Digital Commons Network^™

Increased Fungal Burden In The Gastrointestinal Tract Of Brain-Dead Organ Donors, Erika J Nachman, Colleen K Ardis, A Kyle B Ardis, Javier Nieto, Madeline M Bresson, Clare M Robertson, Maggie N Seale, Nora M Villafuerte, Zhe Lyu, Eva C Preisner, Heather A Danhof, Sara C Di Rienzi, Yolanda T Becker, Robert A Britton

Faculty, Staff and Students Publications

Approximately 3% of organ transplant recipients will be diagnosed with an invasive fungal infection (IFI), with 10%-47% being fatal. The source of IFI is typically not known, but Candida spp. cause the majority of IFI cases. We obtained intestines from two types of organ donors, brain-dead (BD) (n = 7) and donation after circulatory death (DCD) (n = 5), to sample microbes from the mucosal surface and the lumen. BD donors were parenterally fed and treated with corticosteroids in the days before procurement, whereas DCD donors were enterally fed and not given corticosteroids. We found fungi present in …

Rescue Of Male Infertility By Human Prss55 In Transgenic Mice Establishes A Contraceptive Research Model, Courtney M Sutton, Kohei Umezu, Daisuke Mashiko, Masahito Ikawa, Irina V Larina, Thomas X Garcia, Martin M Matzuk

Faculty, Staff and Students Publications

The development of non-hormonal male contraceptives requires validated preclinical models. This study investigated whether human orthologs of two mouse testis-specific serine proteases, PRSS55 and TMPRSS12, both essential for male fertility in mice, could functionally rescue the infertility phenotypes of their respective knockout mouse lines. We generated transgenic mouse lines expressing human PRSS55 with either an extracellularly or intracellularly positioned C-terminal 3xFLAG tag (RES GPI or RES TM), and a line expressing human TMPRSS12 with a C-terminal 3xFLAG tag (T12 RES), all on their respective mouse null backgrounds. Fertility was assessed through continuous mating trials, and sperm parameters were evaluated. Both …

Rare Variants In Bmal1 Are Associated With A Neurodevelopmental Syndrome, Vishnu Anand Cuddapah, Dechun Chen, Bumsik Cho, Rebecca Moore, Mohnish Suri, Hana Safraou, Frederic Tran-Mau-Them, Ashley Wilson, Jacqueline Odgis, Atteeq U Rehman, Carol Saunders, Shiva Ganesan, Vaidehi Jobanputra, Stephen W Scherer, Ingo Helbig, Amita Sehgal

Duncan NRI Faculty and Staff Publications

Children with neurodevelopmental disorders exhibit highly penetrant sleep and circadian dysfunction, but the underlying mechanisms are unclear. We asked whether a subset of individuals with neurodevelopmental disorders might have genetic variants in genes known to drive circadian rhythms. Through international collaboration, we identified ten individuals with very rare genetic variants in BMAL1, a core component of the molecular clock. These individuals exhibited overlapping signs and symptoms including developmental delay, autism spectrum disorder, and variably penetrant marfanoid features. We functionally tested the identified BMAL1 variants in cell culture and in vivo and found disrupted BMAL1 function. These findings demonstrate that …

Genetic Overlap Between Functional Impairment And Depression And Anxiety Symptom Severity: Evidence From The Glad Study, Megan Skelton, Jessica Mundy, Abigail Ter Kuile, Brett Adey, Cherie Armour, Joshua Buckman, Jonathan Coleman, Molly Davies, Colette R. Hirsch, Matthew Hotopf, Ian Jones, Gursharan Kalsi, Georgina Krebs, Sang Hyuck Lee, Yuhao Lin, Andrew M. Mcintosh, Alicia J. Peel, Christopher Rayner, Katharine Rimes, Daniel J. Smith, Katherine N. Thompson, David Veale, James T.R. Walters, Christopher Hübel, Gerome Breen, Thalia C. Eley

School of Psychology

BACKGROUND: Functional impairment in daily activities, such as work and socializing, is part of the diagnostic criteria for major depressive disorder and most anxiety disorders. Despite evidence that symptom severity and functional impairment are partially distinct, functional impairment is often overlooked. To assess whether functional impairment captures diagnostically relevant genetic liability beyond that of symptoms, we aimed to estimate the heritability of, and genetic correlations between, key measures of current depression symptoms, anxiety symptoms, and functional impairment.

METHODS: In 17,130 individuals with lifetime depression or anxiety from the Genetic Links to Anxiety and Depression (GLAD) Study, we analyzed total scores …

Integrating Ctdna Analysis And Radiomics For Dynamic Risk Assessment In Localized Lung Cancer, Everett J Moding, Mohammad Shahrokh Esfahani, Cheng Jin, Angela B Hui, Barzin Y Nabet, Yufei Liu, Jacob J Chabon, Michael S Binkley, David M Kurtz, Emily G Hamilton, Aadel A Chaudhuri, Chih Long Liu, Zhe Li, Rene F Bonilla, Alice L Jiang, Brianna C Lau, Pablo Lopez, Jianzhong He, Yawei Qiao, Ting Xu, Luyang Yao, Saumil Gandhi, Zhongxing Liao, Millie Das, Kavitha J Ramchandran, Sukhmani K Padda, Joel W Neal, Heather A Wakelee, Michael F Gensheimer, Billy W Loo, Ruijiang Li, Steven H Lin, Ash A Alizadeh, Maximilian Diehn

Faculty, Staff and Student Publications

The complementarity and clinical utility of combining liquid biopsies and radiomic image analysis has not been demonstrated. Circulating tumor DNA (ctDNA) minimal residual disease after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is highly prognostic, but on-treatment biomarkers are needed to enable response-adapted therapies. Here, we analyzed 418 patients with NSCLC undergoing CRT to develop and validate a novel dynamic risk model that accurately predicts ultimate progression-free survival during treatment. We optimize tissue-free variant calling from plasma samples to facilitate ctDNA monitoring and demonstrate the importance of accounting for persistent clonal hematopoiesis variants. We show that mid-CRT ctDNA concentration …

Depletion Of Effector Regulatory T Cells Associates With Major Response To Induction Dual Immune Checkpoint Blockade, Xianli Jiang, Nils-Petter Rudqvist, Bo Jiang, Shengbin Ye, Shan He, Qingnan Liang, Jinzhuang Dou, Michelle D Williams, Joe Dan Dunn, Jason M Johnson, Keiko Akagi, Weihong Xiao, Shaoheng Liang, Satvik Elayavalli, Baohua Sun, Edwin R Parra, Renata Ferrarotto, Adam S Garden, Clifton David Fuller, Jay Reddy, Neil D Gross, Miriam N Lango, Cheuk Hong Leung, Suyu Liu, Diane D Liu, Meng Li, J Jack Lee, Michael A Curran, Jack Phan, Ken Chen, Maura L Gillison

Faculty, Staff and Student Publications

In a phase II trial, patients with local-regionally advanced human papillomavirus-positive oropharyngeal carcinoma (n = 35) received ipilimumab (anti-CTLA4) and nivolumab (anti-PD-1) as induction immunotherapy and concurrently with radiotherapy (NCT03799445). Coprimary endpoints included 6-month complete metabolic response rate (94%) and 2-year progression-free survival (84%). Induction yielded a 46% major histopathologic response rate. Single-cell profiling revealed responders had higher baseline intratumoral CD8+ T cells with a tumor-reactive, tissue-resident memory (TRM) phenotype and a treatment-related decrease in effector regulatory T (eTreg) cells. The eTreg decrease correlated with CD8+ T-cell clonotype transitioning from TRM to effector memory and IFNG+ effector cells. …

Detection Of Brain Cancer Using Genome-Wide Cell-Free Dna Fragmentomes, Dimitrios Mathios, Et Al.

2020-Current year OA Pubs

UNLABELLED: Diagnostic delays in patients with brain cancer are common and can impact patient outcome. Development of a blood-based assay for detection of brain cancers could accelerate brain cancer diagnosis. In this study, we analyzed genome-wide cell-free (cfDNA) fragmentomes, including fragmentation profiles and repeat landscapes, from the plasma of individuals with (n = 148) or without (n = 357) brain cancer. Machine learning analyses of cfDNA fragmentome features detected brain cancer across all-grade gliomas (AUC = 0.90; 95% confidence interval, 0.87-0.93), and these results were validated in an independent prospectively collected cohort. cfDNA fragmentome changes in patients with gliomas represented …

An Ethanol-Induced Loss Of The Lipid Droplet-Associated Segregase Vcp/P97 Leads To Hepatic Steatosis, Sandhya Sen, Shaun Weller, Ryan J Schulze, Donglin Ding, Carol A Casey, Conrad Weihl, Mark A Mcniven

2020-Current year OA Pubs

The liver stores substantial numbers of neutral lipid organelles termed lipid droplets (LDs) that accumulate within hepatocytes in response to chronic ethanol (EtOH) consumption leading to hepatic steatosis. Mass spectrometry analysis of LDs isolated from EtOH-damaged rat livers revealed a substantial reduction in the valosin-containing protein ATPase (VCP/p97) that acts to remove targeted proteins from cellular membranes for degradation. Experimental disruption of VCP function resulted in an increase in LD content in hepatocytes and mouse livers along with a marked increase in LD-associated hydroxysteroid dehydrogenase (HSD17β13) known to contribute to hepatic steatosis. Surprisingly, treatment of hepatocytes with the proteasome inhibitor …

Enhancing Patient Positioning Accuracy: Evaluating Daily Cone Beam Computed Tomography In The Halcyon System., Duong Thanh Tai, Luong Tien Phat, Tran Trung Kien, Nguyen Ngoc Anh, Nguyen Xuan Hai, Peter Sandwall, David Bradley, James C L Chow

Oncology Articles

BACKGROUND: Precise patient positioning is crucial for successful radiotherapy, ensuring accurate delivery of radiation to tumors while minimizing exposure to healthy tissues. Positional errors can significantly impact treatment efficacy and increase side effects. This study evaluates the effectiveness of daily cone beam computed tomography (CBCT) imaging in the Halcyon system for detecting and correcting patient misalignments across various cancer types and treatment sites.

METHODS: A retrospective analysis was conducted on 411 patients treated with the Varian Halcyon linear accelerator from August 2022 to August 2024. Patients were grouped based on tumor location: Head and Neck (118 patients), Chest (188 patients), …

Rsph4a-Pcdx: An Index To Predict Lung Function Decline In Primary Ciliary Dyskinesia, Gabriel Román-Ríos, Gabriel Rosario-Ortiz, Marcos J Ramos-Benitez, Ricardo A Mosquera, Wilfredo De Jesús-Rojas

Faculty, Staff and Student Publications

Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disorder that impairs mucociliary clearance and leads to progressive lung disease. This study aimed to characterize lung function decline in a genetically homogeneous cohort of Puerto Rican patients with

Inhibition Of Epithelial Cell Yap-Tead/Lox Signaling Attenuates Pulmonary Fibrosis In Preclinical Models, Darcy Elizabeth Wagner, Hani N Alsafadi, Nilay Mitash, Aurelien Justet, Qianjiang Hu, Ricardo Pineda, Claudia Staab-Weijnitz, Martina Korfei, Nika Gvazava, Kristin Wannemo, Ugochi Onwuka, Molly Mozurak, Adriana Estrada-Bernal, Juan Cala-Garcia, Katrin Mutze, Rita Costa, Deniz Bölükbas, John Stegmayr, Wioletta Skronska-Wasek, Stephan Klee, Chiharu Ota, Hoeke A Baarsma, Jingtao Wang, John Sembrat, Anne Hilgendorff, Jun Ding, Andreas Günther, Rachel Chambers, Ivan Rosas, Stijn De Langhe, Naftali Kaminski, Mareike Lehmann, Oliver Eickelberg, Melanie Königshoff

Faculty, Staff and Students Publications

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease characterized by excessive extracellular matrix deposition. Current IPF therapies slow disease progression but do not stop or reverse it. The (myo)fibroblasts are thought to be the main cellular contributors to excessive extracellular matrix production in IPF. Here we show that fibrotic alveolar type II cells regulate production and crosslinking of extracellular matrix via the co-transcriptional activator YAP. YAP leads to increased expression of Lysl oxidase (LOX) and subsequent LOX-mediated crosslinking by fibrotic alveolar type II cells. Pharmacological YAP inhibition via verteporfin reverses fibrotic alveolar type II cell reprogramming and LOX …

Mitochondrial Complex I Deficiency Induces Alzheimer's Disease-Like Signatures That Are Reversible By Targeted Therapy., Huanyao Gao, Kate Jensen, Jarred Nesbitt, Mark Ostroot, Gregory Cary, Jesse Wiley, Sergey Trushin, Jens O Watzlawik, Wolfdieter Springer, Alexander Galkin, Priyanka Baloni, Cory Funk, Eugenia Trushina

Faculty Research 2025

INTRODUCTION: Mitochondrial dysfunction is implicated in Alzheimer's disease (AD), but whether it drives AD-associated changes is unclear. We assessed transcriptomic alterations in the brains of Ndufs4

METHODS: Cortico-hippocampal tissue from Ndufs4

RESULTS: Knockout of Ndufs4-mediated mtCI deficiency disrupted mitochondrial homeostasis, energy metabolism, and synaptic gene expression, recapitulating transcriptomic signatures of AD. CP2 treatment partially reversed these changes, with female Ndufs4

DISCUSSION: Loss of mtCI activity alone is sufficient to induce AD-like molecular changes in the brain, independent of amyloid beta or phosphorylated tau. CP2-mediated rescue highlights the potential of targeting mitochondria as a therapeutic strategy for AD. Sex-specific responses suggest …

Biomechanical Analysis Of 3d Correction And Bone-Screw Forces As A Function Of Rod Insertion Sequence And Orientation Relative To The Sagittal Plane In Adolescent Idiopathic Scoliosis Instrumentation., Camille Pillot, Xiaoyu Wang, Alexandria Mallinos, Todd Ritzman, Lorena Floccari, Richard M. Schwend, Carl-Eric Aubin

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: In adolescent idiopathic scoliosis instrumentation, rods are typically aligned with the sagittal plane during the initial translation maneuver. Surgeons often empirically orient the rod slightly opposite to the scoliotic curve, but the optimal orientation and insertion sequence, as well as their influence on 3D correction and forces, remain unclear. This study investigates the biomechanical influence of these rod parameters on scoliosis correction.

METHODS: Patient-specific multi-body biomechanical models were developed for 30 adolescent idiopathic scoliosis patients (11 hypo-, 12 normo-, 7 hyper-kyphotic thoracic curves) to simulate posterior instrumentation with a primary segmental translation correction maneuver. Rod insertion was tested in …

Genetic Study Of Von Willebrand Factor Antigen Levels ≤ 50 Iu/Dl Identifies Variants Associated With Increased Risk Of Von Willebrand Disease And Bleeding, Rachel K Friedman, Adam S Heath, Jennifer E Huffman, James T Baker, Natalie R Hasbani, Sarah A Gagliano Taliun, Ming-Huei Chen, Tom E Howard, Joshua P Lewis, Nathan Pankratz, Snehal Patil, Alex P Reiner, Florian Thibord, Lisa R Yanek, Jie Yao, Hung-Hsin Chen, Joanne E Curran, Nauder Faraday, Xiuqing Guo, Marsha M Wheeler, Kathleen A Ryan, Xiang Zhou, Kelly Cho, Laura Almasy, Paul L Auer, Lewis C Becker, Peter W F Wilson, Eric Boerwinkle, Jeffrey R O'Connell, Stephen S Rich, David C Samuels, National Heart, Lung And Blood Institute (Nhlbi) Trans-Omics For Precision Medicine (Topmed) Consortium, Topmed Hematology & Hemostasis Working Group, Va Million Veteran Program, John Blangero, Myriam Fornage, Charles Kooperberg, Rasika A Mathias, Braxton D Mitchell, Jerome I Rotter, Andrew D Johnson, Nicholas L Smith, Zeynep H Coban-Akdemir, Jennifer E Below, Alanna C Morrison, Jill M Johnsen, Paul S De Vries

Faculty, Staff and Student Publications

Background: von Willebrand disease (VWD) is a common inherited bleeding disorder caused by low levels or activity of circulating von Willebrand factor (VWF). Genetic susceptibility to VWF antigen (VWF:Ag) below normal (≤ 50 IU/dL) in the general population is underexplored.

Objectives: To identify genetic variants influencing VWF:Ag levels ≤ 50 IU/dL.

Methods: We performed a genome-wide association study in 926 cases with VWF:Ag levels ≤ 50 IU/dL and 12 846 controls from 7 studies from the Trans-Omics for Precision Medicine program. We then examined whether significant genome-wide findings were also associated with clinical diagnosis of VWD in 5 biobanks with …

Linking Chronic Kidney Disease To Incident Heart Failure And Adverse Cardiac Remodeling Through The Plasma Proteome: The Aric Study, Leo F Buckley, Pranav Dorbala, Victoria Lamberson, Brian L Claggett, Yue Ren, Morgan E Grams, Josef Coresh, Kunihiro Matsushita, Ryan T Demmer, Ruth F Dubin, Rajat Deo, Peter Ganz, Christie M Ballantyne, Ron C Hoogeveen, Bing Yu, Amil M Shah

Faculty, Staff and Student Publications

Background: Investigation of circulating plasma proteins may reveal insights into molecular pathways that contribute to the development of heart failure (HF) among people with chronic kidney disease.

Objectives: The authors aimed to identify circulating kidney function-related plasma proteins that are associated with the risk of incident HF.

Methods: The authors studied participants of the ongoing longitudinal ARIC (Atherosclerosis Risk In Communities) study. Relative plasma concentrations of 4,697 unique proteins were measured with the use of an aptamer assay (Somalogic). Each protein was tested for associations with estimated glomerular filtration rate (eGFR), log-transformed urine albumin-to-creatinine ratio (UACR), and incident HF by …

A Large-Scale Genome-Wide Study Of Gene-Sleep Duration Interactions For Blood Pressure In 811,405 Individuals From Diverse Populations, Pavithra Nagarajan, Thomas W Winkler, Amy R Bentley, Clint L Miller, Aldi T Kraja, Karen Schwander, Songmi Lee, Wenyi Wang, Michael R Brown, John L Morrison, Ayush Giri, Jeffrey R O'Connell, Traci M Bartz, Lisa De Las Fuentes, Valborg Gudmundsdottir, Xiuqing Guo, Sarah E Harris, Zhijie Huang, Mart Kals, Minjung Kho, Christophe Lefevre, Jian'an Luan, Leo-Pekka Lyytikäinen, Massimo Mangino, Yuri Milaneschi, Nicholette D Palmer, Varun Rao, Rainer Rauramaa, Botong Shen, Stefan Stadler, Quan Sun, Jingxian Tang, Sébastien Thériault, Adriaan Van Der Graaf, Peter J Van Der Most, Yujie Wang, Stefan Weiss, Kenneth E Westerman, Qian Yang, Tabara Yasuharu, Wei Zhao, Wanying Zhu, Drew Altschul, Md Abu Yusuf Ansari, Pramod Anugu, Anna D Argoty-Pantoja, Michael Arzt, Hugues Aschard, John R Attia, Lydia Bazzanno, Max A Breyer, Jennifer A Brody, Brian E Cade, Hung-Hsin Chen, Yii-Der Ida Chen, Zekai Chen, Paul S De Vries, Latchezar M Dimitrov, Anh Do, Jiawen Du, Charles T Dupont, Todd L Edwards, Michele K Evans, Tariq Faquih, Stephan B Felix, Susan P Fisher-Hoch, James S Floyd, Mariaelisa Graff, Charles Gu, Dongfeng Gu, Kristen G Hairston, Anthony J Hanley, Iris M Heid, Sami Heikkinen, Heather M Highland, Michelle M Hood, Mika Kähönen, Carrie A Karvonen-Gutierrez, Takahisa Kawaguchi, Setoh Kazuya, Tanika N Kelly, Pirjo Komulainen, Daniel Levy, Henry J Lin, Peter Y Liu, Pedro Marques-Vidal, Joseph B Mccormick, Hao Mei, James B Meigs, Cristina Menni, Kisung Nam, Ilja M Nolte, Natasha L Pacheco, Lauren E Petty, Hannah G Polikowsky, Michael A Province, Bruce M Psaty, Laura M Raffield, Olli T Raitakari, Stephen S Rich, Renata L Riha, Lorenz Risch, Martin Risch, Edward A Ruiz-Narvaez, Rodney J Scott, Colleen M Sitlani, Jennifer A Smith, Tamar Sofer, Maris Teder-Laving, Uwe Völker, Peter Vollenweider, Guanchao Wang, Ko Willems Van Dijk, Otis D Wilson, Rui Xia, Jie Yao, Kristin L Young, Ruiyuan Zhang, Xiaofeng Zhu, Jennifer E Below, Carsten A Böger, David Conen, Simon R Cox, Marcus Dörr, Mary F Feitosa, Ervin R Fox, Nora Franceschini, Sina A Gharib, Vilmundur Gudnason, Sioban D Harlow, Jiang He, Elizabeth G Holliday, Zoltan Kutalik, Timo A Lakka, Deborah A Lawlor, Seunggeun Lee, Terho Lehtimäki, Changwei Li, Ching-Ti Liu, Reedik Mägi, Fumihiko Matsuda, Alanna C Morrison, Brenda Wjh Penninx, Patricia A Peyser, Jerome I Rotter, Harold Snieder, Tim D Spector, Lynne E Wagenknecht, Nicholas J Wareham, Alan B Zonderman, Kari E North, Myriam Fornage, Million Veteran Program, Adriana M Hung, Alisa K Manning, James Gauderman, Han Chen, Patricia B Munroe, Dabeeru C Rao, Diana Van Heemst, Susan Redline, Raymond Noordam, Heming Wang

Faculty, Staff and Student Publications

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discovered 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes' functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health …

White Matter Abnormalities And Cognition In Aging And Alzheimer Disease, Christopher Peter, Aditi Sathe, Niranjana Shashikumar, Kimberly R Pechman, Abigail W Workmeister, T Bryan Jackson, Yuankai Huo, Shubhabrata Mukherjee, Jesse Mez, Logan C Dumitrescu, Katherine A Gifford, Corey J Bolton, Leslie S Gaynor, Shannon L Risacher, Lori L Beason-Held, Yang An, Konstantinos Arfanakis, Guray Erus, Christos Davatzikos, Duygu Tosun-Turgut, Mohamad Habes, Di Wang, Arthur W Toga, Paul M Thompson, Panpan Zhang, Kurt G Schilling, Marilyn Albert, Walter Kukull, Sarah A Biber, Bennett A Landman, Barbara B Bendlin, Sterling C Johnson, Julie Schneider, Lisa L Barnes, David A Bennett, Angela L Jefferson, Susan M Resnick, Andrew J Saykin, Paul K Crane, Michael L Cuccaro, Timothy J Hohman, Derek B Archer, Dimitrios Zaras, Yisu Yang, Alaina Durant, Praitayini Kanakaraj, Michael E Kim, Chenyu Gao, Nancy R Newlin, Karthik Ramadass, Nazirah Mohd Khairi, Zhiyuan Li, Tianyuan Yao, Seo-Eun Choi, Brandon Klinedinst, Michael L Lee, Phoebe Scollard, Emily H Trittschuh, Elizabeth A Sanders

Faculty, Staff and Student Publications

Importance: There has yet to be a large-scale study quantifying the association between white matter microstructure and cognitive performance and decline in aging and Alzheimer disease (AD).

Objective: To investigate the associations between tract-specific white matter microstructure and cognitive performance and decline in aging and AD-related cognitive impairment.

Design setting and participants: This prognostic study of aging and AD, a secondary data analysis of multisite cohort studies, acquired data from 9 cohorts between September 2002 and November 2022. Participants were eligible if they had diffusion-weighted magnetic resonance imaging (dMRI) data, domain-specific cognitive composite z scores, demographic and clinical data, were …

Large-Scale Genome-Wide Analyses Of Stuttering, Hannah G Polikowsky, Alyssa C Scartozzi, Douglas M Shaw, Dillon G Pruett, Hung-Hsin Chen, Lauren E Petty, Alexander S Petty, Emily J Lowther, Shu-Hsien Cho, Yao Yu, Sahar Mozaffari, Christy L Avery, Kathleen Mullan Harris, Reyna L Gordon, Janet M Beilby, Kathryn Z Viljoen, Robin M Jones, Chad D Huff, Heather M Highland, Shelly Jo Kraft, Jennifer E Below

Faculty, Staff and Student Publications

Developmental stuttering is a highly heritable, common speech condition characterized by prolongations, blocks and repetitions of speech. Although stuttering is highly heritable and enriched within families, the genetic architecture is largely understudied. We reasoned that there are both shared and distinct genetic variants impacting stuttering risk within sex and ancestry groups. To test this idea, we performed eight primary genome-wide association analyses of self-reported stuttering that were stratified by sex and ancestry, as well as secondary meta-analyses of more than one million individuals (99,776 cases and 1,023,243 controls), identifying 57 unique loci. We validated the genetic risk of self-reported stuttering …

Does Midbrain Atrophy Distinguish Progressive Supranuclear Palsy From Frontotemporal Dementia?, Mauro César Quintão E Silva Cunningham, Sarah Teixeira Camargos, Vinícius Ribeiro Jeunon, Natalia Pessoa Rocha, Antônio Lúcio Teixeira, Thiago De Oliveira Maciel, Elisa De Paula França Resende, Francisco Eduardo Costa Cardoso, Paulo Caramelli, Leonardo Cruz De Souza

Faculty, Staff and Student Publications

Background: The diagnostic value of midbrain atrophy for distinguishing behavioral variant frontotemporal dementia (bvFTD) from progressive supranuclear palsy (PSP) is unclear.

Objective: To investigate whether measures of midbrain atrophy differentiate PSP from bvFTD.

Methods: We included four groups: healthy controls (n = 19), PSP-Richardson syndrome (n = 20), bvFTD (n = 19) and Parkinson's disease (PD; n = 12). The following quantitative and qualitative measures were calculated: Hummingbird sign rating scale [HBS-RS], global midbrain atrophy [GMA], midbrain area, midbrain/pons ratio, the Magnetic Resonance Parkinsonism Index (MRPI), the MRPI 2.0 and brainstem volume.

Results: Compared to controls, PSP and bvFTD had …

Computed Tomography Radiomics-Based Cross-Sectional Detection Of Mandibular Osteoradionecrosis In Head And Neck Cancer Survivors, Serageldin Kamel, Laia Humbert-Vidan, Zaphanlene Kaffey, Sarah Mirbahaeddin, Abdulrahman Abusaif, David T A Fuentes, Kareem Wahid, Cem Dede, Mohamed A Naser, Renjie He, Ahmed W Moawad, Khaled M Elsayes, Melissa M Chen, Adegbenga O Otun, Jillian Rigert, Mark S Chambers, Andrew Hope, Erin Watson, Kristy K Brock, Katherine Hutcheson, Lisanne Van Dijk, Amy C Moreno, Stephen Y Lai, Clifton D Fuller, Abdallah S R Mohamed, Md Anderson Head And Neck Cancer Symptom Working Group

Faculty, Staff and Student Publications

Purpose: This study aims to identify radiomic features from contrast-enhanced CT (CECT) scans that differentiate osteoradionecrosis (ORN) from normal mandibular bone in head and neck cancer (HNC) patients treated with radiotherapy (RT).

Materials and methods: CECT images from 150 patients with confirmed ORN diagnosis (2008-2018) at MD Anderson Cancer Center (MDACC) were analyzed (80 % train, 20 % test). Radiomic features were extracted using PyRadiomics from manually segmented ORN regions and automated contralateral healthy mandible regions. Correlation analysis (r > 0.95) reduced features for model training. A random Forest (RF) classifier with Recursive Feature Elimination identified discriminative features. Explainability was assessed …

Associative Coding Of Conditioned Fear In The Thalamic Nucleus Reuniens In Rodents And Humans, Tuğçe Tuna, Michael S Totty, Muhammad Badarnee, Flávio Afonso Gonçalves Mourão, Shaun Peters, Mohammad R Milad, Stephen Maren

Faculty, Staff and Student Publications

The nucleus reuniens (RE) is a midline thalamic structure interconnecting the medial prefrontal cortex (mPFC) and the hippocampus (HPC). Recent work in both rodents and humans implicates the RE in the adaptive regulation of emotional memories, including the suppression of learned fear. However, the neural correlates of aversive learning in the RE of rodents and humans remain unclear. To address this, we recorded RE activity in humans (BOLD fMRI) and rats (fiber photometry) during Pavlovian fear conditioning and extinction. In both rats and humans, we found that conditioned stimulus (CS)-evoked activity in RE reflects the associative value of the CS. …

Sex-Related Measurement Bias In Autism Spectrum Disorder Symptoms In The Baby Siblings Research Consortium, Catherine A Burrows, Natasha Marrus, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Disparities exist in age of diagnosis and prevalence of autism spectrum disorder (ASD) for female compared with male children. Correcting for sources of bias is critical for improving equitable ASD identification.

OBJECTIVE: To determine whether sex differences exist in measurement of ASD symptoms using the Autism Diagnostic Observation Schedule (ADOS) among young children at high familial likelihood (HFL) and low familial likelihood (LFL) of ASD.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study collected longitudinal, prospective data from the Baby Siblings Research Consortium between January 1, 2003, and December 31, 2021. Participants included 3106 children who had an older sibling …

Disruption Of The Cerebrospinal Fluid-Plasma Protein Balance In Cognitive Impairment And Aging, Amelia Farinas, Daniel Western, Jigyasha Timsina, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

The brain barrier system, including the choroid plexus, meninges and brain vasculature, regulates substrate transport and maintains differential protein concentrations between blood and cerebrospinal fluid (CSF). Aging and neurodegeneration disrupt brain barrier function, but proteomic studies of the effects on blood-CSF protein balance are limited. Here we used SomaScan proteomics to characterize paired CSF and plasma samples from 2,171 healthy or cognitively impaired older individuals from multiple cohorts, including the Global Neurodegeneration Proteomics Consortium. We identified proteins with correlated CSF and plasma levels that are produced primarily outside the brain and are enriched for structural domains that may enable their …

Human Thalamocortical Structural Connectivity Develops In Line With A Hierarchical Axis Of Cortical Plasticity, Valerie J Sydnor, Deanna M Barch, Et Al.

2020-Current year OA Pubs

Human cortical development follows a hierarchical, sensorimotor-to-association sequence. The brain's capacity to enact this sequence indicates that it relies on unknown mechanisms to regulate regional differences in the timing of cortical maturation. Given evidence from animal systems that thalamic axons mechanistically regulate periods of cortical plasticity, here we evaluate in humans whether the development of structural connections between the thalamus and cortex aligns with cortical maturational heterochronicity. By deriving a new tractography atlas of human thalamic connections and applying it to diffusion data from three youth samples (8-23 years; total n = 2,676), we demonstrate that thalamocortical connectivity matures in …

Shared And Disease-Specific Pathways In Frontotemporal Dementia And Alzheimer's And Parkinson's Diseases, Muhammad Ali, Yike Chen, Ying Xu, Katherine Gong, Menghan Liu, Jigyasha Timsina, Daniel Western, Chengran Yang, Gyujin Heo, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD) and frontotemporal dementia (FTD), exhibit distinct yet overlapping pathological mechanisms. Leveraging large-scale plasma proteomics data from the Global Neurodegeneration Proteomics Consortium, we analyzed 10,527 plasma samples (1,936 AD, 525 PD, 163 FTD, 1,638 dementia and 6,265 controls) to identify disease-specific and shared proteins across NDs. We identified 5,187 proteins significantly associated with AD, 3,748 with PD and 2,380 with FTD that revealed both common and divergent proteomic signatures, which were confirmed by multiple analytical approaches and orthogonal validation. PD and FTD showed the highest overlap (r

Longer Scans Boost Prediction And Cut Costs In Brain-Wide Association Studies, Leon Qi Rong Ooi, Scott Marek, Nico U F Dosenbach, Timothy O Laumann, Evan M Gordon, Et Al.

2020-Current year OA Pubs

A pervasive dilemma in brain-wide association studies

Rest-Activity Rhythm Phenotypes In Adults With Epilepsy And Intellectual Disability, Nandani Adhyapak, Grace E Cardenas, Mark A Abboud, Vaishnav Krishnan

Faculty, Staff and Students Publications

Objective: Rest-activity rhythms (RARs) are perturbed in many forms of neuropsychiatric illness. In this study, we applied wrist actigraphy to describe RAR perturbations in intellectually disabled adults with epilepsy ("E + ID"), using a cross-sectional case-control design. We examined whether RAR phenotypes correlated with epilepsy severity, deficits in adaptive function, and/or comorbid psychopathology.

Methods: Caregivers of E + ID subjects provided informed consent during routine ambulatory clinic visits and were asked to complete standardized surveys of overall epilepsy severity (GASE, Global Assessment of Severity of Epilepsy), adaptive function (ABAS-3, Adaptive Behavior Assessment System-3) and psychopathology (ABCL, Adult Behavior Checklist). Caregivers …

Prevalence Of Fibrosis In Hepatic Explants And Biopsies From Individuals With Urea Cycle Disorders, Saima Ali, Aisha Nisar, Anqing Zhang, Sandesh Nagamani, Nathalie M Aceves-Ewing, Brandy Rawls, Thu Quan, Greg Enns, John Goss, Daniel H Leung, Benjamin L Shneider, Shilpa Jain, Florette K Hazard, Deborah Schady, Lindsay C Burrage

Faculty, Staff and Students Publications

Background: Various forms of liver disease have been increasingly reported in individuals with urea cycle disorders (UCDs). In this study, we performed the first systematic and standardized histopathological assessment of the prevalence of fibrosis and steatosis in a large sample of hepatic explants and biopsies from individuals with UCDs at two liver transplantation centers.

Methods: Sixty-seven hepatic tissue samples from 66 individuals with UCDs were staged by two pathologists for hepatic fibrosis and steatosis using standard scoring systems at two large liver transplantation centers in the United States. Histopathological findings were correlated with clinical parameters, including UCD type, laboratory parameters, …

Effective Algorithm To Differentiate Nbs Mcadd Cases From Carriers And Non-Carriers And An Assessment Of The Utility Of The Second Newborn Screen For Mcadd, Matthew T Snyder, Kristian Divin, Ning Liu, Qin Sun, Yue Wang, Xi Luo, Yishay Ben-Moshe, Lindsay C Burrage, V Reid Sutton

Faculty, Staff and Students Publications

False positives are an inherent part of newborn screening that can increase both costs to the healthcare system and parental anxiety. Previous studies primarily examined presumptive positive rates for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) in places conducting one newborn screen (NBS), with predominantly white, non-Hispanic subjects. Texas performs two NBSs and there is a majority Hispanic population in our region. This study aims to analyze biochemical and DNA data to more easily distinguish affected individuals from carriers or healthy non-carriers and identify benefits and challenges of a second NBS for MCADD. Biochemical and targeted DNA data from NBS dried blood …

Characterization Of Visual Field Loss Over 4 Years In The Rate Of Progression In Ush2a-Related Retinal Degeneration (Rush2a) Study, Jacque L Duncan, Maureen G Maguire, Lee S Mcdaniel, Nicole R Doucet, Isabelle Audo, Allison R Ayala, Janet K Cheetham, Peiyao Cheng, Todd A Durham, Rachel M Huckfeldt, Robert B Hufnagel, K Thiran Jayasundera, Naheed Khan, Brett Malbin, Ramiro S Maldonado, Michel Michaelides, Mark E Pennesi, Christina Y Weng, Alex Zmejkoski, Shobana Aravind, Hiroshi Ishikawa, David G Birch

Faculty, Staff and Students Publications

Purpose: To report visual field loss using static perimetry (SP) and kinetic perimetry (KP) over 4 years in the Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A) study.

Design: Prospective, observational cohort study.

Subjects, participants, and/or controls: Participants had USH2A-related rod-cone degeneration, visual acuity ≥20/80, and KP III4e ≥10° at baseline in the study eye. Preserved cohorts with baseline visual fields sufficient to detect progression were identified.

Methods: Participants were examined annually through 4 years. Mixed-effects models were used to estimate the annual, standardized rate, and percentage rates of change.

Main outcome measures: SP measures included hill of vision (total: …