Single-cell analysis identifies conserved features of immune dysfunction in simulated microgravity and spaceflight

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июнь 11, 2024

Abstract Microgravity is associated with immunological dysfunction, though the mechanisms are poorly understood. Here, using single-cell analysis of human peripheral blood mononuclear cells (PBMCs) exposed to short term (25 hours) simulated microgravity, we characterize altered genes and pathways at basal stimulated states a Toll-like Receptor-7/8 agonist. We validate by RNA sequencing super-resolution microscopy, against data from Inspiration-4 (I4) mission, JAXA (Cell-Free Epigenome) Twins study, spleens mice on International Space Station. Overall, microgravity alters specific for optimal immunity, including cytoskeleton, interferon signaling, pyroptosis, temperature-shock, innate inflammation (e.g., Coronavirus pathogenesis pathway IL-6 signaling), nuclear receptors, sirtuin signaling. directs monocyte inflammatory parameters, impairs T cell NK functionality. Using machine learning, identify numerous compounds linking immune transcription, demonstrate that flavonol, quercetin, can reverse most abnormal pathways. These results define alterations in provide opportunities countermeasures maintain normal immunity space.

Язык: Английский

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Advancing preclinical drug evaluation through automated 3D imaging for high-throughput screening with kidney organoids

Biofabrication, Год журнала: 2024, Номер 16(3), С. 035003 - 035003

Опубликована: Март 28, 2024

High-throughput drug screening is crucial for advancing healthcare through discovery. However, a significant limitation arises from availablein vitromodels using conventional 2D cell culture, which lack the proper phenotypes and architectures observed in three-dimensional (3D) tissues. Recent advancements stem biology have facilitated generation of organoids-3D tissue constructs that mimic human organsin vitro. Kidney organoids, derived pluripotent cells, represent breakthrough disease representation. They encompass major kidney types organized within distinct nephron segments, surrounded by stroma endothelial cells. This allows assessment structural alterations such as loss, characteristic chronic disease. Despite these advantages, complexity 3D structures has hindered use organoids large-scale screening, pipelines utilizing complexin remain to be established high-throughput screening. In this study, we address technical limitations fully automated imaging, aided machine-learning approach automatic profiling segment-specific epithelial morphometry. were exposed nephrotoxic agent cisplatin model severe acute injury. An U.S. Food Drug Administration (FDA)-approved library was tested therapeutic nephrotoxicity The pipeline image acquisition analysis identified or drugs during chemotherapy. potential aligned with previousin vivoand reports. Additionally, Imatinib, tyrosine kinase inhibitor used hematological malignancies, preventive therapy cisplatin-induced Our proof-of-concept report demonstrates process, morphometric assays enables constructs.

Язык: Английский

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The fatty liver disease–causing protein PNPLA3-I148M alters lipid droplet–Golgi dynamics

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(18)

Опубликована: Апрель 24, 2024

Nonalcoholic fatty liver disease, recently renamed metabolic dysfunction-associated steatotic disease (MASLD), is a progressive disorder that begins with aberrant triglyceride accumulation in the and can lead to cirrhosis cancer. A common variant gene

Язык: Английский

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Modular segmentation, spatial analysis and visualization of volume electron microscopy datasets

Nature Protocols, Год журнала: 2024, Номер 19(5), С. 1436 - 1466

Опубликована: Фев. 29, 2024

Язык: Английский

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Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer’s disease

Nature Medicine, Год журнала: 2025, Номер unknown

Опубликована: Март 6, 2025

Alzheimer's disease (AD) therapies utilizing amyloid-β (Aβ) immunization have shown potential in clinical trials. Yet, the mechanisms driving Aβ clearance immunized AD brain remain unclear. Here, we use spatial transcriptomics to explore effects of both active and passive brain. We compare actively patients with nonimmunized neurologically healthy controls, identifying distinct microglial states associated clearance. Using high-resolution alongside single-cell RNA sequencing, delve deeper into transcriptional pathways involved removal after lecanemab treatment. uncover spatially responses that vary by region. Our analysis reveals upregulation triggering receptor expressed on myeloid cells 2 (TREM2) apolipoprotein E (APOE) microglia across approaches, which correlate positively antibody removal. Furthermore, show complement signaling contributes immunization. These findings provide new insights orchestrating shed light role immune-mediated Importantly, our work uncovers molecular targets could enhance Aβ-targeted immunotherapies, offering avenues for developing more effective therapeutic strategies combat AD.

Язык: Английский

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Intraneuronal Aβ accumulation causes tau hyperphosphorylation via endolysosomal leakage

Alzheimer s & Dementia, Год журнала: 2025, Номер 21(3)

Опубликована: Март 1, 2025

Abstract INTRODUCTION Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) peptide plaques and intracellular neurofibrillary tangles formed hyperphosphorylated tau. Many attempts have been made to clarify the link between Aβ tau in pathogenesis, but conclusive data describing a pathway for this connection are still lacking. METHODS We developed neuronal model of Aβ‐induced toxicity studied downstream effects intraneuronal Aβ42 accumulation on hyperphosphorylation using confocal microscopy live cell imaging. RESULTS added medium was endocytosed into neurons, inducing formation endolysosomal protofibrils leakage, which turn promoted hyperphosphorylation. Asparaginyl endopeptidase (AEP) released from disrupted lysosomes, inhibition peptidase activity reduced DISCUSSION The suggest mechanism AD accumulates aggregates gradually neurons over time, leading leakage release AEP, subsequently triggers Highlights endocytosis leads its time. polymerizes causes leakage. Tau induced asparagine inhibited an inhibitor.

Язык: Английский

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EmbedSeg: Embedding-based Instance Segmentation for Biomedical Microscopy Data

Medical Image Analysis, Год журнала: 2022, Номер 81, С. 102523 - 102523

Опубликована: Июль 4, 2022

Язык: Английский

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Proteomic Analysis of Huntington’s Disease Medium Spiny Neurons Identifies Alterations in Lipid Droplets

Molecular & Cellular Proteomics, Год журнала: 2023, Номер 22(5), С. 100534 - 100534

Опубликована: Март 22, 2023

Huntington's disease (HD) is a neurodegenerative caused by CAG repeat expansion in the Huntingtin (HTT) gene. The resulting polyglutamine (polyQ) tract alters function of HTT protein. Although expressed different tissues, medium-spiny projection neurons (MSNs) striatum are particularly vulnerable HD. Thus, we sought to define proteome human HD patient-derived MSNs. We differentiated HD72-induced pluripotent stem cells and isogenic controls into MSNs carried out quantitative proteomic analysis. Using data-dependent acquisitions with FAIMS for label-free quantification on Orbitrap Lumos mass spectrometer, identified 6323 proteins at least two unique peptides. Of these, 901 were altered significantly more HD72-MSNs than controls. Functional enrichment analysis upregulated demonstrated extracellular matrix DNA signaling (DNA replication pathway, double-strand break repair, G1/S transition) highest significance. Conversely, processes associated downregulated included neurogenesis-axogenesis, brain-derived neurotrophic factor-signaling Ephrin-A:EphA regulation synaptic plasticity, triglyceride homeostasis cholesterol, plasmid lipoprotein particle immune response, interferon-γ signaling, system major histocompatibility complex, lipid metabolism, cellular response stimulus. Moreover, involved formation maintenance axons, dendrites, synapses (e.g., septin protein members) dysregulated HD72-MSNs. Importantly, metabolism pathways altered, using image analysis, found that droplets accumulated HD72-MSN, suggesting deficit turnover lipids possibly through lipophagy. Our proteomics relevant confirm current new therapeutic targets

Язык: Английский

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Applications and Advances of Multicellular Tumor Spheroids: Challenges in Their Development and Analysis

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(8), С. 6949 - 6949

Опубликована: Апрель 8, 2023

Biomedical research requires both in vitro and vivo studies order to explore disease processes or drug interactions. Foundational investigations have been performed at the cellular level using two-dimensional cultures as gold-standard method since early 20th century. However, three-dimensional (3D) emerged a new tool for tissue modeling over last few years, bridging gap between animal model studies. Cancer has worldwide challenge biomedical community due its high morbidity mortality rates. Various methods developed produce multicellular tumor spheroids (MCTSs), including scaffold-free scaffold-based structures, which usually depend on demands of cells used related biological question. MCTSs are increasingly utilized involving cancer cell metabolism cycle defects. These massive amounts data, demand elaborate complex tools thorough analysis. In this review, we discuss advantages disadvantages several up-to-date construct MCTSs. addition, also present advanced analyzing MCTS features. As more closely mimic environment, compared 2D monolayers, they can evolve be an appealing biology

Язык: Английский

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Using Deep Learning to Segment Retinal Vascular Leakage and Occlusion in Retinal Vasculitis

Ocular Immunology and Inflammation, Год журнала: 2024, Номер unknown, С. 1 - 8

Опубликована: Янв. 23, 2024

Purpose Retinal vasculitis (RV) is characterised by retinal vascular leakage, occlusion or both on fluorescein angiography (FA). There no standard scheme available to segment RV features. We aimed develop a deep learning model leakage and in RV.

Язык: Английский

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