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Microbiota-dependent early-life programming of gastrointestinal motility

iScience 2024年第10期27卷 110895页

作者： Frith, Mary E. Kashyap, Purna C. Linden, David R. Theriault, Betty 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 Department of Surgery University of Chicago Chicago 60637 IL United States

Gastrointestinal microbes modulate peristalsis and stimulate the enteric nervous system (ENS), whose development, as in the central nervous system (CNS), continues into the murine postweaning period. Given that adult CNS function depends on stimuli received during critical periods of postnatal development, we hypothesized that adult ENS function, namely motility, depends on microbial stimuli during similar critical periods. We gave fecal microbiota transplantation (FMT) to germ-free mice at weaning or as adults and found that only the mice given FMT at weaning recovered normal transit, while those given FMT as adults showed limited improvements. RNA sequencing (RNA-seq) of colonic muscularis propria revealed enrichments in neuron developmental pathways in mice exposed to gut microbes earlier in life, while mice exposed later—or not at all—showed exaggerated expression of inflammatory pathways. These findings highlight a microbiota-dependent sensitive period in ENS development, pointing to potential roles of the early-life microbiome in later-life dysmotility. © 2024 The Author(s)

关键词： Developmental neuroscience Microbiome neuroscience

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Development of 3D-printing composite inks based on photoreactive cartilage extracellular matrix and gelatin nanoparticles

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Bioprinting 2023年 36卷

作者： Hogan, Katie J. Perez, Marissa R. Öztatlı, Hayriye Si, Sophia Wang, Ziwen Jiang, Emily Y. Diba, Mani Garipcan, Bora Mikos, Antonios G. Department of Bioengineering Rice University Houston 77030 TX United States Baylor College of Medicine Medical Scientist Training Program Houston 77030 TX United States Institute of Biomedical Engineering Boğaziçi University İstanbul Turkey

Decellularized extracellular matrix (dECM)-based materials possess innate biochemical cues to drive cell recruitment and differentiation and are of interest for cartilage tissue engineering. While 3D-printing (3DP) provides a means for achieving the precise architecture needed for cartilage tissue engineering, dECM hydrogels have proven difficult to translate to 3DP due to low viscosity and weak mechanical properties. In this study, a cartilage dECM (cdECM, 3 w/v%) was combined with varied amounts of gelatin nanoparticles (GNPs;10, 12.5, 15 w/v%) to form novel hydrogel-colloidal composite materials for 3DP. The addition of GNPs increased the viscosity and rheological properties of the cdECM hydrogel in a dose-dependent manner, directly improving the printability of cdECM 3DP inks. Additionally, functionalization of both materials yielded a UV-crosslinkable material for post-printing crosslinking, and increased GNP content increased post-UV storage moduli with 15 w/v% GNPs yielding a storage modulus 26x greater than that of cdECM alone. 3DP construct swelling and degradation were decreased as a function of increased UV-crosslinking dosage (0, 1.5, and 3 J/cm²). After 14 d of swelling in PBS, construct non-porous area was increased by ∼40 % and pore area was increased by ∼30 % for uncrosslinked (0 J/cm²) constructs versus highly crosslinked (3 J/cm²) constructs. Roughly 40 % higher mass retention was observed across GNP content groups for 3 J/cm² versus 0 J/cm² UV exposure after 14 d of enzymatic degradation, showing the potential for tuning physicochemical properties via UV exposure. Likewise, the retention of key biochemical components of cdECM over the course of degradation was evaluated. Sulfated glycosaminoglycans, a key reservoir for tissue-specific growth factors, were found to be retained within scaffolds over 14 d of degradation and to be released relative to construct degradation and UV-crosslinking. The

关键词： 3D-printing Cartilage tissue engineering Colloidal gel Decellularized extracellular matrix

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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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NF-κB memory coordinates transcriptional responses to dynamic inflammatory stimuli

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Cell Reports 2022年第7期40卷 000-000页

作者： Wang, Andrew G. Son, Minjun Kenna, Emma Thom, Nicholas Tay, Savaş Pritzker School of Molecular Engineering University of Chicago Chicago 60637 IL United States Medical Scientist Training Program University of Chicago Chicago 60637 IL United States

Many scenarios in cellular communication require cells to interpret multiple dynamic signals. It is unclear how exposure to inflammatory stimuli alters transcriptional responses to subsequent stimulus. Using high-throughput microfluidic live-cell analysis, we systematically profile the NF-κB response to different signal sequences in single cells. We find that NF-κB dynamics store the short-term history of received signals: depending on the prior pathogenic or cytokine signal, the NF-κB response to subsequent stimuli varies from no response to full activation. Using information theory, we reveal that these stimulus-dependent changes in the NF-κB response encode and reflect information about the identity and dose of the prior stimulus. Small-molecule inhibition, computational modeling, and gene expression profiling show that this encoding is driven by stimulus-dependent engagement of negative feedback modules. These results provide a model for how signal transduction networks process sequences of inflammatory stimuli to coordinate cellular responses in complex dynamic environments. © 2022 The Authors

关键词： cellular memory CP: Immunology inflammation information theory innate immune signaling live-cell imaging mathematical modeling microfluidics NF-κB pathogen-associated molecular patterns signaling dynamics

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Airway transcriptome networks identify susceptibility to frequent asthma exacerbations in children

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Journal of Allergy and Clinical Immunology 2023年第1期152卷 73-83页

作者： Phelan, Kieran J. Dill-McFarland, Kimberly A. Kothari, Arjun Segnitz, R. Max Burkle, Jeff Grashel, Brittany Jenkins, Seth Spagna, Daniel Martin, Lisa J. Haslam, David B. Biagini, Jocelyn M. Kalra, Maninder McCoy, Karen S. Ross, Kristie R. Jackson, Daniel J. Mersha, Tesfaye B. Altman, Matthew C. Khurana Hershey, Gurjit K. Divison of Asthma Research Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States Division of Human Genetics Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States Division of Infectious Diseases Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States Department of Pediatrics Dayton Children's Hospital Dayton OH United States Department of Pediatrics-Pulmonary Rainbow Babies and Children's Hospital Cleveland Ohio United States Division of Pediatric Pulmonology Nationwide Children's Hospital Columbus OH United States Department of Pediatrics University of Wisconsin School of Medicine and Public Health Madison Wis United States Division of Allergy and Infectious Diseases University of Washington Seattle Wash United States Systems Immunology Program Benaroya Research Institute Seattle Wash United States Department of Pediatrics University of Cincinnati College of Medicine Cincinnati Ohio United States Medical Scientist Training Program University of Cincinnati College of Medicine Cincinnati Ohio United States

Background: Frequent asthma exacerbators, defined as those experiencing more than 1 hospitalization in a year for an asthma exacerbation, represent an important subgroup of individuals with asthma. However, this group remains poorly defined and understudied in children. Objective: Our aim was to determine the molecular mechanisms underlying asthma pathogenesis and exacerbation frequency. Methods: We performed RNA sequencing of upper airway cells from both frequent and nonfrequent exacerbators enrolled in the Ohio Pediatric Asthma Repository. Results: Through molecular network analysis, we found that nonfrequent exacerbators display an increase in modules enriched for immune system processes, including type 2 inflammation and response to infection. In contrast, frequent exacerbators showed expression of modules enriched for nervous system processes, such as synaptic formation and axonal outgrowth. Conclusion: These data suggest that the upper airway of frequent exacerbators undergoes peripheral nervous system remodeling, representing a novel mechanism underlying pediatric asthma exacerbation. © 2023 American Academy of Allergy, Asthma & Immunology

关键词： Asthma exacerbation frequent exacerbator neuronal pediatric transcriptomics

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Stress Relaxation and Composition of Hydrazone-Crosslinked Hybrid Biopolymer-Synthetic Hydrogels Determine Spreading and Secretory Properties of MSCs (Adv. Healthcare Mater. 14/2022)

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ADVANCED HEALTHCARE MATERIALS 2022年第14期11卷 2200393-2200393页

作者： Borelli, Alexandra N. Young, Mark W. Kirkpatrick, Bruce E. Jaeschke, Matthew W. Mellett, Sarah Porter, Seth Blatchley, Michael R. Rao, Varsha V. Sridhar, Balaji V. Anseth, Kristi S. Department of Chemical and Biological Engineering University of Colorado Boulder Boulder CO 80303 USA The BioFrontiers Institute University of Colorado Boulder Boulder CO 80303 USA Medical Scientist Training Program University of Colorado Anschutz Medical Campus Aurora CO 80045 USA Department of Physical Medicine and Rehabilitation University of Colorado Aurora CO 80231 USA

Mesenchymal Stromal Cells Mesenchymal stromal cells (MSCs) are bone-marrow derived stem cells isolated for culture in vitro or in vivo. In article number 2200393 by Kristi S. Anseth and co-workers, MSCs are cultured in vitro, where the red stain, rhodamine phalloidin, visualizes the cell-membrane, and the blue stain, DAPI, visualizes the cell nuclei. This image shows the ability of MSCs to cluster within a stress-relaxing 3D environment.

关键词： hydrogels mesenchymal stromal cells stress relaxation

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Landmark Based Bronchoscope Localization for Needle Insertion Under Respiratory Deformation

Landmark Based Bronchoscope Localization for Needle Insertio...

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IEEE/RSJ International Conference on Intelligent Robots and Systems (IROS)

作者： Inbar Fried Janine Hoelscher Jason A. Akulian Stephen Pizer Ron Alterovitz Department of Computer Science University of North Carolina at Chapel Hill Chapel Hill NC USA Medical Scientist Training Program University of North Carolina School of Medicine Chapel Hill NC USA Division of Pulmonary Diseases and Critical Care Medicine University of North Carolina at Chapel Hill NC USA

Bronchoscopy is currently the least invasive method for definitively diagnosing lung cancer, which kills more people in the United States than any other form of cancer. Successfully diagnosing suspicious lung nodules requires accurate localization of the bronchoscope relative to a planned biopsy site in the airways. This task is challenging because the lung deforms intraoperatively due to respiratory motion, the airways lack photometric features, and the anatomy's appearance is repetitive. In this paper, we introduce a real-time camera-based method for accurately localizing a bronchoscope with respect to a planned needle insertion pose. Our approach uses deep learning and accounts for deformations and overcomes limitations of global pose estimation by estimating pose relative to anatomical landmarks. Specifically, our learned model considers airway bifurcations along the airway wall as landmarks because they are distinct geometric features that do not vary significantly with respiratory motion. We evaluate our method in a simulated dataset of lungs undergoing respiratory motion. The results show that our method generalizes across patients and localizes the bronchoscope with accuracy sufficient to access the smallest clinically-relevant nodules across all levels of respiratory deformation, even in challenging distal airways. Our method could enable physicians to perform more accurate biopsies and serve as a key building block toward accurate autonomous robotic bronchoscopy.

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Now you see me, now you don't: New approaches to sparing nonmalignant cells from CAR T cell therapies

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Med (New York, N.Y.) 2023年第11期4卷 749-751页

作者： Nicholas E Petty Justin Thomas Stefan Radtke Hans-Peter Kiem Stem Cell and Gene Therapy Program Translational Science and Therapeutics Division Fred Hutchinson Cancer Center Seattle WA 98109 USA Medical Scientist Training Program University of Washington School of Medicine Seattle WA 98195 USA. Stem Cell and Gene Therapy Program Translational Science and Therapeutics Division Fred Hutchinson Cancer Center Seattle WA 98109 USA. Department of Medicine University of Washington School of Medicine Seattle WA 98195 USA Department of Pathology University of Washington School of Medicine Seattle WA 98195 USA. Electronic address: hkiem@***.

While new immunotherapies have revolutionized the field of oncology, they have been limited by their inability to distinguish between cancerous cells and healthy HSPCs. Work by Casirati et al. and Wellhausen et al. in epitope editing antigens commonly expressed on AML and HSPCs has unlocked several new targets for immunotherapies.

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#7. Downstream effects of Gli2 targeting on tumor-immune cell crosstalk in bone metastatic breast cancer

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Journal of Bone Oncology 2024年 45卷 100545-100545页

作者： Bennett, Natalie Rhoades, Julie Vanderbilt Program in Cancer Biology Vanderbilt Medical Scientist Training Program Department of Veterans Affairs USA Vanderbilt Program in Cancer Biology Department of Veterans Affairs Vanderbilt Department of Biomedical Engineering Vanderbilt Department of Medicine USA

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Clusterin induced by OPC phagocytosis blocks IL-9 secretion to inhibit myelination in a model of Alzheimer's disease

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Heliyon 2025年第1期11卷 e41635页

作者： Beiter, Rebecca M. Raghavan, Tula P. Suchocki, Olivia Ennerfelt, Hannah E. Rivet-Noor, Courtney R. Merchak, Andrea R. Phillips, Jennifer L. Bathe, Tim Lukens, John R. Prokop, Stefan Dupree, Jeffrey L. Gaultier, Alban Center for Brain Immunology and Glia Department of Neuroscience Charlottesville 22908 VA United States Graduate Program in Neuroscience Charlottesville 22908 VA United States Department of Neurobiology UMass Chan Medical School Worcester 01655 MA United States Medical Scientist Training Program University of Virginia School of Medicine Charlottesville 22908 VA United States Center for Translational Research in Neurodegenerative Disease College of Medicine University of Florida Gainesville 32610 FL United States Department of Pathology College of Medicine University of Florida Gainesville 32610 United States McKnight Brain Institute College of Medicine University of Florida Gainesville 32610 FL United States Department of Anatomy and Neurobiology Virginia Commonwealth University Richmond 23298 VA United States

Background: Variants in the CLUSTERIN gene have been identified as a risk factor for late-onset Alzheimer's disease and are linked to decreased white matter integrity in healthy adults. However, the specific role for clusterin in myelin maintenance in the context of Alzheimer's disease remains unclear. Methods: We employed a combination of immunofluorescence and transmission electron microscopy techniques, primary culture of OPCs, and an animal model of Alzheimer's disease. Results: We found that phagocytosis of debris such as amyloid beta, myelin, and apoptotic cells, increases clusterin expression in oligodendrocyte progenitors. We further discovered that exposure to clusterin inhibits differentiation of oligodendrocyte progenitors. Mechanistically, clusterin blunts production of IL-9 and addition of exogenous IL-9 can rescue clusterin-inhibited myelination. Lastly, we demonstrate that clusterin deletion in mice prevents myelin loss in the 5XFAD model. Discussion: Our data suggest that clusterin could play a key role in Alzheimer's disease myelin pathology. © 2025 The Authors

关键词： Alzheimer's disease Astrocyte Clusterin IL-9 Myelin Oligodendrocyte progenitor cells

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