homozygous carriers of the rs31489 C-allele exhibited increased susceptibility to bronchial CORRESPONDENCE 5 obstruction (OR 1.82, 95% CI 1.24–2.69; p 0.002). A similar association was observed for D. Lambrechts diffusing capacity of the lung for carbon monoxide (p50.004). Consistent with this, CC-carriers Vesalius Research Center, VIB had an increased risk of emphysema (OR 2.04, 95% CI 1.41–2.94; p51.73610-4) and displayed KU Leuven greater alveolar destruction. -
CIHR STAGE Program Advisory Committee Meeting January 24 & 25, 2013 Toronto, Ontario PROGRESS REPORT RECRUITMENT and BUDGET
2012 ANNUAL REPORT CIHR STAGE Program Advisory Committee Meeting January 24 & 25, 2013 Toronto, Ontario PROGRESS REPORT RECRUITMENT AND BUDGET Page Page 01 01 Co-Directors Message 1 STAGE Competitions: Applicant-Publication 20 02 Records-Comparison Co-principal Investigators, Co-investigators, 3 02 and Collaborators Projected and Actual Admissions 22 03 03 Summary of Changes 5 Current Trainees 23 04 04 Progress 8 Alumni 25 05 05 List of Acronyms 17 Trainee Productivity 26 06 06 Governance Structure 18 Trainee Awards, Distinctions, and Honours 27 07 Budget 29 CURRICULUM APPENDICES Page A Summary of Grant Proposal 01 Components, Training Objectives, and 30 B List of Trainee Publications Assessable Outcomes C Representative Trainee Publications 02 Integrative and Cross-disciplinary Courses 32 D List of Mentors 03 International Speaker Seminar Series 34 E Mentors-Mentee Agreement F Syllabi-Integrative Courses G Steering Committee Meeting Minutes, Oct. 2012 H STAGE International Internship and Travel Award Programs I Syllabi and Agendas for Professional Development Courses and Workshops J Trainee Annual Progress Report and Exit Survey K GAW18 Workshop - Resulting Papers and Participating STAGE Mentors and Trainees L Mentoring Commitment Message STAGE - PAC 2012 Annual Report Page 5 01 CO-DIRECTORS MESSAGE Drs. SHELLEY B. BULL & FRANCE GAGNON Dear members of the Program Advisory Committee: Thank you very much for your wise counsel and valuable guidance regarding the progress of STAGE and its future directions. Your critical evaluation of how STAGE fulfils its mission and objectives, and how it can improve is essential. The program’s midterm review by the Canadian Institutes for Health Research (CIHR) (Strategic Training Initiative in Health Research (STIHR) Program) on November 2013 will determine funding for the last three years of operation, until 2016. -
Focused Analysis of Exome Sequencing Data for Rare Germline Mutations in Familial and Sporadic Lung Cancer
ORIGINAL ARTICLE Focused Analysis of Exome Sequencing Data for Rare Germline Mutations in Familial and Sporadic Lung Cancer Yanhong Liu, PhD,a Farrah Kheradmand, MD,a Caleb F. Davis, PhD,a Michael E. Scheurer, PhD,a David Wheeler, PhD,a Spiridon Tsavachidis, MS,a Georgina Armstrong, MPH,a Claire Simpson, PhD,b Diptasri Mandal, PhD,c Elena Kupert, MS,d Marshall Anderson, PhD,e Ming You, MD, PhD,e Donghai Xiong, PhD,e Claudio Pikielny, PhD,f Ann G. Schwartz, PhD,g Joan Bailey-Wilson, PhD,h Colette Gaba, MPH,i Mariza De Andrade, PhD,j Ping Yang, MD, PhD,j Susan M. Pinney, PhD,d The Genetic Epidemiology of Lung Cancer Consortium, Christopher I. Amos, PhD,f Margaret R. Spitz, MDa,* aBaylor College of Medicine, Houston, TX, USA bNational Institutes of Health, Baltimore, MD, USA cLouisiana State University Health Sciences Center, New Orleans, LA, USA dUniversity of Cincinnati College of Medicine, Cincinnati, OH, USA eMedical College of Wisconsin, Milwaukee, WI, USA fDartmouth College, Lebanon, NH, USA gKarmanos Cancer Institute, Wayne State University, Detroit, MI, USA hHuman Genome Research Institute, Bethesda, MD, USA iThe University of Toledo College of Medicine, Toledo, OH, USA jMayo Clinic College of Medicine, Rochester, MN, USA Received 21 July 2015; revised 21 September 2015; accepted 25 September 2015 ABSTRACT dopamine b-hydroxylase (DBH) gene at 9q34.2 was identified in two sporadic cases; the minor allele frequency of this mutation Introduction: The association between smoking-induced is 0.0034 according to the 1000 Genomes database. We chronic obstructive pulmonary disease (COPD) and lung cancer also observed three suggestive rare mutations on 15q25.1: (LC) is well documented. -
Platform Abstracts
The 12th International Congress of Human Genetics and the American Society of Human Genetics 61st Annual Meeting October 11-15, 2011 Montreal, Canada PLATFORM ABSTRACTS Abstract/ Abstract/ Program Program Numbers Numbers Plenary Session Concurrent Platform Session C (51-60) Wednesday, October 12, 8:00 am – 10:00 am Friday, October 14, 4:15 pm – 6:15 pm SESSION 3 – Plenary Session on Epigenetics 1-2 SESSION 51 – Cancer Genetics II: Ovarian and Breast 163-170 These two abstracts were selected by the Scientific Program SESSION 52 – Genomics III: Genome Expression 171-178 Committee to be included in this invited plenary session with Douglas SESSION 53 – Molecular Basis III: Ciliopathies 179-186 Wallace and Emma Whitelaw. SESSION 54 – Statistical Genetics III: Analysis of 187-194 Sequence Data Concurrent Platform Sessions A (10-19) SESSION 55 – Epigenetics 195-202 Wednesday, October 12, 4:15 pm – 6:15 pm SESSION 56 – Complex Traits I: Approaches and Methods 203-210 SESSION 10 – Population Genetics 3-10 SESSION 57 – Cardiovascular Genetics II: Single Gene and 211-218 SESSION 11 – Genomics I: Structural Variation 11-18 Chromosomal Conditions SESSION 12 – Neurogenetics I: Autism 19-26 SESSION 58 – Neurogenetics III: Alzheimer, Parkinson and 219-226 SESSION 13 – Clinical Genetics I: Genotype-Phenotype 27-34 Neurodegenerative Diseases Correlation in Syndromes SESSION 59 – Clinical Genetics II: Neurodevelopmental 227-234 SESSION 14 – Chromosome Organization and Cancer 35-42 Disorders Cytogenetics SESSION 60 – Ethical, Legal, Social and Policy Issues -
The TERT-CLPTM1L Locus for Lung Cancer Predisposes to Bronchial Obstruction and Emphysema
ERJ Express. Published on May 26, 2011 as doi: 10.1183/09031936.00187110 The TERT-CLPTM1L locus for lung cancer predisposes to bronchial obstruction and emphysema 1,2,3* 1,2* 4 4 Els Wauters , Dominiek Smeets , Johan Coolen , Johny Verschakelen , Paul De Leyn5, Marc Decramer3, Johan Vansteenkiste3, Wim Janssens3, Diether Lambrechts1,2 1. Vesalius Research Center (VRC), VIB, 3000 Leuven, Belgium. 2. Vesalius Research Center (VRC), K.U.Leuven, 3000 Leuven, Belgium. 3. Respiratory Division, University Hospital Gasthuisberg, K.U.Leuven, Belgium. 4. Department of Radiology, University Hospital Gasthuisberg, K.U.Leuven, Belgium. 5. Department of Thoracic surgery, University Hospital Gasthuisberg, K.U.Leuven, Belgium. * These authors contributed equally to this work Corresponding author: Diether Lambrechts, MSc, PhD. Vesalius Research Center VIB, KULeuven Campus Gasthuisberg, Herestraat 49, box 912 B-3000, Leuven, Belgium Tel: +32-16-34.61.31; Fax: +32-16-34.59.90 E-mail: [email protected] Funding: E.W. is supported by the Vlaamse Liga tegen Kanker (VLK), W.J. by the Fund for Scientific Research Flanders (FWO). Keywords: chronic obstructive pulmonary disease, emphysema, lung cancer, susceptibility, telomerase reverse transcriptase gene Running title: The 5p15.33 locus in bronchial obstruction and emphysema Copyright 2011 by the European Respiratory Society. ABSTRACT Clinical studies suggest that bronchial obstruction and emphysema increase susceptibility to lung cancer. We assess the possibility of a common genetic origin and investigate whether the lung cancer susceptibility locus on chromosome 5p15.33 increases the risk for bronchial obstruction and emphysema. Three variants in the 5p15.33 locus encompassing the TERT and CLPTM1L genes were genotyped in 777 heavy smokers and 212 lung cancer patients.