iScience. 2025 Jun 14;28(7):112901. doi: 10.1016/j.isci.2025.112901. eCollection 2025 Jul 18.

ABSTRACT

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxide accumulation, induces lethal oxidative damage and disrupts cell membrane integrity. Its role in malignant tumors, such as esophageal carcinoma (EC), is increasingly recognized, offering a promising therapeutic avenue to overcome treatment resistance. Emerging evidence highlights the involvement of genes, proteins, the metabolism of metal ions, and tumor microenvironmental factors in modulating ferroptosis-associated resistance mechanisms in EC. This review systematically outlines current insights into ferroptosis in EC resistance and explores novel therapeutic strategies, including ferroptosis-targeted agents, nanotechnology, natural compounds, and multimodal approaches. Nevertheless, overcoming EC resistance remains a significant clinical challenge, warranting further investigation.

PMID:40687837 | PMC:PMC12272825 | DOI:10.1016/j.isci.2025.112901

iScience. 2025 Jun 21;28(7):112978. doi: 10.1016/j.isci.2025.112978. eCollection 2025 Jul 18.

ABSTRACT

Toxicogenomic data provide key insights into molecular mechanisms underlying drug-induced organ toxicities. To simplify transcriptomic data interpretation, we applied weighted gene co-expression network analysis (WGCNA) to rat kidney transcriptomics data from TG-GATEs (TG) and DrugMatrix (DM), covering time- and dose-response data for 180 compounds. A total of 347 gene modules were incorporated into the rat kidney TXG-MAPr web-tool, that interactively visualizes and quantifies module activity using eigengene scores (EGSs). Several modules annotated for cellular stress, injury, and inflammation were associated with renal pathologies and included established and candidate biomarker genes. Many rat kidney modules were preserved across transcriptome datasets, suggesting potential applicability to other kidney injury contexts. Cross-species preservation analysis using human kidney data further supported the translational potential of these rat-derived modules. The TXG-MAPr platform facilitates upload and analysis of gene expression data in the context of rat kidney co-expression networks, which could identify mechanisms and safety liabilities of chemical or drug exposures.

PMID:40687826 | PMC:PMC12274721 | DOI:10.1016/j.isci.2025.112978

HRB Open Res. 2025 Jun 9;7:16. doi: 10.12688/hrbopenres.13822.2. eCollection 2024.

ABSTRACT

BACKGROUND: Molecular diagnostics are critical for informing cancer patient care. In Ireland, the National Cancer Control Programme (NCCP) develops cancer therapy regimens, which include relevant information on molecular indications. Here, we present a collated overview of the current molecular indications of all NCCP systemic anti-cancer therapy regimens and the funding statuses of their associated drugs. Furthermore, we also provide estimates for the scale of required molecular testing in cancer therapy and for the clinical genetic sequencing capacity of Ireland, and provide a summary of current cancer clinical trials in Ireland which have molecular components.

METHODS: Through a combination of web scraping, keyword search, and manual review, we performed a full review of all 856 indications included in the 533 therapy regimens published to date by the NCCP to identify therapy indications with explicit molecular criteria. For all cancer types identified in these indications, we obtained incidence rates in Ireland from National Cancer Registry Ireland to predict the number of patients yearly who stand to benefit from a molecular test. We then applied molecular subtype rates from published literature to estimate the number of patients who would then qualify for a relevant molecularly guided therapy.

RESULTS: We identified 246 indications for 175 NCCP therapy regimens that include molecular criteria. These 246 molecular indications encompassed 101 genetic criteria, 161 cellular biomarker criteria, 63 molecularly informed drugs, and over 20 cancer types. We estimated that up to approximately 55% of cancer patients in Ireland could qualify for a molecular test and that the majority of tested patients would qualify for a treatment informed by a molecular test.

CONCLUSIONS: As personalised cancer medicine continues to develop in Ireland, this study will provide a baseline understanding of current practices. We anticipate that work such as this will help to inform planning in the healthcare system.

PMID:40687499 | PMC:PMC12272048 | DOI:10.12688/hrbopenres.13822.2

iScience. 2025 Jun 25;28(8):113009. doi: 10.1016/j.isci.2025.113009. eCollection 2025 Aug 15.

ABSTRACT

Motivationally significant events, such as rewards and threats, modify neural representations of the environment where they occur. The medial prefrontal cortex (mPFC) forms map-like representations anchored to these events. Using miniscope calcium imaging, we investigated how unexpected threats affected mPFC cell activity in mice, navigating a familiar path toward rewards. The introduction of threats increased the density of active cells near the threat location and triggered the emergence of a distinct population activity pattern that spanned the entire path. Notably, the difference between the new and original patterns was greater in the path segment leading to the new threats than in the segment leading to the existing rewards. This differentiation persisted during the subsequent learning of threat probabilities but ceased upon completion. Thus, event-induced remapping of mPFC population activity is scaled by the proximity to new events, enabling seamless integration of new events into the mental map of familiar environments.

PMID:40686619 | PMC:PMC12275950 | DOI:10.1016/j.isci.2025.113009

J Med Virol. 2025 Jul;97(7):e70506. doi: 10.1002/jmv.70506.

ABSTRACT

Sex-biased differences in COVID-19 outcomes in relation to individual SARS-CoV-2 variants are not well understood. In this study, lungs and nasal cavities of age-matched female and male K18-hACE2 transgenic mice were collected for dissecting sex-specific differences in pathology after infection of SARS-CoV-2 614 G, Delta, or Omicron variant. Overall, Delta infection induced the most severe inflammation and pathology in nasal cavity and lung followed by the 614 G, then Omicron variant. Sex differences in host responses to SARS-CoV-2 infection were variant-specific. Delta-infected males showed increased pulmonary infiltration of CD163+ "M2" macrophages, Ly6G+ neutrophils, and NKR-P1C + NK cells during early onset of infection, and elevated lung inflammatory cytokines such as IL-10, IL-6, and IP-10 than Delta-infected females. Conversely, females had increased lung CD4 + T cell recruitment after Omicron infection and significantly elevated lung MCP-1 secretion after Delta infection than males. Lung spatial transcriptomics data revealed that Delta-infected females had enriched gene pathways related to humoral immune response and interferon signaling, while males had enriched pathways associated with extracellular matrix production, chemokine signaling, and cell chemotaxis. Taken together, this study highlights the complex infection dynamics with respect to individual SARS-CoV-2 variants and underscores the importance of sex as a confounding factor for COVID-19 pathology.

PMID:40686017 | DOI:10.1002/jmv.70506

Gut Microbes. 2025 Dec;17(1):2530157. doi: 10.1080/19490976.2025.2530157. Epub 2025 Jul 20.

ABSTRACT

The involvement of the intestinal microbiome in the pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC), is well-established. Bacteria interact with immune cells at sites of intestinal inflammation, but also in the CRC tumor microenvironment. We hypothesized that bacterial remnants translocate within peripheral blood mononuclear cells (PBMCs) into the circulation and thus explored the composition of the detectable microbiome in PBMCs of patients with CRC or IBD compared to healthy controls. The PBMC microbiome profiles partially align with the tumor-derived or intestinal tissue-derived microbiome signatures obtained from the same patients with CRC or IBD, respectively. Our metagenomics data, supported by 16S-rRNA-FISH-Flow, imaging flow cytometry and species-specific qPCR, revealed the presence of translocated bacterial genetic sequences in the patients with CRC and IBD. Thus, our data suggest that in patients with intestinal barrier leakage, there is the potential for the translocation of bacterial remnants into the circulation via PBMCs.

PMID:40685618 | DOI:10.1080/19490976.2025.2530157

Bioorg Chem. 2025 Jul 14;163:108748. doi: 10.1016/j.bioorg.2025.108748. Online ahead of print.

ABSTRACT

The bioconversion of natural products by cytochrome P450 enzymes can represent a sustainable alternative to classical chemical synthesis. In this study, we applied a colorimetric assay based on styrene oxidation, to select natural compounds as candidate substrates for cytochrome P450-mediated biocatalysis. One of the tested molecules, bergamottin, was identified as a new substrate for cytochrome P450 BM3 and its D251G/Q307H double mutant, that demonstrated enhanced catalytic efficiency, achieving 87 % conversion within one hour, significantly outperforming the wild-type enzyme. We observed also a 3-fold increase in the total turnover number when comparing engineered enzyme with the wild-type protein. The enzymatic reaction yielded three bergamottin epoxy-derivatives. They were isolated and identified by LC-MS as 2',3'-epoxybergamottin, 6',7'-epoxybergamottin, and 2',3'-6',7'-diepoxybergamottin. Notably, it is the first time that a bacterial P450 is reported to catalyze epoxidation reaction on bergamottin. Biological assays demonstrated that epoxidation markedly altered bergamottin bioactivity. In particular, 2',3'-6',7'-diepoxybergamottin exhibited novel antimicrobial properties and 2',3'-epoxybergamottin had a beneficial effect on fibroblast viability. These findings highlight the potential of engineered cytochrome P450 enzymes for generating bioactive molecules that do not naturally occur, expanding the scope of biocatalytic strategies for drug discovery and natural product modification.

PMID:40684723 | DOI:10.1016/j.bioorg.2025.108748

Asian J Psychiatr. 2025 Jul 7;110:104615. doi: 10.1016/j.ajp.2025.104615. Online ahead of print.

ABSTRACT

Mental health disorders, including depression, anxiety, post-traumatic stress disorder, and dementia, are increasingly recognized as exacerbated by social isolation and loneliness, prompting growing interest in Artificial Intelligence (AI) driven and robotic interventions for social support. Traditional interventions such as animal-assisted therapy (AAT) have demonstrated effectiveness by leveraging the human-animal bond to reduce stress, enhance social engagement, and improve emotional well-being. However, AAT faces logistical challenges, including availability, cost, and animal welfare concerns. In response, robot-assisted therapy (RAT) has emerged as a scalable alternative, offering consistent social interaction and emotional support without the limitations of live animals. Advances in AI have enhanced RAT's potential by enabling more adaptive, engaging interactions, yet questions remain regarding these connections' emotional significance and depth. This review critically evaluates the efficacy of AAT and RAT in addressing mental health disorders, comparing their impact on loneliness, stress, and mental health outcomes. While AAT has demonstrated moderate yet significant benefits across various populations, its accessibility remains limited. Early RAT studies suggest potential in mitigating loneliness and improving mood, particularly in older adults and individuals with neurodevelopmental disorders. However, methodological limitations and uncertainties about emotional depth persist. Future research should enhance robotic interventions through greater emotional responsiveness, personalization, and long-term engagement. Ethical concerns surrounding data privacy and user attachment must be addressed to ensure responsible implementation. By examining the strengths and limitations of both approaches, this review discusses the evolving role of social robotics in mental healthcare, highlighting the need for further investigation to optimize therapeutic potential.

PMID:40684500 | DOI:10.1016/j.ajp.2025.104615

HGG Adv. 2025 Jul 18:100481. doi: 10.1016/j.xhgg.2025.100481. Online ahead of print.

ABSTRACT

RNA Polymerase III (POLR3)-related disorders (POLR3-RD) are a group of clinical entities characterized by causal variants in genes encoding Pol III subunits, including POLR3A, POLR3B, POLR1C, POLR1D, POLR3D, POLR3E, POLR3F, POLR3GL, POLR3H, and POLR3K. These typically cause developmental phenotypes affecting the central nervous system, the eyes, connective tissues including bones, teeth, endocrine axes, and the reproductive system. Similar phenotypes can be caused by variants in separate subunit genes (multigenic). In contrast, variants in the same gene can cause different phenotypes (pleiotropy), making genotype-phenotype correlation challenging. POLR3-RD, though individually rare, have never been analyzed collectively. To bridge this gap, we developed an extensive database encompassing all published and unpublished cases of POLR3-RD and conducted the first comprehensive genotype-phenotype correlation study across their entire spectrum. This work contributed new cases, representing 13% of all documented cases in the literature, along with 31 novel variants, accounting for 8% of all identified variants. This database was constructed by systematically reviewing the literature and integrating data from patients under the care of our international network of collaborators. The dataset includes genotype curation, bioinformatics, prior publications, and individual patient outcome information. By leveraging this comprehensive data, we were able to establish clear genotype-phenotype correlations for some pathogenic variants, which will help provide optimal clinical care, genetic counseling (including insights into disease phenotypes and progression), and offer valuable guidance for future clinical trial design and patient stratification.

PMID:40684265 | DOI:10.1016/j.xhgg.2025.100481

Sci Rep. 2025 Jul 19;15(1):26248. doi: 10.1038/s41598-025-10795-4.

ABSTRACT

Analysis of system-wide cellular communication changes in Alzheimer's disease (AD) has recently been enabled by single nucleus RNA sequencing (snRNA-seq) and new computational methods. Here, we combined these to analyze data from postmortem human tissue from the entorhinal cortex of people with AD and compared our findings to those from multiomic data from the 5xFAD amyloidogenic mouse model at two different time points. Using the cellular communication inference tool CellChat we found that disease-related changes were largely related to neuronal excitability as well as synaptic communication, with specific signaling pathways including BMP, EGF, and EPHA, and relatively poor conservation of glial-related changes during disease. Further analysis using the neuron-specific NeuronChat revealed changes relating to metabotropic glutamate receptors as well as neuronal adhesion molecules including neurexins and neuroligins. Our results that cellular processes relating to excitotoxicity are the best conserved between 5xFAD mice and AD suggest that excitotoxicity is the main common feature between pathogenesis in 5xFAD mice and people with AD.

PMID:40683902 | DOI:10.1038/s41598-025-10795-4

Methods Cell Biol. 2025;196:87-112. doi: 10.1016/bs.mcb.2025.01.003. Epub 2025 Feb 6.

ABSTRACT

The tumor microenvironment and, particularly, tumor-infiltrating immune cells can profoundly influence tumor progression and response to therapy. Deconvolution is a powerful computational technique to estimate cell-type fractions from bulk RNA sequencing (RNA-seq) data leveraging expression signatures specific to the cell types of interest. Recently, a new generation of deconvolution algorithms has emerged, making it possible to directly learn cell-type-specific signatures to be used for deconvolution from annotated single-cell RNA-seq (scRNA-seq) datasets. Thanks to their flexibility, these next-generation methods can extend deconvolution to any cell type, tissue, and organism for which a suitable single-cell reference is available. However, these methodologies are highly diverse in terms of programming languages, computational workflows, and input/output data, which complicate their usage and comparison. To overcome these challenges, we developed omnideconv, an R package that integrates several deconvolution methods, streamlining their usage and unifying their semantics. In this chapter, we demonstrate how omnideconv can be integrated with an annotated scRNA-seq dataset, comprising both malignant and normal cells from the breast cancer microenvironment, to quantify the cellular composition of bulk RNA-seq data from a cohort of breast cancer patients.

PMID:40683686 | DOI:10.1016/bs.mcb.2025.01.003

Mucosal Immunol. 2025 Jul 17:S1933-0219(25)00076-5. doi: 10.1016/j.mucimm.2025.07.005. Online ahead of print.

ABSTRACT

Intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IEL) provide continuous surveillance of the intestinal epithelium. We report that mice harboring a microbiota-specific hyperproliferative γδ IEL (γδHYP) phenotype also upregulate the expression of the ectonucleotidase CD39, a marker of regulatory γδ T cells. Enhanced TCR and IL-15 signaling correlates with a progression from a naïve-like CD39neg γδ IEL to a more mature, tissue-adapted CD39hi IEL population. We found that TCR γδ activation drives CD122-mediated CD39 upregulation on γδHYP IELs and increased mucosal IL-15 further amplifies CD39 expression in these cells. Further investigation revealed that CD39 induction requires sustained exposure to the γδHYP-associated microbiota. Moreover, CD39hi γδ IELs exhibit a reduced capacity to produce pro-inflammatory cytokine, which may explain the lack of histopathology in γδHYP mice. Overall, our study identifies a previously unappreciated mechanism by which an altered microbiota amplifies CD39 expression on γδHYP IELs, leading to the expansion of γδ IELs with regulatory potential.

PMID:40683453 | DOI:10.1016/j.mucimm.2025.07.005

J Struct Biol. 2025 Jul 17:108231. doi: 10.1016/j.jsb.2025.108231. Online ahead of print.

ABSTRACT

Cryogenic correlative light and electron microscopy (cryo-CLEM) is an imaging strategy that integrates specific molecular labeling and molecular resolution structural information. However, there is a resolution gap of more than two orders of magnitude between diffraction-limited fluorescence microscopy and electron microscopy (EM). Single-molecule localization microscopy (SMLM) performed at cryogenic temperatures promises to bridge this resolution gap. Nevertheless, the high excitation laser powers required for SMLM risk the devitrification of frozen biological samples, leading to perturbation of their native-like state. Here, we investigate how base cooling temperature, immersion medium, and EM grid support materials influence sample devitrification. Using finite element simulations and experimental validation, we show that a cryo-immersion medium enhances heat dissipation for carbon supports, while metallic supports in a cold nitrogen gas medium tolerate higher laser intensities due to lower base temperatures. Gold supports illuminated at 640nm exhibit markedly high laser thresholds, similar to silver-coated grids. Additionally, metallic supports maintain efficient heat dissipation in vacuum-based cryostats. Our findings provide quantitative insights that aid in optimization of cryo-SMLM setups for improved cryo-CLEM imaging.

PMID:40683427 | DOI:10.1016/j.jsb.2025.108231

J Biotechnol. 2025 Jul 17:S0168-1656(25)00185-3. doi: 10.1016/j.jbiotec.2025.07.014. Online ahead of print.

ABSTRACT

This study investigated glycerol and oleic acid as carbon sources on RL production and congener diversity in Burkholderia thailandensis E264 (BSL 1), a safer alternative to Pseudomonas aeruginosa, using an untargeted metabolomic approach. B. thailandensis E264 was grown in triplicate for nine days at 30 °C, extracted using ethyl acetate, and analysed using LC/Q-TOF/MS. Results showed 84 RL congeners with different adducts were annotated. Cultures with glycerol primarily produced di-RLs with carbon chain lengths from C12:2 to C16-C14, whereas cultures with oleic acid produced mono-RLs (C8:2 to C16-C16). Multivariate analysis of PLS-DA revealed distinct RL profiles in response to different carbon sources, with di-RL-C10-C12 (VIP = 2.15) and mono-RL-C10-C14:1 (VIP = 1.90) identified as key congeners in the glycerol and oleic acid cultures, respectively. The heatmap highlighted significant fold changes in RL congener abundance (2.94-fold higher di-RL-C14 in glycerol culture and 4.38-fold higher mono-RL-C8-C10 in oleic acid culture). These findings demonstrate that the carbon source significantly affects RL congener production in B. thailandensis E264, suggesting the potential for RL production optimisation and tailoring congener profiles for specific applications.

PMID:40683386 | DOI:10.1016/j.jbiotec.2025.07.014

J Plant Physiol. 2025 Jul 14;312:154568. doi: 10.1016/j.jplph.2025.154568. Online ahead of print.

ABSTRACT

This study investigates the relationship between microRNAs (miRNAs) and F-box proteins (FBPs) in Persicaria minor, under methyl jasmonate (MeJA) treatment. miRNAs regulate gene expression by targeting mRNAs via cleaving or modifying the mRNAs through base pairing, while FBPs, as part of the SCF (Skp1-Cullin-F-box) complex, mediates protein degradation via the ubiquitin-26S proteasome system (UPS). These post-transcriptional and post-translational regulators work together to activate plant responses. Integrated in silico analysis and experimental validation identified five miRNA-FBP pairs: miR156a-PmFBK2, miR396a-PmFBX1, miR156a/c-PmFBX2, miR408-PmFBK3, and miR398-PmFBL1. Among these, miR156a and miR408 showed negative expression correlations with their FBP targets, further confirmed by RLM-RACE cleavage assays, suggesting direct post-transcriptional regulation. Both target genes encode FBP containing kelch repeat (FBK), a subfamily abundant in plants and associated with stress-responsive pathways. Further analysis of the miR156a target through yeast two-hybrid (Y2H) revealed that, PmFBK2 protein targets SAMS2, PAL1 and GID1, proteins involved in metabolic and hormonal regulation linked to stress responses These findings suggest that miRNA-mediated regulation of FBP may influence protein interaction networks relevant to stress adaptation. This study presents foundational evidence for the involvement of specific miRNA-FBP interactions in plant stress responses, laying the groundwork for future functional validation and crop improvement.

PMID:40683030 | DOI:10.1016/j.jplph.2025.154568

J Plant Physiol. 2025 Jul 11;312:154566. doi: 10.1016/j.jplph.2025.154566. Online ahead of print.

ABSTRACT

Advances in remote and proximal sensing have facilitated temporal high-throughput phenotyping of crop populations grown in field conditions. The resulting time-series phenotypic data capture single or multiple growth- and yield-related traits at different temporal resolution. Whilst classical quantitative genetics approaches can readily be used with these temporal data by considering the measurement of a character at a given time point as a separate trait, this strategy fully neglects inter-trait integration over time. Here, we provide a classification of computational approaches that can be used to effectively analyze temporal phenotyping data from crop populations, focusing on genomic prediction, identification of quantitative trait loci, and genome-wide association studies. We point out the existing challenges due to the consideration of time-resolved data, and stress the extent to which these challenges are addressed by the available computational solutions. Finally, we highlight recent breakthroughs that make use of time-resolved data for multiple traits and are poised to revolutionize breeding efforts of climate-resilient crops.

PMID:40683029 | DOI:10.1016/j.jplph.2025.154566

Cell Mol Neurobiol. 2025 Jul 19;45(1):72. doi: 10.1007/s10571-025-01582-w.

ABSTRACT

Depression during pregnancy is often overlooked and undertreated. Ketamine has been shown to exert prompt and sustained antidepressant effects in patients with depression, although concerns of potential neurotoxicity prohibit its use in pregnant women. Here, we aim to investigate the neurobehavioral effects of subanesthetic ketamine on pregnant mice and their offspring. We found that pregnant C57BL/6 mice receiving ketamine (10 mg/kg/day intraperitoneal) from gestation day 15 to 17 exhibited less depression-like behaviors. Prenatal ketamine treatment induced male-specific reduction in depression- and anxiety-like behaviors in adult offspring, without alterations in social and memory performance. These behavioral outcomes were associated with a male-specific increase in dendritic spine density of dentate gyrus granule cells, while neither dendritic architecture nor hippocampal neurogenesis was affected. N-methyl-D-aspartate receptor subunits GluN2A and GluN3A were expressed at significantly higher levels in the hippocampus of male as compared to female mouse embryos, suggesting sex-dependent actions of ketamine on developing brain. Overall, our study showed that prenatal exposure to subanesthetic ketamine could exert long-lasting neurobehavioral effects in a sex-dependent manner, with male offspring being more resilient to stress. These findings may have implications concerning ketamine use during pregnancy, and also provide clues about the developmental origins of emotional problems.

PMID:40682689 | DOI:10.1007/s10571-025-01582-w

J Obstet Gynaecol Res. 2025 Jul;51(7):e16360. doi: 10.1111/jog.16360.

ABSTRACT

BACKGROUND: Epithelial ovarian cancer (EOC), originating from the ovarian epithelial cells, represents approximately 90% of all ovarian cancer cases and includes several subtypes.

AIM: This study investigates the role of hub ribonucleoprotein genes in EOC progression.

METHODS: Microarray datasets GSE28799 and GSE54388 from GEO were analyzed using Transcriptome Analysis Console (TAC) software for differential expression (p ≤ 0.05, LogFC ≥4). Upregulated RNP genes, including FBL and HNRNPC, were identified. Protein-protein interactions were analyzed using STRING and visualized in Cytoscape. Clustering was performed with Gephi software. Gene expression and alterations were validated using the HPA and cBioPortal databases.

RESULTS: FBL and HNRNPC were significantly upregulated in EOC, playing key roles in tumor progression. Network analysis showed close interactions within the same gene cluster. Pathway enrichment linked them to spliceosome and ribosome biogenesis, affecting gene regulation and cellular function. Samples with FBL and HNRNPC deletions showed lower mRNA expression. Survival analysis indicated that their upregulation negatively affects patient survival, suggesting that disrupting these genes could slow cancer progression.

CONCLUSION: This study highlights the crucial role of FBL and HNRNPC in EOC. These genes are significantly upregulated and actively contribute to key cellular processes like spliceosome function and ribosome biogenesis, which help sustain tumor growth. Through network and pathway analyses, researchers have uncovered their strong functional connection, further emphasizing their importance in cancer biology. Notably, higher expression levels of these genes are linked to poorer patient survival. Targeting and disrupting their expression may provide new strategies to slow tumor progression and improve patient outcomes.

PMID:40682526 | DOI:10.1111/jog.16360

Respir Res. 2025 Jul 18;26(1):250. doi: 10.1186/s12931-025-03310-w.

ABSTRACT

RATIONALE: Immunoglobulins (Ig) protect against pathogens frequently implicated in COPD exacerbations. We previously demonstrated an association of low-normal serum IgA and IgG concentrations with prospective exacerbation risk, but responsible mechanisms are undefined. Here, we examined associations of lower respiratory tract bacterial diversity to Ig levels in serum and bronchoalveolar lavage (BAL) and to the memory phenotypes of blood and BAL B cells.

METHODS: We analyzed data from phase I of SPIROMICS, an observational cohort study of smoking-related COPD. A subset of participants completed comprehensive research bronchoscopies, including analysis of BAL bacterial microbiota by 16 S rRNA gene (V4 region) sequencing and of blood and BAL B-cells by 12-color flow cytometry. In some participants, we also analyzed serum and BAL Ig levels by ELISA. We constructed linear regression models including either serum or BAL (albumin-corrected) Ig measurements as the independent variable and separate dependent variables, including B-cell subsets, BAL bacterial diversity metrics (Faith phylogenetic diversity, inverse Simpson, and richness indices), and clinical measures (FEV1% predicted, risk of prospective exacerbations), adjusted by age, sex, race, educational attainment, smoking status, and use of inhaled corticosteroids.

RESULTS: Serum IgG and IgA (n = 66 participants) were 1,486.1 ± 510.6 mg/dL [mean ± standard deviation (SD)] and 237.7 ± 131.6 mg/dL, respectively. Albumin-corrected BAL IgG and IgA (n = 117) were 0.03 ± 0.02 mg/dL and 0.01 ± 0.01 mg/dL, respectively. B-cells (n = 82) comprised 3.5 ± 3.0% of blood leukocytes. Serum IgA was associated with higher blood switched memory (IgD- CD27+) B-cell percentages (β 6.06, p = 0.01) and inversely associated with blood double-negative (IgD-CD27-) B-cell percentages (β - 9.96, p = 0.02). Available BAL microbiome data (n = 107) showed that reduced lung bacterial diversity associated with lower serum IgG, but not with serum IgA, BAL IgA, or BAL IgG concentrations. Neither BAL IgG nor IgA were associated with lung function or exacerbations.

CONCLUSIONS: These results demonstrate an association of low serum IgG with reduced lung bacterial diversity, a feature of dysbiosis that may predispose to exacerbation. Defining the role of Ig in specific anatomic compartments is relevant to designing vaccine strategies.

PMID:40682114 | DOI:10.1186/s12931-025-03310-w

Nature. 2025 Jul 18. doi: 10.1038/s41586-025-09225-2. Online ahead of print.

ABSTRACT

The expression and location of proteins in tissues represent key determinants of health and disease. Although recent advances in multiplexed imaging have expanded the number of spatially accessible proteins1-3, the integration of biological layers (that is, cell structure, subcellular domains and signalling activity) remains challenging. This is due to limitations in the compositions of antibody panels and image resolution, which together restrict the scope of image analysis. Here we present pathology-oriented multiplexing (PathoPlex), a scalable, quality-controlled and interpretable framework. It combines highly multiplexed imaging at subcellular resolution with a software package to extract and interpret protein co-expression patterns (clusters) across biological layers. PathoPlex was optimized to map more than 140 commercial antibodies at 80 nm per pixel across 95 iterative imaging cycles and provides pragmatic solutions to enable the simultaneous processing of at least 40 archival biopsy specimens. In a proof-of-concept experiment, we identified epithelial JUN activity as a key switch in immune-mediated kidney disease, thereby demonstrating that clusters can capture relevant pathological features. PathoPlex was then used to analyse human diabetic kidney disease. The framework linked patient-level clusters to organ disfunction and identified disease traits with therapeutic potential (that is, calcium-mediated tubular stress). Finally, PathoPlex was used to reveal renal stress-related clusters in individuals with type 2 diabetes without histological kidney disease. Moreover, tissue-based readouts were generated to assess responses to inhibitors of the glucose cotransporter SGLT2. In summary, PathoPlex paves the way towards democratizing multiplexed imaging and establishing integrative image analysis tools in complex tissues to support the development of next-generation pathology atlases.

PMID:40681898 | DOI:10.1038/s41586-025-09225-2