Medicine and Health Sciences Commons^™

Presynaptic Nanoscale Components Of Retrograde Synaptic Signaling, Benjámin Barti, Barna Dudok, Kata Kenesei, Miklós Zöldi, Vivien Miczán, Gyula Y Balla, Diana Zala, Mariana Tasso, Claudia Sagheddu, Máté Kisfali, Blanka Tóth, Marco Ledri, E Sylvester Vizi, Miriam Melis, László Barna, Zsolt Lenkei, Iván Soltész, István Katona

Faculty, Staff and Students Publications

While our understanding of the nanoscale architecture of anterograde synaptic transmission is rapidly expanding, the qualitative and quantitative molecular principles underlying distinct mechanisms of retrograde synaptic communication remain elusive. We show that a particular form of tonic cannabinoid signaling is essential for setting target cell–dependent synaptic variability. It does not require the activity of the two major endocannabinoid-producing enzymes. Instead, by developing a workflow for physiological, anatomical, and molecular measurements at the same unitary synapse, we demonstrate that the nanoscale stoichiometric ratio of type 1 cannabinoid receptors (CB1Rs) to the release machinery is sufficient to predict synapse-specific release probability. Accordingly, …

Rebuilding The Health Sector In Gaza: Alternative Humanitarian Voices, Karl Blanchet, Martine Najem, Lina Shadid, Rouba Ali Fehmi, Fawzi Al Hammouri, Ghassan Saed, Khaled J Saleh, Mosab Nasser, Nidal Moukaddam, Jonathan Polonsky, Omar Lattouf

Faculty, Staff and Students Publications

In November 2023, a variety of disparate health organizations formed an international coalition to consolidate efforts and develop collaborative strategies in response to the increasing critical healthcare challenges caused by the recent war in Gaza. The coalition includes medical and public health experts, humanitarian practitioners, academics, and health policy-makers from across the world. Their membership has not much to do with mainstream humanitarian organisations. It is lead by the diaspora from the region. Their vision is the long-term reconstruction of the health system in Gaza while responding the most urgent needs. This collective effort will require explicit efforts to speak …

Multifactoral Immune Modulation Potentiates Durable Remission In Multiple Models Of Aggressive Malignancy, Matthew M Halpert, Briana A Burns, Spencer R Rosario, Henry G Withers, Akshar J Trivedi, Colby J Hofferek, Benjamin D Gephart, Haotong Wang, Jonathan Vazquez-Perez, Sharon B Amanya, Sean T Hyslop, Jianhua Yang, Jan O Kemnade, Vlad C Sandulache, Vanaja Konduri, William K Decker

Faculty, Staff and Students Publications

Tumors typically lack canonical danger signals required to activate adaptive immunity and also frequently employ substantial immunomodulatory mechanisms that downregulate adaptive responses and contribute to escape from immune surveillance. Given the variety of mechanisms involved in shielding tumors from immune recognition, it is not surprising that single-agent immunomodulatory approaches have been largely unsuccessful in generating durable antitumor responses. Here we report a unique combination of immunomodulatory and cytostatic agents that recondition the tumor microenvironment and eliminate complex and/or poor-prognosis tumor types including the non-immunogenic 4T-1 model of TNBC, the aggressive MOC-2 model of HNSCC, and the high-risk MYCN-amplified model of …

Variant-Specific Pathophysiological Mechanisms Of Aff3 Differently Influence Transcriptome Profiles, Sissy Bassani, Jacqueline Chrast, Giovanna Ambrosini, Norine Voisin, Frédéric Schütz, Alfredo Brusco, Fabio Sirchia, Lydia Turban, Susanna Schubert, Rami Abou Jamra, Jan-Ulrich Schlump, Desiree Demille, Pinar Bayrak-Toydemir, Gary Rex Nelson, Kristen Nicole Wong, Laura Duncan, Mackenzie Mosera, Christian Gilissen, Lisenka E L M Vissers, Rolph Pfundt, Rogier Kersseboom, Hilde Yttervik, Geir Åsmund Myge Hansen, Marie Falkenberg Smeland, Kameryn M Butler, Michael J Lyons, Claudia M B Carvalho, Chaofan Zhang, James R Lupski, Lorraine Potocki, Leticia Flores-Gallegos, Rodrigo Morales-Toquero, Florence Petit, Binnaz Yalcin, Annabelle Tuttle, Houda Zghal Elloumi, Lane Mccormick, Mary Kukolich, Oliver Klaas, Judit Horvath, Marcello Scala, Michele Iacomino, Francesca Operto, Federico Zara, Karin Writzl, Aleš Maver, Maria K Haanpää, Pia Pohjola, Harri Arikka, Anneke J A Kievit, Camilla Calandrini, Christian Iseli, Nicolas Guex, Alexandre Reymond

Faculty, Staff and Students Publications

BACKGROUND: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects.

METHODS: Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants.

RESULTS: We identified …

Catheter-Based Fetal Cardiac Interventions, Betul Yilmaz Furtun, Shaine Alaine Morris

Faculty, Staff and Students Publications

Fetal cardiac intervention (FCI) is an emerging and rapidly advancing group of interventions designed to improve outcomes for fetuses with cardiovascular disease. Currently, FCI is comprised of pharmacologic therapies (e.g., trans-placental antiarrhythmics for fetal arrhythmia), open surgical procedures (e.g., surgical resection of pericardial teratoma), and catheter-based procedures (e.g., fetal aortic valvuloplasty for aortic stenosis). This review focuses on the rationale, criteria for inclusion, technical details, and current outcomes of the three most frequently performed catheter-based FCI procedures: (1) aortic valvuloplasty for critical aortic stenosis (AS) associated with evolving hypoplastic left heart syndrome (HLHS), (2) atrial septal intervention for HLHS with …

Cosmetic Penile Enhancement Procedures: An Smsna Position Statement, Landon Trost, Daniel N Watter, Serge Carrier, Mohit Khera, Faysal A Yafi, Helen L Bernie, Matthew Ziegelmann, Tobias Köhler

Faculty, Staff and Students Publications

Background: Penile cosmetic enhancement procedures have been performed for many years with varying success. However, they have historically been relegated to niche areas of sexual medicine, with limited data, and have not achieved mainstream adoption. More recently, the topic has been increasingly discussed within academic congresses due to availability of novel techniques, therapies, and procedures. Given their distinctive nature, the Sexual Medicine Society of North America (SMSNA) felt that it was pertinent to develop formal position statements to help guide both patients and sexual medicine providers on the current state of the scientific literature and to give recommendations for future …

Factors Associated With Intention To Implement Sbi And Sud Treatment: A Survey Of Primary Care Clinicians In Texas Enrolled In An Online Course, Alicia Kowalchuk, Tiffany G Ostovar-Kermani, Kylie Schaper, Larissa Grigoryan, Jacqueline M Hirth, Maria Carmenza Mejia, Kiara K Spooner, Roger J Zoorob

Faculty, Staff and Students Publications

BACKGROUND: Substance use disorder (SUD) presents a range of public health challenges and consequences. Despite the prevention potential of screening and brief intervention (SBI) in the primary care setting, implementation is low. The purpose of this study was to assess associations of primary care clinicians' knowledge of SBI and SUD treatment, subjective norms, and perceived behavioral control with intention to incorporate SBI and SUD treatment into regular clinical practice.

METHODS: This online survey was administered to primary care clinicians who practice in Texas between March 1, 2021, and February 5, 2023. Survey questions were mapped to factors in the Theory …

A Technology-Assisted Web Application For Consumer Access To A Nonprescription Statin Medication, Steven E Nissen, Howard G Hutchinson, Kathy Wolski, Karol Watson, Seth S Martin, Erin D Michos, William S Weintraub, Melanie Morris, Leslie Cho, Luke Laffin, Douglas Jacoby, Christie M Ballantyne, Jan Ekelund, Filip Birve, Venu Menon, Michelle Strzelecki, Paul M Ridker

Faculty, Staff and Students Publications

Background: Although statins reduce adverse cardiovascular outcomes, less than one-half of eligible patients receive treatment. A nonprescription statin has the potential to improve access to statins.

Objectives: This study sought to assess concordance between clinician and consumer assessment of eligibility for nonprescription statin treatment using a technology assisted self-selection Web application (Web App) and evaluate effect on low-density lipoprotein cholesterol (LDL-C) levels.

Methods: This study was a prospective actual use 6-month study to evaluate use of a Web App to qualify participants without a medical background for a moderate-intensity statin based on current guidelines. Participants entered demographic information, cholesterol values, …

Compensation Between Foxp Transcription Factors Maintains Proper Striatal Function, Newaz I Ahmed, Nitin Khandelwal, Ashley G Anderson, Emily Oh, Rachael M Vollmer, Ashwinikumar Kulkarni, Jay R Gibson, Genevieve Konopka

Faculty, Staff and Students Publications

Spiny projection neurons (SPNs) of the striatum are critical in integrating neurochemical information to coordinate motor and reward-based behavior. Mutations in the regulatory transcription factors expressed in SPNs can result in neurodevelopmental disorders (NDDs). Paralogous transcription factors Foxp1 and Foxp2, which are both expressed in the dopamine receptor 1 (D1) expressing SPNs, are known to have variants implicated in NDDs. Utilizing mice with a D1-SPN-specific loss of Foxp1, Foxp2, or both and a combination of behavior, electrophysiology, and cell-type-specific genomic analysis, loss of both genes results in impaired motor and social behavior as well as increased firing of the D1-SPNs. …

Spontaneous Coronary Artery Dissection Outcomes Among Pregnant Vs. Non-Pregnant Women, Chayakrit Krittanawong, Neelkumar Patel, Dhrubajyoti Bandyopadhyay, Neil Sagar Maitra, Muzamil Khawaja, Zhen Wang, Mahboob Alam, Jacob Shani, Robert Frankel, Samin Sharma, Hani Jneid

Faculty, Staff and Students Publications

Aims: Spontaneous coronary artery dissection (SCAD) has become increasingly recognized. It accounts for < 1-4% of acute coronary syndrome presentations. Overall, however, it makes up over 40% of pregnancy-associated myocardial infarction. Furthermore, pregnancy-associated spontaneous coronary artery dissection (P-SCAD) is described to have a greater degree of clinical manifestations, including left ventricular dysfunction, shock, and left main or multivessel involvement. The findings are disconcerting, though many studies evaluating P-SCAD are based on case series data or are single centre studies.

Methods and results: The aim of this study was to evaluate a larger national dataset to evaluate the outcomes of SCAD and specifically P-SCAD in an attempt to better characterize the severity and clinical nature of this condition. To conduct this study, we analysed the National Readmission Database from January 2016 to December 2020. Propensity matching was done using the Greedy 1:1 method. Multivariate logistics and time-to-event Cox regression analysis models were built by including all confounders significantly associated with the outcome on univariable analysis with a …

Pulmonary Hypertension And Hyperglycemia-Not A Sweet Combination, Or Bruck, L M Pandit

Faculty, Staff and Students Publications

Hyperglycemia and pulmonary hypertension (PH) share common pathological pathways that lead to vascular dysfunction and resultant cardiovascular complications. These shared pathologic pathways involve endothelial dysfunction, inflammation, oxidative stress, and hormonal imbalances. Individuals with hyperglycemia or pulmonary hypertension also possess shared clinical factors that contribute to increased morbidity from both diseases. This review aims to explore the relationship between PH and hyperglycemia, highlighting the mechanisms underlying their association and discussing the clinical implications. Understanding these common pathologic and clinical factors will enable early detection for those at-risk for complications from both diseases, paving the way for improved research and targeted therapeutics.

Therapeutic Strategies Against Metabolic Imbalance In A Male Mouse Model With 5-Ht2cr Loss-Of-Function, Hailan Liu, Zhaoxun Liu, Hueyxian Kelly Wong, Nathan Xu, Qingzhuo Liu, Yongxiang Li, Yao Liu, Hueyzhong Wong, Megan E Burt, Sanika V Jossy, Junying Han, Yang He

Faculty, Staff and Students Publications

The serotonin 2C receptor (5-HT2CR)-melanocortin pathway plays well-established roles in the regulation of feeding behavior and body weight homeostasis. Dysfunctions in this system, such as loss-of-function mutations in the Htr2c gene, can lead to hyperphagia and obesity. In this study, we aimed to investigate the potential therapeutic strategies for ameliorating hyperphagia, hyperglycemia, and obesity associated with a loss-of-function mutation in the Htr2c gene (Htr2cF327L/Y). We demonstrated that reexpressing functional 5-HT2CR solely in hypothalamic pro-opiomelanocortin (POMC) neurons is sufficient to reduce food intake and body weight in Htr2cF327L/Y mice subjected to a high-fat diet (HFD). In addition, 5-HT2CR expression restores the …

Generation Of Oviductal Glycoprotein 1 Cre Mouse Model For The Study Of Secretory Epithelial Cells Of The Oviduct, Emily A Mcglade, Jiude Mao, Kalli K Stephens, Andrew M Kelleher, Lisette A Maddison, Miranda L Bernhardt, Francesco J Demayo, John P Lydon, Wipawee Winuthayanon

Faculty, Staff and Students Publications

The epithelial cell lining of the oviduct plays an important role in oocyte pickup, sperm migration, preimplantation embryo development, and embryo transport. The oviduct epithelial cell layer comprises ciliated and nonciliated secretory cells. The ciliary function has been shown to support gamete and embryo movement in the oviduct, yet secretory cell function has not been well characterized. Therefore, our goal was to generate a secretory cell-specific Cre recombinase mouse model to study the role of the oviductal secretory cells. A knock-in mouse model, Ovgp1Cre:eGFP, was created by expressing Cre from the endogenous Ovgp1 (oviductal glycoprotein 1) locus, with enhanced green …

Outcomes Of Endoscopic Submucosal Dissection In Cirrhotic Patients: First American Cohort, Robert Luke Pecha, Fares Ayoub, Ankur Patel, Abdullah Muftah, Michael W Wright, Mai A Khalaf, Mohamed O Othman

Faculty, Staff and Students Publications

BACKGROUND: Among patients with cirrhosis and pre-malignant or early malignant mucosal lesions, surgical intervention carries a much higher bleeding risk. When such lesions are discovered, endoscopic submucosal dissection (ESD) may offer curative therapy with lower risks than surgery and improved outcomes compared to traditional endoscopic resection.

AIM: To evaluate the outcomes of ESD in patients with cirrhosis.

METHODS: Patients with cirrhosis undergoing ESD between July 2015 and August 2022 were retrospectively matched in 1:2 fashion to controls based on lesion location, size, and anticoagulation use. Procedural outcomes were compared between groups.

RESULTS: A total of 64 Lesions from 59 patients …

Glioblastoma Disrupts Cortical Network Activity At Multiple Spatial And Temporal Scales, Jochen Meyer, Kwanha Yu, Estefania Luna-Figueroa, Benjamin Deneen, Jeffrey Noebels

Faculty, Staff and Students Publications

The emergence of glioblastoma in cortical tissue initiates early and persistent neural hyperexcitability with signs ranging from mild cognitive impairment to convulsive seizures. The influence of peritumoral synaptic density, expansion dynamics, and spatial contours of excess glutamate upon higher order neuronal network modularity is unknown. We combined cellular and widefield imaging of calcium and glutamate fluorescent reporters in two glioblastoma mouse models with distinct synaptic microenvironments and infiltration profiles. Functional metrics of neural ensembles are dysregulated during tumor invasion depending on the stage of malignant progression and tumor cell proximity. Neural activity is differentially modulated during periods of accelerated and …

Genetic Or Pharmacological Ghsr Blockade Has Sexually Dimorphic Effects In Rodents On A High-Fat Diet, András H Lékó, Adriana Gregory-Flores, Renata C N Marchette, Juan L Gomez, Janaina C M Vendruscolo, Vez Repunte-Canonigo, Vicky Choung, Sara L Deschaine, Kimberly E Whiting, Shelley N Jackson, Maria Paula Cornejo, Mario Perello, Zhi-Bing You, Michael Eckhaus, Karuna Rasineni, Kim D Janda, Barry Zorman, Pavel Sumazin, George F Koob, Michael Michaelides, Pietro P Sanna, Leandro F Vendruscolo, Lorenzo Leggio

Faculty, Staff and Students Publications

The stomach-derived hormone ghrelin regulates essential physiological functions. The ghrelin receptor (GHSR) has ligand-independent actions; therefore, GHSR gene deletion may be a reasonable approach to investigate the role of this system in feeding behaviors and diet-induced obesity (DIO). Here, we investigate the effects of a long-term (12-month) high-fat (HFD) versus regular diet on obesity-related measures in global GHSR-KO and wild-type (WT) Wistar male and female rats. Our main findings are that the GHSR gene deletion protects against DIO and decreases food intake during HFD in male but not in female rats. GHSR gene deletion increases thermogenesis and brain glucose uptake …

Profiling Complex Repeat Expansions In Rfc1 In Parkinson’S Disease, Pilar Alvarez Jerez, Kensuke Daida, Abigail Miano-Burkhardt, Hirotaka Iwaki, Laksh Malik, Guillaume Cogan, Mary B Makarious, Roisin Sullivan, Jana Vandrovcova, Jinhui Ding, J Raphael Gibbs, Androo Markham, Mike A Nalls, Rupesh K Kesharwani, Fritz J Sedlazeck, Bradford Casey, John Hardy, Henry Houlden, Cornelis Blauwendraat, Andrew B Singleton, Kimberley J Billingsley

Faculty, Staff and Students Publications

A biallelic (AAGGG) expansion in the poly(A) tail of an AluSx3 transposable element within the gene RFC1 is a frequent cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), and more recently, has been reported as a rare cause of Parkinson's disease (PD) in the Finnish population. Here, we investigate the prevalence of RFC1 (AAGGG) expansions in PD patients of non-Finnish European ancestry in 1609 individuals from the Parkinson's Progression Markers Initiative study. We identified four PD patients carrying the biallelic RFC1 (AAGGG) expansion and did not identify any carriers in controls.

Incidence And Characteristics Of Cerebellar Atrophy/Volume Loss In Children With Confirmed Diagnosis Of Tuberous Sclerosis Complex, Livja Mertiri, Eugen Boltshauser, Stephen F Kralik, Nilesh K Desai, Maarten H Lequin, Thierry A G M Huisman

Faculty, Staff and Students Publications

Objectives: The goal of our study was to determine the incidence of cerebellar atrophy, assess the imaging findings in the posterior fossa and determine the incidence of hippocampal sclerosis in a cohort of pediatric patients with confirmed tuberous sclerosis complex (TSC).

Material and methods: MRI studies of 98 TSC pediatric patients (mean age 7.67 years) were evaluated for cerebellar atrophy, cerebral/cerebellar tubers, white matter lesions, subependymal nodules, subependymal giant cell astrocytomas, ventriculomegaly, and hippocampal sclerosis. Clinical charts were revisited for clinical symptoms suggesting cerebellar involvement, for seizures and treatment for seizures, behavioral disorders and autism.

Results: Cerebral tubers were present …

Reversible Male Contraception By Targeted Inhibition Of Serine/Threonine Kinase 33, Angela F Ku, Kiran L Sharma, Hai Minh Ta, Courtney M Sutton, Kurt M Bohren, Yong Wang, Srinivas Chamakuri, Ruihong Chen, John M Hakenjos, Ravikumar Jimmidi, Katarzyna Kent, Feng Li, Jian-Yuan Li, Lang Ma, Chandrashekhar Madasu, Murugesan Palaniappan, Stephen S Palmer, Xuan Qin, Matthew B Robers, Banumathi Sankaran, Zhi Tan, Yasmin M Vasquez, Jian Wang, Jennifer Wilkinson, Zhifeng Yu, Qiuji Ye, Damian W Young, Mingxing Teng, Choel Kim, Martin M Matzuk

Faculty, Staff and Students Publications

Men or mice with homozygous serine/threonine kinase 33 (STK33) mutations are sterile owing to defective sperm morphology and motility. To chemically evaluate STK33 for male contraception with STK33-specific inhibitors, we screened our multibillion-compound collection of DNA-encoded chemical libraries, uncovered potent STK33-specific inhibitors, determined the STK33 kinase domain structure bound with a truncated hit CDD-2211, and generated an optimized hit CDD-2807 that demonstrates nanomolar cellular potency (half-maximal inhibitory concentration = 9.2 nanomolar) and favorable metabolic stability. In mice, CDD-2807 exhibited no toxicity, efficiently crossed the blood-testis barrier, did not accumulate in brain, and induced a reversible contraceptive effect that …

Impact Of Combinatorial Histone Modifications On Acetyllysine Recognition By The Atad2 And Atad2b Bromodomains, Margaret Phillips, Kiera L Malone, Brian W Boyle, Cameron Montgomery, Isabelle A Kressy, Faith M Joseph, Kathleen M Bright, Samuel P Boyson, Sunsik Chang, Jay C Nix, Nicolas L Young, Victoria Jeffers, Seth Frietze, Karen C Glass

Faculty, Staff and Students Publications

The ATPase family AAA+ domain containing 2 (ATAD2) protein and its paralog ATAD2B have a C-terminal bromodomain (BRD) that functions as a reader of acetylated lysine residues on histone proteins. Using a structure–function approach, we investigated the ability of the ATAD2/B BRDs to select acetylated lysine among multiple histone post-translational modifications. The ATAD2B BRD can bind acetylated histone ligands that also contain adjacent methylation or phosphorylation marks, while the presence of these modifications significantly weakened the acetyllysine binding activity of the ATAD2 BRD. Our structural studies provide mechanistic insights into how ATAD2/B BRD-binding pocket residues coordinate the acetyllysine group in …

Twist1 Drives Cytotoxic Cd8+ T-Cell Exhaustion Through Transcriptional Activation Of Cd274 (Pd-L1) Expression In Breast Cancer Cells, Xiaobin Yu, Jianming Xu

Faculty, Staff and Students Publications

In breast cancer, epithelial-mesenchymal transition (EMT) is positively associated with programmed death ligand 1 (PD-L1) expression and immune escape, and TWIST1 silences ERα expression and induces EMT and cancer metastasis. However, how TWIST1 regulates PD-L1 and immune evasion is unknown. This study analyzed TWIST1 and PD-L1 expression in breast cancers, investigated the mechanism for TWIST1 to regulate PD-L1 transcription, and assessed the effects of TWIST1 and PD-L1 in cancer cells on cytotoxic CD8+ T cells. Interestingly, TWIST1 expression is correlated with high-level PD-L1 expression in ERα-negative breast cancer cells. The overexpression and knockdown of TWIST1 robustly upregulate and downregulate PD-L1 …

Ciliary Tip Actin Dynamics Regulate Photoreceptor Outer Segment Integrity, Roly Megaw, Abigail Moye, Zhixian Zhang, Fay Newton, Fraser Mcphie, Laura C Murphy, Lisa Mckie, Feng He, Melissa K Jungnickel, Alex Von Kriegsheim, Peter A Tennant, Chloe Brotherton, Christine Gurniak, Alecia K Gross, Laura M Machesky, Theodore G Wensel, Pleasantine Mill

Faculty, Staff and Students Publications

As signalling organelles, cilia regulate their G protein-coupled receptor content by ectocytosis, a process requiring localised actin dynamics to alter membrane shape. Photoreceptor outer segments comprise an expanse of folded membranes (discs) at the tip of highly-specialised connecting cilia, into which photosensitive GPCRs are concentrated. Discs are shed and remade daily. Defects in this process, due to mutations, cause retinitis pigmentosa (RP). Whilst fundamental for vision, the mechanism of photoreceptor disc generation is poorly understood. Here, we show membrane deformation required for disc genesis is driven by dynamic actin changes in a process akin to ectocytosis. We show RPGR, a …

An Unexpected Path For Malat1 In Neurons: Trafficking Out Of The Nucleus For Translation, Bradley W Wright, Jeremy E Wilusz

Faculty, Staff and Students Publications

The Malat1 (metastasis-associated lung adenocarcinoma transcript 1) long noncoding RNA is highly and broadly expressed in mammalian tissues, accumulating in the nucleus where it modulates expression and pre-mRNA processing of many protein-coding genes. In this issue of Genes & Development, Xiao and colleagues (doi:10.1101/gad.351557.124) report that a significant fraction of Malat1 transcripts in cultured mouse neurons are surprisingly exported from the nucleus. These transcripts are packaged with Staufen proteins in RNA granules and traffic down the lengths of neurites. They then can be released in a stimulus-dependent manner to be locally translated into a microprotein that alters neuronal gene …

Targeting The Substrate For Atrial Fibrillation: Jacc Review Topic Of The Week, Mark D Mccauley, Gianluca Iacobellis, Na Li, Stanley Nattel, Jeffrey J Goldberger

Faculty, Staff and Students Publications

The identification of the pulmonary veins as a trigger source for atrial fibrillation (AF) has established pulmonary vein isolation (PVI) as a key target for AF ablation. However, PVI alone does not prevent recurrent AF in many patients, and numerous additional ablation strategies have failed to improve on PVI outcomes. This therapeutic limitation may be due, in part, to a failure to identify and intervene specifically on the pro-fibrillatory substrate within the atria and pulmonary veins. In this review paper, we highlight several emerging approaches with clinical potential that target atrial cardiomyopathy-the underlying anatomic, electrical, and/or autonomic disease affecting the …

Empowering Personalized Pharmacogenomics With Generative Ai Solutions, Mullai Murugan, Bo Yuan, Eric Venner, Christie M Ballantyne, Katherine M Robinson, James C Coons, Liwen Wang, Philip E Empey, Richard A Gibbs

Faculty, Staff and Students Publications

Objective: This study evaluates an AI assistant developed using OpenAI's GPT-4 for interpreting pharmacogenomic (PGx) testing results, aiming to improve decision-making and knowledge sharing in clinical genetics and to enhance patient care with equitable access.

Materials and methods: The AI assistant employs retrieval-augmented generation (RAG), which combines retrieval and generative techniques, by harnessing a knowledge base (KB) that comprises data from the Clinical Pharmacogenetics Implementation Consortium (CPIC). It uses context-aware GPT-4 to generate tailored responses to user queries from this KB, further refined through prompt engineering and guardrails.

Results: Evaluated against a specialized PGx question catalog, the AI assistant showed …

Comparative Analysis Of In-Silico Tools In Identifying Pathogenic Variants In Dominant Inherited Retinal Diseases, Daniel C Brock, Meng Wang, Hafiz Muhammad Jafar Hussain, David E Rauch, Molly Marra, Mark E Pennesi, Paul Yang, Lesley Everett, Radwan S Ajlan, Jason Colbert, Fernanda Belga Ottoni Porto, Anna Matynia, Michael B Gorin, Robert K Koenekoop, Irma Lopez, Ruifang Sui, Gang Zou, Yumei Li, Rui Chen

Faculty, Staff and Students Publications

Inherited retinal diseases (IRDs) are a group of rare genetic eye conditions that cause blindness. Despite progress in identifying genes associated with IRDs, improvements are necessary for classifying rare autosomal dominant (AD) disorders. AD diseases are highly heterogenous, with causal variants being restricted to specific amino acid changes within certain protein domains, making AD conditions difficult to classify. Here, we aim to determine the top-performing in-silico tools for predicting the pathogenicity of AD IRD variants. We annotated variants from ClinVar and benchmarked 39 variant classifier tools on IRD genes, split by inheritance pattern. Using area-under-the-curve (AUC) analysis, we determined the …

Missing Wedge Completion Via Unsupervised Learning With Coordinate Networks, Dave Van Veen, Jesús G Galaz-Montoya, Liyue Shen, Philip Baldwin, Akshay S Chaudhari, Dmitry Lyumkis, Michael F Schmid, Wah Chiu, John Pauly

Faculty, Staff and Students Publications

Cryogenic electron tomography (cryoET) is a powerful tool in structural biology, enabling detailed 3D imaging of biological specimens at a resolution of nanometers. Despite its potential, cryoET faces challenges such as the missing wedge problem, which limits reconstruction quality due to incomplete data collection angles. Recently, supervised deep learning methods leveraging convolutional neural networks (CNNs) have considerably addressed this issue; however, their pretraining requirements render them susceptible to inaccuracies and artifacts, particularly when representative training data is scarce. To overcome these limitations, we introduce a proof-of-concept unsupervised learning approach using coordinate networks (CNs) that optimizes network weights directly against input …

Feasibility Of Fit24, A Digital Diabetes Prevention Program For Hispanic Adolescents: Qualitative Evaluation Study, Erica G Soltero, Salma M Musaad, Teresia M O'Connor, Debbe Thompson, Keith Norris, Bettina M Beech

Faculty, Staff and Students Publications

BACKGROUND: Digital health interventions are promising for reaching and engaging high-risk youth in disease prevention opportunities; however, few digital prevention interventions have been developed for Hispanic youth, limiting our knowledge of these strategies among this population.

OBJECTIVE: This study qualitatively assessed the feasibility and acceptability of Fit24, a 12-week goal-setting intervention that uses a Fitbit watch (Fitbit Inc) and theoretically grounded SMS text messages to promote physical activity and sleep among Hispanic adolescents (aged between 14 and 16 years) with obesity.

METHODS: After completing the intervention, a subsample of youth (N=15) participated in an in-depth interview. We categorized the themes …

Data Mining For Second Malignancies After Car-T, Helen E Heslop

Faculty, Staff and Students Publications

No abstract provided.

Mrd At The End Of Induction And Efs In T-Cell Lymphoblastic Lymphoma: Children’S Oncology Group Trial Aall1231, Robert J Hayashi, Michelle L Hermiston, Brent L Wood, David T Teachey, Meenakshi Devidas, Zhiguo Chen, Robert D Annett, Barbara L Asselin, Keith August, Steve Cho, Kimberly P Dunsmore, Jason Lawrence Freedman, Paul J Galardy, Paul Harker-Murray, Terzah M Horton, Alok Jaju, Allison Lam, Yoav H Messinger, Rodney R Miles, Maki Okada, Samir Patel, Eric S Schafer, Tal Schechter, Kristin A Shimano, Neelam Singh, Amii Steele, Maria L Sulis, Sarah L Vargas, Stuart S Winter, Charlotte Wood, Patrick A Zweidler-Mckay, Mignon L Loh, Stephen P Hunger, Elizabeth A Raetz, Catherine M Bollard, Carl E Allen

Faculty, Staff and Students Publications

Defining prognostic variables in T-lymphoblastic lymphoma (T-LL) remains a challenge. AALL1231 was a Children’s Oncology Group phase 3 clinical trial for newly diagnosed patients with T acute lymphoblastic leukemia or T-LL, randomizing children and young adults to a modified augmented Berlin-Frankfurt-Münster backbone to receive standard therapy (arm A) or with addition of bortezomib (arm B). Optional bone marrow samples to assess minimal residual disease (MRD) at the end of induction (EOI) were collected in T-LL analyzed to assess the correlation of MRD at the EOI to event-free survival (EFS). Eighty-six (41%) of the 209 patients with T-LL accrued to this …