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Protocol to characterize longitudinal gut motility in mice using transit time, tissue harvest, and whole-mount immunostaining

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STAR Protocols 2025年第2期6卷 103761页

作者： Frith, Mary E. Kashyap, Purna C. Linden, David R. Chang, Eugene B. Interdisciplinary Scientist Training Program University of Chicago Chicago 60637 IL United States Department of Medicine University of Chicago Chicago 60637 IL United States Division of Gastroenterology and Hepatology Department of Medicine Mayo Clinic Rochester 55905 MN United States Enteric Neuroscience Program Department of Physiology and Biomedical Engineering Mayo Clinic Rochester 55905 MN United States

Transit time is a key in vivo metric of gastrointestinal (GI) motility, which is a physiologic readout of cellular communication within the enteric system. Here, we present a protocol to characterize longitudinal gut motility in mice. We describe steps for transit testing, whole-mount immunostaining, and tissue harvest. We then detail procedures for image processing and manual cell counting. This protocol seeks to minimize inter-trial variability while assessing cellular and molecular features that may underpin motility differences between experimental conditions. For complete details on the use and execution of this protocol, please refer to Frith et al.¹ © 2025 The Authors

关键词： Metabolism Model Organisms Systems biology

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Semaphorin7A and PD-L1 cooperatively drive immunosuppression during mammary involution and breast cancer

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Cell Reports 2025年第5期44卷 115676页

作者： Elder, Alan M. Fairchild, Heather R. Kines, Kelsey T. Cozzens, Lauren M. Becks, Alexandria R. Slansky, Jill E. Anderson, Steven M. Lyons, Traci R. Division of Medical Oncology Department of Medicine School of Medicine University of Colorado Anschutz Medical Campus Aurora CO United States Cancer Biology Graduate Training Program University of Colorado Anschutz Medical Campus Aurora CO United States Medical Scientist Training Program University of Colorado Anschutz Medical Campus Aurora CO United States University of Colorado Cancer Center Aurora CO United States Department of Immunology and Microbiology School of Medicine University of Colorado Anschutz Medical Campus Aurora CO United States Young Women's Breast Cancer Translational Program University of Colorado Anschutz Medical Campus Aurora CO United States

Postpartum mammary gland remodeling after a pregnancy/lactation cycle is characterized by mechanisms of cell death and inflammation. Here, we show that SEMA7A promotes PD-L1 expression in immune cells of the mammary tissue during involution. These same phenotypes are mimicked in the microenvironment of SEMA7A-expressing tumors, which partially respond to αPD-1/αPD-L1 treatments in vivo. However, cells that remain after treatment are enriched for SEMA7A expression. Therefore, we tested a monoclonal antibody that directly targets SEMA7A-expressing tumors, in part, by reducing SEMA7A-mediated upregulation of PD-L1. In vivo, the SEMA7A monoclonal antibody reduces tumor growth and/or promotes complete regression of mouse mammary tumors, reduces some immunosuppressive phenotypes in the tumor microenvironment, and restores cytotoxic T cells, suggesting that SEMA7A may be a candidate for immune-based therapy for breast cancer patients. © 2025 The Author(s)

关键词： breast cancer CP: Cancer macrophage mammary gland involution PD-L1 semaphorin 7a tumor immunology tumor microenvironment

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Impact of substance use disorders on critical care management and health outcomes in septic adolescents

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Annals of Intensive Care 2025年第1期15卷 1-9页

作者： Markus, Havell Ceneviva, Gary D. Thomas, Neal J. Krawiec, Conrad Pennsylvania State University College of Medicine P.O. Box 850 500 University Drive Hershey 17033-0850 PA United States Program in Bioinformatics and Genomics Pennsylvania State University Huck Life Sciences Building University Park 16802 PA United States Medical Scientist Training Program Pennsylvania State University College of Medicine 500 University Drive Hershey 17033 PA United States Pediatric Critical Care Medicine Department of Pediatrics Penn State Hershey Children’s Hospital P.O. Box 850 500 University Drive Hershey 17033-0850 PA United States Department of Public Health Sciences Pennsylvania State University College of Medicine 500 University Drive Hershey 17033-0850 PA United States

Background: Adult septic patients with substance abuse disorder (SUD) are at increased risk of poor outcomes, but the impact on adolescents is unknown. We aimed to determine if pre-existing SUD is associated with increased adverse outcomes and critical care resources in critically ill adolescents hospitalized with sepsis. We hypothesize that SUD is associated with increased risk of adverse outcomes and usage of critical care resources in this adolescent patient population. Methods: This was a retrospective cohort study utilizing the TriNetX© electronic health record (EHR) database, which consists of EHR from participating healthcare organizations predominantly in the United States. Critically ill adolescents with sepsis aged 12–21 years were divided into two groups (SUD history and no-SUD history). Data related to demographics, diagnostic, procedural, and medication codes were analyzed. The primary outcomes were organ dysfunction, critical care therapies, and all-cause 1-year mortality. Results: We included 5,436 critically ill adolescents with sepsis [730 (13.43%) SUD history and 4706 (86.57%) no-SUD history]. SUD history was associated with increased odds of organ dysfunction (adjusted odds ratio [aOR] 1.84;95% confidence interval [CI] 1.56–2.16;p < 0.001), vasoactive/inotropic drug usage (aOR 1.29;95% CI 1.10–1.52;p = 0.002), mechanical ventilation (aOR 2.19;95% CI 1.85–2.59;p < 0.001), but not mortality (aOR 1.03;95% CI 0.76–1.41;p = 0.83). Conclusions: Our retrospective analysis suggests history of SUD in critically ill septic adolescent patients is associated with increased utilization of critical care resources and organ dysfunction. Further study is needed to determine if substance abuse represents a potentially modifiable risk factor for critical illness in adolescent patients. © The Author(s) 2025.

关键词： Adolescent Critical care Electronic health records Substance use disorders Young adult

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Vascular smooth muscle cell plasticity in the tumor microenvironment

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Cancer Communications 2025年第2期45卷 167-171页

作者： Caitlin F.Bell Richard A.Baylis Nicolas G.Lopez Wei Feng Ma Hua Gao Fudi Wang Sharika Bamezai Changhao Fu Yoko Kojima Shaunak S.Adkar Lingfeng Luo Clint L.Miller Nicholas J.Leeper Department of Medicine Division of Cardiovascular MedicineStanford University School of MedicineStanfordCaliforniaUSA Stanford Cardiovascular Institute Stanford UniversityStanfordCaliforniaUSA Department of Medicine Division of CardiologyUniversity of Colorado Anschutz Medical CampusAuroraColoradoUSA Department of Surgery Division of Vascular SurgeryStanford University School of MedicineStanfordCaliforniaUSA Department of Medicine Division of CardiologyUniversity of California San FranciscoSan FranciscoCaliforniaUSA Center for Public Health Genomics University of VirginiaCharlottesvilleVirginiaUSA Medical Scientist Training Program University of Virginia School of MedicineCharlottesvilleVirginiaUSA Department of Biochemistry and Molecular Genetics University of VirginiaCharlottesvilleVirginiaUSA

Smooth muscle cell(SMC)plasticity plays a prominent role in the pathogenesis of multiple *** phenomenon is characterized by the loss of canonical SMC marker gene expression(such as Acta2 and Myh11),increased proliferation and migration,and the upregulation of genes typically associated with other cell types,such as macrophages[1–3].This process is best described in atherosclerosis,where phenotype switching,clonal expansion,and the aberrant expression of inflammatory and matrix proteins contribute to lesion progression and plaque instability[1–4].However,this phenomenon has not been studied in the context of ***,we investigated whether SMC diversity and plasticity play a role in the tumor microenvironment(TME)using wellestablished SMC-lineage tracing mouse models,single cell RNA sequencing(scRNA-seq),and in silico ligandreceptor *** study methods are described in the supplementary materials and methods *** goal of this work was to determine if vascular SMC plasticity should be prioritized as a translational target in oncology.

关键词： plasticity typically translational

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DNA methylation in melanoma immunotherapy: mechanisms and therapeutic opportunities

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Clinical Epigenetics 2025年第1期17卷 1-14页

作者： Deshmukh, Maya G. Brooks, Veronica T. Roy, Simon F. Milette, Simon Bosenberg, Marcus Micevic, Goran Medical Scientist Training Program (MD-PhD) Yale School of Medicine New Haven 06520 CT United States Department of Immunobiology Yale School of Medicine New Haven 06520 CT United States Department of Pathology Yale School of Medicine New Haven 06520 CT United States Department of Dermatology Yale School of Medicine New Haven 06520 CT United States Yale Cancer Center Yale School of Medicine New Haven 06520 CT United States Yale Center for Immuno-Oncology Yale School of Medicine New Haven 06520 CT United States

Abnormal DNA methylation is a hallmark of cancer and a nearly universal feature of melanoma. DNA methylation plays well-appreciated melanoma cell-intrinsic roles, including silencing tumor-suppressor genes, regulating genomic stability, deregulating expression of oncogenes to potentiate proliferative signaling and tumor migration. With the recent success of immunological therapies for melanoma, important roles for DNA methylation are also emerging at the interface between melanoma and immune cells with the potential to regulate the anti-tumor immune response. These newly recognized roles for DNA methylation in controlling melanoma cell immunogenicity, expression of MHC and immune checkpoint molecules as well as T cell phenotypes in the tumor microenvironment raise the possibility of using DNA methylation to develop improved therapies and methylation-based biomarkers. In addition to reviewing the “immune dimension” of DNA methylation, we summarize recent developments with potential clinical applications in melanoma, such as targeted DNA methylation editing, single-cell methylation approaches, and measurement of circulating methylated DNA. An improved understanding of the immune roles of DNA methylation presents an exciting opportunity for continued improvement of care and outcomes for patients with melanoma. © The Author(s) 2025.

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Frequent exacerbator—a novel endotype of pediatric asthma

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Journal of Allergy and Clinical Immunology 2025年

作者： Kieran J. Phelan Gurjit K. Khurana Hershey the Division of Asthma Research the Medical Scientist Training Program the Department of Pediatrics University of Cincinnati College of Medicine

Asthma is a complex and chronic respiratory condition that affects both adult and pediatric populations. Several asthma endotypes have been described; they include endotypes characterized by T H 2 cell inflammation, response to viral infection, and exposure to air pollution. Recent evidence has revealed a novel endotype of pediatric asthma, termed the frequent exacerbator (FE) endotype, which is characterized by recurrent exacerbations. In this review, we provide an overview of the FE endotype. We review its epidemiology, its definition, and its environmental and clinical associations. We also detail findings from recent molecular characterizations of a pediatric FE endotype, with a specific focus on airway gene expression studies. As asthma exacerbations drive mortality and economic burden associated with disease, understanding the factors leading to frequent exacerbations is an important step in development of novel therapeutics and treatment strategies.

关键词： Asthma endotypes exacerbation frequent exacerbators

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473. Patterns of Differential Gene Expression and Co-Expression in Layer 3 Pyramidal Neurons Across 3 Regions of the Human Cortical Visuospatial Working Memory Network in Schizophrenia

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Biological Psychiatry 2025年第9期97卷 S292-S292页

作者： Kevin Dowling John Enwright Dominique Arion David Lewis University of Pittsburgh Carnegie Mellon University Medical Scientist Training Program University of Pittsburgh University of Pittsburgh School of Medicine

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The emerging role of microbiota derived SCFAs in neurodegenerative disorders

Brain, Behavior, & Immunity - Health

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Brain, Behavior, & Immunity - Health 2025年 46卷 101012-101012页

作者： Samuel Wachamo Alban Gaultier Department of Neuroscience University of Virginia Charlottesville VA USA Neuroscience Graduate Program University of Virginia Charlottesville VA USA Center for Brain Immunology and Glia University of Virginia Charlottesville VA USA Medical Scientist Training Program School of Medicine University of Virginia Charlottesville VA USA

The microbiota-gut-brain axis (MGBA), the bidirectional communication network between the gastrointestinal tract and the central nervous system, plays a significant role in the pathophysiology of neurodegenerative disorders. Emerging research highlights how gut microbiota dysbiosis, or an imbalance in the microbial community, is linked to the etiology and pathology of these conditions. Microbiota dysbiosis leads to changes in the production of microbial metabolites, such as short-chain fatty acids (SCFAs), which can cross the intestinal barrier and influence the brain either directly or indirectly. Understanding the mechanisms by which dysfunction in the MGBA contributes to neurodegeneration opens potential avenues for novel therapeutic strategies, including microbiota-targeted interventions. This review introduces the MGBA, discusses the role of SCFAs within the MGBA in the context of neurodegenerative disorders, and suggests future research directions.

关键词： Microbiota Microbiota-gut-brain axis (MGBA) Dysbiosis Short-chain fatty acids (SCFAs) Neurodegenerative disorders

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Machine learning identification of enhancers in the rhesus macaque genome

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Neuron 2025年第10期113卷 1548-1561.e8页

作者： He, Jing Phan, BaDoi N. Kerkhoff, Willa G. Alikaya, Aydin Hong, Tao Brull, Olivia R. Fredericks, J. Megan Sedorovitz, Morgan Srinivasan, Chaitanya Leone, Michael J. Wirfel, Olivia M. Brown, Ashley Dauby, Samuel Tittle, Rachel K. Lin, Meng K. Hooks, Bryan M. Bostan, Andreea C. Gharbawie, Omar A. Byrne, Leah C. Pfenning, Andreas R. Stauffer, William R. Department of Neurobiology University of Pittsburgh Pittsburgh 15213 PA United States Computational Biology Department Carnegie Mellon University Pittsburgh 15213 PA United States Neuroscience Institute Carnegie Mellon University Pittsburgh 15213 PA United States University of Pittsburgh-Carnegie Mellon University Medical Scientist Training Program Pittsburgh 15213 PA United States Program in Neural Computation Carnegie Mellon University Pittsburgh 15213 PA United States Department of Ophthalmology University of Pittsburgh Pittsburgh 15213 PA United States

Nonhuman primate (NHP) neuroanatomy and cognitive complexity make NHPs ideal models to study human neurobiology and disease. However, NHP circuit-function investigations are limited by the availability of molecular reagents that are effective in NHPs. This calls for reagent development approaches that prioritize NHPs. Therefore, we derived enhancers from the NHP genome. We defined cell-type-specific open chromatin regions (OCRs) in single-cell data from rhesus macaques. We trained machine-learning models to rank those OCRs according to their potential as cell-type-specific enhancers for cells in the dorsolateral prefrontal cortex (DLPFC). We packaged the top-ranked layer-3-pyramidal-neuron enhancer into AAV and injected it into the macaque DLPFC. Expression was mostly restricted to layers 2 and 3 and confirmed with light-driven activation of channelrhodopsin. These results provide a crucial tool for studying the causal functions of DLPFC and provide a roadmap for optimized gene delivery in primates. © 2025 The Authors

关键词： AAV cell types cell-type-specific cognition DLPFC dorsolateral prefrontal cortex enhancer machine learning optogenetics rhesus monkey

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Reusable specimen-level inference in computational pathology

arXiv

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arXiv 2025年

作者： Kaczmarzyk, Jakub R. Sharma, Rishul Koo, Peter K. Saltz, Joel H. Department of Biomedical Informatics Stony Brook University Stony BrookNY United States Simons Center for Quantitative Biology Cold Spring Harbor Laboratory Cold Spring HarborNY United States Medical Scientist Training Program Stony Brook University Stony BrookNY United States Jericho High School JerichoNY United States

Foundation models for computational pathology have shown great promise for specimen-level tasks and are increasingly accessible to researchers. However, specimen-level models built on these foundation models remain largely unavailable, hindering their broader utility and impact. To address this gap, we developed SpinPath, a toolkit designed to democratize specimen-level deep learning by providing a zoo of pretrained specimen-level models, a Python-based inference engine, and a JavaScript-based inference platform. We demonstrate the utility of SpinPath in metastasis detection tasks across nine foundation models. SpinPath may foster reproducibility, simplify experimentation, and accelerate the adoption of specimen-level deep learning in computational pathology research. © 2025, CC BY-NC-SA.

关键词： Inference engines

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