Medicine and Health Sciences Commons^™

Polyaminer-Bulk Is A Deep Learning-Based Algorithm That Decodes Alternative Polyadenylation Dynamics From Bulk Rna-Seq Data, Venkata Soumith Jonnakuti, Eric J Wagner, Mirjana Maletić-Savatić, Zhandong Liu, Hari Krishna Yalamanchili

Faculty, Staff and Students Publications

Alternative polyadenylation (APA) is a key post-transcriptional regulatory mechanism; yet, its regulation and impact on human diseases remain understudied. Existing bulk RNA sequencing (RNA-seq)-based APA methods predominantly rely on predefined annotations, severely impacting their ability to decode novel tissue- and disease-specific APA changes. Furthermore, they only account for the most proximal and distal cleavage and polyadenylation sites (C/PASs). Deconvoluting overlapping C/PASs and the inherent noisy 3' UTR coverage in bulk RNA-seq data pose additional challenges. To overcome these limitations, we introduce PolyAMiner-Bulk, an attention-based deep learning algorithm that accurately recapitulates C/PAS sequence grammar, resolves overlapping C/PASs, captures non-proximal-to-distal APA changes, …

Scgist: Gene Panel Design For Spatial Transcriptomics With Prioritized Gene Sets, Mashrur Ahmed Yafi, Md Hasibul Husain Hisham, Francisco Grisanti, James F Martin, Atif Rahman, Md Abul Hassan Samee

Faculty, Staff and Students Publications

A critical challenge of single-cell spatial transcriptomics (sc-ST) technologies is their panel size. Being based on fluorescence in situ hybridization, they are typically limited to panels of about a thousand genes. This constrains researchers to build panels from only the marker genes of different cell types and forgo other genes of interest, e.g., genes encoding ligand-receptor complexes or those in specific pathways. We propose scGIST, a constrained feature selection tool that designs sc-ST panels prioritizing user-specified genes without compromising cell type detection accuracy. We demonstrate scGIST's efficacy in diverse use cases, highlighting it as a valuable addition to sc-ST's algorithmic …

Impaired Bone Morphogenetic Protein (Bmp) Signaling Pathways Disrupt Decidualization In Endometriosis, Zian Liao, Suni Tang, Peixin Jiang, Ting Geng, Dominique I Cope, Timothy N Dunn, Joie Guner, Linda Alpuing Radilla, Xiaoming Guan, Diana Monsivais

Faculty, Staff and Students Publications

Endometriosis is linked to increased infertility and pregnancy complications due to defective endometrial decidualization. We hypothesized that identification of altered signaling pathways during decidualization could identify the underlying cause of infertility and pregnancy complications. Our study reveals that transforming growth factor β (TGFβ) pathways are impaired in the endometrium of individuals with endometriosis, leading to defective decidualization. Through detailed transcriptomic analyses, we discovered abnormalities in TGFβ signaling pathways and key regulators, such as SMAD4, in the endometrium of affected individuals. We also observed compromised activity of bone morphogenetic proteins (BMP), a subset of the TGFβ family, that control endometrial receptivity. …

Juvenile Eosinophilic Fasciitis: A Single Center Case Series, Leigh A Stubbs, Oluwaseun Ogunbona, Emily Beil, Vibha Szafron, Adekunle Adesina, Sara Anvari, Jamie Lai, Andrea Ramirez, Matthew G Ditzler, Marietta Deguzman

Faculty, Staff and Students Publications

BACKGROUND: Eosinophilic fasciitis (EF) is a rare disease characterized by skin induration and musculoskeletal abnormalities. Diagnostic criteria for EF are based on adult populations. There is a need to expand the literature on EF in children due to limited reported cases and potential differences compared to adults.

METHODS: We conducted a retrospective review of medical records for six pediatric patients diagnosed with EF at our institution between November 2011 and April 2023. Inclusion criteria required patients to be under 18 years of age at the time of diagnosis and to have confirmed diagnosis through clinical history, imaging, and histology.

RESULTS: …

Clonal Gene Signatures Predict Prognosis In Mesothelioma And Lung Adenocarcinoma, Yupei Lin, Bryan M Burt, Hyun-Sung Lee, Thinh T Nguyen, Hee-Jin Jang, Claire Lee, Wei Hong, Robert Taylor Ripley, Christopher I Amos, Chao Cheng

Faculty, Staff and Students Publications

Malignant pleural mesothelioma (MPM) is a rare but lethal pleural cancer with high intratumor heterogeneity (ITH). A recent study in lung adenocarcinoma has developed a clonal gene signature (ORACLE) from multiregional transcriptomic data and demonstrated high prognostic values and reproducibility. However, such a strategy has not been tested in other types of cancer with high ITH. We aimed to identify biomarkers from multi-regional data to prognostically stratify MPM patients. We generated a multiregional RNA-seq dataset for 78 tumor samples obtained from 26 MPM patients, each with one sample collected from a superior, lateral, and inferior region of the tumor. By …

Factors Affecting Selection Of Trainee For Neurointervention (Fasten), Mohamed Elfil, Rami Z Morsi, Sherief Ghozy, Ahmed Elmashad, Adnan Siddiqui, Alhamza R Al-Bayati, Ali Alaraj, Allan Brook, Anthony W Kam, Arindam Rano Chatterjee, Athos Patsalides, Ben Waldau, Charles J Prestigiacomo, Charles Matouk, Clemens M Schirmer, David Altschul, David T Parrella, Gabor Toth, Gaurav Jindal, Hamza A Shaikh, Jaydevsinh N Dolia, Johanna T Fifi, Justin F Fraser, Justin Thomas Do, Krishna Amuluru, Louis J Kim, Mark Harrigan, Matthew R Amans, Max Kole, Max Mokin, Michael Abraham, Mouhammad Jumaa, Nazli Janjua, Osama Zaidat, Patrick P Youssef, Priyank Khandelwal, Qingliang Tony Wang, Ramesh Grandhi, Ricardo Hanel, Ryan T Kellogg, Santiago Ortega-Gutierrez, Sunil Sheth, Thanh N Nguyen, Viktor Szeder, Yin C Hu, Albert J Yoo, Omar Tanweer, Brian Jankowitz, Jeremy J Heit, Richard Williamson, Tareq Kass-Hout, Richard W Crowley, Mohammad El-Ghanem, Fawaz Al-Mufti

Faculty, Staff and Students Publications

BACKGROUND AND IMPORTANCE: Neurointervention is a very competitive specialty in the United States due to the limited number of training spots and the larger pool of applicants. The training standards are continuously updated to ensure solid training experiences. Factors affecting candidate(s) selection have not been fully established yet. Our study aims to investigate the factors influencing the selection process.

METHODS: A 52-question survey was distributed to 93 program directors (PDs). The survey consisted of six categories: (a) Program characteristics, (b) Candidate demographics, (c) Educational credentials, (d) Personal traits, (e) Research and extracurricular activities, and (f) Overall final set of characteristics. …

Treatment Strategies For Anti-Vegf Resistance In Neovascular Age-Related Macular Degeneration By Targeting Arteriolar Choroidal Neovascularization, Yingbin Fu, Zhao Zhang, Keith A Webster, Yannis M Paulus

Faculty, Staff and Students Publications

Despite extensive use of intravitreal anti-vascular endothelial growth factor (anti-VEGF) biologics for over a decade, neovascular age-related macular degeneration (nAMD) or choroidal neovascularization (CNV) continues to be a major cause of irreversible vision loss in developed countries. Many nAMD patients demonstrate persistent disease activity or experience declining responses over time despite anti-VEGF treatment. The underlying mechanisms of anti-VEGF resistance are poorly understood, and no effective treatment strategies are available to date. Here we review evidence from animal models and clinical studies that supports the roles of neovascular remodeling and arteriolar CNV formation in anti-VEGF resistance. Cholesterol dysregulation, inflammation, and ensuing …

Immunogenicity Phase Ii Study Evaluating Booster Capacity Of Nonadjuvanted Aks-452 Sars-Cov-2 Rbd Fc Vaccine, David G Alleva, Eline A Feitsma, Yester F Janssen, Hendrikus H Boersma, Thomas M Lancaster, Thillainaygam Sathiyaseelan, Sylaja Murikipudi, Andrea R Delpero, Melanie M Scully, Ramya Ragupathy, Sravya Kotha, Jeffrey R Haworth, Nishit J Shah, Vidhya Rao, Shashikant Nagre, Shannon E Ronca, Freedom M Green, Stephen A Shaw, Ari Aminetzah, Schelto Kruijff, Maarten Brom, Gooitzen M Van Dam, Todd C Zion

Faculty, Staff and Students Publications

AKS-452, a subunit vaccine comprising an Fc fusion of the ancestral wild-type (WT) SARS-CoV-2 virus spike protein receptor binding domain (SP/RBD), was evaluated without adjuvant in a single cohort, non-randomized, open-labelled phase II study (NCT05124483) at a single site in The Netherlands for safety and immunogenicity. A single 90 µg subcutaneous booster dose of AKS-452 was administered to 71 adults previously primed with a registered mRNA- or adenovirus-based vaccine and evaluated for 273 days. All AEs were mild and no SAEs were attributable to AKS-452. While all subjects showed pre-existing SP/RBD binding and ACE2-inhibitory IgG titers, 60-68% responded to AKS-452 …

Revascularization Strategies For Acute And Chronic Mesenteric Ischemia: A Narrative Review, Jacob J Gries, Takashi Sakamoto, Bing Chen, Hafeez Ul Hassan Virk, Mahboob Alam, Chayakrit Krittanawong

Faculty, Staff and Students Publications

Mesenteric ischemia is a challenging condition characterized by insufficient blood perfusion to the mesentery and, consequently, intestinal tissues that continues to perplex clinicians. Despite its low prevalence, the condition’s variable clinical presentation and elusive radiographic diagnosis can delay life-saving interventions in the acute setting and deteriorate the quality of life of patients when left undiagnosed or misdiagnosed. Purpose: Review and summarize recent diagnostic updates and emergent intervention strategies for acute and chronic mesenteric ischemia. Methods: A narrative review of all relevant studies from January 2022 through September 2023. Results: A total of 11 studies from MEDLINE, supplemented with 44 studies …

A Stool Based Qpcr For The Diagnosis Of Tb In Children And People Living With Hiv In Uganda, Eswatini And Mozambique (Stool4tb): A Protocol For A Multicenter Diagnostic Evaluation, Lucia Carratala-Castro, Willy Ssengooba, Alex Kay, Sozinho Acácio, Joanna Ehrlich, Andrew R Dinardo, Nosisa Shiba, Joachim K Nsubuga, Shilzia Munguambe, Belén Saavedra-Cervera, Patricia Manjate, Durbbin Mulengwa, Busizwe Sibandze, Mangaliso Ziyane, George Kasule, Edson Mambuque, Moorine Penninah Sekadde, Eric Wobudeya, Moses L Joloba, Jan Heyckendorf, Christoph Lange, Sabine Hermans, Anna Mandalakas, Alberto L García-Basteiro, Elisa Lopez-Varela, Stool4tb Global Partnership

Faculty, Staff and Students Publications

BACKGROUND: Tuberculosis (TB) is a major cause of mortality worldwide. Children and people living with HIV (PLHIV) have an increased risk of mortality, particularly in the absence of rapid diagnosis. The main challenges of diagnosing TB in these populations are due to the unspecific and paucibacillary disease presentation and the difficulty of obtaining respiratory samples. Thus, novel diagnostic strategies, based on non-respiratory specimens could improve clinical decision making and TB outcomes in high burden TB settings. We propose a multi-country, prospective diagnostic evaluation study with a nested longitudinal cohort evaluation to assess the performance of a new stool-based qPCR, developed …

Association Of Lifestyle Intervention With Risk For Cardiovascular Events Differs By Level Of Glycated Hemoglobin, Michael P Bancks, Scott J Pilla, Ashok Balasubramanyam, Hsin-Chieh Yeh, Karen C Johnson, Joseph Rigdon, Lynne E Wagenknecht, Mark A Espeland

Faculty, Staff and Students Publications

Purpose: We reevaluated the Action for Health in Diabetes (Look AHEAD) intensive lifestyle intervention (ILI) to assess whether the effect of ILI on cardiovascular disease (CVD) prevention differed by baseline glycated hemoglobin (HbA1c).

Methods: Look AHEAD randomized 5145 adults, aged 45 to 76 years with type 2 diabetes and overweight/obesity to ILI or a diabetes support and education (DSE) control group for a median of 9.6 years. ILI focused on achieving weight loss through decreased caloric intake and increased physical activity. We assessed the parent trial's primary composite CVD outcome. We evaluated additive and multiplicative heterogeneity of the intervention on …

Recombinant Rod Domain Of Vimentin Reduces Sars-Cov-2 Viral Replication By Blocking Spike Protein-Ace2 Interactions, Fong Wilson Lam, Cameron August Brown, Shannon Elizabeth Ronca

Faculty, Staff and Students Publications

Although the SARS-CoV-2 vaccination is the primary preventive intervention, there are still few antiviral therapies available, with current drugs decreasing viral replication once the virus is intracellular. Adding novel drugs to target additional points in the viral life cycle is paramount in preventing future pandemics. The purpose of this study was to create and test a novel protein to decrease SARS-CoV-2 replication. We created the recombinant rod domain of vimentin (rhRod) in E. coli and used biolayer interferometry to measure its affinity to the SARS-CoV-2 S1S2 spike protein and the ability to block the SARS-CoV-2–ACE2 interaction. We performed plaque assays …

Inhibition Of Csf1r And Kit With Pexidartinib Reduces Inflammatory Signaling And Cell Viability In Endometriosis, Timothy N Dunn, Dominique I Cope, Suni Tang, Tirupataiah Sirupangi, Sydney E Parks, Zian Liao, Fei Yuan, Chad J Creighton, Ramya P Masand, Linda Alpuing Radilla, Xiaoming Guan, Laura Detti, Diana Monsivais, Martin M Matzuk

Faculty, Staff and Students Publications

Endometriosis is a common and debilitating disease, affecting ∼170 million women worldwide. Affected patients have limited therapeutic options such as hormonal suppression or surgical excision of the lesions, though therapies are often not completely curative. Targeting receptor tyrosine kinases (RTKs) could provide a nonhormonal treatment option for endometriosis. We determined that 2 RTKs, macrophage-colony stimulating factor 1 receptor (CSF1R) and mast/stem cell growth factor receptor KIT (KIT), are overexpressed in endometriotic lesions and could be novel nonhormonal therapeutic targets for endometriosis. The kinase activity of CSF1R and KIT is suppressed by pexidartinib, a small molecule inhibitor that was recently approved …

The Frequency Of Pathogenic Variation In The All Of Us Cohort Reveals Ancestry-Driven Disparities, Eric Venner, Karynne Patterson, Divya Kalra, Marsha M Wheeler, Yi-Ju Chen, Sara E Kalla, Bo Yuan, Jason H Karnes, Kimberly Walker, Joshua D Smith, Sean Mcgee, Aparna Radhakrishnan, Andrew Haddad, Philip E Empey, Qiaoyan Wang, Lee Lichtenstein, Diana Toledo, Gail Jarvik, Anjene Musick, Richard A Gibbs

Faculty, Staff and Students Publications

Disparities in data underlying clinical genomic interpretation is an acknowledged problem, but there is a paucity of data demonstrating it. The All of Us Research Program is collecting data including whole-genome sequences, health records, and surveys for at least a million participants with diverse ancestry and access to healthcare, representing one of the largest biomedical research repositories of its kind. Here, we examine pathogenic and likely pathogenic variants that were identified in the All of Us cohort. The European ancestry subgroup showed the highest overall rate of pathogenic variation, with 2.26% of participants having a pathogenic variant. Other ancestry groups …

P90rsk Pathway Inhibition Synergizes With Cisplatin In Tmem16a Overexpressing Head And Neck Cancer, Abdulkader Yassin-Kassab, Suman Chatterjee, Nayel Khan, Nathaniel Wang, Vlad C Sandulache, Eric H-B Huang, Timothy F Burns, Umamaheswar Duvvuri

Faculty, Staff and Students Publications

Head and neck squamous cell carcinoma (HNSCC) constitutes one of the most common types of human cancers and often metastasizes to lymph nodes. Platinum-based chemotherapeutic drugs are commonly used for treatment of a wide range of cancers, including HNSCC. Its mode of action relies on its ability to impede DNA repair mechanisms, inducing apoptosis in cancer cells. However, due to acquired resistance and toxic side-effects, researchers have been focusing on developing novel combinational therapeutic strategies to overcome cisplatin resistance. In the current study, we identified p90RSK, an ERK1/2 downstream target, as a key mediator and a targetable signaling node against …

Adaptation Of Chagas Disease Screening Recommendations For A Community Of At-Risk Hiv In The United States, Jesica Hayon, Sofia Lupo, Cristina Poveda, Kathryn M Jones, Qian Qian, Hulin Wu, Thomas P Giordano, Charles J Fleischmann, Caryn Bern, Jeffrey D Whitman, Eva H Clark

Faculty, Staff and Students Publications

Chagas disease (CD), caused by Trypanosoma cruzi, is underdiagnosed in the United States. Improved screening strategies are needed, particularly for people at risk for life-threatening sequelae of CD, including people with human immunodeficiency virus (HIV, PWH). Here we report results of a CD screening strategy applied at a large HIV clinic serving an at-risk population.

Deciphering Early-Stage Molecular Mechanisms Of Negative Pressure Wound Therapy In A Murine Model, Yu-Chiau Shyu, Ting-Shuo Huang, Hua-Sheng Chiu, Pavel Sumazin, Xin-Yu Lin, Po-Cheng Liao, Cai-Cin Liou, Fang-Chia Hsu, Jyuan-Siou Lin, Chih-Chin Hsu, Pang-Hung Hsu, Chi-Chin Sun, Chien-Tzung Chen

Faculty, Staff and Students Publications

Negative Pressure Wound Therapy (NPWT) is a commonly employed clinical strategy for wound healing, yet its early-stage mechanisms remain poorly understood. To address this knowledge gap and overcome the limitations of human trials, we establish an NPWT C57BL/6JNarl mouse model to investigate the molecular mechanisms involved in NPWT. In this study, we investigate the intricate molecular mechanisms through which NPWT expedites wound healing. Our focus is on NPWT's modulation of inflammatory immune responses and the concurrent orchestration of multiple signal transduction pathways, resulting in shortened coagulation time and reduced inflammation. Notably, we observe a significant rise in dickkopf-related protein 1 …

Author Correction: The Cerebellum Contributes To Generalized Seizures By Altering Activity In The Ventral Posteromedial Nucleus, Jaclyn Beckinghausen, Joshua Ortiz-Guzman, Tao Lin, Benjamin Bachman, Luis E Salazar Leon, Yu Liu, Detlef H Heck, Benjamin R Arenkiel, Roy V Sillitoe

Faculty, Staff and Students Publications

No abstract provided.

Virtual Facilitation Best Practices And Research Priorities: A Scoping Review, Asya Agulnik, Derrecka Boykin, Denalee M O'Malley, Julia Price, Mia Yang, Mark Mckone, Geoffrey Curran, Mona J Ritchie

Faculty, Staff and Students Publications

Background: Facilitation is an implementation strategy that supports the uptake of evidence-based practices. Recently, use of virtual facilitation (VF), or the application of facilitation using primarily video-based conferencing technologies, has become more common, especially since the COVID-19 pandemic. Thorough assessment of the literature on VF, however, is lacking. This scoping review aimed to identify and describe conceptual definitions of VF, evaluate the consistency of terminology, and recommend "best" practices for its use as an implementation strategy.

Methods: We conducted a scoping review to identify literature on VF following the PRISMA-ScR guidance. A search of PubMed, Embase, Web of Science, and …

Cpsf3 Inhibition Blocks Pancreatic Cancer Cell Proliferation Through Disruption Of Core Histone Mrna Processing, Abdulrahman A Alahmari, Aditi H Chaubey, Venkata S Jonnakuti, Arwen A Tisdale, Carla D Schwarz, Abigail C Cornwell, Kathryn E Maraszek, Emily J Paterson, Minsuh Kim, Swati Venkat, Eduardo Cortes Gomez, Jianmin Wang, Katerina V Gurova, Hari Krishna Yalamanchili, Michael E Feigin

Faculty, Staff and Students Publications

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target cleavage and polyadenylation specificity factor 3 (CPSF3), the 3′ endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation in vitro and tumor growth in vivo. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation …

Pulmonary Fibrosis Stakeholder Summit: A Joint Nhlbi, Three Lakes Foundation, And Pulmonary Fibrosis Foundation Workshop Report, Sydney B Montesi, Christian R Gomez, Michael Beers, Robert Brown, Ishanu Chattopadhyay, Kevin R Flaherty, Christine Kim Garcia, Brigitte Gomperts, Lida P Hariri, Cory M Hogaboam, R Gisli Jenkins, Naftali Kaminski, Grace Hyun J Kim, Melanie Königshoff, Martin Kolb, Darrell N Kotton, Jonathan A Kropski, Joseph Lasky, Chelsea M Magin, Toby M Maher, Mark Mccormick, Bethany B Moore, Cheryl Nickerson-Nutter, Justin Oldham, Anna J Podolanczuk, Ganesh Raghu, Ivan Rosas, Steven M Rowe, William T Schmidt, David Schwartz, Jessica E Shore, Cathie Spino, J Matthew Craig, Fernando J Martinez

Faculty, Staff and Students Publications

Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8–9, 2022. This workshop was held virtually and was organized into three topic …

Guideline Concordance For Timely Chest Imaging After New Presentations Of Dyspnoea Or Haemoptysis In Primary Care: A Retrospective Cohort Study, Minjoung Monica Koo, Luke T A Mounce, Meena Rafiq, Matthew E J Callister, Hardeep Singh, Gary A Abel, Georgios Lyratzopoulos

Faculty, Staff and Students Publications

Background: Guidelines recommend urgent chest X-ray for newly presenting dyspnoea or haemoptysis but there is little evidence about their implementation.

Methods: We analysed linked primary care and hospital imaging data for patients aged 30+ years newly presenting with dyspnoea or haemoptysis in primary care during April 2012 to March 2017. We examined guideline-concordant management, defined as General Practitioner-ordered chest X-ray/CT carried out within 2 weeks of symptomatic presentation, and variation by sociodemographic characteristic and relevant medical history using logistic regression. Additionally, among patients diagnosed with cancer we described time to diagnosis, diagnostic route and stage at diagnosis by guideline-concordant status. …

Ldl-C Lowering In Prevention Of Atherosclerotic Cardiovascular Disease: Another Step Forward In This Lifelong Marathon, Vijay Nambi, Layla A Abushamat

Faculty, Staff and Students Publications

No abstract provided.

The Prevalence, Etiology And Treatment Of Gastroduodenal Ulcers And Perforation: A Systematic Review, Rizki Amalia, Amie Vidyani, Reny I'Tishom, Wiwin Is Efendi, Edwin Danardono, Bogi Pratomo Wibowo, Muhammad Lutfi Parewangi, Muhammad Miftahussurur, Hoda M Malaty

Faculty, Staff and Students Publications

(1) Background: Gastroduodenal perforation (GDP) is a life-threatening condition caused by a spontaneous or traumatic event. Treatment should be based on the mechanism of damage, timing, location, extent of the injury, and the patient's clinical condition. We aimed to examine several etiologic factors associated with gastroduodenal perforation and to search for the best method(s) for its prevention and treatment. (2) Methods: We conducted extensive literature reviews by searching numerous studies obtained from PubMed, Science Direct, and Cochrane for the following keywords: gastroduodenal perforation,

Matrin3 Mediates Differentiation Through Stabilizing Chromatin Loop-Domain Interactions And Yy1 Mediated Enhancer-Promoter Interactions, Tianxin Liu, Qian Zhu, Yan Kai, Trevor Bingham, Stacy Wang, Hye Ji Cha, Stuti Mehta, Thorsten M Schlaeger, Guo-Cheng Yuan, Stuart H Orkin

Faculty, Staff and Students Publications

Although emerging evidence indicates that alterations in proteins within nuclear compartments elicit changes in chromosomal architecture and differentiation, the underlying mechanisms are not well understood. Here we investigate the direct role of the abundant nuclear complex protein Matrin3 (Matr3) in chromatin architecture and development in the context of myogenesis. Using an acute targeted protein degradation platform (dTAG-Matr3), we reveal the dynamics of development-related chromatin reorganization. High-throughput chromosome conformation capture (Hi-C) experiments revealed substantial chromatin loop rearrangements soon after Matr3 depletion. Notably, YY1 binding was detected, accompanied by the emergence of novel YY1-mediated enhancer-promoter loops, which occurred concurrently with changes in …

Mesoscopic Calcium Imaging In A Head-Unrestrained Male Non-Human Primate Using A Lensless Microscope, Jimin Wu, Yuzhi Chen, Ashok Veeraraghavan, Eyal Seidemann, Jacob T Robinson

Faculty, Staff and Students Publications

Mesoscopic calcium imaging enables studies of cell-type specific neural activity over large areas. A growing body of literature suggests that neural activity can be different when animals are free to move compared to when they are restrained. Unfortunately, existing systems for imaging calcium dynamics over large areas in non-human primates (NHPs) are table-top devices that require restraint of the animal’s head. Here, we demonstrate an imaging device capable of imaging mesoscale calcium activity in a head-unrestrained male non-human primate. We successfully miniaturize our system by replacing lenses with an optical mask and computational algorithms. The resulting lensless microscope can fit …

In Vivo Dynamic Volumetric Imaging Of Mouse Testis And Epididymis With Optical Coherence Tomography†, Kohei Umezu, Guzel R Musina, Irina V Larina

Faculty, Staff and Students Publications

The implementation of live imaging in reproductive research is crucial for studying the physiological dynamics. Sperm transport is a highly dynamic process regulated by tubular contractions and luminal flows within the male reproductive tract. However, due to the lack of imaging techniques to capture these dynamics in vivo, there is little information on the physiological and biomechanical regulation of sperm transport through the male reproductive tract. Here, we present a functional in vivo imaging approach using optical coherence tomography, enabling live, label-free, depth-resolved, three-dimensional, high-resolution visualization of the mouse testis and epididymis. With this approach, we spatiotemporally captured tubular contractility …

Development And Validation Of Parent-Reported Gastrointestinal Health Scale In Mecp2 Duplication Syndrome, Davut Pehlivan, Sukru Aras, Daniel G Glaze, Muharrem Ak, Bernhard Suter, Kathleen J Motil

Faculty, Staff and Students Publications

BACKGROUND/AIMS: We aimed to develop a validated patient-reported Gastrointestinal Health Scale (GHS) specific to MECP2 Duplication Syndrome (MDS) to be used in clinical trials.

METHODS: MDS parents completed a Gastrointestinal Health Questionnaire (GHQ) to investigate the most relevant and important items associated with gastrointestinal problems in MECP2-related disorders. Item reduction was executed according to EORTC guidelines. We performed reliability and validity studies for the finalized scale.

RESULTS: A total of 106 surveys were eligible for item reduction and validation processes. The initial 55 items were reduced to 38 items based on parent responses, expert opinion, and initial confirmatory factor analysis …

Agreement Among High-Sensitivity Cardiac Troponin Assays And Non-Invasive Testing, Clinical Outcomes, And Quality-Of-Care Outcomes Based On The 2020 European Society Of Cardiology Guidelines, Júlia Karády, Thomas Mayrhofer, James L Januzzi, James E Udelson, Jerome L Fleg, Bela Merkely, Michael T Lu, William F Peacock, John T Nagurney, Wolfgang Koenig, Maros Ferencik, Udo Hoffmann

Faculty, Staff and Students Publications

AIMS: Quality-of-care and safety of patients with suspected acute coronary syndrome (ACS) would benefit if management was independent of which high-sensitivity cardiac troponin (hs-cTn) assay was used for risk stratification. We aimed to determine the concordance of hs-cTn assays to risk-stratify patients with suspected ACS according to the European Society of Cardiology (ESC) 2020 Guidelines.

METHODS AND RESULTS: Blood samples were obtained at arrival and at 2 h from patients with suspected ACS using four hs-cTn assays. The patients were classified into rule-out/observe/rule-in strata based on the ESC 2020 Guidelines. Concordance was determined among the assays for rule-out/observe/rule-in strata. The …

Design, Synthesis, X-Ray Crystallography, And Biological Activities Of Covalent, Non-Peptidic Inhibitors Of Sars-Cov-2 Main Protease, Md Ashraf-Uz-Zaman, Teck Khiang Chua, Xin Li, Yuan Yao, Bala Krishna Moku, Chandra Bhushan Mishra, Vasanthi Avadhanula, Pedro A Piedra, Yongcheng Song

Faculty, Staff and Students Publications

Highly contagious SARS-CoV-2 coronavirus has infected billions of people worldwide with flu-like symptoms since its emergence in 2019. It has caused deaths of several million people. The viral main protease (Mpro) is essential for SARS-CoV-2 replication and therefore a drug target. Several series of covalent inhibitors of Mpro were designed and synthesized. Structure-activity relationship studies show that 1) several chloroacetamide- and epoxide-based compounds targeting Cys145 are potent inhibitors with IC50 values as low as 0.49 μM, and 2) Cys44 of Mpro is not nucleophilic for covalent inhibitor design. High resolution X-ray studies revealed the protein-inhibitor interactions and mechanisms of inhibition. …