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Full-Text Articles in Life Sciences

Translational Approaches To Understanding Resilience To Alzheimer's Disease., Sarah M Neuner, Maria Telpoukhovskaia, Vilas Menon, Kristen M S O'Connell, Timothy J Hohman, Catherine Kaczorowski May 2022

Translational Approaches To Understanding Resilience To Alzheimer's Disease., Sarah M Neuner, Maria Telpoukhovskaia, Vilas Menon, Kristen M S O'Connell, Timothy J Hohman, Catherine Kaczorowski

Faculty Research 2022

Individuals who maintain cognitive function despite high levels of Alzheimer's disease (AD)-associated pathology are said to be 'resilient' to AD. Identifying mechanisms underlying resilience represents an exciting therapeutic opportunity. Human studies have identified a number of molecular and genetic factors associated with resilience, but the complexity of these cohorts prohibits a complete understanding of which factors are causal or simply correlated with resilience. Genetically and phenotypically diverse mouse models of AD provide new and translationally relevant opportunities to identify and prioritize new resilience mechanisms for further cross-species investigation. This review will discuss insights into resilience gained from both ...


A Forward-Thinking Approach To Addressing The New Synthetic Opioid 2-Benzylbenzimidazole Nitazene Analogs By Liquid Chromatography-Tandem Quadrupole Mass Spectrometry (Lc-Qqq-Ms), Sara E Walton, Alex J Krotulski, Barry K Logan Mar 2022

A Forward-Thinking Approach To Addressing The New Synthetic Opioid 2-Benzylbenzimidazole Nitazene Analogs By Liquid Chromatography-Tandem Quadrupole Mass Spectrometry (Lc-Qqq-Ms), Sara E Walton, Alex J Krotulski, Barry K Logan

College of Life Sciences Faculty Papers

Novel psychoactive substances (NPS) continue to represent a threat to public health and safety. The number of new drugs in the latest emergent synthetic opioid class-the 2-benzylbenzimidazole analogs-also called the nitazenes-has begun to dominate the current new synthetic opioid (NSO) subclass of NPS. We describe a liquid chromatography-tandem quadrupole mass spectrometry method for the quantification of nine analogs and/or metabolites of drugs in this series: isotonitazene, metonitazene, protonitazene, etonitazene, clonitazene, flunitazene, N-desethyl isotonitazene, 5-amino isotonitazene and 4'-hydroxy nitazene in human whole blood, urine, and tissue. Samples were prepared for analysis using a basic liquid-liquid extraction. Chromatographic separation was ...


Rare Coding Variants In Rcn3 Are Associated With Blood Pressure, Karen Y. He, Tanika N. Kelly, Heming Wang, Jingjing Liang, Luke Zhu, Brian E. Cade, Themistocles L. Assimes, Lewis C. Becker, Amber L. Beitelshees, Lawrence F. Bielak, Adam P. Bress, Jennifer A. Brody, Yen-Pei Christy Chang, Yi-Cheng Chang, Paul S. De Vries, Ravindranath Duggirala, Ervin R. Fox, Nora Franceschini, Anna L. Furniss, Yan Gao, Donna K. Arnett Feb 2022

Rare Coding Variants In Rcn3 Are Associated With Blood Pressure, Karen Y. He, Tanika N. Kelly, Heming Wang, Jingjing Liang, Luke Zhu, Brian E. Cade, Themistocles L. Assimes, Lewis C. Becker, Amber L. Beitelshees, Lawrence F. Bielak, Adam P. Bress, Jennifer A. Brody, Yen-Pei Christy Chang, Yi-Cheng Chang, Paul S. De Vries, Ravindranath Duggirala, Ervin R. Fox, Nora Franceschini, Anna L. Furniss, Yan Gao, Donna K. Arnett

Epidemiology Faculty Publications

BACKGROUND: While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals ...


Spatiotemporal Dynamics Of Clonal Selection And Diversification In Normal Endometrial Epithelium., Manako Yamaguchi, Hirofumi Nakaoka, Kazuaki Suda, Kosuke Yoshihara, Tatsuya Ishiguro, Nozomi Yachida, Kyota Saito, Haruka Ueda, Kentaro Sugino, Yutaro Mori, Kaoru Yamawaki, Ryo Tamura, Sundaramoorthy Revathidevi, Teiichi Motoyama, Kazuki Tainaka, Roel G W Verhaak, Ituro Inoue, Takayuki Enomoto Feb 2022

Spatiotemporal Dynamics Of Clonal Selection And Diversification In Normal Endometrial Epithelium., Manako Yamaguchi, Hirofumi Nakaoka, Kazuaki Suda, Kosuke Yoshihara, Tatsuya Ishiguro, Nozomi Yachida, Kyota Saito, Haruka Ueda, Kentaro Sugino, Yutaro Mori, Kaoru Yamawaki, Ryo Tamura, Sundaramoorthy Revathidevi, Teiichi Motoyama, Kazuki Tainaka, Roel G W Verhaak, Ituro Inoue, Takayuki Enomoto

Faculty Research 2022

It has become evident that somatic mutations in cancer-associated genes accumulate in the normal endometrium, but spatiotemporal understanding of the evolution and expansion of mutant clones is limited. To elucidate the timing and mechanism of the clonal expansion of somatic mutations in cancer-associated genes in the normal endometrium, we sequence 1311 endometrial glands from 37 women. By collecting endometrial glands from different parts of the endometrium, we show that multiple glands with the same somatic mutations occupy substantial areas of the endometrium. We demonstrate that "rhizome structures", in which the basal glands run horizontally along the muscular layer and multiple ...


Comprehensive Analysis Of Alternative Splicing In Gastric Cancer Identifies Epithelial-Mesenchymal Transition Subtypes Associated With Survival., Yukyung Jun, Yun-Suhk Suh, Sunghee Park, Jieun Lee, Jong-Il Kim, Sanghyuk Lee, Wan-Ping Lee, Olga Anczuków, Han-Kwang Yang, Charles Lee Feb 2022

Comprehensive Analysis Of Alternative Splicing In Gastric Cancer Identifies Epithelial-Mesenchymal Transition Subtypes Associated With Survival., Yukyung Jun, Yun-Suhk Suh, Sunghee Park, Jieun Lee, Jong-Il Kim, Sanghyuk Lee, Wan-Ping Lee, Olga Anczuków, Han-Kwang Yang, Charles Lee

Faculty Research 2022

Alternatively spliced RNA isoforms are a hallmark of tumors, but their nature, prevalence, and clinical implications in gastric cancer have not been comprehensively characterized. We systematically profiled the splicing landscape of 83 gastric tumors and matched normal mucosa, identifying and experimentally validating eight splicing events that can classify all gastric cancers into three subtypes: epithelial-splicing (EpiS), mesenchymal-splicing (MesS), and hybrid-splicing. These subtypes were associated with distinct molecular signatures and epithelial-mesenchymal transition markers. Subtype-specific splicing events were enriched in motifs for splicing factors RBM24 and ESRP1, which were upregulated in MesS and EpiS tumors, respectively. A simple classifier based only on ...


Common Genetic Variants Contribute To Risk Of Transposition Of The Great Arteries., Doris Škorić-Milosavljević, Rafik Tadros, Fernanda M Bosada, Federico Tessadori, Jan Hendrik Van Weerd, Odilia I Woudstra, Fleur V Y Tjong, Najim Lahrouchi, Fanny Bajolle, Heather J Cordell, A J Agopian, Gillian M Blue, Daniela Q C M Barge-Schaapveld, Marc Gewillig, Christoph Preuss, Elisabeth M Lodder, Phil Barnett, Aho Ilgun, Leander Beekman, Karel Van Duijvenboden, Regina Bokenkamp, Martina Müller-Nurasyid, Hubert W Vliegen, Thelma C Konings, Joost P Van Melle, Arie P J Van Dijk, Roland R J Van Kimmenade, Jolien W Roos-Hesselink, Gertjan T Sieswerda, Folkert Meijboom, Hashim Abdul-Khaliq, Felix Berger, Sven Dittrich, Marc-Phillip Hitz, Julia Moosmann, Frank-Thomas Riede, Stephan Schubert, Pilar Galan, Mark Lathrop, Hans M Munter, Ammar Al-Chalabi, Christopher E Shaw, Pamela J Shaw, Karen E Morrison, Jan H Veldink, Leonard H Van Den Berg, Sylvia Evans, Marcelo A Nobrega, Ivy Aneas, Milena Radivojkov-Blagojević, Thomas Meitinger, Erwin Oechslin, Tapas Mondal, Lynn Bergin, John F Smythe, Luis Altamirano-Diaz, Jane Lougheed, Berto J Bouma, Marie-A Chaix, Jennie Kline, Anne S Bassett, Gregor Andelfinger, Roel L F Van Der Palen, Patrice Bouvagnet, Sally-Ann B Clur, Jeroen Breckpot, Wilhelmina S Kerstjens-Frederikse, David S Winlaw, Ulrike M M Bauer, Seema Mital, Elizabeth Goldmuntz, Bernard Keavney, Damien Bonnet, Barbara J Mulder, Michael W T Tanck, Jeroen Bakkers, Vincent M Christoffels, Cornelis J Boogerd, Alex V Postma, Connie R Bezzina Jan 2022

Common Genetic Variants Contribute To Risk Of Transposition Of The Great Arteries., Doris Škorić-Milosavljević, Rafik Tadros, Fernanda M Bosada, Federico Tessadori, Jan Hendrik Van Weerd, Odilia I Woudstra, Fleur V Y Tjong, Najim Lahrouchi, Fanny Bajolle, Heather J Cordell, A J Agopian, Gillian M Blue, Daniela Q C M Barge-Schaapveld, Marc Gewillig, Christoph Preuss, Elisabeth M Lodder, Phil Barnett, Aho Ilgun, Leander Beekman, Karel Van Duijvenboden, Regina Bokenkamp, Martina Müller-Nurasyid, Hubert W Vliegen, Thelma C Konings, Joost P Van Melle, Arie P J Van Dijk, Roland R J Van Kimmenade, Jolien W Roos-Hesselink, Gertjan T Sieswerda, Folkert Meijboom, Hashim Abdul-Khaliq, Felix Berger, Sven Dittrich, Marc-Phillip Hitz, Julia Moosmann, Frank-Thomas Riede, Stephan Schubert, Pilar Galan, Mark Lathrop, Hans M Munter, Ammar Al-Chalabi, Christopher E Shaw, Pamela J Shaw, Karen E Morrison, Jan H Veldink, Leonard H Van Den Berg, Sylvia Evans, Marcelo A Nobrega, Ivy Aneas, Milena Radivojkov-Blagojević, Thomas Meitinger, Erwin Oechslin, Tapas Mondal, Lynn Bergin, John F Smythe, Luis Altamirano-Diaz, Jane Lougheed, Berto J Bouma, Marie-A Chaix, Jennie Kline, Anne S Bassett, Gregor Andelfinger, Roel L F Van Der Palen, Patrice Bouvagnet, Sally-Ann B Clur, Jeroen Breckpot, Wilhelmina S Kerstjens-Frederikse, David S Winlaw, Ulrike M M Bauer, Seema Mital, Elizabeth Goldmuntz, Bernard Keavney, Damien Bonnet, Barbara J Mulder, Michael W T Tanck, Jeroen Bakkers, Vincent M Christoffels, Cornelis J Boogerd, Alex V Postma, Connie R Bezzina

Faculty Research 2022

RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored.

OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA.

METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1 ...


The Human Disease Ontology 2022 Update., Lynn M Schriml, James B Munro, Mike Schor, Dustin Olley, Carrie Mccracken, Victor Felix, J Allen Baron, Rebecca Jackson, Susan M. Bello, Cynthia Bearer, Richard Lichenstein, Katharine Bisordi, Nicole Campion Dialo, Michelle Giglio, Carol Greene Jan 2022

The Human Disease Ontology 2022 Update., Lynn M Schriml, James B Munro, Mike Schor, Dustin Olley, Carrie Mccracken, Victor Felix, J Allen Baron, Rebecca Jackson, Susan M. Bello, Cynthia Bearer, Richard Lichenstein, Katharine Bisordi, Nicole Campion Dialo, Michelle Giglio, Carol Greene

Faculty Research 2022

The Human Disease Ontology (DO) (www.disease-ontology.org) database, has significantly expanded the disease content and enhanced our userbase and website since the DO's 2018 Nucleic Acids Research DATABASE issue paper. Conservatively, based on available resource statistics, terms from the DO have been annotated to over 1.5 million biomedical data elements and citations, a 10× increase in the past 5 years. The DO, funded as a NHGRI Genomic Resource, plays a key role in disease knowledge organization, representation, and standardization, serving as a reference framework for multiscale biomedical data integration and analysis across thousands of clinical, biomedical and ...


An Artifact In Intracellular Cytokine Staining For Studying T Cell Responses And Its Alleviation., Zheng Gong, Qing Li, Jiayuan Shi, Guangwen Ren Jan 2022

An Artifact In Intracellular Cytokine Staining For Studying T Cell Responses And Its Alleviation., Zheng Gong, Qing Li, Jiayuan Shi, Guangwen Ren

Faculty Research 2022

Intracellular cytokine staining (ICS) is a widely employed ex vivo method for quantitative determination of the activation status of immune cells, most often applied to T cells. ICS test samples are commonly prepared from animal or human tissues as unpurified cell mixtures, and cell-specific cytokine signals are subsequently discriminated by gating strategies using flow cytometry. Here, we show that when ICS samples contain Ly6G+ neutrophils, neutrophils are ex vivo activated by an ICS reagent - phorbol myristate acetate (PMA) - which leads to hydrogen peroxide (H2O2) release and death of cytokine-expressing T cells. This artifact is likely to result ...


Pulmonary Capillary Recruitment And Distention In Mammalian Lungs: Species Similarities, David Langleben, Benjamin D. Fox, Stylianos E. Orfanos, Michele Giovinazzo, John D. Catravas Jan 2022

Pulmonary Capillary Recruitment And Distention In Mammalian Lungs: Species Similarities, David Langleben, Benjamin D. Fox, Stylianos E. Orfanos, Michele Giovinazzo, John D. Catravas

Bioelectrics Publications

Pulmonary arterial pressure rises minimally during exercise. The pulmonary microcirculation accommodates increasing blood flow via recruitment of pulmonary capillaries and, at higher flows, by distention of already perfused capillaries. The flow transition range between recruitment and distention has not been studied or compared across mammalian species, including humans. We hypothesised that the range would be similar. Functional pulmonary capillary surface area (FCSA) can be estimated using validated metabolic techniques. We reviewed data from previous studies in three mammalian species (perfused rabbit lungs and dog lung lobes, and exercising humans) and generated blood flow-FCSA curves over a range of flows. We ...


Rickettsial Pathogen Perturbs Tick Circadian Gene To Infect The Vertebrate Host, Supreet Khanal, Vikas Taank, John F. Anderson, Hameeda Sultana, Girish Neelakanta Jan 2022

Rickettsial Pathogen Perturbs Tick Circadian Gene To Infect The Vertebrate Host, Supreet Khanal, Vikas Taank, John F. Anderson, Hameeda Sultana, Girish Neelakanta

Biological Sciences Faculty Publications

Ixodes scapularis is a medically important tick that transmits several microbes to humans, including rickettsial pathogen Anaplasma phagocytophilum. In nature, these ticks encounter several abiotic factors including changes in temperature, humidity, and light. Many organisms use endogenously generated circadian pathways to encounter abiotic factors. In this study, we provide evidence for the first time to show that A. phagocytophilum modulates the arthropod circadian gene for its transmission to the vertebrate host. We noted a circadian oscillation in the expression of arthropod clock, bmal1, period and timeless genes when ticks or tick cells were exposed to alternate 12 h light: 12 ...


Spatial Concordance Of Dna Methylation Classification In Diffuse Glioma., Niels Verburg, Floris P Barthel, Kevin J Anderson, Kevin C Johnson, Thomas Koopman, Maqsood M Yaqub, Otto S Hoekstra, Adriaan A Lammertsma, Frederik Barkhof, Petra J W Pouwels, Jaap C Reijneveld, Annemieke J M Rozemuller, Jeroen A M Beliën, Ronald Boellaard, Michael D Taylor, Sunit Das, Joseph F Costello, William Peter Vandertop, Pieter Wesseling, Philip C De Witt Hamer, Roel G W Verhaak Dec 2021

Spatial Concordance Of Dna Methylation Classification In Diffuse Glioma., Niels Verburg, Floris P Barthel, Kevin J Anderson, Kevin C Johnson, Thomas Koopman, Maqsood M Yaqub, Otto S Hoekstra, Adriaan A Lammertsma, Frederik Barkhof, Petra J W Pouwels, Jaap C Reijneveld, Annemieke J M Rozemuller, Jeroen A M Beliën, Ronald Boellaard, Michael D Taylor, Sunit Das, Joseph F Costello, William Peter Vandertop, Pieter Wesseling, Philip C De Witt Hamer, Roel G W Verhaak

Faculty Research 2021

BACKGROUND: Intratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence.

METHODS: We used neuronavigation to acquire 133 image-guided and spatially separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast-enhanced T1-weighted and fluid-attenuated inversion ...


Acute Consumption Of A Sugar-Sweetened Beverage Impairs Microvascular Function In Midwestern Hispanic Males, Emma Hirshman, Anne R. Crecelius Dec 2021

Acute Consumption Of A Sugar-Sweetened Beverage Impairs Microvascular Function In Midwestern Hispanic Males, Emma Hirshman, Anne R. Crecelius

Health and Sport Science Faculty Publications

Hispanic males are at risk for cardiovascular disease and consume high levels of sugar-sweetened beverages (SSB); yet, their acute vascular response to SSBs is unknown. Ten healthy Hispanic men (18-45 years old) consumed a SSB and reactive hyperemia was performed prior to, immediately following, and 1-hr post-consumption. Both peak and total (area under the curve) forearm blood flow were attenuated immediately following consumption but returned to at or above pre-consumption levels at the 1-hr test.


Sedation And Acute Encephalopathy In A Pediatric Patient Following Ingestion Of Delta-8-Tetrahydrocannabinol Gummies, Peter Akpunonu, Regan A. Baum, Andrew Reckers, Blake Davidson, Ross Ellison, Matthew Riley, Jordan Trecki, Roy Gerona Nov 2021

Sedation And Acute Encephalopathy In A Pediatric Patient Following Ingestion Of Delta-8-Tetrahydrocannabinol Gummies, Peter Akpunonu, Regan A. Baum, Andrew Reckers, Blake Davidson, Ross Ellison, Matthew Riley, Jordan Trecki, Roy Gerona

Emergency Medicine Faculty Publications

BACKGROUND Delta-8 tetrahydrocannabinol (delta-8 THC) is an isomer of delta-9-tetrahydrocannabinol (delta-9 THC), the primary psychoactive cannabinoid in the marijuana plant. Typically found at lower concentrations in marijuana, delta-8 THC exhibits psychoactive properties similar to delta-9 THC. Products containing delta-8 THC are readily available across the US and currently there is a lack of available confirmatory testing specific to delta-8 THC as there is cross-reactivity to other naturally occurring cannabinoids in standard immunoassays. Pediatric exposures to this substance are on the rise.

CASE REPORT We present a case with laboratory confirmation of a previously healthy 2-year-old girl ingesting approximately 15 mg ...


Attitudes And Interactions Of Indigenous And Non-Indigenous People With Wildlife In The Northern Talamanca Mountains Of Costa Rica, Carolina Saenz-Bolaños Oct 2021

Attitudes And Interactions Of Indigenous And Non-Indigenous People With Wildlife In The Northern Talamanca Mountains Of Costa Rica, Carolina Saenz-Bolaños

Doctoral Dissertations

In this study I investigated wildlife and human use of landscapes in the northern Talamanca Mountains of Costa Rica (Pacuare-Barbilla sector), including three contiguous protected areas (a national park, a forest reserve, and an indigenous territory), as well as surrounding unprotected areas. I describe and compare perceptions of wildlife by different social actors in the Pacuare-Barbilla sector, collecting information with a questionnaire as an instrument. I also inventoried and monitored the abundance and distribution of a variety of wildlife species occurring throughout the area using camera traps. The species with greater abundance or only occurrence in the national park were ...


Fusion And Beyond: Satellite Cell Contributions To Loading-Induced Skeletal Muscle Adaptation, Kevin A. Murach, Christopher S. Fry, Esther E. Dupont-Versteegden, John J. Mccarthy, Charlotte A. Peterson Sep 2021

Fusion And Beyond: Satellite Cell Contributions To Loading-Induced Skeletal Muscle Adaptation, Kevin A. Murach, Christopher S. Fry, Esther E. Dupont-Versteegden, John J. Mccarthy, Charlotte A. Peterson

Center for Muscle Biology Faculty Publications

Satellite cells support adult skeletal muscle fiber adaptations to loading in numerous ways. The fusion of satellite cells, driven by cell-autonomous and/or extrinsic factors, contributes new myonuclei to muscle fibers, associates with load-induced hypertrophy, and may support focal membrane damage repair and long-term myonuclear transcriptional output. Recent studies have also revealed that satellite cells communicate within their niche to mediate muscle remodeling in response to resistance exercise, regulating the activity of numerous cell types through various mechanisms such as secretory signaling and cell–cell contact. Muscular adaptation to resistance and endurance activity can be initiated and sustained for a ...


Functional Characterization Of T2d-Associated Snp Effects On Baseline And Er Stress-Responsive Β Cell Transcriptional Activation., Shubham Khetan, Susan Kales, Romy Kursawe, Alexandria Jillette, Jacob C Ulirsch, Steven K Reilly, Duygu Ucar, Ryan Tewhey, Michael L. Stitzel Sep 2021

Functional Characterization Of T2d-Associated Snp Effects On Baseline And Er Stress-Responsive Β Cell Transcriptional Activation., Shubham Khetan, Susan Kales, Romy Kursawe, Alexandria Jillette, Jacob C Ulirsch, Steven K Reilly, Duygu Ucar, Ryan Tewhey, Michael L. Stitzel

Faculty Research 2021

Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) at >250 loci in the human genome to type 2 diabetes (T2D) risk. For each locus, identifying the functional variant(s) among multiple SNPs in high linkage disequilibrium is critical to understand molecular mechanisms underlying T2D genetic risk. Using massively parallel reporter assays (MPRA), we test the cis-regulatory effects of SNPs associated with T2D and altered in vivo islet chromatin accessibility in MIN6 β cells under steady state and pathophysiologic endoplasmic reticulum (ER) stress conditions. We identify 1,982/6,621 (29.9%) SNP-containing elements that activate transcription in MIN6 ...


Comprehensive Characterization Of 536 Patient-Derived Xenograft Models Prioritizes Candidatesfor Targeted Treatment., Hua Sun, Song Cao, R Jay Mashl, Chia-Kuei Mo, Simone Zaccaria, Michael C Wendl, Sherri R Davies, Matthew H Bailey, Tina M Primeau, Jeremy Hoog, Jacqueline L Mudd, Dennis A Dean, Rajesh Patidar, Li Chen, Matthew A Wyczalkowski, Reyka G Jayasinghe, Fernanda Martins Rodrigues, Nadezhda V Terekhanova, Yize Li, Kian-Huat Lim, Andrea Wang-Gillam, Brian A Van Tine, Cynthia X Ma, Rebecca Aft, Katherine C Fuh, Julie K Schwarz, Jose P Zevallos, Sidharth V Puram, John F Dipersio, Nci Pdxnet Consortium, Brandi Davis-Dusenbery, Matthew J Ellis, Michael T Lewis, Michael A Davies, Meenhard Herlyn, Bingliang Fang, Jack A Roth, Alana L Welm, Bryan E Welm, Funda Meric-Bernstam, Feng Chen, Ryan C Fields, Shunqiang Li, Ramaswamy Govindan, James H Doroshow, Jeffrey A Moscow, Yvonne A Evrard, Jeffrey Chuang, Benjamin J Raphael, Li Ding, Carol J Bult, Peter N Robinson Aug 2021

Comprehensive Characterization Of 536 Patient-Derived Xenograft Models Prioritizes Candidatesfor Targeted Treatment., Hua Sun, Song Cao, R Jay Mashl, Chia-Kuei Mo, Simone Zaccaria, Michael C Wendl, Sherri R Davies, Matthew H Bailey, Tina M Primeau, Jeremy Hoog, Jacqueline L Mudd, Dennis A Dean, Rajesh Patidar, Li Chen, Matthew A Wyczalkowski, Reyka G Jayasinghe, Fernanda Martins Rodrigues, Nadezhda V Terekhanova, Yize Li, Kian-Huat Lim, Andrea Wang-Gillam, Brian A Van Tine, Cynthia X Ma, Rebecca Aft, Katherine C Fuh, Julie K Schwarz, Jose P Zevallos, Sidharth V Puram, John F Dipersio, Nci Pdxnet Consortium, Brandi Davis-Dusenbery, Matthew J Ellis, Michael T Lewis, Michael A Davies, Meenhard Herlyn, Bingliang Fang, Jack A Roth, Alana L Welm, Bryan E Welm, Funda Meric-Bernstam, Feng Chen, Ryan C Fields, Shunqiang Li, Ramaswamy Govindan, James H Doroshow, Jeffrey A Moscow, Yvonne A Evrard, Jeffrey Chuang, Benjamin J Raphael, Li Ding, Carol J Bult, Peter N Robinson

Faculty Research 2021

Development of candidate cancer treatments is a resource-intensive process, with the research community continuing to investigate options beyond static genomic characterization. Toward this goal, we have established the genomic landscapes of 536 patient-derived xenograft (PDX) models across 25 cancer types, together with mutation, copy number, fusion, transcriptomic profiles, and NCI-MATCH arms. Compared with human tumors, PDXs typically have higher purity and fit to investigate dynamic driver events and molecular properties via multiple time points from same case PDXs. Here, we report on dynamic genomic landscapes and pharmacogenomic associations, including associations between activating oncogenic events and drugs, correlations between whole-genome duplications ...


Tet2 Controls The Responses Of Β Cells To Inflammation In Autoimmune Diabetes., Jinxiu Rui, Songyan Deng, Ana Luisa Perdigoto, Gerald Ponath, Romy Kursawe, Nathan Lawlor, Tomokazu Sumida, Maya Levine-Ritterman, Michael L. Stitzel, David Pitt, Jun Lu, Kevan C Herold Aug 2021

Tet2 Controls The Responses Of Β Cells To Inflammation In Autoimmune Diabetes., Jinxiu Rui, Songyan Deng, Ana Luisa Perdigoto, Gerald Ponath, Romy Kursawe, Nathan Lawlor, Tomokazu Sumida, Maya Levine-Ritterman, Michael L. Stitzel, David Pitt, Jun Lu, Kevan C Herold

Faculty Research 2021

β cells may participate and contribute to their own demise during Type 1 diabetes (T1D). Here we report a role of their expression of Tet2 in regulating immune killing. Tet2 is induced in murine and human β cells with inflammation but its expression is reduced in surviving β cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate β cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells.Tet2-KO β cells show ...


Glis1 Regulates Trabecular Meshwork Function And Intraocular Pressure And Is Associated With Glaucoma In Humans., K Saidas Nair, Chitrangda Srivastava, Robert V Brown, Swanand Koli, Hélène Choquet, Hong Soon Kang, Yien-Ming Kuo, Sara A Grimm, Caleb Sutherland, Alexandra Badea, G Allan Johnson, Yin Zhao, Jie Yin, Kyoko Okamoto, Graham Clark, Terete Borrás, Gulab Zode, Krishnakumar Kizhatil, Subhabrata Chakrabarti, Simon W M John, Eric Jorgenson, Anton M Jetten Aug 2021

Glis1 Regulates Trabecular Meshwork Function And Intraocular Pressure And Is Associated With Glaucoma In Humans., K Saidas Nair, Chitrangda Srivastava, Robert V Brown, Swanand Koli, Hélène Choquet, Hong Soon Kang, Yien-Ming Kuo, Sara A Grimm, Caleb Sutherland, Alexandra Badea, G Allan Johnson, Yin Zhao, Jie Yin, Kyoko Okamoto, Graham Clark, Terete Borrás, Gulab Zode, Krishnakumar Kizhatil, Subhabrata Chakrabarti, Simon W M John, Eric Jorgenson, Anton M Jetten

Faculty Research 2021

Chronically elevated intraocular pressure (IOP) is the major risk factor of primary open-angle glaucoma, a leading cause of blindness. Dysfunction of the trabecular meshwork (TM), which controls the outflow of aqueous humor (AqH) from the anterior chamber, is the major cause of elevated IOP. Here, we demonstrate that mice deficient in the Krüppel-like zinc finger transcriptional factor GLI-similar-1 (GLIS1) develop chronically elevated IOP. Magnetic resonance imaging and histopathological analysis reveal that deficiency in GLIS1 expression induces progressive degeneration of the TM, leading to inefficient AqH drainage from the anterior chamber and elevated IOP. Transcriptome and cistrome analyses identified several glaucoma- ...


Predictive Biomarkers For 5-Fluorouracil And Oxaliplatin-Based Chemotherapy In Gastric Cancers Via Profiling Of Patient-Derived Xenografts., Deukchae Na, Jeesoo Chae, Sung-Yup Cho, Wonyoung Kang, Ahra Lee, Seoyeon Min, Jinjoo Kang, Min Jung Kim, Jaeyong Choi, Woochan Lee, Dongjin Shin, Ahrum Min, Yu-Jin Kim, Kyung-Hun Lee, Tae-Yong Kim, Yun-Suhk Suh, Seong-Ho Kong, Hyuk-Joon Lee, Woo-Ho Kim, Hansoo Park, Seock-Ah Im, Han-Kwang Yang, Charles Lee, Jong-Il Kim Aug 2021

Predictive Biomarkers For 5-Fluorouracil And Oxaliplatin-Based Chemotherapy In Gastric Cancers Via Profiling Of Patient-Derived Xenografts., Deukchae Na, Jeesoo Chae, Sung-Yup Cho, Wonyoung Kang, Ahra Lee, Seoyeon Min, Jinjoo Kang, Min Jung Kim, Jaeyong Choi, Woochan Lee, Dongjin Shin, Ahrum Min, Yu-Jin Kim, Kyung-Hun Lee, Tae-Yong Kim, Yun-Suhk Suh, Seong-Ho Kong, Hyuk-Joon Lee, Woo-Ho Kim, Hansoo Park, Seock-Ah Im, Han-Kwang Yang, Charles Lee, Jong-Il Kim

Faculty Research 2021

Gastric cancer (GC) is commonly treated by chemotherapy using 5-fluorouracil (5-FU) derivatives and platinum combination, but predictive biomarker remains lacking. We develop patient-derived xenografts (PDXs) from 31 GC patients and treat with a combination of 5-FU and oxaliplatin, to determine biomarkers associated with responsiveness. When the PDXs are defined as either responders or non-responders according to tumor volume change after treatment, the responsiveness of PDXs is significantly consistent with the respective clinical outcomes of the patients. An integrative genomic and transcriptomic analysis of PDXs reveals that pathways associated with cell-to-cell and cell-to-extracellular matrix interactions enriched among the non-responders in both ...


The Age Presents Introduction To Geroscience Video Lecture Series., Alessandro Bitto, Mitchell B Lee, Cristal M Hill, Ron Korstanje, Matt Kaeberlein Aug 2021

The Age Presents Introduction To Geroscience Video Lecture Series., Alessandro Bitto, Mitchell B Lee, Cristal M Hill, Ron Korstanje, Matt Kaeberlein

Faculty Research 2021

The AGE Presents Introduction to Geroscience video lecture series is a collection of high-quality didactic video lectures and associated teaching materials focused on foundational topics in aging biology. The videos are made freely available on YouTube and are targeted toward an audience familiar with concepts learned in the first year of a college undergraduate biology/biomedical major. Members of the American Aging Association also receive the original lecture slides and lecture notes, with additional course materials to be developed in the future. We expect that these lectures will enhance understanding of geroscience among the general public while also providing tools ...


In Situ Chromatin Interaction Analysis Using Paired-End Tag Sequencing., Ping Wang, Yuliang Feng, Kun Zhu, Haoxi Chai, Ya-Ting Chang, Xiaofei Yang, Xiyuan Liu, Chen Shen, Eva Gega, Byoungkoo Lee, Minji Kim, Xiaoan Ruan, Yijun Ruan Aug 2021

In Situ Chromatin Interaction Analysis Using Paired-End Tag Sequencing., Ping Wang, Yuliang Feng, Kun Zhu, Haoxi Chai, Ya-Ting Chang, Xiaofei Yang, Xiyuan Liu, Chen Shen, Eva Gega, Byoungkoo Lee, Minji Kim, Xiaoan Ruan, Yijun Ruan

Faculty Research 2021

Chromatin Interaction Analysis Using Paired-End Tag Sequencing (ChIA-PET) is an established method to map protein-mediated chromatin interactions. A limitation, however, is that it requires a hundred million cells per experiment, which hampers its broad application in biomedical research, particularly in studies in which it is impractical to obtain a large number of cells from rare samples. To reduce the required input cell number while retaining high data quality, we developed an in situ ChIA-PET protocol, which requires as few as 1 million cells. Here, we describe detailed step-by-step procedures for performing in situ ChIA-PET from cultured cells, including both an ...


Profiling Variable-Number Tandem Repeat Variation Across Populations Using Repeat-Pangenome Graphs., Tsung-Yu Lu, Human Genome Structural Variation Consortium, Mark J P Chaisson, Charles Lee, Qihui Zhu Jul 2021

Profiling Variable-Number Tandem Repeat Variation Across Populations Using Repeat-Pangenome Graphs., Tsung-Yu Lu, Human Genome Structural Variation Consortium, Mark J P Chaisson, Charles Lee, Qihui Zhu

Faculty Research 2021

Variable number tandem repeats (VNTRs) are composed of consecutive repetitive DNA with hypervariable repeat count and composition. They include protein coding sequences and associations with clinical disorders. It has been difficult to incorporate VNTR analysis in disease studies that use short-read sequencing because the traditional approach of mapping to the human reference is less effective for repetitive and divergent sequences. In this work, we solve VNTR mapping for short reads with a repeat-pangenome graph (RPGG), a data structure that encodes both the population diversity and repeat structure of VNTR loci from multiple haplotype-resolved assemblies. We develop software to build a ...


Homozygous Mtap Deletion In Primary Human Glioblastoma Is Not Associated With Elevation Of Methylthioadenosine., Yasaman Barekatain, Jeffrey J Ackroyd, Victoria C Yan, Sunada Khadka, Lin Wang, Ko-Chien Chen, Anton H Poral, Theresa Tran, Dimitra K Georgiou, Kenisha Arthur, Yu-Hsi Lin, Nikunj Satani, Elliot S Ballato, Eliot I Behr, Ana C Decarvalho, Roel G W Verhaak, John De Groot, Jason T Huse, John M Asara, Raghu Kalluri, Florian L Muller Jul 2021

Homozygous Mtap Deletion In Primary Human Glioblastoma Is Not Associated With Elevation Of Methylthioadenosine., Yasaman Barekatain, Jeffrey J Ackroyd, Victoria C Yan, Sunada Khadka, Lin Wang, Ko-Chien Chen, Anton H Poral, Theresa Tran, Dimitra K Georgiou, Kenisha Arthur, Yu-Hsi Lin, Nikunj Satani, Elliot S Ballato, Eliot I Behr, Ana C Decarvalho, Roel G W Verhaak, John De Groot, Jason T Huse, John M Asara, Raghu Kalluri, Florian L Muller

Faculty Research 2021

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP's substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further ...


Long Non-Coding Rnas And Their Targets As Potential Biomarkers In Breast Cancer., Maryam Khalid, Rehan Zafar Paracha, Maryum Nisar, Sumaira Malik, Salma Tariq, Iqra Arshad, Amnah Siddiqa, Zamir Hussain, Jamil Ahmad, Amjad Ali Jul 2021

Long Non-Coding Rnas And Their Targets As Potential Biomarkers In Breast Cancer., Maryam Khalid, Rehan Zafar Paracha, Maryum Nisar, Sumaira Malik, Salma Tariq, Iqra Arshad, Amnah Siddiqa, Zamir Hussain, Jamil Ahmad, Amjad Ali

Faculty Research 2021

Breast cancer is among the lethal types of cancer with a high mortality rate, globally. Its high prevalence can be controlled through improved analysis and identification of disease-specific biomarkers. Recently, long non-coding RNAs (lncRNAs) have been reported as key contributors of carcinogenesis and regulate various cellular pathways through post-transcriptional regulatory mechanisms. The specific aim of this study was to identify the novel interactions of aberrantly expressed genetic components in breast cancer by applying integrative analysis of publicly available expression profiles of both lncRNAs and mRNAs. Differential expression patterns were identified by comparing the breast cancer expression profiles of samples with ...


Reduced Mitochondrial Dna And Oxphos Protein Content In Skeletal Muscle Of Children With Cerebral Palsy, Ferdinand Von Walden, Ivan J. Vechetti Jr., Davis A. Englund, Vandré C. Figueiredo, Rodrigo Fernandez-Gonzalo, Kevin A. Murach, Jessica Pingel, John J. Mccarthy, Per Stål, Eva Pontén Jun 2021

Reduced Mitochondrial Dna And Oxphos Protein Content In Skeletal Muscle Of Children With Cerebral Palsy, Ferdinand Von Walden, Ivan J. Vechetti Jr., Davis A. Englund, Vandré C. Figueiredo, Rodrigo Fernandez-Gonzalo, Kevin A. Murach, Jessica Pingel, John J. Mccarthy, Per Stål, Eva Pontén

Physiology Faculty Publications

AIM: To provide a detailed gene and protein expression analysis related to mitochondrial biogenesis and assess mitochondrial content in skeletal muscle of children with cerebral palsy (CP).

METHOD: Biceps brachii muscle samples were collected from 19 children with CP (mean [SD] age 15y 4mo [2y 6mo], range 9-18y, 16 males, three females) and 10 typically developing comparison children (mean [SD] age 15y [4y], range 7-21y, eight males, two females). Gene expression (quantitative reverse transcription polymerase chain reaction [PCR]), mitochondrial DNA (mtDNA) to genomic DNA ratio (quantitative PCR), and protein abundance (western blotting) were analyzed. Microarray data sets (CP/aging/bed ...


Endometrial Receptivity And Implantation Require Uterine Bmp Signaling Through An Acvr2a-Smad1/Smad5 Axis., Diana Monsivais, Takashi Nagashima, Renata Prunskaite-Hyyryläinen, Kaori Nozawa, Keisuke Shimada, Suni Tang, Clark Hamor, Julio E Agno, Fengju Chen, Ramya P Masand, Steven L Young, Chad J Creighton, Francesco J Demayo, Masahito Ikawa, Se-Jin Lee, Martin M Matzuk Jun 2021

Endometrial Receptivity And Implantation Require Uterine Bmp Signaling Through An Acvr2a-Smad1/Smad5 Axis., Diana Monsivais, Takashi Nagashima, Renata Prunskaite-Hyyryläinen, Kaori Nozawa, Keisuke Shimada, Suni Tang, Clark Hamor, Julio E Agno, Fengju Chen, Ramya P Masand, Steven L Young, Chad J Creighton, Francesco J Demayo, Masahito Ikawa, Se-Jin Lee, Martin M Matzuk

Faculty Research 2021

During early pregnancy in the mouse, nidatory estrogen (E2) stimulates endometrial receptivity by activating a network of signaling pathways that is not yet fully characterized. Here, we report that bone morphogenetic proteins (BMPs) control endometrial receptivity via a conserved activin receptor type 2 A (ACVR2A) and SMAD1/5 signaling pathway. Mice were generated to contain single or double conditional deletion of SMAD1/5 and ACVR2A/ACVR2B receptors using progesterone receptor (PR)-cre. Female mice with SMAD1/5 deletion display endometrial defects that result in the development of cystic endometrial glands, a hyperproliferative endometrial epithelium during the window of implantation, and ...


Discovery Of Widespread Transcription Initiation At Microsatellites Predictable By Sequence-Based Deep Neural Network., Mathys Grapotte, Manu Saraswat, Chloé Bessière, Christophe Menichelli, Jordan A Ramilowski, Jessica Severin, Yoshihide Hayashizaki, Masayoshi Itoh, Michihira Tagami, Mitsuyoshi Murata, Miki Kojima-Ishiyama, Shohei Noma, Shuhei Noguchi, Takeya Kasukawa, Akira Hasegawa, Harukazu Suzuki, Hiromi Nishiyori-Sueki, Martin C Frith, Fantom Consortium, Clément Chatelain, Piero Carninci, Michiel J L De Hoon, Wyeth W Wasserman, Laurent Bréhélin, Charles-Henri Lecellier, Judith A. Blake, Carol J Bult Jun 2021

Discovery Of Widespread Transcription Initiation At Microsatellites Predictable By Sequence-Based Deep Neural Network., Mathys Grapotte, Manu Saraswat, Chloé Bessière, Christophe Menichelli, Jordan A Ramilowski, Jessica Severin, Yoshihide Hayashizaki, Masayoshi Itoh, Michihira Tagami, Mitsuyoshi Murata, Miki Kojima-Ishiyama, Shohei Noma, Shuhei Noguchi, Takeya Kasukawa, Akira Hasegawa, Harukazu Suzuki, Hiromi Nishiyori-Sueki, Martin C Frith, Fantom Consortium, Clément Chatelain, Piero Carninci, Michiel J L De Hoon, Wyeth W Wasserman, Laurent Bréhélin, Charles-Henri Lecellier, Judith A. Blake, Carol J Bult

Faculty Research 2021

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep ...


Functional Impact Of A Germline Ret Mutation In Alveolar Rhabdomyosarcoma., Noah E Berlow, Kenneth A Crawford, Carol J Bult, Christopher Noakes, Ido Sloma, Erin R Rudzinski, Charles Keller Jun 2021

Functional Impact Of A Germline Ret Mutation In Alveolar Rhabdomyosarcoma., Noah E Berlow, Kenneth A Crawford, Carol J Bult, Christopher Noakes, Ido Sloma, Erin R Rudzinski, Charles Keller

Faculty Research 2021

Specific mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia type 2A, a hereditary syndrome characterized by tumorigenesis in multiple glandular elements. In rare instances, MEN2A-associated germline RET mutations have also occurred with non-MEN2A associated cancers. One such germline mutant RET mutation occurred concomitantly in a young adult diagnosed with alveolar rhabdomyosarcoma, a pediatric and young adult soft-tissue cancer with a generally poor prognosis. Although tumor tissue samples were initially unable to provide a viable cell culture for study, tumor tissues were sequenced for molecular characteristics. Through a hierarchical clustering approach, the index case sample was matched to ...


Integrating Genomics And Metabolomics For Scalable Non-Ribosomal Peptide Discovery., Bahar Behsaz, Edna Bode, Alexey Gurevich, Yan-Ni Shi, Florian Grundmann, Deepa Acharya, Andrés Mauricio Caraballo-Rodríguez, Amina Bouslimani, Morgan Panitchpakdi, Annabell Linck, Changhui Guan, Julia Oh, Pieter C Dorrestein, Helge B Bode, Pavel A Pevzner, Hosein Mohimani May 2021

Integrating Genomics And Metabolomics For Scalable Non-Ribosomal Peptide Discovery., Bahar Behsaz, Edna Bode, Alexey Gurevich, Yan-Ni Shi, Florian Grundmann, Deepa Acharya, Andrés Mauricio Caraballo-Rodríguez, Amina Bouslimani, Morgan Panitchpakdi, Annabell Linck, Changhui Guan, Julia Oh, Pieter C Dorrestein, Helge B Bode, Pavel A Pevzner, Hosein Mohimani

Faculty Research 2021

Non-Ribosomal Peptides (NRPs) represent a biomedically important class of natural products that include a multitude of antibiotics and other clinically used drugs. NRPs are not directly encoded in the genome but are instead produced by metabolic pathways encoded by biosynthetic gene clusters (BGCs). Since the existing genome mining tools predict many putative NRPs synthesized by a given BGC, it remains unclear which of these putative NRPs are correct and how to identify post-assembly modifications of amino acids in these NRPs in a blind mode, without knowing which modifications exist in the sample. To address this challenge, here we report NRPminer ...