Digital Commons Network^™

Cholecalciferol (Vitamin D3) Is An Agonist Of The Alzheimer's Disease-Associated Immune Receptor Trem2, Hunter B Dean, Ryan A Tuckey, Rory A Greer, Jessica A Greven, Shan-Zhong Yang, Daniel S Elston, Gunnar N Eastep, Yuwei Song, Thomas J Brett, Yuhua Song, Erik D Roberson

2020-Current year OA Pubs

Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is one of the strongest genetic risk factors for late-onset Alzheimer's disease (AD). Several TREM2 ligands are known, including charged lipids and AD-associated proteins like apolipoprotein E and amyloid-β, but the full range of endogenous ligands for TREM2 remains unknown. Here we combined virtual screening of the Human Metabolome Database with molecular dynamics simulations, binding free energy estimation, and biolayer interferometry to identify novel TREM2 ligands and map their binding sites. Cholecalciferol, the unmodified parent form of vitamin D3, emerged as a top candidate. Structural modeling indicated that cholecalciferol binds TREM2 at …

Astrocyte-Specific Deletion Of Lrrc8a Causes Neurological Dysfunction But Not Chronic White Matter Edema, Sven Kerst, Leoni Hoogterp, Marjolein Breur, Gemma M Van Rooijen-Van Leeuwen, Marianna Bugiani, Rajan Sah, Huibert D Mansvelder, Marjo S Van Der Knaap, Rogier Min

2020-Current year OA Pubs

Volume-regulated anion channels (VRACs) are central to cell volume homeostasis. They mediate swelling-induced efflux of chloride and organic osmolytes to drive regulatory volume decrease. In the brain, VRACs have been proposed to play a key role in astrocytic volume regulation. Genetic defects in astrocytic VRAC modulating proteins (MLC1, GlialCAM, Aquaporin-4, GPRC5B) cause the leukodystrophy Megalencephalic leukoencephalopathy with subcortical cysts (MLC), characterized by chronic white matter edema and myelin vacuolization. Disrupted VRAC activity in MLC-patient-derived lymphoblasts and primary astrocytes from MLC mice further supports a pathogenic link between defective VRAC activity and MLC. Here, we studied the physiological and pathological consequences …

Omni: A Modular Open-Source Framework For Interactive Multi-Omics Data Integration And Visualization., Grace Potter, Jacob A Beierle, Camron Bryant, Sadhna Phanse, Carl White, Andrew Emili, Indranil Paul

Faculty Research 2026

Omics Notebook Interactive (OmNI) is an R-based, open-source, and modular framework engineered for streamlined multi-omics data inte- gration and analysis across diverse data types, incorporating interactive visualizations at each processing step. OmNI performs differential expression analysis utilizing customizable linear models, accommodating various covariates and complex experimental designs. For cross- omic layer integration, OmNI employs a modified S-score statistic, ensuring sensitive detection of differential features. The framework also integrates network and metabolomics data, offering detailed insights into regulatory mechanisms through comprehensive enrichment analy- sis using multiple pathway databases. Outputs include interactive HTML reports, CSV/TSV files, and Cytoscape-compatible objects. OmNI is readily …

Aging Reduces Motivation Through Decreased Bdnf Expression In The Ventral Tegmental Area, Hanyue Cecilia Lei, Kyle E Parker, Chao-Cheng Kuo, Carla M Yuede, Jordan G Mccall, Shin-Ichiro Imai

2020-Current year OA Pubs

Age-associated reduced motivation is a hallmark of neuropsychiatric disorders in the elderly. In our rapidly aging societies, it is critical to keep motivation levels high enough to promote healthspan and lifespan. However, how motivation is reduced during aging remains unknown. Here, we used multiple mouse models to evaluate motivation and related affective states in young and old mice. We also compared the effect of social isolation, a common stressor in aged populations, to those of aging. We found that both social isolation and aging decreased motivation in mice, but that Bdnf expression in the ventral tegmental area (VTA) was selectively …

Bach2 Regulates T Cell Lineage State To Enhance Car T Cell Function, Tien-Ching Chang, Amanda Heard, John Lattin, John M Warrington, Amanda Barrett, Jack H Landmann, Yangdon Tenzin, Vishaal Ganesh, Bryant Thompson, Sadia Afrin, Deepesh Kumar Gupta, Ju-Fang Chang, Julie Ritchey, Mehmet Emrah Selli, Yu-Sung Hsu, A J Federico, Avery Horn, Michael P Meers, John F Dipersio, Nathan Singh, Et Al.

2020-Current year OA Pubs

Nearly all chimeric antigen receptors (CARs) signal in the absence of antigen, referred to as 'tonic signaling'. Tonic signaling of CARs containing 41BB domains enhances T cell fitness and function, in contrast to the exhaustion driven by CD28-containing CARs. Here we show that 41BB induces BACH2, a transcriptional regulator that directs stem and memory programs. Overexpression of BACH2 successfully prevented exhaustion but locked CAR T cells in a quiescent state. We linked BACH2 to a degradation domain to tune BACH2, enabling us to prevent exhaustion while enabling potent effector function that broadly enhanced the long-term efficacy of CAR T cells …

Cdk4/6 Inhibition Mitigates Chemotherapy-Induced Expansion Of Tp53-Mutant Clonal Hematopoiesis, Irenaeus C C Chan, Giulia Petrone, J Scott Beeler, Duc Tran, Griffen Mustion, Catrina Fronick, Carlos Cruchaga, Kelly L Bolton, Et Al.

2020-Current year OA Pubs

Therapy-related myeloid neoplasm (tMN) is a fatal consequence of exposure to cytotoxic therapy administered in the treatment of cancer. Individuals with pre-existing TP53 clonal hematopoiesis (CH) are at high risk of tMN, with avoidance of therapy being the only strategy to reduce tMN risk. Here, in four randomized clinical trials, we show that the CDK4/6 inhibitor trilaciclib, given in conjunction with a variety of chemotherapeutic regimens and across diverse populations of patients with cancer, mitigates chemotherapy-related expansion of CH clones with mutations in DNA damage response genes, including TP53. This finding was also observed in a syngeneic mouse model of …

Signal Peptidase Complex Mediates Rotavirus Vp7 Processing And Virion Assembly, Xuejiao Zhu, Enkai Li, Liliana Sanchez-Tacuba, Wandy Beatty, Bin Li, Siyuan Ding

2020-Current year OA Pubs

For viruses that replicate in the proximity of or bud at the endoplasmic reticulum (ER) associated membranes, proper processing of their glycoproteins is critical for successful infection. Rotavirus outer capsid protein VP7 is an ER-resident protein. However, its N-terminal signal peptide is removed by an unknown proteolytic mechanism. In this study, we leveraged tandem affinity purification followed by high-resolution mass spectrometry to profile host proteins that interact with VP7. We identified members of the signal peptidase complex (SPC) family as important host factors that facilitate rotavirus infection. CRISPR knockout or siRNA knockdown of distinct SPC subunits resulted in significant decrease …

Synovial Fibroblast Responses To Different Types Of Injury Resulting In Cartilage Repair Or Osteoarthritis, Fraser L Collins, Alexander J Knights, Tristan Maerz, Anke J Roelofs, Cosimo De Bari

2020-Current year OA Pubs

OBJECTIVE: Single-cell RNA-sequencing (scRNA-seq) has advanced our understanding of the heterogeneity of synovial fibroblasts and their roles in tissue repair and osteoarthritis. Here, we compared the fibroblast responses to different types and duration of joint injury in mice.

DESIGN: Published scRNA-seq data of synovial fibroblasts from a model of joint surface injury (JSI, day 6) and two post-traumatic osteoarthritis models, destabilisation of the medial meniscus (DMM, day 7 and 2 months) and anterior cruciate ligament rupture (ACLR, day 7 and day 28), were integrated and analysed using clustering, DEG, gene-set enrichment, regulon, pseudotime trajectory and cell-cycle analyses.

RESULTS: The response …

Diversity And Immune Dynamics Of Choroid Plexus Macrophages Are Shaped By Distinct Developmental Origins, Siling Du, Khai M Nguyen, Alina Ulezko Antonova, Jose L Fachi, Patrick Fernandes Rodrigues, Alice Verdiani, Martina Molgora, Igor Smirnov, Jasmin Herz, Tornike Mamuladze, Jennifer Ponce, Amanda Swain, Mattia Bugatti, Susan Gilfillan, Marina Cella, William Vermi, Jonathan Kipnis, Marco Colonna, Simone Brioschi

The Brown Foundation: Institute of Molecular Medicine

The choroid plexus forms a key barrier and signaling interface between the brain and peripheral circulation, yet its immune landscape remains incompletely understood. Using single-cell transcriptomics combined with lineage and spatial tracing methods, we identified three biologically distinct populations of choroid plexus macrophages, defined by differential expression of CD163, MHCII or CD9. These subsets arise from separate hematopoietic waves, occupy distinct anatomical niches and differentially rely on CSF1 and IL-34 for survival. We found that TGFβ signaling is essential to maintain their tissue-specific identities, and deletion of Tgfbr2 in these cells induces broad phenotypic reprogramming. During neuroinflammation, choroid plexus macrophages …

Glutamatergic Dysfunction Of Astrocytes In Paraventricular Nucleus Of Thalamus Contributes To Adult Anxiety Susceptibility In Adolescent Ethanol Exposed Mice, Aubrey Bennett, Hyunjung Kim, David Thomas, Peter Biggs, Roxan Ara, Asamoah Bosomtwi, Seungwoo Kang

The Brown Foundation: Institute of Molecular Medicine

Repeated ethanol exposure during adolescence increases adult anxiety risk, but the underlying mechanisms remain unclear. The paraventricular nucleus of the thalamus (PVT) has been considered a hub for controlling anxiety and is affected by experiences from early life. Thus, this study investigated how adolescent intermittent repeated ethanol exposure (AIE) affects the PVT activities and anxiety-related behaviors in adulthood. We found that AIE triggers anxiety-like behaviors and parallelly exhibited elevated firing rates and increased calcium signaling in the PVT neurons compared to control counterpart mice. Chemogenetic inhibition of PVT neurons reduced anxiety-like behaviors in AIE-treated animals, confirming PVT's role in adolescent …

Lipids Grease The Chain Of Cancer Progression, Joseph Rupert, Pham Hong Anh Cao, Daniel E Frigo, Mikhail G Kolonin

The Brown Foundation: Institute of Molecular Medicine

The role of lipids in cancer progression has become a fervent area of exploration. The crosstalk of tumors with adipose tissue is a complex but well-regulated orchestration of signaling pathways, lipid transporters, and enzymes. They regulate fatty acid synthesis, their deposition into lipid droplets (LDs) as triglycerides, induction of lipolysis, shuttling lipids across cells, and their systemic trafficking, modification, and catabolism. For the latter, lipid oxidation has emerged as a metabolic process of particular clinical importance. Products of lipid processing can become secondary messengers, contribute to reactive oxygen species (ROS) generation, stimulate the production of antioxidants, and, if left unchecked, …

Pharmacokinetic Modeling Strategies For Dynamic Hyperpolarized Urea Imaging, Keith A Michel, Collin J Harlan, Christopher M Walker, Matthew E Merritt, Yunyun Chen, Stephen Y Lai, James A Bankson

Faculty, Staff and Student Publications

Purpose: To evaluate pharmacokinetic modeling methods for quantification of tissue perfusion/permeability with hyperpolarized 13C urea.

Methods: Three models for quantitative analysis of dynamic HP urea imaging data were proposed and evaluated in numerical simulations and a thyroid cancer mouse model. A multicompartment model resembling the extended Tofts model for DCE-MRI (Model I) and two simplified models were used. The simplified models each eliminate a volume parameter representing vascular (Model II) or impermeable cellular space (Model III). Signal curves were generated from Model I, and models were fit to these synthetic data to quantify the effects of acquisition settings, bias in …

Shiga Toxin Increases Intestinal Transit To Displace Resident Microbes And Facilitate Pathogen Colonization, Max A Odem, Sabona B Simbassa, Cecilia Fadhel Alvarez, Oliyad Jeilu, Shelby R Simar, Rachel Bosserman, Soumita Dutta, Walter Galdamez, Hossaena Ayele, Blake M Hanson, Diana M Proctor, Anne Marie Krachler

Faculty, Staff and Student Publications

Shiga toxin (Stx)-producing Escherichia coli (STEC) is a major cause of food-borne illnesses, and disease severity correlates with the production of Shiga toxins. While clinical symptoms such as bloody diarrhea and hemolytic uremic syndrome have been attributed to Stx, its contribution to bacterial fitness is not well understood. Here, we demonstrate that Stx2 enhances STEC colonization of the zebrafish gut by facilitating the partial displacement of gut resident microbes. Infection with Stx2-producing STEC strains or direct exposure of fish to purified Stx2 induces alterations in the zebrafish microbiome structure, impacting several bacterial phyla and genera, notably Pseudomonads. We show that …

Alpha 7 Nicotinic Acetylcholine Receptor Contributes To Long-Term Cognitive Recovery Following Ischemic Stroke, Dustin T Nguyen, Kate Mendoza, Cassandra Hall, Chunfeng Tan, Anjali Chauhan

Faculty, Staff and Student Publications

Stroke is associated with autonomic dysfunction and reduced acetylcholine (ACh), a neurotransmitter critical for cognition. ACh signals in part through the alpha-7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated ion channel involved in synaptic plasticity, learning, and memory. Impaired α7nAChR signaling has been linked to heightened neuroinflammation and poor acute stroke recovery. Here, we investigated whether α7nAChR contributes to post-stroke cognitive recovery in young male mice. Wild-type (WT) and α7nAChR knockout (α7n0KO) mice underwent 60-min middle cerebral artery occlusion (MCAO). In a pharmacology cohort, the α7nAChR agonist GTS-21 was administered immediately after reperfusion and then daily for 20 days. Cognitive performance …

Beyond Short Microhomologies: Mismatch-Compatible Pol Θ-Mediated Dna Damage Repair, Yuzhen Li, Richard D Wood

Faculty, Staff and Student Publications

DNA polymerase θ (Pol θ)-mediated end-joining (TMEJ), one of several pathways for repairing DNA double-strand breaks, is traditionally thought to initiate via anchoring at short, consecutive, and perfectly matched microhomologies (MHs). Emerging evidence indicates that Pol θ can utilize MHs containing mismatches both in vitro and in vivo. This revised definition of MH provides a mechanistic explanation for a broader spectrum of Pol θ-dependent repair outcomes. Here, we summarize recent findings on the revised definition of MHs utilized by Pol θ, assess the applicability of this concept across species, and compare TMEJ with other (micro)hom(e)ology-mediated repair pathways. We explore how …

Selective Deletion Of Fgfr1 In Agrp Neurons Impairs Energy Homeostasis Under High-Fat Diet In Mice, Daniel Shookster, Shea O'Connell, Patel Darshan, Taylor Landry, Wyatt Bunner, Zhiying Jiang, Qingchun Tong, Hu Huang

Faculty, Staff and Student Publications

Background: The global obesity crisis and the limited success of current treatments underscore the need to identify novel regulatory pathways. While central administration of α-Klotho exerts anti-obesity effects in rodents through AgRP neurons, the intracellular signaling mechanisms that mediate this process remain undefined.

Methods: To define the role of FGFR1 within the α-Klotho signaling pathway in AgRP neurons, we performed a targeted deletion of the receptor in adult mice using an AAV-mediated CRISPR/Cas9 system alongside transgenic models.

Results: Deletion of FGFR1 in AgRP neurons disrupted energy homeostasis, promoting weight gain induced by a high-fat diet. Electrophysiological recordings revealed that FGFR1 …

Cd44v9 As A Therapeutic Target For Antibody-Drug Conjugate In Advanced Breast Cancer, Dileep R Reddy, Mckenna E Flynn, Yasuaki Anami, Zhaoxuan Yang, Jayden Aleman, Minji Seo, Kyoji Tsuchikama, Jennifer A Maynard, Naoto T Ueno, Jangsoon Lee

Faculty, Staff and Student Publications

Antibody-drug conjugates (ADCs) have revolutionized breast cancer therapy. HER2 is the only validated biomarker guiding ADC therapy in breast cancer. However, their clinical benefit remains confined to HER2- and TROP2-targeted therapies. Tumor heterogeneity and acquired resistance often limit durable responses, underscoring the need for novel, tumor-specific ADC targets. CD44 variant isoform 9 (CD44v9), a splice variant of the CD44 family, is largely absent in normal tissues but enriched in aggressive breast cancers, where it contributes to stemness, redox regulation, and therapy resistance. In this study, we developed a chimeric monoclonal antibody against CD44v9 (clone SUM24.1, IgG1) and conjugated it to …

Fgl2-Knockout Tumor Cells Serve As A Vaccine Inducing Long-Duration Brain-Resident Memory T Cells That Reject Subsequent Intracranial Tumor Cell Challenges, Sheng Zhang, Yining Jin, Zhiliang Jia, Xueqing Xia, Yang Li, Qi Wang, Jing Wang, Jian Wang, Joya Chandra, Gregory K Friedman, Shulin Li

Faculty, Staff and Student Publications

The failure to prevent brain tumors, including both recurrent primary and metastatic brain tumors, is the primary cause of patients' mortality. We developed a novel whole tumor-cell vaccine to rapidly induce long-duration brain-resident memory T (TRM) cells that prevent brain tumor progression. Ten Fgl2-KO primary and metastatic tumor cell lines, generated via CRISPR/Cas9, were used to vaccinate mice and for intracranial challenges with the WT tumor cells. Not only did vaccinated mice reject these tumor cell challenges, but also more than half of these mice became long-duration survivors. Transplanting brain immune cells from vaccinated mice into naïve mice enabled this …

Histone Demethylase Jmjd1a Protects Mice From Enteric Bacterial Infection By Upregulating Ccl8 Expression To Recruit Macrophages And Cd4+ T Cells, Guifang Lin, Lichun Yang, Shuyan Jiang, Yong Zhang, Ping Luo, Weihua Li, Jianming Xu, Gongpeng Xiong, Chundong Yu, Wenbo Chen

Faculty, Staff and Students Publications

Jumonji domain-containing 1A (JMJD1A, also known as KDM3A) is a histone demethylase that specifically demethylates H3K9me1/2 to enhance gene expression. The roles of JMJD1A in many physiological and pathological processes have been revealed. However, it is unclear whether JMJD1A is involved in host defense against enteric pathogen infection. In this study, we found that enteric infection with C. rodentium induced JMJD1A expression in colonic epithelial cells at the transcriptional level partly mediated by IRF1. After C. rodentium infection, JMJD1A-/- mice exhibited increased mortality, colonic injury, and C. rodentium load and systemic spread, suggesting that JMJD1A protects host against C. rodentium …

Influence Of Exercise Training On Nitric Oxide Pathways And Their Physiological Effects, Jonas Benjamim, Stephen J Bailey, Leonardo Da Silva Gonçalves, Mia Burleigh, Mario Siervo, Andrew R Coggan, Raúl Bescos

School of Health Professions

Nitric oxide (NO) is a critical signalling molecule in cardiovascular, metabolic, and muscular function. Endogenous NO production occurs via two primary metabolic pathways: 1) the classical nitric oxide synthases (NOS) pathway, and 2) the alternative (nitrate-nitrite-NO) pathway, in which inorganic nitrate (NO 3 -) is sequentially reduced to nitrite (NO 2 -) and other NO intermediates (e.g., S-nitrosothiol). The latter pathway relies heavily on the oral microbiota, which catalyze the two-electron partial reduction of NO 3 - to NO 2 -, which is influenced by oral physiology, microbial composition and salivary flow. While the role of exercise training in enhancing …

Spatial Profiling Reveals Distinct Molecular And Immune Evolution Of Mouse Lung Adenocarcinoma Precancers With Or Without Carcinogen Exposure, Bo Zhu, Muhammad Aminu, Pingjun Chen, Jian-Rong Li, Chuanpeng Dong, Chenyang Li, Yanhua Tian, Shao-Wei Lu, Hong Chen, Chenxi Ma, Xin Hu, Jie Ye, Andrew Y Liu, Beibei Huang, Frank R Rojas, Parra Cuentas Edwin Roger, Ou Shi, Monique B Nilsson, Alissa Poteete, Khaja B Khan, Wei Lu, Luisa M Solis Soto, Junya Fujimoto, Cara Haymaker, Ignacio I Wistuba, Zhubo Wei, Linghua Wang, Don L Gibbons, Ken Chen, Alexandre Reuben, Jason M Schenkel, John V Heymach, Chao Cheng, Jia Wu, Jianjun Zhang

Faculty, Staff and Student Publications

Tumor evolution involves genetic, transcriptional, and phenotypic alterations that shape cancer cell behavior and interactions with the microenvironment. While single‐cell technologies have advanced our understanding of this process, spatial dynamics remain incompletely characterized. Here, whole‐exome sequencing (WES), imaging mass cytometry (IMC), and spatial transcriptomics (ST) were integrated to study molecular evolution and immune responses in two lung adenocarcinoma (LUAD) mouse models: a genetically engineered model (129S4/Sv‐KrasLSL‐G12D, termed 129S4 K) and a carcinogen‐induced precancer model (129S4 U). Compared to 129S4 K, 129S4 U tumors exhibited higher mutational, neoantigen but lower copy number variation (CNV) burdens at matched developmental timepoints, consistent with …

The Evolving Therapeutic Landscape Of Pcsk9 Inhibition, Brett S Mansfield, Yakubu Bene-Alhasan, Christie M Ballantyne, Frederick J Raal

Faculty, Staff and Students Publications

Cardiovascular disease remains the leading cause of death worldwide with low density lipoprotein being a major, yet modifiable, risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a central role in regulating low density lipoprotein (LDL) receptor expression. Naturally occurring loss-of-function variants in the PCSK9 gene result in lifelong lower LDL cholesterol (LDL-C) levels and significantly lower risk of atherosclerotic cardiovascular disease (ASCVD), providing strong genetic validation of PCSK9 as a therapeutic target. This insight has driven the development of therapies directed at PCSK9 for the management of hypercholesterolaemia, particularly in patients who fail to meet LDL-C targets despite maximally …

Toward Scientific Rigor: Setting Standards For Indirect Calorimetry Analysis And Reporting, Elizabeth L Lieu, Mark A Herman, Sean M Hartig

Faculty, Staff and Students Publications

Indirect calorimetry determines energy expenditure by measuring respiratory gas exchange. The approach is based on the principle that nutrient metabolism consumes O2 and produces CO2 and water in predictable ratios that can be compared with heat production. Due to the impracticality and high cost of direct calorimetry, indirect calorimetry is the major approach for modern metabolic studies in preclinical models. Despite the broad adoption of this method in rodent phenotyping, the field has lacked standardized methods for analyzing, representing, and sharing these data, limiting scientific progress. The recent review in Nature Metabolism by the International Indirect Calorimetry Consensus Committee (IICCC) …

Distributed Battery-Free Bioelectronic Implants With Improved Network Power Transfer Efficiency Via Magnetoelectrics, Joshua E Woods, Fatima Alrashdan, Ellie C Chen, Wendy Tan, Mathews John, Lukas Jaworski, Drew Bernard, Allison Post, Angel Moctezuma-Ramirez, Abdelmotagaly Elgalad, Alexander G Steele, Sean M Barber, Philip J Horner, Amir H Faraji, Dimitry G Sayenko, Mehdi Razavi, Jacob T Robinson

Faculty, Staff and Students Publications

Networks of miniature implants could enable simultaneous sensing and stimulation at different locations in the body, such as the heart and central or peripheral nervous system. This capability would support precise disease tracking and treatment or enable prosthetic technologies with many degrees of freedom. However, wireless power and data transfer are often inefficient through biological tissues, particularly as the number of implanted devices increases. Here we show that magnetoelectric wireless data and power transfer supports a network of millimetre-sized bioelectronic implants in which system efficiency improves with additional devices. We demonstrate wireless, battery-free networks ranging from one to six implants, …

Rab4 Spatially And Functionally Converges With Rab7 In The Degradative Endolysosomal Network, Stephen M Farmer, Shiyu Xu, Yue Yu, Xin Ye, Haoyi Yang, Jing Cai, Beatriz Rios, Wen-Wen Lin, Daniela Covarrubias, Vicky Chuong, Lili Ye, German Zylberberg, Charissa Wang, Erin Furr-Stimming, Qingchun Tong, Oguz Kanca, Hugo J Bellen, Travis I Moore, Sheng Zhang

Faculty, Staff and Students Publications

Rab GTPases are key regulators of endosomal trafficking in eukaryotes. In mammalian cells, Rab4 and Rab7 were shown to localize to distinct compartments, with Rab4 on early endosomes for fast recycling and Rab7 on late endosomes for degradation. Here, we show that in Drosophila, endogenous Rab4 and Rab7 extensively colocalize across tissues and developmental stages. Recruited to the same compartments through mechanisms that do not require the activity of the other, they have opposing effects on endolysosomal size: Rab4 overexpression or Rab7 impairment leads to enlarged endolysosomes, whereas Rab4 loss or constitutively active Rab7 reduces their sizes. Rab4 deficiency suppresses …

Non-Synaptic Function And Localization Of Syntaxin-Binding Protein 1 In A Mouse Model Of Stxbp1-Related Epileptic Encephalopathy, Tao Yang, Rajat Banerjee, Yamei Deng, Sheetal Jahagirdar, Joo Hyun Kim, Wu Chen, Mingshan Xue, Alexey I Nesvizhskii, Michael D Uhler, Jack M Parent, Yu Wang

Duncan NRI Faculty and Staff Publications

Objective: De novo mutations in the syntaxin-binding protein 1 (STXBP1), encoded by STXBP1, are among the most prevalent causes of variable neurodevelopmental disorders, including epileptic encephalopathy, developmental delay, and movement disorders. Although STXBP1 has been proposed as a critical presynaptic protein controlling synaptic vesicle exocytosis, clinical phenotypes also suggest that its biological function could be more diverse.

Methods: The expression pattern of STXBP1 was studied using immunostaining in vitro and in vivo. Synaptosome isolation was performed to investigate the synaptic and non-synaptic localization of STXBP1 in the brain. STXBP1 immunoprecipitation followed by mass spectrometry (MS) was conducted to identify protein …

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, …

Single Zonular Fiber Extraction And Characterization: A Platform For Biomechanical, Biochemical And Structural Analyses, Riley Forinash, Sean Staggs, Steven Bassnett, Juan Rodriguez

2020-Current year OA Pubs

Zonular fibers are essential for suspending the lens within the eye and, in primates, for transmitting forces generated by the ciliary body to drive ocular accommodation. Despite their biomechanical importance, the response of these fibers to sudden strains, and the molecular basis of their exceptional durability remain poorly understood. This is due, in part, to the absence of tools for studying them in isolation. Here, we present a custom-built, cost-effective apparatus designed to isolate, manipulate, and characterize individual zonular fibers under controlled physical and chemical conditions. The apparatus enables quantification of elastic moduli, stress-relaxation behavior, Poisson's ratio, and response to …

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 …

Prenatal Stress Induces Changes In Behavior, Hpa Axis, Inflammation, And Oxidative Stress In Adult Rats Offspring, Jorge M Aguiar-Geraldo, Jefté Peper-Nascimento, José Henrique Cararo, Taise Possamai-Della, Alexandra I Zugno, Anilkumar Pillai, João Quevedo, Samira S Valvassori

Faculty, Staff and Student Publications

Prenatal stress is related to the development of psychiatric disorders involving inflammation, oxidative stress, and hypothalamic-pituitary-adrenal (HPA) axis. Therefore, the aim of the present study was to evaluate the effects of prenatal stress on behavior, inflammation, oxidative stress, and the HPA-axis in the dams and their offspring treated with lithium. Thirteen pregnant Wistar rats were exposed to a prenatal chronic unpredictable stress protocol from the 14th day of gestation until birth. At the 60th postnatal day (PND), a treatment protocol was carried out in the offspring with lithium (intraperitoneally - 47.5 mg/kg) or saline for seven days (twice a day). …