Medicine and Health Sciences Commons^™

Genome-Wide Study Investigating Effector Genes And Polygenic Prediction For Kidney Function In Persons With Ancestry From Africa And The Americas, Odessica Hughes, Amy R Bentley, Charles E Breeze, Francois Aguet, Xiaoguang Xu, Girish Nadkarni, Quan Sun, Bridget M Lin, Thomas Gilliland, Mariah C Meyer, Jiawen Du, Laura M Raffield, Holly Kramer, Robert W Morton, Mateus H Gouveia, Elizabeth G Atkinson, Adan Valladares-Salgado, Niels Wacher-Rodarte, Nicole D Dueker, Xiuqing Guo, Yang Hai, Adebowale Adeyemo, Lyle G Best, Jianwen Cai, Guanjie Chen, Michael Chong, Ayo Doumatey, James Eales, Mark O Goodarzi, Eli Ipp, Marguerite Ryan Irvin, Minzhi Jiang, Alana C Jones, Charles Kooperberg, Jose E Krieger, Ethan M Lange, Matthew B Lanktree, James P Lash, Paulo A Lotufo, Ruth J F Loos, Vy Thi Ha My, Jesús Peralta-Romero, Lihong Qi, Leslie J Raffel, Stephen S Rich, Erik J Rodriquez, Eduardo Tarazona-Santos, Kent D Taylor, Jason G Umans, Jia Wen, Bessie A Young, Zhi Yu, Ying Zhang, Yii-Der Ida Chen, Tanja Rundek, Jerome I Rotter, Miguel Cruz, Myriam Fornage, Maria Fernanda Lima-Costa, Alexandre C Pereira, Guillaume Paré, Pradeep Natarajan, Shelley A Cole, April P Carson, Leslie A Lange, Yun Li, Eliseo J Perez-Stable, Ron Do, Fadi J Charchar, Maciej Tomaszewski, Josyf C Mychaleckyj, Charles Rotimi, Andrew P Morris, Nora Franceschini

Faculty, Staff and Students Publications

Chronic kidney disease is a leading cause of death and disability globally and impacts individuals of African ancestry (AFR) or with ancestry in the Americas (AMS) who are under-represented in genome-wide association studies (GWASs) of kidney function. To address this bias, we conducted a large meta-analysis of GWASs of estimated glomerular filtration rate (eGFR) in 145,732 AFR and AMS individuals. We identified 41 loci at genome-wide significance (p < 5 × 10−8), of which two have not been previously reported in any ancestry group. We integrated fine-mapped loci with epigenomic and transcriptomic resources to highlight potential effector genes relevant to kidney physiology and disease, and reveal key regulatory elements and pathways involved in renal function and development. We demonstrate the varying but increased predictive power offered by a multi-ancestry polygenic score for eGFR and highlight the importance of population diversity in GWASs and multi-omics resources to enhance opportunities for clinical translation for all.

Precision Microbial Intervention Improves Social Behavior But Not Autism Severity: A Pilot Double-Blind Randomized Placebo-Controlled Trial, Luigi Mazzone, Sean W Dooling, Elisabetta Volpe, Mirko Uljarević, Jillian L Waters, Andrea Sabatini, Lucrezia Arturi, Roberta Abate, Assia Riccioni, Martina Siracusano, Marcela Pereira, Lars Engstrand, Fernanda Cristofori, Domenico Adduce, Ruggiero Francavilla, Mauro Costa-Mattioli, Antonio Y Hardan

Faculty, Staff and Students Publications

Autism spectrum disorder (ASD) is characterized by the presence of restricted/repetitive behaviors and social communication deficits. Because effective treatments for ASD remain elusive, novel therapeutic strategies are necessary. Preclinical studies show that L. reuteri selectively reversed social deficits in several models for ASD. Here, in a double-blind, randomized, placebo-controlled trial, we tested the effect of L. reuteri (a product containing a combination of strains ATCC-PTA-6475 and DSM-17938) in children with ASD. The treatment does not alter overall autism severity, restricted/repetitive behaviors, the microbiome composition, or the immune profile. However, L. reuteri combination yields significant improvements in social functioning that generalized …

Overcoming Resolution Attenuation During Tilted Cryo-Em Data Collection, Sriram Aiyer, Philip R Baldwin, Shi Min Tan, Zelin Shan, Juntaek Oh, Atousa Mehrani, Marianne E Bowman, Gordon Louie, Dario Oliveira Passos, Selena Đorđević-Marquardt, Mario Mietzsch, Joshua A Hull, Shuichi Hoshika, Benjamin A Barad, Danielle A Grotjahn, Robert Mckenna, Mavis Agbandje-Mckenna, Steven A Benner, Joseph A P Noel, Dong Wang, Yong Zi Tan, Dmitry Lyumkis

Faculty, Staff and Students Publications

Structural biology efforts using cryogenic electron microscopy are frequently stifled by specimens adopting "preferred orientations" on grids, leading to anisotropic map resolution and impeding structure determination. Tilting the specimen stage during data collection is a generalizable solution but has historically led to substantial resolution attenuation. Here, we develop updated data collection and image processing workflows and demonstrate, using multiple specimens, that resolution attenuation is negligible or significantly reduced across tilt angles. Reconstructions with and without the stage tilted as high as 60° are virtually indistinguishable. These strategies allowed the reconstruction to 3 Å resolution of a bacterial RNA polymerase with …

Integrating Genetic Regulation And Single-Cell Expression With Gwas Prioritizes Causal Genes And Cell Types For Glaucoma, Andrew R Hamel, Wenjun Yan, John M Rouhana, Aboozar Monovarfeshani, Xinyi Jiang, Puja A Mehta, Jayshree Advani, Yuyang Luo, Qingnan Liang, Skanda Rajasundaram, Arushi Shrivastava, Katherine Duchinski, Sreekar Mantena, Jiali Wang, Tavé Van Zyl, Louis R Pasquale, Anand Swaroop, Puya Gharahkhani, Anthony P Khawaja, Stuart Macgregor, Rui Chen, Veronique Vitart, Joshua R Sanes, Janey L Wiggs, Ayellet V Segrè

Faculty, Staff and Students Publications

Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of >240 POAG and IOP genome-wide association study (GWAS) loci and overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina prioritizes causal genes for 60% of loci. These genes are enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq …

Retrospective Analysis Of The Impact Of High- And Low-Quality Donor Livers For Patients With High-Acuity Illness, Ron K Varghese, Greta E Handing, Ashley E Montgomery, Abbas A Rana, John A Goss

Faculty, Staff and Students Publications

BACKGROUND Patients with high-acuity liver failure have increased access to marginal and split liver options, owing to historically high waitlist mortality rates. While most research states that donor liver quality has no impact on patients with high-acuity illness, there have been inconsistencies in recent research on how liver quality impacts post-transplant outcomes for these patients. We aimed to quantify donor liver quality with various post-transplantation patient outcomes for patients with high-acuity illness. MATERIAL AND METHODS Using the liver donor risk index (LDRI), model for end stage liver disease (MELD), and clinically relevant recipient factors, we used multivariate logistic regression to …

Correction: Mechanisms Of Ferroptosis And Targeted Therapeutic Approaches In Lymphoma, Tiantian Yu, Zijun Y Xu-Monette, Li Yu, Yong Li, Ken H Young

Faculty, Staff and Students Publications

No abstract provided.

The Immune System And Metabolic Products In Epilepsy And Glioma-Associated Epilepsy: Emerging Therapeutic Directions, Shashwat Tripathi, Cody L Nathan, Matthew C Tate, Craig M Horbinski, Jessica W Templer, Joshua M Rosenow, Timothy L Sita, Charles D James, Benjamin Deneen, Stephen D Miller, Amy B Heimberger

Faculty, Staff and Students Publications

Epilepsy has a profound impact on quality of life. Despite the development of new antiseizure medications (ASMs), approximately one-third of affected patients have drug-refractory epilepsy and are nonresponsive to medical treatment. Nearly all currently approved ASMs target neuronal activity through ion channel modulation. Recent human and animal model studies have implicated new immunotherapeutic and metabolomic approaches that may benefit patients with epilepsy. In this Review, we detail the proinflammatory immune landscape of epilepsy and contrast this with the immunosuppressive microenvironment in patients with glioma-related epilepsy. In the tumor setting, excessive neuronal activity facilitates immunosuppression, thereby contributing to subsequent glioma progression. …

Pearls & Oy-Sters: Cacna1a-Related Paroxysmal Tonic Upgaze With Ataxia Responsive To Acetazolamide, Steven M Lazar, Farida Abid

Faculty, Staff and Students Publications

A 9-month-old male infant was evaluated for sudden onset of paroxysmal episodes of forced, conjugate upward eye deviation. Extensive in-hospital evaluation including electrophysiology and neuroimaging studies were reassuring against seizures or a structural abnormality. Given the clinical presentation of sudden onset intermittent upward eye deviations, downbeating saccades, associated ataxia, and typical development, a clinical diagnosis of paroxysmal tonic upgaze (PTU) with ataxia was made. Targeted genetic testing of CACNA1A was performed, which revealed a variant of undetermined significance, which was later classified as a de novo pathogenic variant after protein modeling and parental testing performed. Off-label use of oral acetazolamide …

Psychological Distress And Social Support Among Community Paediatric Palliative Care Programme Caregivers: Longitudinal Analysis, Esther Chui Yan Wong, Phillip Lung Wai Au-Doung, Yvonne Yuen Ling Chu, Sandy Sin Yuet Wong, Chi Kong Li, Yin Ting Cheung

Faculty, Staff and Students Publications

No abstract provided.

Amphiregulin Exerts Proangiogenic Effects In Developing Murine Lungs, Shyam Thapa, Nithyapriya Shankar, Amrit Kumar Shrestha, Monish Civunigunta, Amos S Gaikwad, Binoy Shivanna

Faculty, Staff and Students Publications

Interrupted lung angiogenesis is a hallmark of bronchopulmonary dysplasia (BPD); however, druggable targets that can rescue this phenotype remain elusive. Thus, our investigation focused on amphiregulin (Areg), a growth factor that mediates cellular proliferation, differentiation, migration, survival, and repair. While Areg promotes lung branching morphogenesis, its effect on endothelial cell (EC) homeostasis in developing lungs is understudied. Therefore, we hypothesized that Areg promotes the proangiogenic ability of the ECs in developing murine lungs exposed to hyperoxia. Lung tissues were harvested from neonatal mice exposed to normoxia or hyperoxia to determine Areg expression. Next, we performed genetic loss-of-function and pharmacological gain-of-function …

Developmental Basis Of Shh Medulloblastoma Heterogeneity, Maxwell P Gold, Winnie Ong, Andrew M Masteller, David R Ghasemi, Julie Anne Galindo, Noel R Park, Nhan C Huynh, Aneesh Donde, Veronika Pister, Raul A Saurez, Maria C Vladoiu, Grace H Hwang, Tanja Eisemann, Laura K Donovan, Adam D Walker, Joseph Benetatos, Christelle Dufour, Livia Garzia, Rosalind A Segal, Robert J Wechsler-Reya, Jill P Mesirov, Andrey Korshunov, Kristian W Pajtler, Scott L Pomeroy, Olivier Ayrault, Shawn M Davidson, Jennifer A Cotter, Michael D Taylor, Ernest Fraenkel

Faculty, Staff and Students Publications

Many genes that drive normal cellular development also contribute to oncogenesis. Medulloblastoma (MB) tumors likely arise from neuronal progenitors in the cerebellum, and we hypothesized that the heterogeneity observed in MBs with sonic hedgehog (SHH) activation could be due to differences in developmental pathways. To investigate this question, here we perform single-nucleus RNA sequencing on highly differentiated SHH MBs with extensively nodular histology and observed malignant cells resembling each stage of canonical granule neuron development. Through innovative computational approaches, we connect these results to published datasets and find that some established molecular subtypes of SHH MB appear arrested at different …

Variants In The Wdr44 Wd40-Repeat Domain Cause A Spectrum Of Ciliopathy By Impairing Ciliogenesis Initiation, Andrea Accogli, Saurabh Shakya, Taewoo Yang, Christine Insinna, Soo Yeon Kim, David Bell, Kirill R Butov, Mariasavina Severino, Marcello Niceta, Marcello Scala, Hyun Sik Lee, Taekyeong Yoo, Jimmy Stauffer, Huijie Zhao, Chiara Fiorillo, Marina Pedemonte, Maria C Diana, Simona Baldassari, Viktoria Zakharova, Anna Shcherbina, Yulia Rodina, Christina Fagerberg, Laura Sønderberg Roos, Jolanta Wierzba, Artur Dobosz, Amanda Gerard, Lorraine Potocki, Jill A Rosenfeld, Seema R Lalani, Tiana M Scott, Daryl Scott, Mahshid S Azamian, Raymond Louie, Hannah W Moore, Neena L Champaigne, Grace Hollingsworth, Annalaura Torella, Vincenzo Nigro, Rafal Ploski, Vincenzo Salpietro, Federico Zara, Simone Pizzi, Giovanni Chillemi, Marzia Ognibene, Erin Cooney, Jenny Do, Anders Linnemann, Martin J Larsen, Suzanne Specht, Kylie J Walters, Hee-Jung Choi, Murim Choi, Marco Tartaglia, Phillippe Youkharibache, Jong-Hee Chae, Valeria Capra, Sung-Gyoo Park, Christopher J Westlake

Faculty, Staff and Students Publications

WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities. We demonstrate that WDR44 variants associated with more severe disease impair ciliogenesis initiation and ciliary signaling. Because WDR44 negatively regulates ciliogenesis, it was surprising that pathogenic missense variants showed reduced abundance, which we link to misfolding of …

D-Mannose Reduces Cellular Senescence And Nlrp3/Gasdermind/Il-1Β-Driven Pyroptotic Uroepithelial Cell Shedding In The Murine Bladder, Chetanchandra S Joshi, Arnold M Salazar, Caihong Wang, Marianne M Ligon, Rayvanth R Chappidi, Bisiayo E Fashemi, Paul A Felder, Amy Mora, Sandra L Grimm, Cristian Coarfa, Indira U Mysorekar

Faculty, Staff and Students Publications

Aging is a risk factor for disease via increased susceptibility to infection, decreased ability to maintain homeostasis, inefficiency in combating stress, and decreased regenerative capacity. Multiple diseases, including urinary tract infection (UTI), are more prevalent with age; however, the mechanisms underlying the impact of aging on the urinary tract mucosa and the correlation between aging and disease remain poorly understood. Here, we show that, relative to young (8-12 weeks) mice, the urothelium of aged (18-24 months) female mice accumulates large lysosomes with reduced acid phosphatase activity and decreased overall autophagic flux in the aged urothelium, indicative of compromised cellular homeostasis. …

Mechanism Of Anion Exchange And Small-Molecule Inhibition Of Pendrin, Lie Wang, Anthony Hoang, Eva Gil-Iturbe, Arthur Laganowsky, Matthias Quick, Ming Zhou

Faculty, Staff and Students Publications

Pendrin (SLC26A4) is an anion exchanger that mediates bicarbonate (HCO3−) exchange for chloride (Cl−) and is crucial for maintaining pH and salt homeostasis in the kidney, lung, and cochlea. Pendrin also exports iodide (I−) in the thyroid gland. Pendrin mutations in humans lead to Pendred syndrome, causing hearing loss and goiter. Inhibition of pendrin is a validated approach for attenuating airway hyperresponsiveness in asthma and for treating hypertension. However, the mechanism of anion exchange and its inhibition by drugs remains poorly understood. We applied cryo-electron microscopy to determine structures of pendrin from Sus scrofa in the presence of either Cl−, …

A High-Protein Diet Promotes Atrial Arrhythmogenesis Via Absent-In-Melanoma 2 Inflammasome, Jia Song, Jiao Wu, Dexter J Robichaux, Tingting Li, Shuyue Wang, Maria J Arredondo Sancristobal, Bingning Dong, Dobromir Dobrev, Jason Karch, Sandhya S Thomas, Na Li

Faculty, Staff and Students Publications

High-protein diets (HPDs) offer health benefits, such as weight management and improved metabolic profiles. The effects of HPD on cardiac arrhythmogenesis remain unclear. Atrial fibrillation (AF), the most common arrhythmia, is associated with inflammasome activation. The role of the Absent-in-Melanoma 2 (AIM2) inflammasome in AF pathogenesis remains unexplored. In this study, we discovered that HPD increased susceptibility to AF. To demonstrate the involvement of AIM2 signaling in the pathogenesis of HPD-induced AF, wildtype (WT) and Aim2^−/− mice were fed normal-chow (NC) and HPD, respectively. Four weeks later, inflammasome activity was upregulated in the atria of WT-HPD mice, but not …

Clinicalomicsdb: Exploring Molecular Associations Of Oncology Drug Responses In Clinical Trials, Chang In Moon, John Michael Elizarraras, Jonathan Thomas Lei, Byron Jia, Bing Zhang

Faculty, Staff and Students Publications

Matching patients to optimal treatment is challenging, in part due to the limited availability of real-world clinical datasets for predictive biomarker identification. The growing integration of omics profiling into clinical trials presents a new opportunity to tackle this challenge. Here, we introduce ClinicalOmicsDB, a web application for exploring molecular associations of oncology drug responses in clinical trials. This database includes transcriptomic data from 40 clinical trial studies, with 5913 patients spanning 11 cancer types. These studies include 67 treatment arms with a variety of chemotherapy, targeted therapy and immunotherapy drugs, and their combinations, which we organize based on an established …

A Syndromic Neurodevelopmental Disorder Caused By Rare Variants In Ppfia3, Maimuna S Paul, Sydney L Michener, Hongling Pan, Hiuling Chan, Jessica M Pfliger, Jill A Rosenfeld, Vanesa C Lerma, Alyssa Tran, Megan A Longley, Richard A Lewis, Monika Weisz-Hubshman, Mir Reza Bekheirnia, Nasim Bekheirnia, Lauren Massingham, Michael Zech, Matias Wagner, Hartmut Engels, Kirsten Cremer, Elisabeth Mangold, Sophia Peters, Jessica Trautmann, Jessica L Mester, Maria J Guillen Sacoto, Richard Person, Pamela P Mcdonnell, Stacey R Cohen, Laina Lusk, Ana S A Cohen, Jean-Baptiste Le Pichon, Tomi Pastinen, Dihong Zhou, Kendra Engleman, Caroline Racine, Laurence Faivre, Sébastien Moutton, Anne-Sophie Denommé-Pichon, Hyun Yong Koh, Annapurna Poduri, Jeffrey Bolton, Cordula Knopp, Dong Sun Julia Suh, Andrea Maier, Mehran Beiraghi Toosi, Ehsan Ghayoor Karimiani, Reza Maroofian, Gerald Bradley Schaefer, Vijayalakshmi Ramakumaran, Pradeep Vasudevan, Chitra Prasad, Matthew Osmond, Sarah Schuhmann, Georgia Vasileiou, Sophie Russ-Hall, Ingrid E Scheffer, Gemma L Carvill, Heather Mefford, Undiagnosed Diseases Network, Carlos A Bacino, Brendan H Lee, Hsiao-Tuan Chao

Faculty, Staff and Students Publications

PPFIA3 encodes the protein-tyrosine phosphatase, receptor-type, F-polypeptide-interacting-protein-alpha-3 (PPFIA3), which is a member of the LAR-protein-tyrosine phosphatase-interacting-protein (liprin) family involved in synapse formation and function, synaptic vesicle transport, and presynaptic active zone assembly. The protein structure and function are evolutionarily well conserved, but human diseases related to PPFIA3 dysfunction are not yet reported in OMIM. Here, we report 20 individuals with rare PPFIA3 variants (19 heterozygous and 1 compound heterozygous) presenting with developmental delay, intellectual disability, hypotonia, dysmorphisms, microcephaly or macrocephaly, autistic features, and epilepsy with reduced penetrance. Seventeen unique PPFIA3 variants were detected in 18 families. To determine the pathogenicity …

Proteogenomic Characterization Of Small Cell Lung Cancer Identifies Biological Insights And Subtype-Specific Therapeutic Strategies, Qian Liu, Jing Zhang, Chenchen Guo, Mengcheng Wang, Chenfei Wang, Yilv Yan, Liangdong Sun, Di Wang, Lele Zhang, Huansha Yu, Likun Hou, Chunyan Wu, Yuming Zhu, Gening Jiang, Hongwen Zhu, Yanting Zhou, Shanhua Fang, Tengfei Zhang, Liang Hu, Junqiang Li, Yansheng Liu, Hui Zhang, Bing Zhang, Li Ding, Ana I Robles, Henry Rodriguez, Daming Gao, Hongbin Ji, Hu Zhou, Peng Zhang

Faculty, Staff and Students Publications

We performed comprehensive proteogenomic characterization of small cell lung cancer (SCLC) using paired tumors and adjacent lung tissues from 112 treatment-naive patients who underwent surgical resection. Integrated multi-omics analysis illustrated cancer biology downstream of genetic aberrations and highlighted oncogenic roles of FAT1 mutation, RB1 deletion, and chromosome 5q loss. Two prognostic biomarkers, HMGB3 and CASP10, were identified. Overexpression of HMGB3 promoted SCLC cell migration via transcriptional regulation of cell junction-related genes. Immune landscape characterization revealed an association between ZFHX3 mutation and high immune infiltration and underscored a potential immunosuppressive role of elevated DNA damage response activity via inhibition of the …

A Phase 2 Trial Of Cd24fc For Prevention Of Graft-Versus-Host Disease, John Magenau, Samantha Jaglowski, Joseph Uberti, Sherif S Farag, Mary Mansour Riwes, Attaphol Pawarode, Sarah Anand, Monalisa Ghosh, John Maciejewski, Thomas Braun, Martin Devenport, Susan Lu, Bhramori Banerjee, Carolyn Dasilva, Steven Devine, Mei-Jie Zhang, Linda J Burns, Yang Liu, Pan Zheng, Pavan Reddy

Faculty, Staff and Students Publications

Patients who undergo human leukocyte antigen–matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning for hematologic malignancies often develop acute graft-versus-host disease (GVHD) despite standard calcineurin inhibitor–based prophylaxis in combination with methotrexate. This trial evaluated a novel human CD24 fusion protein (CD24Fc/MK-7110) that selectively targets and mitigates inflammation due to damage-associated molecular patterns underlying acute GVHD while preserving protective immunity after myeloablative conditioning. This phase 2a, multicenter study evaluated the pharmacokinetics, safety, and efficacy of CD24Fc in combination with tacrolimus and methotrexate in preventing acute GVHD in adults undergoing MUD HSCT for hematologic malignancies. A double-blind, …

Doxycycline For Transgene Control Disrupts Gut Microbiome Diversity Without Compromising Acute Neuroinflammatory Response, Emily J Koller, Caleb A Wood, Zoe Lai, Ella Borgenheimer, Kristi L Hoffman, Joanna L Jankowsky

Faculty, Staff and Students Publications

The tetracycline transactivator (tTA) system provides controllable transgene expression through oral administration of the broad-spectrum antibiotic doxycycline. Antibiotic treatment for transgene control in mouse models of disease might have undesirable systemic effects resulting from changes in the gut microbiome. Here we assessed the impact of doxycycline on gut microbiome diversity in a tTA-controlled model of Alzheimer's disease and then examined neuroimmune effects of these microbiome alterations following acute LPS challenge. We show that doxycycline decreased microbiome diversity in both transgenic and wild-type mice and that these changes persisted long after drug withdrawal. Despite the change in microbiome composition, doxycycline treatment …

An Evolutionary Perspective On Complex Neuropsychiatric Disease, Jon M Mcclellan, Anthony W Zoghbi, Joseph D Buxbaum, Carolina Cappi, James J Crowley, Jonathan Flint, Dorothy E Grice, Suleyman Gulsuner, Conrad Iyegbe, Sanjeev Jain, Po-Hsiu Kuo, Maria Claudia Lattig, Maria Rita Passos-Bueno, Meera Purushottam, Dan J Stein, Anna B Sunshine, Ezra S Susser, Christopher A Walsh, Olivia Wootton, Mary-Claire King

Faculty, Staff and Students Publications

The forces of evolution-mutation, selection, migration, and genetic drift-shape the genetic architecture of human traits, including the genetic architecture of complex neuropsychiatric illnesses. Studying these illnesses in populations that are diverse in genetic ancestry, historical demography, and cultural history can reveal how evolutionary forces have guided adaptation over time and place. A fundamental truth of shared human biology is that an allele responsible for a disease in anyone, anywhere, reveals a gene critical to the normal biology underlying that condition in everyone, everywhere. Understanding the genetic causes of neuropsychiatric disease in the widest possible range of human populations thus yields …

Biallelic Variants In Rbm42 Cause A Multisystem Disorder With Neurological, Facial, Cardiac, And Musculoskeletal Involvement, Yiyao Chen, Bingxin Yang, Xiaoyu Merlin Zhang, Songchang Chen, Minhui Wang, Liya Hu, Nina Pan, Shuyuan Li, Weihui Shi, Zhenhua Yang, Li Wang, Yajing Tan, Jian Wang, Yanlin Wang, Qinghe Xing, Zhonghua Ma, Jinsong Li, He-Feng Huang, Jinglan Zhang, Chenming Xu

Faculty, Staff and Students Publications

Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 gene. The patient is a 2-year-old female with severe central nervous system (CNS) abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing (WES) reveals that the patient has two compound heterozygous variants, c.304C>T (p.R102*) and c.1312G>A (p.A438T), in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein family. The p.A438T variant is in the RRM domain which impairs RBM42 protein stability in vivo. Additionally, p.A438T disrupts the interaction of …

Effect Of Anti-Interleukin-6 Agents On Psychopathology In A Sample Of Patients With Post-Covid-19 Syndrome: An Observational Study, Alessio Simonetti, Antonio Restaino, Evelina Bernardi, Ottavia Marianna Ferrara, Stella Margoni, Antonio Maria D'Onofrio, Federica Ranieri, Delfina Janiri, Vincenzo Galluzzo, Matteo Tosato, Georgios D Kotzalidis, Francesco Landi, Gabriele Sani

Faculty, Staff and Students Publications

Interleukin 6 (IL-6) receptor inhibitors tocilizumab and sarilumab have recently been approved for severe coronavirus disease 2019 (COVID-19). They also affect mood, even though their effect on the post-COVID-19 syndrome-related psychopathology still has to be investigated. The aim of this study was to investigate their effect on psychopathology in a sample of patients with post-COVID-19 syndrome. We included 246 patients (34% female, 66% male) aged 18–75 years who had been hospitalized for COVID. Patients were split into those who received anti-IL-6 receptor agents (Anti-IL-6-R, N = 88) and those who did not (Ctrl, N = 158). The former group was …

Heat Shock Factor 1 Directly Regulates Transsulfuration Pathway To Promote Prostate Cancer Proliferation And Survival, J Spencer Hauck, David Moon, Xue Jiang, Mu-En Wang, Yue Zhao, Lingfan Xu, Holly Quang, William Butler, Ming Chen, Everardo Macias, Xia Gao, Yiping He, Jiaoti Huang

Faculty, Staff and Students Publications

There are limited therapeutic options for patients with advanced prostate cancer (PCa). We previously found that heat shock factor 1 (HSF1) expression is increased in PCa and is an actionable target. In this manuscript, we identify that HSF1 regulates the conversion of homocysteine to cystathionine in the transsulfuration pathway by altering levels of cystathionine-β-synthase (CBS). We find that HSF1 directly binds the CBS gene and upregulates CBS mRNA levels. Targeting CBS decreases PCa growth and induces tumor cell death while benign prostate cells are largely unaffected. Combined inhibition of HSF1 and CBS results in more pronounced inhibition of PCa cell …

Features Of Acute Covid-19 Associated With Post-Acute Sequelae Of Sars-Cov-2 Phenotypes: Results From The Impacc Study, Al Ozonoff, Naresh Doni Jayavelu, Shanshan Liu, Esther Melamed, Carly E Milliren, Jingjing Qi, Linda N Geng, Grace A Mccomsey, Charles B Cairns, Lindsey R Baden, Joanna Schaenman, Albert C Shaw, Hady Samaha, Vicki Seyfert-Margolis, Florian Krammer, Lindsey B Rosen, Hanno Steen, Caitlin Syphurs, Ravi Dandekar, Casey P Shannon, Rafick P Sekaly, Lauren I R Ehrlich, David B Corry, Farrah Kheradmand, Mark A Atkinson, Scott C Brakenridge, Nelson I Agudelo Higuita, Jordan P Metcalf, Catherine L Hough, William B Messer, Bali Pulendran, Kari C Nadeau, Mark M Davis, Ana Fernandez Sesma, Viviana Simon, Harm Van Bakel, Seunghee Kim-Schulze, David A Hafler, Ofer Levy, Monica Kraft, Chris Bime, Elias K Haddad, Carolyn S Calfee, David J Erle, Charles R Langelier, Walter Eckalbar, Steven E Bosinger, Bjoern Peters, Steven H Kleinstein, Elaine F Reed, Alison D Augustine, Joann Diray-Arce, Holden T Maecker, Matthew C Altman, Ruth R Montgomery, Patrice M Becker, Nadine Rouphael

Faculty, Staff and Students Publications

Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B …

Gene Regulation And Speciation In A Migratory Divide Between Songbirds, Matthew I M Louder, Hannah Justen, Abigail A Kimmitt, Koedi S Lawley, Leslie M Turner, J David Dickman, Kira E Delmore

Faculty, Staff and Students Publications

Behavioral variation abounds in nature. This variation is important for adaptation and speciation, but its molecular basis remains elusive. Here, we use a hybrid zone between two subspecies of songbirds that differ in migration - an ecologically important and taxonomically widespread behavior---to gain insight into this topic. We measure gene expression in five brain regions. Differential expression between migratory states was dominated by circadian genes in all brain regions. The remaining patterns were largely brain-region specific. For example, expression differences between the subspecies that interact with migratory state likely help maintain reproductive isolation in this system and were documented in …

Appelmans Protocol – A Directed In Vitro Evolution Enables Induction And Recombination Of Prophages With Expanded Host Range, Thao Nguyen Vu, Justin Ryan Clark, Eris Jang, Roshan D'Souza, Le Phuong Nguyen, Naina Adren Pinto, Seongjun Yoo, Ricardo Abadie, Anthony William Maresso, Dongeun Yong

Faculty, Staff and Students Publications

Infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) present significant healthcare challenges due to limited treatment options. Bacteriophage (phage) therapy offers potential as an alternative treatment. However, the high host specificity of phages poses challenges for their therapeutic application. To broaden the phage spectrum, laboratory-based phage training using the Appelmans protocol was employed in this study. As a result, the protocol successfully expanded the host range of a phage cocktail targeting CRAB. Further analysis revealed that the expanded host range phages isolated from the output cocktail were identified as recombinant derivatives originating from prophages induced from encountered bacterial strains. These findings …

Combinatorial Effects Of Ion Channel Mis-Splicing As A Cause Of Myopathy In Myotonic Dystrophy, Larissa Nitschke, Thomas A Cooper

Faculty, Staff and Students Publications

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder caused by an unstable expanded CTG repeat located in the 3'-UTR of the DM1 protein kinase (DMPK) gene. The pathogenic mechanism results in misregulated alternative splicing of hundreds of genes, creating the dilemma of establishing which genes contribute to the mechanism of DM1 skeletal muscle pathology. In this issue of the JCI, Cisco and colleagues systematically tested the combinatorial effects of DM1-relevant mis-splicing patterns in vivo and identified the synergistic effects of mis-spliced calcium and chloride channels as a major contributor to DM1 skeletal muscle impairment. The authors further demonstrated …

Novel Techniques In Imaging Congenital Heart Disease: Jacc Scientific Statement, Ritu Sachdeva, Aimee K Armstrong, Rima Arnaout, Lars Grosse-Wortmann, B Kelly Han, Luc Mertens, Ryan A Moore, Laura J Olivieri, Anitha Parthiban, Andrew J Powell

Faculty, Staff and Students Publications

Recent years have witnessed exponential growth in cardiac imaging technologies, allowing better visualization of complex cardiac anatomy and improved assessment of physiology. These advances have become increasingly important as more complex surgical and catheter-based procedures are evolving to address the needs of a growing congenital heart disease population. This state-of-the-art review presents advances in echocardiography, cardiac magnetic resonance, cardiac computed tomography, invasive angiography, 3-dimensional modeling, and digital twin technology. The paper also highlights the integration of artificial intelligence with imaging technology. While some techniques are in their infancy and need further refinement, others have found their way into clinical workflow …

Time To Continuous Renal Replacement Therapy Initiation And 90-Day Major Adverse Kidney Events In Children And Young Adults, Katja M Gist, Shina Menon, Pilar Anton-Martin, Amee M Bigelow, Gerard Cortina, Akash Deep, Sara De La Mata-Navazo, Ben Gelbart, Stephen Gorga, Isabella Guzzo, Kenneth E Mah, Nicholas J Ollberding, H Stella Shin, Sameer Thadani, Amanda Uber, Huaiyu Zang, Michael Zappitelli, David T Selewski, We-Rock Investigators

Faculty, Staff and Students Publications

IMPORTANCE: In clinical trials, the early or accelerated continuous renal replacement therapy (CRRT) initiation strategy among adults with acute kidney injury or volume overload has not demonstrated a survival benefit. Whether the timing of initiation of CRRT is associated with outcomes among children and young adults is unknown.

OBJECTIVE: To determine whether timing of CRRT initiation, with and without consideration of volume overload (VO;

DESIGN, SETTING, AND PARTICIPANTS: This multinational retrospective cohort study was conducted using data from the Worldwide Exploration of Renal Replacement Outcome Collaborative in Kidney Disease (WE-ROCK) registry from 2015 to 2021. Participants included children and young …