Interferon-gamma receptor signaling regulates innate immunity during Staphylococcus aureus craniotomy infection

Journal of Neuroinflammation, Год журнала: 2025, Номер 22(1)

Опубликована: Фев. 22, 2025

A craniotomy is a neurosurgical procedure performed to access the intracranial space. In 3–5% of cases, infections can develop, most caused by Staphylococcus aureus biofilm formation on skull surface. Medical management this infection difficult, as properties confer immune and antimicrobial recalcitrance necessitate additional surgical procedures. Furthermore, treatment failure rates be appreciably high. These factors, compounded with rapidly expanding resistance, highlight need develop alternative strategies target reverse dysfunction that occurs during infection. Our recent work has identified CD4+ Th1 Th17 cells potent regulators innate cell activation Here, we report role IFN-γ, versus other Th1- Th17-derived cytokines, in programing response using both global type-specific IFN-γR1-deficient (Ifngr1−/−) mice. Bacterial burdens were significantly higher Ifngr1−/− relative WT animals despite few changes abundance. Single-cell transcriptomics candidate explanations for phenotype alterations death pathways, activation, MHC-II expression, T responses reduced While caspase-1 PMNs macrophage/microglial expression regulated IFN-γ signaling, no phenotypes observed either granulocyte- or macrophage/microglia conditional knockout mice, suggestive redundancy. Instead, decreased Th1/Th17 ratio was corroborated elevated IL-17 levels correlated dysfunctional cell-innate communication. Further, less effective than promoting S. bactericidal activity microglia macrophages. Collectively, identifies key protective enhancing macrophage microglial antibacterial activity. Therefore, controlled programming may represent novel therapeutic strategy chronic infections.

Язык: Английский

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Immune status and selection of patients for immunotherapy in myeloma: a Proposal

Blood Advances, Год журнала: 2024, Номер 8(10), С. 2424 - 2432

Опубликована: Апрель 2, 2024

Abstract Newer immune-based approaches based on recruitment and redirection of endogenous and/or synthetic immunity such as chimeric antigen receptor T cells or bispecific antibodies are transforming the clinical management multiple myeloma (MM). Contributions immune system to antitumor effects therapies also increasingly appreciated. Clinical malignancy in MM originates setting systemic alterations that begin early myelomagenesis regional changes affected by spatial contexture. Preexisting therapy-induced correlate with outcomes patients including after therapies. Here, we discuss insights from limitations available data about status MM. variation is emerging a major determinant efficacy current well vaccines. However, multifocal malignancy. As solid tumors, integrating aspects tumor consideration targets biology may be critical optimizing application therapy, T-cell redirection, We propose 5 distinct types provide an initial framework for optimal specific MM: depleted, permissive, excluded, suppressed, resistant. Such considerations help optimize rational patient selection improve outcomes.

Язык: Английский

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Single-cell RNA sequencing and AlphaFold 3 insights into cytokine signaling and its role in uveal melanoma

Frontiers in Immunology, Год журнала: 2025, Номер 15

Опубликована: Янв. 23, 2025

Background Uveal melanoma (UVM) is a form of eye cancer with poor prognosis, particularly in metastatic patients. This study aimed to elucidate the cellular heterogeneity within UVM and identify prognostic biomarkers. Methods We performed single-cell RNA sequencing (scRNA-seq) on primary samples. A UVM-specific gene signature was constructed using LASSO regression validated via ROC curve analysis TCGA-UVM GSE84976 cohorts. AlphaFold 3 used predict 3D structures key proteins. T-cell populations were analyzed pseudotime trajectory mapping interaction network visualization. CRISPR-Cas9 screening conducted hub genes cytokine pathways that may serve as therapeutic targets. Additionally, we Dictionary Immune Responses Cytokines at resolution evaluate signatures. Results ScRNA-seq revealed five major cell types UVMs subdivided them into seven distinct subtypes. Cytokine signaling differential expression immune-related (CSIRGs) across these subtypes tumors. The demonstrated high predictive accuracy associated overall survival Kaplan–Meier analyses. predicted proteins confidence. population complex developmental networks UVM. Myeloid-derived suppressor cells (MDSCs) found be increased UVM, correlating enrichment GM-CSF. identified low effect scores lines, indicating their potential importance Conclusion critical biomarkers shedding light targeted therapies. insights dynamics microenvironment provide foundation for developing personalized strategies improve patient outcomes.

Язык: Английский

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Cell atlas of human psoriasis and epidermal specific Ube2l3 deficiency mouse highlighting CXCL16/CXCR6 orchestrating the development of psoriasis

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Фев. 28, 2025

Psoriasis is a chronic, complex immune-mediated inflammatory disorder with cutaneous and systemic manifestations in which keratinocytes, dendritic cells T have central roles. UBE2L3 may be protective biomarker that regulates the pathogenesis of psoriasis. Here, we identified IL-17A signaling similarity between human psoriatic skin Ube2l3 conditional knockout mouse epidermis rather than dermis. was regulated by CXCR6⁺ Vγ2⁺ γδT while CXCR6⁺ CD8⁺ T human. CXCL16 only chemokines whose bind to stimulate CXCR6. reduction keratinocytes activated IL-1β then promote expression through STAT3 signaling. Up-regulated cDC2/mDC attracted γδT17 or CD8^{+ secrete form positive feedback loop supporting lesion. Thus, keratinocyte-intrinsic suppressor epidermal IL-17 production CXCL16/CXCR6 pathway}

Язык: Английский

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Multi-modal Diffusion Model with Dual-Cross-Attention for Multi-Omics Data Generation and Translation

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Abstract Single-cell multi-omics data have a high potential for deciphering complex cellular mechanisms. But simultaneously measuring from the same cells is still challenging, which calls computational methods to integrate of multiple modalities and generate unobserved data. In this paper, we present scDiffusion-X, latent diffusion model tailored task. The uses autoencoders map multi-modalities into low-dimensional spaces, coupled with Dual-Cross-Attention (DCA) module invented learn hidden links between modalities. DCA enables unravel interactions among features interpretable integration We designed framework extract comprehensive relationships genes regulatory elements. scDiffusion-X not only excels in generating under various conditions, but also can translate fidelity, cannot be achieved existing simulators. Extensive benchmarking experiments showed that has superior performance scalability, quality generated data, interpretability compared methods. It serve as powerful tool unleashing single-cell studying multifaceted mechanisms cells.

Язык: Английский

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Unlocking the Code of Innovation: TRIZ Theory’s Blueprint for Precision Medicine Breakthroughs

Опубликована: Янв. 1, 2025

Abstract Is there a fundamental “grand unified theory” that can systematically explain and predict innovations inventions in precision medicine? An approach is more than 70 years old may be able to answer this question. The Theory of Inventive Problem Solving (TRIZ) has revolutionized the space innovation problem-solving since its inception mid-twentieth century. Based on analysis hundreds thousands many fields, it extrapolated matrix contradictory patterns (problems) generalizable principles solve these problems. Research TRIZ culminates three findings: (1) Problems solutions are repeated across industries sciences. (2) Patterns technical evolution replicated (3) have scientific effects outside field which they were developed. This chapter suggests large parts Precision Medicine (PM) could interpreted as an application principles. Basically, PM seen implementation first principle, segmentation. For example, one most important applications PM, targeted cancer therapy, based segmentation tumors or tumor genetics analogous principle (segmentation). Another example single-cell multi-omics subtyping (patient, disease segmentation) for directing state-of-the-art therapeutics oncology other medical fields. Artificial intelligence machine learning playing increasing role process. question whether further point way get side therapies under control.

Язык: Английский

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circ0066187 promotes pulmonary fibrogenesis through targeting STAT3-mediated metabolism signal pathway

Cellular and Molecular Life Sciences, Год журнала: 2025, Номер 82(1)

Опубликована: Фев. 19, 2025

Язык: Английский

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Single-cell genomics and spatial transcriptomics in islet transplantation for diabetes treatment: advancing towards personalized therapies

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Фев. 20, 2025

Diabetes mellitus (DM) is a global health crisis affecting millions, with islet transplantation emerging as promising treatment strategy to restore insulin production. This review synthesizes the current research on single-cell and spatial transcriptomics in context of transplantation, highlighting their potential revolutionize DM management. Single-cell RNA sequencing, offers detailed look into diversity functionality within grafts, identifying specific cell types states that influence graft acceptance function. Spatial complements this by mapping gene expression tissue's context, crucial for understanding microenvironment surrounding transplanted islets interactions host tissues. The integration these technologies comprehensive view cellular microenvironments, elucidating mechanisms underlying function, survival, rejection. instrumental developing targeted therapies enhance performance patient outcomes. emphasizes significance avenues informing clinical practices improving outcomes patients through more effective strategies. Future directions include application personalized medicine, developmental biology, regenerative predict disease progression responses. Addressing ethical technical challenges will be successful implementation integrated approaches practice, ultimately enhancing our ability manage improve quality life.

Язык: Английский

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Modeling causal signal propagation in multi-omic factor space with COSMOS

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 17, 2024

Abstract Understanding complex diseases requires approaches that jointly analyze omic data across multiple biological layers, including signaling, gene regulation, and metabolism. Existing data-driven multi-omic analysis methods, such as factor (MOFA), can identify associations between molecular features phenotypes, but they are not designed to integrate existing mechanistic knowledge, which provide further actionable insights. We introduce an approach connects of with systematic integration prior knowledge using COSMOS+ (Causal Oriented Search Multi-Omics Space). show how analysis’ output be used estimate activities transcription factors kinases well ligand-receptor interactions, in turn integrated network-level prior-knowledge generate hypotheses about paths connecting deregulated features. Our offers interpretable framework insights from particularly suited for high dimensional datasets patient cohorts. Figure

Язык: Английский

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Omics in allergy and asthma

Journal of Allergy and Clinical Immunology, Год журнала: 2024, Номер unknown

Опубликована: Окт. 1, 2024

Язык: Английский

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