Medical Molecular Biology Commons^™

Calcium Signaling And Postsynaptic Density Dynamics: The Roles Of Calmodulin In Synaptic Protein Regulation, Keyaa Dilip Shah, Yonghong Zhang

School of Integrative Biological & Chemical Sciences Faculty Publications

Calcium signaling in neuronal cells is the principal mechanism underlying learning and synaptic plasticity, whereas the postsynaptic density (PSD) is an important center where calcium-dependent processes are organized and regulated. This review explores the roles of calmodulin (CaM) in facilitating calcium-dependent modulation of the activities of synaptic proteins in the PSD. We focus on the molecular processes through which CaM interacts with calcium signals to regulate the function, localization, and interactions of central synaptic proteins, including calcium/calmodulin-dependent protein kinase II (CaMKII), membrane-associated guanylate kinases (MAGUKs), and N-methyl-D-aspartate (NMDA) receptors. We aim to summarize recent advances in structural, biochemical, and imaging …

An Obligatory Role For Agrp Neurons In Maintaining Body Temperature During Time-Restricted Feeding, Cunjin Su, Jing Cai, Yuanzhong Xu, Benjamin R Arenkiel, Qingchun Tong

The Brown Foundation: Institute of Molecular Medicine

Homeotherms maintain a steady body temperature through thermoregulation, a process critical for survival during fasting, in which the brain has to defend energy-costly body temperature while reducing energy expenditure to conserve energy reserve; however, the neural basis for defending body temperature remains unclear. Here, we demonstrated that AgRP neuron lesion led to lethality during time-restricted feeding on chow but not on HFD, and caused no obvious impact on HFD-induced obesity or obesity-reducing responses to glucagon-like peptide-1 receptor agonism. The lesion disrupted adaptive feeding behaviors during time-restricted feeding and reduced motivational feeding on chow. Notably, the lethality was caused by hypothermia …

Selective And Differential Roles Of Pvhcrh Neurotransmitters In Diet-Induced Obesity In Mice, Zhiying Jiang, Yuhan Cao, Michelle He, Cunjin Su, Runzhou Yang, Maojie Yang, Jing Cai, Hongli Li, Yuanzhong Xu, Shi-Bin Li, Hiroshi Yamaguchi, Luis De Lecea, Benjamin R Arenkiel, Qingchun Tong

The Brown Foundation: Institute of Molecular Medicine

Stress and diet are known to synergistically promote risks of obesity but the underlying neural basis remains elusive. Corticotropin-releasing hormone neurons in the paraventricular hypothalamus (PVHCRH) are stress responsive and release both CRH and glutamate. Here we generated a mouse model with gain or loss of release in CRH or glutamate from PVHCRH neurons. While these models showed no changes in body weight when fed chow, they exhibited contrasting effects when fed high-fat high-caloric diets (HFD). Whereas disrupting glutamate release from PVHCRH neurons led to diet-induced obesity (DIO), that of CRH caused no impact. Conversely, augmented CRH release led to …

Advances In Glp-1 Receptor Agonists Delivery Systems For Obesity And Diabetes, Mehrnaz Abbasi, Kai Sun, Kevin W Huggins, Braeden Heath, Hannah Deloit, Lauren Mcginness, Kate Mccamy

The Brown Foundation: Institute of Molecular Medicine

Obesity and diabetes are chronic metabolic diseases affecting millions worldwide. Current treatments, including lifestyle changes, medications, and surgery, face challenges like poor adherence and side effects. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are recommended innovative medications for these conditions, with studies showing significant clinical benefits. GLP-1RAs are traditionally delivered orally or via subcutaneous injections, but these methods have limitations, including low bioavailability, poor solubility, the need for high doses, gastrointestinal side effects, and frequent dosing requirements. Novel delivery technologies offer promising strategies to overcome these challenges and enhance therapeutic effectiveness. Recent advances in drug delivery technologies, including nanocarrier- and microcarrier-based systems, …

Characterization Of Circulating Extracellular Proteome In Plasma Samples Of Triple-Negative Breast Cancer Patients, Brionna Wilson

Honors Theses

Extracellular vesicles (EVs) are membrane-bound vesicles secreted by cells in the body that play an important role in intercellular signaling, immune modulation, and transfer of biomolecules between cells. EV s reflect the physiological state of their cells of origin, so they are being explored as potential noninvasive biomarkers for cancer detection and monitoring. Triple-negative breast cancer (TNBC), an aggressive subtype lacking targeted therapies, is difficult to detect early and currently has no reliable prognostic biomarkers. This study aimed to quantify EV concentrations in the blood serum of TNBC patients (n=40) compared with cancer-free healthy controls (n=35) as well as determine …

Validation Of A Real-Time Pcr Laboratory Developed Test For The Detection Of Pneumocystis Jirovecii In Bronchoalveolar Lavage Samples, Caitlyn Moon

Honors Scholar Theses

Pneumocystis jirovecii is an opportunistic, host-obligate fungal pathogen responsible for causing P. jirovecii pneumonia (PJP) in humans. PJP is treated with trimethoprim-sulfamethoxazole (TMP-SMX), a strong broad-spectrum antibiotic that carries risk of renal and hepatotoxicity. Therefore, rapid diagnosis or exclusion of PJP is crucial to ensure PJP-positive patients receive effective treatment and PJP-negative patients avoid unnecessary antibiotics. Unlike most microorganisms, P. jirovecii cannot be cultured, presenting complications for the typical methods of diagnosing fungal pathogens. Historically, the gold standard for diagnosis was direct microscopic examination with stains such as methenamine silver and calcofluor white, but this diagnostic technique requires highly skilled …

The Development Of A Crispr-Based Calibrated Functional Assay For Classifying Pathogenicity Of Msh2 And Msh6 Variants In Lynch Syndrome, Olivia N. Amodeo

Honors Scholar Theses

Lynch syndrome is a hereditary disease caused by the inheritance of a mismatch repair gene variant. Individuals with this condition are predisposed to cancer development, most commonly colorectal cancer. Current guidelines for variant classification are based on numerous evidence categories, including functional evidence. However, many novel clinical variants are not well characterized, and evidence is difficult to obtain if functional assays are not calibrated.

To address this, our lab created a calibrated functional assay that calculates an odds of pathogenicity score for MSH2 and MSH6 gene variants that can be used as evidence for classifying variants of uncertain significance. This …

Platelet Gαz Regulates Ovarian Tumor Growth And Mediates The Effects Of Chronic Stress, María G. Torres Carrizalez

Dissertations and Theses (Open Access)

Ovarian cancer is the most aggressive gynecologic cancer, with 12,450 estimated deaths in 2026. Elevated platelet counts are commonly observed in patients with ovarian cancer and are associated with enhanced tumor growth and poor prognosis. Patients with ovarian cancer are frequently exposed to elevated levels of stress, which has been correlated with accelerated disease progression and increased mortality. Interestingly, the platelet Gαz protein is activated by epinephrine through the α2A-adrenergic receptor, suggesting a potential mechanistic link between stress signaling and platelet-driven tumor progression. To investigate this, I evaluated the role of platelet Gαz in ovarian cancer using control (Gz^{fl/fl …}

Inhibition Of Epac1 Prevents Neuronal Death Mediated By Diesel Exhaust Particles In Ferroptotic Cell Death Conditions, Hong Yan, Leshan Zhang, Ana L Manzano-Covarrubias, Phoeja S Gadjdjoe, Anja Land, Christina H J T M Van Der Veen, Teresa Mitchell-Garcia, Heba A Fayyaz, Marco Venema, Christoffer Åberg, Marieke Van Der Hart, Frank Lezoualc'h, Xiaodong Cheng, Amalia M Dolga, Martina Schmidt

The Brown Foundation: Institute of Molecular Medicine

Air pollution is a growing hazard to global health. Epidemiological studies have reported a potential role of air pollutant exposure in the development or aggravation of neurodegenerative diseases. However, the underlying mechanisms are ill-defined. Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of cell death that drives neuronal loss in neurodegenerative diseases. Our previous studies reported the involvement of adenosine 3',5'-cyclic monophosphate (cAMP) and EPAC (exchange protein directly activated by cAMP) in ferroptotic cell death. Here, we investigated the effects of diesel exhaust particles (DEP) in mouse hippocampal (HT22) neuronal cells. Our data showed that toxicity induced by …

Effects Of Limb Dominance On Dopaminergic Neurodegeneration In A 6-Ohda Rat Model Of Parkinson’S Disease Assessed By Immunoblotting, Jasin Aziz Porshia, Deanna Chaialee, Dipesh Pokharel, Kala Venkiteswaran, Thyagarajan Subramanian, Dilshan Beligala

ONU Student Research Colloquium

Effects of Limb Dominance on Dopaminergic Neurodegeneration in a 6-OHDA Rat Model of Parkinson’s Disease Assessed by Immunoblotting

Jasin Porshia^a , Deanna Chaialee^a , Dipesh Pokharel^b,c , Kala Venkiteswaran^{b, c, d} , Thyagarajan Subramanian^{b, c, d}, Dilshan Beligala^a

^aDepartment of Biological Sciences, Ohio Northern University, Ada, OH, USA

^bDepartment of Neurosciences and Psychiatry, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA

^cDepartment of Neurology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA

^dDepartment of Neurology, Howard University, Washington, DC, …

Functional Requirement For Dicer Helicase Arginine Methylation In 26 G Sirna Biogenesis And Oocyte Meiotic Program, Nick Newkirk, Shin-Yu Chen, Tokiko Furuta, Kenneth A Trimmer, Leilei Shi, Sabrina Stratton, Hongyuan Li, Xiaodong Cheng, Mark T Bedford, Swathi Arur

The Brown Foundation: Institute of Molecular Medicine

Spatiotemporal regulation of Dicer is essential for small RNA biogenesis and fertility, yet how its helicase domain is controlled remains unclear. Using Caenorhabditis elegans, we identify a regulatory role for the arginine-rich GRARR motif within helicase domain motif VI of DCR-1. Mutating conserved arginines in this sequence disrupts maternal 26 G endo-siRNA production, impairs oocyte meiosis I and II, and reduces fertility. Biochemically, an asymmetrically dimethylated DCR-1 GRA[R495*]R peptide enhances interaction with ERI-5, a tandem-Tudor protein in the ERIC complex, while loss of DCR-1(R495) diminishes this interaction in vivo. Genetically, eri-5 deletion phenocopies the dcr-1 R495K mutant, supporting a functional …

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 …

Claudins Interact With Lilrb Immune Inhibitory Receptors To Promote Myeloid Immunosuppression In Cancer, Xiaoye Liu, Ryan Huang, Zhiqiang Ku, Jingjing Xie, Heyu Chen, Yubo He, Qi Lou, Chengcheng Zhang, Xing Yang, Cheryl Lewis, Jade Homsi, Ankit Gupta, Lei Dong, Kenian Chen, Annabel Tu, Liming Du, Hailong Yu, Qing Hu, Meng Fang, Bufan Li, A E M Adan Khan, Caroline Simith, Samuel John, Lin Xu, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang

The Brown Foundation: Institute of Molecular Medicine

The mechanisms underlying tumor cell-myeloid cell interactions in the tumor microenvironment (TME) remain unclear, and predictive biomarkers for patient response to myeloid checkpoint blockade are lacking. This study identified specific binding between tight junction claudins (CLDNs) and leukocyte immunoglobulin-like receptor subfamily B2 (LILRB2) and LILRB5. In multiple human cancer cohorts, the spatial proximity of LILRB2-positive macrophages to CLDN-expressing cancer cells correlated with clinical outcomes, highlighting this spatial relationship as a potential biomarker. In syngeneic LILRB2-transgenic and humanized mouse models, CLDN18.2-LILRB2 interactions triggered bidirectional signaling, enhanced the immunosuppressive activity of myeloid cells, and accelerated tumor progression. These effects were reversed by …

Human Osteosarcoma Cell Line That Overexpresses Cd4/Ccr5 Or Cd4/Cxcr4 To Study Hiv-Host Interactions, Harry Baffour Awuah

Biotechnology Theses

Human immunodeficiency virus type 1 (HIV-1) entry into host cells occurs through interactions between the viral surface envelope glycoprotein (Env) and the host receptor CD4, and co-receptors CCR5 or CXCR4. However, understanding these interactions in membrane contexts remains limited due to low receptor and coreceptor densities in commonly used cell models. To address this, we developed cellular systems with elevated CD4 expression and either CCR5 or CXCR4. Human osteosarcoma cells (HOS), which lack endogenous surface expression of HIV receptor (CD4) and co-receptors (CCR5 or CXCR4), were engineered via lentiviral transduction to overexpress CD4 and either CCR5 or CXCR4. Cells were …

Transfusion In Transit: A Decade Of Prehospital Blood Transfusion In Pediatric Trauma, Krysta M Sutyak, Eunise C Chen, Lea Mock, Rudolfo Cabrera, Jeannette M Joly, Kuojen Tsao, Bryan A Cotton, David E Meyer, Charles S Cox, Kevin P Lally, Natalie A Drucker

The Brown Foundation: Institute of Molecular Medicine

Background: Prehospital blood transfusion improves mortality in adults, with limited evidence in children. This study describes prehospital blood transfusion in pediatric trauma patients and the impact on shock index, pediatric adjusted (SIPA).

Methods: This study is a retrospective cohort study of trauma patients younger than 18 years who received blood transfusions during helicopter transport to a Level 1 pediatric trauma center from 2011 to 2023. Primary outcome was change in SIPA at time of emergency department (ED) arrival with prehospital transfusion. Secondary subgroup analysis was performed based on transport origin.

Results: Of 137 patients, 58% (80 of 137 patients) were …

Affinity-Optimized Trop2 Antibodies Support Potent Antitumor Activity In Antibody-Drug Conjugates, Aiko Yamaguchi, Junping Hong, Leike Li, Kiyotaka Kobayashi, Chisato M Yamazaki, Summer Y Y Ha, Yasuaki Anami, Wei Xiong, Junquan Liu, Zhiqiang An, Ningyan Zhang, Kyoji Tsuchikama

The Brown Foundation: Institute of Molecular Medicine

Background: Trophoblast cell surface antigen 2 (TROP2) is frequently overexpressed in epithelial tumors and is associated with poor prognosis, making it an attractive therapeutic target. Antibody-drug conjugates (ADCs) directed against TROP2 show clinical benefit, but expression in normal tissues such as skin raises concerns about on-target, off-tumor toxicity. Strategies that improve antitumor efficacy without increasing toxicity are needed.

Methods: Using an in-house phage library, we identified and characterized a novel fully human monoclonal antibody recognizing a unique conformational epitope of TROP2 with reduced binding affinity. This antibody was engineered into homogeneous ADCs carrying auristatin and/or duocarmycin payloads. Comparative studies with …

Telomerase Knockout In Myeloid Cells Predisposes Mice To Foam Cell Formation, Dyslipidemia, Lung Fibrosis, And Cardiac Dysfunction, Zhanguo Gao, Yongmei Yu, David Wiggins, Eva M Sevick-Muraca, Mikhail G Kolonin

The Brown Foundation: Institute of Molecular Medicine

Aging-associated changes in myeloid cells are incompletely understood. One of the culprits of aging is the downregulation of the Tert gene coding for the catalytic subunit of telomerase. Studies of mouse models with Tert knockout (KO) in specific cells have revealed the importance of the telomere-independent noncanonical function of TERT in supporting mitochondrial metabolism and protection from cell senescence. To investigate the role of TERT in myeloid cells (MCs), we analyzed mice with Tert KO in the LysM+ lineage, indelibly labeled with membrane green fluorescent protein (mG). Macrophage numbers and properties in various organs were compared. Changes in the vasculature, …

Lab-Made 100 Bp Dna Ladder Using Polymerase Chain Reaction And Human Dna, Muhammad Ilmam Bariqi, Zulham Yamamoto, Putri Chalya Firjatu, Luthfi Umam Hakim Nasution, Oryza Sativa Lubis

Makara Journal of Science

Polymerase chain reaction (PCR) is a rapid, molecular biology technique widely used in disease diagnosis and genetic engineering. Conventional PCR products require agarose gel electrophoresis, which employs a DNA ladder as a size reference. Most commercial ladders are plasmid-based and reliable but require additional culture time. We suggest a more efficient method for producing a DNA ladder using DNA derived from human blood. DNA was isolated using a commercial kit. Primer sets generating 100–1000 base pair (bp)-long fragments bearing target regions p12, p13, and p14 were designed using Primer-BLAST. DNA was amplified by routine PCR, visualized on a 1% (w/v) …

Molecular Characterization Of Humanized Apoe Mouse Models Reveals Source And Genotype Dependent Differences, Na Wang, Gefei Yu, Zhen Wang, Alla Alnobani, Suren Jeevaratnam, Xue Zhang, Meghan Mcreynolds, Yuzhou Chang, Fangfang Qi, William Tauer, Cassandra Rosenberg, Melissa Wren, Tadafumi C Ikezu, Yuka A Martens, Minghui Wang, Bin Zhang, Gregory W Carter, Michael Sasner, David M Holtzman, Junmin Peng, Long-Jun Wu, Takahisa Kanekiyo, Chia-Chen Liu, Guojun Bu

The Brown Foundation: Institute of Molecular Medicine

Background

Humanized APOE targeted-replacement (TR) mice are essential tools for studying apoE isoform effects in Alzheimer’s disease (AD) and other apoE-related disorders. Despite their widespread use, existing APOE mouse models, generated with different gene targeting strategies, have not been directly compared in terms of apoE isoform expression, lipid profiles, and transcriptomic signatures. Such differences could impact how we interpret APOE genotype-related outcomes, as well as related underlying molecular mechanisms.

Methods

We conducted a comprehensive molecular comparison of humanized APOE mouse models from three sources: Taconic Biosciences (TAC), the Cure Alzheimer’s Fund (CAF), and The Jackson Laboratory (JAX). We assessed apoE …

Γδ T Cells At The Interface Of Innate And Adaptive Immunity In Cancer, Arnau Solé Casaramona, Martin F Bachmann, Eva Sevick-Muraca, Mona O Mohsen

The Brown Foundation: Institute of Molecular Medicine

γδ T cells are unconventional lymphocytes that bridge innate and adaptive immunity by combining recognition of stress-induced ligands independently of classical major histocompatibility complex molecules with the capacity to undergo clonal expansion and long-term adaptation. Their unusual ability to detect malignant transformation using semi-invariant T-cell receptors, butyrophilin recognition and natural killer-like receptors positions them as powerful effector cells in tumors that evade classical immune escape mechanisms. Furthermore, distinct γδ subsets have distinct phenotyping and specific tissue-residencies, which could be leveraged to modulate immunological responses. We evaluate engineered therapies and different experimental platforms for studying γδ T cell biology. We conclude …

Brain-Engrafted Monocyte-Derived Macrophages From Blood And Skull-Bone Marrow Exhibit Distinct Properties, Siling Du, Feiya Ou, Antoine Drieu, Eric Z Xu, Yumeng Cheng, Steffen E Storck, Tornike Mamuladze, Jay Cao, Nora Abduljawad, Bishan Bhattarai, Justin Rustenhoven, Niall Mortimer, Simone Brioschi, Khai Nguyen, Patrick Fernandes Rodrigues, Igor Smirnov, Daniel Gibson, J Michael White, Wandy Beatty, David Denardo, Qingyun Li, Michael Meers, Claudia Z Han, Na Sun, Florent Ginhoux, Marina Cella, Marco Colonna, Jonathan Kipnis

The Brown Foundation: Institute of Molecular Medicine

Microglia arise from yolk sac progenitors and are thought to persist throughout life with minimal input from adult hematopoiesis. However, whether brain-engrafted monocyte-derived macrophages (MDMs) exist at homeostasis and during turnover and how they function relative to yolk-sac-derived microglia (YSMs) remain unsettled. Here, we combine lineage tracing, pharmacological microglia depletion, and multi-omics profiling to define the ontogeny, identity, and function of brain parenchymal macrophages. Despite sharing the parenchymal milieu, MDMs display transcriptional and epigenetic landscapes distinct from YSMs. Fate-mapping reveals that brain-engrafted MDMs transiently express CD206, echoing a developmental stage of microglial precursors. MDM engraftment and polarization are modulated by …

Single Ventricle Physiology May Not Preclude Cardiac Repair In The Setting Of Congenital Diaphragmatic Hernia, Kylie I Holden, Michael C Scott, Ashley H Ebanks, Amir M Khan, D Michael Mcmullan, Anthony Johnson, Charles S Cox, Matthew T Harting, Damien J Lapar

The Brown Foundation: Institute of Molecular Medicine

Objective: Management for congenital heart disease (CHD) with congenital diaphragmatic hernia (CDH), particularly in single ventricle physiology, is challenging, with limited studies showing poor outcomes. This investigation evaluated outcomes for these complex patients.

Methods: This retrospective cohort study (2007-2022) from the CDH Study Group analyzed mortality in patients with CDH and single ventricle physiology, using standard statistical methods and Cox regression for estimation.

Results: A total of 9,261 CDH patients were identified, including 1,886 with CDH + CHD and 131 with single ventricle physiology. The median gestational age was 38 weeks and birthweight was 2.8 kg. Of 131 patients, 34 …

Estimating Population Structure Using Epigenome-Wide Methylation Data, Ziqing Wang, Kent D Taylor, Jerome I Rotter, Stephen S Rich, Yinan Zheng, Lifang Hou, Xiuqing Guo, Jan Bressler, Laura M Raffield, Yongmei Liu, Robert Kaplan, Donald M Lloyd-Jones, Alanna C Morrison, Myriam Fornage, Bruce M Psaty, Jennifer A Brody, Tamar Sofer

The Brown Foundation: Institute of Molecular Medicine

Population stratification is one of the source of inflation in epigenome-wide association studies (EWAS) when not properly accounted for. To address this, we developed methylation population scores (MPSs) to predict genetic principal components (GPCs) using a feature selection approach. We used multi-ethnic DNA methylation data from Illumina EPIC arrays across five cohorts, including MESA (n = 929), CARDIA (n = 1123), JHS (n = 1365), ARIC (n = 2338), and HCHS/SOL (n = 1475), randomly splitting participants into training (85%) and test (15%) sets. Within each cohort, associations between GPCs and CpG sites were estimated using linear regression adjusting for …

Human-Centered Design Of Patient Interviews: Capturing The Experiences Of Patients Recovering From Emergency Abdominal Surgery, Jenna L Marquard, Christie L Martin, Elizabeth C Wick, Amanda C Trofholz, Matthew S Loth, Suhyun Park, Genevieve B Melton

The Brown Foundation: Institute of Molecular Medicine

Objectives: Recognizing the challenges of at-home recovery following a truncated presurgical pathway for emergency laparotomy (EL) patients, we sought to identify barriers and facilitators to optimal recovery. This study aimed to develop a human-centered interview guide to capture the experiences of patients recovering at home after EL.

Methods: We employed an iterative human-centered design (HCD) approach to interview guide development, structured across 3 cycles. Each cycle refined the interview guide based on mock interviews and feedback from an interdisciplinary team. In cycle 1, we focused on creating a patient-centered, understandable guide. In cycle 2, we introduced a preinterview survey to …

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 …

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, …

Neutralization Of Sars-Cov-2 By Igm-14 Via Engagement Of Two Distinct Spike Epitopes, Yan Wang, Yanping Hu, Zhiqiang Ku, Jason Yeung, Jing Zou, Michael Woodson, Nikolai S Prokhorov, Ekaterina S Knyazhanskaya, Haiqing Zhao, Michael B Sherman, Zhiqiang An, Stephen F Carroll, Pei-Yong Shi, Petr G Leiman, Xuping Xie

The Brown Foundation: Institute of Molecular Medicine

Engineered immunoglobulin M (IgM) antibodies typically exhibit superior neutralization potency and avidity compared to their parental IgG counterparts, primarily due to multivalent binding to repeated epitopes on a targeting antigen. In this study, we characterize the neutralization breadth and mechanism of action of IgM-14, a previously reported intranasally deliverable antibody targeting SARS-CoV-2. IgM-14 demonstrates remarkably potent antiviral activity against all pre-Omicron variants but significantly reduced efficacy against Omicron BA.1, and complete loss of activity against the later subvariant JN.1. Resistance selection identified two key mutations in the receptor-binding domain (RBD), G476D and F486P, which disrupt IgM-14 binding and confer strong …

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 …

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 …

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 …