Nat Commun. 2025 Jul 1;16(1):5585. doi: 10.1038/s41467-025-60642-3.

ABSTRACT

Cross-linking mass spectrometry (XL-MS) is a powerful technology for mapping protein-protein interactions (PPIs) at the systems level. While bivalent cross-links are effective for defining protein interactions and structures, multivalent cross-links offer enhanced spatial resolution to facilitate characterization of heterogeneous protein complexes. However, their identification remains challenging due to fragmentation complexity and the vast expansion of database search space. Here, we present tris-succinimidyl trioxane (TSTO), a novel trioxane-based, MS-cleavable homotrifunctional cross-linker capable of targeting three proximal lysines simultaneously. TSTO's unique MS-cleavability enables concurrent release of cross-linked peptide constituents during collision-induced dissociation, permitting their unambiguous identification. The TSTO-based XL-MS platform is effective for mapping cellular networks from intact cells and tissues, illustrating its versatility for complex biological systems. Trimeric interactions captured by TSTO reveal structural details inaccessible to bifunctional reagents, enhancing modeling accuracy and precision. Furthermore, this development opens a new avenue for designing multifunctional MS-cleavable cross-linkers to further advance structural systems biology.

PMID:40593561 | DOI:10.1038/s41467-025-60642-3

Sci Rep. 2025 Jul 1;15(1):20816. doi: 10.1038/s41598-025-05276-7.

ABSTRACT

Breast cancer is a leading health concern in Saudi Arabia, characterized by unique demographic and clinical profiles. This study analyzed breast cancer cases at King Fahad Specialist Hospital-Dammam (KFSH-D), focusing on age at diagnosis, disease stage, histological type, and hormonal receptor status. A retrospective cohort study included 5,954 breast cancer patients diagnosed between 2006 and 2022 from the KFSH-D database. Data were extracted via a Real-World Evidence Digital Platform adhering to international standards. Statistical analyses included descriptive statistics, Chi-square tests, t-tests, incidence and mortality rate calculations, survival analysis, and predictive modeling for future incidence trends. The cohort had a mean age at diagnosis of 49 years (SD = 12.0), with most patients aged 40-59 years. Over 99% were female and predominantly Saudi nationals. Approximately two-thirds presented with locally advanced disease, with invasive ductal carcinoma being the most common type (81%). Al Ahsa region accounted for 31% of referral cases. Hormonal receptor status showed 59% HER2-negative, 61% ER-positive, and 56% PR-positive. Predictive modeling forecasted an 80% increase in new cases by 2028, with incidence rates expected to double. This study highlights a younger median age at diagnosis and a high prevalence of late-stage disease. These findings underscore the urgent need for improved screening programs, targeted public health interventions, and better healthcare access in Saudi Arabia.

PMID:40592998 | DOI:10.1038/s41598-025-05276-7

Cell Death Dis. 2025 Jul 1;16(1):467. doi: 10.1038/s41419-025-07784-w.

ABSTRACT

Early studies have shown that erythrocytes have caspase-3 and caspase-8 and are capable of dying through an apoptotic-like cell death triggered by Ca2+ ionophores. This cell death is associated with apoptosis-like morphological signs, including cell shrinkage, membrane blebbing, and phosphatidylserine externalization. To emphasize that mature erythrocytes don't have the apoptotic mitochondrial machinery and distinguish this unique cell death modality from apoptosis, it was named "eryptosis". Over recent decades, our knowledge of eryptosis has been significantly expanded, providing more insights into the uniqueness of cell death pathways in erythrocytes. In this review, we aim to summarize our current understanding of eryptosis, formulate the nomenclature and guidelines to interpret results of eryptosis studies, provide a synopsis of morphological and biochemical features of eryptosis, and highlight the role of eryptosis in health and disease, including its druggability.

PMID:40592821 | DOI:10.1038/s41419-025-07784-w

Biomol Ther (Seoul). 2025 Jul 1;33(4):594-605. doi: 10.4062/biomolther.2025.065. Epub 2025 Jun 30.

ABSTRACT

Depressive amnesia, involving memory impairment and mood dysregulation, frequently co-occurs with depression and neurodegenerative diseases. Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to depressive-like behaviors and cognitive deficits. This study evaluated the therapeutic potential of 2',4',6'-trimethoxyacetophenone (TMA), a bioactive compound from Lycoris sanguinea var. koreana, in a mouse model of MGO-induced depressive amnesia. Mice received MGO (60 mg/kg) followed by TMA (5 or 20 mg/kg), and behavioral tests were conducted to assess mood, cognition, and locomotor activity. TMA significantly reduced immobility in tail suspension and forced swim tests, improved locomotion and exploration in the open field, and restored memory in novel object recognition and Y-maze tests. Histological analysis showed that TMA preserved hippocampal integrity, modulated glucocorticoid receptor expression, and reduced cortisol levels, indicating involvement in stress regulation. TMA also attenuated neuroinflammation by lowering IL-1β and microglial activation while increasing IL-10. Additionally, it reduced amyloidogenic markers, including oligomeric Aβ and amyloid precursor protein. These findings highlight the neuroprotective and antidepressant potential of TMA and support its use as a natural therapeutic candidate for treating depression-related cognitive impairment.

PMID:40592762 | DOI:10.4062/biomolther.2025.065

J Microbiol Immunol Infect. 2025 Jun 25:S1684-1182(25)00129-X. doi: 10.1016/j.jmii.2025.06.007. Online ahead of print.

ABSTRACT

BACKGROUND: Pollen sensitization is not as common as mite sensitization in Taiwan. The dearth of regional aeropalynological studies and relevant clinical analyses has, therefore, led to an underestimation of the prevalence of pollen allergies. To investigate this impact, we evaluated the alteration of pollen sensitization and its association with climate change in northern Taiwan.

METHODS: We enrolled the patients from National Taiwan University Hospital who lived in Taipei and New Taipei City, tested positive for pollen-specific immunoglobulin E (IgE) on an OPTIGEN® allergen-specific IgE assay, and had relevant symptoms. Their data were cross-referenced with climate data from the Central Weather Bureau for the same period.

RESULTS: In total, 11,895 patients were enrolled, of whom 930 (7.8 %) tested positive for pollen-specific IgE. Black willow was the most common pollen allergen identified. According to the Cochran-Armitage test, the annual sensitization to Bermuda grass, Japanese cedar, pigweed, ragweed mix, and black willow pollen varied significantly. According to Spearman's correlation test, the annual sensitization to Bermuda grass, white mulberry, ragweed mix, timothy grass, and black willow positively correlated with the mean winter temperature, whereas that to white mulberry and timothy grass negatively correlated with mean winter rainfall.

CONCLUSION: The pollen sensitization pattern has changed gradually in northern Taiwan over recent years. Warm mean temperatures and low mean rainfall in winter significantly correlated with annual sensitization to some pollen allergens. Climate change may have exacerbated the prevalence of pollen sensitization, and the emerging burden of pollen allergies should not be neglected in Taiwan.

PMID:40592617 | DOI:10.1016/j.jmii.2025.06.007

J R Soc Interface. 2025 Jul;22(228):20240910. doi: 10.1098/rsif.2024.0910. Epub 2025 Jul 2.

ABSTRACT

Avian influenza A(H5N1) poses a public health risk due to its pandemic potential should the virus mutate to become human-to-human transmissible. To date, reported influenza A(H5N1) human cases have typically occurred in the lower respiratory tract with a high case fatality rate. There is prior evidence of some influenza A(H5N1) strains being a small number of amino acid mutations away from achieving droplet transmissibility, possibly allowing them to be spread between humans. We present a mechanistic within-host influenza A(H5N1) infection model, novel for its explicit consideration of the biological differences between the upper and lower respiratory tracts. We then estimate a distribution of viral lifespans and effective replication rates in human H5N1 influenza cases. By combining our within-host model with a viral mutation model, we determine the probability of an infected individual generating a droplet transmissible strain of influenza A(H5N1) through mutation. For three mutations, we found a peak probability of approximately [Formula: see text] that a human case of H5N1 influenza produces at least one virion during the infectious period. Our findings provide insights into the risk of differing infectious pathways of influenza A(H5N1) (namely avian-human versus avian-mammal-human routes), demonstrating the three-mutation pathway being a cause of concern in human cases.

PMID:40592463 | DOI:10.1098/rsif.2024.0910

Ecotoxicol Environ Saf. 2025 Jun 30;302:118587. doi: 10.1016/j.ecoenv.2025.118587. Online ahead of print.

ABSTRACT

The increasing environmental detection of antidepressants such as amitriptyline (AT) has raised toxicological concerns, yet its long-term safety profile remains poorly characterized. We applied an integrative strategy combining phenome-wide association studies (PheWAS), Mendelian randomization (MR), network toxicology, and molecular docking to systematically evaluate potential adverse effects of AT. PheWAS analyses were performed across 784 phenotypes using UK Biobank and FinnGen (R10). Among these, loss-of-function mutations in AT targets SLC6A2 and SLC6A4 showed significant associations after multiple-testing correction with pancreatic cancer and erythematous conditions, respectively. Complementary MR analyses using GTEx v8 tissue-specific cis-expression quantitative trait loci (eQTLs) and multiple autoimmune and inflammatory genome-wide association study (GWAS) datasets demonstrated that elevated expression of SLC6A2 and SLC6A4 conferred protective effects against systemic lupus erythematosus, psoriasis, rosacea, and erythema nodosum across tissues, supporting the causal relevance of these pathways. Network toxicology based on protein-protein interactions (STRING v11.5, Cytoscape v3.10.1) and functional enrichment (ClusterProfiler v4.10.0) highlighted immunoinflammatory, neuroendocrine, and ion channel regulatory mechanisms potentially involved in AT-induced toxicity. Finally, molecular docking simulations (AutoDock Vina v1.2.7, AlphaFold structures) provided structural evidence for AT interactions with key targets including TRPV1. Collectively, these findings suggest that pharmacological inhibition or environmental accumulation of AT may contribute to inflammatory skin reactions and pancreatic tumorigenesis through multiple converging molecular pathways.

PMID:40592148 | DOI:10.1016/j.ecoenv.2025.118587

Food Chem. 2025 Jun 18;491:145215. doi: 10.1016/j.foodchem.2025.145215. Online ahead of print.

ABSTRACT

To broadly summarize acetogenin characterization based on spectroscopic and chromatographic hallmarks, the water-insoluble acetogenins obtained from Mexico Hass avocado pulp and seed were separated and then purified by HPLC. The components were identified in the water-insoluble fraction of methanolic extracts exploiting the diagnostic NMR pattern of their functional groups. Following HPLC separation, the individual compounds were characterized by MS and NMR assignments. The toxicity of the crude extract and two isolated components was evaluated using Caenorhabditis elegans. For the L1 larvae of this nematode, exposure to crude extracts containing 2.5 μM avocadene, 4.3 μM persenone A, and species with terminal methyl or acetate was lethal, whereas median lethal doses of 10.0 ± 0.1 and 9.1 ± 0.4 μM were measured for persenone A and persin, respectively. Though further efforts are necessary for the chromatographically unresolved species, the collected analytical signatures can enable assessing gross compositions of extracts from different avocado varieties.

PMID:40592068 | DOI:10.1016/j.foodchem.2025.145215

Yale J Biol Med. 2025 Jun 30;98(2):171-186. doi: 10.59249/FTXB7704. eCollection 2025 Jun.

ABSTRACT

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic, autoimmune disorder characterized by inflammation along the gastrointestinal tract. Global prevalence of the disease is increasing and patients often experience delays in diagnosis accessing effective therapy, highlighting an urgent need to develop a predictive biomarker for therapeutic response to reduce healthcare costs and disease burdens. Despite the advances to identifying genetic biomarkers for prediction of disease remission in IBD, patient responses vary widely, suggesting that inherited genetic variations alone cannot account for these differences. As autoimmune diseases like IBD are largely environmental in etiology, epigenetic modifications like DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) also have the potential to be candidates for predictive biomarkers of patient disease development and treatment response. This review will explore the novel field of pharmacoepigenetics and the development of predictive epigenetic biomarkers for treatment response in IBD, highlighting new research in the field. While research is still in the early stages, the studies reviewed have demonstrated that epigenetic profiling can be utilized to predict treatment response in IBD patients. Additional pharmacoepigenetic cohorts with more diverse participants could help enhance current models, improving predictability of treatment response and clinical outcomes. As research in this field progresses, epigenetic biomarkers should be integrated into the clinical environment to expedite diagnosis, reduce trial-and-error approach to treatment, and lay the foundations for individualized therapeutic strategies for IBD patients.

PMID:40589936 | PMC:PMC12204032 | DOI:10.59249/FTXB7704

Front Cell Infect Microbiol. 2025 Jun 16;15:1597690. doi: 10.3389/fcimb.2025.1597690. eCollection 2025.

ABSTRACT

INTRODUCTION: The human oral cavity is a complex and dynamic microbial ecosystem integral to oral and overall health. While the specific roles of microbial communities in health and disease are not fully understood, dysbiosis of the oral microbiota is, along with inadequate immune fitness, recognized as a key factor driving the onset of inflammatory conditions such as gingivitis. Gingivitis, an early and reversible stage of periodontal disease, involves shifts in microbial composition and diversity. This study aimed to investigate the compositional dynamics of the oral microbiota during the early stages of gingival inflammation, focusing on changes across multiple oral niches and their relationship to clinical outcomes.

METHODS: We conducted an experimental gingivitis intervention study with 41 healthy volunteers. After a two-week baseline period, participants refrained from oral hygiene for two weeks to induce gingivitis, followed by a one-week resolution phase with resumed oral hygiene. Clinical parameters, including plaque and bleeding scores, were monitored at seven time points. Samples from saliva and five oral niches (tongue, keratinized gingiva, supragingival, subgingival, and interproximal dental plaque) were collected and analyzed using 16S rRNA gene sequencing. Multivariate statistical analyses were applied to evaluate microbial dynamics and their associations with clinical outcomes.

RESULTS: The study revealed pronounced microbial changes, particularly in supragingival plaque, where Leptotrichia and Prevotella increased while Streptococcus decreased. Alpha diversity significantly increased in supragingival plaque, tongue, and saliva during gingivitis induction, highlighting shifts in microbial complexity. Clinical correlations indicated that plaque presence was primarily associated with bacterial load, while gingival bleeding was driven by compositional changes in supragingival plaque and tongue biofilms. These findings suggest that microbial density and composition independently contribute to gingivitis markers.

CONCLUSION: This study concludes that occurrence of dental plaque and gingival bleeding are independent clinical parameters, linked to bacterial load and composition, respectively. Interactions between multiple niches, especially the tongue, influence clinical outcomes, highlighting a complex, nonlinear dynamic behavior in the oral microbiota. These findings suggest intricate ecological interactions that may approach tipping points, advancing understanding of microbial dynamics during gingival inflammation and informing future strategies for managing gingivitis.

PMID:40589868 | PMC:PMC12206739 | DOI:10.3389/fcimb.2025.1597690

Iran J Psychiatry. 2024 Oct;19(4):367-383. doi: 10.18502/ijps.v19i4.16550.

ABSTRACT

Objective: Major depressive disorder (MDD) stands as one of the serious psychiatric conditions that detrimentally affect patients' quality of life and leads to a significant part of disability worldwide. Due to the limited understanding of the basic molecular mechanisms of depression and antidepressant medications, a clear understanding of the onset and development of MDD is unavailable. This study aims to figure out the pivotal genes and pathways implicated in the MDD development and identify medications that can potentially improve MDD treatment based on their relation with the key genes. Method : Symbols of human coding genes were retrieved from the HUGO Gene Nomenclature Committee database. These symbols were then queried for MDD-related associations using a Python script in PubMed. Subsequently, genes with two or more related articles to MDD were selected. A union of our search data and MDD-related genes in the DisGeNET database was found. The gene interaction network was generated and analyzed utilizing the STRING and Cytoscape, respectively. Finally, a drug-gene network was constructed and medications that can affect multiple genes were selected. Results: The union of our search data and DisGeNET data contained 1734 genes. Based on network analysis, TNF, IL1B, IL6, STAT1, and STAT3 were identified as the key genes in the MDD pathogenesis. Eleven drugs that affect more than one gene were detected through a drug-gene network. These medications include Acitretin, Adalimumab, Alteplase, Cisplatin, Digoxin, Etanercept, Infliximab, Insulin, Omeprazole, Pentoxifylline, and Rabeprazole. Conclusion: In summary, our findings identified five genes as key genes in MDD development, as well as medications related to key genes. This study provides a new vision of the pathogenesis and treatment of MDD. However, further experimental and clinical studies are necessary.

PMID:40589842 | PMC:PMC12206463 | DOI:10.18502/ijps.v19i4.16550

Front Immunol. 2025 Jun 16;16:1607770. doi: 10.3389/fimmu.2025.1607770. eCollection 2025.

ABSTRACT

INTRODUCTION: Although natural killer (NK) cells play crucial roles in the immune response to Mycobacterium tuberculosis (M.tb) infection, systematic investigations delineating the immune characteristics of NK cells across the tuberculosis (TB) disease spectrum are scarce.

METHODS: This multiomics study employed transcriptomic, proteomic, and RT-qPCR analyses to characterize and validate CD56+ NK cells from 165 participants stratified by TB infection status (active TB (ATB), latent TB infection (LTBI), and healthy control (HC)). Peripheral blood samples from an independent cohort of 85 participants were subjected to flow cytometry analysis and validation.

RESULTS AND DISCUSSION: Enrichment analyses of transcriptomic and proteomic data revealed that the NK cell-mediated cytotoxicity and apoptosis pathways were enriched in LTBI and ATB groups, whereas chemotaxis-related pathway enrichment was specific to ATB. Further analysis revealed that the expression of genes mediating the NK cell-mediated cytotoxicity signaling pathway through perforin-granzyme was upregulated in the LTBI state, whereas that of those associated with death receptors was elevated in ATB, potentially indicating a transformation of NK cell function in different TB infection states. Moreover, analysis of ATB-specific chemotaxis genes suggested that the migration of NK cells was likely to occur in the ATB state. Flow cytometry revealed an increased frequency of CD56dim NK cells and a decreased frequency of CD56bright NK cells in individuals with LTBI versus that in HCs in an independent cohort. In addition, RT-qPCR validation identified a four-biomarker combination (SLC7A5, PDE4D, CXCR4, and SOCS3) distinguishing ATB from HCs, a three-biomarker combination (SLC7A5, PER1, and PDE4D) differentiating LTBI from HC, and a three-biomarker combination (SOCS3, GZMK, and HIST1H3B) differentiating ATB from LTBI. These findings elucidate the immune clearance mechanism of NK cells in TB and provide clinically actionable biomarkers for infection staging, advancing our understanding of TB immunopathogenesis.

PMID:40589756 | PMC:PMC12206628 | DOI:10.3389/fimmu.2025.1607770

Front Aging Neurosci. 2025 Jun 16;17:1559388. doi: 10.3389/fnagi.2025.1559388. eCollection 2025.

ABSTRACT

BACKGROUND: Vascular cognitive impairment (VCI) is the second most frequent form of cognitive disorder. It is mainly caused by a diseased cerebral vasculature and affects patients' cognition and activities of daily living (ADL). Previous studies have demonstrated that acupuncture therapy is a promising complementary treatment that significantly improves cognitive status and ADL in VCI patients. This study aimed to investigate the effects of different types of acupuncture therapies and conventional treatments on cognitive status and ADL in VCI patients to provide evidence-based clinical recommendations.

METHODS: We searched seven electronic databases for randomized controlled trials comparing acupuncture therapies [including manual acupuncture (MA), scalp acupuncture (SA), electroacupuncture (EA), and auricular acupuncture (AA)] with conventional treatment [pharmacotherapy (P), cognitive rehabilitation (CR)] or standard care (SC) in patients with VCI. The primary outcome was cognitive improvement, while secondary outcomes included improvement in ADL and the risk of severe adverse effects. A frequentist random-effects network meta-analysis was performed under a consistency model. Study quality was assessed using the RoB 2.0 tool. Inconsistency was examined via node-splitting. Subgroup analysis, meta-regression, and sensitivity analysis were conducted to explore heterogeneity and assess robustness. Publication bias was evaluated using funnel plots and Egger's test.

RESULTS: Through stepwise exclusion of studies contributing to publication bias and inconsistency, a robust bias-adjusted network meta-analysis dataset was established. The results showed that among all interventions, SA+P+SC demonstrated the greatest efficacy in improving cognitive status compared to SC (SMD: 2.04; 95% CI: 1.21-2.86) with substantial heterogeneity (I2 = 71.0%), no significant inconsistency, and relative low publication bias (p = 0.7020).

CONCLUSION: Acupuncture, particularly SA combined with P and SC, appears to be a safe and effective adjunctive treatment for patients with VCI. Future studies are warranted to establish VCI-specific MCID thresholds and to validate these findings through large-scale, high-quality RCTs.

SYSTEMATIC REVIEW REGISTRATION: https://inplasy.com/inplasy-2023-5-0114/, identifier INPLASY202350114.

PMID:40589623 | PMC:PMC12206881 | DOI:10.3389/fnagi.2025.1559388

Elife. 2025 Jul 1;14:e89929. doi: 10.7554/eLife.89929.

ABSTRACT

Bees' remarkable visual learning abilities make them ideal for studying active information acquisition and representation. Here, we develop a biologically inspired model to examine how flight behaviours during visual scanning shape neural representation in the insect brain, exploring the interplay between scanning behaviour, neural connectivity, and visual encoding efficiency. Incorporating non-associative learning-adaptive changes without reinforcement-and exposing the model to sequential natural images during scanning, we obtain results that closely match neurobiological observations. Active scanning and non-associative learning dynamically shape neural activity, optimising information flow and representation. Lobula neurons, crucial for visual integration, self-organise into orientation-selective cells with sparse, decorrelated responses to orthogonal bar movements. They encode a range of orientations, biased by input speed and contrast, suggesting co-evolution with scanning behaviour to enhance visual representation and support efficient coding. To assess the significance of this spatiotemporal coding, we extend the model with circuitry analogous to the mushroom body, a region linked to associative learning. The model demonstrates robust performance in pattern recognition, implying a similar encoding mechanism in insects. Integrating behavioural, neurobiological, and computational insights, this study highlights how spatiotemporal coding in the lobula efficiently compresses visual features, offering broader insights into active vision strategies and bio-inspired automation.

PMID:40589182 | DOI:10.7554/eLife.89929

Stud Health Technol Inform. 2025 Jun 26;328:158-162. doi: 10.3233/SHTI250693.

ABSTRACT

Traditional methods can miss subtle patterns or abnormalities in movement, speech, and language behavior, which are early signs of developmental disorders in young children. Artificial intelligence (AI) technologies offer a multi-modal approach, capturing a wider range of digital biomarkers. By analyzing video and speech data on child development, AI can detect abnormalities earlier. This study explored the attitudes, needs, and concerns of parents, healthcare (HC) professionals, and youth HC managers regarding AI's use in monitoring children's development as a prerequisite for its potential successful implementation and usage. Semi-structured interviews with 28 participants showed generally positive attitudes towards AI, recognizing its potential to enhance efficiency, support HC professionals, and improve monitoring. Parents and managers appreciated reducing visits for healthy children and allowing more time for those identified through triage, while HC professionals emphasized objective and standardized tests, and maintaining personal interactions. Concerns included AI's accuracy, privacy, consent, and ethical issues.

PMID:40588901 | DOI:10.3233/SHTI250693

Nat Microbiol. 2025 Jun 30. doi: 10.1038/s41564-025-02041-4. Online ahead of print.

ABSTRACT

Determining why only a fraction of encountered or applied strains engraft in a given person's microbiome is crucial for understanding and engineering these communities. Previous work has established that metabolic competition between bacteria can restrict colonization success in vivo, but other mechanisms may also prevent successful engraftment. Here we combine genomic analysis and high-throughput agar competition assays to demonstrate that intraspecies warfare presents a significant barrier to strain coexistence in the human skin microbiome by profiling 14,884 pairwise interactions between Staphylococcus epidermidis isolates cultured from 18 people from 6 families. We find that intraspecies antagonisms are abundant, mechanistically diverse, independent of strain relatedness and consistent with rapid evolution via horizontal gene transfer. Critically, these antagonisms are significantly depleted among strains residing on the same person relative to random assemblages, indicating a significant in vivo role. Wide variation in antimicrobial production and resistance suggests trade-offs between these factors and other fitness determinants. Together, our results emphasize that accounting for intraspecies warfare may be essential to the design of long-lasting probiotic therapeutics.

PMID:40588591 | DOI:10.1038/s41564-025-02041-4

Nat Rev Microbiol. 2025 Jun 30. doi: 10.1038/s41579-025-01195-6. Online ahead of print.

ABSTRACT

Originating from aquatic unicellular ancestors, over the course of ~1 billion years, the fungi have evolved to occupy nearly all aerobic environments on the planet, diversified into millions of different 'species' and have developed complex multicellular structures. Their relatively small, simple genomes have facilitated massive-scale sequencing and allowed us to explore genome evolution across an ancient eukaryotic kingdom. With thousands of genomes from diverse lineages now available, this Review will discuss insights into fungal biology and evolution gleaned with genomics and other multi-omics approaches. Using published genomes available through GenBank and the Joint Genome Institute's MycoCosm platform, we generated kingdom-wide phylogenies and used them to highlight how fungal genomes have changed over time. With this phylogeny as a guide, we also discuss major evolutionary transitions that occurred across the fungal kingdom. Although progress has been made, these efforts are hampered by biases in genome representation and limited characterization of gene functions. Here, we discuss these challenges and possible future directions to address them, including initiatives to characterize conserved genes of unknown function and scale up sequencing towards 10,000 annotated fungal genomes.

PMID:40588585 | DOI:10.1038/s41579-025-01195-6

Mol Syst Biol. 2025 Jun 30. doi: 10.1038/s44320-025-00115-3. Online ahead of print.

ABSTRACT

Gene expression programs that establish and maintain specific cellular states are orchestrated through a regulatory network composed of transcription factors, cofactors, and chromatin regulators. Dysregulation of this network can lead to a broad range of diseases by altering gene programs. This article presents LaGrACE, a novel method designed to estimate dysregulation of gene programs combining omics data with clinical information. This approach facilitates the grouping of samples exhibiting similar patterns of gene program dysregulation, thereby enhancing the discovery of underlying molecular mechanisms in disease subpopulations. We rigorously evaluated LaGrACE's performance using synthetic data, bulk RNA-seq clinical datasets (breast cancer, chronic obstructive pulmonary disease (COPD)), and single-cell RNA-seq drug perturbation datasets. Our findings demonstrate that LaGrACE is exceptionally robust in identifying biologically meaningful and prognostic molecular subtypes. In addition, it effectively discerns drug response signals at a single-cell resolution. Moreover, the COPD analysis uncovered a new role of LEF1 regulator in COPD molecular mechanisms associated with mortality. Collectively, these results underscore the utility of LaGrACE as a valuable tool for elucidating the underlying mechanisms of diseases.

PMID:40588571 | DOI:10.1038/s44320-025-00115-3

Nat Genet. 2025 Jun 30. doi: 10.1038/s41588-025-02239-6. Online ahead of print.

ABSTRACT

Transposable elements (TEs) are abundant in the human genome, and they provide the source for genetic and functional diversity. Previous studies have suggested that TEs are repressed by DNA methylation and chromatin modifications. Here through integrating transcriptome and 3D genome architecture studies, we showed that haploinsufficient loss of NIPBL selectively activates alternative promoters (altPs) at the long terminal repeats (LTRs) of the TE subclasses. This activation occurs through the reorganization of topologically associating domain (TAD) hierarchical structures and the recruitment of proximal enhancers. These observations indicate that TAD hierarchy restricts transcriptional activation of LTRs that already possess open chromatin features. Perturbation of hierarchical chromatin topology can lead to co-option of LTRs as functional altPs, driving aberrant transcriptional activation of oncogenes. These data uncovered a new layer of regulatory mechanisms of TE expression and posit TAD hierarchy dysregulation as a new mechanism for altP-mediated oncogene activation and transcriptional diversity in cancer.

PMID:40588507 | DOI:10.1038/s41588-025-02239-6

Signal Transduct Target Ther. 2025 Jun 30;10(1):205. doi: 10.1038/s41392-025-02292-x.

ABSTRACT

The Wnt/β-catenin pathway is strongly relevant to pancreatic cancer progression, poor prognostic outcomes, and elevated cancer-related mortality. However, the mechanism underlying continuously activated Wnt/β-catenin signaling in pancreatic cancer, a context in which adenomatous polyposis coli (APC) mutations are rarely observed, remains poorly understood. In this study, we investigated the role of STYK1 in regulating canonical Wnt/β-catenin signaling and pancreatic cancer tumorigenesis using the LSL-KrasG12D; Trp53R172H/+; Pdx1Cre mouse model. Our findings demonstrate that STYK1 directly binds to β-catenin and GSK3β, inhibiting GSK3β activity by increasing the level of its kinase-inactive form, which is phosphorylated at S9, and promoting its sequestration into MVBs. We further showed that STYK1-mediated GSK3β sequestration is impaired by autophagy inhibitors or in ATG7 knockout cells, linking this process to autophagic regulation. Structural analysis identified conserved tyrosine-based (Y191QRL194) and dileucine-based (GDLL203-204) sorting motifs in STYK1, which facilitate clathrin/AP2-dependent internalization essential for GSK3β sequestration. The phosphorylation of STYK1 at Y191 by BLK kinase enhances its interaction with AP2, thereby accelerating GSK3β sequestration and subsequent Wnt/β-catenin pathway activation. Notably, inhibitory peptides targeting either the STYK1-β-catenin or the STYK1-GSK3β interface significantly suppressed pancreatic cancer development in vitro and in vivo, underscoring their therapeutic potential. Collectively, these results elucidate a novel STYK1-driven mechanism for Wnt/β-catenin activation in APC-independent pancreatic cancer and provide preclinical evidence for targeting STYK1-mediated signaling as a therapeutic strategy.

PMID:40588478 | DOI:10.1038/s41392-025-02292-x