Life Sciences Commons^™

Direct Cell-To-Cell Transfer In Stressed Tumor Microenvironment Aggravates Tumorigenic Or Metastatic Potential In Pancreatic Cancer., Giyong Jang, Jaeik Oh, Eunsung Jun, Jieun Lee, Jee Young Kwon, Jaesang Kim, Sang-Hyuk Lee, Song Cheol Kim, Sung-Yup Cho, Charles Lee

Faculty Research 2022

Pancreatic cancer exhibits a characteristic tumor microenvironment (TME) due to enhanced fibrosis and hypoxia and is particularly resistant to conventional chemotherapy. However, the molecular mechanisms underlying TME-associated treatment resistance in pancreatic cancer are not fully understood. Here, we developed an in vitro TME mimic system comprising pancreatic cancer cells, fibroblasts and immune cells, and a stress condition, including hypoxia and gemcitabine. Cells with high viability under stress showed evidence of increased direct cell-to-cell transfer of biomolecules. The resulting derivative cells (CD44

Rgs12 Polarizes The Gpsm2-Gnai Complex To Organize And Elongate Stereocilia In Sensory Hair Cells., Anil Akturk, Matthew Day, Basile Tarchini

Faculty Research 2022

Inhibitory G proteins (GNAI/Gα(i)) bind to the scaffold G protein signaling modulator 2 (GPSM2) to form a conserved polarity complex that regulates cytoskeleton organization. GPSM2 keeps GNAI in a guanosine diphosphate (GDP)-bound state, but how GPSM2-GNAI is generated or relates to heterotrimeric G protein signaling remains unclear. We find that RGS12, a GTPase-activating protein (GAP), is required to polarize GPSM2-GNAI at the hair cell apical membrane and to organize mechanosensory stereocilia in rows of graded heights. Accordingly, RGS12 and the guanine nucleotide exchange factor (GEF) DAPLE are asymmetrically co-enriched at the hair cell apical junction, and Rgs12 mouse mutants are …

The Immune Signatures Data Resource, A Compendium Of Systems Vaccinology Datasets., Joann Diray-Arce, Helen E R Miller, Evan Henrich, Bram Gerritsen, Matthew P Mulè, Slim Fourati, Jeremy Gygi, Thomas Hagan, Lewis Tomalin, Dmitry Rychkov, Dmitri Kazmin, Daniel G Chawla, Hailong Meng, Patrick Dunn, John Campbell, The Human Immunology Project Consortium (Hipc), Minnie Sarwal, John S Tsang, Ofer Levy, Bali Pulendran, Rafick Sekaly, Aris Floratos, Raphael Gottardo, Steven H Kleinstein, Mayte Suárez-Fariñas

Faculty Research 2022

Vaccines are among the most cost-effective public health interventions for preventing infection-induced morbidity and mortality, yet much remains to be learned regarding the mechanisms by which vaccines protect. Systems immunology combines traditional immunology with modern 'omic profiling techniques and computational modeling to promote rapid and transformative advances in vaccinology and vaccine discovery. The NIH/NIAID Human Immunology Project Consortium (HIPC) has leveraged systems immunology approaches to identify molecular signatures associated with the immunogenicity of many vaccines. However, comparative analyses have been limited by the distributed nature of some data, potential batch effects across studies, and the absence of multiple relevant studies …

Mendelian Gene Identification Through Mouse Embryo Viability Screening., Pilar Cacheiro, Carl Henrik Westerberg, Jesse Mager, Mary E Dickinson, Lauryl M J Nutter, Violeta Muñoz-Fuentes, Chih-Wei Hsu, Ignatia B Van Den Veyver, Ann M Flenniken, Colin Mckerlie, Stephen A Murray, Lydia Teboul, Jason D Heaney, K C Kent Lloyd, Louise Lanoue, Robert E Braun, Jacqueline K White, Amie K Creighton, Valerie Laurin, Ruolin Guo, Dawei Qu, Sara Wells, James Cleak, Rosie Bunton-Stasyshyn, Michelle Stewart, Jackie Harrisson, Jeremy Mason, Hamed Haseli Mashhadi, Helen Parkinson, Ann-Marie Mallon, International Mouse Phenotyping Consortium, Genomics England Research Consortium, Damian Smedley

Faculty Research 2022

BACKGROUND: The diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property.

METHODS: Here we further dissected this spectrum by assessing the embryonic stage at which homozygous …

A Dpagt1 Missense Variant Causes Degenerative Retinopathy Without Myasthenic Syndrome In Mice, Lillian F Hyde, Yang Kong, Lihong Zhao, Sriganesh Ramachandra Rao, Jieping Wang, Lisa Stone, Andrew Njaa, Gayle B. Collin, Mark P. Krebs, Bo Chang, Steven J Fliesler, Patsy M. Nishina, Juergen K. Naggert

Faculty Research 2022

Congenital disorders of glycosylation (CDG) are a heterogenous group of primarily autosomal recessive mendelian diseases caused by disruptions in the synthesis of lipid-linked oligosaccharides and their transfer to proteins. CDGs usually affect multiple organ systems and vary in presentation, even within families. There is currently no cure, and treatment is aimed at ameliorating symptoms and improving quality of life. Here, we describe a chemically induced mouse mutant,

Functional Genomics Of Complex Cancer Genomes., Francesca Menghi, Edison Liu

Faculty Research 2022

Cancer functional genomics is the study of how genetic, epigenetic, and transcriptional alterations affect cancer phenotypes, such as growth and therapeutic response. Here, we comment on how, taking advantage of next generation sequencing, functional genomics, often combined with systems biology approaches, has revealed novel cancer vulnerabilities beyond the original paradigm of one gene-one phenotype.

Lineage-Coupled Clonal Capture Identifies Clonal Evolution Mechanisms And Vulnerabilities Of Braf, Ze-Yan Zhang, Yingwen Ding, Ravesanker Ezhilarasan, Tenzin Lhakhang, Qianghu Wang, Jie Yang, Aram S Modrek, Hua Zhang, Aristotelis Tsirigos, Andrew Futreal, Giulio F Draetta, Roel G W Verhaak, Erik P Sulman

Faculty Research 2022

Targeted cancer therapies have revolutionized treatment but their efficacies are limited by the development of resistance driven by clonal evolution within tumors. We developed "CAPTURE", a single-cell barcoding approach to comprehensively trace clonal dynamics and capture live lineage-coupled resistant cells for in-depth multi-omics analysis and functional exploration. We demonstrate that heterogeneous clones, either preexisting or emerging from drug-tolerant persister cells, dominated resistance to vemurafenib in BRAF

Genetic Quality: A Complex Issue For Experimental Study Reproducibility., Atsushi Yoshiki, Gregory Ballard, Ana V Perez

Faculty Research 2022

Laboratory animal research involving mice, requires consideration of many factors to be controlled. Genetic quality is one factor that is often overlooked but is essential for the generation of reproducible experimental results. Whether experimental research involves inbred mice, spontaneous mutant, or genetically modified strains, exercising genetic quality through careful breeding, good recordkeeping, and prudent quality control steps such as validation of the presence of mutations and verification of the genetic background, will help ensure that experimental results are accurate and that reference controls are representative for the particular experiment. In this review paper, we will discuss various techniques used for …

Autosomal Recessive Lrp1-Related Syndrome Featuring Cardiopulmonary Dysfunction, Bone Dysmorphology, And Corneal Clouding., Paul R Mark, Stephen A. Murray, Tao Yang, Alexandra Eby, Angela Lai, Di Lu, Jacob Zieba, Surender Rajasekaran, Elizabeth A Vansickle, Linda Z Rossetti, Lucia Guidugli, Kelly Watkins, Meredith S Wright, Caleb P Bupp, Jeremy W Prokop

Faculty Research 2022

We provide the first study of two siblings with a novel autosomal recessive LRP1-related syndrome identified by rapid genome sequencing and overlapping multiple genetic models. The patients presented with respiratory distress, congenital heart defects, hypotonia, dysmorphology, and unique findings, including corneal clouding and ascites. Both siblings had compound heterozygous damaging variants, c.11420G > C (p.Cys3807Ser) and c.12407T > G (p.Val4136Gly) in

Animals, Quality And The Pursuit Of Relevance., Karen L. Svenson, Stephen D Krasinski, Michael Ellis, Nadia Rosenthal, Edison Liu, Kenneth H Fasman

Faculty Research 2022

In 2021, the National Institutes of Health Advisory Committee to the Director (ACD) announced recommendations to improve the reproducibility of biomedical research using animals. In response, The Jackson Laboratory faculty and institutional leaders identified key strategies to further address this important issue. Taking inspiration from the evolution of clinical trials over recent decades in response to similar challenges, we identified opportunities for improvement, including establishment of common standards, use of genetically diverse populations, requirement for robust study design with appropriate statistical methods, and improvement in public databases to facilitate meta-analyses. In this Perspective, we share our response to ACD recommendations, …

A Standardized Nomenclature For Mammalian Histone Genes., Ruth L Seal, Paul Denny, Elspeth A Bruford, Anna K Gribkova, David Landsman, William F Marzluff, Monica Mcandrews, Anna R Panchenko, Alexey K Shaytan, Paul B Talbert

Faculty Research 2022

Histones have a long history of research in a wide range of species, leaving a legacy of complex nomenclature in the literature. Community-led discussions at the EMBO Workshop on Histone Variants in 2011 resulted in agreement amongst experts on a revised systematic protein nomenclature for histones, which is based on a combination of phylogenetic classification and historical symbol usage. Human and mouse histone gene symbols previously followed a genome-centric system that was not applicable across all vertebrate species and did not reflect the systematic histone protein nomenclature. This prompted a collaboration between histone experts, the Human Genome Organization (HUGO) Gene …

Lesion Environments Direct Transplanted Neural Progenitors Towards A Wound Repair Astroglial Phenotype In Mice., T M O'Shea, Y Ao, S Wang, A L Wollenberg, J H Kim, R A Ramos Espinoza, Anne M. Czechanski, Laura G. Reinholdt, T J Deming, M V Sofroniew

Faculty Research 2022

Neural progenitor cells (NPC) represent potential cell transplantation therapies for CNS injuries. To understand how lesion environments influence transplanted NPC fate in vivo, we derived NPC expressing a ribosomal protein-hemagglutinin tag (RiboTag) for transcriptional profiling of transplanted NPC. Here, we show that NPC grafted into uninjured mouse CNS generate cells that are transcriptionally similar to healthy astrocytes and oligodendrocyte lineages. In striking contrast, NPC transplanted into subacute CNS lesions after stroke or spinal cord injury in mice generate cells that share transcriptional, morphological and functional features with newly proliferated host astroglia that restrict inflammation and fibrosis and isolate lesions from …

Evaluation Of Phenotype-Driven Gene Prioritization Methods For Mendelian Diseases., Julius O B Jacobsen, Catherine Kelly, Valentina Cipriani, Peter N Robinson, Damian Smedley

Faculty Research 2022

Yuan et al. recently described an independent evaluation of several phenotype-driven gene prioritization methods for Mendelian disease on two separate, clinical datasets. Although they attempted to use default settings for each tool, we describe three key differences from those we currently recommend for our Exomiser and PhenIX tools. These influence how variant frequency, quality and predicted pathogenicity are used for filtering and prioritization. We propose that these differences account for much of the discrepancy in performance between that reported by them (15-26% diagnoses ranked top by Exomiser) and previously published reports by us and others (72-77%). On a set of …

Epigenetic Activation Of The Flt3 Gene By Znf384 Fusion Confers A Therapeutic Susceptibility In Acute Lymphoblastic Leukemia., Xujie Zhao, Ping Wang, Jonathan D Diedrich, Brandon Smart, Noemi Reyes, Satoshi Yoshimura, Jingliao Zhang, Wentao Yang, Kelly Barnett, Beisi Xu, Zhenhua Li, Xin Huang, Jiyang Yu, Kristine Crews, Allen Eng Juh Yeoh, Marina Konopleva, Chia-Lin Wei, Ching-Hon Pui, Daniel Savic, Jun J Yang

Faculty Research 2022

FLT3 is an attractive therapeutic target in acute lymphoblastic leukemia (ALL) but the mechanism for its activation in this cancer is incompletely understood. Profiling global gene expression in large ALL cohorts, we identify over-expression of FLT3 in ZNF384-rearranged ALL, consistently across cases harboring different fusion partners with ZNF384. Mechanistically, we discover an intergenic enhancer element at the FLT3 locus that is exclusively activated in ZNF384-rearranged ALL, with the enhancer-promoter looping directly mediated by the fusion protein. There is also a global enrichment of active enhancers within ZNF384 binding sites across the genome in ZNF384-rearranged ALL cells. Downregulation of ZNF384 blunts …

Single-Cell Rna Sequencing Reveals Molecular Features Of Heterogeneity In The Murine Retinal Pigment Epithelium., Ravi S Pandey, Mark P. Krebs, Mohan Bolisetty, Jeremy R. Charette, Juergen K. Naggert, Paul Robson, Patsy M. Nishina, Gregory W. Carter

Faculty Research 2022

Transcriptomic analysis of the mammalian retinal pigment epithelium (RPE) aims to identify cellular networks that influence ocular development, maintenance, function, and disease. However, available evidence points to RPE cell heterogeneity within native tissue, which adds complexity to global transcriptomic analysis. Here, to assess cell heterogeneity, we performed single-cell RNA sequencing of RPE cells from two young adult male C57BL/6J mice. Following quality control to ensure robust transcript identification limited to cell singlets, we detected 13,858 transcripts among 2667 and 2846 RPE cells. Dimensional reduction by principal component analysis and uniform manifold approximation and projection revealed six distinct cell populations. All …

Promoting Validation And Cross-Phylogenetic Integration In Model Organism Research., Keith C Cheng, Rebecca D Burdine, Mary E Dickinson, Stephen C Ekker, Alex Y Lin, K C Kent Lloyd, Cathleen Lutz, Calum A Macrae, John H Morrison, David H O'Connor, John H Postlethwait, Crystal D Rogers, Susan Sanchez, Julie H Simpson, William S Talbot, Douglas C Wallace, Jill M Weimer, Hugo J Bellen

Faculty Research 2022

Model organism (MO) research provides a basic understanding of biology and disease due to the evolutionary conservation of the molecular and cellular language of life. MOs have been used to identify and understand the function of orthologous genes, proteins, cells and tissues involved in biological processes, to develop and evaluate techniques and methods, and to perform whole-organism-based chemical screens to test drug efficacy and toxicity. However, a growing richness of datasets and the rising power of computation raise an important question: How do we maximize the value of MOs? In-depth discussions in over 50 virtual presentations organized by the National …

Pts Is Activated By Atf4 And Promotes Lung Adenocarcinoma Development Via The Wnt Pathway, Wei Ma, Chao Wang, Ruzhen Li, Zhaohui Han, Yuanzhu Jiang, Xiangwei Zhang, Duilio Divisi, Enrico Capobianco, Lin Zhang, Wei Dong

Faculty Research 2022

BACKGROUND: The effects and mechanism of 6-pyruvoyl-tetrahydropterin synthase (

METHODS:

RESULTS:

CONCLUSIONS:

R-Loop Formation In Meiosis: Roles In Meiotic Transcription-Associated Dna Damage., Yasuhiro Fujiwara, Mary Ann Handel, Yuki Okada

Faculty Research 2022

Meiosis is specialized cell division during gametogenesis that produces genetically unique gametes via homologous recombination. Meiotic homologous recombination entails repairing programmed 200-300 DNA double-strand breaks generated during the early prophase. To avoid interference between meiotic gene transcription and homologous recombination, mammalian meiosis is thought to employ a strategy of exclusively transcribing meiotic or post-meiotic genes before their use. Recent studies have shown that R-loops, three-stranded DNA/RNA hybrid nucleotide structures formed during transcription, play a crucial role in transcription and genome integrity. Although our knowledge about the function of R-loops during meiosis is limited, recent findings in mouse models have suggested …

Germline Thymidylate Synthase Deficiency Impacts Nucleotide Metabolism And Causes Dyskeratosis Congenita., Hemanth Tummala, Amanda Walne, Roberto Buccafusca, Jenna Alnajar, Anita Szabo, Peter N Robinson, Allyn Mcconkie-Rosell, Meredith Wilson, Suzanne Crowley, Veronica Kinsler, Anna-Maria Ewins, Pradeepa M Madapura, Manthan Patel, Nikolas Pontikos, Veryan Codd, Tom Vulliamy, Inderjeet Dokal

Faculty Research 2022

Dyskeratosis congenita (DC) is an inherited bone-marrow-failure disorder characterized by a triad of mucocutaneous features that include abnormal skin pigmentation, nail dystrophy, and oral leucoplakia. Despite the identification of several genetic variants that cause DC, a significant proportion of probands remain without a molecular diagnosis. In a cohort of eight independent DC-affected families, we have identified a remarkable series of heterozygous germline variants in the gene encoding thymidylate synthase (TYMS). Although the inheritance appeared to be autosomal recessive, one parent in each family had a wild-type TYMS coding sequence. Targeted genomic sequencing identified a specific haplotype and rare variants in …

Phenotype-Driven Approaches To Enhance Variant Prioritization And Diagnosis Of Rare Disease., Julius O B Jacobsen, Catherine Kelly, Valentina Cipriani, Genomics England Research Consortium, Christopher J Mungall, Justin Reese, Daniel Danis, Peter N Robinson, Damian Smedley

Faculty Research 2022

Rare disease diagnostics and disease gene discovery have been revolutionized by whole-exome and genome sequencing but identifying the causative variant(s) from the millions in each individual remains challenging. The use of deep phenotyping of patients and reference genotype-phenotype knowledge, alongside variant data such as allele frequency, segregation, and predicted pathogenicity, has proved an effective strategy to tackle this issue. Here we review the numerous tools that have been developed to automate this approach and demonstrate the power of such an approach on several thousand diagnosed cases from the 100,000 Genomes Project. Finally, we discuss the challenges that need to be …

Jackie: Fast Enumeration Of Genome-Wide Single- And Multicopy Crispr Target Sites And Their Off-Target Numbers., Jacqueline Jufen Zhu, Albert Cheng

Faculty Research 2022

Zinc finger protein-, transcription activator like effector-, and CRISPR-based methods for genome and epigenome editing and imaging have provided powerful tools to investigate functions of genomes. Targeting sequence design is vital to the success of these experiments. Although existing design software mainly focus on designing target sequence for specific elements, we report here the implementation of Jackie and Albert's Comprehensive K-mer Instances Enumerator (JACKIE), a suite of software for enumerating all single- and multicopy sites in the genome that can be incorporated for genome-scale designs as well as loaded onto genome browsers alongside other tracks for convenient web-based graphic-user-interface-enabled design. …

Sex Differences In The Genetic Architecture Of Cognitive Resilience To Alzheimer's Disease., Jaclyn M Eissman, Logan Dumitrescu, Emily R Mahoney, Alexandra N Smith, Shubhabrata Mukherjee, Michael L Lee, Phoebe Scollard, Seo Eun Choi, William S Bush, Corinne D Engelman, Qiongshi Lu, David W Fardo, Emily H Trittschuh, Jesse Mez, Catherine C Kaczorowski, Hector Hernandez Saucedo, Keith F Widaman, Rachel F Buckley, Michael J Properzi, Elizabeth C Mormino, Hyun Sik Yang, Theresa M Harrison, Trey Hedden, Kwangsik Nho, Shea J Andrews, Douglas Tommet, Niran Hadad, R Elizabeth Sanders, Douglas M Ruderfer, Katherine A Gifford, Xiaoyuan Zhong, Neha S Raghavan, Badri N Vardarajan, Margaret A Pericak-Vance, Lindsay A Farrer, Li San Wang, Carlos Cruchaga, Gerard D Schellenberg, Nancy J Cox, Jonathan L Haines, C Dirk Keene, Andrew J Saykin, Eric B Larson, Reisa A Sperling, Richard Mayeux, Michael L Cuccaro, David A Bennett, Julie A Schneider, Paul K Crane, Angela L Jefferson, Timothy J Hohman

Faculty Research 2022

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts …

Regulated Dicing Of Pre-Mir-144 Via Reshaping Of Its Terminal Loop., Renfu Shang, Dmitry A Kretov, Scott I Adamson, Thomas Treiber, Nora Treiber, Jeffrey Vedanayagam, Jeffrey H Chuang, Gunter Meister, Daniel Cifuentes, Eric C Lai

Faculty Research 2022

Although the route to generate microRNAs (miRNAs) is often depicted as a linear series of sequential and constitutive cleavages, we now appreciate multiple alternative pathways as well as diverse strategies to modulate their processing and function. Here, we identify an unusually profound regulatory role of conserved loop sequences in vertebrate pre-mir-144, which are essential for its cleavage by the Dicer RNase III enzyme in human and zebrafish models. Our data indicate that pre-mir-144 dicing is positively regulated via its terminal loop, and involves the ILF3 complex (NF90 and its partner NF45/ILF2). We provide further evidence that this regulatory switch involves …

Integrated Dna Copy Number And Expression Profiling Identifies Igf1r As A Prognostic Biomarker In Pediatric Osteosarcoma., Aaron M Taylor, Jiayi M Sun, Alexander Yu, Horatiu Voicu, Jianhe Shen, Donald A Barkauskas, Timothy J Triche, Julie M Gastier-Foster, Tsz-Kwong Man, Ching C Lau

Faculty Research 2022

Osteosarcoma is a primary malignant bone tumor arising from bone-forming mesenchymal cells in children and adolescents. Despite efforts to understand the biology of the disease and identify novel therapeutics, the survival of osteosarcoma patients remains dismal. We have concurrently profiled the copy number and gene expression of 226 osteosarcoma samples as part of the Strategic Partnering to Evaluate Cancer Signatures (SPECS) initiative. Our results demonstrate the heterogeneous landscape of osteosarcoma in younger populations by showing the presence of genome-wide copy number abnormalities occurring both recurrently among samples and in a high frequency. Insulin growth factor receptor 1 (IGF1R) is a …

Age And Diet Shape The Genetic Architecture Of Body Weight In Diversity Outbred Mice., Kevin M Wright, Andrew Deighan, Andrea Di Francesco, Adam Freund, Vladimir Jojic, Gary Churchill, Anil Raj

Faculty Research 2022

Understanding how genetic variation shapes a complex trait relies on accurately quantifying both the additive genetic and genotype-environment interaction effects in an age-dependent manner. We used a linear mixed model to quantify diet-dependent genetic contributions to body weight measured through adulthood in diversity outbred female mice under five diets. We observed that heritability of body weight declined with age under all diets, except the 40% calorie restriction diet. We identified 14 loci with age-dependent associations and 19 loci with age- and diet-dependent associations, with many diet-dependent loci previously linked to neurological function and behavior in mice or humans. We found …

Prophylactic Evaluation Of Verubecestat On Disease- And Symptom-Modifying Effects In 5xfad Mice., Adrian L Oblak, Zackary A Cope, Sara K Quinney, Ravi S Pandey, Carla Biesdorf, Andi R Masters, Kristen D. Onos, Leslie Haynes, Kelly J Keezer, Jill A Meyer, Jonathan S Peters, Scott A Persohn, Amanda A Bedwell, Kierra Eldridge, Rachael Speedy, Gabriela Little, Sean-Paul Williams, Brenda Noarbe, Andre Obenaus, Michael Sasner, Gareth R Howell, Gregory W. Carter, Harriet M. Jackson, Bruce T Lamb, Paul R Territo, Stacey J Sukoff Rizzo

Faculty Research 2022

Introduction: Alzheimer's disease (AD) is the most common form of dementia. Beta-secretase (BACE) inhibitors have been proposed as potential therapeutic interventions; however, initiating treatment once disease has significantly progressed has failed to effectively stop or treat disease. Whether BACE inhibition may have efficacy when administered prophylactically in the early stages of AD has been under-investigated. The present studies aimed to evaluate prophylactic treatment of the BACE inhibitor verubecestat in an AD mouse model using the National Institute on Aging (NIA) resources of the Model Organism Development for Late-Onset Alzheimer's Disease (MODEL-AD) Preclinical Testing Core (PTC) Drug Screening Pipeline.

Methods: 5XFAD …

Mortality Prediction Analysis Among Covid-19 Inpatients Using Clinical Variables And Deep Learning Chest Radiography Imaging Features., Xuan V Nguyen, Engin Dikici, Sema Candemir, Robyn L Ball, Luciano M Prevedello

Faculty Research 2022

The emergence of the COVID-19 pandemic over a relatively brief interval illustrates the need for rapid data-driven approaches to facilitate clinical decision making. We examined a machine learning process to predict inpatient mortality among COVID-19 patients using clinical and chest radiographic data. Modeling was performed with a de-identified dataset of encounters prior to widespread vaccine availability. Non-imaging predictors included demographics, pre-admission clinical history, and past medical history variables. Imaging features were extracted from chest radiographs by applying a deep convolutional neural network with transfer learning. A multi-layer perceptron combining 64 deep learning features from chest radiographs with 98 patient clinical …

A Research Agenda To Support The Development And Implementation Of Genomics-Based Clinical Informatics Tools And Resources., Ken Wiley, Laura Findley, Madison Goldrich, Tejinder K Rakhra-Burris, Ana Stevens, Pamela Williams, Carol J Bult, Rex Chisholm, Patricia Deverka, Geoffrey S Ginsburg, Eric D Green, Gail Jarvik, George A Mensah, Erin Ramos, Mary V Relling, Dan M Roden, Robb Rowley, Gil Alterovitz, Samuel Aronson, Lisa Bastarache, James J Cimino, Erin L Crowgey, Guilherme Del Fiol, Robert R Freimuth, Mark A Hoffman, Janina Jeff, Kevin Johnson, Kensaku Kawamoto, Subha Madhavan, Eneida A Mendonca, Lucila Ohno-Machado, Siddharth Pratap, Casey Overby Taylor, Marylyn D Ritchie, Nephi Walton, Chunhua Weng, Teresa Zayas-Cabán, Teri A Manolio, Marc S Williams

Faculty Research 2022

OBJECTIVE: The Genomic Medicine Working Group of the National Advisory Council for Human Genome Research virtually hosted its 13th genomic medicine meeting titled "Developing a Clinical Genomic Informatics Research Agenda". The meeting's goal was to articulate a research strategy to develop Genomics-based Clinical Informatics Tools and Resources (GCIT) to improve the detection, treatment, and reporting of genetic disorders in clinical settings.

MATERIALS AND METHODS: Experts from government agencies, the private sector, and academia in genomic medicine and clinical informatics were invited to address the meeting's goals. Invitees were also asked to complete a survey to assess important considerations needed to …

Interchromosomal Interaction Of Homologous Stat92e Alleles Regulates Transcriptional Switch During Stem-Cell Differentiation., Matthew Antel, Romir Raj, Madona Y G Masoud, Ziwei Pan, Sheng Li, Barbara G Mellone, Mayu Inaba

Faculty Research 2022

Pairing of homologous chromosomes in somatic cells provides the opportunity of interchromosomal interaction between homologous gene regions. In the Drosophila male germline, the Stat92E gene is highly expressed in a germline stem cell (GSC) and gradually downregulated during the differentiation. Here we show that the pairing of Stat92E is always tight in GSCs and immediately loosened in differentiating daughter cells, gonialblasts (GBs). Disturbance of Stat92E pairing by relocation of one locus to another chromosome or by knockdown of global pairing/anti-pairing factors both result in a failure of Stat92E downregulation, suggesting that the pairing is required for the decline in transcription. …

Programmable Rna-Guided Large Dna Transgenesis By Crispr/Cas9 And Site-Specific Integrase Bxb1., Vishnu Hosur, Benjamin E. Low, Michael V. Wiles

Faculty Research 2022

The inability to insert large DNA constructs into the genome efficiently and precisely is a key challenge in genomic engineering. Random transgenesis, which is widely used, lacks precision, and comes with a slew of drawbacks. Lentiviral and adeno-associated viral methods are plagued by, respectively, DNA toxicity and a payload capacity of less than 5 kb. Homology-directed repair (HDR) techniques based on CRISPR-Cas9 can be effective, but only in the 1-5 kb range. In addition, long homology arms-DNA sequences that permit construct insertion-of lengths ranging from 0.5 to 5 kb are required by currently known HDR-based techniques. A potential new method …