Medicine and Health Sciences Commons^™

Gramseq-Dta: A Grammar-Based Drug-Target Affinity Prediction Approach Fusing Gene Expression Information, Kasul Debnath, Pratip Rana, Preetam Ghosh

Computer Science Faculty Publications

Drug–target affinity (DTA) prediction is a critical aspect of drug discovery. The meaningful representation of drugs and targets is crucial for accurate prediction. Using 1D string-based representations for drugs and targets is a common approach that has demonstrated good results in drug–target affinity prediction. However, these approach lacks information on the relative position of the atoms and bonds. To address this limitation, graph-based representations have been used to some extent. However, solely considering the structural aspect of drugs and targets may be insufficient for accurate DTA prediction. Integrating the functional aspect of these drugs at the genetic level can enhance …

A Survey On Deep Learning For Drug-Target Binding Prediction: Models, Benchmarks, Evaluation, And Case Studies, Kusal Debnath, Pratip Rana, Preetam Ghosh

Computer Science Faculty Publications

Conventional drug discovery is expensive, time-consuming, and prone to failure. Artificial intelligence has become a potent substitute over the last decade, providing strong answers to challenging biological issues in this field. Among these difficulties, drug-target binding (DTB) is a key component of drug discovery techniques. In this context, drug-target affinity and drug–target interaction are complementary and essential frameworks that work together to improve our comprehension of DTB dynamics. In this work, we thoroughly analyze the most recent deep learning models, popular benchmark datasets, and assessment metrics for DTB prediction. We look at the paradigm shift in the development of drug …

Coldstartcpi: Induced-Fit Theory-Guided Dti Predictive Model With Improved Generalization Performance, Qichang Zhao, Haochen Zhao, Linyuan Gao, Kai Zheng, Yajie Li, Qiao Ling, Jing Tang, Yaohang Li, Jianxin Wang

Computer Science Faculty Publications

Predicting compound-protein interactions (CPIs) plays a crucial role in drug discovery. Traditional methods, based on the key-lock theory and rigid docking, often fail with novel compounds and proteins due to their inability to account for molecular flexibility and the high sparsity of CPI data. Here, we introduce ColdstartCPI, a framework inspired by induced-fit theory, which leverages unsupervised pre-training features and a Transformer module to learn both compound and protein characteristics. ColdstartCPI treats proteins and compounds as flexible molecules during inference, aligning with biological insights. It outperforms state-of-the-art sequence-based models, particularly for unseen compounds and proteins, and shows strong generalization capability …

Obesity, Metabolic Health, And Diabetic Complications In People With Type 1 Diabetes., Yuanjie Mao, Jen-Tzer Gau, Ning Jiang

Ambulatory and Primary Care Articles

AIM: The concept of metabolically healthy obesity (MHO) has not been studied in type 1 diabetes (T1D). By analysing datasets from the DCCT/EDIC study, we compared the development of diabetic complications by obesity and metabolic health over 30 years of follow up.

MATERIALS AND METHODS: Insulin resistance was calculated by estimated glucose disposal rate (eGDR). The participants (n = 1127) were then divided into four groups based on time-weighted mean body mass index and mean eGDR: metabolically healthy non-obesity (MHN, n = 874), metabolically unhealthy non-obesity (MUN, n = 66), MHO (n = 146) and metabolically unhealthy obesity (MUO, n …

Emcreg-International Multidisciplinary Consensus Panel On Management Of Hyperkalemia In Chronic Kidney Disease And Heart Failure, Natalie Kreitzer, Nancy M. Albert, Alpesh N. Amin, Craig J. Beavers, Richard C. Becker, Gregg Fonarow, W. Brian Gibler, Katherine W. Kwon, Robert J. Mentz, Biff F. Palmer, Charles V. Pollack, Iliana L. Piña

Division of Cardiology Faculty Papers

BACKGROUND: Hyperkalemia, generally defined as serum potassium levels greater than 5.0 mEq/L, poses significant clinical risks, including cardiac toxicity and muscle weakness. Its prevalence and severity increase in patients with chronic kidney disease (CKD), diabetes mellitus, and heart failure (HF), particularly when compounded by medications like angiotensin converting inhibitors, angiotensin receptor blockers, and potassium sparing diuretics. Hyperkalemia arises from disruptions in potassium regulation involving intake, excretion, and intracellular-extracellular distribution. In CKD and acute kidney injury, these regulatory mechanisms are impaired, leading to heightened risk. The management of chronic hyperkalemia presents a challenge due to the necessity of balancing effective cardiovascular …

Prevention Of Substance Related Deaths Through Mental Health Counseling, Lindsey Tout, Camille Zonfa

Scholarship in Medicine - All Papers

Background: Substance abuse, particularly alcohol and drug use, remains a critical public safety issue in Ohio. Those suffering with abuse disorders are likely to often have accompanying mental health disorders, however, there lies a significant gap in treatment.
Objective: This study examines trends in alcohol-related driving deaths, drug overdose deaths, excessive drinking, and mental health provider availability from 2016 to 2023 in rural and urban counties of Ohio.
Methods: Data collected from the public source, County Health Rankings and Roadmaps, was analyzed using statistical methods to assess changes between 2016 to 2023 for the 88 counties of Ohio. Urban versus …

Factors Driving Potentially Preventable Hospitalizations In Ohio And Surrounding States, Ann Walter, Andy Russell

Scholarship in Medicine - All Papers

No abstract provided.

An Analysis Of Alcohol, Mental Health, And Suicide, Motassem Bayyoud, Megan Galluch

Scholarship in Medicine - All Papers

Suicide rates in Montana, Iowa, Ohio, and New Jersey vary strongly and encompass the wide range seen across all fifty states in America. Previous research has told us that there is a significant relationship between Alcohol Use Disorder and the ideation, attempt, and completion of suicide. Additionally, most people who are victims of suicide suffer from mental disorders. People use alcohol to cope with mental health and alcohol leads to deteriorating and adverse outcomes in a person’s life. To attempt to better understand the relationship between these variables and why suicide rates differ so widely, an analysis of binge drinking, …

Impact Of Abortion Restrictions On Childhood Health Outcomes, Rico Carter, Griffin Suppa

Scholarship in Medicine - All Papers

Abortion has been a topic for debate in the U.S. for decades. With the Supreme Court’s recent overturning of Roe v. Wade, many pro-abortion advocates fear for the looming effects this policy change will have on healthcare. In this study we aim to study how abortion access or lack thereof influences childhood healthcare outcomes. Past research has shown a negative impact of abortion restrictions on infant survival, future socioeconomic success, and the U.S. foster care system. Using data collected from County Health Rankings & Roadmaps and three abortion restriction levels created from Guttmacher, we found that states with restrictions had …

Food Insecurity Rates And Its Related Factors In The State Of Ohio, Sophia Danchine, Maia Sethi

Scholarship in Medicine - All Papers

Food insecurity is an ongoing issue across Ohio counties, influenced by socioeconomic factors, geographical location, and age and ethnic demographics. This study explores food insecurity rates from 2016 to 2023, comparing urban and rural counties, various social determinants of health, such as income, education, and age, and exploring correlations with racial and ethnic demographics. Using data from the County Health Rankings and Roadmaps database, statistical analyses revealed key findings that food insecurity was not significantly different when comparing rural versus urban counties in Ohio. The most significant predictor to food insecurity in 2023 was median household income, followed by percent …

Social And Structural Determinants Of Mammography Screening Rates Among Female Medicare Beneficiaries: A Retrospective Analysis, Stephen Fuglsang, Rakhsha Khatri

Scholarship in Medicine - All Papers

Introduction: Despite Medicare fully covering annual mammogram costs, less than one half of female Ohio residents aged 65-74 sought yearly mammograms. As such, our analyses explore which social and structural determinants of health predict the likelihood that a woman aged 65-74 on Medicare will receive an annual mammogram.
Methods: This retrospective analysis utilized data from the County Health Rankings database, focusing on female Medicare enrollees aged 65-74. Mammography screening rates were compared across counties within Ohio, Michigan, and Missouri. Pearson and Spearman correlation tests were employed to examine relationships between English non-proficiency, high school graduation rates, residential segregation, primary care …

The Effect Of Socioeconomic Factors On Childhood Mortality, Sathvika Madisetty, Benjamin Curl

Scholarship in Medicine - All Papers

Objective: This study investigates the impact of socioeconomic factors specifically childhood poverty, uninsurance, and severe housing problems on childhood mortality rates in Ohio in 2016 and 2023.
Methods: The study analyzes county-level data from Ohio in 2016 and 2023, focusing on childhood mortality, childhood poverty, uninsurance, and severe housing problems using data from County Health Rankings and Roadmaps1. Statistical analyses, including paired t-tests, Spearman correlations, and linear regression, were performed to examine associations and predictive relationships.
Results: Childhood poverty was found to have a moderate, statistically significant correlation with childhood mortality in Ohio for 2023, emerging as the strongest predictor …

The Importance Of Solution Studies For The Structural Characterization Of The Enterovirus 5' Cloverleaf, Morgan G. Daniels, Meagan E. Werner, Xiaobing Zuo, Steven M. Pascal

Chemistry & Biochemistry Faculty Publications

Enteroviruses initiate genomic replication via a highly conserved mechanism that is controlled by an RNA platform, also known as the 5' cloverleaf (5'CL). Here, we present a biophysical analysis of the 5'CL conformation of three enterovirus serotypes under various ionic conditions, utilizing CD spectroscopy, size-exclusion chromatography, and small-angle X-ray scattering. In general, a tendency toward a smaller monomeric hydrodynamic radius in the presence of salts was observed, but the exact structural signature of each 5'CL varied depending upon the serotype. Rhinovirus B14 (RVB14) exhibited at least two monomeric conformations and a low propensity for dimerization, while poliovirus 1 (PV1) showed …

Research For All: Building A Diverse Researcher Community For The All Of Us Research Program, Rubin Baskir, Minnkyong Lee, Sydney J Mcmaster, Jessica Lee, Faith Blackburne-Proctor, Romuladus Azuine, Nakia Mack, Sheri D Schully, Martin Mendoza, Janeth Sanchez, Yong Crosby, Erica Zumba, Michael Hahn, Naomi Aspaas, Ahmed Elmi, Shanté Alerté, Elizabeth Stewart, Danielle Wilfong, Meag Doherty, Margaret M Farrell, Grace B Hébert, Sula Hood, Cheryl M Thomas, Debra D Murray, Brendan Lee, Louisa A Stark, Megan A Lewis, Jen D Uhrig, Laura R Bartlett, Edgar Gil Rico, Adolph Falcón, Elizabeth Cohn, Mitchell R Lunn, Juno Obedin-Maliver, Linda Cottler, Milton Eder, Fornessa T Randal, Jason Karnes, Kitani Lemieux, Nelson Lemieux, Nelson Lemieux, Lilanta Bradley, Ronnie Tepp, Meredith Wilson, Monica Rodriguez, Chris Lunt, Karriem Watson

Faculty, Staff and Students Publications

OBJECTIVES: The NIH All of Us Research Program (All of Us) is engaging a diverse community of more than 10 000 registered researchers using a robust engagement ecosystem model. We describe strategies used to build an ecosystem that attracts and supports a diverse and inclusive researcher community to use the All of Us dataset and provide metrics on All of Us researcher usage growth.

MATERIALS AND METHODS: Researcher audiences and diversity categories were defined to guide a strategy. A researcher engagement strategy was codeveloped with program partners to support a researcher engagement ecosystem. An adapted ecological model guided the ecosystem …

Igf-1 Impacts Neocortical Interneuron Connectivity In Epileptic Spasm Generation And Resolution, Carlos J Ballester-Rosado, John T Le, Trang T Lam, Anne E Anderson, James D Frost, John W Swann

Faculty, Staff and Students Publications

Little is known about the mechanisms that generate epileptic spasms following perinatal brain injury. Recent studies have implicated reduced levels of Insulin-like Growth Factor 1 (IGF-1) in these patients' brains. Other studies have reported low levels of the inhibitory neurotransmitter, GABA. In the TTX brain injury model of epileptic spasms, we undertook experiments to evaluate the impact of IGF-1 deficiencies on neocortical interneurons and their role in spasms. Quantitative immunohistochemical analyses revealed that neocortical interneurons that express glutamic acid decarboxylase, parvalbumin, or synaptotagmin 2 co-express IGF-1. In epileptic rats, expression of these three interneuron markers were reduced in the neocortex. …

Analysis Of 1,25-Dihydroxyvitamin D Genomic Action In Human Enteroids And Colonoids Reveals Multiple Regulatory Effects Of Vitamin D In Human Intestinal Physiology, Zachary K Criss, Kali Deans-Fielder, James C Fleet, Sylvia Christakos, Noah Shroyer

Faculty, Staff and Students Publications

Introduction: The intestine has molecular and functional diversity across the proximal-distal and the crypt-villus axes, so it is imperative to determine the common and compartment-specific molecular actions of vitamin D. However, very little work on vitamin D mediated gene regulation has been done in normal human intestine. Here, we examined the impact of 1,25-dihydroxyvitamin D (1,25(OH)2D3) on cultures of human intestinal epithelium derived from duodenum (Dd) and distal colon (Co) biopsies of 6 subjects per tissue.

Methods: Human enteroids and colonoids were cultured for 3 days to promote a stem cell phenotype (undifferentiated, Un) or to induce differentiation (Diff) and …

Outcomes In Pediatric Cholesteatoma, Katherine M Miller, Yi-Chun Carol Liu, Jaqueline E Weinstein, Michael S Cohen, David H Chi, Samantha Anne

Faculty, Staff and Students Publications

OBJECTIVE: The objective of the study is to evaluate the outcomes of surgical management options for cholesteatoma using a national database.

STUDY DESIGN: Database analysis of the Pediatric Health Information System database to identify children undergoing surgical intervention for cholesteatoma from October 2015 to December 2022.

METHODS: Patients were categorized by initial surgical modality: tympanoplasty (TM), tympanoplasty with canal wall-up tympanomastoidectomy (TM-CWU), and tympanoplasty with canal wall-down tympanomastoidectomy (TM-CWD). Group comparisons were done on number of surgical revisions and number of patients identified with recommendations for hearing aids.

RESULTS: A total of 6304 patients were identified in the database who …

Zic1 Is A Context-Dependent Medulloblastoma Driver In The Rhombic Lip, John J Y Lee, Ran Tao, Zhen You, Parthiv Haldipur, Anders W Erickson, Hamza Farooq, Liam D Hendriske, Namal Abeysundara, Cory M Richman, Evan Y Wang, Neha Das Gupta, Jennifer Hadley, Melissa Batts, Christopher W Mount, Xiaochong Wu, Alex Rasnitsyn, Swneke Bailey, Florence M G Cavalli, Sorana Morrissy, Livia Garzia, Kulandaimanuvel Antony Michealraj, Abhi Visvanathan, Vernon Fong, Jonelle Palotta, Raul Suarez, Bryn G Livingston, Miao Liu, Betty Luu, Craig Daniels, James Loukides, Anne Bendel, Pim J French, Johan M Kros, Andrey Korshunov, Marcel Kool, Fernando Chico Ponce De León, Mario Perezpeña-Diazconti, Boleslaw Lach, Sheila K Singh, Sarah E S Leary, Byung-Kyu Cho, Seung-Ki Kim, Kyu-Chang Wang, Ji-Yeoun Lee, Teiji Tominaga, William A Weiss, Joanna J Phillips, Shizhong Dai, Gelareh Zadeh, Ali G Saad, László Bognár, Almos Klekner, Ian F Pollack, Ronald L Hamilton, Young-Shin Ra, Wieslawa A Grajkowska, Marta Perek-Polnik, Reid C Thompson, Anna M Kenney, Michael K Cooper, Stephen C Mack, Nada Jabado, Mathieu Lupien, Marco Gallo, Vijay Ramaswamy, Mario L Suva, Hiromichi Suzuki, Kathleen J Millen, L Frank Huang, Paul A Northcott, Michael D Taylor

Faculty, Staff and Students Publications

Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that ZIC1 exhibits loss-of-function (LOF) somatic events in group 4 (G4) medulloblastoma through recurrent point mutations, subchromosomal deletions and mono-allelic epigenetic repression (60% of G4 medulloblastoma). In contrast, highly similar SHH medulloblastoma exhibits distinct and diametrically opposed gain-of-function mutations and copy number gains (20% of SHH medulloblastoma). Overexpression of ZIC1 suppresses the growth of group 3 medulloblastoma models, whereas it promotes the proliferation of SHH medulloblastoma precursor cells. SHH medulloblastoma ZIC1 mutants show increased activity versus wild-type ZIC1, whereas G4 medulloblastoma …

Maternal Rest Improves Growth In Small-For-Gestational-Age Fetuses (<10th Percentile), Greggory R Devore, Bardo Polanco, Wesley Lee, Jeffrey Brian Fowlkes, Emma E Peek, Manesha Putra, John C Hobbins

Faculty, Staff and Students Publications

BACKGROUND: Optimal management of fetuses diagnosed as small for gestational age based on an estimated fetal weight ofHowever, maternal bed rest has not been recommended based on the results of a randomized clinical trial that showed that maternal rest does not improve fetal growth in small-for-gestational-age fetuses. This study was conducted to revisit this question.

OBJECTIVE: This study aimed to determine whether maternal bed rest was associated with an increase in the fetal biometric parameters that reflect growth after the diagnosis of a small-for-gestational-age fetus.

STUDY DESIGN: A retrospective study was conducted on fetuses who were diagnosed as small for …

Transposable Element Activity Captures Human Pluripotent Cell States, Florencia Levin-Ferreyra, Srikanth Kodali, Yingzhi Cui, Alison R S Pashos, Patrizia Pessina, Justin Brumbaugh, Bruno Di Stefano

Faculty, Staff and Students Publications

Human pluripotent stem cells (hPSCs) exist in multiple, transcriptionally distinct states and serve as powerful models for studying human development. Despite their significance, the molecular determinants and pathways governing these pluripotent states remain incompletely understood. Here, we demonstrate that transposable elements act as sensitive indicators of distinct pluripotent cell states. We engineered hPSCs with fluorescent reporters to capture the temporal expression dynamics of two state-specific transposable elements, LTR5_Hs, and MER51B. This dual reporter system enables real-time monitoring and isolation of stem cells transitioning from naïve to primed pluripotency and further towards differentiation, serving as a more accurate readout of pluripotency …

Promotion Of Hiv Clearance By Sensitization Of Hiv Reservoirs To Cell Death, Min Li, Baichao Sun, Jing Dong, Jian-Rong Li, Laurie J Minze, Min Chen, Chao Cheng, Jin Wang

Faculty, Staff and Students Publications

Introduction: HIV integrates its proviral DNA into the host genome to establish persistent infection. To promote HIV clearance, we have designed an approach for selective elimination of host cells harboring replication-competent HIV (SECH), through inhibition of autophagy and anti-apoptotic molecules during viral reactivation. SECH approach can clear HIV-infected cells in approximately 50% humanized mice. However, the mechanisms for the resistance of reservoirs to depletion in mice with failure in HIV clearance are unclear.

Methods: We have performed single cell transcriptome analyses of HIV-infected T cells that escaped the treatments, in order to identify cellular pathways that could be targeted to …

Reliable Rna-Seq Analysis From Ffpe Specimens As A Means To Accelerate Cancer-Related Health Disparities Research, Mitchell J Frederick, Dannelys Perez-Bello, Pedram Yadollahi, Patricia Castro, Alan Frederick, Andrew Frederick, Rashid A Osman, Fonma Essien, Imelda Yebra, Ashley Hamlin, Thomas J Ow, Heath D Skinner, Vlad C Sandulache

Faculty, Staff and Students Publications

Whole transcriptome sequencing (WTS/ RNA-Seq) is a ubiquitous tool for investigating cancer biology. RNA isolated from frozen sources limits possible studies for analysis of associations with phenotypes or clinical variables requiring long-term follow-up. Although good correlations are reported in RNA-Seq data from paired frozen and formalin fixed paraffin embedded (FFPE) samples, uncertainties regarding RNA quality, methods of extraction, and data reliability are hurdles to utilization of archival samples. We compared three different platforms for performing RNA-seq using archival FFPE oropharyngeal squamous carcinoma (OPSCC) specimens stored up to 20 years, as part of an investigation of transcriptional profiles related to health …

Tobacco Exposure Linked To Warthin’S Tumor Being The Most Common Benign Parotid Neoplasm In Veterans: A Retrospective Cohort Study, Louis Abarca, Linda K Green, Ray Y Wang, Vlad C Sandulache, David J Hernandez

Faculty, Staff and Students Publications

Objective: Parotid gland neoplasms account for a large proportion of benign salivary gland tumors, with pleomorphic adenomas (PA) being the most common in the civilian population, followed by Warthin's tumor (WT). However, the distinct risk profiles of Veterans significantly influence the incidence and prevalence of salivary gland neoplasms. We investigated the diagnostic and management algorithms for benign parotid gland neoplasms in Veterans.

< >Methods: Retrospective cohort study. Descriptive statistics were calculated using Microsoft Excel. Categorical variables were compared using chi square tests, and were reported with 95% confidence intervals, with statistical significance set at P <  .05.

Results: The study included 158 patients …

Relationships Of Personality Traits With The Taxonomic Composition Of The Gut Microbiome Among Psychiatric Inpatients, William Orme, Sandra L Grimm, Divya S N Vella, J Christopher Fowler, B Christopher Frueh, Benjamin L Weinstein, Joseph Petrosino, Cristian Coarfa, Alok Madan

Faculty, Staff and Students Publications

Objective: Through the brain-gut-microbiome axis, myriad psychological functions that affect behavior share a dynamic, bidirectional relationship with the intestinal microbiome. Little is known about the relationship between personality-a stable construct that influences social- and health-related behaviors-and the bacterial ecosystem. The authors of this exploratory study examined the relationship between general and maladaptive personality traits and the composition of the gut microbiome.

Methods: In total, 105 psychiatric inpatients provided clinical data and fecal samples. Personality traits were measured with the five-factor model of personality, the Structured Clinical Interview for DSM-IV Axis II Personality Disorders, and the Personality Inventory for DSM-5; 16S …

Monoallelic Expression Can Govern Penetrance Of Inborn Errors Of Immunity, O'Jay Stewart, Conor Gruber, Haley E Randolph, Roosheel Patel, Meredith Ramba, Enrica Calzoni, Lei Haley Huang, Jay Levy, Sofija Buta, Angelica Lee, Christos Sazeides, Zoe Prue, David P Hoytema Van Konijnenburg, Ivan K Chinn, Luis A Pedroza, James R Lupski, Erica G Schmitt, Megan A Cooper, Anne Puel, Xiao Peng, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Satoshi Okada, Marta Martin-Fernandez, Jordan S Orange, Jean-Laurent Casanova, Joshua D Milner, Dusan Bogunovic

Faculty, Staff and Students Publications

Inborn errors of immunity (IEIs) are genetic disorders that underlie susceptibility to infection, autoimmunity, autoinflammation, allergy and/or malignancy1. Incomplete penetrance is common among IEIs despite their monogenic basis2. Here we investigate the contribution of autosomal random monoallelic expression (aRMAE), a somatic commitment to the expression of one allele3,4, to phenotypic variability observed in families with IEIs. Using a clonal primary T cell system to assess aRMAE status of genes in healthy individuals, we find that 4.30% of IEI genes and 5.20% of all genes undergo aRMAE. Perturbing H3K27me3 and DNA methylation alters …

A Natural Small Molecule Isoginkgetin Alleviates Hypercholesterolemia And Atherosclerosis By Targeting Acly, Zhidan Zhang, Meijie Chen, Yitong Xu, Zhihua Wang, Zhenghong Liu, Chenyang He, Fanshun Zhang, Xiaojun Feng, Xiayun Ni, Yuanli Chen, Jixia Wang, Xinmiao Liang, Zhifu Xie, Jingya Li, Maciej Banach, Jaroslav Pelisek, Yuqing Huo, Yunhui Hu, Paul C Evans, Li Wang, Xiao-Yu Tian, Jianbo Xiao, Yuhua Shang, Yijun Zheng, Xunde Xian, Jianping Weng, Suowen Xu

Faculty, Staff and Students Publications

Rationale: Atherosclerotic cardiovascular disease (ASCVD) represents the predominant cause of mortality and morbidity globally. Given the established role of hypercholesterolemia as a significant risk factor for ASCVD, the discovery of new lipid-lowering medications is of paramount importance. ATP citrate lyase (ACLY) is a crucial enzyme in cellular metabolism, providing acetyl-CoA as the building block for the biosynthesis of fatty acids and cholesterol. Consequently, it has emerged as a promising drug target for innovative treatments of lipid metabolic disorders.

Methods: Virtual screening of a natural product library was performed to identify small-molecule ACLY inhibitors, leading to the discovery of isoginkgetin (ISOGK). …

Recessive Loss-Of-Function Variants In Dph1 Identified As The Molecular Cause In A Sibling Pair Previously Diagnosed With Fine-Lubinsky Syndrome, Emily R Waskow, Lisa T Emrick, Jill A Rosenfeld, Shamika Ketkar, Lindsay C Burrage, Daryl A Scott

Faculty, Staff and Students Publications

Fine-Lubinsky syndrome is a rare clinically defined syndrome sometimes referred to as brachycephaly, deafness, cataract, microstomia, and impaired intellectual development syndrome. Here we provide a clinical and molecular update for a sibling pair diagnosed with Fine-Lubinsky syndrome. An extensive genetic work-up, including chromosomal microarray analysis and quad exome sequencing, was nondiagnostic. However, a research reanalysis of their exome sequencing data revealed that both were homozygous for an intronic c.749+39G>A [NM_001383.6] variant in DPH1. RNAseq analysis performed on RNA from fibroblasts revealed significantly reduced expression of DPH1 transcripts suggestive of abnormal splicing followed by nonsense mediated mRNA decay. Since the …

Critiques Of The Cass Review: Fact-Checking The Peer-Reviewed And Grey Literature, Kathleen Mcdeavitt, J Cohn, Stephen B Levine

Faculty, Staff and Students Publications

The Cass Review's final report, published in April 2024, made recommendations to the UK's National Health Service regarding structuring of services for minors with gender-related distress. It recommended cautious use of hormonal interventions in this population and use of research protocols. Some clinician-researchers disagree with the Cass Review's recommendations and have written critiques. A critique of the Cass Review posted on Yale Law School's website in July 2024 has received extensive media coverage. Its references identified three other critiques. In these papers, there were multiple claims that were incorrect or that lacked essential clarification/contextualization. These claims involved (1) the Cass …

Biallelic Variation In The Choline And Ethanolamine Transporter Flvcr1 Underlies A Severe Developmental Disorder Spectrum, Daniel G Calame, Jovi Huixin Wong, Puravi Panda, Dat Tuan Nguyen, Nancy C P Leong, Riccardo Sangermano, Sohil G Patankar, Mohamed S Abdel-Hamid, Lama Alabdi, Sylvia Safwat, Kyle P Flannery, Zain Dardas, Jawid M Fatih, Chaya Murali, Varun Kannan, Timothy E Lotze, Isabella Herman, Farah Ammouri, Brianna Rezich, Stephanie Efthymiou, Shahryar Alavi, David Murphy, Zahra Firoozfar, Mahya Ebrahimi Nasab, Amir Bahreini, Majid Ghasemi, Nourelhoda A Haridy, Hamid Reza Goldouzi, Fatemeh Eghbal, Ehsan Ghayoor Karimiani, Amber Begtrup, Houda Elloumi, Varunvenkat M Srinivasan, Vykuntaraju K Gowda, Haowei Du, Shalini N Jhangiani, Zeynep Coban-Akdemir, Dana Marafi, Lance Rodan, Sedat Isikay, Jill A Rosenfeld, Subhadra Ramanathan, Michael Staton, Kerby C Oberg, Robin D Clark, Catharina Wenman, Sam Loughlin, Ramy Saad, Tazeen Ashraf, Alison Male, Shereen Tadros, Reza Boostani, Ghada M H Abdel-Salam, Maha Zaki, Ali Mardi, Farzad Hashemi-Gorji, Ebtesam Abdalla, M Chiara Manzini, Davut Pehlivan, Jennifer E Posey, Richard A Gibbs, Henry Houlden, Fowzan S Alkuraya, Kinga Bujakowska, Reza Maroofian, James R Lupski, Long N Nguyen

Faculty, Staff and Students Publications

Purpose: FLVCR1 encodes a solute carrier protein implicated in heme, choline, and ethanolamine transport. Although Flvcr1-/- mice exhibit skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia (DBA), biallelic FLVCR1 variants in humans have previously only been linked to childhood or adult-onset ataxia, sensory neuropathy, and retinitis pigmentosa.

Methods: We identified individuals with undiagnosed neurodevelopmental disorders and biallelic FLVCR1 variants through international data sharing and characterized the functional consequences of their FLVCR1 variants.

Results: We ascertained 30 patients from 23 unrelated families with biallelic FLVCR1 variants and characterized a novel FLVCR1-related phenotype: severe developmental disorders with profound developmental delay, microcephaly …

Targeted Analysis Of Dyslexia-Associated Regions On Chromosomes 6, 12 And 15 In Large Multigenerational Cohorts, Nicola H Chapman, Patrick A Navas, Michael O Dorschner, Michele Mehaffey, Karen G Wigg, Kaitlyn M Price, Oxana Y Naumova, Elizabeth N Kerr, Sharon L Guger, Maureen W Lovett, Elena L Grigorenko, Virginia Berninger, Cathy L Barr, Ellen M Wijsman, Wendy H Raskind

Faculty, Staff and Students Publications

Dyslexia is a common learning impairment with a genetic basis that affects word reading and spelling. An increasing list of loci and genes have been implicated, but analyses to-date have investigated only limited genomic variation within each locus with no confirmed pathogenic variants identified. Our study is the first to comprehensively sequence both coding and cis-acting regulatory regions of such genes in a large study sample. In a collection of >2000 participants in families from three independent sites, we performed targeted capture and comprehensive sequencing of all exons and some regulatory elements of five candidate risk genes (DNAAF4, CYP19A1, DCDC2, …