Medicine and Health Sciences Commons^™

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 …

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 …

Antibody Responses To Sars-Cov-2 After Infection Or Vaccination In Children And Young Adults With Inflammatory Bowel Disease., Joelynn Dailey, Lina Kozhaya, Mikail Dogan, Dena Hopkins, Blaine Lapin, Katherine Herbst, Michael Brimacombe, Kristen Grandonico, Fatih Karabacak, John Schreiber, Bruce Tsan-Liang Liang, Juan C Salazar, Derya Unutmaz, Jeffrey S Hyams

Faculty Research 2022

BACKGROUND: Characterization of neutralization antibodies to SARS-CoV-2 infection or vaccination in children and young adults with inflammatory bowel disease (IBD) receiving biologic therapies is crucial.

METHODS: We performed a prospective longitudinal cohort study evaluating SARS-CoV-2 spike protein receptor binding domain (S-RBD) IgG positivity along with consistent clinical symptoms in patients with IBD receiving infliximab or vedolizumab. Serum was also obtained following immunization with approved vaccines. The IgG antibody to the spike protein binding domain of SARS-CoV-2 was assayed with a fluorescent bead-based immunoassay that takes advantage of the high dynamic range of fluorescent molecules using flow cytometry. A sensitive and …

Transcriptional And Translational Dynamics Of Zika And Dengue Virus Infection., Kamini Singh, Maria Guadalupe Martinez, Jianan Lin, James Gregory, Trang Uyen Nguyen, Rawan Abdelaal, Kristy Kang, Kristen Brennand, Arnold Grünweller, Zhengqing Ouyang, Hemali Phatnani, Margaret Kielian, Hans-Guido Wendel

Faculty Research 2022

Zika virus (ZIKV) and dengue virus (DENV) are members of the Flaviviridae family of RNA viruses and cause severe disease in humans. ZIKV and DENV share over 90% of their genome sequences, however, the clinical features of Zika and dengue infections are very different reflecting tropism and cellular effects. Here, we used simultaneous RNA sequencing and ribosome footprinting to define the transcriptional and translational dynamics of ZIKV and DENV infection in human neuronal progenitor cells (hNPCs). The gene expression data showed induction of aminoacyl tRNA synthetases (ARS) and the translation activating PIM1 kinase, indicating an increase in RNA translation capacity. …

Cdc20 Regulates Sensitivity To Chemotherapy And Radiation In Glioblastoma Stem Cells., Diane D Mao, Ryan T Cleary, Amit D Gujar, Tatenda Mahlokozera, Albert H Kim

Faculty Research 2022

Glioblastoma stem cells (GSCs) are an important subpopulation in glioblastoma, implicated in tumor growth, tumor recurrence, and radiation resistance. Understanding the cellular mechanisms for chemo- and radiation resistance could lead to the development of new therapeutic strategies. Here, we demonstrate that CDC20 promotes resistance to chemotherapy and radiation therapy. CDC20 knockdown does not increase TMZ- and radiation-induced DNA damage, or alter DNA damage repair, but rather promotes cell death through accumulation of the pro-apoptotic protein, Bim. Our results identify a CDC20 signaling pathway that regulates chemo- and radiosensitivity in GSCs, with the potential for CDC20-targeted therapeutic strategies in the treatment …

Effects Of Paternal High-Fat Diet And Maternal Rearing Environment On The Gut Microbiota And Behavior., Austin C Korgan, Christine L Foxx, Heraa Hashmi, Saydie A Sago, Christopher E Stamper, Jared D Heinze, Elizabeth O'Leary, Jillian L King, Tara S Perrot, Christopher A Lowry, Ian C G Weaver

Faculty Research 2022

Exposing a male rat to an obesogenic high-fat diet (HFD) influences attractiveness to potential female mates, the subsequent interaction of female mates with infant offspring, and the development of stress-related behavioral and neural responses in offspring. To examine the stomach and fecal microbiome's potential roles, fecal samples from 44 offspring and stomach samples from offspring and their fathers were collected and bacterial community composition was studied by 16 small subunit ribosomal RNA (16S rRNA) gene sequencing. Paternal diet (control, high-fat), maternal housing conditions (standard or semi-naturalistic housing), and maternal care (quality of nursing and other maternal behaviors) affected the within-subjects …

Pluripotent Cell States And Unexpected Fates., Martin Pera

Faculty Research 2022

Pluripotent stem cells provide a powerful model for the study of human development and its disorders. Recent studies, including two in this issue of Stem Cell Reports, raise important questions concerning the developmental potential of human pluripotent stem cells, and how the behavior of these cells in vitro mirrors normal embryogenesis.

Deep Learning Features Encode Interpretable Morphologies Within Histological Images., Ali Foroughi Pour, Brian S White, Jonghanne Park, Todd B Sheridan, Jeffrey H Chuang

Faculty Research 2022

Convolutional neural networks (CNNs) are revolutionizing digital pathology by enabling machine learning-based classification of a variety of phenotypes from hematoxylin and eosin (H&E) whole slide images (WSIs), but the interpretation of CNNs remains difficult. Most studies have considered interpretability in a post hoc fashion, e.g. by presenting example regions with strongly predicted class labels. However, such an approach does not explain the biological features that contribute to correct predictions. To address this problem, here we investigate the interpretability of H&E-derived CNN features (the feature weights in the final layer of a transfer-learning-based architecture). While many studies have incorporated CNN features …

The Rd-Connect Genome-Phenome Analysis Platform: Accelerating Diagnosis, Research, And Gene Discovery For Rare Diseases., Steven Laurie, Davide Piscia, Leslie Matalonga, Alberto Corvó, Marcos Fernández-Callejo, Carles Garcia-Linares, Carles Hernandez-Ferrer, Cristina Luengo, Inés Martínez, Anastasios Papakonstantinou, Daniel Picó-Amador, Joan Protasio, Rachel Thompson, Raul Tonda, Mònica Bayés, Gemma Bullich, Jordi Camps-Puchadas, Ida Paramonov, Jean-Rémi Trotta, Angel Alonso, Marcella Attimonelli, Christophe Béroud, Virginie Bros-Facer, Orion J Buske, Andrés Cañada-Pallarés, José M Fernández, Mats G Hansson, Rita Horvath, Julius O B Jacobsen, Rajaram Kaliyaperumal, Séverine Lair-Préterre, Luana Licata, Pedro Lopes, Estrella López-Martín, Deborah Mascalzoni, Lucia Monaco, Luis A Pérez-Jurado, Manuel Posada De La Paz, Jordi Rambla, Ana Rath, Olaf Riess, Peter N Robinson, David Salgado, Damian Smedley, Dylan Spalding, Peter A C 'T Hoen, Ana Töpf, Irina Zaharieva, Holm Graessner, Ivo G Gut, Hanns Lochmüller, Sergi Beltran

Faculty Research 2022

Rare disease patients are more likely to receive a rapid molecular diagnosis nowadays thanks to the wide adoption of next-generation sequencing. However, many cases remain undiagnosed even after exome or genome analysis, because the methods used missed the molecular cause in a known gene, or a novel causative gene could not be identified and/or confirmed. To address these challenges, the RD-Connect Genome-Phenome Analysis Platform (GPAP) facilitates the collation, discovery, sharing, and analysis of standardized genome-phenome data within a collaborative environment. Authorized clinicians and researchers submit pseudonymised phenotypic profiles encoded using the Human Phenotype Ontology, and raw genomic data which is …

Prenatal Phenotyping: A Community Effort To Enhance The Human Phenotype Ontology., Ferdinand Dhombres, Patricia Morgan, Bimal P Chaudhari, Isabel Filges, Teresa N Sparks, Pablo Lapunzina, Tony Roscioli, Umber Agarwal, Shagun Aggarwal, Claire Beneteau, Pilar Cacheiro, Leigh Carmody, Sophie Collardeau-Frachon, Esther A Dempsey, Andreas Dufke, Michael Henri Duyzend, Mirna El Ghosh, Jessica L Giordano, Ragnhild Glad, Ieva Grinfelde, Dominic G Iliescu, Markus S Ladewig, Monica C Munoz-Torres, Marzia Pollazzon, Francesca Clementina Radio, Carlota Rodo, Raquel Gouveia Silva, Damian Smedley, Jagadish Chandrabose Sundaramurthi, Sabrina Toro, Irene Valenzuela, Nicole A Vasilevsky, Ronald J Wapner, Roni Zemet, Melissa A Haendel, Peter N Robinson

Faculty Research 2022

Technological advances in both genome sequencing and prenatal imaging are increasing our ability to accurately recognize and diagnose Mendelian conditions prenatally. Phenotype-driven early genetic diagnosis of fetal genetic disease can help to strategize treatment options and clinical preventive measures during the perinatal period, to plan in utero therapies, and to inform parental decision-making. Fetal phenotypes of genetic diseases are often unique and at present are not well understood; more comprehensive knowledge about prenatal phenotypes and computational resources have an enormous potential to improve diagnostics and translational research. The Human Phenotype Ontology (HPO) has been widely used to support diagnostics and …

Recurrent Inversion Polymorphisms In Humans Associate With Genetic Instability And Genomic Disorders., David Porubsky, Wolfram Höps, Hufsah Ashraf, Pinghsun Hsieh, Bernardo Rodriguez-Martin, Feyza Yilmaz, Jana Ebler, Pille Hallast, Flavia Angela Maria Maggiolini, William T Harvey, Barbara Henning, Peter A Audano, David S Gordon, Peter Ebert, Patrick Hasenfeld, Eva Benito, Qihui Zhu, Charles Lee, Francesca Antonacci, Matthias Steinrücken, Christine R Beck, Ashley D Sanders, Tobias Marschall, Evan E Eichler, Jan O Korbel

Faculty Research 2022

Unlike copy number variants (CNVs), inversions remain an underexplored genetic variation class. By integrating multiple genomic technologies, we discover 729 inversions in 41 human genomes. Approximately 85% of inversionsretrotransposition; 80% of the larger inversions are balanced and affect twice as many nucleotides as CNVs. Balanced inversions show an excess of common variants, and 72% are flanked by segmental duplications (SDs) or retrotransposons. Since flanking repeats promote non-allelic homologous recombination, we developed complementary approaches to identify recurrent inversion formation. We describe 40 recurrent inversions encompassing 0.6% of the genome, showing inversion rates up to 2.7 × 10

Super-Resolution Visualization Of Chromatin Loop Folding In Human Lymphoblastoid Cells Using Interferometric Photoactivated Localization Microscopy., Zofia Parteka-Tojek, Jacqueline Jufen Zhu, Byoungkoo Lee, Karolina Jodkowska, Ping Wang, Jesse Aaron, Teng-Leong Chew, Krzysztof Banecki, Dariusz Plewczynski, Yijun Ruan

Faculty Research 2022

The three-dimensional (3D) genome structure plays a fundamental role in gene regulation and cellular functions. Recent studies in 3D genomics inferred the very basic functional chromatin folding structures known as chromatin loops, the long-range chromatin interactions that are mediated by protein factors and dynamically extruded by cohesin. We combined the use of FISH staining of a very short (33 kb) chromatin fragment, interferometric photoactivated localization microscopy (iPALM), and traveling salesman problem-based heuristic loop reconstruction algorithm from an image of the one of the strongest CTCF-mediated chromatin loops in human lymphoblastoid cells. In total, we have generated thirteen good quality images …

Transcriptional Profiling Of Macrophages In Situ In Metastatic Melanoma Reveals Localization-Dependent Phenotypes And Function., Jan Martinek, Jianan Lin, Kyung In Kim, Victor G Wang, Te-Chia Wu, Michael Chiorazzi, Hannah Boruchov, Ananya Gulati, Shamreethaa Seeniraj, Lili Sun, Florentina Marches, Paul Robson, Anthony Rongvaux, Richard A Flavell, Joshy George, Jeffrey Chuang, Jacques Banchereau, Karolina Palucka

Faculty Research 2022

Modulation of immune function at the tumor site could improve patient outcomes. Here, we analyze patient samples of metastatic melanoma, a tumor responsive to T cell-based therapies, and find that tumor-infiltrating T cells are primarily juxtaposed to CD14⁺ monocytes/macrophages rather than melanoma cells. Using immunofluorescence-guided laser capture microdissection, we analyze transcriptomes of CD3⁺ T cells, CD14 ⁺ monocytes/macrophages, and melanoma cells in non-dissociated tissue. Stromal CD14⁺ cells display a specific transcriptional signature distinct from CD14⁺ cells within tumor nests. This signature contains LY75, a gene linked with antigen capture and regulation of tolerance and immunity in …

Nsaid Use And Clinical Outcomes In Covid-19 Patients: A 38-Center Retrospective Cohort Study., Justin T Reese, Ben D Coleman, Lauren Chan, Hannah Blau, Tiffany J Callahan, Luca Cappelletti, Tommaso Fontana, Katie R Bradwell, Nomi L Harris, Elena Casiraghi, Giorgio Valentini, Guy Karlebach, Rachel Deer, Julie A Mcmurry, Melissa A Haendel, Christopher G Chute, Emily Pfaff, Richard Moffitt, Heidi Spratt, Jasvinder A Singh, Christopher J Mungall, Andrew E Williams, Peter N Robinson

Faculty Research 2022

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to reduce pain, fever, and inflammation but have been associated with complications in community-acquired pneumonia. Observations shortly after the start of the COVID-19 pandemic in 2020 suggested that ibuprofen was associated with an increased risk of adverse events in COVID-19 patients, but subsequent observational studies failed to demonstrate increased risk and in one case showed reduced risk associated with NSAID use.

METHODS: A 38-center retrospective cohort study was performed that leveraged the harmonized, high-granularity electronic health record data of the National COVID Cohort Collaborative. A propensity-matched cohort of 19,746 COVID-19 inpatients was …

Combining Genomic And Epidemiological Data To Compare The Transmissibility Of Sars-Cov-2 Variants Alpha And Iota., Mary E Petrone, Jessica E Rothman, Mallery I Breban, Isabel M Ott, Alexis Russell, Erica Lasek-Nesselquist, Hamada Badr, Kevin Kelly, Gregory Omerza, Nicholas Renzette, Anne E Watkins, Chaney C Kalinich, Tara Alpert, Anderson F Brito, Rebecca Earnest, Irina R Tikhonova, Christopher Castaldi, John P Kelly, Matthew Shudt, Jonathan Plitnick, Erasmus Schneider, Steven Murphy, Caleb Neal, Eva Laszlo, Ahmad Altajar, Claire Pearson, Anthony Muyombwe, Randy Downing, Jafar Razeq, Linda Niccolai, Madeline S Wilson, Margaret L Anderson, Jianhui Wang, Chen Liu, Pei Hui, Shrikant Mane, Bradford P Taylor, William P Hanage, Marie L Landry, David R Peaper, Kaya Bilguvar, Joseph R Fauver, Chantal B F Vogels, Lauren M Gardner, Virginia E Pitzer, Kirsten St George, Mark D Adams, Nathan D Grubaugh

Faculty Research 2022

SARS-CoV-2 variants shaped the second year of the COVID-19 pandemic and the discourse around effective control measures. Evaluating the threat posed by a new variant is essential for adapting response efforts when community transmission is detected. In this study, we compare the dynamics of two variants, Alpha and Iota, by integrating genomic surveillance data to estimate the effective reproduction number (R_t) of the variants. We use Connecticut, United States, in which Alpha and Iota co-circulated in 2021. We find that the R_t of these variants were up to 50% larger than that of other variants. We then …

Central Nervous System Immune Interactome Is A Function Of Cancer Lineage, Tumor Microenvironment, And Stat3 Expression., Hinda Najem, Martina Ott, Cynthia Kassab, Arvind Rao, Ganesh Rao, Anantha Marisetty, Adam M Sonabend, Craig Horbinski, Roel G W Verhaak, Anand Shankar, Santhoshi N Krishnan, Frederick S Varn, Víctor A Arrieta, Pravesh Gupta, Sherise D Ferguson, Jason T Huse, Gregory N Fuller, James P Long, Daniel E Winkowski, Ben A Freiberg, Charles David James, Leonidas C Platanias, Maciej S Lesniak, Jared K Burks, Amy B Heimberger

Faculty Research 2022

BACKGROUNDImmune cell profiling of primary and metastatic CNS tumors has been focused on the tumor, not the tumor microenvironment (TME), or has been analyzed via biopsies.METHODSEn bloc resections of gliomas (n = 10) and lung metastases (n = 10) were analyzed via tissue segmentation and high-dimension Opal 7-color multiplex imaging. Single-cell RNA analyses were used to infer immune cell functionality.RESULTSWithin gliomas, T cells were localized in the infiltrating edge and perivascular space of tumors, while residing mostly in the stroma of metastatic tumors. CD163+ macrophages were evident throughout the TME of metastatic tumors, whereas in gliomas, CD68+, CD11c+CD68+, and CD11c+CD68+CD163+ …

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 human and …

Svanna: Efficient And Accurate Pathogenicity Prediction Of Coding And Regulatory Structural Variants In Long-Read Genome Sequencing., Daniel Danis, Julius O B Jacobsen, Parithi Balachandran, Qihui Zhu, Feyza Yilmaz, Justin Reese, Matthias Haimel, Gholson J Lyon, Ingo Helbig, Christopher J Mungall, Christine R Beck, Charles Lee, Damian Smedley, Peter N Robinson

Faculty Research 2022

Structural variants (SVs) are implicated in the etiology of Mendelian diseases but have been systematically underascertained owing to sequencing technology limitations. Long-read sequencing enables comprehensive detection of SVs, but approaches for prioritization of candidate SVs are needed. Structural variant Annotation and analysis (SvAnna) assesses all classes of SVs and their intersection with transcripts and regulatory sequences, relating predicted effects on gene function with clinical phenotype data. SvAnna places 87% of deleterious SVs in the top ten ranks. The interpretable prioritizations offered by SvAnna will facilitate the widespread adoption of long-read sequencing in diagnostic genomics. SvAnna is available at https://github.com/TheJacksonLaboratory/SvAnn a …

Long Noncoding Rna Zfp36l2-As Functions As A Metabolic Modulator To Regulate Muscle Development., Bolin Cai, Manting Ma, Jing Zhang, Shaofen Kong, Zhen Zhou, Zhenhui Li, Bahareldin Ali Abdalla, Haiping Xu, Xiquan Zhang, Raman Akinyanju Lawal, Qinghua Nie

Faculty Research 2022

Skeletal muscle is the largest metabolic organ in the body, and its metabolic flexibility is essential for maintaining systemic energy homeostasis. Metabolic inflexibility in muscles is a dominant cause of various metabolic disorders, impeding muscle development. In our previous study, we found lncRNA ZFP36L2-AS (for "ZFP36L2-antisense transcript") is specifically enriched in skeletal muscle. Here, we report that ZFP36L2-AS is upregulated during myogenic differentiation, and highly expressed in breast and leg muscle. In vitro, ZFP36L2-AS inhibits myoblast proliferation but promotes myoblast differentiation. In vivo, ZFP36L2-AS facilitates intramuscular fat deposition, as well as activates fast-twitch muscle phenotype and induces muscle atrophy. Mechanistically, …

Comparative Transmissibility Of Sars-Cov-2 Variants Delta And Alpha In New England, Usa., Rebecca Earnest, Rockib Uddin, Nicholas Matluk, Nicholas Renzette, Sarah E Turbett, Katherine J Siddle, Christine Loreth, Gordon Adams, Christopher H Tomkins-Tinch, Mary E Petrone, Jessica E Rothman, Mallery I Breban, Robert Tobias Koch, Kendall Billig, Joseph R Fauver, Chantal B F Vogels, Kaya Bilguvar, Bony De Kumar, Marie L Landry, David R Peaper, Kevin Kelly, Greg Omerza, Heather Grieser, Sim Meak, John Martha, Hannah B Dewey, Susan Kales, Daniel Berenzy, Kristin Carpenter-Azevedo, Ewa King, Richard C Huard, Vlad Novitsky, Mark Howison, Josephine Darpolor, Akarsh Manne, Rami Kantor, Sandra C Smole, Catherine M Brown, Timelia Fink, Andrew S Lang, Glen R Gallagher, Virginia E Pitzer, Pardis C Sabeti, Stacey Gabriel, Bronwyn L Macinnis, New England Variant Investigation Team, Ryan Tewhey, Mark D Adams, Daniel J Park, Jacob E Lemieux, Nathan D Grubaugh

Faculty Research 2022

The SARS-CoV-2 Delta variant rose to dominance in mid-2021, likely propelled by an estimated 40%-80% increased transmissibility over Alpha. To investigate if this ostensible difference in transmissibility is uniform across populations, we partner with public health programs from all six states in New England in the United States. We compare logistic growth rates during each variant's respective emergence period, finding that Delta emerged 1.37-2.63 times faster than Alpha (range across states). We compute variant-specific effective reproductive numbers, estimating that Delta is 63%-167% more transmissible than Alpha (range across states). Finally, we estimate that Delta infections generate on average 6.2 (95% …

Harmonizing Model Organism Data In The Alliance Of Genome Resources., Alliance Of Genome Resources Consortium, Anna V. Anagnostopoulos, Susan M. Bello, Judith A. Blake, Olin Blodgett, Carol J. Bult, Karen R. Christie, Mary E. Dolan, Paul Hale, James A. Kadin, Monica S. Mcandrews, Howie Motenko, David R. Shaw, Constance M. Smith, Cynthia L. Smith, Monika Tomczuk, Laurens G. Wilming

Faculty Research 2022

The Alliance of Genome Resources (the Alliance) is a combined effort of 7 knowledgebase projects: Saccharomyces Genome Database, WormBase, FlyBase, Mouse Genome Database, the Zebrafish Information Network, Rat Genome Database, and the Gene Ontology Resource. The Alliance seeks to provide several benefits: better service to the various communities served by these projects; a harmonized view of data for all biomedical researchers, bioinformaticians, clinicians, and students; and a more sustainable infrastructure. The Alliance has harmonized cross-organism data to provide useful comparative views of gene function, gene expression, and human disease relevance. The basis of the comparative views is shared calls of …

Epistemic Beliefs: Relationship To Future Expectancies And Quality Of Life In Cancer Patients., Paul K J Han, Elizabeth Scharnetzki, Eric Anderson, John Dipalazzo, Tania D Strout, Caitlin Gutheil, F Lee Lucas, Emily A Edelman, Jens Rueter

Faculty Research 2022

CONTEXT: Expectations about the future (future expectancies) are important determinants of psychological well-being among cancer patients, but the strategies patients use to maintain positive and cope with negative expectancies are incompletely understood.

OBJECTIVES: To obtain preliminary evidence on the potential role of one strategy for managing future expectancies: the adoption of "epistemic beliefs" in fundamental limits to medical knowledge.

METHODS: A sample of 1307 primarily advanced-stage cancer patients participating in a genomic tumor testing study in community oncology practices completed measures of epistemic beliefs, positive future expectancies, and mental and physical health-related quality of life (HRQOL). Descriptive and linear regression …

Auriculocondylar Syndrome 2 Results From The Dominant-Negative Action Of Plcb4 Variants., Stanley M Kanai, Caleb Heffner, Timothy C Cox, Michael L Cunningham, Francisco A Perez, Aaron M Bauer, Philip Reigan, Cristan Carter, Stephen A. Murray, David E Clouthier

Faculty Research 2022

Auriculocondylar syndrome 2 (ARCND2) is a rare autosomal dominant craniofacial malformation syndrome linked to multiple genetic variants in the coding sequence of phospholipase C β4 (PLCB4). PLCB4 is a direct signaling effector of the endothelin receptor type A (EDNRA)-Gq/11 pathway, which establishes the identity of neural crest cells (NCCs) that form lower jaw and middle ear structures. However, the functional consequences of PLCB4 variants on EDNRA signaling is not known. Here, we show, using multiple signaling reporter assays, that known PLCB4 variants resulting from missense mutations exert a dominant-negative interference over EDNRA signaling. In addition, using CRISPR/Cas9, we find that …

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

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 …

Selective Elimination Of Pluripotent Stem Cells By Pikfyve Specific Inhibitors., Arup R Chakraborty, Alex Vassilev, Sushil K Jaiswal, Constandina E O'Connell, John F Ahrens, Barbara S Mallon, Martin Pera, Melvin L Depamphilis

Faculty Research 2022

Inhibition of PIKfyve phosphoinositide kinase selectively kills autophagy-dependent cancer cells by disrupting lysosome homeostasis. Here, we show that PIKfyve inhibitors can also selectively eliminate pluripotent embryonal carcinoma cells (ECCs), embryonic stem cells, and induced pluripotent stem cells under conditions where differentiated cells remain viable. PIKfyve inhibitors prevented lysosome fission, induced autophagosome accumulation, and reduced cell proliferation in both pluripotent and differentiated cells, but they induced death only in pluripotent cells. The ability of PIKfyve inhibitors to distinguish between pluripotent and differentiated cells was confirmed with xenografts derived from ECCs. Pretreatment of ECCs with the PIKfyve specific inhibitor WX8 suppressed their …

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 1,237 patients …

Single-Cell Multi-Omics Reveals Dyssynchrony Of The Innate And Adaptive Immune System In Progressive Covid-19., Avraham Unterman, Tomokazu S Sumida, Nima Nouri, Xiting Yan, Amy Y Zhao, Victor Gasque, Jonas C Schupp, Hiromitsu Asashima, Yunqing Liu, Carlos Cosme, Wenxuan Deng, Ming Chen, Micha Sam Brickman Raredon, Kenneth B Hoehn, Guilin Wang, Zuoheng Wang, Giuseppe Deiuliis, Neal G Ravindra, Ningshan Li, Christopher Castaldi, Patrick Wong, John Fournier, Santos Bermejo, Lokesh Sharma, Arnau Casanovas-Massana, Chantal B F Vogels, Anne L Wyllie, Nathan D Grubaugh, Anthony Melillo, Hailong Meng, Yan Stein, Maksym Minasyan, Subhasis Mohanty, William E Ruff, Inessa Cohen, Khadir Raddassi, Laura E Niklason, Albert I Ko, Ruth R Montgomery, Shelli F Farhadian, Akiko Iwasaki, Albert C Shaw, David Van Dijk, Hongyu Zhao, Steven H Kleinstein, David A Hafler, Naftali Kaminski, Charles S Dela Cruz

Faculty Research 2022

Dysregulated immune responses against the SARS-CoV-2 virus are instrumental in severe COVID-19. However, the immune signatures associated with immunopathology are poorly understood. Here we use multi-omics single-cell analysis to probe the dynamic immune responses in hospitalized patients with stable or progressive course of COVID-19, explore V(D)J repertoires, and assess the cellular effects of tocilizumab. Coordinated profiling of gene expression and cell lineage protein markers shows that S100A