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Natural killer (NK) cells undergo stepwise differentiation from multipotent progenitors within secondary lymphoid tissues. Despite the central importance of the tissue microenvironment in their development, little is known about cell-cell interactions that regulate human NK cell trafficking and maturation. Here, we identify the chemokine receptor CXCR4 and its ligand CXCL12 as regulators of stromal-NK cell interactions required for NK cell maturation. We demonstrate that CXCR4 is expressed throughout human NK cell development in peripheral blood and tonsil, and CXCL12 is enriched in stromal niches containing developing NK cells. Pharmacologic blockade or genetic disruption of CXCR4 resulted in diminished adhesion to integrin ligands, and high-resolution imaging demonstrated crosstalk between CXCR4 and integrins, providing a mechanistic basis for chemokine-dependent modulation of adhesion. Further, CXCR4 blockade resulted in altered contact-dependent motility on stromal cells and integrin ligands, with decreased stable stromal engagement and increased cell speed. Consistent with a requirement for these interactions, treatment with the CXCR4 antagonist plerixafor (AMD3100) impaired NK cell generation from CD34+ precursors. Analysis of NK cells from WHIM syndrome patients with CXCR4 gain-of-function mutations treated with plerixafor revealed similar defects in migration and adhesion, supporting the in-vivo relevance of CXCR4-dependent regulation of NK cell adhesion and motility.

The biophysical properties of cells determine cellular physiology. Leveraging these properties for biomedical applications demands the ability to measure multiple parameters simultaneously across millions of cells and diverse cell types. However, current technologies are limited by throughput and low dimensionality. Here we introduce spectral biophysical cytometry (SBC), a high-throughput platform that integrates environment-sensitive nanosensors with spectral flow cytometry to resolve multiparametric biophysical properties of immune cells at single-cell resolution. By using fluorescent nanosensors that report membrane order, mitochondrial potential and membrane potential, SBC enables simultaneous quantification of key cellular physical states across diverse immune cell populations. When applied to peripheral blood mononuclear cells, SBC reveals cell-type-specific biophysical heterogeneity and identifies distinct remodelling signatures associated with atherosclerosis. In particular, T-cell subsets exhibit substantial alterations in membrane order and mitochondrial depolarization, reflecting coordinated changes in lipid composition and metabolic pathways. Integration with lipidomics and transcriptomics demonstrates that the nanosensors can detect biophysical shifts that correlate with dysregulated lipid metabolism and mitochondrial function, providing mechanistic insight into immune dysfunction in disease. Importantly, SBC achieves rapid, label-efficient profiling using commercially available instrumentation, enabling scalable biomarker discovery directly from blood samples and establishing a powerful strategy for linking biophysical phenotypes to immune cell function.

Chronic oxidative stress has long been implicated in renal pathologies, but whether sustained oxidative damage primarily promotes chronic kidney disease (CKD) or tumorigenesis remains unclear. To address this question, we investigated the long-term effects of oxidative stress on human embryonic kidney (HEK293T) cells chronically exposed to a low dose of hydrogen peroxide (H2O2, 50 μM H2O2) for 9 months, generating two adapted lines, 50R30 and 50R45. These cells exhibited enhanced survival and tolerance to acute high-dose H2O2 challenge, indicating an oxidative stress-resistant phenotype. Despite this adaptation, both cell lines showed markedly reduced proliferation and migration, reflecting loss of cellular vitality and function typical of renal degeneration. Transcriptomic and protein analyses revealed upregulation of genes and proteins involved in cell-cycle arrest (p53 and p21), senescence, and the NF-κB/IL-6-driven senescence-associated secretory phenotype (SASP), oxidative stress responses, together with elevated heat shock factor 1 (HSF1) expression indicative of biomolecular damage and impaired adaptive capacity. Collectively, these findings suggest that chronic oxidative stress drives cellular aging and dysfunction rather than malignant transformation, leading to degenerative changes resembling CKD pathology. Moreover, prolonged oxidative stress alone appears insufficient to induce carcinogenic transformation; additional genetic or epigenetic alterations, together with specific cellular machinery, are likely required to drive kidney malignancy. This study therefore provides mechanistic insight into how sustained oxidative stress promotes renal cell senescence and contributes to CKD progression.

Immune dysfunction, spanning pathogenic autoimmunity and impaired host defense, represents a convergent mechanism across neurological autoimmune and inflammatory diseases and opportunistic infections. Despite advances in immunomodulatory and anti-infective therapies, many patients remain treatment-refractory, reflecting limitations of conventional agents. Adoptive T-cell therapies introduce dynamic "living drugs" capable of in vivo expansion, adaptation, and persistence. These promising characteristics have led to a rapid proliferation of preliminary reports and clinical trials in inflammatory and infectious diseases of the nervous system, placing neurologists at the forefront of this evolving therapeutic landscape. In this Update, we advance a disease-centred conceptual framework designed to reposition T-cell-based therapies within neurological practice. Rather than adopting a technology-driven perspective, we organize disorders according to major patterns of immune dysfunction. Immune deficiency predisposing to opportunistic infection and immune dysregulation driving autoimmunity constitute the principal axes of neurological immune pathology. Within the autoimmune spectrum, distinct immunopathological archetypes (autoantibody-mediated, mixed B- and T-cell-driven, and disorders at the interface of inflammation and neurodegeneration) provide a pragmatic structure for therapeutic reasoning. Building on this classification, we delineate how adoptive T-cells (chimeric antigen receptor T-cells, virus-specific T-cells, and regulatory T-cells) may be differentially aligned with underlying disease biology, linking mechanistic insight to clinical strategy.

Ex vivo expansion of human hematopoietic stem cells (HSCs) holds promise for overcoming their limited availability, a major barrier to broader clinical application. Although recent advances in culture systems can increase HSC numbers, these conditions frequently impair self-renewal and induce myeloid bias, and the underlying molecular mechanisms remain poorly understood. Here, we performed single-cell multiome sequencing (scMultiome-seq) on human umbilical cord blood-derived CD34⁺ hematopoietic stem and progenitor cells to co-profile transcriptional and epigenetic adaptations within the same cells during ex vivo culture. Our analyses revealed reduced transcriptional and epigenetic HSC signatures, accompanied by markedly increased activity of myeloid-associated transcription factor motifs, providing molecular insight into the functional decline and myeloid bias of cultured HSCs. We further observed substantial functional heterogeneity among phenotypically defined HSCs following culture. To address these limitations, we established a niche-mimetic culture system that integrates intrinsic and extrinsic bone marrow regulatory cues, including pharmacologic inhibition of the m6A reader YTHDF2 using the small molecule Y13-27, a three-dimensional microenvironment, and N-cadherin-mediated adhesion. This condition (3D-NcadP-Y) robustly preserved long-term repopulating capacity. When combined with the self-renewal agonist UM729, the resulting platform (3D-NcadP-Y-UM) uniquely enabled the expansion of serially transplantable long-term HSCs with balanced multilineage potential. scMultiome-seq and cellular analyses demonstrated that this condition preserves transcriptional and epigenetic long-term HSC signatures, maintains multilineage-associated transcription factor motifs, and limits excessive cell-cycle activation. Together, these findings elucidate molecular mechanisms underlying culture-induced HSC dysfunction and establish a niche-mimetic strategy for expanding functional human long-term HSCs while preserving key features of stemness.

Neurodegenerative diseases are increasingly linked to systemic metabolic dysfunction, with brain insulin resistance (BIR) positioned as a central mediator. Yet translating this insight into effective therapies has proven remarkably difficult. This review argues that BIR-driven neurodegeneration should be interpreted at two distinct but interconnected levels: cell-type-specific disruption of brain homeostasis by BIR, and the direct, mechanistic role of BIR in driving the proteinopathies that define Alzheimer's and Parkinson's diseases. We first show how BIR produces distinct functional deficits across neurons, astrocytes, microglia, and oligodendrocytes, impairing synaptic plasticity, metabolic coupling, immunometabolic homeostasis, and myelination, resulting in a cellular milieu that favors proteinopathy. We then map molecular pathways through which BIR directly distrubs the metabolism of amyloid-β, tau, and α-synuclein. We further examine how islet amyloid polypeptide cross-seeds cerebral amyloid pathology, suggesting a direct molecular interaction between the peripheral drivers of BIR and protein aggregation. In this framework, BIR functions not as a passive risk factor, but as an active, upstream driver of proteostatic collapse. Cellular dysfunction combined with proteostatic failure, defines the therapeutic target space. We evaluate interventions accordingly, distinguishing those that primarily restore cellular function from those that enhance protein clearance, and those that achieve both. For each strategy, we assess the translational evidence, critically appraising the barriers that have limited their clinical success, including patient heterogeneity, narrow therapeutic windows, and inadequate central nervous system delivery. By integrating cell-type-specific biology with proteostatic mechanisms and a clinically oriented therapeutic framework, this review aims to provide a foundation for multi-target strategies that address the BIR-neurodegeneration axis at its mechanistic roots.

Zinc (Zn) is essential for immune cell function, while mesenchymal stem cells (MSCs) exert immunomodulatory effects primarily through the secretion of soluble factors. Considering the ability of MSCs and Zn to modulate the immune and inflammatory systems, this study investigated, in vitro, the effects of Zn supplementation on MSC responses to inflammatory stimuli and the subsequent modulation of macrophages and lymphocytes. Using the C3H10T1/2 line as a MSC model, we determined that 1 µM ZnSO4 enhanced MSC metabolic activity without affecting viability or cell-cycle distribution, whereas higher concentrations reduced cell viability. Under lipopolysaccharide (LPS) stimulation, Zn inhibited NFκB phosphorylation and increased AMPK phosphorylation, indicating anti-inflammatory and adaptive metabolic responses. Similarly, under TNF-α stimulation, Zn also reduced NFκB phosphorylation. Zn supplementation altered MSC secretory profiles, reducing IL-6, IL-10, and nitric oxide (NO) production while increasing TGF-β and prostaglandin E2 (PGE2) levels, indicating that Zn modifies MSC-derived soluble factor production under inflammatory conditions. Conditioned media from Zn-treated MSCs attenuated IL-6 and IL-12 production in macrophages, indicating a reduced pro-inflammatory cytokine response, whereas lymphocyte responses were unaffected. Importantly, Zn modulation of cytokine production was observed under LPS stimulation but not under TNF-α exposure, suggesting that Zn preferentially interferes with signaling pathways triggered by microbial stimuli. Overall, this study provides mechanistic insight into how Zn affects the secretory profile and inflammatory signaling pathways of C3H10T1/2 cells. These findings support further studies in primary MSCs to determine whether Zn supplementation may represent a useful strategy for modulating MSC-mediated immune regulation in therapeutic settings.

Immune checkpoint inhibitor (ICI) therapy has become standard of care for late stage non-small cell lung cancer (NSCLC), producing durable responses in a subset of patients. However, inflammatory side eKects termed immune-related adverse events (irAEs) occur in up to 40% of ICI-treated NSCLC patients. Current approaches to alleviate irAEs include treatment with immune-suppressing corticosteroids. However, these treatments may undermine the eKicacy of ICIs by suppressing both the irAE and the anti-tumour immune response. To identify more specific therapeutic targets, a better understanding of the complex immunopathology underlying the development of irAEs in NSCLC is required. In this study, pre-treatment blood samples were prospectively collected from 72 NSCLC patients, including 23 who subsequently developed irAEs. Of these 72 samples, PBMCs from 59 were characterised using high-parameter mass cytometry. Plasma from 30 samples was analysed using the SomaScan platform that provides in depth characterisation of over 10,000 proteins, and the plasma metabolome of 30 samples was explored using liquid chromatograph-mass spectrometry (LC-MS). A unique peripheral immunophenotype was observed in patients who subsequently developed irAEs, characterised by decreased memory B cell abundance, heightened Th2 immunity, and an increase in plasma cytokines. Investigation into baseline metabolites revealed dysregulation of fatty acid metabolism associated with development of irAEs. Analysis of additional paired PBMC (n = 17) and plasma (n = 12) samples collected early on treatment allowed exploration of the immunological, proteomic, and metabolic changes associated with irAE development. ICItreatment of patients who developed irAEs induced a significant increase in the abundance of CD8 memory cells and plasma histones. This points to the induction of a strong and potentially pathogenic immune response early following ICI treatment in patients who subsequently develop overt toxicity. Overall, through application of a high-parameter multiomic approach, we have identified key cellular, proteomic and metabolomic features that predispose patients to developing immunotherapy toxicity. These findings provide insight into the complex biology underlying the development of ICI-related adverse events and inform potential treatment strategies.

Zika virus (ZIKV) is primarily transmitted through mosquito bites, and the skin acts as the initial site of viral entry into the host. Consequently, resident skin cells are among the first targets of infection. The epidermis, mainly composed of keratinocytes, can mount an antiviral response against arboviruses through the production of interferons, interferon-stimulated genes, cytokines, and antimicrobial peptides (AMPs), including the Trappin-2/Elafin (Tr2/E) peptide. However, the antiviral activity of Tr2/E during ZIKV infection remains poorly understood, therefore, this study aimed to investigate the antiviral activity of Tr2/E in human keratinocytes during ZIKV infection. In this study, we evaluated the permissiveness of the human keratinocyte cell line HaCaT to infection with a Mexican isolate of ZIKV and observed that these cells support productive viral infection. We then assessed whether ZIKV infection induces endogenous expression of Tr2/E. Tr2/E transcripts were detected in infected cells and showed increased expression over time post-infection, which correlated with the presence of its corresponding protein. Furthermore, we evaluated the antiviral potential of this peptide through exogenous treatment of infected keratinocytes. A significant reduction in ZIKV infection following Tr2/E treatment was observed. Collectively, these findings provide additional insight into the involvement of AMPs in the antiviral response to ZIKV infection and highlight Tr2/E as a potential antiviral factor.

Datopotamab deruxtecan (Dato-DXd) is a novel antibody-drug conjugate currently under investigation in clinical trials of various solid tumors. In this manuscript, an international steering committee formed by medical oncologists, ophthalmologists, and pulmonologists reached consensus to provide multidisciplinary healthcare professionals (HCPs) with practical recommendations for Dato-DXd adverse event (AE) prevention, monitoring, and management in patients with advanced/metastatic non-small cell lung cancer. Experts' recommendations focused on the following AEs: oral mucositis/stomatitis, interstitial lung disease/pneumonitis, ocular surface events, nausea, and vomiting. Based on available guidelines, clinical trials data, and real-world experience, 55 statements were developed and, as per Delphi methodology, all reached consensus with more than 75% of experts' agreement. The key recommendations include preventive measures, such as proactive communication between patients and caretakers, regular clinical examinations, collaboration with multidisciplinary HCPs; and monitoring measures, such as treatment dosage and care planning decisions based on the level of severity of each AE. Experts pointed out real-world challenges and local differences on AEs management and gave insight into implementation of regional strategies with a multidisciplinary collaboration approach. Dato-DXd AEs awareness, understanding, and proper management via a well-established multidisciplinary collaboration is crucial to guarantee patients' quality of life. This international consensus aims to provide comprehensive recommendations for Dato-DXd AEs management, considering the regional and institutional differences present in the healthcare system, such as access to examinations and treatment possibilities. International expert consensus on the prevention and management of side effects from Dato-DXd treatment in non-small cell lung cancer Datopotamab deruxtecan (Dato-DXd) is a new drug being tested for the treatment of different cancer types. In this publication, an international group of oncologists, eye specialists and lung specialists provides practical recommendations to help healthcare teams prevent, monitor and manage side effects caused by treatment with Dato-DXd in patients with metastatic non-small cell lung cancer. Based on clinical data, existing guidelines, and real-world experience, these experts agreed on 55 recommendations for the management of mouth sores, lung inflammation, eye-related problems, nausea and vomiting. The experts highlight the importance of preventing side effects through clear communication with patients, regular check-ups, and close collaboration among different medical specialties. They give specific recommendations on how to monitor patients and adjust treatment based on the severity of each side effect. The experts discuss real-world challenges in managing side effects, which may vary across regions due to differences in healthcare systems, access to tests, and available treatments, and they suggest ways to adapt these strategies locally based on active collaboration between different specialists. Overall, awareness, a good understanding of how to manage these side effects, early recognition and coordinated multidisciplinary care are essential to ensure patients’ quality of life.

B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy occurring in children and a leading cause of cancer-related mortality, thus there is an urgent need for development of novel therapeutic strategies for high risk B-ALL patients. The significance of IKZF1 gene alterations in B-ALL cases is controversial, as some studies have shown those to be associated with poor prognosis, while others have reported that deletion of exons 4-7 of the IKZF1 gene, which results in generation of IKAROS isoform 6, is related favorable prognosis. For the present study, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 was employed for knockout of the IKZF1 gene and various IKAROS knockout lines were established, which allowed for investigation of precise functions of the gene by comparing four lines with different IKAROS isoform 1 and 6 statuses. The results clearly showed induction of significant differentiation and cell cycle progression in IKAROS isoform 6 knockout clones. Furthermore, knockout of IKAROS isoform 6 resulted in significant upregulation of the expression of IKAROS isoform 1 as well as signal transducer and activator of transcription 5 (STAT5) activity, which are considered to be related to the observed features. Further investigations are warranted to provide greater mechanistic insight regarding IKAROS-mediating pathways, which will lead to development of novel therapy for human B-ALL.

Hypoxic stress triggers transcriptional signaling mainly through hypoxia-inducible transcription factors (HIFs), which bind hypoxia response elements (HREs) in gene regulatory regions. However, only a small proportion (~1%) of known HREs are occupied by HIFs during hypoxia, suggesting the involvement of additional hypoxia-responsive factors. To address this gap, we utilized MNase-defined cistrome Occupancy Analysis sequencing (MOA-seq), with the term cistrome referring to all genomic regions where transcription factors and other trans-acting regulators are bound to cis-acting elements across the genome for a particular cell type or treatment. This MNase-based assay enables genome-wide, high-resolution (<30 bp) identification of transcription factor (TF) occupancy footprints embedded within larger regions, most of which were previously annotated as open or accessible chromatin. Applying this in situ cistrome mapping to fixed nuclei from endothelial cells under normoxia or hypoxia (1, 3, or 24 hr) revealed thousands of hypoxia-responsive genomic sites with dynamic TF footprints. The affected genes were enriched in canonical hypoxia-induced pathways, such as angiogenesis. Motif analysis identified over 100 candidate TFs potentially mediating these multifaceted genomic responses. By grouping hypoxia-modified occupancy signals across the hypoxia exposure times, we clustered differentially occupied MOA sites into defined 10 distinct TF kinetic clusters, half of which were associated with HIF1A. HIF1A-proximal binding sites suggested co-activators, while non-HIF1A clusters pointed to additional TFs that may have HIF1A-independent roles. This analysis provides insight into how multiple TF networks coordinate hypoxia responses and highlights the power of cistrome profiling to deepen our understanding of the complex genomic response to low oxygen conditions.

To explore circadian involvement in periodontitis and provide insight into mechanisms. Clinical samples from patients with periodontitis and a ligature-induced periodontitis mouse model were used in the present research. The rhythmic pattern of cortisol, the core circadian rhythm proteins BMAL1 and CLOCK, the expression of senescence markers (p16, p21, and p53), and the percentage and length of primary cilia were detected in hPDLSCs (human periodontal ligament stem cells) exposed to cortisol as an in&#xa0;vitro model of cortisol-associated circadian disruption. BMAL1 expression was manipulated by siRNA transfection to knock down BMAL1 expression, and SR8278 treatment was used to modulate BMAL1-related circadian regulation. Moreover, the effects of SR8278 on the progression of periodontitis were evaluated by micro-CT, mouse behavior tests, the number of primary cilia, and senescence assays. Patients with periodontitis and ligature-induced periodontitis mice exhibited elevated cortisol levels, reduced BMAL1 expression, increased senescence-associated markers, and decreased primary cilia abundance. Elevated cortisol was associated with circadian disruption, accompanied by reduced BMAL1 expression and impaired ciliary homeostasis. BMAL1 regulated ARL13B expression, a key regulator of ciliogenesis. BMAL1 knockdown impaired Hedgehog signaling and induced hPDLSC senescence. SR8278 partially recovered BMAL1-related circadian alterations and primary cilia abundance while attenuating cellular senescence in both periodontitis model mice and cortisol-treated hPDLSCs. Collectively, these findings support the involvement of the cortisol-BMAL1-ARL13B pathway in periodontitis-associated primary cilium dysfunction and hPDLSC senescence. Modulation of BMAL1 partially restored primary cilium homeostasis and attenuated periodontal tissue damage, supporting its potential as a therapeutic target for periodontitis.

COVID-19 continues to present ongoing global health challenges driven by diverse immune responses and heterogeneous clinical outcomes. The ACCORD trial evaluated 3 investigational treatments-bemcentinib, tozorakimab, and zilucoplan-in patients hospitalized with COVID-19, each of which has demonstrated clinical efficacy. To better understand their molecular mechanisms, we conducted a mechanistic follow-up study, integrating transcriptomic and clinical data from 65 patients and applying cellular deconvolution, differential expression, coexpression, and pathway enrichment analyses to uncover treatment-specific immune responses. Each therapy induced transcriptional shifts and modulated distinct immune pathways implicated in severe disease. Bemcentinib primarily modulated myeloid cell populations and inflammatory signalling; zilucoplan enhanced B-cell signalling and lymphocyte-associated pathways; and tozorakimab exerted broad immune and cellular responses across immune cell types. Co-expression analysis revealed gene networks associated with clinical improvement, each driven by distinct treatment-specific hub genes, indicating diverse regulatory mechanisms across treatments. Improved outcomes correlated with gene expression shifts in 4 key immunological pathways: B-cell signalling, antiviral defense, innate inflammation, and platelet/coagulation activity. In contrast, nonresponders had persistent dysregulation of 1 or more of these gene signatures. Our findings define molecular signatures of treatment response and failure in COVID-19, providing mechanistic insight into how distinct therapies modulate the immune system. These insights support the need for adaptive precision medicine approaches tailored to individual, evolving immune trajectories. Moreover, the immunological mechanisms targeted by these repurposed immunomodulatory therapies may inform treatment strategies across a broader spectrum of immune-mediated diseases beyond COVID-19.

Obstructive nephropathy is a significant and preventable contributor to chronic kidney disease, yet no disease-modifying anti-fibrotic agents are currently available.We hypothesized that interferon regulatory factor 5 (IRF5) functions as a macrophage transcriptional regulator that directly transactivates matrix metalloproteinase 9 (MMP9) to initiate early extracellular matrix (ECM) remodeling. Analysis of 30 human obstructive nephropathy biopsy specimens demonstrated that IRF5+CD68+ macrophage density increased progressively with fibrosis severity and correlated significantly with &#x3b1;-smooth muscle actin (&#x3b1;-SMA) positive areas. In the murine unilateral ureteral obstruction (UUO) model, both global and myeloid-specific Irf5 deletion significantly attenuated collagen deposition, immune cell infiltration, and fibrotic gene expression compared with wild-type controls. Cleavage under targets and tagmentation (CUT&Tag) analysis demonstrated that IRF5 directly binds the Mmp9 enhancer region and increases chromatin accessibility. Consequently, myeloid-specific Irf5 knockout significantly reduced Mmp9 mRNA and MMP9 protein levels. Pharmacological inhibition using the IRF5 inhibitor N5-1 mitigated established fibrosis, down-regulated &#x3b1;-SMA and MMP9 expression, and reduced CD68+ macrophage infiltration. These findings identify the IRF5-MMP9 axis as a therapeutically targetable pathway driving macrophage-mediated ECM expansion and provide pre-clinical evidence supporting IRF5 inhibition as a potential treatment strategy for patients with obstructive nephropathy.

In mammals, glutathione peroxidase 7 (GPx-7) is a member of the GPx family that exhibits peroxidase activity. Its immunological functions, especially in host defense against bacterial infection, remain unexplored in lower vertebrates. In this study, we identified a GPx-7 homolog from Paralichthys olivaceus (PoGPx-7) and investigated its roles during Vibrio alginolyticus infection. PoGPx-7 possesses a conserved GSH-Px domain and carries positive net charges. PoGPx-7 was constitutively expressed in various tissues, with significant upregulation upon bacterial challenge. Recombinant PoGPx-7 (rPoGPx-7) exhibited GPx activity and bound to V. alginolyticus via interaction with lipopolysaccharide and peptidoglycan. In addition, rPoGPx-7 could directly kill bacteria by disrupting membrane integrity, leading to severe structural damage and content leakage. The bactericidal activity was modulated by protein concentration, pH, temperature, and Zn2+. Furthermore, rPoGPx-7 bound to peripheral blood leukocytes (PBLs), reduced bacterial attachment and LDH release, and protected PBLs from cell death. It also significantly enhanced phagocytosis, respiratory burst, and acid phosphatase activity of PBLs. In vivo administration showed that rPoGPx-7 reduced bacterial loads in the tissues, and improved fish survival, whereas knockdown of PoGPx-7 increased susceptibility to infection. These findings provide the first evidence that teleosts GPx-7 functions as a dual-effector molecule with direct bactericidal activity and immunomodulatory capacity, providing an immunological insight of GPx family members on resistance bacterial infection.

Outcomes in squamous cell carcinomas (SCCa) of the head and neck, esophagus, and lungs are increasingly linked to the complex interplay between social determinants of health (SDoH) and biological pathways. The emerging field of social genomics provides mechanistic insight into how the environmental and socioeconomic conditions may influence tumor biology through stress-mediated pathways, epigenetic modifications, and altered gene expression. This review explores the role of adverse socioeconomic conditions such as neighborhood deprivation in shaping SCCa outcomes and the potential underlying mechanisms. In response to chronic stress, hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system become activated, leading to dysregulated immune signaling and proinflammatory gene expression pattern collectively known as the Conserved Transcriptional Response to Adversity (CTRA). We discuss epigenetic modifications including DNA methylation (DNAm), histone modification, and micro RNA (miRNA) dysregulation as potential mediators of these stress-related effects. Studies show that SCCa may have distinct race- and neighborhood-specific DNAm patterns including differential methylation of PAX5, HOXA7, and TFPI genes, and altered expression of xenobiotic metabolism genes regulated by Nrf2, a major stress response transcription factor. Therapeutic strategies targeting these biological mediators including &#x3b2;-adrenergic blockers, DNA methyltransferase inhibitors (e.g., azacytidine, decitabine), histone deacetylase inhibitors (e.g., vorinostat), and BET inhibitors have shown variable efficacy in preclinical and clinical SCCa models. Incorporating social context into tumor genomic analysis through geospatial modeling and neighborhood epigenomic profiling may offer a novel opportunity for identifying population-level cancer risk patterns and therapeutic targets. Social genomics provides a deeper understanding of the interaction of socio-environmental exposures with the epigenome and tumor biology influencing disparities in SCCa outcomes. Future research should integrate geospatial and multi-omics data to inform personalized cancer prevention and treatment strategies.

Patients with kidney stones (KS) often have an increased risk of atherosclerosis (AS). Because endothelial dysfunction (ED) is closely associated with AS, its role in KS remains unclear. This study aimed to examine the roles and mechanisms of AS-related ED genes in KS. Three datasets (GSE73680, GSE117518, and GSE132651) were analyzed. Differential expression analysis was conducted to identify differentially expressed genes (DEGs). To identify potential biomarkers, least absolute shrinkage and selection operator (LASSO) regression analysis and expression validation were conducted. Further analyses including GeneMANIA, gene set enrichment analysis (GSEA), examination of biomarkers within immune cells and subcellular localization analysis, molecular regulatory network analysis, tissue specificity analysis, and competing endogenous (ceRNA) network analysis were employed to comprehensively explore the functions and regulatory mechanisms of the identified biomarkers. Moreover, drug prediction analysis was conducted. Finally, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was proceeded to verify the expression levels of the biomarkers. A total of 22 DEGs associated with KS and AS were identified. Lasso regression selected 4 candidate biomarkers (MMP10, UCHL1, NEK2, and HEY1), among which UCHL1 and NEK2 were validated as key biomarkers. GeneMANIA and GSEA analyses uncovered the potential involvement of these biomarkers in cell adhesion molecules, focal adhesion, and lysosome pathways. Analysis of immune cells and subcellular localization provided insight into the biological functions and intracellular distribution of the biomarkers. Transcription factor regulatory network and ceRNA network analyses elucidated potential upstream regulatory mechanisms. Drug prediction analysis identified 17 potential drugs, including pazopanib and palbociclib, that may target NEK2. RT-qPCR demonstrated that NEK2 was significantly overexpressed in KS samples. This study identified biomarkers associated with KS and AS and comprehensively analyzed their molecular regulatory networks. These findings provide novel understandings of the molecular mechanism underlying KS and lay the foundation for future personalized treatment and drug development.

Methylglyoxal is a highly reactive by-product of glycolysis that is elevated in diabetes and contributes to the development of diabetic peripheral neuropathy (DPN). DPN is characterized by nerve degeneration, typically manifesting in patients' extremities. This leads to patients experiencing numbness, burning, and pain. It has been established that elevated methylglyoxal levels lead to nociception, but the broader cellular effects of methylglyoxal on neurons in the dorsal root ganglia (DRG) remain poorly understood. This review provides mechanistic insight regarding methylglyoxal's impact on various cell types and disease contexts. Five main mechanisms were identified: protein glycation, proteostasis change, oxidative stress, metabolic changes, and increased inflammation. These mechanisms are thoroughly interconnected, contributing to cellular dysfunction associated with DPN. We propose that methylglyoxal functions as a central mediator in cellular stress, linking hyperglycemia and elevated glycolysis to neuronal dysfunction in DPN. There is extensive evidence that these mechanisms are methylglyoxal-driven in other cell types and diseases, but a gap in the field remains in determining whether and how they occur in DRG neurons. This is particularly important, as DPN is a frequent comorbidity in diabetes and metabolic diseases and greatly affects patients' quality of life. Understanding the effect of methylglyoxal on DRG in relation to these mechanisms will provide novel insights into the development of DPN and lead to new therapeutic targets.