Digital Commons Network^™

Structural Dynamics In Α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid Receptor Gating, Cuauhtemoc U Gonzalez, Vasanthi Jayaraman

Faculty, Staff and Student Publications

The ionotropic glutamate receptors (iGluRs) are comprised of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-d-aspartate receptor, kainate, and delta subtypes and are pivotal in neuronal plasticity. Recent structural studies on AMPA receptors reveal intricate conformational changes during activation and desensitization elucidating the steps from agonist binding to channel opening and desensitization. Additionally, interactions with auxiliary subunits, including transmembrane AMPA-receptor regulatory proteins, germ-cell-specific gene 1-like protein, and cornichon homologs, intricately modulate AMPA receptors. We discuss the recent high-resolution structures of these complexes that unveil stoichiometry, subunit positioning, and differences in specific side-chain interactions that influence these functional modulations.

Stratifying Heart Failure Patients With Graph Neural Network And Transformer Using Electronic Health Records To Optimize Drug Response Prediction, Shaika Chowdhury, Yongbin Chen, Pengyang Li, Sivaraman Rajaganapathy, Andrew Wen, Xiao Ma, Qiying Dai, Yue Yu, Sunyang Fu, Xiaoqian Jiang, Zhe He, Sunghwan Sohn, Xiaoke Liu, Suzette J Bielinski, Alanna M Chamberlain, James R Cerhan, Nansu Zong

Faculty, Staff and Student Publications

Objectives: Heart failure (HF) impacts millions of patients worldwide, yet the variability in treatment responses remains a major challenge for healthcare professionals. The current treatment strategies, largely derived from population based evidence, often fail to consider the unique characteristics of individual patients, resulting in suboptimal outcomes. This study aims to develop computational models that are patient-specific in predicting treatment outcomes, by utilizing a large Electronic Health Records (EHR) database. The goal is to improve drug response predictions by identifying specific HF patient subgroups that are likely to benefit from existing HF medications.

Materials and methods: A novel, graph-based model capable …

Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants That Confer Risk For Breast Cancer, Xiaohui Sun, Shiv P Verma, Guochong Jia, Xinjun Wang, Jie Ping, Xingyi Guo, Xiao-Ou Shu, Jianhong Chen, Andriy Derkach, Qiuyin Cai, Xiaolin Liang, Jirong Long, Kenneth Offit, Jung H Oh, Anne S Reiner, Gordon P Watt, Meghan Woods, Yaohua Yang, Christine B Ambrosone, Stefan Ambs, Yu Chen, Patrick Concannon, Montserrat Garcia-Closas, Jian Gu, Christopher A Haiman, Jennifer J Hu, Dezheng Huo, Esther M John, Julia A Knight, Christopher I Li, Charles F Lynch, Lene Mellemkjær, Katherine L Nathanson, Barbara Nemesure, Olufunmilayo I Olopade, Andrew F Olshan, Tuya Pal, Julie R Palmer, Michael F Press, Maureen Sanderson, Dale P Sandler, Melissa A Troester, Wei Zheng, Jonine L Bernstein, Matthew F Buas, Xiang Shu

Faculty, Staff and Student Publications

Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case genome-wide association study (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead …

Why Do Patients With Cancer Die?, Adrienne Boire, Katy Burke, Thomas R Cox, Theresa Guise, Mariam Jamal-Hanjani, Tobias Janowitz, Rosandra Kaplan, Rebecca Lee, Charles Swanton, Matthew G Vander Heiden, Erik Sahai

Faculty, Staff and Student Publications

Cancer is a major cause of global mortality, both in affluent countries and increasingly in developing nations. Many patients with cancer experience reduced life expectancy and have metastatic disease at the time of death. However, the more precise causes of mortality and patient deterioration before death remain poorly understood. This scarcity of information, particularly the lack of mechanistic insights, presents a challenge for the development of novel treatment strategies to improve the quality of, and potentially extend, life for patients with late-stage cancer. In addition, earlier deployment of existing strategies to prolong quality of life is highly desirable. In this …

A Cell Cycle-Aware Network For Data Integration And Label Transferring Of Single-Cell Rna-Seq And Atac-Seq, Jiajia Liu, Jian Ma, Jianguo Wen, Xiaobo Zhou

Faculty, Staff and Student Publications

In recent years, the integration of single-cell multi-omics data has provided a more comprehensive understanding of cell functions and internal regulatory mechanisms from a non-single omics perspective, but it still suffers many challenges, such as omics-variance, sparsity, cell heterogeneity, and confounding factors. As it is known, the cell cycle is regarded as a confounder when analyzing other factors in single-cell RNA-seq data, but it is not clear how it will work on the integrated single-cell multi-omics data. Here, a cell cycle-aware network (CCAN) is developed to remove cell cycle effects from the integrated single-cell multi-omics data while keeping the cell …

Outcome Of 3q262/Mecom Rearrangements In Chronic Myeloid Leukemia, Hiroki Akiyama, Hagop Kantarjian, Elias Jabbour, Ghayas Issa, Fadi G Haddad, Nicholas J Short, Shimin Hu, Jo Ishizawa, Michael Andreeff, Koji Sasaki

Faculty, Staff and Student Publications

Study aims: To evaluate the outcomes of patients with 3q26.2/MECOM-rearranged chronic myeloid leukemia (CML).

Methods: We reviewed consecutive adult patients with 3q26.2/MECOM-rearranged CML between January 1, 1998 and February 16, 2023. Rearrangements of 3q26.2/MECOM were confirmed by conventional cytogenetics, and fluorescence in situ hybridization starting in 2015.

Results: We identified 55 patients with MECOM-rearranged CML, including 23 in chronic phase (CP) or accelerated phase (AP) and 32 in blast phase (BP). Nine patients (16%) achieved a major cytogenetic response (MCyR) or deeper. At a median follow-up of 89 months, median survival was 14 months. The 5-year survival rate was 19% …

Safety And Efficacy Of Percutaneous Image-Guided Ablation For Soft Tissue Sarcoma Metastases To The Liver, Ahmed Awad, Koustav Pal, Steven Yevich, Joshua D Kuban, Alda Tam, Bruno C Odisio, Sanjay Gupta, Peiman Habibollahi, Andrew J Bishop, Anthony Paul Conley, Neeta Somaiah, Dejka M Araujo, Maria Alejandra Zarzour, Ravin Ratan, Christina L Roland, Emily Z Keung, Steven Y Huang, Rahul A Sheth

Faculty, Staff and Student Publications

Purpose: To evaluate outcomes following percutaneous image-guided ablation of soft tissue sarcoma metastases to the liver.

Materials and methods: A single-institution retrospective analysis of patients with a diagnosis of metastatic soft tissue sarcoma who underwent percutaneous image-guided ablation of hepatic metastases between January 2011 and December 2021 was performed. Patients with less than 60 days of follow-up after ablation were excluded. The primary outcome was local tumor progression-free survival (LPFS). Secondary outcomes included overall survival, liver-specific progression-free survival. and chemotherapy-free survival.

Results: Fifty-five patients who underwent percutaneous ablation for 84 metastatic liver lesions were included. The most common histopathological subtypes …

Acute Myeloid Leukemia With Mast Cell Differentiation Is Characterized By Interstitial Mast Cells, Complex Karyotype, Do Hwan Kim, Sa A Wang, Wei Wang, Guilin Tang, Shaoying Li, C Cameron Yin, Pei Lin, Marina Konopleva, M James You, Roberto N Miranda, Xiaoqiong Wang, Qing Wei, L Jeffrey Medeiros, Jie Xu

Faculty, Staff and Student Publications

No abstract provided.

T-Cell-Rich Hodgkin Lymphoma With Features Of Classic Hodgkin Lymphoma And Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Borderline Category With Overlapping Morphologic And Immunophenotypic Features, Siba El Hussein, Hong Fang, Fatima Zahra Jelloul, Wei Wang, Sanam Loghavi, Roberto N Miranda, Jonathan W Friedberg, W Richard Burack, Andrew G Evans, Jie Xu, L Jeffrey Medeiros

Faculty, Staff and Student Publications

Context.—: It is known that a subset of cases of classic Hodgkin lymphoma (CHL) with B-cell-rich nodules (lymphocyte-rich CHL) exhibits morphologic and immunophenotypic features that overlap with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), raising diagnostic difficulties that can be resolved in most cases by performing an adequate battery of immunohistochemical studies.

Objective.—: To fully characterize cases of T-cell-rich Hodgkin lymphoma where a specific diagnosis of NLPHL (ie, pattern D) or CHL could not be made even after complete immunophenotypic investigation.

Design.—: The clinical, immunomorphologic, and molecular (when applicable) presentation of 3 cases of T-cell-rich Hodgkin lymphoma was thoroughly investigated.

Results.—: These …

Cluster-Based Toxicity Estimation Of Osteoradionecrosis Via Unsupervised Machine Learning: Moving Beyond Single Dose-Parameter Normal Tissue Complication Probability By Using Whole Dose-Volume Histograms For Cohort Risk Stratification, Seyedmohammadhossein Hosseinian, Mehdi Hemmati, Cem Dede, Travis C Salzillo, Lisanne V Van Dijk, Abdallah S R Mohamed, Stephen Y Lai, Andrew J Schaefer, Clifton D Fuller

Faculty, Staff and Student Publications

PURPOSE: Given the limitations of extant models for normal tissue complication probability estimation for osteoradionecrosis (ORN) of the mandible, the purpose of this study was to enrich statistical inference by exploiting structural properties of data and provide a clinically reliable model for ORN risk evaluation through an unsupervised-learning analysis that incorporates the whole radiation dose distribution on the mandible.

METHODS AND MATERIALS: The analysis was conducted on retrospective data of 1259 patients with head and neck cancer treated at The University of Texas MD Anderson Cancer Center between 2005 and 2015. During a minimum 12-month posttherapy follow-up period, 173 patients …

Human Platelet Lysate Enhances In Vivo Activity Of Car-Vδ2 T Cells By Reducing Cellular Senescence And Apoptosis, Feiyan Mo, Chiou-Tsun Tsai, Rong Zheng, Chonghui Cheng, Helen E Heslop, Malcolm K Brenner, Maksim Mamonkin, Norihiro Watanabe

Faculty, Staff and Students Publications

BACKGROUND AIMS: Vγ9Vδ2 T cells are an attractive cell platform for the off-the-shelf cancer immunotherapy as the result of their lack of alloreactivity and inherent multi-pronged cytotoxicity, which could be further amplified with chimeric antigen receptors (CARs). In this study, we sought to enhance the in vivo longevity of CAR-Vδ2 T cells by modulating ex vivo manufacturing conditions and selecting an optimal CAR costimulatory domain.

METHODS: Specifically, we compared the anti-tumor activity of Vδ2 T cells expressing anti-CD19 CARs with costimulatory endodomains derived from CD28, 4-1BB or CD27 and generated in either standard fetal bovine serum (FBS)- or human platelet …

The Role Of The Cerebellum In Learning To Predict Reward: Evidence From Cerebellar Ataxia, Jonathan Nicholas, Christian Amlang, Chi-Ying R Lin, Leila Montaser-Kouhsari, Natasha Desai, Ming-Kai Pan, Sheng-Han Kuo, Daphna Shohamy

Faculty, Staff and Students Publications

Recent findings in animals have challenged the traditional view of the cerebellum solely as the site of motor control, suggesting that the cerebellum may also be important for learning to predict reward from trial-and-error feedback. Yet, evidence for the role of the cerebellum in reward learning in humans is lacking. Moreover, open questions remain about which specific aspects of reward learning the cerebellum may contribute to. Here we address this gap through an investigation of multiple forms of reward learning in individuals with cerebellum dysfunction, represented by cerebellar ataxia cases. Nineteen participants with cerebellar ataxia and 57 age- and sex-matched …

Cerebellar Functions Beyond Movement And Learning, Linda H Kim, Detlef H Heck, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

The cerebellum has a well-established role in controlling motor functions, including coordination, posture, and the learning of skilled movements. The mechanisms for how it carries out motor behavior remain under intense investigation. Interestingly though, in recent years the mechanisms of cerebellar function have faced additional scrutiny since nonmotor behaviors may also be controlled by the cerebellum. With such complexity arising, there is now a pressing need to better understand how cerebellar structure, function, and behavior intersect to influence behaviors that are dynamically called upon as an animal experiences its environment. Here, we discuss recent experimental work that frames possible neural …

Large-Scale Genotype Prediction From Rna Sequence Data Necessitates A New Ethical And Policy Framework, Mary A Majumder, Jeffrey T Leek, Kasper D Hansen, Afrooz Razi, Amy L Mcguire

Center for Medical Ethics and Health Policy Staff Publications

Genotype prediction from RNA-seq data has become widespread. RNA-seq data, unlike DNA-seq data, are available as raw reads for many projects, with related protocols and consent terms typically inaccessible. However, there is a lack of clarity in current policy and inconsistency in practice with regard to the handling of these data. Here, we call for a framework for management of RNA-seq data and the predicted genotypes that includes registered access for RNA-seq data, controlled access for predicted genotypes, and a code of conduct for data access and use, as well as enhanced downstream protections.

Complement C3ar Signaling: Immune And Metabolic Modulation And Its Impact On Alzheimer’S Disease, Manasee Gedam, Hui Zheng

Center on Aging Staff Publications

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia among the elderly population. Despite its widespread prevalence, our comprehension of the intricate mechanisms governing the pathogenesis of the disease remains incomplete, posing a challenge for the development of efficient therapies. Pathologically characterized by the presence of amyloid β plaques and neurofibrillary tau tangles, AD is also accompanied by the hyperactivation of glial cells and the immune system. The complement cascade, the evolutionarily conserved innate immune pathway, has emerged as a significant contributor to AD. This review focuses on one of the complement components, the …

Chick Embryo Chorioallantoic Membrane As A Platform For Assessing The In Vivo Efficacy Of Chimeric Antigen Receptor T-Cell Therapy In Solid Tumors, Allison J Nipper, Emilie A K Warren, Kershena S Liao, Hsuan-Chen Liu, Chieko Michikawa, Caroline E Porter, Gabrielle A Wells, Mariana Villanueva, Fabio Henrique Brasil Da Costa, Ratna Veeramachaneni, Hugo Villanueva, Masataka Suzuki, Andrew G Sikora

Faculty, Staff and Student Publications

The fertilized chicken egg chorioallantoic membrane (CAM), a highly vascularized membrane nourishing the developing embryo, also supports rapid growth of three-dimensional vascularized tumors from engrafted cells and tumor explants. Because murine xenograft models suffer limitations of time, cost, and scalability, we propose CAM tumors as a rapid, efficient screening tool for assessing anti-tumor efficacy of chimeric Ag receptor (CAR) T cells against solid tumors. We tested the efficacy of human epidermal growth factor receptor 2 (HER2)-specific CAR T cells against luminescent, HER2-expressing (FaDu, SCC-47) or HER2-negative (MDA-MB-468) CAM-engrafted tumors. Three days after tumor engraftment, HER2-specific CAR T cells were applied …

Secondary Endpoint Utilization And Publication Rate Among Phase Iii Oncology Trials, Esther J Beck, Alexander D Sherry, Marcus A Florez, Ramez Kouzy, Joseph Abi Jaoude, Timothy A Lin, Avital M Miller, Adina H Passy, Gabrielle S Kupferman, Roshal R Patel, Fumiko Chino, Victoria Serpas Higbie, Christine M Parseghian, Michael J Overman, Bruce D Minsky, Charles R Thomas, Chad Tang, Pavlos Msaouel, Ethan B Ludmir

Faculty, Staff and Student Publications

UNLABELLED: Secondary endpoints (SEP) provide crucial information in the interpretation of clinical trials, but their features are not yet well understood. Thus, we sought to empirically characterize the scope and publication rate of SEPs among late-phase oncology trials. We assessed SEPs for each randomized, published phase III oncology trial across all publications and ClinicalTrials.gov, performing logistic regressions to evaluate associations between trial characteristics and SEP publication rates. After screening, a total of 280 trials enrolling 244,576 patients and containing 2,562 SEPs met the inclusion criteria. Only 22% of trials (62/280) listed all SEPs consistently between ClinicalTrials.gov and the trial protocol. …

Systematic Transcriptome Profiling Of Hpsc-Derived Osteoblasts Unveils Corin’S Mastery In Governing Osteogenesis Through Cebpd Modulation, Dandan Zhu, Mo-Fan Huang, An Xu, Xueqin Gao, Yu-Wen Huang, Trinh T T Phan, Linchao Lu, Ting-Yen Chi, Yulin Dai, Lon Kai Pang, Julian A Gingold, Jian Tu, Zijun Huo, Danielle A Bazer, Rachel Shoemaker, Jun Wang, Catherine G Ambrose, Jingnan Shen, Jun Kameoka, Zhongming Zhao, Lisa L Wang, Yang Zhang, Ruiying Zhao, Dung-Fang Lee

Faculty, Staff and Student Publications

The commitment of stem cells to differentiate into osteoblasts is a highly regulated and complex process that involves the coordination of extrinsic signals and intrinsic transcriptional machinery. While rodent osteoblastic differentiation has been extensively studied, research on human osteogenesis has been limited by cell sources and existing models. Here, we systematically dissect human pluripotent stem cell-derived osteoblasts to identify functional membrane proteins and their downstream transcriptional networks involved in human osteogenesis. Our results reveal an enrichment of type II transmembrane serine protease CORIN in humans but not rodent osteoblasts. Functional analyses demonstrated that CORIN depletion significantly impairs osteogenesis. Genome-wide chromatin …

Impact Of Pretreatment Body Mass Index On The Survival Of Head And Neck Cancer Patients, Zheng Yang, Jobran Mansour, Peng Sun, Peng Wei, Kristina R Dahlstrom, Mark Zafereo, Guojun Li, Neil D Gross

Faculty, Staff and Student Publications

Background: Differences in pretreatment body mass index (BMI) have been associated with survival in squamous cell carcinoma of head and neck (SCCHN). We examined effects of BMI on survival in SCCHN patients after stratifying patients by tumor human papillomavirus (HPV) status and subsite.

Methods: Totally 2204 SCCHN patients in a prospective study were included in this secondary analysis. Multivariable Cox models were used to evaluate associations between pretreatment BMI and overall survival, disease-specific survival, and disease-free survival.

Results: BMI was significantly higher among patients with HPV-positive tumors than HPV-negative tumors. BMI >25 kg/m2 was associated with improved survival, while BMI …

Generating Clinical-Grade Gene-Disease Validity Classifications Through The Clingen Data Platforms, Matt W Wright, Courtney L Thaxton, Tristan Nelson, Marina T Distefano, Juliann M Savatt, Matthew H Brush, Gloria Cheung, Mark E Mandell, Bryan Wulf, T J Ward, Scott Goehringer, Terry O'Neill, Phil Weller, Christine G Preston, Ingrid M Keseler, Jennifer L Goldstein, Natasha T Strande, Jennifer Mcglaughon, Danielle R Azzariti, Ineke Cordova, Hannah Dziadzio, Lawrence Babb, Kevin Riehle, Aleksandar Milosavljevic, Christa Lese Martin, Heidi L Rehm, Sharon E Plon, Jonathan S Berg, Erin R Riggs, Teri E Klein

Center for Medical Ethics and Health Policy Staff Publications

Clinical genetic laboratories must have access to clinically validated biomedical data for precision medicine. A lack of accessibility, normalized structure, and consistency in evaluation complicates interpretation of disease causality, resulting in confusion in assessing the clinical validity of genes and genetic variants for diagnosis. A key goal of the Clinical Genome Resource (ClinGen) is to fill the knowledge gap concerning the strength of evidence supporting the role of a gene in a monogenic disease, which is achieved through a process known as Gene-Disease Validity curation. Here we review the work of ClinGen in developing a curation infrastructure that supports the …

Fine-Tuning Ampk In Physiology And Disease Using Point-Mutant Mouse Models, Naghmana Ashraf, Jeanine L Van Nostrand

Faculty, Staff and Students Publications

AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that monitors the cellular energy status to adapt it to the fluctuating nutritional and environmental conditions in an organism. AMPK plays an integral part in a wide array of physiological processes, such as cell growth, autophagy and mitochondrial function, and is implicated in diverse diseases, including cancer, metabolic disorders, cardiovascular diseases and neurodegenerative diseases. AMPK orchestrates many different physiological outcomes by phosphorylating a broad range of downstream substrates. However, the importance of AMPK-mediated regulation of these substrates in vivo remains an ongoing area of investigation to better understand its precise …

De Novo Variants In The Rnu4-2 Snrna Cause A Frequent Neurodevelopmental Syndrome, Yuyang Chen, Ruebena Dawes, Hyung Chul Kim, Alicia Ljungdahl, Sarah L Stenton, Susan Walker, Jenny Lord, Gabrielle Lemire, Alexandra C Martin-Geary, Vijay S Ganesh, Jialan Ma, Jamie M Ellingford, Erwan Delage, Elston N D'Souza, Shan Dong, David R Adams, Kirsten Allan, Madhura Bakshi, Erin E Baldwin, Seth I Berger, Jonathan A Bernstein, Ishita Bhatnagar, Ed Blair, Natasha J Brown, Lindsay C Burrage, Kimberly Chapman, David J Coman, Alison G Compton, Chloe A Cunningham, Precilla D'Souza, Petr Danecek, Emmanuèle C Délot, Kerith-Rae Dias, Ellen R Elias, Frances Elmslie, Care-Anne Evans, Lisa Ewans, Kimberly Ezell, Jamie L Fraser, Lyndon Gallacher, Casie A Genetti, Anne Goriely, Christina L Grant, Tobias Haack, Jenny E Higgs, Anjali G Hinch, Matthew E Hurles, Alma Kuechler, Katherine L Lachlan, Seema R Lalani, François Lecoquierre, Elsa Leitão, Anna Le Fevre, Richard J Leventer, Jan E Liebelt, Sarah Lindsay, Paul J Lockhart, Alan S Ma, Ellen F Macnamara, Sahar Mansour, Taylor M Maurer, Hector R Mendez, Kay Metcalfe, Stephen B Montgomery, Mariya Moosajee, Marie-Cécile Nassogne, Serena Neumann, Michael O'Donoghue, Melanie O'Leary, Elizabeth E Palmer, Nikhil Pattani, John Phillips, Georgia Pitsava, Ryan Pysar, Heidi L Rehm, Chloe M Reuter, Nicole Revencu, Angelika Riess, Rocio Rius, Lance Rodan, Tony Roscioli, Jill A Rosenfeld, Rani Sachdev, Charles J Shaw-Smith, Cas Simons, Sanjay M Sisodiya, Penny Snell, Laura St Clair, Zornitza Stark, Helen S Stewart, Tiong Yang Tan, Natalie B Tan, Suzanna E L Temple, David R Thorburn, Cynthia J Tifft, Eloise Uebergang, Grace E Vannoy, Pradeep Vasudevan, Eric Vilain, David H Viskochil, Laura Wedd, Matthew T Wheeler, Susan M White, Monica Wojcik, Lynne A Wolfe, Zoe Wolfenson, Caroline F Wright, Changrui Xiao, David Zocche, John L Rubenstein, Eirene Markenscoff-Papadimitriou, Sebastian M Fica, Diana Baralle, Christel Depienne, Daniel G Macarthur, Joanna M M Howson, Stephan J Sanders, Anne O'Donnell-Luria, Nicola Whiffin

Faculty, Staff and Students Publications

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of …

Cardiomyopathy, An Uncommon Phenotype Of Congenital Disorders Of Glycosylation: Recommendations For Baseline Screening And Follow-Up Evaluation, Roni Zemet, Kyle D Hope, Andrew C Edmondson, Rameen Shah, Maria Patino, Abigail M Yesso, Justin H Berger, Kyriakie Sarafoglou, Austin Larson, Christina Lam, Eva Morava, Fernando Scaglia

Faculty, Staff and Students Publications

Introduction:

Congenital disorders of glycosylation (CDG) are a continuously expanding group of monogenic disorders that disrupt glycoprotein and glycolipid biosynthesis, leading to multi-systemic manifestations. These disorders are categorized into various groups depending on which part of the glycosylation process is impaired. The cardiac manifestations in CDG can significantly differ, not only across different types but also among individuals with the same genetic cause of CDG. Cardiomyopathy is an important phenotype in CDG. The clinical manifestations and progression of cardiomyopathy in CDG patients have not been well characterized. This study aims to delineate common patterns of cardiomyopathy across a range of …

Sinus Arrest Related To Dexmedetomidine Infusion In An Infant; A Case Report And Review Of Current Literature, Alexandra Dennee, Thomas P Fogarty, Taylor S Howard, Ryan Brandon Hunter

Faculty, Staff and Students Publications

Background: Dexmedetomidine, an alpha 2 agonist, has emerged as a desirable sedative agent in the pediatric intensive care unit due to its minimal effect on respiratory status and reduction in delirium. Bradycardia and hypotension are common side effects, however there are emerging reports of more serious cardiovascular events, including sinus arrest and asystole. These case reports have been attributed to high vagal tone or underlying cardiac conduction dysfunction.

Objectives: To describe the development of sinus arrest during sedation with dexmedetomidine in a patient without clinical features of high vagal tone, underlying cardiac conduction dysfunction, or intervening episodes of bradycardia.

Case …

Developmental Delay Can Precede Neurologic Regression In Early Onset Metachromatic Leukodystrophy, Laura Ann Adang, Samuel Groeschel, Chloe Grzyb, Russell D'Aiello, Francesco Gavazzi, Omar Sherbini, Nowa Bronner, Akshilkumar Patel, Ariel Vincent, Anjana Sevagamoorthy, Sylvia Mutua, Kayla Muirhead, Johanna Schmidt, Amy Pizzino, Emily Yu, Danielle Jin, Florian Eichler, Jamie L Fraser, Lisa Emrick, Keith Van Haren, Jean-Martin Boulanger, Maura Ruzhnikov, Michel Sylvain, Cam-Tu Émilie Nguyen, Ana Potic, Stephanie Keller, Ali Fatemi, Eloise Uebergang, Michele Poe, Pouneh Amir Yazdani, John Bernat, Kristen Lindstrom, Joshua L Bonkowsky, Genevieve Bernard, Chloe A Stutterd, Paul Orchard, Ashish O Gupta, Merete Ljungberg, Sabine Groenborg, Alberto Zambon, Sara Locatelli, Francesca Fumagalli, Saskia Elguen, Christiane Kehrer, Ingeborg Krägeloh-Mann, Justine Shults, Adeline Vanderver, Maria L Escolar

Faculty, Staff and Students Publications

Objective: Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disorder. Emerging therapies are most effective in the presymptomatic phase, and thus defining this window is critical. We hypothesize that early development delay may precede developmental plateau. With the advent of presymptomatic screening platforms and transformative therapies, it is essential to define the onset of neurologic disease.

Methods: The specific ages of gain and loss of developmental milestones were captured from the medical records of individuals affected by MLD. Milestone acquisition was characterized as: on target (obtained before the age limit of 90th percentile plus 2 standard deviations compared to a normative …

Mechanisms Of Neurodevelopmental Toxicity Of Topiramate, John W Steele, Vaishnav Krishnan, Richard H Finnell

Faculty, Staff and Students Publications

Prescriptions for antiseizure medications (ASMs) have been rapidly growing over the last several decades due, in part, to an expanding list of clinical indications for which they are now prescribed. This trend has raised concern for potential adverse neurodevelopmental outcomes in ASM-exposed pregnancies. Recent large scale population studies have suggested that the use of topiramate (TOPAMAX, Janssen-Cilag), when prescribed for seizure control, migraines, and/or weight management, is associated with an increased risk for autism spectrum disorder (ASD), intellectual disability, and attention-deficit/hyperactivity disorder (ADHD) in exposed offspring. Here, we critically review epidemiologic evidence demonstrating the neurobehavioral teratogenicity of topiramate and speculate …

Frontiers In Congenital Disorders Of Glycosylation Consortium, A Cross-Sectional Study Report At Year 5 Of 280 Individuals In The Natural History Cohort, Christina Lam, Fernando Scaglia, Gerard T Berry, Austin Larson, Kyriakie Sarafoglou, Hans C Andersson, Evgenia Sklirou, Queenie K G Tan, Rodrigo T Starosta, Mustafa Sadek, Lynne Wolfe, Seishu Horikoshi, May Ali, Rita Barone, Teresa Campbell, Irene J Chang, Kiaira Coles, Edward Cook, Erik A Eklund, Nicole M Engelhardt, Mary Freeman, Jennifer Friedman, Debbie Y T Fu, Grace Botzo, Brandy Rawls, Christien Hernandez, Christin Johnsen, Kierstin Keller, Sara Kramer, Bryce Kuschel, Angela Leshinski, Ivan Martinez-Duncker, Gina L Mazza, Saadet Mercimek-Andrews, Bradley S Miller, Karthik Muthusamy, Juanita Neira, Marc C Patterson, Natalie Pogorelc, Lex N Powers, Elizabeth Ramey, Michaela Reinhart, Audrey Squire, Jenny Thies, Jerry Vockley, Hayden Vreugdenhil, Peter Witters, Mehdi Youbi, Aziza Zeighami, Roni Zemet, Andrew C Edmondson, Eva Morava

Faculty, Staff and Students Publications

Objective: Our report describes clinical, genetic, and biochemical features of participants with a molecularly confirmed congenital disorder of glycosylation (CDG) enrolled in the Frontiers in Congenital Disorders of Glycosylation (FCDGC) Natural History cohort at year 5 of the study.

Methods: We enrolled individuals with a known or suspected CDG into the FCDGC Natural History Study, a multicenter prospective and retrospective natural history study of all genetic causes of CDG. We conducted a cross-sectional analysis of baseline study visit data from participants with confirmed CDG who were consented into the FCDGC Natural History Study (5U54NS115198) from October 2019 to November 2023. …

Histone H3k18 & H3k23 Acetylation Directs Establishment Of Mll-Mediated H3k4 Methylation, Geoffrey C Fox, Karl F Poncha, B Rutledge Smith, Lara N Van Der Maas, Nathaniel N Robbins, Bria Graham, Jill M Dowen, Brian D Strahl, Nicolas L Young, Kanishk Jain

Faculty, Staff and Students Publications

In an unmodified state, positively charged histone N-terminal tails engage nucleosomal DNA in a manner which restricts access to not only the underlying DNA but also key tail residues subject to binding and/or modification. Charge-neutralizing modifications, such as histone acetylation, serve to disrupt this DNA-tail interaction, facilitating access to such residues. We previously showed that a polyacetylation-mediated chromatin "switch" governs the read-write capability of H3K4me3 by the MLL1 methyltransferase complex. Here, we discern the relative contributions of site-specific acetylation states along the H3 tail and extend our interrogation to other chromatin modifiers. We show that the contributions of H3 tail …

Associations Of Mid-To-Late-Life Inflammation With Late-Life Mobility And The Influences Of Chronic Comorbidities, Race, And Social Determinants Of Health: The Atherosclerosis Risk In Communities Study, Kirby G Parker, B Gwen Windham, Chad Blackshear, Keenan A Walker, Sara B Parker, Ron C Hoogeveen, Christie M Ballantyne, Anna Kucharska-Newton, Priya Palta, Elizabeth Selvin, Maria Vassilaki, Thomas H Mosley, Michael E Griswold

Faculty, Staff and Students Publications

Background: Relationships of midlife inflammation with late-life mobility and influences of chronic health conditions, race, and social determinants of health (SDoH) on these relationships are poorly understood.

Methods: Among 4758 community-dwelling participants (41% men, 20% Black), high-sensitivity C-reactive protein (hsCRP) was measured over 20+ years: in midlife at study visit 2 (V2: 1990-1992, 47-68 years); at V4 (1996-1998, 53-74 years); and with concurrent late-life 4-m gait speed at V5 (2011-2013, 67-88 years, mean 75 years). SDoH measures included race, the national-rank area deprivation index, education, and income. We examined associations of late-life gait speed with midlife hsCRP (V2 continuous and …

Sinus Arrest Related To Dexmedetomidine Infusion In An Infant; A Case Report And Review Of Current Literature, Alexandra Dennee, Thomas P Fogarty, Taylor S Howard, Ryan Brandon Hunter

Faculty, Staff and Students Publications

Background: Dexmedetomidine, an alpha 2 agonist, has emerged as a desirable sedative agent in the pediatric intensive care unit due to its minimal effect on respiratory status and reduction in delirium. Bradycardia and hypotension are common side effects, however there are emerging reports of more serious cardiovascular events, including sinus arrest and asystole. These case reports have been attributed to high vagal tone or underlying cardiac conduction dysfunction.

Objectives: To describe the development of sinus arrest during sedation with dexmedetomidine in a patient without clinical features of high vagal tone, underlying cardiac conduction dysfunction, or intervening episodes of bradycardia.

Case …