BMB Rep. 2025 Jun 11:6453. Online ahead of print.

ABSTRACT

Ferroptosis, an iron-dependent form of programmed cell death, is primarily driven by the accumulation of lipid peroxides through radical generation, notably via the Fenton reaction. Emerging evidence highlights the intricate link between ferroptosis and cellular metabolism, with metabolic enzymes playing pivotal roles in its regulation. Sulfide quinone oxidoreductase (SQOR), traditionally recognized for its role in hydrogen sulfide (H2S) detoxification and electron transport chain (ETC) activation, has recently been identified as a promiscuous enzyme with a novel function in ferroptosis regulation. This review explores SQOR's canonical function in H2S metabolism and its emerging role in ferroptosis resistance through the production of ubiquinol and hydropersulfides, radical-trapping antioxidants. Additionally, we provide insights into potential future research directions, emphasizing SQOR's therapeutic relevance in ferroptosis-associated diseases.

PMID:40495478

Cell Rep Methods. 2025 Jun 2:101074. doi: 10.1016/j.crmeth.2025.101074. Online ahead of print.

ABSTRACT

Analysis of biological samples often requires integrating diverse imaging modalities to gain a comprehensive understanding. While supervised biomedical image translation methods have shown success in synthesizing images across different modalities, they require paired data, which are often impractical to obtain due to challenges in data alignment and sample preparation. Unpaired methods, while not requiring paired data, struggle to preserve the precise spatial and quantitative information essential for accurate analysis. To address these challenges, we introduce STABLE (spatial and quantitative information preserving biomedical image translation), an unpaired image-to-image translation method that emphasizes the preservation of spatial and quantitative information by enforcing information consistency and employing dynamic, learnable upsampling operators to achieve pixel-level accuracy. We validate STABLE across various biomedical imaging tasks, including translating calcium imaging data from zebrafish brains and virtual histological staining, demonstrating its superior ability to preserve spatial details, signal intensities, and accurate alignment compared to existing methods.

PMID:40494359 | DOI:10.1016/j.crmeth.2025.101074

Cell. 2025 Jun 3:S0092-8674(25)00562-8. doi: 10.1016/j.cell.2025.05.012. Online ahead of print.

ABSTRACT

Understanding the mechanisms underlying mammalian regeneration may enable development of novel regenerative therapies. We present a mechanism wherein Desert hedgehog (Dhh), secreted from epithelial neuroendocrine cells, elicits a regenerative/protective response from mesenchymal cells. In mammalian airway, this mesenchymal response strikingly amplifies the initial signal from rare neuroendocrine cells to activate the entire tissue for survival and regeneration upon injury from SO2 gas inhalation or following influenza or SARS-CoV-2 infection. Similar epithelial-mesenchymal feedback (EMF) signaling directed by Dhh from neuroendocrine β cells likewise protects mouse pancreatic islets from streptozotocin (STZ) injury. A role for EMF signaling in human pancreatic islets is suggested by higher incidence of diabetes in patients treated with Hedgehog pathway inhibitors. Remarkably, EMF augmentation by small-molecule Hedgehog pathway agonism protects against STZ injury of pancreatic β cells and shields against airway injury from SO2 and influenza infection, with potential protective/therapeutic utility in chemical or infectious airway injury and in diabetes.

PMID:40494346 | DOI:10.1016/j.cell.2025.05.012

Curr Biol. 2025 Jun 9;35(11):R463-R469. doi: 10.1016/j.cub.2025.01.053.

ABSTRACT

Fungi include mushrooms, molds, lichens, yeasts, and zoosporic forms that occur as free-living or symbiotic organisms in every ecosystem on Earth. About 155,000 species of Fungi have been described, and possibly millions more remain to be named. Recent focus on aquatic habitats has illuminated major groups near the boundary between Fungi and protists. Fungal systematists have made remarkable progress toward resolving the major branches of the phylogeny, although some deep nodes have proven recalcitrant. Fungal taxonomists steadily describe about 3,000 new species per year, and fungal molecular ecologists routinely detect many thousands of unidentifiable 'dark fungi' through metagenomic analyses. To assemble the complete fungal tree of life, it will be necessary to connect the main branches of the phylogeny to information on all described species and integrate the vast and rapidly growing corpus of dark fungi.

PMID:40494297 | DOI:10.1016/j.cub.2025.01.053

Curr Biol. 2025 Jun 9;35(11):2554-2566.e7. doi: 10.1016/j.cub.2025.04.039.

ABSTRACT

Sri Lanka has played a key role in the peopling of South Asia, with archaeological evidence for human presence on the island dating back to ⁓40,000 years ago. Present-day Indigenous peoples of the island, the Adivasi, are proposed to have descended from early inhabitants of the region, while urban populations like the Sinhalese, the major ethnic group on the island, migrated from India in historical times. Using whole genomes from 19 Adivasi individuals belonging to two clans and from 35 Sinhalese, we find that the Adivasi and Sinhalese share high genetic similarities with each other and with other Sri Lankan and Indian populations, especially those with greater genetic affinity to Ancestral South Indians (ASI). Admixture modeling of the Sri Lankan groups reveals that despite shared ancestral components, the Adivasi retain higher genetic contributions from ancient hunter-gatherers compared with the Sinhalese. Additionally, in contrast to the Sinhalese, the Adivasi have maintained low effective population size and undergone strong founder events, which is consistent with their hunter-gatherer lifestyle, historic relocations, and habitat fragmentation. While the two Adivasi clans are genetically more similar to each other than to any other populations, we observe differing demographic histories, with the Interior Adivasi experiencing a stronger bottleneck than the Coastal Adivasi since their split. This whole-genome-based study addresses gaps in our understanding of the demographic and migratory history of two key Sri Lankan groups and, consequently, of broader South Asia by illuminating complex population structure that has been shaped by both demographic and socio-cultural factors.

PMID:40494279 | DOI:10.1016/j.cub.2025.04.039

Int Immunopharmacol. 2025 Jun 9;161:115028. doi: 10.1016/j.intimp.2025.115028. Online ahead of print.

ABSTRACT

INTRODUCTION: Pseudomonas aeruginosa-caused ocular infections are dangerous since they can cause corneal inflammation, damage, and blindness. This work aims to carefully assess the histomorphometric and clinical changes in rabbit corneas caused by Pseudomonas aeruginosa infection, focusing on investigating the potential therapeutic benefits of cold plasma.

MATERIALS AND METHODS: The right eye served as an untreated control, and the animals were randomly divided into four groups: Hariprasad et al. (2008) [1] Control group (the left eye infected with P. aeruginosa); Statham et al. (2008) [2] Antibiotic-treated group; Chaudhry (2013) [3] Non-infected plasma group; and (Speaker et al., 1991 [4]) Infected plasma-treated group. Exams of the left eye were performed on twenty rabbits, divided into four groups: non-infected plasma treatment, plasma-treated infection, plasma-treated infection, and antibiotic-treated infection. Clinical factors were quantified by an ophthalmologist using pre-established scoring systems. Evaluations were conducted on keratocyte expression levels, keratocyte cell count, and histomorphometric indices. Additionally, ELISA tests were used to measure the levels interleukin-6, and C-reactive protein and colony count assays were used to quantify bacteria. HMOX-1 and NRF-2 gene expressions were examined using a real-time PCR technique.

RESULTS: A higher frequency of clinical markers, such as tear production, destruction of the eyelid margin, abnormalities, swelling, viscous secretions, corneal swelling, stromal edema, shortened distance between the eyelid margins, corneal hyperemia, intraocular bleeding, and conjunctival inflammation, was noted in the control group. All evaluated clinical indicators were dramatically reduced by both the plasma and antibiotic treatments. Histomorphometric analysis showed significant differences in keratinocyte levels, corneal endothelium, and epithelial thickness between the treatment groups and the control group. The control group's lymphocyte count and stromal layers were notably different from those of the other groups. Plasma treatment significantly raised keratinocytes and the thickness of the cornea's endothelial and epithelial layers while simultaneously lowering the number of lymphocytes and stromal layers. When compared to the infected control, the NRF-2 gene expression in the groups treated with plasma and antibiotics showed a notable decrease, with the plasma-treated group showing the most significant decline. Similarly, both the plasma- and antibiotic-treated groups' HMOX-1 gene expression showed a significant decline, with the plasma-treated group showing the largest decline. The group receiving plasma therapy had a considerable increase in keratinocyte expression. Furthermore, bacterial count, C-reactive protein, and interleukin-6 concentrations markedly decreased in the plasma treatment group compared to the control group.

CONCLUSION: This study highlights how well cold plasma therapy works to reduce the negative consequences of corneal infection. The results validate the anti-inflammatory characteristics of plasma and its capacity to inhibit bacterial growth.

PMID:40494206 | DOI:10.1016/j.intimp.2025.115028

Sci Total Environ. 2025 Jun 9;988:179820. doi: 10.1016/j.scitotenv.2025.179820. Online ahead of print.

ABSTRACT

For osmoconforming organisms, prolonged exposure to reduced salinity requires an adjustment to intracellular osmolyte levels to ensure an osmotic balance is maintained between the cell and external sea water. However, osmolytes-low-molecular-mass micromolecules-may also serve overlapping roles in freeze avoidance, desiccation resistance, and protein stabilisation. In Antarctic species living at or below 0 °C, multiple environmental stressors likely shape species-specific osmolyte profiles. Yet, the osmolytes utilised in osmotic acclimation and the broader micromolecular profile of Antarctic marine organisms remain poorly characterised. This study employed gas chromatography-mass spectrometry (GC-MS) to analyse the organic osmolyte composition of two endemic Antarctic echinoderms, the sea star Odontaster validus and sea urchin, Sterechinus neumayeri, following long-term acclimation (>12 weeks) to reduced salinity levels (29 ‰ and 24 ‰). Significant reductions in total tissue organic solute (osmolyte) concentrations after low salinity exposure indicated active cell volume regulation to reduce intracellular osmotic pressure. The osmolyte metabolic profiles of these Antarctic species appeared distinct from those of temperate echinoderms and other marine osmoconformers, suggesting a specialised adaptive response. Notably, the use of branched-chain amino acids (valine, leucine, and isoleucine) in cell volume regulation in O. validus, and to a lesser extent in S. neumayeri, suggests a micromolecular adaptation tailored to the extreme cold of the Antarctic environment.

PMID:40494059 | DOI:10.1016/j.scitotenv.2025.179820

Blood. 2025 Jun 10:blood.2024024719. doi: 10.1182/blood.2024024719. Online ahead of print.

ABSTRACT

AL amyloidosis is a disorder characterized by expansion of clonal plasma cells in the bone marrow and distant end organ damage mediated by misfolded immunoglobulin free light chains. There are currently limited data regarding the functional characteristics of AL amyloidosis plasma cells and their surrounding bone marrow microenvironment. We performed 5' single cell RNA sequencing on newly diagnosed, treatment naïve AL amyloidosis patients and healthy subjects. We identified generalized suppression of normal bone marrow hematopoiesis with distinct expansion of monocytes and subsets of CD4+ T cells in AL amyloidosis patients. We detected significant transcriptional changes broadly occurring among immune cells with increased TNF-a signaling and interferon response accompanied by increased inflammatory response in bone marrow plasma as measured via quantitative proteomics with specific elevation of co-stimulatory molecule soluble CD276 (sB7-H3). A transcriptionally distinct population of non-malignant plasma cells was disproportionately expanded in AL amyloidosis patients and characterized by increased expression of CRIP1. Finally, clonal AL amyloidosis plasma cells were identified based on their unique VDJ rearrangement and showed increased expression of genes involved in proteostasis when compared to autologous, polyclonal plasma cells. Inter-patient transcriptional heterogeneity was evident, with transcriptional states reflective of common genomic translocations easily identifiable. This study defines the transcriptional characteristics of AL amyloidosis plasma cells and their surrounding bone marrow microenvironment with identification of altered genes previously involved in the pathogenesis of other protein deposition disorders. Our data provide the rationale for functional validations of these genes in future studies.

PMID:40493887 | DOI:10.1182/blood.2024024719

Proc Natl Acad Sci U S A. 2025 Jun 17;122(24):e2502872122. doi: 10.1073/pnas.2502872122. Epub 2025 Jun 10.

ABSTRACT

Effector-Triggered Immunity (ETI) is an important part of the plant immune system, allowing plants to sense and respond to harmful pathogen proteins known as "effectors." Effectors can be sensed directly or indirectly by NLR (Nucleotide-binding Leucine-rich Repeat) proteins, many of which "guard" the plant proteins targeted by effectors. Although a few effector-target-NLR interactions have been characterized, a general understanding of how these molecular interactions give rise to a functioning immune system is lacking. Here, we present a physics-based model of ETI based on protein-protein interactions. We show that the simplest physical model consistent with the biology gives rise to a robust immune sensor and explains the empirical phenomenon of effector interference as a generic consequence of molecules competing for binding partners. Using the evolutionarily conserved ZAR1 defense gene as a model, we explain how more complex interaction networks integrate multiple pathogen signals into a single response. We then examine alternatives to a guarding architecture, including direct sensing, decoys, and blended "integrated decoy" strategies, and reveal that these sensing architectures obey functional trade-offs between their sensitivity, target protection, and proteomic cost. This allows a quantitative analysis of the trade-offs between different forms of ETI. We discuss these findings in the context of the evolutionary forces shaping the plant immune system.

PMID:40493200 | DOI:10.1073/pnas.2502872122

Glycobiology. 2025 Jun 10:cwaf035. doi: 10.1093/glycob/cwaf035. Online ahead of print.

ABSTRACT

Aberrant O-glycosylation of mucin-type glycopeptide 1 (MUC1) is implicated in cancerous cellular processes involving the manipulation of immune response to favour tumour growth and metastasis. There is an unmet need for systems glycobiology models to probe the relationship between MUC1 O-glycosylation and immune cells within the tumour microenvironment. We expand on the sparsely understood MUC1 and immune cell interactions by building a complete systems model that combines the glycosylation network in the tumour cell with downstream biological networks. An ordinary differential equations-based model of the effect of aberrant glycosylation on immune modulation in breast cancer was constructed. The model comprises three interdependent component models that are MUC1-type O-glycosylation in the tumour cell, chemokine secretion in macrophages, and signal transduction in the tumour cells. A comparative CytoCopasi algorithm was developed to sequentially perturb the networks by an aberrant O-glycosylation. Comparative simulations revealed that upregulation of tumour-associated MUC1 sialyl-T antigen in Luminal A breast cancer stimulated the upregulation of the chemokine CXCL5 in tumour-associated macrophages. Consequently, increased CXCL5 binding by the tumour cell led to a positive feedback loop through overactive signal transduction and autocrine CXCL5 production. Finally, perturbing the glycosylation network with the sialyltransferase inhibitor Soyasaponin-I abrogated the cancerous upregulations in the downstream networks.

PMID:40492697 | DOI:10.1093/glycob/cwaf035

Elife. 2025 Jun 10;14:RP106042. doi: 10.7554/eLife.106042.

ABSTRACT

Understanding developmental changes in neuronal lineages is crucial to elucidate how they assemble into functional neural networks. Studies investigating nervous system development in model systems have only focused on select regions of the CNS due to the limited availability of genetic drivers that target specific neuronal lineages throughout development and adult life. This has hindered our understanding of how distinct neuronal lineages interconnect to form neuronal circuits during development. Here, we present a split-GAL4 library composed of genetic driver lines, which we generated via editing the genomic locus of lineage-specific transcription factors and demonstrate that we can use this library to specifically target most individual neuronal hemilineages in the Drosophila ventral nerve cord (VNC) throughout development and into adulthood. Using these genetic driver lines, we found striking morphological changes in neuronal processes within a lineage during metamorphosis. We also demonstrated how neurochemical features of neuronal classes can be quickly assessed. Lastly, we documented behaviors elicited in response to optogenetic activation of individual neuronal lineages and generated a comprehensive lineage-behavior map of the entire fly VNC. Looking forward, this lineage-specific split-GAL4 driver library will provide the genetic tools needed to address the questions emerging from the analysis of the recent VNC connectome and transcriptome datasets.

PMID:40492493 | DOI:10.7554/eLife.106042

NAR Genom Bioinform. 2025 Jun 9;7(2):lqaf076. doi: 10.1093/nargab/lqaf076. eCollection 2025 Jun.

ABSTRACT

Reference-based metagenomic profiling requires large genome libraries to maximize detection and minimize false positives. However, as libraries grow, classification accuracy suffers, particularly in k-mer-based tools, as the growing overlap in genomic regions among organisms results in more high-level taxonomic assignments, blunting precision. To address this, we propose sample-tailored minimizer libraries, which improve on the minimizer-lowest common ancestor classification algorithm from the widely used Kraken 2. In this method, an initial filtering step using a large library removes non-resemblance genomes, followed by a refined classification step using a dynamically built smaller minimizer library. This 2-step classification method shows significant performance improvements compared to the state of the art. We develop a new computational tool called Slacken, a distributed and highly scalable platform based on Apache Spark, to implement the 2-step classification method, which improves speed while keeping the cost per sample comparable to Kraken 2. Specifically, in the CAMI2 'strain madness' samples, the fraction of reads classified at species level increased by 3.5×, while for in silico samples, it increased by 2.2×. The 2-step method achieves the sensitivity of large genomic libraries and the specificity of smaller ones, unlocking the true potential of large reference libraries for metagenomic read profiling.

PMID:40491974 | PMC:PMC12147018 | DOI:10.1093/nargab/lqaf076

iScience. 2025 Apr 18;28(5):112472. doi: 10.1016/j.isci.2025.112472. eCollection 2025 May 16.

ABSTRACT

Nucleosomes are the basic repeating unit, each spanning ≈150bp, that structures DNA in the nucleus and their positions have major consequences on gene activity. Here, through analyzing DNA signatures across 1117 microeukaryote genomes, we discovered ≈150bp shifts in A/T content associated with nucleosome organization. Often consecutively arrayed across the genome, A/T peaks were enriched surrounding transcriptional start sites in specific clades. Most nucleosomes (both in vitro and in vivo) across eukaryotes aligned with A/T peaks, even in the presence of DNA modifications. Using artificial intelligence-based approaches, we describe DNA features associated with nucleosomes and construct a deep learning (DL) model for improved nucleosome occupancy prediction. Using this model, we found that ≈70% of "random" transfer DNA inserts from an in vivo fungal RB-TDNAseq library avoided DL predicted nucleosome-bound regions. This study reveals a eukaryote-wide strategy for generating cassettes of nucleosome-favorable DNAs that has a profound impact on nucleosome organization.

PMID:40491964 | PMC:PMC12146615 | DOI:10.1016/j.isci.2025.112472

J Diabetes Metab Disord. 2025 Jun 7;24(1):141. doi: 10.1007/s40200-025-01659-9. eCollection 2025 Jun.

ABSTRACT

BACKGROUND: Diabesotension, an overlapping triad of diabetes, hypertension, and obesity, remains a diagnostic challenge due to its complex underlying molecular mechanisms. Individuals with diabesotension face twice the risk of microvascular and macrovascular complications compared to those with either condition alone. However, the complexity of diabesotension poses significant diagnostic challenges due to limited knowledge of this disease trifecta.

METHODS: The protein network was constructed, and the DPClusOST algorithm was applied to determine the protein clusters with a density ranging from 0.1 to 1.0 and those relevant to the pathophysiology of diabesotension. The significance score (SScore) was computed using the p-value from Fisher's exact test to evaluate each cluster, and the clusters containing proteins associated with diabesotension were classified using receiver operating characteristic (ROC) analysis. The significant density of the cluster, as indicated by the AUC, was determined and subsequently subjected to pathway enrichment analysis using ShinyGO.

RESULTS: At densities of 0.6 and 0.8, 14 proteins (STX3, VAMP2, STX4, SYT1, DNAJC5, HSD17B10, DLD, AIFM1, PDHA1, PDHB, DLAT, PDHX, OGDH, and STAT5A) from clusters 13 and 53 were significantly identified as potential diabesotension-related proteins. Key pathways associated with the tripartite interplay of the three pathologies were found to involve amino acid metabolism, glycolysis/gluconeogenesis, SNARE-mediated vesicle transport, insulin and salivary secretion, and the glucagon and HIF-1 signaling pathways, thus identifying novel candidates for diabesotension biomarkers and therapeutic targets.

CONCLUSIONS: This study highlights the use of graph clustering to identify potential biomarkers for the comorbid triad, which could enhance personalized future treatment strategies.

PMID:40491693 | PMC:PMC12145358 | DOI:10.1007/s40200-025-01659-9

Front Psychiatry. 2025 May 26;16:1627536. doi: 10.3389/fpsyt.2025.1627536. eCollection 2025.

NO ABSTRACT

PMID:40491680 | PMC:PMC12146301 | DOI:10.3389/fpsyt.2025.1627536

iScience. 2025 May 2;28(6):112567. doi: 10.1016/j.isci.2025.112567. eCollection 2025 Jun 20.

ABSTRACT

The rate-limiting isozyme of de novo guanosine biosynthesis, IMPDH2, was identified as an essential gene in Merkel cell carcinoma (MCC) but the consequences of its functional disruption were unclear. Inhibition of IMPDH2 led to reduced MCC cell viability, independent of functional p53 or Merkel cell polyomavirus status, but dependent on depletion of guanylate nucleotides. In contrast to other cancer models, inhibition of IMPDH2 in MCC led to rapid ablation of nascent DNA synthesis and the onset of replication stress without a significant effect on total or ribosomal RNA biosynthesis. Combining IMPDH inhibitors with ataxia telangiectasia mutated and Rad3-related (ATR) inhibitors significantly increased levels of replication stress in vitro and reduced tumor growth in vivo. These findings support replication stress as the dominant consequence of IMPDH2 inhibition in MCC and, when combined with ATR inhibition, indicate a potential therapeutic strategy.

PMID:40491496 | PMC:PMC12148403 | DOI:10.1016/j.isci.2025.112567

iScience. 2025 Apr 29;28(6):112548. doi: 10.1016/j.isci.2025.112548. eCollection 2025 Jun 20.

ABSTRACT

Allogeneic natural killer (NK) cell-based therapies with an outstanding safety profile, are a compelling alternative to autologous T cell-based approaches for cancer immunotherapy, offering innate tumor-killing ability that can be further augmented via introduction of tumor antigen-specific chimeric antigen receptors (CARs). In this study, we genetically engineered primary human hematopoietic stem cells using an optimized lentiviral backbone carrying CD19 CAR cassettes with varied hinge, transmembrane, and signaling domains to evaluate their role in CAR-NK development and function. Our platform integrates early genetic modification with our unique expansion/differentiation system, enabling high CAR expression with low vector copy numbers. Notably, CARs incorporating CD28 transmembrane and signaling domains with CD3ζ, promoted enhanced tonic signaling, accelerated NK differentiation, enhanced antigen-specific kinome activation, and improved cytotoxicity and persistence both in vitro and in vivo. These findings offer a robust strategy for development of stem cell-based CAR-NK immunotherapies, combining potent innate, and antigen-specific antitumor responses.

PMID:40491480 | PMC:PMC12148404 | DOI:10.1016/j.isci.2025.112548

iScience. 2025 May 9;28(6):112625. doi: 10.1016/j.isci.2025.112625. eCollection 2025 Jun 20.

ABSTRACT

Dysregulated angiogenesis signaling leads to pathological vascular growth and leakage, and is a hallmark of many diseases including cancer and ocular diseases. In peripheral arterial disease, the concomitant increase in vascular permeability presents significant challenges in therapeutic efforts to improve perfusion by stimulating vascular growth. Building a mechanistic understanding of the endothelial control of vascular growth and permeability signaling is crucial to guide our efforts to identify therapeutic strategies that permit blood vessel growth while maintaining vascular stability. We develop a mechanistic systems biology model of the endothelial signaling network formed by the vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-Tie pathways, two major signaling pathways regulating vascular growth and stability. Our model, calibrated and validated against experimental data, reveals the mechanisms through which chronic Ang1 stimulation protects endothelial cells from VEGF-induced hyperpermeability, and predicts that combining Src inhibition with Tie2 activation can inhibit vascular leakage without disturbing angiogenesis signaling.

PMID:40491479 | PMC:PMC12148613 | DOI:10.1016/j.isci.2025.112625

iScience. 2025 Apr 28;28(6):112538. doi: 10.1016/j.isci.2025.112538. eCollection 2025 Jun 20.

ABSTRACT

Extracellular calcium export by the breast ductal epithelium is crucial during lactation and plays a significant role in breast cancer progression. Intraductal calcium deposition is a hallmark of aggressive premalignant lesions. This study tested the hypothesis that microbiome-derived extracellular vesicles (EVs) influence calcium modulation in premalignant breast cancer lesions. Based on the analysis of plasma, serum, saliva, and tissue collected from breast cancer patients and controls (N = 150), Lactobacillus rhamnosus (Lr) was chosen as the model microbiota. In a BT-474 human breast cancer cell line monolayer culture under acute calcium stress, Lr EVs enhanced intracellular calcium intake. In a BT474 3D spheroid model under chronic calcium stress, Lr EVs increased extracellular calcium deposition and mRNA expression of calcium export channel plasma membrane calcium-transporting ATPase 2 (PMCA2) and stromal interaction molecule 1 (STIM1) in a dose-dependent manner. We propose that Lr EVs influence calcium regulation and mineral deposition, thereby affecting premalignant breast cancer progression.

PMID:40491474 | PMC:PMC12148604 | DOI:10.1016/j.isci.2025.112538

EMBO J. 2025 Jun 9. doi: 10.1038/s44318-025-00481-6. Online ahead of print.

ABSTRACT

Influenza A viruses (IAV) display a broad variety of morphologies ranging from spherical to long filamentous virus particles. These diverse phenotypes are believed to allow the virus to overcome various immunological and pulmonary barriers during entry into the airway epithelium, and to influence the viral entry pathway. Notably, laboratory-adapted IAV strains predominantly adopt a spherical form, yet the factors driving this preference as well as the factors favoring filamentous morphology in physiological settings remain unclear. To address this, we generated fluorescent reporter viruses with identical surface glycoproteins but distinct morphologies and developed a correlative light and scanning electron microscopy workflow. This enabled us to investigate the impact of viral morphology on spread, and to identify conditions favoring either form. Our findings demonstrate that filamentous IAV spread significantly slower in various cell lines, consistent with delayed entry kinetics and in-cell cryo-electron tomography, explaining the predominance of spherical forms in laboratory-adapted strains. Cellular junction integrity, neuraminidase activity, and mucin do not inhibit IAV spread in a morphology-dependent manner. However, filamentous virions confer a selective advantage under neutralizing-antibody pressure against hemagglutinin.

PMID:40490555 | DOI:10.1038/s44318-025-00481-6