Digital Commons Network^™

Adoptive Cell Therapies For Glioblastoma: A Quest For Cures From Within, Jia-Shiun Leu, Xin Ge, Charles Robin Yu, Guang Peng, Jiyong Liang

The Brown Foundation: Institute of Molecular Medicine

Glioblastomas (GBMs) are the most aggressive form of brain cancer recalcitrant to both current standard-of-care and immune checkpoint therapies that benefit other cancer patients. Adoptive cell therapies (ACT) using patients' own immune cells have long been explored as a treatment strategy, including the historically studied lymphokine-activated killer (LAK) cells, the evolving chimeric antigen receptor (CAR) directed immune cells, the newly emerging tumor-infiltrating T lymphocyte (TIL) therapies, and others. Preclinical and clinical studies have shown promise but also highlighted significant challenges. In this review, we summarize these findings, highlight recent developments, discuss current limitations, and emphasize how ACT may benefit from …

Engineering Of Genetically Encoded Programmable Calcium Channel Inhibitory Binders, Xiaoxuan Liu, Sher Ali, Tien-Hung Lan, Decheng Wang, Brendan Mckee, Tatsuki Nonomura, Siyao Liu, Feng Zhao, Michael X Zhu, Yun Huang, Qing Deng, Guolin Ma, Yubin Zhou

Faculty, Staff and Student Publications

Store-operated Ca2+ release-activated Ca2+ (CRAC) channels, composed of STIM and ORAI, are essential for immune and developmental processes, and their dysregulation underlies channelopathies such as Stormorken syndrome. Here, we report the engineering of genetically encoded CRAC channel inhibitory binders (CRABs) derived from the ORAI C-terminal tail. Guided by deep mutational scanning, we optimize a membrane-anchored CRAB variant that potently inhibits Ca2+ influx and NFAT signaling, and rescues thrombocytopenia-like phenotypes in a zebrafish model of Stormorken syndrome. To enable tunable inhibition, we further design oligomeric, optogenetic (Opto-CRAB), and chemogenetic (Chemo-CRAB) variants, providing graded and real-time control of CRAC activity. Chemo-CRAB further …

Whole-Genome Variant Detection In Long-Read Sequencing Data From Ultra-Low Input Patient Samples, Egor Dolzhenko, Adam English, Tom Mokveld, Guilherme De Sena Brandine, Zev Kronenberg, Galen Wright, Britt Drögemöller, William J Rowell, Aaron M Wenger, Xiao Chen, Mark F Bennett, Ben Weisburd, Graham S Erwin, Peng Jin, David Nelson, Harriet Dashnow, Fritz J Sedlazeck, Michael A Eberle

Faculty, Staff and Students Publications

Tandem repeats (TRs) exhibit high levels of somatic mosaicism, which is increasingly recognized as an important modifier of repeat expansion disorders. Long-read sequencing can capture full-length repeat alleles, yet robust frameworks for quantifying instability across TRs genome-wide are still needed. Here, we introduce a general-purpose model for quantifying TR instability in a given long-read sequencing dataset, without explicitly distinguishing biological mosaicism from technical noise, and which is broadly applicable to both simple and structurally complex loci. This model accurately characterizes allelic instability at each TR locus by representing the distribution of read-to-consensus deviations for each allele. Using HiFi sequencing data …

"I Wasn't Broken": Addressing Stigma Associated With Dementia While Walking The Talk For Dementia, Kate Irving, Fernando Aguzzoli Peres, Walter D. Dawson, Jonathan Adrián Zegarra-Valdivia, Lingani Mbakile-Mahlanza, Sherril B. Gelmon

Institute on Aging Publications

INTRODUCTION:Walking the Talk for Dementia (WTD) convenes people from every continent and multiple perspectives, including people with lived experience, in a 40- km walk followed by a 2-day symposium. The aim is collective reflective dialogue about dementia stigma without the burden of professional hierarchies.

METHODS: Qualitative reflections during and immediately following the walk were analyzed using content analysis to identify common themes.

RESULTS: Three themes demonstrate an evolution of perspectives about dementia and stigma: “meeting the person not the label”, “a community in solidarity”, and “I wasn’t treated like I was broken, and I wasn’t broken.”

DISCUSSION: WTD created an …

Constitutive Ampk Activation Prevents Hepatocellular Carcinoma Development Through Inhibition Of Hnf4Α Activity, Zhen Sun, Bernard Linares, Cassidy Urdiales, Fiyad Alsarmi, Boyuan Sang, Nagireddy Putluri, Jeanine L Van Nostrand

Faculty, Staff and Students Publications

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality and is largely driven by metabolic disorders such as obesity and type 2 diabetes. The AMP-activated protein kinase (AMPK) is a master regulator of metabolism, and its activation has been proposed as a therapeutic strategy for treating metabolic disorders. However, although AMPK activity is down-regulated in HCC, the precise role of AMPK in HCC development has not been clearly delineated. Here, we investigated the ability of constitutive AMPK activation to prevent HCC development using a constitutively active AMPK transgenic mouse model and a pharmacological AMPK activator. We observed that AMPK …

A Multidomain Peptide Hydrogel-Liposome Composite For Controlled Release Of A Cyclic Dinucleotide In Oral Cancer, Joseph W R Swain, Andrea H Molina, Gemalene M Sunga, Danielle Chew-Martinez, Neeraja Dharmaraj, Alejandra Cobos Perez, Arghadip Dey, Ephraim J Vázquez-Rosado, Simon Young, Jeffrey D Hartgerink

Faculty, Staff and Student Publications

While immunotherapy is a promising treatment strategy for cancer, the majority of head and neck squamous cell carcinoma (HNSCC) patients treated with single-agent immunotherapy do not respond. Therefore, researchers are investigating combination treatments with immunostimulatory molecules that can maximize anti-tumor responses. Cyclic dinucleotides (CDNs) are STING agonists that hold promise in combination approaches, but they require frequent intratumoral administration when used in both preclinical models of HNSCC and clinical trials. To reduce administration frequency, we have created a peptide hydrogel–liposome composite system, K2-Lip(CDN), for local and prolonged availability of CDN. We investigated the loading limits of cationic liposomes in both …

A Machine-Learning-Based Tool For Stroke Risk Prediction In Blunt Cerebrovascular Injury: Development And Preliminary Evaluation, Victoria Wagner, Joshua D Preston, Alejandro De Leon Castro, William F Mueller, Jonathan Nguyen, Manuel Garcia-Toca, Elizabeth R Benjamin, S Rob Todd, Jason D Sciarretta

Faculty, Staff and Student Publications

Purpose: Stroke risk correlates with the Biffl grading system in blunt cerebrovascular injury (BCVI). Although anti-thrombotic therapy is the mainstay of stroke prevention, no point-of-care clinical decision-support tool exists to guide timing for therapy. We sought to develop an interactive online calculator that incorporates patient-specific demographic and injury characteristics to estimate stroke risk and risk reduction with anti-thrombotic (AT) administration.

Methods: Data from BCVI patients (n = 1,197) at a Level I Trauma Center were retrospectively collected. Six machine learning methods were employed to predict stroke risk with and without AT therapy. Class imbalance was addressed using downsampling and/or class …

A Rare Case Of Cutaneous Extramedullary Hematopoiesis In Chronic Myeloid Leukemia, Bennett Christie-Nguyen, Hanadi El Achi, Levani Iashvili, Amer Wahed, Brenda Mai, Jacob Armstrong

Faculty, Staff and Student Publications

Cutaneous extramedullary hematopoiesis (CEH) is a rare manifestation of extramedullary hematopoiesis (EMH), a process typically associated with fetal development or myeloproliferative neoplasms. EMH most commonly involves the spleen, liver, and lymph nodes, with CEH being exceedingly rare in chronic myeloid leukemia (CML). Here, we present a 34-year-old Hispanic male with multiple bilateral lower extremity lesions, right buttock and leg pain, fatigue, and splenomegaly, who was found to have chronic-phase CML. Punch biopsy of one of the skin lesions demonstrated dermal infiltration by maturing hematopoietic elements, including granulocytes, megakaryocytes, and erythroid precursors, with fluorescence in situ hybridization (FISH) testing confirming a …

A Tv-Bm3d Iterative Algorithm For Vmat-Ct Reconstruction, Chia-Lung Chien, Beibei Guo, Rui Zhang

Faculty, Staff and Students Publications

Volumetric modulated arc therapy-computed tomography (VMAT-CT), which is the CT reconstructed using the portal images collected during VMAT, can potentially be an effective onsite imaging tool. The goal of this study was to propose an iterative reconstruction algorithm that can further improve the image quality of VMAT-CT and reduce the number of failed reconstructions. An iterative algorithm combining total variation (TV) with block-matching and 3D filtering (BM3D) was proposed, addressing the L1-L2 regularization problem using the split Bregman method. We collected portal images from 67 VMAT cases including 50 phantom and 17 real-patient cases. Both Feldkamp-Davis-Kress (FDK) and TV-BM3D iterative …

H3 Dopaminylation And Camkii Modulate Diffuse Midline Glioma Response To Cdk9 Inhibition, Rebecca L Murdaugh, Brittany R Eberl, Rosemary U Richard, Ena I Campos-Hensley, Adanze N Nnyagu, W Austin Elam, Ai-Ni Tsao, Jack R Tremblay, Ruiying Ma, Alfred K Dei-Ampeh, Kieu Pham, Daniel C Kraushaar, Kwanha Yu, Calla M Olson, Akdes Serin-Harmanci, Benjamin Deneen, Jamie N Anastas

Faculty, Staff and Students Publications

Aberrant neurotransmitter signaling and transcriptional dysregulation are hallmarks of gliomagenesis and represent potential therapeutic targets. Monoamine neurotransmitters such as dopamine and serotonin primarily activate GPCRs but can also function epigenetically as histone H3 modifications. Here, we uncover mechanisms of crosstalk between monoamine neurotransmitter signaling, H3 dopaminylation, and RNA polymerase II (Pol2) transcription in diffuse midline glioma (DMG). We find that co-treatment with Pol2-targeting CDK9 inhibitors (CDK9i) and FDA-approved neuropsychiatric drugs, including selective serotonin reuptake inhibitors (SSRIs), synergistically reduces DMG growth. Mechanistically, CDK9i+SSRI treatment alters H3 dopaminylation patterns and represses synaptic and neurodevelopmental gene transcription associated with CDK9i resistance. Further phospho-proteomic …

Condensate State As Determinant Of Amyloid Pathology In Neurodegeneration, Lathan Lucas, Josephine C Ferreon, Allan Chris M Ferreon

Faculty, Staff and Students Publications

Neurodegenerative diseases arise when normally functional aggregation-prone proteins transition into stable cross-β amyloid fibrils. Although these fibrils share a conserved architecture, the pathways that lead to fibrillation vary across proteins and cellular environments. Liquid-liquid phase separation is now recognized as a central organizer of intracellular biochemistry that modulates protein aggregation. Physiological condensation can buffer aggregation by maintaining macromolecular solubility and providing partner interactions that compete against pathological protein-protein interactions. However, condensates can transform and age into gel-like states that can favor the emergence of β-rich oligomers and solid-state fibrils. Across six disease-linked proteins that include Tau, α-synuclein, amyloid-β, TDP-43, FUS, …

Single-Cell Tcr Mapping Reveals Spatially Coordinated T Cell States In Head And Neck Cancer, Kelli A Mccord, Emerald Kan, Sean Hyslop, Amanda Y Xia, Colby J Hofferek, James S Lewis, Andreas Wieland, David J Hernandez, Vlad C Sandulache, William H Hudson

Faculty, Staff and Students Publications

Current spatial T cell receptor (TCR) profiling approaches lack the resolution needed to link clonal identity, transcriptional state, and spatial positioning of individual T cells in the tumor microenvironment. Here, we introduce a spatial TCR profiling strategy that resolves individual T cell clones together with their transcriptional states at single-cell resolution and applied the method to human head and neck squamous cell carcinoma. Presumed tumor-specific T cells were broadly dispersed throughout the tumor microenvironment, and cells of the same clone occupied distinct transcriptional states in different locations: Immune-rich regions contained more plastic or progenitor cells, whereas tumor-dense regions were enriched …

Loss Of Znrf3/Rnf43 Unleashes Egrfr In Cancer, Fei Yue, Amy T Ku, Payton D Stevens, Megan N Michalski, Weiyu Jiang, Jianghua Tu, Zhongcheng Shi, Yongchao Dou, Yi Wang, Xin-Hua Feng, Galen Hostetter, Xiangwei Wu, Shixia Huang, Noah F Shroyer, Bing Zhang, Bart O Williams, Qingyun Liu, Xia Lin, Yi Li

Faculty, Staff and Students Publications

ZNRF3 and RNF43 are closely related transmembrane E3 ubiquitin ligases with significant roles in development and cancer. Conventionally, their biological functions have been associated with regulating WNT signaling receptor ubiquitination and degradation. However, our proteogenomic studies have revealed EGFR as the protein most negatively correlated with ZNRF3/RNF43 mRNA levels in multiple human cancers. Through biochemical investigations, we demonstrate that ZNRF3/RNF43 interact with EGFR via their extracellular domains, leading to EGFR ubiquitination and subsequent degradation facilitated by the E3 ligase RING domain. Overexpression of ZNRF3 reduces EGFR levels and suppresses cancer cell growth in vitro and in vivo, whereas knockout of …

Contributing Factors Of Contralateral Breast Cancer In Patients With Brca Mutation (On-Brca Ii Study, Korea-Bsg 11), Seon-Hi Shin, Sung Gwe Ahn, Jai Min Ryu, Sae Byul Lee, Hyung Seok Park, Eun-Shin Lee, Janghee Lee, Byeongju Kang, Sanghwa Kim, Eun Young Kim, Young-Joon Kang, Sun Young Min, Moohyun Lee, Se-Kang Kim, Hong-Kyu Kim, Chihwan David Cha

Faculty, Staff and Students Publications

Background: The cumulative risk of contralateral breast cancer (CBC) in BRCA1/2 carriers is remarkably higher than in non-carriers. This study aimed to investigate the clinicopathological predictors associated with the risk of metachronous CBC among breast cancer patients with BRCA1/2 mutations using correspondence analysis.

Methods: This retrospective study included patients who underwent BRCA testing between January 2008 and December 2018. The inclusion criterion was patients being between 20 and 80-years-old with invasive breast cancer (pT1-3, N0-3). We performed univariate and multivariate survival analyses to assess the risks associated with BRCA mutations, and conducted correspondence analysis to identify contributing factors for CBC …

Tracking Hiv Through Wastewater: Ethical Considerations In Public Health Surveillance, Faith E Fletcher, Olive R Pertuit, Catherine Troisi, Jelani Kerr, Dakotah Kinsella, Grace Elizabeth White, Steven Vargas, Anthony Maresso, Thomas P Giordano

Faculty, Staff and Students Publications

Ending the HIV epidemic requires timely identification of new HIV infections and promptly linking patients to high-quality care. Innovative methods are needed to capture real-time HIV incidence data to more effectively identify persons in need of HIV care access. Emerging advancements in wastewater surveillance (WWS) offer the potential to identify geographic areas with elevated prevalence of detectable viral loads among people who are undiagnosed or no longer receiving care, enabling more targeted interventions to reduce HIV transmission. The introduction of new public health technologies requires balancing potential risks with the significant clinical and population-level benefits of decreasing the number of …

Bi-Allelic Variants In Ap5z1 And Ap5b1 Lead To Retinal Degeneration, Hafiz Muhammad Jafar Hussain, Meng Wang, Paul Yang, Behnoosh Tasharrofi, Yumei Li, Rebecca Lynn Clark, Emma Fale-Olsen, Grace Waldow, Mohammad Keramatipour, Mostafa Asadollahi, Mark E Pennesi, Rui Chen

Faculty, Staff and Students Publications

Inherited retinal diseases (IRDs) comprise a diverse group of disorders that frequently lead to progressive vision impairment and blindness. Despite advances in genetic testing, a significant number of IRD cases remain genetically unsolved, often due to unidentified disease-associated genes or variants. This study reports additional cases for the newly discovered IRD genes of the AP-5 complex. A comprehensive ophthalmological evaluation was performed for all patients, including retinal imaging (multimodal imaging), visual field testing, and electroretinogram (ERG) testing. Whole-genome and -exome sequencing (WGS and WES) were performed for clinically unsolved IRD patients, and data were analyzed to identify underlying causal variants. …

Co-Occurrence Of Transcriptionally Distinct Persister Cell States Underpins Neoadjuvant Therapy Resistance In Triple-Negative Breast Cancer, Yu Zhang, Fatemeh Ahmadi Moughari, Ioanna Mavrommati, Nora J Doleschall, Kate Moore, Gareth Muirhead, Ram Rajaram Srinivasan, Ping Gong, Jonathan T Lei, Amy Fleming, Hwei Minn Khoo, Naomi Guppy, Gabrielle Elshtein, Mohammed Inayatullah, Vijay K Tiwari, Lacey E Dobrolecki, Michael T Lewis, Syed Haider, Rachael Natrajan

Faculty, Staff and Students Publications

Background

Although the addition of neoadjuvant immune checkpoint blockade to chemotherapy has improved patient outcome in early triple‑negative breast cancer (TNBC), some patients continue to have poor disease outcomes.

Methods

To characterise neoadjuvant chemotherapy (NAC) resistant cell populations that persist post-NAC, we created a high-resolution single-cell atlas of 129,433 cells from fourteen TNBC patient-derived xenograft (PDX) models with residual disease post-NAC. We identified transcriptionally distinct cancer subpopulations or cell states using unsupervised clustering and characterised‑ their regulatory network as well as clinical associations with treatment response, metastatic progression and survival. Findings were validated using multiple independent TNBC cohorts.

Results

Four …

The Use Of Radiofrequency In The Treatment Of Erectile Dysfunction, Sarah Ponce, Nikola Rakic, Beatriz Hernandez, Mohit Khera

Faculty, Staff and Students Publications

No abstract provided.

Evaluating The Utility Of Rnaseq In Prenatal Diagnostics: Expression Profiles Of Cultured Chorionic Villus And Amniotic Fluid Samples, Maria C Vladoiu, Sen Zhao, Roni Zemet, Christian M Parobek, Jefferson Cruz Sinson, Stacy Tankersley, Ignatia B Van Den Veyver, Pengfei Liu

Duncan NRI Faculty and Staff Publications

Objective: While RNAseq has enhanced variant interpretation in postnatal cases, its potential in the prenatal setting remains underexplored. This study investigates the utility of RNAseq in prenatal diagnostics by analyzing the expression profiles of cultured chorionic villus samples (cCVS) and amniotic fluid (cAF) samples.

Methods: We performed RNAseq on 25 prenatal samples (10 cCVS and 15 cAF) and compared their expression profiles with those of postnatal tissues-blood and skin fibroblasts.

Results: To evaluate the clinical relevance of gene expression in these samples, we curated a list of genes associated with fetal-onset genetic disorders (n = 375). Using this curated list …

Evapecognition: An 18-Year Dataset Of Great Ape Cognition, Alejandro Sánchez-Amaro, Sonja J Ebel Van Wijk, Carin Molenaar, Akzira Abuova, Lizbeth Mujica-Manrique, Sarah M Leisterer-Peoples, Bret Beheim, Luke Maurits, Anna Albiach-Serrano, Matthias Allritz, Nazli Altınok, Federica Amici, Alice Mi Auersperg, Filippo Aureli, Elisa Bandini, Jochen Barth, Leïla Benziad, Bettina E Bläsing, Manuel Bohn, Marie Bourjade, Juliane Bräuer, Marie-Hélène Broihanne, Sarah F Brosnan, Nereida Bueno-Guerra, Thomas Bugnyar, David Buttelmann, Frances Buttelmann, Trix Cacchione, Malinda Carpenter, Fernando Colmenares, Catherine Crockford, Katherine A Cronin, África De Las Heras, Arianna De Marco, Sarah E Detroy, Valérie Dufour, Shona Duguid, Robin I M Dunbar, Johanna Eckert, Jan M Engelmann, Joel Fagot, Julia Fischer, Sofia Ingrid Fredrika Forss, Martina Funk, György Gergely, Julia R Greenberg, Johannes Großmann, Sebastian Grüneisen, Marta Halina, Daniel Hanus, Sarah R Heilbronner, Christophe Heintz, Robert Hepach, Esther Herrmann, Satoshi Hirata, Alenka Hribar, Gabriele Janzen, Juliane Kaminski, Patricia Kanngiesser, Fumihiro Kano, Katharina C Kirchhofer, Hagen Knofe, Kathrin S Kopp, Christopher Krupenye, Isabelle Barbara Laumer, Stephen C Levinson, Ulf Liszkowski, Héctor M Manrique, Gema Martin-Ordas, Emma Suvi Mcewen, Richard T Moore, Enric Munar, Marcos Nadal, Christian Nawroth, Suska Nolte, Marie Pelé, Patrizia Potì, Hannes Rakoczy, Julia Riedel, Amélie Romain, Federico Rossano, Yvan I Russell, Gloria Sabbatini, Marie Schäfer, Marina Scheumann, Martin Schmelz, Benjamin Schmid, Vanesa Schmitt, Carla Sebastián-Enesco, Amanda Madeleine Seed, Chikako Suda-King, Tibor Tauzin, Sebastian Tempelmann, Claudio Tennie, Valentina Truppa, Jana Uher, Amrisha Vaish, Edwin J C Van Leeuwen, Elisabetta M Visalberghi, Christoph J Völter, Victoria Vonau, Claudia A F Wascher, Roman M Wittig, Wouter Wolf, Michael Tomasello, Katja Liebal, Josep Call, Daniel B M Haun

Faculty, Staff and Students Publications

The study of great ape cognition offers insights into the evolutionary origins of human intelligence, but is hindered by small sample sizes and restricted access to data. To address this, we present the EVApeCognition Dataset, a publicly available resource comprising 262 experimental datasets from 150 scientific publications from the Wolfgang Köhler Primate Research Center (2004-2021) in Leipzig, Germany. Eighty-one apes participated in 150 studies, with a majority (N = 78) participating in more than one study. Publication of the dataset aims to make these unique datasets accessible for future meta-analyses and correlational analyses, helping us better understand how our great …

Correction: Exploiting Prmt5 As A Target For Combination Therapy In Mantle Cell Lymphoma Characterized By Frequent Atm And Tp53 Mutations, Yuxuan Che, Yang Liu, Yixin Yao, Holly A Hill, Yijing Li, Qingsong Cai, Fangfang Yan, Preetesh Jain, Wei Wang, Lixin Rui, Michael Wang

Faculty, Staff and Student Publications

No abstract provided.

An Artificial Intelligence Optimized Hepatic Differentiation Unveils Nr5a2 And Ap-1 Transcriptional Regulation In Hepatic Maturation, Zijun Huo, Jian Tu, Wei-Lei Yang, Mo-Fan Huang, Ruoyu Wang, Chih-Wei Chu, An Xu, Yao Yu, Tara N Tavakol, Mikal Kizilbash, Megan E Fisher, Yu-Wen Huang, Dandan Zhu, Trinh T T Phan, Rachel Shoemaker, Ya-Wen Chen, Yang Zhang, Chad D Huff, Shih-Yu Chen, Tien-Jen Liu, Haipeng Xiao, Dung-Fang Lee, Ruiying Zhao

Faculty, Staff and Student Publications

The generation of hepatocyte-like cells (HLCs) from human pluripotent stem cells (hPSCs) holds great promise for drug discovery and cell-based therapy for liver disease. However, current differentiation protocols are complicated and unstable, and the underlying gene regulatory mechanisms of hepatic differentiation remain incompletely defined. Here, we developed a machine learning-based artificial intelligence (AI) tool using phase-contrast images of hepatic progenitor cells (HPCs), which are essential for generating HLCs. The AI tool significantly improves the success rate of hepatic differentiation without the need for immunostaining or lineage tracing. By optimizing the methodology, we achieved an impressive purity of 90-95% for HLCs …

The Effects Of Orexin Receptor Antagonism During Early Withdrawal In Stimulant Use Disorder: Protocol For A Proof-Of-Concept Study, Heather Webber, Nikky Tran, Rita Blake, Sarah Goldman, Trevor George, Bill Bailey, Robert Suchting, Jin Yoon, Jessica Vincent, Michael Weaver, Joy Schmitz, Scott Lane

Faculty, Staff and Student Publications

Background: Stimulant use disorders (StimUDs), including cocaine and methamphetamine use disorders, remain a major public health concern in the United States with no US Food and Drug Administration (FDA)-approved pharmacological treatments. The early recovery period following stimulant use is marked by sleep disturbances, heightened stress reactivity, and dysregulated reward processing, contributing to high rates of resumption of use. Evidence from animal and human studies supports the orexin neuropeptide system as a promising therapeutic target for minimizing these disruptive mechanisms. Suvorexant, an FDA-approved dual orexin receptor antagonist for insomnia, has previously been shown to improve sleep, reduce stress, and attenuate craving …

Overlapping Mhc Class I/Ii Epitopes Program Cdc1-Like Differentiation Of Monocyte-Derived Dendritic Cells Via Mtorc1 Signaling Inhibition, S B Amanya, A Murthy, N Bisht, Z N Bullock, K J Ernste, J Vasquez-Perez, W Liu, A Trivedi, D Oyewole-Said, A Paul, L Umokoro, V Akhanov, M Samuel, Z Shi, M H Nguyen, S Huang, M Jeong, P Iakova, K A Jain, K Pham, D C Kraushaar, V Konduri, W K Decker

Faculty, Staff and Students Publications

Viral infection polarizes monocyte-derived dendritic cells (moDC) to initiate type 1 immunity. The availability of overlapping (homologous) MHC class I and II epitopes, an occurrence frequently and primarily associated with intracellular infection, significantly enhances this process; however, the underlying mechanism(s) are unclear. We demonstrate that moDC loaded with homologous MHC epitopes acquire a cDC1-like phenotype in a process governed by mTORC1. mTORC1 pathway inhibition leads to NF-κB-mediated expression of IL-12 and other type I immune polarizing genes. The observed cDC1-like gene signature was also significantly enhanced in clinical moDC vaccine products made through methodologies that enforced class I and II …

Clingen Api Platform For Classification Of Human Genetic Variants, Neethu Shah, Tierra Farris, Arturo Alejandro Zuniga, Andrew R Jackson, Jessie Arce, Kevin Riehle, Christine G Preston, Mark E Mandell, Bryan Wulf, Gloria Cheung, Keyang Yu, Deborah I Ritter, Dubravka Jevtic, Miroslav Milinkov, Novak Martinovic, Nevena Vucinic, Aleksandar Mihajlovic, Alan F Rubin, Melissa S Cline, Marina Distefano, Malachi Griffith, Obi L Griffith, Matt W Wright, Teri E Klein, Sharon E Plon, Aleksandar Milosavljevic

Faculty, Staff and Students Publications

In this commentary, we describe how the Clinical Genome Resource's (ClinGen's) application programming interface-based microservices accelerate growth and dissemination of knowledge about human genetic variation. By exposing findable, accessible, interoperable, reusable, and AI-ready variant data, ClinGen lays a foundation for next-generation software applications, AI systems, and variant classification workflows.

Protocol For Inducing Focal Striatal Stroke In Mice Using Photothrombosis, Bridget R. Boyle, Eileen Collyer, Andrea P. Berghella, Elena Blanco-Suarez

Department of Neuroscience Faculty Papers

Here, we present a protocol for inducing focal striatal stroke in mice using photothrombosis. We describe steps for photothrombotic striatal surgery, magnetic resonance imaging, open field behavioral assessment of stroke-induced motor deficits, and post-stroke monitoring. We then detail procedures for tissue collection and immunofluorescence. This protocol provides a standardized approach for consistently modeling striatal stroke in mice, enabling mechanistic studies and preclinical therapeutic testing.

Developing Endpoints For The Cardiac Burden In Myotonic Dystrophy Type 1: A Workshop Report, Julia M Hartman, Samuel Carrell, William J Groh, Thomas A Cooper, Jordana Kron, Greg Hundley, Jennifer Jordan, Amy Ladd, Man Hung, Nicholas E Johnson

Faculty, Staff and Students Publications

Cardiac disease is a well-established manifestation of myotonic dystrophy type 1 (DM1), characterized by progressive cardiac conduction slowing with increased risk of atrial and ventricular arrhythmias, heart block, and sudden cardiac death. Multiple disease modifying therapies are in clinical trials for DM1 and show promise in improving skeletal muscle weakness and myotonia. Testing the effects of these medicines, or others, in the heart is of critical importance, but requires identification of endpoints of cardiac function that accurately reflect the state of DM1 cardiac disease. To better define cardiac endpoints, the Myotonic Dystrophy Clinical Research Network (DMCRN) and the Myotonic Dystrophy …

Versatile Smad2 And Smad3 Epitope-Tagged Mouse Models For Genomic Profiling Of Tgfβ Signaling: Uncovering Gdf9-Smad2/3 Targets, Zian Liao, Qian Zhang, Keisuke Shimada, Kaori Nozawa, Suni Tang, Masahito Ikawa, Diana Monsivais, Martin M Matzuk

Faculty, Staff and Students Publications

Transforming growth factor β (TGFβ) signaling pathways are integral for a plethora of biological processes. SMAD2 and SMAD3 are the principal transcriptional effectors of TGFβ superfamily ligands, yet quantitative, genome-wide mapping of their DNA-associated complexes under physiological contexts has remained limited due to the lack of specific, robust models. Here, we generated two versatile epitope-tagged mouse models in which endogenous SMAD2 and SMAD3 proteins are globally tagged with hemagglutinin (HA) and podoplanin (PA) sequences, respectively, enabling high-fidelity profiling of SMAD2 and SMAD3 binding across tissues. To demonstrate the broad application of our models, we exemplified the usage of our lines …

Multi-Organ Physiologic Deficits During Exercise Identify Clinical And Molecular Predisposition To Heart Failure With Preserved Ejection Fraction, Isabela Landsteiner, Lindsey K Stolze, Tess E Peterson, Andrew Perry, Phillip Lin, Quanhu Sheng, Shilin Zhao, Kaushik Amancherla, Michael Y Mi, Takenori Ikoma, Laura P Cohen, Ilya Giverts, Joseph Campain, Joao A C Lima, Wendy S Post, Kent D Taylor, Robert Gerszten, Stephen S Rich, Russell Tracy, Peter Durda, Alexis C Wood, Rajeev Malhotra, Jerome I Rotter, Clary Clish, Matthew Nayor, Eric R Gamazon, Ravi V Shah, Gregory D Lewis

Faculty, Staff and Students Publications

Background: Exercise unmasks limitations in multi-organ system reserve capacity characteristic of heart failure with preserved ejection fraction (HFpEF). However, the metabolic and genetic underpinnings of exercise deficits, and their cumulative contribution to HFpEF severity and prognosis, remain incompletely understood.

Methods: We used invasive cardiopulmonary exercise testing (iCPET), metabolite profiling, and genomics to simultaneously characterize seven exercise physiologic deficits in HFpEF patients: reduced exercise stroke volume and heart rate, steep pulmonary capillary wedge pressure/cardiac output (PCWP/CO) slope, elevated pulmonary vascular resistance, pulmonary mechanical limitation to exercise, impaired peripheral oxygen extraction, and obesity-related exaggerated metabolic cost of initiating exercise. We first mapped …

Structure-Preserving Multivariate Hypothesis Testing For Mass Spectrometry Imaging And Single-Cell Data, Keziah E Liebenberg, Erin Craig, Robert Tibshirani, Livia S Eberlin

Faculty, Staff and Students Publications

Motivation: Mass spectrometry imaging (MSI) and single-cell RNA sequencing (scRNA-seq) offer high-resolution views into tissue and cellular heterogeneity. However, conventional statistical analyses often treat sub-measurements (pixels or cells) as independent, ignoring their nested origin from individual samples. This assumption inflates the effective sample size, increases false discoveries, and undermines biological interpretation. Pixel- or cell-level averaging avoids this but sacrifices spatial or cellular resolution.

Results: We evaluated block-SAM on both simulated and real-world datasets. In DESI-MSI data from kidney, lung, and ovarian tumors, block-SAM consistently identified fewer-but more reliable-differential features compared to traditional-SAM. For example, in the kidney dataset, traditional-SAM identified …