Nature. 2025 May 21. doi: 10.1038/s41586-025-09041-8. Online ahead of print.

ABSTRACT

Current approaches used to track stem cell clones through differentiation require genetic engineering1,2 or rely on sparse somatic DNA variants3,4, which limits their wide application. Here we discover that DNA methylation of a subset of CpG sites reflects cellular differentiation, whereas another subset undergoes stochastic epimutations and can serve as digital barcodes of clonal identity. We demonstrate that targeted single-cell profiling of DNA methylation5 at single-CpG resolution can accurately extract both layers of information. To that end, we develop EPI-Clone, a method for transgene-free lineage tracing at scale. Applied to mouse and human haematopoiesis, we capture hundreds of clonal differentiation trajectories across tens of individuals and 230,358 single cells. In mouse ageing, we demonstrate that myeloid bias and low output of old haematopoietic stem cells6 are restricted to a small number of expanded clones, whereas many functionally young-like clones persist in old age. In human ageing, clones with and without known driver mutations of clonal haematopoieis7 are part of a spectrum of age-related clonal expansions that display similar lineage biases. EPI-Clone enables accurate and transgene-free single-cell lineage tracing on hematopoietic cell state landscapes at scale.

PMID:40399669 | DOI:10.1038/s41586-025-09041-8

Nat Commun. 2025 May 21;16(1):4720. doi: 10.1038/s41467-025-59656-8.

ABSTRACT

Ribosome biogenesis follows a cascade of pre-rRNA folding and processing steps, coordinated with ribosomal protein incorporation. Nucleolar 90S pre-ribosomes are well-described stable intermediates, composed of pre-18S rRNA, ribosomal S-proteins, U3 snoRNA, and ~70 assembly factors. However, how numerous snoRNAs control pre-rRNA modification and folding during early maturation events remains unclear. We identify snR30 (human U17), the only essential H/ACA snoRNA in yeast, which binds with Cbf5-Gar1-Nop10-Nhp2 to a pre-18S rRNA subdomain containing platform helices and ES6 of the 40S central domain. Integration into the 90S is blocked by RNA hybridization with snR30. The snoRNP complex coordinates the recruitment of early assembly factors Krr1-Utp23-Kri1 and ribosomal proteins uS11-uS15, enabling isolated subdomain assembly. Krr1-dependent release of snR30 culminates in integration of the platform into the 90S. Our study reveals the essential role of snR30 in chaperoning central domain formation as a discrete assembly unit externalized from the pre-ribosomal core.

PMID:40399280 | DOI:10.1038/s41467-025-59656-8

Neuroscience. 2025 May 19:S0306-4522(25)00393-8. doi: 10.1016/j.neuroscience.2025.05.031. Online ahead of print.

ABSTRACT

The sense of smell is essential for human perception. Olfactory function declines with increasing age, affecting a substantial portion of the elderly population, and this decline is more pronounced in men. This reduction can be attributed to anatomical and degenerative changes in the brain and olfactory receptors. There is robust clinical evidence indicating an association between olfactory perception decline/deficit (OPD) and major neurodegenerative diseases, with severe deficits observed in Alzheimer's and Parkinson's disease and milder effects noted in other conditions. However, its molecular bases have not yet been identified. Here, we explored the molecular connection between OPD and Parkinson's disease by conducting data-mining, gene enrichment analysis, and examining protein-interaction networks using systems biology approaches. We found pathways associated with both OPD and Parkinson's disease, identifying over 300 relevant genes. These genes belong to biologically relevant gene families, including transporters, kinases, nuclear receptors, transcription factors, and olfactory and other G protein-coupled receptors. Functional enrichment analysis revealed shared biological processes between OPD and Parkinson's disease, such as synaptic signalling and neuroinflammation. Mitochondrial gene enrichment was unique to Parkinson's. Both conditions exhibited a scarcity of associated genes on the Y chromosome but an even distribution on the non-pseudoautosomal region of the X chromosome, potentially explaining gender prevalence differences. In conclusion, our study suggests olfactory testing may help diagnose cognitive decline in neurodegenerative diseases. Further research is needed to understand the connection between OPD, aging, and other diseases and to examine olfactory performance in screening individuals at risk of Parkinson's disease and similar conditions.

PMID:40398724 | DOI:10.1016/j.neuroscience.2025.05.031

Int J Biochem Cell Biol. 2025 May 19:106790. doi: 10.1016/j.biocel.2025.106790. Online ahead of print.

ABSTRACT

In eukaryotes, protein arginine methylation is a prevalent post-translational modification found in a multitude of proteins responsible for key biological processes, ranging from transcription to signaling. One model suggests that phosphorylation of serine 9 (S9) in the Saccharomyces cerevisiae major protein arginine methyltransferase Hmt1 is critical for its oligomerization and activity. In this study, we used classic biochemical approaches to demonstrate that neither the S9 phosphomimetic nor the non-phosphorylatable substitution mutants of Hmt1 affect its oligomerization. These mutants remain active in vivo, retaining their ability to methylate the SR-/hnRNP-like protein Npl3 and displaying a monomethylarginine and asymmetric dimethylarginine banding profile similar to that of the wild-type. In cells lacking Dbf2, the proposed kinase responsible for phosphorylating Hmt1 at S9, Npl3 remains methylated. Additionally, monomethylarginine and asymmetric dimethylarginine banding profiles in cells lacking Dbf2 mostly resemble those observed in the wild-type rather than in hmt1Δ cells. Synchronized yeast cells expressing either S9 substitution exhibit entry into the M phase of the cell cycle at a rate similar to that of both wild-type and hmt1Δ cells. Our results suggest that the C-terminal epitope tagging of Hmt1 is responsible for the previously observed loss of enzymatic activities, rather than the S9 phosphorylation status of Hmt1. Finally, we demonstrate that S9 phosphorylation plays a role in maintaining Hmt1 protein levels in vivo. Overall, our finding demonstrates a novel role for Hmt1 S9 phosphorylation in tuning its in vivo protein levels.

PMID:40398714 | DOI:10.1016/j.biocel.2025.106790

Metab Eng. 2025 May 19:S1096-7176(25)00083-7. doi: 10.1016/j.ymben.2025.05.007. Online ahead of print.

ABSTRACT

Isoprenol (3-methyl-3-buten-1-ol) is a precursor to aviation fuels and other commodity chemicals and can be microbially synthesized from renewable carbon streams. Its production has been demonstrated in Pseudomonas putida KT2440 but its titers, rates, and yields have yet to reach commercially viable levels, potentially due to toxicity to the bacterial chassis. We hypothesized that utilization of Tolerization Adaptive Laboratory Evolution (TALE) would generate P. putida hosts more tolerant to isoprenol and suitable for enhanced production phenotypes. Here, we performed a comprehensive TALE campaign using three strains, the wild-type and two strains lacking subsets of known isoprenol catabolism and transport functions in quadruplicate independently evolved lineages. Several evolved clones from each starting strain displayed robust growth (up to 0.2 h-1) at 8 g/L of isoprenol, where starting strains could not grow. Whole genome resequencing of the 12 independent strain lineages identified convergent mutations. Reverse engineering each of the four commonly mutated regions individually (gnuR, ttgB-PP_1394, PP_3024-PP_5558, PP_1695) resulted in a partial recovery of the tolerance phenotypes observed in the evolved strains. Additionally, a proteomics-guided deletion of the master motility regulator, fleQ, in an evolved clone alleviated the tolerance vs. production trade-off, restoring isoprenol titers and consumption to levels observed in the starting strains. Collectively, this work demonstrated that an integrated strategy of laboratory evolution and rational engineering was effective to develop robust biofuel production hosts with minimized product toxicity.

PMID:40398593 | DOI:10.1016/j.ymben.2025.05.007

Curr Biol. 2025 May 15:S0960-9822(25)00562-7. doi: 10.1016/j.cub.2025.04.065. Online ahead of print.

ABSTRACT

Plants rely on water and light for photosynthesis, but water droplets on leaves can focus light into high-intensity spots, risking photodamage. Excessive light can impair growth or induce cell death, making it essential for plants to detect and respond to light fluctuations. While Ca2+ signaling has been linked to high light (HL) acclimation, the subcellular dynamics remain unclear. Here, we investigate Ca2+ responses to HL exposure in Arabidopsis thaliana. Using a glass bead to simulate light-focusing by water droplets, a biphasic increase of Ca2+ concentration was detected in the chloroplast stroma by the genetically encoded calcium indicator YC3.6 and confirmed using a newly established stroma-localized R-GECO1 (NTRC-R-GECO1). The stromal response was largely independent of light wavelength and unaffected in phot1 phot2 and cry1 cry2 mutants. Chemical inhibition of photosynthetic electron transport, microscopy-based Fv/Fm experiments, and measurement of the reactive oxygen species (ROS)-redox balance with roGFP-based reporters and Singlet Oxygen Sensor Green (SOSG) chemical dye suggested that photodamage and singlet oxygen contribute to the stromal Ca2+ response. While blue and white light also triggered a Ca2+ response in the cytosol and nucleus, pharmacological inhibition with cyclopiazonic acid (CPA) and loss-of-function mutants of the Ca2+ transporters BIVALENT CATION TRANSPORTER 2 (BICAT2) and endoplasmic reticulum (ER)-type Ca2+-ATPase (ECA) suggested that the HL response depends on a Ca2+ exchange between the ER and chloroplast stroma. The response was primarily light dependent but accelerated by increasing external temperature. This study implicates a novel Ca2+-mediated acclimation mechanism to HL stress, a process of growing relevance in the context of climate change.

PMID:40398414 | DOI:10.1016/j.cub.2025.04.065

EBioMedicine. 2025 May 20;116:105772. doi: 10.1016/j.ebiom.2025.105772. Online ahead of print.

ABSTRACT

BACKGROUND: Opportunistic premise plumbing pathogens (OPPPs) can establish reservoirs in hospital plumbing and cause healthcare associated infections (HAIs). There is currently no widely accepted protocol for sink drain cleaning to reduce OPPP burden.

METHODS: We implemented a sink cleaning intervention in 12 intensive care unit (ICU) rooms. At low frequency (1×/week) and high frequency (5×/week) intervals, we wiped sink surfaces with 10% bleach wipes and pumped a foamed preacid disinfectant into sink drains. We also maintained untreated rooms (0×/week). We used E-swabs to sample sink drains and surrounding surfaces during one baseline, two intervention, and two post-intervention periods over 23 months. Samples were selectively cultured for bacterial growth and antimicrobial resistant organism (ARO) isolation. We conducted whole-genome sequencing (WGS) on Pseudomonas spp. and Stenotrophomonas spp. isolates to track impacts on reservoirs over time. We also collected and analysed clinical isolates from patients occupying the study rooms and information about HAIs that occurred.

FINDINGS: The intervention reduced the proportion of sink drains yielding Gram-negative bacteria by up to 85% (95% CI: 56-114%) in high frequency rooms versus the baseline period, but this was not significant in low frequency rooms. It also reduced the proportion of sink drains yielding Pseudomonas spp. and Stenotrophomonas spp. by up to 100% (95% CI: 79-121%) and 95% (95% CI: 65-125%) versus the baseline period in high frequency rooms and up to 71% (95% CI: 50-92%, p < 0.001) and 66% (95% CI: 27-105%, p < 0.05) in low frequency rooms, respectively. WGS showed strains of Pseudomonas aeruginosa and Stenotrophomonas maltophilia that colonised sink drains for over 3 years across two studies. Following the intervention periods, P. aeruginosa reservoirs were replaced with new strains, while S. maltophilia reservoirs returned with the same strains.

INTERPRETATION: This environmental hygiene intervention may be effective in reducing the burden of OPPPs in hospital sinks.

FUNDING: Agency for Healthcare Research and Quality (R01HS027621), National Institute of Allergy and Infectious Diseases (U01AI123394, 1K23AI137321), Barnes-Jewish Hospital Foundation (5102), Washington University Institute of Clinical and Translational Sciences (4462) from the National Center for Advancing Translational Sciences (UL1TR002345).

PMID:40398352 | DOI:10.1016/j.ebiom.2025.105772

Exp Mol Pathol. 2025 May 20;143:104973. doi: 10.1016/j.yexmp.2025.104973. Online ahead of print.

ABSTRACT

BACKGROUND: The incidence of malignant pleural mesothelioma (MPM) has surged due to widespread asbestos exposure, particularly since the mid-20th century. Despite significant advancements in cancer treatment, an effective cure for MPM remains elusive, largely due to a limited understanding of the molecular mechanisms underlying asbestos-related carcinogenesis. This exploratory study aims to uncover gene expression patterns uniquely altered in mesothelioma patients with documented asbestos exposure, providing a solid foundation for future research focused on identifying novel prognostic and predictive biomarkers.

METHODS: Publicly available RNA sequencing data were analyzed through a bioinformatics pipeline to perform differential gene expression analysis. Additionally, functional enrichment analysis was applied to highlight significantly enriched Gene Ontology (GO) terms related to biological processes, molecular functions, and cellular components, offering insights into the molecular pathways involved in MPM development.

RESULTS: The analysis uncovered a set of differentially expressed genes (DEGs) in MPM patients with documented asbestos exposure, as well as key GO terms. These enriched biological terms reflect processes such as ion homeostasis and oxidative stress response, providing crucial information on the cellular alterations driven by asbestos exposure.

CONCLUSION: This study's findings deepen our understanding of the molecular landscape underlying asbestos-induced carcinogenesis in MPM. The identification of specific DEGs and enriched GO terms lays the foundation for future investigations, including the development of biomarkers, with potential implications for the diagnostic and prognostic assessment of MPM.

PMID:40398085 | DOI:10.1016/j.yexmp.2025.104973

J Med Internet Res. 2025 May 21;27:e60284. doi: 10.2196/60284.

ABSTRACT

BACKGROUND: The recent emergence of wearable devices has made feasible the passive gathering of intensive, longitudinal data from large groups of individuals. This form of data is effective at capturing physiological changes between participants (interindividual variability) and changes within participants over time (intraindividual variability). The emergence of longitudinal datasets provides an opportunity to quantify the contribution of such longitudinal data to the control of these sources of variability for applications such as responder analysis, where traditional, sparser sampling methods may hinder the categorization of individuals into these phenotypes.

OBJECTIVE: This study aimed to quantify the gains made in statistical power and effect size among statistical comparisons when controlling for interindividual variability and intraindividual variability compared with controlling for neither.

METHODS: Here, we test the gains in statistical power from controlling for interindividual and intraindividual variability of resting heart rate, collected in 2020 for over 40,000 individuals as part of the TemPredict study on COVID-19 detection. We compared heart rate on weekends with that on weekdays because weekends predictably change the behavior of most individuals, though not all, and in different ways. Weekends also repeat consistently, making their effects on heart rate feasible to assess with confidence over large populations. We therefore used weekends as a model system to test the impact of different statistical controls on detecting a recurring event with a clear ground truth. We randomly and iteratively sampled heart rate from weekday and weekend nights, controlling for interindividual variability, intraindividual variability, both, or neither.

RESULTS: Between-participant variability appeared to be a greater source of structured variability than within-participant fluctuations. Accounting for interindividual variability through within-individual sampling required 40× fewer pairs of samples to achieve statistical significance with 4× to 5× greater effect size at significance. Within-individual sampling revealed differential effects of weekends on heart rate, which were obscured by aggregated sampling methods.

CONCLUSIONS: This work highlights the leverage provided by longitudinal, within-individual sampling to increase statistical power among populations with heterogeneous effects.

PMID:40397926 | DOI:10.2196/60284

ACS Appl Mater Interfaces. 2025 May 21. doi: 10.1021/acsami.5c04355. Online ahead of print.

ABSTRACT

Osteoarthritis (OA) is a common joint disorder that causes significant disability. Previous studies suggested that the predominance of M1 macrophages (MΦs) exacerbates inflammation and cartilage degradation in OA, suggesting that shifting the polarization toward M2 MΦs could be a promising therapeutic strategy. We recently developed CRISPRa-engineered macrophages, termed Elite MΦs, that express IL-10 and maintain a stable M2 phenotype. However, achieving effective and sustained delivery of these cells to the OA joint remains a challenge. In this study, we synthesized two injectable aldehyde hyaluronic acid-based hydrogels, CHO/CDH and ACHO/CDH hydrogels, to serve as Elite MΦ delivery platforms. Comprehensive analyses identified the ACHO/CDH hydrogel as superior due to its enhanced suitability for encapsulating and delivering Elite MΦs. When loaded with Elite MΦs, the ACHO/CDH hydrogel was able to not only localize Elite MΦs but also enhance their anti-inflammatory and reparative effects. Furthermore, intra-articular injection of the Elite MΦ-loaded ACHO/CDH hydrogel in an OA mouse model resulted in notable improvements in the joint's cellular environment, alleviating cartilage degradation and synovial inflammation. These results highlight the ability of the ACHO/CDH hydrogel to rebalance the inflammatory imbalance and promote cartilage repair. This approach not only targets the underlying inflammatory processes more directly than traditional therapies but also harnesses the regenerative potential of macrophages, offering a transformative strategy for OA management.

PMID:40397763 | DOI:10.1021/acsami.5c04355

J Burn Care Res. 2025 May 21:iraf012. doi: 10.1093/jbcr/iraf012. Online ahead of print.

ABSTRACT

A dysregulated immune response after severe burn injury is associated with detrimental short and long-term clinical outcomes. Key changes to gene expression within the first 24 h after burn injury have been identified, but longitudinal data is lacking. Therefore, this study aims to characterize gene expression during the first 3 weeks after burn injury and identify specific genes and pathways associated with distinct clinical outcomes. Patients presenting within 4 h of injury had blood RNA isolated for microarray gene expression at admission and set timepoints to 21 days. Inter- and intra-group comparisons were performed between 4 groups (G1 died within 7 days; G2 died after 7 days; G3 discharged after 7 days; and G4 discharged within 7 days). A total of 17 289 transcripts were quantified from 116 patients. At admission, there were 110, 80, and 31 differentially expressed genes in G1, G2, and G3, respectively, compared to G4, and were largely nonoverlapping. Longitudinal intra-group analyses also showed distinct group- and time-dependent patterns. Upregulation of genes and pathways related to the innate immune response and unfolded protein response predominated during early time points, while persistent upregulation of coagulation pathways and downregulation of immune-related pathways were identified days to weeks following injury. Overall, burn injury induces widespread transcriptomic responses, with larger and more sustained changes observed in patients with worse clinical outcomes. These gene expression signatures reveal underlying molecular mechanisms that occur immediately following injury and may have prognostic and diagnostic utility in the care of burn-injured patients.

PMID:40397518 | DOI:10.1093/jbcr/iraf012

Bioinformatics. 2025 May 21:btaf315. doi: 10.1093/bioinformatics/btaf315. Online ahead of print.

ABSTRACT

MOTIVATION: Massively Parallel Reporter Assays (MPRAs) have emerged as pivotal tools for systematically profiling cis-regulatory element activity, playing critical roles in deciphering gene regulation mechanisms and synthetic regulatory element engineering. However, MPRA experiments involve multi-step library processing procedures coupled with high-throughput sequencing. Operational errors during these complex workflows can lead to substantial resource depletion and experimental delays. Thus robust and user-friendly quality control methods are essential to minimize experimental failures and ensure reproducibility between replicates.

RESULTS: Here, we present esMPRA, an integrated quality control and analysis pipeline designed for MPRA experiments. Building on our experience in MPRA and its derivative techniques, coupled with systematic analysis of public MPRA datasets, we established standardized quality control metrics and developed a stepwise quality monitoring framework. esMPRA generates stage-specific diagnostic reports and provides experimental recommendations to avoid potential risks throughout the workflow. Designed for maximal accessibility, esMPRA features a one-line command-line interface and requires minimal bioinformatics expertise. Beyond quality assessment, the pipeline delivers processed data outputs, comprehensive analysis reports, and interface files compatible with downstream analyses, establishing an end-to-end solution for MPRA experimentation.

AVAILABILITY: esMPRA is released as an open-source software under the MIT license. The source code for esMPRA is available on Zenodo (DOI: 10.5281/zenodo.15362711) and GitHub (https://github.com/WangLabTHU/esMPRA/) for Linux, macOS, and Windows, and is available via PyPI as esMPRA. Data for testing and reference is available via Zenodo repository at https://zenodo.org/records/15034449.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:40397077 | DOI:10.1093/bioinformatics/btaf315

Bot Stud. 2025 May 21;66(1):13. doi: 10.1186/s40529-025-00460-4.

ABSTRACT

BACKGROUND: Mangosteen (Garcinia mangostana L.) pericarp extract has demonstrated potential against Alzheimer's disease (AD) and diabetes mellitus (DM). This study introduces a rapid dereplication and comparative approach to identify and characterize acetylcholinesterase (AChE) and α-glucosidase inhibitors in mangosteen pericarp. Using protein-subtraction, MS profiling, and computational modeling is effective for screening, identifying, and analyzing enzyme-inhibiting compounds from plant sources, and quantitative analysis of the main components has been performed.

RESULTS: The Mangosteen pericarp extract observed significant inhibitory activity against α-glucosidase and AChE, with IC50 values of 31.02 and 70.56 µg/mL, respectively. By comparing profiles of protein-subtracted extracts with non-treated extracts, eight potential inhibitors for each enzyme were identified: 8-desoxygartanin, gartanin, 3-isomangostin, β-mangostin, 9-hydroxycalabaxanthone, γ-mangostin, α-mangostin, and garcinone E. The α-mangostin was the most abundant, comprising 39.589% of the extract. Molecular docking revealed these inhibitors target the peripheral anionic site of AChE and the active site of α-glucosidase, forming key hydrogen bonds and pi-pi stacking interactions.

CONCLUSION: This study emphasizes mangosteen pericarp as a promising natural source of these inhibitors, with potential for use in developing nutraceuticals and pharmaceuticals. The study validated a systems biology approach by applying dereplication and comparative UPLC-ESI-MS/MS metabolomics profiling to identify target-binding molecules in both protein-treated and untreated plant extracts. Further confirmation was obtained through molecular docking predictions, mechanism analysis, and compound quantification assays.

PMID:40397045 | DOI:10.1186/s40529-025-00460-4

mSystems. 2025 May 21:e0041825. doi: 10.1128/msystems.00418-25. Online ahead of print.

ABSTRACT

Staphylococcus epidermidis, a commensal bacterium inhabiting collagen-rich areas like human skin, has gained significance due to its probiotic potential in the nasal microbiome and as a leading cause of nosocomial infections. While infrequently leading to severe illnesses, S. epidermidis exerts a significant influence, particularly in its close association with implant-related infections and its role as a classic opportunistic biofilm former. Understanding its opportunistic nature is crucial for developing novel therapeutic strategies, addressing both its beneficial and pathogenic aspects, and alleviating the burdens it imposes on patients and healthcare systems. Here, we employ genome-scale metabolic modeling as a powerful tool to elucidate the metabolic capabilities of S. epidermidis. We created a comprehensive computational resource for understanding the organism's growth conditions within diverse habitats by reconstructing and analyzing a manually curated and experimentally validated metabolic model. The final network, iSep23, incorporates 1,415 reactions, 1,051 metabolites, and 705 genes, adhering to established community standards and modeling guidelines. Benchmarking with the Metabolic Model Testing suite yields a high score, indicating the model's remarkable semantic quality. Following the findable, accessible, interoperable, and reusable (FAIR) data principles, iSep23 becomes a valuable and publicly accessible asset for subsequent studies. Growth simulations and carbon source utilization predictions align with experimental results, showcasing the model's predictive power. Ultimately, this work provides a robust foundation for future research aimed at both exploiting the probiotic potential and mitigating the pathogenic risks posed by S. epidermidis.

IMPORTANCE: Staphylococcus epidermidis, a bacterium commonly found on human skin, has shown probiotic effects in the nasal microbiome and is a notable causative agent of hospital-acquired infections. While these infections are typically non-life-threatening, their economic impact is considerable, with annual costs reaching billions of dollars in the United States. To better understand its opportunistic nature, we employed genome-scale metabolic modeling to construct a detailed network of S. epidermidis's metabolic capabilities. This model, comprising over a thousand reactions, metabolites, and genes, adheres to established standards and demonstrates solid benchmarking performance. Following the findable, accessible, interoperable, and reusable (FAIR) data principles, the model provides a valuable resource for future research. Growth simulations and predictions closely match experimental data, underscoring the model's predictive accuracy. Overall, this work lays a solid foundation for future studies aimed at leveraging the beneficial properties of S. epidermidis while mitigating its pathogenic potential.

PMID:40396730 | DOI:10.1128/msystems.00418-25

ISME J. 2025 May 21:wraf100. doi: 10.1093/ismejo/wraf100. Online ahead of print.

ABSTRACT

The legume-rhizobia symbiosis possesses great potential for sustainable agriculture because of its ability to fix atmospheric nitrogen, reducing crop dependence on nitrogen fertilizers. Rhizobia recognize the host legume through flavonoids released by the roots. These signals are detected by bacteria typically over a few millimeters. Recent research has shown that arbuscular mycorrhizal fungi extend this recognition beyond 15 cm by transporting flavonoids along their hyphae. In soil, common mycorrhizal networks linking plants are formed by arbuscular mycorrhizal fungi. We hypothesized that such networks linking different legumes can transmit host-specific signals, guiding rhizobia to their appropriate hosts. Using in vitro and greenhouse microcosms, we linked Medicago truncatula and Glycine max via a common mycorrhizal network of Rhizophagus irregularis and inoculated GFP-labeled Sinorhizobium meliloti and mCherry-labeled Bradyrhizobium diazoefficiens on the hyphae. S. meliloti preferentially migrated towards M. truncatula, whereas B. diazoefficiens preferentially migrated towards G. max (155 ± 8 and 13 ± 3 nodules, respectively). This was confirmed in the greenhouse with a higher concentration of S. meliloti (2.1-2.5 × 105 CFU·g-1) near M. truncatula and a higher concentration of B. diazoefficiens (1.5-1.6 × 105 CFU·g-1) near G. max (71-82 and 15-18 nodules, respectively). Metabolomics revealed host-specific flavonoids in hyphal exudates: M. truncatula-connected hyphae released DL-liquiritigenin, naringenin, sakuranetin, and 3,7-dimethylquercetin, whereas G. max-connected hyphae released daidzin, 6"-O-malonyldaidzin, irilone, and erylatissin A. These findings establish that common mycorrhizal networks constitute a "navigation system", using chemical signals to orient rhizobia towards their specific hosts, thereby improving nodulation with potential applications in agriculture.

PMID:40396656 | DOI:10.1093/ismejo/wraf100

Nucleic Acids Res. 2025 May 21:gkaf408. doi: 10.1093/nar/gkaf408. Online ahead of print.

ABSTRACT

Whereas alignment has been fundamental to sequence-based assessments of protein homology, it is ineffective for intrinsically disordered regions (IDRs) due to their lowered sequence conservation and unique sequence properties. Here, we present a web server implementation of SHARK (bio-shark.org), an alignment-free algorithm for homology classification that compares the overall amino acid composition and short regions (k-mers) shared between sequences (SHARK-scores). The output of such k-mer-based comparisons is used by SHARK-dive, a machine learning classifier to detect homology between unalignable, disordered sequences. SHARK-web provides sequence-versus-database assessment of protein sequence homology akin to conventional tools such as BLAST and HMMER. Additionally, we provide precomputed sets of IDR sequences from 16 model organism proteomes facilitating searches against species-specific IDR-omes. SHARK-dive offers superior overall homology detection performance to BLAST and HMMER, driven by a large increase in sensitivity to low sequence identity homologs, and can be used to facilitate the study of sequence-function relationships in disordered, difficult-to-align regions.

PMID:40396357 | DOI:10.1093/nar/gkaf408

Eur Heart J. 2025 May 21:ehaf324. doi: 10.1093/eurheartj/ehaf324. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and impaired metabolic efficiency. This study investigates the therapeutic potential of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin (EMPA) in ameliorating these pathological features in a mouse model carrying the myosin R403Q mutation.

METHODS: Male mice harbouring the R403Q mutation were treated with EMPA for 16 weeks. Multi-nuclear magnetic resonance spectroscopy (31P, 13C, and 23Na MRS), echocardiography, transcriptomic, proteomic, and phosphoproteomic profiling were utilized to assess metabolic, structural, and functional changes.

RESULTS: Empagliflozin facilitated the coupling of glycolysis with glucose oxidation and normalized elevated intracellular sodium levels. Treatment resulted in a significant reduction in LVH and myocardial fibrosis as evidenced by echocardiography and histopathology. These structural improvements correlated with enhancements in mitochondrial adenosine triphosphate (ATP) synthesis, fatty acid oxidation, and branched-chain amino acid catabolism. Furthermore, EMPA improved left ventricular diastolic function and contractile reserve, underscored by improved ATP production and reduced energy cost of contraction. Notably, these benefits were linked to down-regulation of the mammalian target of rapamycin signalling pathway and normalization of myocardial substrate metabolic fluxes.

CONCLUSIONS: Empagliflozin significantly mitigates structural and metabolic dysfunctions in a mouse model of HCM, underscoring its potential as a therapeutic agent for managing this condition. These findings suggest broader applicability of SGLT2i in cardiovascular diseases, including those due to myocardial-specific mutations, warranting further clinical investigation.

PMID:40396194 | DOI:10.1093/eurheartj/ehaf324

Mechanobiol Med. 2024 Dec 14;3(1):100112. doi: 10.1016/j.mbm.2024.100112. eCollection 2025 Mar.

ABSTRACT

Mechanotransduction is the process that enables the conversion of mechanical cues into biochemical signaling. While all our cells are well known to be sensitive to such stimuli, the details of the systemic interaction between mechanical input and inflammation are not well integrated. Often, indeed, they are considered and studied in relatively compartmentalized areas, and we therefore argue here that to understand the relationship of mechanical stimuli with inflammation - with a high translational potential - it is crucial to offer and analyze a unified view of mechanotransduction. We therefore present here pathway representation, recollected with the standard systems biology markup language (SBML) and explored with network biology approaches, offering RAC1 as an exemplar and emerging molecule with potential for medical translation.

PMID:40396134 | PMC:PMC12082120 | DOI:10.1016/j.mbm.2024.100112

Clin Cosmet Investig Dermatol. 2025 May 15;18:1191-1198. doi: 10.2147/CCID.S518751. eCollection 2025.

ABSTRACT

INTRODUCTION: Lesion segmentation in dermoscopic images significantly enhances the diagnostic performance of AI-based classification models. However, conventional methods often require pixel-level annotations, which are resource-intensive and prone to errors caused by external artifacts, such as hair and skin markings.

METHODS: We propose a hybrid framework called SAM-enhanced YOLO, which integrates the Segment Anything Model (SAM) with You Only Look Once (YOLO) for precise pixel-level segmentation. This method combines YOLO's efficient lesion localization with SAM's advanced zero-shot segmentation capabilities. To further validate the framework, we compared it against traditional methods, including GrabCut and Otsu's thresholding, as well as SAM used without YOLO (SAM-only). For SAM-only, lesion segmentation was initialized at the image center to simulate a typical dermoscopic imaging setup.

RESULTS: SAM-enhanced YOLO demonstrated superior segmentation performance, achieving an Intersection over Union (IoU) of 0.738 and an F1-score (the harmonic mean of precision and recall) of 0.833, compared to 0.578 and 0.683 with SAM-only, respectively. This represents a 28% improvement in IoU and a 22% improvement in F1-score compared to SAM-only. The results were consistent across lesion shapes and contrast conditions, with SAM-enhanced YOLO exhibiting the lowest variability and highest robustness among the evaluated methods.

CONCLUSION: By reducing the need for pixel-level annotations and outperforming both standalone SAM and traditional methods, SAM-enhanced YOLO provides a scalable and resource-efficient solution for dermoscopic lesion segmentation. This framework holds significant potential for improving diagnostic workflows in clinical and resource-limited settings.

PMID:40396125 | PMC:PMC12089257 | DOI:10.2147/CCID.S518751

Autophagy Rep. 2022 Apr 24;1(1):183-186. doi: 10.1080/27694127.2022.2065602. eCollection 2022.

ABSTRACT

In plants, macroautophagy/autophagy is an essential mechanism responsible for a large variety of processes throughout the plant's lifecycle, including nutrient processing, immunity, stress responses and senescence. Previous studies had observed the presence of autophagosomes in an Arabidopsis sexual reproduction system that prevents self-fertilization (self-incompatibility), but their requirement in this pathway was unclear. Using autophagy-deficient mutants, we have recently found that autophagy is a key contributor in the Arabidopsis self-incompatibility response to reject self-pollen.

PMID:40395998 | PMC:PMC11864688 | DOI:10.1080/27694127.2022.2065602