Digital Commons Network^™

Frontotemporal Network Interactions Causally Support Rapid Concreteness Judgments During Reading, Elliot Murphy, Oscar Woolnough, Cale W Morse, Xavier Scherschligt, Nitin Tandon

Faculty, Staff and Student Publications

Neurobiological models of conceptual processing have been limited in spatiotemporal resolution, and uncertainty remains about the causal role of specific regions in concept representation. We utilized intracranial recordings in human neurosurgical patients with epilepsy (n = 19) during a concreteness judgement paradigm of single word reading. Concrete concepts showed greater high-frequency activation across a frontal and ventrotemporal network, while greater activation for abstract words was found in lateral posterior middle temporal cortex. Intercortical communications, measured by high-frequency partial direct coherence, revealed bidirectional frontal and ventral plus lateral temporal interactions. Words occupying the middle range of the concreteness scale (e.g., "profit") …

Tuscan: Tumor Segmentation And Classification Analysis In Spatial Transcriptomics, Chenxuan Zang, Charles C Guo, Yaohong Wang, Peng Wei, Ziyi Li

Faculty, Staff and Student Publications

The identification of tumor cells is pivotal for understanding tumor heterogeneity and the tumor microenvironment. Recent advances in spatially resolved transcriptomics (SRT) have revolutionized the way that transcriptomic profiles are characterized and have enabled the simultaneous quantification of transcript locations in intact tissue samples. SRT is a promising alternative method to study gene expression patterns in spatial domains. Nevertheless, the precise detection of tumor regions within intact tissue remains a great challenge. A common strategy for identifying tumor cells is via tumor-specific marker gene expression signatures, which are highly dependent on marker accuracy. Another effective approach is through aneuploid copy …

Severe Renal Phenotype Across A Multigenerational Tuberous Sclerosis Complex (Tsc) Family, Elena Tuller, Joshua A Samuels, Hope Northrup, Kate Richardson

Faculty, Staff and Student Publications

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by the formation of hamartomas in the brain, kidney, and heart, along with other complex clinical manifestations, including TSC-associated neuropsychiatric disorder (TAND). Development of genotype-phenotype correlations within TSC can aid clinicians in providing prognostic data and improve clinical management. We present here a multigenerational family who has a pathogenic variant in TSC2 displaying a severe renal phenotype.

Methods: A 23-year-old Caucasian male (Patient 1) was determined to have a molecularly confirmed diagnosis of TSC at approximately 2 months of age. The nonsense pathogenic variant (c.1372C>T (p.Arg458*)) in …

Segmental Tracheal Resection For Thyroid Cancer: Perioperative Morbidity, Locoregional Control, And Survival, Anastasios Maniakas, David C Wilde, Isabelle Fournier, Emily K Hyde, Li Xu, Jennifer R Wang, Neil D Gross, Erich M Sturgis, Victoria Banuchi, Naifa L Busaidy, Maria E Cabanillas, Priyanka Iyer, Ramona Dadu, Steven G Waguespack, Mimi I Hu, G Brandon Gunn, Michael Kwon, Salmaan Ahmed, Michelle D Williams, Mark E Zafereo

Faculty, Staff and Student Publications

Background: Segmental tracheal resection is rarely needed for advanced thyroid cancer but is among the most complex, high-risk thyroid surgeries.

Methods: Retrospective study of patients undergoing segmental tracheal resection for thyroid cancer at MD Anderson Cancer Center (2005-2024).

Results: We identified 120 patients with a median follow-up of 4.6 years (range 0.02-16.38). Papillary thyroid cancer was most common (68%). The median number of tracheal rings resected was 4 (range 1-9). Seventeen (14%) patients had a new tracheostomy placed at the time of surgery, with 11 (9%) remaining trach-dependent at last follow-up. Twenty-six (22%) patients had a return to the operating …

Finding Significant Hits In Networks: A Network-Based Tool For Analyzing Gene-Level P-Values To Identify Significant Genes Missed By Standard Methods, Sandeep Acharya, Vaha Akbary Moghaddam, Wooseok J Jung, Yu S Kang, Shu Liao, Michael A Province, Michael R Brent

2020-Current year OA Pubs

Finding Significant Hits in Networks (FISHNET) uses prior biological knowledge, represented as gene interaction networks and gene function annotations, to identify genes that do not meet the genome-wide significance threshold but replicate, nonetheless. Its input is gene-level P-values from any source, including omicsWAS, aggregation of genome-wide association studies P-values, CRISPR screens, or differential expression analysis. It is based on the idea that genes whose P-values are low purely by chance are distributed randomly across networks and functions, so genes with suggestive P-values that cluster in densely connected subnetworks and share common functions are less likely to reflect chance and more …

Active Bone Marrow Dose Reconstruction In A Large-Scale Cohort Study Of Cancer Patients Treated With Photon Radiotherapy, Keith T Griffin, Kishan J Pithadia, Yeon Soo Yeom, Lior Braunstein, Kelly L Bolton, Lindsay M Morton, Choonsik Lee

2020-Current year OA Pubs

BACKGROUND: Previous studies have investigated the dose-response relationship between external beam radiotherapy (EBRT) and leukemia by reconstructing the mean active bone marrow (ABM) dose as part of the exposure assessment. However, no prior study has leveraged electronic medical records (EMR) to reconstruct ABM dose and dose-volume in an EBRT patient population.

PURPOSE: To support future studies on the relationship between radiation exposure and adverse health effects among EBRT patients, we demonstrate methods to retrospectively calculate ABM dose and dose-volume metrics in a large patient cohort using EMR.

METHODS: We retrieved complete EMR for 639 individuals (five pediatric and 634 adult) …

Nasopharyngeal Microbiome-Epigenome-Wide Association Analysis In Infants With Severe Bronchiolitis, Ryohei Shibata, Yijun Li, Anat Yaskolka Meir, Sara Javornik Cregeen, Matthew Clayton Ross, Janice A Espinola, Ashley F Sullivan, Liming Liang, Kohei Hasegawa, Carlos A Camargo, Zhaozhong Zhu

Faculty, Staff and Students Publications

Background: Bronchiolitis exposes infants to both acute burdens (e.g., hospitalization in cases of severe bronchiolitis) and increased risks for chronic respiratory sequelae (e.g., asthma). In severe bronchiolitis, recent evidence suggests distinct pathobiological roles of microbiota (e.g., viruses, bacteria) and host responses influenced by genetic and epigenetic factors. However, the relationship of airway microbiota with host DNA methylation (DNAm) in infants with severe bronchiolitis remains unknown.

Methods: In a multi-center prospective cohort of 504 multi-ethnic infants with severe bronchiolitis (age < 1 year), using nasopharyngeal microbiome (exposure) and blood DNAm (outcome, Infinium MethylationEPIC BeadChip, Illumina) data within 24 h of the hospitalization, we conducted microbiome-epigenome-wide association studies (mbEWAS). We examined microbiota-associated differentially methylated CpGs (mbDMCs, false discovery rate [FDR] < 0.05), regions (mbDMRs, FDR < 0.05), and DNAm age acceleration. We also determined the associations of DNAm age acceleration with asthma development by age 6 years. Furthermore, we focused on asthma-related pathogenic bacteria-Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae-for functional analyses by examining serum mbDMR-related proteins (Proseek Multiplex, Olink) and their enriched pathways (FDR < 0.10).

Results: Across 23 common taxa-observed at least in 25% of the infants, we identified 1 mbDMC (S. pneumoniae, cg16594639, chr20: 39528675) …

Unilateral Online Ultrasound Stimulation Of Early Visual Cortex Suppresses Responses To Contralateral Visual Stimuli, Suraya Dunsford, Keith Murphy, Ema Darrieutort, Elsa Fouragnan, Giorgio Ganis

School of Psychology

INTRODUCTION: Transcranial ultrasound stimulation (TUS) shows great promise for inducing neuroplastic changes that persist long after stimulation. Evidence of stimulation-locked (online) neural changes would enable the development of closed-loop application of TUS. However, such responses have been difficult to distinguish from coincident neural activity caused by auditory and somatosensory effects of TUS.

METHODS: To dissociate genuine online neuromodulatory effects from peripheral confounds, we leveraged the contralateral retinotopic organization of the early visual cortex in nineteen subjects. Using a hemifield visual stimulation paradigm combined with high-precision, functional MRI-guided TUS, we applied TUS to the left early visual cortex while participants viewed …

Emerging Options And Future Strategies In Immunotherapy For Advanced Lung Squamous-Cell Carcinoma, Y Wang, R Rosell, F R Hirsch, S Lu, R Govindan, K Park, S Peters, J J Zhang

2020-Current year OA Pubs

Advanced-stage lung squamous-cell carcinoma (LUSC) remains a therapeutic challenge. Although immune checkpoint inhibitors (ICIs) have revolutionized LUSC treatment, only a small subset of LUSC patients can achieve durable clinical benefits, underscoring the need for novel strategies. Emerging immunotherapy strategies have demonstrated early evidence of promise for LUSC patients, particularly multi-specific antibodies and fusion proteins, antibody-drug conjugates, adoptive cell therapies, and cancer vaccines. Additionally, advances in multi-omics and artificial intelligence offer potential for precise immunotherapy by deciphering the complex tumor-immune microenvironment and predicting therapeutic responses. The future of LUSC treatment lies in rational multi-target and biological therapies to boost immune cytotoxicity, …

From Damage Signals To Immune Modulators: Oxidized Lipids In Immunometabolic Inflammation, Neetu Srivastava, Xiaoxiao Wan

2020-Current year OA Pubs

Oxidized lipids, once viewed as byproducts of oxidative stress, are now recognized as critical mediators linking metabolism, redox imbalance, and immunity. Generated through enzymatic and nonenzymatic oxidation of polyunsaturated fatty acids, oxidized phospholipids, lipid aldehydes, and oxidized lipoproteins act as context-dependent signals regulating immune activation, resolution, and metabolic adaptation. In metabolic inflammation, these lipids engage scavenger and Toll-like receptors to influence macrophage polarization, dendritic-cell function, and T-cell differentiation. Their context and concentration determine whether oxidized lipids amplify inflammation or promote immune tolerance. Accumulation of these species connects oxidative stress to immune dysfunction, contributing to diseases, such as atherosclerosis, obesity, diabetes, …

Aggregation Of Gene Regulatory Information And Knowledge On Fair Principles Enables Discovery Of Pathogenic Gene Regulatory Variants, Keyang Yu, Haoquan Zhao, Andrea S Wilderman, Tierra R Farris, Jessie E Arce, David Chen, Andrew R Jackson, Yiran Guo, Qi Li, Bosko Jevtic, Dubravka Jevtic, Vuk Milinovic, Yuankun Zhu, Jeremy Costanza, Eric D Wenger, Christopher Nemarich, Lisa Anderson, Aleksandar Mihajlović, Kristin Ardlie, Shaine A Morris, Matthew E Roth, Deanne M Taylor, Adam C Resnick, Lilei Zhang, Aleksandar Milosavljevic

Faculty, Staff and Students Publications

Motivation: Methods for sharing gene regulatory information and knowledge on FAIR principles, particularly in the context of tissue-specific gene regulation, remain poorly defined and implemented, hampering discovery and clinical genetic diagnosis.

Results: We specified FAIR principles for tissue-specific gene regulatory information and knowledge; implemented them by developing a registry of regulatory elements and aggregating FAIR gene regulatory information from several major sources; developed computational tools that utilize these FAIR resources; and demonstrated their utility by associating gene regulatory variants with major subtypes of congenital heart disease.

Alpha And Beta Emitters In Translational Nuclear Medicine: Clinical Advances, Challenges, And Future Direction, Hanieh Karimi, Thomas H. Shaffer, Erik Stauff, Vinay V. R. Kandula, Heidi H. Kecskemethy, Lauren W. Averill, Xuyi Yue

Department of Radiology Faculty Papers

Radiopharmaceutical therapy (RPT) has emerged as a transformative modality in oncology, particularly for patients with metastatic or inoperable tumors. By leveraging molecularly targeted carriers conjugated to cytotoxic radionuclides, RPT enables precise delivery of ionizing radiation to tumor sites while minimizing off-target effects. Central to this approach are alpha (α) and beta (β) particle-emitting radionuclides. This review aims to provide a comprehensive overview of all clinically relevant alpha and beta emitters and incorporates the most recent advances from 2017-2025, offering a comprehensive and up-to-date perspective. Alpha and beta emitters hold significant promises for the future, especially in nuclear medicine, energy, and …

Multi-Ancestry Genome-Wide Association Study And Meta-Analysis Of Lung Function Decline, Bonnie K Patchen, Jingwen Zhang, Nathan Gaddis, Traci M Bartz, Jing Chen, Catherine Debban, Hampton Leonard, Ngoc Quynh H Nguyen, Jungkyun Seo, Courtney Tern, Richard Allen, Dawn L Demeo, Myriam Fornage, Carl Melbourne, Melyssa Minto, Matthew Moll, George T O'Connor, Tess Pottinger, Bruce M Psaty, Stephen S Rich, Jerome I Rotter, Edwin K Silverman, Jeran Stratford, Chengyue Zhang, R Graham Barr, Michael H Cho, Sina A Gharib, Ani Manichaikul, Kari North, Elizabeth C Oelsner, Eleanor M Simonsick, Martin D Tobin, Bing Yu, Seung Hoan Choi, Josée Dupuis, Patricia A Cassano, Dana B Hancock

The Brown Foundation: Institute of Molecular Medicine

Background

Despite evidence for a genetic component, few genetic associations with lung function decline have been identified. We aimed to evaluate genome-wide associations and putative downstream functionality of genetic variants for lung function decline.

Methods

We conducted genome-wide association study (GWAS) analyses of decline in FEV1, FVC, and FEV1/FVC in 52,056 White (N = 44,988), Black (N = 5,788), Hispanic (N = 550), and Chinese American (N = 730) participants across seven general population cohorts. GWAS analyses were stratified by cohort, ancestry, and sex. Results were combined in cross-ancestry and ancestry-specific meta-analyses. Significant variants available in …

Aav Gene Therapy For Mps Iva With Induction Of Immune Tolerance Via Oral Administration Of Epitope Peptides Of N-Acetylgalactosamine-6-Sulfate Sulfatase, Sampurna Saikia, Yasuhiko Ago, Fnu Nidhi, Shaukat Khan, Zhengyu Ma, Shunji Tomatsu

Department of Pediatrics Faculty Papers

Mucopolysaccharidosis IVA (MPS IVA) is caused by the accumulation of undegraded glycosaminoglycans due to the deficiency of the N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme. MPS IVA manifests as progressive systemic skeletal dysplasia. Gene therapy (GT) is potentially a one-time treatment in which the enzyme is continuously produced, circulated, and delivered to target tissues. However, immune responses to gene products can diminish therapeutic efficacy. We hypothesized that oral delivery of tolerogenic peptides induces immune tolerance to human GALNS (hGALNS) in MPS IVA mice, enhancing therapeutic efficacy. Neonatal mice deficient in mouse GALNS (mGALNS) were treated orally with three T-cell/B-cell epitope peptides or hGALNS …

Hiv Infection, Neurotoxicity, Inflammation, Premature Aging, And Therapeutic Challenges To Plwh: An Overview, Mudit Tyagi, Ulhas P. Naik, Kratika Tyagi, Madhulika Sharma, Gagan Kaushal, Alok Bhushan, Michael Bukrinsky, Priya Tyagi

Department of Medicine Faculty Papers

HIV infection remains a major global health challenge due to its complex pathogenesis and lifelong persistence in people living with HIV (PLWH). A central barrier to eradication is the virus's ability to establish long-lived latent reservoirs in different tissues, including the central nervous system (CNS), where it evades immune clearance and antiretroviral therapy (ART). These reservoirs, seeded early during infection, fuel viral rebound if ART is interrupted, requiring lifelong treatment. In the CNS, HIV persists despite systemic viral suppression because of limited ART penetration across the blood-brain barrier (BBB), and infection of long-lived cells such as microglia and perivascular macrophages. …

Recognizing Structural And Social Determinants Of Health In The Diagnosis And Care Of Dementia, Shana D Stites, Sharnita Midgett, Nisha Patel, Kimberly Halberstadter, Rosalie Schumann, Marissa L Streitz, Yidan Shi, John C Morris, Jason Flatt, Crystal M Glover, Dawn Mechanic-Hamilton

2020-Current year OA Pubs

Structural and social determinants of health are environmental conditions that affect individuals' health and functioning across the life course. These determinants are salient factors at the apex of individual psychology, community variables, and larger sociological factors, exerting prominent effects on individuals' wellbeing. The National Institute on Aging seeks to understand their influence on aging and Alzheimer's disease. We propose that the benefits of doing so may reach beyond knowledge of disease mechanisms - it may also improve clinical outcomes. We describe efforts introducing structural and social determinants of health data into the national network of Alzheimer's disease research centers. We …

Supporting Evidence-Based Responses To Emotional Needs In Emphysema (Serene): Protocol For A Randomized, Open-Label Mechanistic Trial Comparing Coping Skills Training And Disease-Specific Education For Depressive Symptoms Conducted In United States Health Systems, Joanna L. Hart, Daniel Carter, Chloe Hinton, James Grilli, Lily A. Brown, Nora Brier, Yingying Lu, Casey Whitman, Michael O. Harhay, Michael Sims, Carmen Alvarez, Lisa R. Miller-Matero, C. Virginia O'Hayer

Department of Psychiatry and Human Behavior Faculty Papers

BACKGROUND: Depressive symptoms and anxiety are highly prevalent among people with chronic obstructive pulmonary disease (COPD), strongly associated with poor outcomes, and rarely recognized or treated. Integrating families into interventions may amplify supportive care treatment effects and overcome common challenges, yet this strategy is understudied. The Supporting Evidence-based Responses to Emotional Needs in Emphysema (SERENE) trial's main objective is to identify the mechanisms through which a family-partnered Coping Skills Training (CST) reduces depressive symptoms among patients with COPD, testing five putative mechanisms: family relationship quality, patient and caregiver self-efficacy, patient loneliness, and caregiver psychological distress.

METHODS: SERENE will enroll 375 …

Eepd1 Evolved A Unique Dna Clamping Dimer Protecting Reversed Replication Forks, Runze Shen, Altaf H Sarker, Yue Chen, Min Liu, Sunetra Roy, Andrew S Arvai, Albino Bacolla, Zamal Ahmed, Panagiotis Katsonis, Michal Hammel, Isao Kuraoka, Miaw-Sheue Tsai, Corydon Irie, Lukas Webb, Olivier Lichtarge, Chi-Lin Tsai, Susan E Tsutakawa, Katharina Schlacher, John A Tainer

Faculty, Staff and Student Publications

Exonuclease/endonuclease/phosphatase (EEP)-fold hydrolases are canonically monomeric phosphodiesterases exemplified by APE1, DNase I, and TDP2 nucleases. While EEP family domain containing protein 1 (EEPD1) acts in DNA stress responses, its proposed nuclease activities are enigmatic. Here, we integrate hybrid structural methods, evolution, biochemistry, cancer genomics, plus molecular and cell biology to define EEPD1 structure, assembly, and function at stalled DNA replication forks. Results imply EEPD1 surprisingly requires both unique EEP domain dimer and distinctive tandem Helix-hairpin-Helix [(HhH)2] domains to clamp double-stranded (ds) DNA at reversed DNA replication forks for fork protection. Small-angle X-ray Scattering (SAXS), crystal, and cryo-EM structures unveil an …

The Path Forward For T Cell Engagers In Patients With Prostate Cancer, Sumit K. Subudhi, Bilal A. Siddiqui, Kevin K. Zarrabi, William K. Kelly, Charles G. Drake

Department of Medical Oncology Faculty Papers

T cell engagers (TCEs) recruit T cells to the tumor microenvironment (TME) to induce antitumor immune responses. TCEs have demonstrated promising clinical responses in patients with metastatic castration-resistant prostate cancer and have advanced into phase 3 clinical trials. Here we provide an overview of the mechanisms of action of TCEs, including both CD3-targeted and CD28-targeted agents, and review the clinical development of these agents for prostate cancer. We propose a path forward for TCEs in prostate cancer, in which innovative clinical trials will facilitate a biological understanding of mechanisms of efficacy and toxicity to inform: (1) development of predictive biomarkers …

Dose-Dependent Ifn Programs In Myeloid Cells After Mrna And Adenovirus Covid-19 Vaccination., Giray N Eryilmaz, Yilmaz Yucehan Yazici, Radu Marches, Eleni P Mimitou, Lisa Kenyon-Pesce, Kim Handrejk, Sonia Jangra, Michael Schotsaert, Adolfo García-Sastre, George A Kuchel, Jacques Banchereau, Duygu Ucar

Faculty Research 2026

BACKGROUND. The SARS-CoV-2 pandemic provided a rare opportunity to study how human immune responses develop to a novel viral antigen delivered through different vaccine platforms. However, to date, no study has directly compared immune responses to all 3 FDA-approved COVID-19 vaccines at single-cell multiomic resolution.

METHODS. We longitudinally profiled SARS-CoV-2–naive adults (n = 31) vaccinated with BNT162b2, mRNA-1273, or Ad26.COV2.S, integrating plasma cytokines, antibody titers, and single-cell multiomic data (DOGMA-Seq).

RESULTS. We discovered a distinct, transient IFN program termed ISG-dim, which emerged specifically 1–2 days after the first mRNA dose in approximately 10% of myeloid cells. This state was …

Dose-Dependent Ifn Programs In Myeloid Cells After Mrna And Adenovirus Covid-19 Vaccination., Giray N Eryilmaz, Yilmaz Yucehan Yazici, Radu Marches, Eleni P Mimitou, Lisa Kenyon-Pesce, Kim Handrejk, Sonia Jangra, Michael Schotsaert, Adolfo García-Sastre, George A Kuchel, Jacques Banchereau, Duygu Ucar

Faculty Research 2026

BACKGROUNDThe SARS-CoV-2 pandemic provided a rare opportunity to study how human immune responses develop to a novel viral antigen delivered through different vaccine platforms. However, to date, no study has directly compared immune responses to all 3 FDA-approved COVID-19 vaccines at single-cell multiomic resolution.METHODSWe longitudinally profiled SARS-CoV-2-naive adults (n = 31) vaccinated with BNT162b2, mRNA-1273, or Ad26.COV2.S, integrating plasma cytokines, antibody titers, and single-cell multiomic data (DOGMA-Seq).RESULTSWe discovered a distinct, transient IFN program termed ISG-dim, which emerged specifically 1-2 days after the first mRNA dose in approximately 10% of myeloid cells. This state was characterized by ISGF3 complex activation and …

Supt16h-Associated Neurodevelopmental Disorder And Neurocristopathy: Genetic And Phenotypic Spectrum, Eunhye Lee, Seungmin Sim, Hee-Jung Choi, Eugene Y Liang, Carolyn Le, Roya Bina, Ryan Cohen, Elizabeth George, Soo Yeon Kim, Gifty Bhat, Erin Falsey, Richard Sidlow, Kristin Clinard, Shay Ben-Shachar, Eleina England, Beatriz Menendez, Isabella Herman, Shelly Nielsen, Jaya Punetha, Priya Bhola, J Austin Hamm, Megan A Keeney, Nike Sitzman, Sara Berger, Lakshmi Mehta, Alison J Conn, Lilian Downie, Myla Ashfaq, Hope Northrup, Ange-Line Bruel, Sylvie Odent, Justin O Szot, Noelia Nunez Martinez, Sunju Park, Julie Refkin, Jean-Marc Good, Fabienne Maurer, Cédric Le Caignec, David J Coman, Erin Anderson, Linda J Richards, Ryan J Dean, Caleb Yang, Chulwon Choi, Byung Joon Hwang, Jin Sook Lee, William B Dobyns, Murim Choi, Elliott H Sherr, Jong-Hee Chae, Yun Kee, Emanuela Argilli

Faculty, Staff and Student Publications

SUPT16H encodes a subunit of the FACT (FAcilitates Chromatin Transcription) complex, a histone chaperone essential for maintaining chromatin integrity during transcription, replication, and DNA repair. Pathogenic de novo SUPT16H missense variants have previously been linked to neurodevelopmental disorders in eight individuals. Here, we expand the genotypic and phenotypic spectrum by identifying 24 additional individuals harboring ultrarare heterozygous missense or truncating variants, who share overlapping clinical features including intellectual disability, autism spectrum disorder, hypotonia, and characteristic craniofacial dysmorphism. To elucidate the underlying mechanisms, we generated a supt16h knockout zebrafish model using CRISPR/Cas9. The supt16h loss-of-function (LOF) model recapitulated key patient phenotypes …

Human Microglia In Brain Assembloids Display Region-Specific Diversity And Respond To Hyperexcitable Neurons Carrying, Jiaxiang Wu, Xiaoling Chen, Jingliang Zhang, Kyle Wettschurack, Morgan Robinson, Weihao Li, Yuanrui Zhao, Ye-Eun Yoo, Brody A Deming, Yue Shu, Akila D Abeyaratna, Zhefu Que, Dongshu Du, Matthew Tegtmeyer, Chongli Yuan, William C Skarnes, Zhong-Yin Zhang, Jean-Christophe Rochet, Long-Jun Wu, Yang Yang

Faculty Research 2026

Microglia critically shape neuronal circuit development and function, yet their region-specific properties and roles in distinct circuits of the human brain remain poorly understood. In this study, we generated region-specific brain organoids (cortical, striatal, and midbrain), each integrated with human microglia, to fill this critical gap. Single-cell RNA sequencing uncovered six distinct microglial subtypes exhibiting unique regional signatures, including a subtype highly enriched for the GABA_B receptor gene within striatal organoids. To investigate the contributions of microglia to neural circuitry, we created microglia-incorporated midbrain-striatal assembloids, modeling a core circuit node for many neuropsychiatric disorders, including autism. Using chemogenetics to …

Human Microglia In Brain Assembloids Display Region-Specific Diversity And Respond To Hyperexcitable Neurons Carrying, Jiaxiang Wu, Xiaoling Chen, Jingliang Zhang, Kyle Wettschurack, Morgan Robinson, Weihao Li, Yuanrui Zhao, Ye-Eun Yoo, Brody A Deming, Yue Shu, Akila D Abeyaratna, Zhefu Que, Dongshu Du, Matthew Tegtmeyer, Chongli Yuan, William C Skarnes, Zhong-Yin Zhang, Jean-Christophe Rochet, Long-Jun Wu, Yang Yang

Faculty Research 2026

Microglia critically shape neuronal circuit development and function, yet their region-specific properties and roles in distinct circuits of the human brain remain poorly understood. In this study, we generated region-specific brain organoids (cortical, striatal, and midbrain), each integrated with human microglia, to fill this critical gap. Single-cell RNA sequencing uncovered six distinct microglial subtypes exhibiting unique regional signatures, including a subtype highly enriched for the GABA_B receptor gene within striatal organoids. To investigate the contributions of microglia to neural circuitry, we created microglia-incorporated midbrain-striatal assembloids, modeling a core circuit node for many neuropsychiatric disorders, including autism. Using chemogenetics to …

Human Microglia In Brain Assembloids Display Region-Specific Diversity And Respond To Hyperexcitable Neurons Carrying Scn2a Mutation, Jiaxiang Wu, Xiaoling Chen, Jingliang Zhang, Kyle Wettschurack, Morgan Robinson, Weihao Li, Yuanrui Zhao, Ye-Eun Yoo, Brody A Deming, Yue Shu, Akila D Abeyaratna, Zhefu Que, Dongshu Du, Matthew Tegtmeyer, Chongli Yuan, William C Skarnes, Zhong-Yin Zhang, Jean-Christophe Rochet, Long-Jun Wu, Yang Yang

The Brown Foundation: Institute of Molecular Medicine

Microglia critically shape neuronal circuit development and function, yet their region-specific properties and roles in distinct circuits of the human brain remain poorly understood. In this study, we generated region-specific brain organoids (cortical, striatal, and midbrain), each integrated with human microglia, to fill this critical gap. Single-cell RNA sequencing uncovered six distinct microglial subtypes exhibiting unique regional signatures, including a subtype highly enriched for the GABAB receptor gene within striatal organoids. To investigate the contributions of microglia to neural circuitry, we created microglia-incorporated midbrain-striatal assembloids, modeling a core circuit node for many neuropsychiatric disorders, including autism. Using chemogenetics to activate …

Nci9673 (Part B): Etctn Randomized Phase Ii Study Of Nivolumab With Or Without Ipilimumab In Refractory, Metastatic Squamous Cell Carcinoma Of The Anal Canal, Van K Morris, Kristen K Ciombor, Lianchun Xiao, Joshua K Ochieng, Enrica Marmonti, Blase Polite, Benjamin A Weinberg, John C Krauss, John Hays, Sarbajit Mukherjee, Olivia Aranha, Syma Iqbal, Tony Shields, Al B Benson, Syed Kazmi, Christopher Lieu, Howard Hochster, Jennifer Whisenant, Cara Haymaker, Cathy Eng

Faculty, Staff and Student Publications

Purpose: In the previously completed NCI9673 (part A) single-arm study, the antiprogrammed death (PD)-ligand-1 antibody nivolumab demonstrated efficacy for patients with metastatic anal cancer. In NCI9673 (Part B), we evaluated the anticytotoxic T-cell lymphocyte antigen-4 (CTLA-4) antibody ipilimumab in combination with nivolumab for patients with incurable anal cancer.

Methods: In this phase II NCI ETCTN trial, 100 patients with refractory, incurable anal cancer were randomly assigned to receive nivolumab (480 mg IV once every 4 weeks) alone or with ipilimumab (1 mg/kg IV once every 8 weeks). The primary end point was progression-free survival (PFS). Secondary endpoints included radiographic response, …

The Neuroprotective Effects Of Alpha-Tocopherol As An Anti-Inflammatory Agent: Mechanistic Insights And Therapeutic Challenges, Megumi H Seese, Yuanzhong Xu

The Brown Foundation: Institute of Molecular Medicine

Vitamin E (alpha-tocopherol, αToc), an antioxidant fat-soluble vitamin that prevents lipid peroxidation and modulates pro-inflammatory cytokine production, is well-known to be critical for neuroprotection. However, the underlying mechanism remains poorly understood. Accumulating evidence demonstrates that αToc influences neuroinflammatory processes. Here, we review recent research progress on the effects of αToc on neuroinflammation. Preclinical studies included in this narrative review were identified through PubMed searches using the keywords "alpha-tocopherol AND neuroinflammation or alpha-tocopherol AND brain AND inflammation". While many studies support a neuroprotective role of αToc, the magnitude and direction of its effects vary substantially depending on dosage, route of administration, …

Unbalanced Chromatin Binding Of Polycomb Complexes Drives Neurodevelopmental Disorders, Rodrigo L Borges, Gretter González-Blanco, Harikumar Arigela, Yingyu Huang, Lucas D Caeiro, Nikolai Fattakhov, Stefano Lepore, Liliana Garcia-Martinez, Matea Maurice, Pushti D Mehta, Emily J Park, Kailynn Macgillivray, Jevithen Nehru, Matthew Chau, Maria C Robayo, Clemer Abad, Alicia Bilbao-Martinez, Fabiola Monteiro, Xi Luo, Song Tan, Daniel Bilbao, Simone Sidoli, Bruno Di Stefano, Katherina Walz, Arneet L Saltzman, Ramiro E Verdun, Ramin Shiekhattar, Lluis Morey

Faculty, Staff and Students Publications

The prevalence of neurodevelopmental disorders (NDDs) in children is increasing, yet their underlying causes remain largely unknown. We identified heterozygous mutations in the Polycomb repressive complex 1 (PRC1) E3 ligases RING1 and RNF2 in individuals with NDDs and revealed distinct mechanisms by which they compromise PRC1 activity. We developed cellular and mouse models carrying the Ring1b

Anti-Apoptotic Bcl-2 Binds To All Three Ip3r Isoforms, Thereby Limiting The Ca2+-Flux Properties Of Ip3r Homo-Tetramers, Ian De Ridder, Claire Cauwelier, Larry E Wagner Ii, Jens Loncke, Vikas Arige, Irina I Serysheva, David I Yule, Geert Bultynck

Faculty, Staff and Student Publications

Anti-apoptotic B-cell lymphoma 2 (BCL-2) controls inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca²+ signalling. As cells typically express all three IP3R isoforms in variable abundances that assemble in hetero-tetrameric channels, the specific effects of BCL-2 on each isoform remain unclear. Here, we employed a reductionist approach using HEK293 cells triple-IP3R knockout reconstituted with a single IP3R isoform to elucidate the impact of BCL-2 on Ca2+ signalling by homo-tetrameric IP3R channels. Co-immunoprecipitation experiments demonstrated that BCL-2 interacts with each IP3R isoform. Live-cell Ca²+ imaging revealed that BCL-2 overexpression suppresses Ca²+ signals evoked by any of the three IP3R isoforms. Moreover, BCL-2 overexpression impaired …

Spatiotemporal Histogenesis Of The Developing Human Cerebellum Reveals Dynamic Layering Of Bergmann Glia, Guanyi He, Simon Du, Henry Tan, Sri Yellampally, Anders W Erickson, Virginia Fernandez, Ferechte Encha-Razavi, Kimberley A Phillips, Christine Haberler, Nicole Amberg, Victor Borrell, Paul A Northcott, Michael D Taylor, Kathleen J Millen, Parthiv Haldipur

Faculty, Staff and Students Publications

Bergmann glia (BG) are a specialized glial population essential for cerebellar development, yet their developmental timeline and molecular identity in the human cerebellum remain poorly understood. Here, we combined detailed histopathological analysis with spatial transcriptomics and single-nucleus RNA sequencing to generate a developmental atlas of human cerebellar BG. Histology revealed that BG emerge around 11 post-conception weeks (PCW), initially serving as a scaffold for Purkinje cells (PCs) migrating into the PC layer of the cerebellar cortex. Following the establishment of a multilayered PC arrangement, BG form a distinct parallel layer separated from the PCs by the lamina dissecans (LD), with …