Digital Commons Network^™

Detection, Persistence, And Rising Prevalence Of Oncogenic Viruses Revealed By Wastewater Metagenomics, Harihara Prakash, Ryan K Perez, Matt Ross, Michael Tisza, Sara J Javornik Cregeen, Jennifer Deegan, Joseph F Petrosino, Eric Boerwinkle, Justin R Clark, Anthony W Maresso

Faculty, Staff and Students Publications

Oncogenic viruses cause high-risk cancers in humans and are responsible for nearly 20% of all cancer cases worldwide. Currently, very limited data exist in the realm of wastewater-based viral epidemiology (WBE) for cancer-causing viruses, with existing studies using targeted approaches (i.e., PCR-based approaches) that lack genomic resolution. In this study, we used a hybrid-capture approach to detect, filter, and sequence all known oncogenic virus signals from wastewater samples collected over 3 years (May 2022-May 2025) in 16 Texas cities, covering nearly 25% of the state's population. Once sequenced, we used custom computational tools designed for wastewater metagenomics to assign reads …

Macropinocytosis Inhibition Attenuates Profibrotic Responses In Lung Fibroblasts And Pulmonary Fibrosis Models, Ivan O Rosas, Aaron K Mcdowell-Sanchez, Santiago Sanchez, Juan D Cala-Garcia, Alan R Waich Cohen, Elisa Ruiz-Echartea, Scott A Ochsner, Daniel C Kraushaar, Lindsay J Celada, Dandan Sun, Francesca Polverino, Cristian Coarfa, Neil J Mckenna, Konstantin Tsoyi

Faculty, Staff and Students Publications

Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disorder with limited treatment options. Macropinocytosis is one of the key cellular processes involved in nutrient consumption from the extracellular environment under stress conditions. Here, we studied the role of macropinocytosis in experimental pulmonary fibrosis models. We found that macropinocytosis is increased in human lung fibroblasts (HLFs) derived from patients with IPF. The inhibition of macropinocytosis with 5-(n-ethyl-n-isopropyl)-amiloride (EIPA) inhibited profibrotic responses in IPF-derived and TGF-β1-stimulated HLFs and reduced pulmonary fibrosis in bleomycin-injured (Bleo-injured) mice. EIPA exerted its antifibrotic effects by regulating amino acid uptake, mammalian target of rapamycin complex 1 …

Autophagic Flux Blockade Under Hypocapnia Reveals Co2-Sensitive Regulation Of Autophagy-Lysosome Homeostasis, Naghmana Ashraf, Zhen Sun, Jeanine L Van Nostrand

Faculty, Staff and Students Publications

Hypocapnia, a reduction in partial pressure of carbon dioxide (CO2), commonly occurs in clinical contexts such as mechanical ventilation, panic disorder, and brain injury, yet its impact on cellular homeostasis remains poorly understood. Given the central role of autophagy in stress adaptation, we investigated how low CO2 influences autophagic flux and lysosomal function. We found that hypocapnia induces autophagosome accumulation while impairing cargo degradation, indicating a blockade in autophagic flux. This response was accompanied by increased lysosome biogenesis but, paradoxically, reduced autophagosome-lysosome fusion and lysosomal proteolytic activity. Mechanistically, hypocapnia promoted TFE3 dephosphorylation and nuclear translocation, driving transcriptional activation of lysosomal …

Single-Nucleus Profiling Reveals A Core Disease Signature And Cell Type-Specific Vulnerabilities In Early Rett Syndrome, Yan Li, Ashley G Anderson, Guantong Qi, Sih-Rong Wu, Jean-Pierre Revelli, Hu Chen, Zhandong Liu, Huda Y Zoghbi

Faculty, Staff and Students Publications

Rett syndrome (RTT) is an X-linked neurological disorder caused by MECP2 mutations, creating distinct cellular environments in females (mosaic) versus males (nonmosaic). Despite female patients representing most cases, how mosaicism contributes molecularly to RTT pathogenesis, particularly in presymptomatic stages, remains poorly understood. To address this question, we profiled hippocampal transcriptomes of young female and male RTT mice using bulk and single-nucleus RNA sequencing. We identified a core disease signature of consistently dysregulated genes only in MeCP2− cells across RTT models. Moreover, we uncovered non–cell autonomous effects exclusively in female MeCP2+ excitatory neurons, suggesting that these circuits are more vulnerable early …

Artificial Intelligence In Biomedical Scientific Publishing, Tomasz J Guzik, Victor Aboyans, Stefan Agewall, Steven Bailey, Adrian Baranchuk, Magnus Bäck, Michael Böhm, Robert O Bonow, George W Booz, Giuseppe Boriani, Biykem Bozkurt, Nico Bruining, Davide Capodanno, Çetin Erol, Péter Ferdinandy, Alessia Gimelli, Gerd Heusch, Thomas Kahan, Chim Choy Lang, Gerald Maurer, Robert J Mentz, Marco Metra, Philip Moons, Daniel Piskorz, Massimo Piepoli, Piotr Ponikowski, Alexandra Popma, Bianca Rocca, Juan Sanchis Fores, Philipp Sommer, Rhian M Touyz, Zoltan Ungvari, Pascal Vranckx, Joseph A Hill, Thomas F Lüscher, Filippo Crea

Faculty, Staff and Students Publications

Artificial intelligence is now embedded across the scientific research and publishing ecosystem, influencing discovery, analysis, knowledge translation, authorship, peer review, and editorial workflows. In cardiovascular and biomedical sciences, these developments offer substantial opportunities to accelerate knowledge generation, integrate complex datasets, and improve efficiency and consistency. At the same time, they introduce new risks related to bias, transparency, data integrity, and authorship responsibility, potentially endangering trust in the scientific record. This commentary examines the evolving role of AI in biomedical publishing, with particular attention to generative models and machine learning tools. We review both benefits and limitations, highlight risks such as …

Statewide Multi-Year Wastewater Sequencing Reveals Dual Origins Of Hiv-1 Signal, Justin R Clark, Dylan Chirman, Harihara Prakash, Austen Terwilliger, Marlene Mcneese, Matt Ross, Mike Tisza, Sara J Javornik Cregeen, Loren Hopkins, Jennifer Deegan, Catherine L Troisi, Eric Boerwinkle, Kristina Mena, Fuqing Wu, Jason T Kimata, Marc Johnson, Devon Gregory, Faith E Fletcher, Thomas P Giordano, Anthony W Maresso

Faculty, Staff and Students Publications

Human immunodeficiency virus 1 (HIV-1) is a retrovirus which has infected 90 million people and resulted in over 40 million deaths. Despite advances in diagnostics, treatment, and prophylaxis, HIV-1 continues to spread due to undiagnosed and untreated infections. Traditional monitoring methods are ineffective when access to testing is limited or people do not seek care, particularly given the long period between infection and symptom onset, allowing undetected transmission to continue. Here, we use a hybrid-capture sequencing approach to track HIV-1 signal in municipal wastewater in 15 different cities over nearly 3 years. We obtain near-complete genomic coverage of HIV-1, enabling …

In Vivo Orf Overexpression Screening Identifies Ccn4 As A Regulator Of Glioblastoma Growth Validated Across Multiple Models, Pushan Dasgupta

Faculty, Staff and Students Publications

Despite current multimodal therapies for glioblastoma (GBM), its prognosis remains grim. Thus, a tremendous need exists to identify new genetic drivers that may serve as potential therapeutic targets in glioblastoma (GBM). We describe an in vivo overexpression screening strategy to identify drivers of glioblastoma where we have leveraged TCGA datasets to conduct a functional genomics screen of prioritized open reading frames (ORFs) that are overexpressed and/or amplified in GBM. To interrogate these potential drivers within a more relevant physiological context, the screening was accomplished in vivo in an orthotopic patient-derived glioma stem-like cell (GSC) model. Among 5 positive "hits" from …

Notch1 Acts As A Tumor Suppressor That Induces Early Differentiation In Head And Neck Cancer, Chenfei Huang, Shhyam Moorthy, Qiuli Li, Kazi M Ahmed, Kalil Saab, Defeng Deng, Jiping Wang, Xiayu Rao, Jiexin Zhang, Yuanxin Xi, Jing Wang, Zhiyi Liu, Noriaki Tanaka, David A Wheeler, Eve Shinbrot, Rami Saade, Curtis R Pickering, Tong-Xin Xie, Adel K El-Naggar, Abdullah A Osman, Kunal Rai, Patrick A Zweidler-Mckay, John V Heymach, Lauren A Byers, Faye M Johnson, Vlad C Sandulache, Jeffrey N Myers, Pedram Yadollahi, Mitchell J Frederick

Faculty, Staff and Students Publications

Inactivating NOTCH1 mutations in head and neck squamous cell carcinoma (HNSCC) were described over a decade ago, suggesting a tumor suppressor function - unlike its oncogenic role in other tumors. Today, much debate persists regarding a putative oncogenic role in HNSCC as well, with reports that NOTCH1 signaling drives tumor growth and a cancer stem cell (CSC) phenotype. In this work, comprehensive experiments unequivocally demonstrate that NOTCH1 is a tumor suppressor in HNSCC regardless of mutation or activation status and that it reduces CSC frequency. We developed a signature of NOTCH1 activation showing the pathway is associated with very early …

Histone Deacetylase Enzyme Activity Is Not The Universal Anticancer Target Of Hdac Inhibitors, Chaitra Rai, Hang Ruan, Xue Li, Wenbo Li, Hyun-Hwan Jeong, Chengchuang Song, Panpan Liu, Yingjie Chang, Hao Fang, Udhaya Kumar S, Yuxiang Sun, M James You, Dongyin Guan, Zhandong Liu, Leng Han, Xuben Hou, Zheng Sun

Faculty, Staff and Students Publications

Histone deacetylase inhibitors (HDIs) are approved for treating hematologic cancers and are currently being evaluated in hundreds of clinical trials for various cancers and other diseases, although their mechanisms of action remain poorly understood. Here, our unbiased bioinformatics analyses found that, for most cancer types, expression levels or genetic variants of histone deacetylase (HDACs) do not consistently correlate with carcinogenesis, do not predict cancer patient survival, and do not associate with cellular responses to HDIs. Whole-genome CRISPR library screens did not identify HDACs as genes affecting cellular responses to HDIs. Overexpression of dominant-negative Class I HDACs causes similar protein hyperacetylation …

Transgenic Hookworm Secretes Anti-Tetrodotoxin Human Single Chain Antibody, Kumar Sachin Singh, Suman Bharti, Bruce A Rosa, Mahdiyeh Bigham, Samuel C Uzoechi, Young-Jun Choi, John C Martin, Danielle Kemper, Slavica Pavlovic Djuranovic, Darren A Pickering, Rachael Ryan, Bethany K Bracken, Maria Elena Bottazzi, Eric C Carnes, Wannaporn Ittiprasert, Matthew Moyle, Paul J Brindley, Alex Loukas, Sergej Djuranovic, Makedonka Mitreva

Faculty, Staff and Students Publications

Biologics, protein- and peptide-based drugs derived from living organisms or cell lines have emerged as effective therapies across a broad range of indications. However, parenteral administration and the need for frequent dosing increase costs and limit compliance, creating an urgent need for innovative platforms capable of continuously, safely, and efficiently delivering sustained biologics in situ within the host. Here, we describe a bioengineered hookworm platform to manufacture and deliver biologic therapeutics in vivo. As proof of concept, we engineer the Ancylostoma ceylanicum secretome by inserting a human single-chain variable fragment antibody (s16-HuScFv) into its genome. Transgene expression does not perturb …

Cytosine Base Editing Of Lpa In Transgenic Mice Averts Large Deletions, Marcel A Chuecos, So Hyun Park, Madhvi M Bhakta, Usosa Too-Chiobi, Daniel Betancourth, Mingming Cao, Marco De Giorgi, Christopher J Walkey, Anjana Tiwari, Biana Godin, Julia M Assini, Donna J Palmer, Philip Ng, Michael B Boffa, Marlys L Koschinsky, Gang Bao, William R Lagor

Faculty, Staff and Students Publications

Lipoprotein(a) (Lp(a)) is a genetically determined causal risk factor for cardiovascular disease, with approximately 20% of the population exhibiting elevated levels. While there are promising drugs in development, there are currently no approved therapies specifically designed to lower Lp(a) levels. For high-risk individuals with extreme levels of Lp(a), liver-directed genome editing could be an effective one-time solution. Genome editing approaches such as CRISPR and TALENs can reduce Lp(a) in LPA-transgenic mouse models, but they frequently induce large and potentially harmful genomic deletions. Here, we report the first application of TadA-derived cytosine base editing (CBE), delivered via helper-dependent adenovirus (HDAdV) and …

Complement Activation In Maternal And Placental Pathology Of Preeclampsia, Manu T Banadakoppa, Madhulatha S Chauhan, Moises J Tacam, Allyson W Nevins, Antonio H Ruano, Simone H Ruano, Jon A Fuson, Chandra Yallampalli

Faculty, Staff and Students Publications

Background: Preeclampsia is a multifactorial, pregnancy-related disorder characterized by new-onset hypertension and proteinuria, with distinct early- and late-onset forms. Although complement dysregulation has been implicated in the pathogenesis of preeclampsia, its causal role remains unclear. In mice, Crry (complement receptor 1-related protein Y) functions as a critical complement regulator at the fetal-maternal interface. Because complete Crry deficiency is embryonically lethal, direct in vivo investigation of complement activation in pregnancy has been challenging.

Methods: We generated a placenta-specific, doxycycline-inducible short hairpin RNA mouse model in which Crry expression can be downregulated in a dose-dependent manner. This system employs Cyp19-driven Cre recombinase …

Reducing Cardiovascular Disease Risk In Obesity: An Unexpected But Welcome Fourier Transformation, Layla A Abushamat, Arsalan Hamid, Vijay Nambi, Huaizhu Wu, Christie M Ballantyne

Faculty, Staff and Students Publications

No abstract provided.

Corneal Innervation Research At A Crossroads: A Tool-Driven Roadmap For The Future, Anna Matynia, Ian D Meng, Brian M Davis, Stephen C Pflugfelder, Anat Galor, Victor L Perez, Elizabeth R Felix, Pedram Hamrah, Pantelimon Rompolas, Raul E Ruiz-Lozano, Shamsuddin A Bhuiyan, Kaveh Moghbeli, Evangelia Semizoglou, William Renthal, Harinder Singh, Jishnu Das, Marcin Golczak, Mary Ann Stepp, Catherine W Morgans, Cintia S De Paiva, Carl Y Saab, Igor Spigelman, Rony R Sayegh, Tally M Largent-Milnes, Hao Wu, Wenqin Luo, Sreya Mitra, Heesuk Yoo, Sina Farsiu, Sejiro Littleton, Eden Jacob, Matthew T Mcpheeters, Maryse Lapierre-Landry, Jordan J Smith, Xi Wang, Roxana Florea, Made Airanthi K Widjaja-Adhi, Scott Holmes, Zane Zemborain, Kate E T Laise, Nicholas J Pondelis, Ki-Soo Jeong, Rui Chen, Michael W Jenkins, Vivian Lee, Eric A Moulton, Deborah S Jacobs, Sue A Aicher, Anthony J St Leger, Daniel R Saban

Faculty, Staff and Students Publications

Corneal innervation research has faced long-standing clinical challenges that only recent technological breakthroughs now make tractable. Advances in single-cell analysis, viral vectors, clinical imaging, and artificial intelligence provide integrated approaches for uncovering molecular mechanisms underlying functional outcomes and facilitating clinical applications. The National Eye Institute's U01-funded consortium on ocular surface innervation addresses major knowledge gaps in characterizing corneal-projecting neurons, understanding neuroimmune and epithelial interactions in the cornea, and translating animal model findings to human pathology. The unique properties of the cornea (transparent, avascular, and densely innervated) make it ideal for neurobiology research on peripheral and central sensory processing. Through a …

Steroid Receptor Coactivators In Immunity – From Function To Emerging Translational Opportunities, Yosef Gilad, David M Lonard

Faculty, Staff and Students Publications

Steroid Receptor Coactivators (SRCs) comprise a family of three paralogous proteins. As transcriptional coactivators SRCs are essential for enabling the full transcriptional output of nuclear receptors (NRs). They regulate the transcriptional activity of nearly all NRs as well as a wide range of non-NR transcription factors. The central role of SRCs in gene regulation is reflected in their broad impact on major physiological and pathological processes, such as development, reproduction, metabolism, immunity and cancer. Although the major impact of SRCs on human health and disease established them as attractive therapeutic targets, their effective pharmacological targeting remained a challenge for nearly …

Retrospective Analysis Of A Washu-Based Knowledge-Based Planning (Kbp) Model For Breast And Chest Wall Planning In Guatemala: Compliance With American Society For Radiation Oncology (Astro) 2026 Guidelines, Milton E Ixquiac Cabrera, Erick O Montenegro, Matthew Schmidt, Baozhou Sun, James A Kavanaugh, Taoran Li, Angel Velarde, Vicky De Falla, Francisco Reynoso

Faculty, Staff and Students Publications

Background/purpose

Breast cancer is among the most prevalent malignancies treated at the Liga Nacional Contra el Cáncer (LNCC) in Guatemala, representing a significant proportion of annual radiotherapy cases. Access to high-quality, standardized treatment planning in resource-constrained settings remains a critical challenge. This study evaluates the dosimetric performance of knowledge-based planning (KBP) models adapted from Washington University (WashU) in St. Louis for breast and chest wall radiotherapy at LNCC, validated against a retrospective 2025 clinical cohort, and benchmarked against the ASTRO 2026 Practical Radiation Oncology guidelines.

Materials and methods

A retrospective analysis of 84 treatment plans (40 left, 44 right) for …

Generation And Characterization Of Twist1 Acetyl-Mimic And Acetyl-Deficient Mouse Models, Mary Elmeniawi, Xiaobin Yu, Samuel Wen, Gunjan A Bhatia, Lan Liao, Jianming Xu, Walid D Fakhouri

Faculty, Staff and Students Publications

TWIST1 encodes a highly conserved basic helix–loop–helix transcription factor essential for embryonic development from Drosophila to humans. TWIST1 activity is regulated by post‐translational modifications, including phosphorylation during development and cancer metastasis. Recent cancer studies identified acetylation of lysines K73 and K76 as a novel regulatory modification that shifts TWIST1 from a repressive to an activating state during epithelial‐to‐mesenchymal transition (EMT). However, the developmental and in vivo functions of TWIST1 acetylation remain unknown. To investigate the physiological role, we generated the first acetyl‐deficient Twist1 K73,76R K73,76R and acetyl‐mimic Twist1 K73,76Q K73,76Q mouse models using CRISPR/Cas9‐mediated genome editing. Targeted sequencing confirmed substitutions, …

Transient Yap Activation Uncovers The Neurogenic Potential Of Proliferative Mammalian Müller Glia, English J Laserna, Irina V Saltykova, Benjamin M Hall, Xuefei Tong, Justin S Dhindsa, Borna Sarker, Ayrea E Hurley, Paul G Swinton, William R Lagor, Nicholas M Tran, James F Martin, Ross A Poché

Faculty, Staff and Students Publications

The Hippo pathway effector YAP promotes spontaneous proliferation of Müller glia (MG), suggesting that bypassing Hippo signaling and activating YAP could enhance retinal regeneration. However, whether proliferative adult MGs retain meaningful neurogenic competence remains unclear. Here, using viral delivery of a Hippo-resistant YAP variant to wild-type adult MGs, we achieved transient YAP activation in adult MGs, inducing proliferation followed by cell-cycle withdrawal and differentiation. Intersectional genetic lineage tracing and EdU labeling, combined with transcriptomic analyses, revealed that YAP-activated MGs predominantly regenerate MGs, whereas only a subset gives rise to bipolar cell-like neurons. These results indicate that proliferative MGs acquire a …

Comprehensive Proteogenomic Characterization Reveals Clinically Relevant Molecular Subtypes Associated With Medulloblastoma Progression, Seong-Min Park, Kyung-Hee Kim, Jong Hyuk Yoon, Fulvio D'Angelo, Seung Ah Choi, Chan Il Kim, Harim Koo, Seungmin Park, Hyondeog Kim, Sreeja Sundara Raj, Sung Soo Kim, Ae Kyung Park, Eun Jung Koh, Seong-Ik Kim, Yu-Mi Shim, Lee Kwang-Hoon, Eric Eunshik Kim, Ji Hoon Phi, Yeon Suk Jo, Do Hyun Nam, Daehee Hwang, Do Young Hyeon, Sunghyun Huh, Hyung Joon Kwon, Seokjun Ha, Sanha Park, Hyeji Shin, Jeong Taik Kwon, Heon Yoo, Ho-Shin Gwak, Michael D Taylor, Bong Jin Park, Jason K Sa, Youngwook Kim, Antonio Iavarone, Sung-Hye Park, Seung-Ki Kim, Jong Bae Park

Faculty, Staff and Students Publications

Current treatment strategies for medulloblastoma remain ineffective owing to extensive tumor heterogeneity. We generated five platforms of omics data including liquid chromatography and mass spectrometry-based proteome and performed integrated multi-omic characterization to improve the conventional molecular classification of medulloblastoma. We identified seven refined distinct subtypes. The sonic hedgehog (SHH) group was reclassified into two subgroups, SHHα and SHHβ, whereas group 4 was divided into three subgroups, G4α, G4β, and G4γ. SHH and group 4 subtypes exhibit two distinct neuronal differentiation trajectories: granular neuron and unipolar brush cell differentiation (SHHβ and G4γ, respectively), both of which associated with more favorable clinical …

Non-Isolated Dandy-Walker Malformation: Exome Sequencing Efficacy And Phenotypic Expansions, Sarah Araji, Xiaonan Zhao, Jill A Rosenfeld, Seema R Lalani, Daryl A Scott

Faculty, Staff and Students Publications

Dandy-Walker malformation (DWM) is a rare congenital abnormality of the posterior fossa and the cerebellum and has an incidence of 1 in 10 000 to 30 000 births. Although DWM can present in isolation, it is often associated with other central nervous system (CNS) abnormalities or extra-CNS anomalies (DWM+). A molecular cause is not identified in the majority of individuals with DWM+. This is due, in part, to uncertainty regarding optimal testing strategies and an incomplete understanding of the genetic causes of DWM+. In this study, we analyzed clinical exome sequencing (cES) data from 91 individuals with DWM+ to determine …

Systems Genetic Dissection Of Brain Gene Expression Reveals Excitotoxic Mechanisms Of Alzheimer’S Disease, Pinghan Zhao, Omar El Fadel, Anh Le, Carl Grant Mangleburg, Justin Dhindsa, Timothy Wu, Jinghan Zhao, Meichen Huang, Bismark Amoh, Aditi Sai Marella, Yarong Li, Nicholas T Seyfried, Allan I Levey, Zhandong Liu, Ismael Al-Ramahi, Juan Botas, Joshua M Shulman

Faculty, Staff and Students Publications

Gene expression changes likely mediate the impact of Alzheimer's disease (AD) neuropathology on cognition, but there are challenges to resolve the proximal causal pathways from postmortem brain transcriptome profiles which lack temporal resolution and are further confounded by mixed pathologies. Here, we functionally dissect 30 AD-associated human brain gene co-expression modules using fruit fly (Drosophila melanogaster) models. Integrating longitudinal RNA-sequencing and behavioral phenotyping, we interrogated the consequences of amyloid beta (Aβ) plaques, tau neurofibrillary tangles, and aging, highlighting hundreds of conserved, differentially expressed genes. To pinpoint causal modules and drivers, we manipulated 344 prioritized targets in vivo, identifying 141 modifiers …

Structural Determinants Of Ligand Response Specificity In The Mast Cell Activating Gpcr, Mrgprx2, Abiodun Adefola R Adeosun, Melina A Agosto, Olivier Lichtarge, Theodore G Wensel

Faculty, Staff and Students Publications

The mast cell-specific G-protein-coupled receptor (GPCR) MRGPRX2 (Mas-Related G Protein-coupled Receptor X2) has roles in itch and pain, and it mediates clinically relevant allergy-like responses to a diverse assortment of drugs. The varied responses of individuals to MRGPRX2 agonists, leading to drug hypersensitivity reactions in some cases, suggests the presence of consequential variants in the population. However, genetic associations with drug responses are poorly understood. We used heterologously-expressed MRGPRX2 to investigate the effect of 18 naturally occurring non-synonymous single nucleotide polymorphisms on activation by representative compounds from several classes, including neuropeptides, opioid agonists, antibiotics, neuromuscular blocking agents, and polycationic aromatic …

Human Neuronal Firing Varies With The Frequency Of Local Field Potential Oscillations, Zahra Jourahmad, Raissa K Mathura, Layth S Mattar, Melissa C Franch, Danika L Paulo, Mohammed Hasen, Nicole R Provenza, Benjamin Y Hayden, Sameer A Sheth, Eleonora Bartoli, Andrew J Watrous

Faculty, Staff and Students Publications

Neural oscillations play a critical role in shaping neuronal firing patterns. While phase-locked neuronal firing ("phase tuning") has been extensively studied in animal models and human invasive recordings, much less is known about whether neurons show preferential firing at specific oscillatory frequencies, termed frequency tuning. Here, we employ human intracranial recordings across several brain regions including hippocampus, entorhinal cortex, anterior and posterior cingulate cortex, and orbitofrontal cortex to test the hypothesis that neurons exhibit frequency-specific firing. We analyzed 357 single units recorded simultaneously with local field potentials in 19 neurosurgical patients during awake resting. We estimated the instantaneous frequency of …

Menopause May Partially Explain Age-Related Increased Risk Of Masld Fibrosis: A Causal Mediation Analysis, Itunu O Sokale, Yan Liu, Hashem B El-Serag, Fasiha Kanwal, Aaron P Thrift, Maya Balakrishnan

Faculty, Staff and Students Publications

No abstract provided.

Identification Of A Persistent Ascaris-Derived Kalirin Epitope Associated With Chronic T Cell Activation In The Lung, Yifan Wu, Leroy Versteeg, Meng-Chih Wu, Jill E Weatherhead

Faculty, Staff and Students Publications

Ascariasis remains a dominant global health burden due to its vast prevalence and associated morbidity. The obligatory migration of Ascaris larvae through pulmonary tissue triggers intense type-2 inflammation which typically presents as acute allergic airway disease. Even after the parasite is eliminated, a single episode of larval migration can result in chronic lung damage and dysfunction, which may be driven by the long-term retention of helminth antigens in macrophages. However, the molecular identity of these retained antigens, and the mechanisms by which they sustain chronic T cell responses, remain unknown. In this study, we utilized immunopeptidomics to identify a retained …

Choline Counteracts Pregnancy Undernutrition-Associated Colitis In Sheep By Restoring Microbiota Driven Bile Acid Metabolism, Weibin Wu, Peng Jiao, Yamei Gu, Huizhen Lu, Caiyun Fan, Zheng Sun, Lizhuang Hao, Shengyong Mao, Jianbo Cheng, Yanfeng Xue

Faculty, Staff and Students Publications

High-fertility sheep experience undernutrition during late gestation, which induces body metabolic disruption and intestinal inflammation. Crucially, the gut microbiota-bile acid axis is a promising intestinal inflammation target, but how choline modulates this axis in livestock enteritis is unknown. This study investigated choline's protective mechanisms against undernutrition-induced intestinal inflammation in sheep, focusing on gut microbiota and bile acid regulation. Choline consistently alleviates colitis severity, restores epithelial barrier integrity, and suppresses intestinal inflammation. These protective effects are accompanied by pronounced remodeling of the colonic microbial ecosystem, characterized by the enrichment of Clostridiales bacterium to elevate bile salt hydrolase activity and regulate bile …

Toxitarget: A Multi-Omics Database For Toxicant-Responsive Molecular Targets, Ravindra Kumar, Tianyi Fu, Prashant Kumar Kuntala, Benpeng Miao, Shuhua Fu, Daofeng Li, Frederick L Tyson, Marisa S Bartolomei, Cheryl L Walker, Ting Wang, Bo A Zhang

Faculty, Staff and Students Publications

Environmental toxicant exposures can induce widespread alterations in both the transcriptome and epigenome of mammals, and directly contribute to the increased risk of various diseases, including cardiovascular disorders, cancer, and neurological disorders. To evaluate how early-life toxicants produce long-term impacts on the transcriptome and epigenome in mice, the Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription II (TaRGET II) Consortium generated a landmark resource comprising 3607 multi-omics datasets from longitudinal studies in mice. The molecular changes in responding to distinct environmental toxicants, including arsenic (As), lead (Pb), bisphenol A (BPA), tributyltin (TBT), di-2-ethylhexyl phthalate (DEHP), dioxin (TCDD), …

Unbiased Niche Labeling Maps Immune-Excluded Niche In Bone Metastasis, Zhan Xu, Fengshuo Liu, Yunfeng Ding, Tianhong Pan, Yi-Hsuan Wu, Yujiao Han, Jun Liu, Igor L Bado, Weijie Zhang, Ling Wu, Yang Gao, Xiaoxin Hao, Liqun Yu, Xuan Li, David G Edwards, Hilda L Chan, Sergio Aguirre, Michael Warren Dieffenbach, Elina Chen, Siyue Wang, Yichao Shen, Dane Hoffman, Luis Becerra Dominguez, Charlotte Helena Rivas, Xiang Chen, Hai Wang, Yibin Kang, Zbigniew Gugala, Robert L Satcher, Xiang H-F Zhang

Faculty, Staff and Students Publications

Metastatic cancer cell fate is shaped by the local microenvironment niches. To unbiasedly define the cellular and molecular features of metastatic niches, we developed sortase A-based microenvironment niche tagging (SAMENT), which selectively labels cells encountered by cancer cells during metastasis. Applying SAMENT across multiple cancer models and target organs revealed shared niche features, including macrophage enrichment and T cell depletion, alongside marked organ-specific phenotype heterogeneity in niche macrophages. In bone, metastatic niches are enriched for macrophages expressing estrogen receptor alpha (ERα) with active ERα signaling. Conditional deletion of Esr1 in macrophages significantly impaired bone colonization by enabling T cell infiltration. …

Icam1high Neutrophils Sculpt Tumor Evolution And Metastasis Through Symbiotic Adhesion And Reverse Migration, Ling Wu, Zhan Xu, Jun Wang, Fengshuo Liu, Yunfeng Ding, Yang Gao, Siyue Wang, Jun Liu, Hilda L Chan, Weiguo Wu, Yi-Hsuan Wu, Liqun Yu, Xiaoxin Hao, Xuan Li, David G Edwards, Cher Sha, Tobie D Lee, Nan Guan, Sergio Aguirre, Luis Becerra-Dominguez, Dane Hoffman, Xiang Chen, Charlotte Helena Rivas, Xiaoyuan G Yan, Igor L Bado, Weijie Zhang, Qian Zhu, Arun Sreekumar, Robert L Satcher, Xiang H-F Zhang

Faculty, Staff and Students Publications

Neutrophils are a prominent component of the tumor microenvironment that can have both pro- and anti-tumor functions. By analyzing neutrophils across different human cancers, we revealed an ICAM1high subset enriched in the tumor microenvironment, which were also observed in murine triple negative breast cancer (TNBC) models. ICAM1high neutrophils exhibited an enhanced capacity for cell-cell adhesion specifically with tumor cells retaining epithelial features, and this adhesion conferred mutual advantages to both cell types. In contrast, cancer cells with mesenchymal-like phenotypes were vulnerable to neutrophil-mediated cytotoxicity due to decreased cell adhesion and elastase resistance. These opposite effects drove tumor evolution toward a …

Development Of A Second-Generation Rarα Selective Antagonist As An Orally Bioavailable, Effective, Safe, And Reversible Male Contraceptive, Rui Shi, Kristen John, Xuan Qin, Ehfazul Haque, Taimeng Liang, Narsihmulu Cheryala, Feng Li, Henry L Wong, Gunda I Georg

Faculty, Staff and Students Publications

We report the design and SAR studies of benzopyran-, benzofuran-, and benzothiophene-derived inhibitors of the retinoic acid receptor alpha (RARα) for male contraception. SAR studies identified critical features influencing activity, such as the optimal positioning of antagonism moieties and substituents, leading to the discovery of (S)-4-(5-(2,8-dimethyl-5-(p-tolyl)-2H-chromen-3-yl)-1H-pyrrol-2-yl)­benzoic acid (compound 23). Compound 23 is a highly potent RARα inhibitor (IC50 = 0.051 nM) with excellent selectivity (>1650-fold over RARβ and >1960-fold over RARγ) and ADMET properties. Compound 23 is orally bioavailable and reduces sperm counts in mice for a full male contraceptive effect …