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2019

JGM

Articles 1 - 30 of 33

Full-Text Articles in Life Sciences

Genomic Data Analysis Workflows For Tumors From Patient-Derived Xenografts (Pdxs): Challenges And Guidelines., Xing Yi Woo, Anuj Srivastava, Joel H Graber, Vinod Yadav, Vishal Kumar Sarsani, Allen K. Simons, Glen L Beane, Stephen C. Grubb, Guruprasad Ananda, Rangjiao Liu, Grace Stafford, Jeffrey Chuang, Susan Airhart, Radha Krishna Murthy Karuturi, Joshy George, Carol J Bult Jul 2019

Genomic Data Analysis Workflows For Tumors From Patient-Derived Xenografts (Pdxs): Challenges And Guidelines., Xing Yi Woo, Anuj Srivastava, Joel H Graber, Vinod Yadav, Vishal Kumar Sarsani, Allen K. Simons, Glen L Beane, Stephen C. Grubb, Guruprasad Ananda, Rangjiao Liu, Grace Stafford, Jeffrey Chuang, Susan Airhart, Radha Krishna Murthy Karuturi, Joshy George, Carol J Bult

Faculty Research 2019

BACKGROUND: Patient-derived xenograft (PDX) models are in vivo models of human cancer that have been used for translational cancer research and therapy selection for individual patients. The Jackson Laboratory (JAX) PDX resource comprises 455 models originating from 34 different primary sites (as of 05/08/2019). The models undergo rigorous quality control and are genomically characterized to identify somatic mutations, copy number alterations, and transcriptional profiles. Bioinformatics workflows for analyzing genomic data obtained from human tumors engrafted in a mouse host (i.e., Patient-Derived Xenografts; PDXs) must address challenges such as discriminating between mouse and human sequence reads and accurately ...


Transcriptional Profiling Unveils Type I And Ii Interferon Networks In Blood And Tissues Across Diseases., Akul Singhania, Christine M Graham, Leona Gabryšová, Lúcia Moreira-Teixeira, Evangelos Stavropoulos, Jonathan M Pitt, Probir Chakravarty, Annika Warnatsch, William J Branchett, Laura Conejero, Jing-Wen Lin, Sophia Davidson, Mark S Wilson, Gregory Bancroft, Jean Langhorne, Eva Frickel, Abdul K Sesay, Simon L Priestnall, Eleanor Herbert, Marianna Ioannou, Qian Wang, Ian R Humphreys, Jonathan Dodd, Peter J M Openshaw, Katrin D Mayer-Barber, Dragana Jankovic, Alan Sher, Clare M Lloyd, Nicole Baldwin, Damien Chaussabel, Venizelos Papayannopoulos, Andreas Wack, Jacques Banchereau, Virginia M Pascual, Anne O'Garra Jun 2019

Transcriptional Profiling Unveils Type I And Ii Interferon Networks In Blood And Tissues Across Diseases., Akul Singhania, Christine M Graham, Leona Gabryšová, Lúcia Moreira-Teixeira, Evangelos Stavropoulos, Jonathan M Pitt, Probir Chakravarty, Annika Warnatsch, William J Branchett, Laura Conejero, Jing-Wen Lin, Sophia Davidson, Mark S Wilson, Gregory Bancroft, Jean Langhorne, Eva Frickel, Abdul K Sesay, Simon L Priestnall, Eleanor Herbert, Marianna Ioannou, Qian Wang, Ian R Humphreys, Jonathan Dodd, Peter J M Openshaw, Katrin D Mayer-Barber, Dragana Jankovic, Alan Sher, Clare M Lloyd, Nicole Baldwin, Damien Chaussabel, Venizelos Papayannopoulos, Andreas Wack, Jacques Banchereau, Virginia M Pascual, Anne O'Garra

Faculty Research 2019

Understanding how immune challenges elicit different responses is critical for diagnosing and deciphering immune regulation. Using a modular strategy to interpret the complex transcriptional host response in mouse models of infection and inflammation, we show a breadth of immune responses in the lung. Lung immune signatures are dominated by either IFN-γ and IFN-inducible, IL-17-induced neutrophil- or allergy-associated gene expression. Type I IFN and IFN-γ-inducible, but not IL-17- or allergy-associated signatures, are preserved in the blood. While IL-17-associated genes identified in lung are detected in blood, the allergy signature is only detectable in blood CD4+ effector cells. Type I IFN-inducible genes ...


Integrated Analysis Of Clinical And Microbiome Risk Factors Associated With The Development Of Oral Candidiasis During Cancer Chemotherapy., Patricia I Diaz, Bo-Young Hong, Amanda K Dupuy, Linda Choquette, Angela Thompson, Andrew L Salner, Peter K Schauer, Upendra Hegde, Joseph A Burleson, Linda D Strausbaugh, Douglas E Peterson, Anna Dongari-Bagtzoglou Jun 2019

Integrated Analysis Of Clinical And Microbiome Risk Factors Associated With The Development Of Oral Candidiasis During Cancer Chemotherapy., Patricia I Diaz, Bo-Young Hong, Amanda K Dupuy, Linda Choquette, Angela Thompson, Andrew L Salner, Peter K Schauer, Upendra Hegde, Joseph A Burleson, Linda D Strausbaugh, Douglas E Peterson, Anna Dongari-Bagtzoglou

Faculty Research 2019

Oral candidiasis is a common side effect of cancer chemotherapy. To better understand predisposing factors, we followed forty-five subjects who received 5-fluorouracil- or doxorubicin-based treatment, during one chemotherapy cycle. Subjects were evaluated at baseline, prior to the first infusion, and at three additional visits within a two-week window. We assessed the demographic, medical and oral health parameters, neutrophil surveillance, and characterized the salivary bacteriome and mycobiome communities through amplicon high throughput sequencing. Twenty percent of all subjects developed oral candidiasis. Using multivariate statistics, we identified smoking, amount of dental plaque, low bacteriome and mycobiome alpha-diversity, and the proportions of specific ...


Fostering Bioinformatics Education Through Skill Development Of Professors: Big Genomic Data Skills Training For Professors., Yingqian Ada Zhan, Charles Gregory Wray, Sandeep Namburi, Spencer T Glantz, Reinhard Laubenbacher, Jeffrey H Chuang Jun 2019

Fostering Bioinformatics Education Through Skill Development Of Professors: Big Genomic Data Skills Training For Professors., Yingqian Ada Zhan, Charles Gregory Wray, Sandeep Namburi, Spencer T Glantz, Reinhard Laubenbacher, Jeffrey H Chuang

Faculty Research 2019

Bioinformatics has become an indispensable part of life science over the past 2 decades. However, bioinformatics education is not well integrated at the undergraduate level, especially in liberal arts colleges and regional universities in the United States. One significant obstacle pointed out by the Network for Integrating Bioinformatics into Life Sciences Education is the lack of faculty in the bioinformatics area. Most current life science professors did not acquire bioinformatics analysis skills during their own training. Consequently, a great number of undergraduate and graduate students do not get the chance to learn bioinformatics or computational biology skills within a structured ...


A Computational Method To Aid The Design And Analysis Of Single Cell Rna-Seq Experiments For Cell Type Identification., Douglas Abrams, Parveen Kumar, Radha Krishna Murthy Karuturi, Joshy George Jun 2019

A Computational Method To Aid The Design And Analysis Of Single Cell Rna-Seq Experiments For Cell Type Identification., Douglas Abrams, Parveen Kumar, Radha Krishna Murthy Karuturi, Joshy George

Faculty Research 2019

BACKGROUND: The advent of single cell RNA sequencing (scRNA-seq) enabled researchers to study transcriptomic activity within individual cells and identify inherent cell types in the sample. Although numerous computational tools have been developed to analyze single cell transcriptomes, there are no published studies and analytical packages available to guide experimental design and to devise suitable analysis procedure for cell type identification.

RESULTS: We have developed an empirical methodology to address this important gap in single cell experimental design and analysis into an easy-to-use tool called SCEED (Single Cell Empirical Experimental Design and analysis). With SCEED, user can choose a variety ...


The Genome Of C57bl/6j "Eve", The Mother Of The Laboratory Mouse Genome Reference Strain., Vishal Kumar Sarsani, Narayanan Raghupathy, Ian T Fiddes, Joel Armstrong, Francoise Thibaud-Nissen, Oraya Zinder, Mohan Bolisetty, Kerstin Howe, Doug Hinerfeld, Xiaoan Ruan, Lucy B. Rowe, Mary Barter, Guruprasad Ananda, Benedict Paten, George M. Weinstock, Gary Churchill, Michael V. Wiles, Valerie A Schneider, Anuj Srivastava, Laura G Reinholdt Jun 2019

The Genome Of C57bl/6j "Eve", The Mother Of The Laboratory Mouse Genome Reference Strain., Vishal Kumar Sarsani, Narayanan Raghupathy, Ian T Fiddes, Joel Armstrong, Francoise Thibaud-Nissen, Oraya Zinder, Mohan Bolisetty, Kerstin Howe, Doug Hinerfeld, Xiaoan Ruan, Lucy B. Rowe, Mary Barter, Guruprasad Ananda, Benedict Paten, George M. Weinstock, Gary Churchill, Michael V. Wiles, Valerie A Schneider, Anuj Srivastava, Laura G Reinholdt

Faculty Research 2019

Isogenic laboratory mouse strains enhance reproducibility because individual animals are genetically identical. For the most widely used isogenic strain, C57BL/6, there exists a wealth of genetic, phenotypic, and genomic data, including a high-quality reference genome (GRCm38.p6). Now 20 years after the first release of the mouse reference genome, C57BL/6J mice are at least 26 inbreeding generations removed from GRCm38 and the strain is now maintained with periodic reintroduction of cryorecovered mice derived from a single breeder pair, aptly named Adam and Eve. To provide an update to the mouse reference genome that more accurately represents the genome ...


One Reference Genome Is Not Enough., Xiaofei Yang, Wan-Ping Lee, Kai Ye, Charles Lee May 2019

One Reference Genome Is Not Enough., Xiaofei Yang, Wan-Ping Lee, Kai Ye, Charles Lee

Faculty Research 2019

A recent study on human structural variation indicates insufficiencies and errors in the human reference genome, GRCh38, and argues for the construction of a human pan-genome.


Composition And Predictive Functional Analysis Of Bacterial Communities Inhabiting Chinese Cordyceps Insight Into Conserved Core Microbiome., Fei Xia, Xin Zhou, Yan Liu, Yuling Li, Xiaohui Bai, Xuanwei Zhou May 2019

Composition And Predictive Functional Analysis Of Bacterial Communities Inhabiting Chinese Cordyceps Insight Into Conserved Core Microbiome., Fei Xia, Xin Zhou, Yan Liu, Yuling Li, Xiaohui Bai, Xuanwei Zhou

Faculty Research 2019

BACKGROUND: Over the past few decades, most attention to Chinese Cordyceps-associated endogenous microorganism was focused on the fungal community that creates critical bioactive components. Bacterial community associated with Chinese Cordyceps has been previously described; however, most studies were only presenting direct comparisons in the Chinese Cordyceps and its microenvironments. In the current study, our objectives were to reveal the bacterial community structure composition and predict their function.

RESULTS: We collected samples of Chinese Cordyceps from five sites located in the Qinghai-Tibet Plateau and used a high throughput sequencing method to compare Chinese Cordyceps-associated bacterial community composition and diversity quantitatively across ...


Toward A Comprehensive View Of Cancer Immune Responsiveness: A Synopsis From The Sitc Workshop., Davide Bedognetti, Michele Ceccarelli, Lorenzo Galluzzi, Rongze Lu, Karolina Palucka, Josue Samayoa, Stefani Spranger, Sarah Warren, Kwok-Kin Wong, Elad Ziv, Diego Chowell, Lisa M Coussens, Daniel D De Carvalho, David G Denardo, Jérôme Galon, Howard L Kaufman, Tomas Kirchhoff, Michael T Lotze, Jason J Luke, Andy J Minn, Katerina Politi, Leonard D. Shultz, Richard Simon, Vésteinn Thórsson, Joanne B Weidhaas, Maria Libera Ascierto, Paolo Antonio Ascierto, James M Barnes, Valentin Barsan, Praveen K Bommareddy, Adrian Bot, Sarah E Church, Gennaro Ciliberto, Andrea De Maria, Dobrin Draganov, Winson S Ho, Heather M Mcgee, Anne Monette, Joseph F Murphy, Paola Nisticò, Wungki Park, Maulik Patel, Michael Quigley, Laszlo Radvanyi, Harry Raftopoulos, Nils-Petter Rudqvist, Alexandra Snyder, Randy F Sweis, Sara Valpione, Lisa H Butterfield, Mary L Disis, Bernard A Fox, Alessandra Cesano, Francesco M Marincola May 2019

Toward A Comprehensive View Of Cancer Immune Responsiveness: A Synopsis From The Sitc Workshop., Davide Bedognetti, Michele Ceccarelli, Lorenzo Galluzzi, Rongze Lu, Karolina Palucka, Josue Samayoa, Stefani Spranger, Sarah Warren, Kwok-Kin Wong, Elad Ziv, Diego Chowell, Lisa M Coussens, Daniel D De Carvalho, David G Denardo, Jérôme Galon, Howard L Kaufman, Tomas Kirchhoff, Michael T Lotze, Jason J Luke, Andy J Minn, Katerina Politi, Leonard D. Shultz, Richard Simon, Vésteinn Thórsson, Joanne B Weidhaas, Maria Libera Ascierto, Paolo Antonio Ascierto, James M Barnes, Valentin Barsan, Praveen K Bommareddy, Adrian Bot, Sarah E Church, Gennaro Ciliberto, Andrea De Maria, Dobrin Draganov, Winson S Ho, Heather M Mcgee, Anne Monette, Joseph F Murphy, Paola Nisticò, Wungki Park, Maulik Patel, Michael Quigley, Laszlo Radvanyi, Harry Raftopoulos, Nils-Petter Rudqvist, Alexandra Snyder, Randy F Sweis, Sara Valpione, Lisa H Butterfield, Mary L Disis, Bernard A Fox, Alessandra Cesano, Francesco M Marincola

Faculty Research 2019

Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes ...


A Mobile Prenatal Care App To Reduce In-Person Visits: Prospective Controlled Trial., Kathryn I Marko, Nihar Ganju, Jill M Krapf, Nancy D Gaba, James A Brown, Joshua J Benham, Julia Oh, Lorna M Richards, Andrew C Meltzer May 2019

A Mobile Prenatal Care App To Reduce In-Person Visits: Prospective Controlled Trial., Kathryn I Marko, Nihar Ganju, Jill M Krapf, Nancy D Gaba, James A Brown, Joshua J Benham, Julia Oh, Lorna M Richards, Andrew C Meltzer

Faculty Research 2019

BACKGROUND: Risk-appropriate prenatal care has been asserted as a way for the cost-effective delivery of prenatal care. A virtual care model for prenatal care has the potential to provide patient-tailored, risk-appropriate prenatal educational content and may facilitate vital sign and weight monitoring between visits. Previous studies have demonstrated a safe reduction in the frequency of in-person prenatal care visits among low-risk patients but have noted a reduction in patient satisfaction.

OBJECTIVE: The primary objective of this study was to test the effectiveness of a mobile prenatal care app to facilitate a reduced in-person visit schedule for low-risk pregnancies while maintaining ...


Cellular Senescence In Progenitor Cells Contributes To Diminished Remyelination Potential In Progressive Multiple Sclerosis., Alexandra M Nicaise, Laura J Wagstaff, Cory M Willis, Carolyn Paisie, Harshpreet Chandok, Paul Robson, Valentina Fossati, Anna Williams, Stephen J Crocker Apr 2019

Cellular Senescence In Progenitor Cells Contributes To Diminished Remyelination Potential In Progressive Multiple Sclerosis., Alexandra M Nicaise, Laura J Wagstaff, Cory M Willis, Carolyn Paisie, Harshpreet Chandok, Paul Robson, Valentina Fossati, Anna Williams, Stephen J Crocker

Faculty Research 2019

Cellular senescence is a form of adaptive cellular physiology associated with aging. Cellular senescence causes a proinflammatory cellular phenotype that impairs tissue regeneration, has been linked to stress, and is implicated in several human neurodegenerative diseases. We had previously determined that neural progenitor cells (NPCs) derived from induced pluripotent stem cell (iPSC) lines from patients with primary progressive multiple sclerosis (PPMS) failed to promote oligodendrocyte progenitor cell (OPC) maturation, whereas NPCs from age-matched control cell lines did so efficiently. Herein, we report that expression of hallmarks of cellular senescence were identified in SOX2+ progenitor cells within white matter lesions of ...


Chemotherapy-Induced Oral Mucositis Is Associated With Detrimental Bacterial Dysbiosis., Bo-Young Hong, Takanori Sobue, Linda Choquette, Amanda K Dupuy, Angela Thompson, Joseph A Burleson, Andrew L Salner, Peter K Schauer, Pujan Joshi, Evan Fox, Dong-Guk Shin, George M. Weinstock, Linda D Strausbaugh, Anna Dongari-Bagtzoglou, Douglas E Peterson, Patricia I Diaz Apr 2019

Chemotherapy-Induced Oral Mucositis Is Associated With Detrimental Bacterial Dysbiosis., Bo-Young Hong, Takanori Sobue, Linda Choquette, Amanda K Dupuy, Angela Thompson, Joseph A Burleson, Andrew L Salner, Peter K Schauer, Pujan Joshi, Evan Fox, Dong-Guk Shin, George M. Weinstock, Linda D Strausbaugh, Anna Dongari-Bagtzoglou, Douglas E Peterson, Patricia I Diaz

Faculty Research 2019

BACKGROUND: Gastrointestinal mucosal injury (mucositis), commonly affecting the oral cavity, is a clinically significant yet incompletely understood complication of cancer chemotherapy. Although antineoplastic cytotoxicity constitutes the primary injury trigger, the interaction of oral microbial commensals with mucosal tissues could modify the response. It is not clear, however, whether chemotherapy and its associated treatments affect oral microbial communities disrupting the homeostatic balance between resident microorganisms and the adjacent mucosa and if such alterations are associated with mucositis. To gain knowledge on the pathophysiology of oral mucositis, 49 subjects receiving 5-fluorouracil (5-FU) or doxorubicin-based chemotherapy were evaluated longitudinally during one cycle, assessing ...


Multi-Platform Discovery Of Haplotype-Resolved Structural Variation In Human Genomes., Mark J P Chaisson, Ashley D Sanders, Xuefang Zhao, Ankit Malhotra, David Porubsky, Tobias Rausch, Eugene J Gardner, Oscar L Rodriguez, Li Guo, Ryan L Collins, Xian Fan, Jia Wen, Robert E Handsaker, Susan Fairley, Zev N Kronenberg, Xiangmeng Kong, Fereydoun Hormozdiari, Dillon Lee, Aaron M Wenger, Alex R Hastie, Danny Antaki, Thomas Anantharaman, Peter A Audano, Harrison Brand, Stuart Cantsilieris, Han Cao, Eliza Cerveira, Chong Chen, Xintong Chen, Chen-Shan Chin, Zechen Chong, Nelson T Chuang, Christine C Lambert, Deanna M Church, Laura Clarke, Andrew Farrell, Joey Flores, Timur Galeev, David U Gorkin, Madhusudan Gujral, Victor Guryev, William Haynes Heaton, Jonas Korlach, Sushant Kumar, Jee Young Kwon, Ernest T Lam, Jong Eun Lee, Joyce Lee, Wan-Ping Lee, Sau Peng Lee, Shantao Li, Patrick Marks, Karine Viaud-Martinez, Sascha Meiers, Katherine M Munson, Fabio C P Navarro, Bradley J Nelson, Conor Nodzak, Amina Noor, Sofia Kyriazopoulou-Panagiotopoulou, Andy W C Pang, Yunjiang Qiu, Gabriel Rosanio, Mallory Ryan, Adrian Stütz, Diana C J Spierings, Alistair Ward, Annemarie E Welch, Ming Xiao, Wei Xu, Chengsheng Zhang, Qihui Zhu, Xiangqun Zheng-Bradley, Ernesto Lowy, Sergei Yakneen, Steven Mccarroll, Goo Jun, Li Ding, Chong Lek Koh, Bing Ren, Paul Flicek, Ken Chen, Mark B Gerstein, Pui-Yan Kwok, Peter M Lansdorp, Gabor T Marth, Jonathan Sebat, Xinghua Shi, Ali Bashir, Kai Ye, Scott E Devine, Michael E Talkowski, Ryan E Mills, Tobias Marschall, Jan O Korbel, Evan E Eichler, Charles Lee Apr 2019

Multi-Platform Discovery Of Haplotype-Resolved Structural Variation In Human Genomes., Mark J P Chaisson, Ashley D Sanders, Xuefang Zhao, Ankit Malhotra, David Porubsky, Tobias Rausch, Eugene J Gardner, Oscar L Rodriguez, Li Guo, Ryan L Collins, Xian Fan, Jia Wen, Robert E Handsaker, Susan Fairley, Zev N Kronenberg, Xiangmeng Kong, Fereydoun Hormozdiari, Dillon Lee, Aaron M Wenger, Alex R Hastie, Danny Antaki, Thomas Anantharaman, Peter A Audano, Harrison Brand, Stuart Cantsilieris, Han Cao, Eliza Cerveira, Chong Chen, Xintong Chen, Chen-Shan Chin, Zechen Chong, Nelson T Chuang, Christine C Lambert, Deanna M Church, Laura Clarke, Andrew Farrell, Joey Flores, Timur Galeev, David U Gorkin, Madhusudan Gujral, Victor Guryev, William Haynes Heaton, Jonas Korlach, Sushant Kumar, Jee Young Kwon, Ernest T Lam, Jong Eun Lee, Joyce Lee, Wan-Ping Lee, Sau Peng Lee, Shantao Li, Patrick Marks, Karine Viaud-Martinez, Sascha Meiers, Katherine M Munson, Fabio C P Navarro, Bradley J Nelson, Conor Nodzak, Amina Noor, Sofia Kyriazopoulou-Panagiotopoulou, Andy W C Pang, Yunjiang Qiu, Gabriel Rosanio, Mallory Ryan, Adrian Stütz, Diana C J Spierings, Alistair Ward, Annemarie E Welch, Ming Xiao, Wei Xu, Chengsheng Zhang, Qihui Zhu, Xiangqun Zheng-Bradley, Ernesto Lowy, Sergei Yakneen, Steven Mccarroll, Goo Jun, Li Ding, Chong Lek Koh, Bing Ren, Paul Flicek, Ken Chen, Mark B Gerstein, Pui-Yan Kwok, Peter M Lansdorp, Gabor T Marth, Jonathan Sebat, Xinghua Shi, Ali Bashir, Kai Ye, Scott E Devine, Michael E Talkowski, Ryan E Mills, Tobias Marschall, Jan O Korbel, Evan E Eichler, Charles Lee

Faculty Research 2019

The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (<50 >bp) and 27,622 SVs (≥50 bp) per genome. We also discover 156 inversions per genome and 58 of the inversions intersect with the critical regions of recurrent microdeletion and microduplication syndromes. Taken together, our SV callsets represent a ...


Mir-181a/B Downregulation Exerts A Protective Action On Mitochondrial Disease Models., Alessia Indrieri, Sabrina Carrella, Alessia Romano, Alessandra Spaziano, Elena Marrocco, Erika Fernandez-Vizarra, Sara Barbato, Mariateresa Pizzo, Yulia Ezhova, Francesca M Golia, Ludovica Ciampi, Roberta Tammaro, Jorge Henao-Mejia, Adam Williams, Richard A Flavell, Elvira De Leonibus, Massimo Zeviani, Enrico M Surace, Sandro Banfi, Brunella Franco Apr 2019

Mir-181a/B Downregulation Exerts A Protective Action On Mitochondrial Disease Models., Alessia Indrieri, Sabrina Carrella, Alessia Romano, Alessandra Spaziano, Elena Marrocco, Erika Fernandez-Vizarra, Sara Barbato, Mariateresa Pizzo, Yulia Ezhova, Francesca M Golia, Ludovica Ciampi, Roberta Tammaro, Jorge Henao-Mejia, Adam Williams, Richard A Flavell, Elvira De Leonibus, Massimo Zeviani, Enrico M Surace, Sandro Banfi, Brunella Franco

Faculty Research 2019

Mitochondrial diseases (MDs) are a heterogeneous group of devastating and often fatal disorders due to defective oxidative phosphorylation. Despite the recent advances in mitochondrial medicine, effective therapies are still not available for these conditions. Here, we demonstrate that the microRNAs miR-181a and miR-181b (miR-181a/b) regulate key genes involved in mitochondrial biogenesis and function and that downregulation of these miRNAs enhances mitochondrial turnover in the retina through the coordinated activation of mitochondrial biogenesis and mitophagy. We thus tested the effect of miR-181a/b inactivation in different animal models of MDs, such as microphthalmia with linear skin lesions and Leber's ...


The Roles Of Cholesterol And Its Metabolites In Normal And Malignant Hematopoiesis., Hideyuki Oguro Apr 2019

The Roles Of Cholesterol And Its Metabolites In Normal And Malignant Hematopoiesis., Hideyuki Oguro

Faculty Research 2019

Hematopoiesis is sustained throughout life by hematopoietic stem cells (HSCs) that are capable of self-renewal and differentiation into hematopoietic progenitor cells (HPCs). There is accumulating evidence that cholesterol homeostasis is an important factor in the regulation of hematopoiesis. Increased cholesterol levels are known to promote proliferation and mobilization of HSCs, while hypercholesterolemia is associated with expansion of myeloid cells in the peripheral blood and links hematopoiesis with cardiovascular disease. Cholesterol is a precursor to steroid hormones, oxysterols, and bile acids. Among steroid hormones, 17β-estradiol (E2) induces HSC division and E2-estrogen receptor α (ERα) signaling causes sexual dimorphism of HSC division ...


Single-Molecule Real-Time (Smrt) Full-Length Rna-Sequencing Reveals Novel And Distinct Mrna Isoforms In Human Bone Marrow Cell Subpopulations., Anne Deslattesmays, Marcel Schmidt, Garrett Graham, Elizabeth Tseng, Primo Baybayan, Robert Sebra, Miloslav Sanda, Jean-Baptiste Mazarati, Anna Riegel, Anton Wellstein Mar 2019

Single-Molecule Real-Time (Smrt) Full-Length Rna-Sequencing Reveals Novel And Distinct Mrna Isoforms In Human Bone Marrow Cell Subpopulations., Anne Deslattesmays, Marcel Schmidt, Garrett Graham, Elizabeth Tseng, Primo Baybayan, Robert Sebra, Miloslav Sanda, Jean-Baptiste Mazarati, Anna Riegel, Anton Wellstein

Faculty Research 2019

Hematopoietic cells are continuously replenished from progenitor cells that reside in the bone marrow. To evaluate molecular changes during this process, we analyzed the transcriptomes of freshly harvested human bone marrow progenitor (lineage-negative) and differentiated (lineage-positive) cells by single-molecule real-time (SMRT) full-length RNA-sequencing. This analysis revealed a ~5-fold higher number of transcript isoforms than previously detected and showed a distinct composition of individual transcript isoforms characteristic for bone marrow subpopulations. A detailed analysis of messenger RNA (mRNA) isoforms transcribed from the ANXA1 and EEF1A1 loci confirmed their distinct composition. The expression of proteins predicted from the transcriptome analysis was evaluated ...


Complex Microbiome In Brain Abscess Revealed By Whole-Genome Culture-Independent And Culture-Based Sequencing., Jyun-Hong Lin, Zong-Yen Wu, Liang Gong, Chee-Hong Wong, Wen-Cheng Chao, Chun-Ming Yen, Ching-Ping Wang, Chia-Lin Wei, Yao-Ting Huang, Po-Yu Liu Mar 2019

Complex Microbiome In Brain Abscess Revealed By Whole-Genome Culture-Independent And Culture-Based Sequencing., Jyun-Hong Lin, Zong-Yen Wu, Liang Gong, Chee-Hong Wong, Wen-Cheng Chao, Chun-Ming Yen, Ching-Ping Wang, Chia-Lin Wei, Yao-Ting Huang, Po-Yu Liu

Faculty Research 2019

Brain abscess is a severe infectious disease with high mortality and mobility. Although culture-based techniques have been widely used for the investigation of microbial composition of brain abscess, these approaches are inherent biased. Recent studies using 16S ribosomal sequencing approaches revealed high complexity of the bacterial community involved in brain abscess but fail to detect fungal and viral composition. In the study, both culture-independent nanopore metagenomic sequencing and culture-based whole-genome sequencing using both the Illumina and the Nanopore platforms were conducted to investigate the microbial composition and genomic characterization in brain abscess. Culture-independent metagenomic sequencing revealed not only a larger ...


Mutations In Dna Repair Genes Are Associated With Increased Neoantigen Burden And A Distinct Immunophenotype In Lung Squamous Cell Carcinoma., Young Kwang Chae, Jonathan F Anker, Michael S Oh, Preeti Bais, Sandeep Namburi, Sarita Agte, Francis J Giles, Jeffrey H Chuang Mar 2019

Mutations In Dna Repair Genes Are Associated With Increased Neoantigen Burden And A Distinct Immunophenotype In Lung Squamous Cell Carcinoma., Young Kwang Chae, Jonathan F Anker, Michael S Oh, Preeti Bais, Sandeep Namburi, Sarita Agte, Francis J Giles, Jeffrey H Chuang

Faculty Research 2019

Deficiencies in DNA repair pathways, including mismatch repair (MMR), have been linked to higher tumor mutation burden and improved response to immune checkpoint inhibitors. However, the significance of MMR mutations in lung cancer has not been well characterized, and the relevance of other processes, including homologous recombination (HR) and polymerase epsilon (POLE) activity, remains unclear. Here, we analyzed a dataset of lung squamous cell carcinoma samples from The Cancer Genome Atlas. Variants in DNA repair genes were associated with increased tumor mutation and neoantigen burden, which in turn were linked with greater tumor infiltration by activated T cells. The subset ...


Evaluation Of Inseq To Identify Genes Essential For, Ramamoorthy Sivakumar, Jothi Ranjani, Udayakumar S Vishnu, Sathyanarayanan Jayashree, Gabriel L Lozano, Jessica Miles, Nichole A Broderick, Changhui Guan, Paramasamy Gunasekaran, Jo Handelsman, Jeyaprakash Rajendhran Mar 2019

Evaluation Of Inseq To Identify Genes Essential For, Ramamoorthy Sivakumar, Jothi Ranjani, Udayakumar S Vishnu, Sathyanarayanan Jayashree, Gabriel L Lozano, Jessica Miles, Nichole A Broderick, Changhui Guan, Paramasamy Gunasekaran, Jo Handelsman, Jeyaprakash Rajendhran

Faculty Research 2019

The reciprocal interaction between rhizosphere bacteria and their plant hosts results in a complex battery of genetic and physiological responses. In this study, we used insertion sequencing (INSeq) to reveal the genetic determinants responsible for the fitness of Pseudomonas aeruginosa PGPR2 during root colonization. We generated a random transposon mutant library of Pseudomonas aeruginosa PGPR2 comprising 39,500 unique insertions and identified genes required for growth in culture and on corn roots. A total of 108 genes were identified as contributing to the fitness of strain PGPR2 on roots. The importance in root colonization of four genes identified in the ...


Association Of The Infant Gut Microbiome With Early Childhood Neurodevelopmental Outcomes: An Ancillary Study To The Vdaart Randomized Clinical Trial., Joanne E Sordillo, Susan Korrick, Nancy Laranjo, Vincent Carey, George M. Weinstock, Diane R Gold, George O'Connor, Megan Sandel, Leonard B Bacharier, Avraham Beigelman, Robert Zeiger, Augusto A Litonjua, Scott T Weiss Mar 2019

Association Of The Infant Gut Microbiome With Early Childhood Neurodevelopmental Outcomes: An Ancillary Study To The Vdaart Randomized Clinical Trial., Joanne E Sordillo, Susan Korrick, Nancy Laranjo, Vincent Carey, George M. Weinstock, Diane R Gold, George O'Connor, Megan Sandel, Leonard B Bacharier, Avraham Beigelman, Robert Zeiger, Augusto A Litonjua, Scott T Weiss

Faculty Research 2019

Importance: In animal models, the early life gut microbiome influences later neurodevelopment. Corresponding data in human populations are lacking.

Objective: To study associations between the gut microbiome in infants and development at preschool age measured by the Ages and Stages Questionnaire, third edition (ASQ-3).

Design, Setting, and Participants: This ancillary cohort study of the Vitamin D Antenatal Asthma Reduction Trial (VDAART) used data from 715 participants who had development assessed at 3 years of age by the ASQ-3, which included scores in 5 domains (gross motor skills, fine motor skills, problem solving, communication, and personal and social skills). A total ...


Evolutionary Dynamics Of Residual Disease In Human Glioblastoma., I Spiteri, G Caravagna, G D Cresswell, A Vatsiou, D Nichol, A Acar, L Ermini, K Chkhaidze, B Werner, R Mair, E Brognaro, Roel G W Verhaak, G Sanguinetti, S G M Piccirillo, C Watts, A Sottoriva Mar 2019

Evolutionary Dynamics Of Residual Disease In Human Glioblastoma., I Spiteri, G Caravagna, G D Cresswell, A Vatsiou, D Nichol, A Acar, L Ermini, K Chkhaidze, B Werner, R Mair, E Brognaro, Roel G W Verhaak, G Sanguinetti, S G M Piccirillo, C Watts, A Sottoriva

Faculty Research 2019

BACKGROUND: Glioblastoma is the most common and aggressive adult brain malignancy against which conventional surgery and chemoradiation provide limited benefit. Even when a good treatment response is obtained, recurrence inevitably occurs either locally (∼80%) or distally (∼20%), driven by cancer clones that are often genomically distinct from those in the primary tumour. Glioblastoma cells display a characteristic infiltrative phenotype, invading the surrounding tissue and often spreading across the whole brain. Cancer cells responsible for relapse can reside in two compartments of residual disease that are left behind after treatment: the infiltrated normal brain parenchyma and the sub-ventricular zone. However, these ...


Symbiotic Organs Shaped By Distinct Modes Of Genome Evolution In Cephalopods., Mahdi Belcaid, Giorgio Casaburi, Sarah J Mcanulty, Hannah Schmidbaur, Andrea M Suria, Silvia Moriano-Gutierrez, M Sabrina Pankey, Todd H Oakley, Natacha Kremer, Eric J Koch, Andrew J Collins, Hoan Nguyen, Sai H Lek, Irina Goncharenko-Foster, Patrick Minx, Erica Sodergren Weinstock, George M. Weinstock, Daniel S Rokhsar, Margaret Mcfall-Ngai, Oleg Simakov, Jamie S Foster, Spencer V Nyholm Feb 2019

Symbiotic Organs Shaped By Distinct Modes Of Genome Evolution In Cephalopods., Mahdi Belcaid, Giorgio Casaburi, Sarah J Mcanulty, Hannah Schmidbaur, Andrea M Suria, Silvia Moriano-Gutierrez, M Sabrina Pankey, Todd H Oakley, Natacha Kremer, Eric J Koch, Andrew J Collins, Hoan Nguyen, Sai H Lek, Irina Goncharenko-Foster, Patrick Minx, Erica Sodergren Weinstock, George M. Weinstock, Daniel S Rokhsar, Margaret Mcfall-Ngai, Oleg Simakov, Jamie S Foster, Spencer V Nyholm

Faculty Research 2019

Microbes have been critical drivers of evolutionary innovation in animals. To understand the processes that influence the origin of specialized symbiotic organs, we report the sequencing and analysis of the genome of Euprymna scolopes, a model cephalopod with richly characterized host-microbe interactions. We identified large-scale genomic reorganization shared between E. scolopes and Octopus bimaculoides and posit that this reorganization has contributed to the evolution of cephalopod complexity. To reveal genomic signatures of host-symbiont interactions, we focused on two specialized organs of E. scolopes: the light organ, which harbors a monoculture of Vibrio fischeri, and the accessory nidamental gland (ANG), a ...


The Global State Of The Genetic Counseling Profession., Maryann Abacan, Lamia Alsubaie, Kristine Barlow-Stewart, Beppy Caanen, Christophe Cordier, Eliza Courtney, Emeline Davoine, Janice Edwards, Niby J Elackatt, Kate Gardiner, Yue Guan, Lian-Hua Huang, Charlotta Ingvoldstad Malmgren, Sahil Kejriwal, Hyon J Kim, Deborah Lambert, Paulina Araceli Lantigua-Cruz, Juliana M H Lee, Marianne Lodahl, Åshild Lunde, Shelley Macaulay, Ivan Macciocca, Sonia Margarit, Anna Middleton, Ramona Moldovan, Joanne Ngeow, Alexandra J Obregon-Tito, Kelly E Ormond, Milena Paneque, Karen Powell, Kunal Sanghavi, Diana Scotcher, Jenna Scott, Clara Serra Juhé, Shiri Shkedi-Rafid, Tina-Marié Wessels, Sook-Yee Yoon, Catherine Wicklund Feb 2019

The Global State Of The Genetic Counseling Profession., Maryann Abacan, Lamia Alsubaie, Kristine Barlow-Stewart, Beppy Caanen, Christophe Cordier, Eliza Courtney, Emeline Davoine, Janice Edwards, Niby J Elackatt, Kate Gardiner, Yue Guan, Lian-Hua Huang, Charlotta Ingvoldstad Malmgren, Sahil Kejriwal, Hyon J Kim, Deborah Lambert, Paulina Araceli Lantigua-Cruz, Juliana M H Lee, Marianne Lodahl, Åshild Lunde, Shelley Macaulay, Ivan Macciocca, Sonia Margarit, Anna Middleton, Ramona Moldovan, Joanne Ngeow, Alexandra J Obregon-Tito, Kelly E Ormond, Milena Paneque, Karen Powell, Kunal Sanghavi, Diana Scotcher, Jenna Scott, Clara Serra Juhé, Shiri Shkedi-Rafid, Tina-Marié Wessels, Sook-Yee Yoon, Catherine Wicklund

Faculty Research 2019

The profession of genetic counseling (also called genetic counselling in many countries) began nearly 50 years ago in the United States, and has grown internationally in the past 30 years. While there have been many papers describing the profession of genetic counseling in individual countries or regions, data remains incomplete and has been published in diverse journals with limited access. As a result of the 2016 Transnational Alliance of Genetic Counseling (TAGC) conference in Barcelona, Spain, and the 2017 World Congress of Genetic Counselling in the UK, we endeavor to describe as fully as possible the global state of genetic ...


Metformin Intervention Prevents Cardiac Dysfunction In A Murine Model Of Adult Congenital Heart Disease., Julia C Wilmanns, Raghav Pandey, Olivia Hon, Anjana Chandran, Jan M Schilling, Elvira Forte, Qizhu Wu, Gael Cagnone, Preeti Bais, Vivek M. Philip, David Coleman, Heidi Kocalis, Stuart K Archer, James T Pearson, Mirana Ramialison, Joerg Heineke, Hemal H Patel, Nadia Rosenthal, Milena B Furtado, Mauro W Costa Feb 2019

Metformin Intervention Prevents Cardiac Dysfunction In A Murine Model Of Adult Congenital Heart Disease., Julia C Wilmanns, Raghav Pandey, Olivia Hon, Anjana Chandran, Jan M Schilling, Elvira Forte, Qizhu Wu, Gael Cagnone, Preeti Bais, Vivek M. Philip, David Coleman, Heidi Kocalis, Stuart K Archer, James T Pearson, Mirana Ramialison, Joerg Heineke, Hemal H Patel, Nadia Rosenthal, Milena B Furtado, Mauro W Costa

Faculty Research 2019

OBJECTIVE: Congenital heart disease (CHD) is the most frequent birth defect worldwide. The number of adult patients with CHD, now referred to as ACHD, is increasing with improved surgical and treatment interventions. However the mechanisms whereby ACHD predisposes patients to heart dysfunction are still unclear. ACHD is strongly associated with metabolic syndrome, but how ACHD interacts with poor modern lifestyle choices and other comorbidities, such as hypertension, obesity, and diabetes, is mostly unknown.

METHODS: We used a newly characterized mouse genetic model of ACHD to investigate the consequences and the mechanisms associated with combined obesity and ACHD predisposition. Metformin intervention ...


Technical And Regulatory Considerations For Taking Liquid Biopsy To The Clinic: Validation Of The Jax Plasmamonitor, Bridgette Sisson, Jasmina Uvalic, Kevin Kelly, Pavalan Selvam, Andrew N Hesse, Guruprasad Ananda, Harshpreet Chandok, Daniel Bergeron, Lauren Holinka, Honey V Reddi Feb 2019

Technical And Regulatory Considerations For Taking Liquid Biopsy To The Clinic: Validation Of The Jax Plasmamonitor, Bridgette Sisson, Jasmina Uvalic, Kevin Kelly, Pavalan Selvam, Andrew N Hesse, Guruprasad Ananda, Harshpreet Chandok, Daniel Bergeron, Lauren Holinka, Honey V Reddi

Faculty Research 2019

The standard of care in oncology has been genomic profiling of tumor tissue biopsies for the treatment and management of disease, which can prove to be quite challenging in terms of cost, invasiveness of procedure, and potential risk for the patient. As the number of available drugs in oncology continues to increase, so too does the demand for technologies and testing applications that can identify genomic alterations targetable by these new therapies. Liquid biopsies that use a blood draw from the diseased patient may offset the many disadvantages of the invasive procedure. However, as with any new technology or finding ...


Bifet: Sequencing Bias-Free Transcription Factor Footprint Enrichment Test., Ahrim Youn, Eladio J Marquez, Nathan Lawlor, Michael L. Stitzel, Duygu Ucar Jan 2019

Bifet: Sequencing Bias-Free Transcription Factor Footprint Enrichment Test., Ahrim Youn, Eladio J Marquez, Nathan Lawlor, Michael L. Stitzel, Duygu Ucar

Faculty Research 2019

Transcription factor (TF) footprinting uncovers putative protein-DNA binding via combined analyses of chromatin accessibility patterns and their underlying TF sequence motifs. TF footprints are frequently used to identify TFs that regulate activities of cell/condition-specific genomic regions (target loci) in comparison to control regions (background loci) using standard enrichment tests. However, there is a strong association between the chromatin accessibility level and the GC content of a locus and the number and types of TF footprints that can be detected at this site. Traditional enrichment tests (e.g. hypergeometric) do not account for this bias and inflate false positive associations ...


Gopher: Generator Of Probes For Capture Hi-C Experiments At High Resolution., Peter Hansen, Salaheddine Ali, Hannah Blau, Daniel Danis, Jochen Hecht, Uwe Kornak, Darío G Lupiáñez, Stefan Mundlos, Robin Steinhaus, Peter N Robinson Jan 2019

Gopher: Generator Of Probes For Capture Hi-C Experiments At High Resolution., Peter Hansen, Salaheddine Ali, Hannah Blau, Daniel Danis, Jochen Hecht, Uwe Kornak, Darío G Lupiáñez, Stefan Mundlos, Robin Steinhaus, Peter N Robinson

Faculty Research 2019

BACKGROUND: Target enrichment combined with chromosome conformation capturing methodologies such as capture Hi-C (CHC) can be used to investigate spatial layouts of genomic regions with high resolution and at scalable costs. A common application of CHC is the investigation of regulatory elements that are in contact with promoters, but CHC can be used for a range of other applications. Therefore, probe design for CHC needs to be adapted to experimental needs, but no flexible tool is currently available for this purpose.

RESULTS: We present a Java desktop application called GOPHER (Generator Of Probes for capture Hi-C Experiments at high Resolution ...


An Ontological Foundation For Ocular Phenotypes And Rare Eye Diseases., Panagiotis I Sergouniotis, Emmanuel Maxime, Dorothée Leroux, Annie Olry, Rachel Thompson, Ana Rath, Peter N Robinson, Hélène Dollfus, Ern-Eye Ontology Study Group Jan 2019

An Ontological Foundation For Ocular Phenotypes And Rare Eye Diseases., Panagiotis I Sergouniotis, Emmanuel Maxime, Dorothée Leroux, Annie Olry, Rachel Thompson, Ana Rath, Peter N Robinson, Hélène Dollfus, Ern-Eye Ontology Study Group

Faculty Research 2019

BACKGROUND: The optical accessibility of the eye and technological advances in ophthalmic diagnostics have put ophthalmology at the forefront of data-driven medicine. The focus of this study is rare eye disorders, a group of conditions whose clinical heterogeneity and geographic dispersion make data-driven, evidence-based practice particularly challenging. Inter-institutional collaboration and information sharing is crucial but the lack of standardised terminology poses an important barrier. Ontologies are computational tools that include sets of vocabulary terms arranged in hierarchical structures. They can be used to provide robust terminology standards and to enhance data interoperability. Here, we discuss the development of the ophthalmology-related ...


Expansion Of The Human Phenotype Ontology (Hpo) Knowledge Base And Resources., Sebastian Köhler, Leigh Carmody, Nicole Vasilevsky, Julius O B Jacobsen, Daniel Danis, Jean-Philippe Gourdine, Michael Gargano, Nomi L Harris, Nicolas Matentzoglu, Julie A Mcmurry, David Osumi-Sutherland, Valentina Cipriani, James P Balhoff, Tom Conlin, Hannah Blau, Gareth Baynam, Richard Palmer, Dylan Gratian, Hugh Dawkins, Michael Segal, Anna C Jansen, Ahmed Muaz, Willie H Chang, Jenna Bergerson, Stanley J F Laulederkind, Zafer Yüksel, Sergi Beltran, Alexandra F Freeman, Panagiotis I Sergouniotis, Daniel Durkin, Andrea L Storm, Marc Hanauer, Michael Brudno, Susan M. Bello, Murat Sincan, Kayli Rageth, Matthew T Wheeler, Renske Oegema, Halima Lourghi, Maria G Della Rocca, Rachel Thompson, Francisco Castellanos, James Priest, Charlotte Cunningham-Rundles, Ayushi Hegde, Ruth C Lovering, Catherine Hajek, Annie Olry, Luigi Notarangelo, Morgan Similuk, Xingmin A Zhang, David Gómez-Andrés, Hanns Lochmüller, Hélène Dollfus, Sergio Rosenzweig, Shruti Marwaha, Ana Rath, Kathleen Sullivan, Cynthia Smith, Joshua D Milner, Dorothée Leroux, Cornelius F Boerkoel, Amy Klion, Melody C Carter, Tudor Groza, Damian Smedley, Melissa A Haendel, Chris Mungall, Peter N Robinson Jan 2019

Expansion Of The Human Phenotype Ontology (Hpo) Knowledge Base And Resources., Sebastian Köhler, Leigh Carmody, Nicole Vasilevsky, Julius O B Jacobsen, Daniel Danis, Jean-Philippe Gourdine, Michael Gargano, Nomi L Harris, Nicolas Matentzoglu, Julie A Mcmurry, David Osumi-Sutherland, Valentina Cipriani, James P Balhoff, Tom Conlin, Hannah Blau, Gareth Baynam, Richard Palmer, Dylan Gratian, Hugh Dawkins, Michael Segal, Anna C Jansen, Ahmed Muaz, Willie H Chang, Jenna Bergerson, Stanley J F Laulederkind, Zafer Yüksel, Sergi Beltran, Alexandra F Freeman, Panagiotis I Sergouniotis, Daniel Durkin, Andrea L Storm, Marc Hanauer, Michael Brudno, Susan M. Bello, Murat Sincan, Kayli Rageth, Matthew T Wheeler, Renske Oegema, Halima Lourghi, Maria G Della Rocca, Rachel Thompson, Francisco Castellanos, James Priest, Charlotte Cunningham-Rundles, Ayushi Hegde, Ruth C Lovering, Catherine Hajek, Annie Olry, Luigi Notarangelo, Morgan Similuk, Xingmin A Zhang, David Gómez-Andrés, Hanns Lochmüller, Hélène Dollfus, Sergio Rosenzweig, Shruti Marwaha, Ana Rath, Kathleen Sullivan, Cynthia Smith, Joshua D Milner, Dorothée Leroux, Cornelius F Boerkoel, Amy Klion, Melody C Carter, Tudor Groza, Damian Smedley, Melissa A Haendel, Chris Mungall, Peter N Robinson

Faculty Research 2019

The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO's interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data ...


A Contraction Stress Model Of Hypertrophic Cardiomyopathy Due To Sarcomere Mutations., Rachel Cohn, Ketan Thakar, Andre Lowe, Feria A Ladha, Anthony M Pettinato, Robert Romano, Emily Meredith, Yu-Sheng Chen, Katherine Atamanuk, Bryan D Huey, J Travis Hinson Jan 2019

A Contraction Stress Model Of Hypertrophic Cardiomyopathy Due To Sarcomere Mutations., Rachel Cohn, Ketan Thakar, Andre Lowe, Feria A Ladha, Anthony M Pettinato, Robert Romano, Emily Meredith, Yu-Sheng Chen, Katherine Atamanuk, Bryan D Huey, J Travis Hinson

Faculty Research 2019

Thick-filament sarcomere mutations are a common cause of hypertrophic cardiomyopathy (HCM), a disorder of heart muscle thickening associated with sudden cardiac death and heart failure, with unclear mechanisms. We engineered four isogenic induced pluripotent stem cell (iPSC) models of β-myosin heavy chain and myosin-binding protein C3 mutations, and studied iPSC-derived cardiomyocytes in cardiac microtissue assays that resemble cardiac architecture and biomechanics. All HCM mutations resulted in hypercontractility with prolonged relaxation kinetics in proportion to mutation pathogenicity, but not changes in calcium handling. RNA sequencing and expression studies of HCM models identified p53 activation, oxidative stress, and cytotoxicity induced by metabolic ...