Digital Commons Network^™

Relationship Between Smoking And Psychiatric And Somatic Comorbidities In Older Age Bipolar Disorder: Lien Entre Le Tabagisme Et Les Affections Psychiatriques Et Somatiques Concomitantes Chez Les Personnes Âgées Atteintes De Trouble Bipolaire, Molly Howland, Arushi Mahajan, Peijun Chen, Osvaldo Almeida, Kürşat Altınbaş, Hilary Blumberg, Annemiek Dols, Nicole Fiorelli, Orestes Forlenza, Beny Lafer, Andrew Olagunju, Melis Orhan, Soham Rej, Martha Sajatovic, Matthew Schurr, Christian Simhandl, Jair Soares, Ashley Sutherland, Shang-Ying Tsai, Sara Weisenbach, Joy Yala, Farren Briggs

Faculty, Staff and Student Publications

Objective

Smoking has been associated with psychiatric and somatic comorbidities in bipolar disorder (BD) populations. However, studies in older age BD (OABD) populations are sparse. We hypothesized that among individuals with OABD, current and former smokers would have worse psychiatric and somatic comorbidities parameters compared to never smokers.

Method

Our study used baseline cross-sectional data from 27 international studies reporting data on adults 50 years old and older (N = 984). Smoking status was categorized into current smokers, former smokers, and never smokers. The distribution of demographic and clinical variables was assessed. The associations between smoking status and the …

Use Of The Selective Cytopheretic Device With Continuous Renal Replacement Therapy In Children: A Comparison Of Contemporary Cohorts, Natalja L Stanski, Jangdong Seo, Todd Jenkins, Kelli A Krallman, Shina Menon, H David Humes, David J Askenazi, Rajit K Basu, Ayse Akcan-Arikan, Stuart L Goldstein, Katja M Gist

Faculty, Staff and Students Publications

Introduction: The selective cytopheretic device (SCD) is a cell-directed extracorporeal therapy approved for use in children with acute kidney injury (AKI) receiving continuous renal replacement therapy (CRRT) with sepsis/sepsis-like conditions. We compared outcomes for children treated with SCD to a contemporary cohort of children treated with CRRT alone.

Methods: Secondary analysis and comparison of patients ≤22 years old and ≥10 kg from a multicenter registry of patients receiving CRRT for AKI and/or fluid overload (WE-ROCK; 2015-2021) to patients from two multicenter, prospective, interventional studies of children with AKI and multiple organ dysfunction (MODS) receiving SCD (SCD-PED-01/SCD-PED-02; 2016-2022).

Results: Eighteen patients …

Cdk4/6 Inhibitors In Breast Cancer-Who Should Receive Them?, Anran Chen, Ze-Yi Zheng, Meenakshi Anurag, Ahmed Elkhanany, Natalie C Chen, Eric C Chang

Faculty, Staff and Students Publications

More than 70% of breast cancers are estrogen receptor-positive (ER+). Endocrine therapy that blocks estrogen signaling remains the cornerstone of treatment, yet relapses continue to affect many patients. Cyclin-dependent kinases 4 and 6 (CDK4/6) regulate the G1-S phase transition in the cell cycle, and pharmacological inhibition of this pathway has been successfully leveraged to reduce recurrence. CDK4/6 inhibitors combined with endocrine therapy are now the standard of care, although determining the optimal patient population for treatment remains a key challenge. A newly published study provides important insight, showing that loss of the NF1/neurofibromin tumor suppressor confers greater sensitivity to CDK4/6 …

Mir147 Promotes Mucosal Integrity And Healing In Intestinal Inflammation, Agnieszka K Czopik, Arash Dabiri, Chia-Hao Tung, Victoria Vaughn, Xiangsheng Huang, Jinlian Wang, Hui Li, Nicolas F Moreno, Natalia V Piwko, Katherine Figarella, Hongfang Liu, Zhongming Zhao, Xiaoyi Yuan, Holger K Eltzschig

Faculty, Staff and Student Publications

The intestinal mucosal epithelium forms a barrier between luminal contents and the body. MicroRNAs (miRNAs) regulate mucosal homeostasis by controlling inflammatory responses and structural integrity. Here, we discovered a protective role for miR147 in intestinal inflammation using a miR147tdTomato reporter mouse. miR147 was enriched in the intestines, with the highest expression in the colonic epithelial cells at the luminal surface, with prominent expression in differentiated enterocytes. Mice with general or intestinal epithelial deletion of miR147 showed increased intestinal inflammation and diminished mucosal healing during colitis. RNA sequencing of miR147-deficient cells showed dysregulated immune signaling, with upregulated proinflammatory cytokine pathways and …

Genome-Wide Association Study Of Childhood B-Cell Acute Lymphoblastic Leukemia Reveals Novel African Ancestry-Specific Susceptibility Loci, Cindy Im, Andrew R Raduski, Lauren J Mills, Kashi Raj Bhattarai, Robert J Mobley, Kelly R Barnett, Zhanni Lu, Kenneth Liao, Nathan Anderson, Rebecca A Johnson, Erica Langer, Anthony J Hooten, Alix E Seif, Kathrin M Bernt, Matthew Tsang, Brandon A Mamou, Luis Gil-De-Gómez, Julie A Wolfson, Danielle N Friedman, Neerav Shukla, Laura J Klesse, Erin L Marcotte, Lingyun Ji, Alice Dang, Minjie Luo, Yiming Zhong, Jalen Langie, Charleston W K Chiang, Adam De Smith, Joseph L Wiemels, Andrew Dewan, Xiaomei Ma, Catherine Metayer, Zhaoming Wang, Heather H Nelson, Nathan Pankratz, Tianzhong Yang, Saonli Basu, Lucie M Turcotte, Jun J Yang, Daniel Savic, Michael E Scheurer, Logan G Spector

Faculty, Staff and Students Publications

B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy. Given racial/ethnic differences in incidence and outcomes, B-ALL genome-wide association studies among children of African ancestry are needed. Leveraging multi-institutional datasets with 840 African American children with B-ALL and 3360 controls, nine loci achieved genome-wide significance (P <  5 × 10−8) after meta-analysis. Two loci were established trans-ancestral susceptibility regions (IKZF1, ARID5B), while the remaining novel loci were specific to African populations. Five-year overall survival among children carrying novel risk alleles was significantly worse (83% versus 96% in non-carriers, P = 4.8 × 10−3). Novel risk variants were also associated with subtype-specific disease (P <  0.05), including higher susceptibility for a subtype overrepresented in African American children (TCF3-PBX1) and lower …

A Quantitative, Bayesian-Informed Approach To Gene-Specific Variant Classification: Updated Expert Panel Recommendations Improve Classification Of Tp53 Germline Variants For Li-Fraumeni Syndrome, Cristina Fortuno, Megan N Frone, Jessica Mester, Miguel De La Hoya, Phuong L Mai, Tina Pesaran, Maria Isabel Achatz, Rebecca Bassett, Carolina Bustamante, Stephanie Crowley, Kelvin Cesar De Andrade, D Gareth Evans, Bingjian Feng, Laura Fuqua, Maria Isabel Harrell, Jessica N Hatton, Robert Huether, Chimene Kesserwan, Kristy Lee, Suzanne P Macfarland, Jamie L Maciaszek, Kara Maxwell, Kelly Mcgoldrick, Maureen Murphy, Bita Nehoray, Judith Penkert, Emilia Modolo Pinto, Sharon E Plon, Alison Schwartz-Levine, Ashley S Thompson, Wenyi Wang, Gerard P Zambetti, Kristin Zelley, Paul A James, Sharon A Savage, Christian P Kratz, Amanda B Spurdle

Faculty, Staff and Students Publications

Background: Germline pathogenic variants in TP53 cause Li-Fraumeni syndrome, with significantly elevated cancer risk from infancy. Accurate classification of TP53 variants is essential to guide clinical management and surveillance, yet many variants remain classified as variants of uncertain significance (VUS). To improve classification accuracy and reduce the proportion of VUS, the ClinGen TP53 Variant Curation Expert Panel (VCEP) has updated its specifications.

Methods: The updated specifications incorporate the latest ClinGen recommendations and methodological advances, providing greater granularity for multiple evidence types, and also introduce the novel use of variant allele fraction as evidence of pathogenicity, particularly in the context of …

Injectable Microparticle-Nanoliposome Hydrogel For Extended Release Of Small Hydrophilic Molecules, Gil Aizik, Wonmin Choi, Claire A Ostertag-Hill, Matthew Torre, Daniel S Kohane

Duncan NRI Faculty and Staff Publications

Achieving sustained local release of small hydrophilic drugs is challenging and is particularly important when the drugs are toxic. To address these challenges, we developed a hybrid system comprising drug-containing microparticles embedded within a nanoliposomal hydrogel matrix. This system forms through salt-induced gelation using physiologically relevant sodium chloride concentrations (0.9%), allowing for microparticle encapsulation without harsh chemical processes. In vitro, the hybrid system exhibited a slower release of encapsulated cargo compared to microparticles or hydrogel alone. In vivo proof of principle was provided with tetrodotoxin (TTX), a small hydrophilic and ultrapotent local anesthetic, which can cause systemic toxicity if the …

Apoa1 Binding Protein Promotes Lymphatic Cell Fate And Lymphangiogenesis By Relieving Caveolae-Mediated Inhibition Of Vegfr3 Signaling, Jun-Dae Kim, Surbhi Chaudhary, Weiqing Chen, Jonathan Astin, Philip S Crosier, Pengchun Yu, John P Cooke, Henry J Pownall, Hugo J Bellen, Nhat-Tu Le, Daniel L Kiss, Guangyu Wang, Stanley G Rockson, Hong Chen, Longhou Fang

Faculty, Staff and Students Publications

The lymphatic system maintains tissue fluid balance, and its dysfunction can result in lymphedema. Although cholesterol is essential for cellular function, its role in lymphatic development has remained unknown. Here, we identify APOA1 binding protein (AIBP) as a key regulator that promotes lymphatic endothelial cell fate specification and lymphangiogenesis. Mechanistically, AIBP reduces plasma membrane cholesterol content, thereby enhancing VEGFR3 signaling by disrupting caveolae—small plasma membrane invaginations formed by the scaffolding protein caveolin-1 (CAV-1)—and relieving CAV-1–mediated inhibition. In zebrafish and mice, AIBP loss impairs VEGFR3 signaling and lymphatic development, defects that can be rescued by CAV-1 deletion or by a VEGFR3 …

Sperm And Offspring Production In A Nonobstructive Azoospermia Mouse Model Via Testicular Mrna Delivery Using Lipid Nanoparticles, Daisuke Mashiko, Chihiro Emori, Yuki Hatanaka, Daisuke Motooka, Chen Pan, Yuki Kaneda, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Microsurgical testicular sperm extraction (microTESE) with intracytoplasmic sperm injection (ICSI) represents the current standard treatment for nonobstructive azoospermia (NOA). However, cures remain unavailable for NOA patients lacking retrievable haploid cells. mRNA supplementation could be a potential treatment for genetic defects leading to impaired spermatogenesis. Lipid nanoparticles (LNPs) have emerged as mRNA delivery vehicles with minimal risk of genome integration; however, their ability to selectively deliver mRNA to specific cell types remains limited. To overcome this, microRNA (miRNA) target sequences were incorporated into mRNA constructs to restrict expression specifically to germ cells. Using pyruvate dehydrogenase E1 subunit alpha 2 (PDHA2) knockout …

Insights, Opportunities, And Challenges Provided By Large Cell Atlases, Martin Hemberg, Federico Marini, Shila Ghazanfar, Ahmad Al Ajami, Najla Abassi, Benedict Anchang, Bérénice A Benayoun, Yue Cao, Ken Chen, Yesid Cuesta-Astroz, Zachary Debruine, Calliope A Dendrou, Iwijn De Vlaminck, Katharina Imkeller, Ilya Korsunsky, Alex R Lederer, Jessica Jingyi Li, Pieter Meysman, Clint L Miller, Kerry A Mullan, Uwe Ohler, Pratibha Panwar, Nikolaos Patikas, Jonas Schuck, Jacqueline H Y Siu, Timothy J Triche, Alex Tsankov, Sander W Van Der Laan, Masanao Yajima, Jean Yang, Fabio Zanini, Ivana Jelic

Faculty, Staff and Student Publications

The field of single-cell biology is growing rapidly, generating large amounts of data from a variety of species, disease conditions, tissues, and organs. Coordinated efforts such as CZI CELLxGENE, HuBMAP, Broad Institute Single Cell Portal, and DISCO allow researchers to access large volumes of curated datasets, including more than just scRNA-seq data. These resources have created an opportunity to build and expand the computational biology ecosystem to develop tools necessary for data reuse and for extracting novel biological insights. We highlight achievements made so far, areas where further development is needed, and specific challenges that need to be overcome.

Biallelic Loss-Of-Function Variants In C19orf44 Lead To Retinal Degeneration, Hafiz Muhammad Jafar Hussain, Wang Meng, Yumei Li, Sabika Firasat, Mark E Pennesi, Michael B Gorin, Bin Guan, Rebecca Lynn Clark, Emma Fale-Olsen, Ranya Al Rawi, Aime Agather, Laryssa A Huryn, Paul Yang, Anna Matynia, Rui Chen

Faculty, Staff and Students Publications

Background: Inherited retinal diseases (IRDs) are a group of disorders often resulting in progressive vision loss, ultimately leading to blindness. A significant portion of their genetic causes remain unresolved, partly due to undiscovered disease-associated genes or variants. This study aimed to identify novel genetic links to IRDs.

Methods: All patients underwent comprehensive ophthalmological evaluation, including retinal imaging (fundus autofluorescence and macular optical coherence tomography) and electroretinogram testing. Whole exome sequencing and whole genome sequencing were performed on patients with clinically unsolved IRD, and data were analysed using an in-house pipeline to identify causal variants. Subsequently, Sanger sequencing was performed to …

Visualization Of Lysosomal Membrane Proteins By Cryo Electron Tomography, Bridget M Mcveigh, José J De Jesús-Pérez, Dirk H Siepe, Prerana Gogoi, Shrawan Kumar Mageswaran, Marian Kalocsay, Elaine M Mihelc, Vera Y Moiseenkova-Bell

Faculty, Staff and Student Publications

Lysosomes are essential organelles for cellular homeostasis and signaling, with dysfunction linked to neurological disorders, lysosomal storage diseases, and cancer. While proteomics has advanced our understanding of lysosomal composition, the structural characterization of lysosomal membrane proteins in their native environment remains a significant challenge. Here, we developed a cryo electron tomography workflow to visualize lysosomal membrane proteins within intact, native lysosomal membranes. We isolated endolysosomes by independently targeting two lysosomal membrane proteins, transient receptor potential mucolipin 1 and transmembrane protein 192, enriching organelles that exhibited the expected morphology and proteomic composition of the endolysosomal system. Sub-tomogram averaging enabled the structural …

Cep76 Impairment At The Centrosome-Cilium Interface Contributes To A Spectrum Of Ciliopathies, Kamal Khan, Erika Tavares, Katherine Bishara, Aysegul Ozanturk, Leila Qebibo, Stephan Frangakis, Daniel G Calame, Isabelle Meunier, Béatrice Bocquet, Rafal Ploski, Mohammad Ayman Al Khateeb, Dana Marafi, Luke Mansard, Lena Damaj, Richard A Lewis, Farid Ullah, Thomas Arbogast, Jackson P Ogden, Madeleine Harion, Marjolaine Willems, Maha S Zaki, Tobias Bartolomaeus, Anne-Françoise Roux, James R Lupski, Malgorzata Rydzanicz, Rami Abou Jamra, Francis Ramond, Elise Heon, Lydie Burglen, Erica E Davis

Faculty, Staff and Students Publications

Dysfunction at the centrosome-cilium interface underlies a broad range of ciliopathies. Here, we identify biallelic variants in CEP76, encoding a centrosomal protein, in eight unrelated individuals presenting with neurodevelopmental, ocular, and variable additional multisystem features. Proband-derived fibroblasts and CEP76-depleted RPE1 cells display ciliary deficits, including impaired cilium formation and length, disrupted transition zone architecture, and impaired IFT88-mediated anterograde intraflagellar transport. Zebrafish cep76 mutants recapitulate key clinical phenotypes, and in vitro complementation assays confirm pathogenicity for all tested human disease-associated variants. Proteomics analysis identifies CEP76 interactors, including known partners CCP110 and CEP97, and highlights clinically and functionally relevant candidates, including …

Equal Survival For Black Americans With Multiple Myeloma When Appropriately Matched To White Americans, David E Mery, Guido Tricot, Samer Al Hadidi, Yihao Zhan, Cody Ashby, Clyde Bailey, Eric R Siegel, Daisy V Alapat, Hongwei Xu, Sandra Mattox, Caroline Schinke, Maurizio Zangari, Sharmilan Thanendrarajan, Qing Yi, Robert Z Orlowski, Frits Van Rhee, John D Shaughnessy, Fenghuang Zhan

Faculty, Staff and Student Publications

No abstract provided.

A Pooled Sample Study Of Opioid Use Disorder Treatment Wait Time Among A Pregnant Population In New York, Stanley Nkemjika, Gulshan Begum, Bolaji Yoade, Vaibhav Vyas, Henry Onyeaka, Olubusola Olatunji, Olaniyi Olayinka, Ayana Jordan

Faculty, Staff and Student Publications

Background and Aim: Opioid use disorder (OUD) during pregnancy has become a major public health issue, with its prevalence rising significantly in recent years. The incidence of neonatal abstinence syndrome (NAS) has also surged, from 1.5 cases per 1000 hospital births in 1999 to 6.0 cases per 1000 in 2013. This study aims to identify and analyze the concerns faced by pregnant people in accessing OUD treatment on time, specifically focusing on New York.

Methods: The pooled sample of 225,275 individuals represents pregnant patients with OUD who received treatment at substance use disorder (SUD) facilities across New York State between …

Genetic Determinants And Genomic Consequences Of Non-Leukemogenic Somatic Point Mutations, Joshua S Weinstock, Sharjeel A Chaudhry, Maria Ioannou, Maria Viskadourou, Paula Reventun, Yasminka A Jakubek, L Alexander Liggett, Cecelia Laurie, Jai G Broome, Alyna Khan, Kent D Taylor, Xiuqing Guo, Patricia A Peyser, Eric Boerwinkle, Nathalie Chami, Eimear E Kenny, Ruth J Loos, Bruce M Psaty, Russell P Tracy, Jennifer A Brody, Jeong H Yun, Michael H Cho, Ramachandran S Vasan, Sharon L Kardia, Jennifer A Smith, Laura M Raffield, Aurelian Bidulescu, Emily C O'Brien, Mariza De Andrade, Jerome I Rotter, Stephen S Rich, Russell P Tracy, Yii Der Ida Chen, C Charles Gu, Chao A Hsiung, Charles Kooperberg, Bernhard Haring, Rami Nassir, Rasika Mathias, Alex Reiner, Vijay G Sankaran, Charles J Lowenstein, Thomas W Blackwell, Goncalo R Abecasis, Albert V Smith, Hyun M Kang, Pradeep Natarajan, Siddhartha Jaiswal, Alexander Bick, Wendy S Post, Paul Scheet, Paul Auer, Theodoros Karantanos, Alexis Battle, Marios Arvanitis

Faculty, Staff and Students Publications

Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as leukemogenic point mutations or mosaic chromosomal alterations (mCAs), are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we use 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic …

Estrogen-Related Receptor Alpha Promotes Skeletal Muscle Regeneration And Mitigates Muscular Dystrophy, Thi Thu Hao Nguyen, Ya Xiang Huang, Svitlana Poliakova, Citu Citu, Eira Mann, Danesh H Sopariwala, Zhongming Zhao, Ashok Kumar, Vihang A Narkar

The Brown Foundation: Institute of Molecular Medicine

Skeletal muscle regeneration in chronic muscle diseases such as Duchenne Muscular Dystrophy (DMD) has remained clinically unsurmountable. Estrogen‐related receptor alpha (ERRα) plays a critical role in adult skeletal muscle metabolism and exercise fitness. Whether ERRα activation can drive muscle regeneration and mitigate dystrophy in DMD is not known. We have investigated ERRα signaling in pre‐clinical models of acute muscle injury and DMD. ERRα is induced in differentiating C2C12 myoblast and regenerating muscle. ERRα silencing suppressed proliferation and differentiation in C2C12 myoblasts. RNA sequencing revealed that angiogenic factor and proliferation genes were downregulated by ERRα knockdown in proliferating cells, whereas oxidative …

Introducing Mcodegpt As A Zero-Shot Information Extraction From Clinical Free Text Data Tool For Cancer Research, Kai Zhang, Tongtong Huang, Bradley A Malin, Travis Osterman, Qi Long, Xiaoqian Jiang

Faculty, Staff and Student Publications

Background: The vast amount of natural language clinical notes about patients with cancer presents a challenge for efficient information extraction, standardization, and structuring. Traditional NLP methods require extensive annotation by domain experts for each type of named entity and necessitate model training, highlighting the need for an efficient and accurate extraction method.

Methods: This study introduces a tool based on the Large Language Model (LLM) for zero-shot information extraction from cancer-related clinical notes into structured data aligned with the minimal Common Oncology Data Elements (mCODE™) structure. We utilize the zero-shot learning capabilities of LLMs for information extraction, eliminating the need …

Tng260 Is A Small-Molecule Corest Inhibitor That Sensitizes Stk11-Mutant Tumors To Anti-Pd-1 Immunotherapy, Leanne G Ahronian, Soumyadip Sahu, Minjie Zhang, Ayushi S Patel, Ke Geng, Reshmee Bhattacharya, Gerald S Falchook, Jonathan W Goldman, Alexander I Spira, Salman R Punekar, David R Spigel, Judy S Wang, Ferdinandos Skoulidis, Janaye Stephens, Mary Meynardie, Jaylen M Powell, Alfonso Lopez, Michela Ranieri, Magdalena A Ploszaj, Yi Jer Tan, Yeuan Ting Lee, Yi Yu, Jiehui Deng, Ting Chen, Patrick Mccarren, Alice Tsai, Suleman S Hussain, Brian Doyon, Kenjie Amemiya, Jacques Ermolieff, Preksha Shahagadkar, Nikitha M Das, Lauren R Flynn, Julie A Shields, Laney Danielczyk, Brian J Mcmillan, Andre Mignault, Samuel R Meier, Hsin-Jung Wu, David J Guerin, Douglas A Whittington, Chengyin Min, Iga Sienczylo, John P Maxwell, Heather J Dibenedetto, Hideo Watanabe, Brian B Haines, Alan Huang, Adam Crystal, Jannik N Andersen, Xinyuan Wu, Kwok-Kin Wong

Faculty, Staff and Student Publications

Patients with non–small cell lung cancer (NSCLC) with loss of the tumor suppressor gene STK11 are resistant to immune checkpoint therapies like anti–PD-1. In this study, we conducted an in vivo CRISPR screen that identified histone deacetylase 1 as a target to reverse anti–PD-1 resistance driven by loss of STK11 and developed TNG260, a potent small-molecule inhibitor of the CoREST complex with selectivity exceeding previously generated inhibitors in this class in preclinical studies. Treatment with TNG260 led to increased expression of immunomodulatory genes in STK11-deficient cancer cells. When combined with anti–PD-1, TNG260 induced immune-mediated stasis and/or regression in STK11 …

Preoperative Brain Mapping Predicts Language Outcomes After Eloquent Tumor Resection, Matthew T Muir, Kyle Noll, Sarah Prinsloo, Hayley Michener, Jeffrey I Traylor, Vinodh A Kumar, Chibawanye I Ene, Sherise Ferguson, Ho-Ling Liu, Jeffrey S Weinberg, Frederick Lang, Brian A Taylor, Stephanie J Forkel, Sujit S Prabhu

Faculty, Staff and Student Publications

When operating on gliomas near critical language regions, surgeons risk either leaving residual tumor or inducing permanent postoperative language deficits (PLDs). Despite the advent of intraoperative mapping techniques, subjective judgments frequently determine important surgical decisions. We aim to inform data-driven surgery by constructing a non-invasive mapping approach that quantitatively predicts the impact of individual surgical decisions on long-term language function. This study included 79 consecutive patients undergoing resection of language-eloquent gliomas. Patients underwent preoperative navigated transcranial magnetic stimulation (TMS) language mapping to identify language-positive sites ("TMS points") and their associated white matter tracts ("TMS tracts") as well as formal language …

Resilience And Vulnerabilities Of Tumor Cells Under Purine Shortage Stress, Jianpeng Yu, Chen Jin, Cheng Su, David Moon, Michael A Sun, Hong Zhang, Xue Jiang, Fan Zhang, Nomi Tserentsoodol, Michelle L Bowie, Christopher J Pirozzi, Daniel J George, Robert Wild, Xia Gao, David M Ashley, Yiping He, Jiaoti Huang

Faculty, Staff and Students Publications

Purpose: Purine metabolism is a promising therapeutic target in cancer; however, how cancer cells respond to purine shortage, particularly their adaptation and vulnerabilities, remains unclear.

Experimental design: Using the recently developed purine shortage-inducing prodrug DRP-104 and genetic approaches, we investigated the responses in prostate, lung, and glioma cancer models.

Results: We demonstrate that when de novo purine biosynthesis is compromised, cancer cells employ microtubules to assemble purinosomes, multiprotein complexes of de novo purine biosynthesis enzymes that enhance purine biosynthesis efficiency. Although this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the …

Sub-Ciliary Localization Of Cep290 And Effects Of Its Loss In Mouse Photoreceptors During Development, Abigail R. Moye, Michael A. Robichaux, Melina A. Agosto, Alexandre P. Moulin, Alexandra Graff-Meyer, Carlo Rivolta, Theodore G. Wensel

Faculty, Staff and Students Publications

No abstract provided.

Alterations Of The Upper Respiratory Microbiome Among Children Living With Hiv Infection In Botswana, Sweta M Patel, John Farirai, Mohamed Z Patel, Sifelane Boiditswe, Leabaneng Tawe, Shimane Lekalake, Mogomotsi Matshaba, Andrew P Steenhoff, Tonya Arscott-Mills, Kristen A Feemster, Samir S Shah, Nathan Thielman, Coleen K Cunningham, Lawrence A David, David M Murdoch, Matthew S Kelly

Faculty, Staff and Students Publications

Children living with HIV (CLWH) are at high risk of colonization and infection by respiratory pathogens, though this risk can be reduced by other microbes in the upper respiratory microbiome. The impact of HIV infection on the pediatric upper respiratory microbiome is poorly understood, and we sought to address this knowledge gap by identifying associations between HIV infection and the nasopharyngeal microbiomes of Batswana children. We enrolled Batswana CLWH (< 5 years) and age- and sex-matched HIV-exposed, uninfected and HIV-unexposed, uninfected children in a cross-sectional study. We used shotgun metagenomic sequencing to compare nasopharyngeal microbiomes by HIV status. Among the 143 children in this study, HIV and HIV-associated immunosuppression were associated with alterations in nasopharyngeal microbiome composition, including lower abundances of Corynebacterium species associated with resistance to bacterial pathogen colonization. These findings suggest that the upper respiratory microbiome may contribute to the high risk of respiratory infections among CLWH.

Differential Bk Channel Potentiation By Vanzacaftor Enantiomers Enables Therapy For Modulator-Ineligible People With Cystic Fibrosis, Nathalie Baumlin, Sumedha Gunewardena, Scott H Randell, Frank T Horrigan, Matthias Salathe

Faculty, Staff and Students Publications

No abstract provided.

Stereoelectroencephalography Reveals Neural Signatures Of Multisensory Integration In The Human Superior Temporal Sulcus During Audiovisual Speech Perception, Yue Zhang, John F Magnotti, Xiang Zhang, Zhengjia Wang, Yingjia Yu, Kathryn A Davis, Sameer A Sheth, H Isaac Chen, Daniel Yoshor, Michael S Beauchamp

Faculty, Staff and Students Publications

Human speech perception is multisensory, integrating auditory information from the talker's voice with visual information from the talker's face. BOLD fMRI studies have implicated the superior temporal gyrus (STG) in processing auditory speech and the superior temporal sulcus (STS) in integrating auditory and visual speech, but as an indirect hemodynamic measure, fMRI is limited in its ability to track the rapid neural computations underlying speech perception. Using stereoelectroencephalography (sEEG) electrodes, we directly recorded from the STG and STS in 42 epilepsy patients (25F, 17M). Participants identified single words presented in auditory, visual, and audiovisual formats with and without added auditory …

Probabilistic Data Linkage To Study The Epidemiology Of Unintentional Fatal Drowning In A Large Metropolitan Region, Rohit P Shenoi, Ned Levine, Elizabeth A Camp, Linh Nguyen, Sandra Mckay, Shaila Zaman

Faculty, Staff and Students Publications

Background: It is difficult to study the epidemiology of drowning at the regional level because of multiple data sources, many of which have a high degree of unstandardized and missing data. We aimed to link multiple datasets to identify demographics and geographic locations of unintentional fatal drowning in a metropolitan region and compare linked data with vital statistic data.

Methods: This cross-sectional study included unintentional drowning fatalities among persons of all ages in metropolitan Houston between 2016 and 2022. Probabilistic linking was used to link multiple datasets and geographical mapping to identify drowning locations. The effectiveness of data linkage was …

Optimizing Genetic Ancestry Adjustment In Dna Methylation Studies: A Comparative Analysis Of Approaches, Kira D Höffler, Seyma Katrinli, Matthew W Halvorsen, Anne-Kristin Stavrum, Kevin S O'Connell, Alexey Shadrin, Srdjan Djurovic, Ole A Andreassen, James J Crowley, Jan Haavik, Kristen Hagen, Gerd Kvale, Kerry Ressler, Bjarne Hansen, Jair C Soares, Gabriel R Fries, Alicia K Smith, Stéphanie Le Hellard

Faculty, Staff and Student Publications

Background: Genetic ancestry is an important factor to account for in DNA methylation studies because genetic variation influences DNA methylation patterns. One approach uses principal components (PCs) calculated from CpG sites that overlap with common SNPs to adjust for ancestry when genotyping data is not available. However, this method does not remove technical and biological variations, such as sex and age, prior to calculating the PCs. The first PC is therefore often associated with factors other than ancestry.

Methods: We developed and adapted the adapted EpiAnceR+ approach, which includes (1) residualizing the CpG data overlapping with common SNPs for control …

Generative Modeling For Interpretable Anomaly Detection In Medical Imaging: Applications In Failure Detection And Data Curation, Mckell E Woodland, Mais Altaie, Caleb S O'Connor, Austin H Castelo, Olubunmi C Lebimoyo, Aashish C Gupta, Joshua P Yung, Paul E Kinahan, Clifton D Fuller, Eugene J Koay, Bruno C Odisio, Ankit B Patel, Kristy K Brock

Faculty, Staff and Students Publications

This work aims to leverage generative modeling-based anomaly detection to enhance interpretability in AI failure detection systems and to aid data curation for large repositories. For failure detection interpretability, this retrospective study utilized 3339 CT scans (525 patients), divided patient-wise into training, baseline test, and anomaly (having failure-causing attributes—e.g., needles, ascites) test datasets. For data curation, 112,120 ChestX-ray14 radiographs were used for training and 2036 radiographs from the Medical Imaging and Data Resource Center for testing, categorized as baseline or anomalous based on attribute alignment with ChestX-ray14. StyleGAN2 networks modeled the training distributions. Test images were reconstructed with backpropagation and …

The Clingen Severe Combined Immunodeficiency Disease Variant Curation Expert Panel: Specifications For Classification Of Variants In Ada, Dclre1c, Il2rg, Il7r, Jak3, Rag1, And Rag2, Vanessa C Jacovas, Michelle Zelnick, Shannon Mcnulty, Justyne E Ross, Namrata Khurana, Xueyang Pan, Alejandro Nieto, Shiloh Martin, Benjamin Mclean, Marwa A Elnagheeb, Morton J Cowan, Jennifer M Puck, Mike S Hershfield, James Verbsky, Jolan Walter, Eric J Allenspach, Alice Y Chan, Nicolai S C Van Oers, Rajarshi Ghosh, Megan Piazza, Bo Yuan, Luigi D Notarangelo, Britt A Johnson, Ivan K Chinn, Severe Combined Immunodeficiency Variant Curation Expert Panel

Faculty, Staff and Students Publications

Purpose: This collaborative study, led by the Clinical Genome Resource Severe Combined Immunodeficiency Disease Variant Curation Expert Panel (ClinGen SCID-VCEP), implemented and adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for interpreting germline variants in genes with established relationships to SCID. The effort focused on the 7 most common SCID-related genes identified by SCID newborn screening in North America: ADA, DCLRE1C, IL2RG, IL7R, JAK3, RAG1, and RAG2.

Methods: The SCID-VCEP conducted a rigorous review of variants that involved database analyses, literature review, and expert feedback to derive gene-specific modifications to the ACMG/AMP guidelines. These …

Understanding The Nutrition Ecology And Related Distal And Proximal Research Gaps Impacting School-Aged Children's And Adolescents' Functioning-A Report From The "Biomarkers Of Nutrition For Development: Knowledge Indicating Dietary Sufficiency (Bond-Kids)" Project Working Group 2., Maureen M Black, Meg M Bruening, Amy Carroll-Scott, Jayna M Dave, Kristie L Ebi, Lora L Iannotti, Susan L Johnson, Lorrene D Ritchie, Elizabeth Y Jimenez, Alison L Steiber, Daniel J Raiten

Children’s Nutrition Research Center Staff Publications

Nutrition is critical to the health, development, and well-being of children and adolescents, operating through nutrients and the social and physical influences of dietary behaviors. Child and adolescent growth and development depend on complex biological systems interacting with the nutrition ecology. In this review, we focus on bidirectional interactions with the multilevel nutrition ecology, including distal systems (climate, geopolitical, and food systems) and proximal systems (community food options; health, social, and food services; and school policies and programs), all mediated by the family. Thus, the impact of nutrition on children's and adolescents' functional outcomes is dependent on understanding the multilevel …