Nat Biomed Eng. 2025 May 23. doi: 10.1038/s41551-025-01381-0. Online ahead of print.

ABSTRACT

Liver fibrosis is an over-reacted wound healing that becomes lethal in its late stage, when hepatic stellate cells (HSCs) trigger fibrotic response, proliferation of connective tissue and build-up of directional fibrous tissue bands (septa). Current in vitro models of liver fibrosis cannot reproduce liver lobule structure and the dynamic formation of septa at the same time, and the known biochemical cues underlying the progression of liver fibrosis cannot explain directional formation of fibrotic tissue. Here we report a microfabricated in vitro model that reproduces both the hexagonal liver lobule structure and the dynamic directionality of septa formation. By using collagen and primary mouse HSCs or human HSC lines, we found that tension was necessary to coordinate the cell migration that contributes to the band-like cell distribution and that HSCs sensed directional biophysical cues through liquid-liquid phase separation. This system allows the study of the biophysical interaction of HSCs and collagen during the formation of septa structures, and could be used to deepen our understanding of liver fibrosis progression.

PMID:40410557 | DOI:10.1038/s41551-025-01381-0

Commun Biol. 2025 May 23;8(1):791. doi: 10.1038/s42003-025-08148-y.

ABSTRACT

The SARS-CoV-2 pandemic has reemphasized the urgent need for broad-spectrum antiviral therapies. We developed a computational workflow using scRNA-Seq data to assess cellular metabolism during viral infection. With this workflow we predicted the capacity of cells to sustain SARS-CoV-2 virion production in patients and found a tissue-wide induction of metabolic pathways that support viral replication. Expanding our analysis to influenza A and dengue viruses, we identified metabolic targets and inhibitors for potential broad-spectrum antiviral treatment. These targets were highly enriched for known interaction partners of all analyzed viruses. Indeed, phenformin, an NADH:ubiquinone oxidoreductase inhibitor, suppressed SARS-CoV-2 and dengue virus replication. Atpenin A5, blocking succinate dehydrogenase, inhibited SARS-CoV-2, dengue virus, respiratory syncytial virus, and influenza A virus with high selectivity indices. In vivo, phenformin showed antiviral activity against SARS-CoV-2 in a Syrian hamster model. Our work establishes host metabolism as druggable for broad-spectrum antiviral strategies, providing invaluable tools for pandemic preparedness.

PMID:40410544 | DOI:10.1038/s42003-025-08148-y

Eur J Hum Genet. 2025 May 23. doi: 10.1038/s41431-025-01876-z. Online ahead of print.

ABSTRACT

Biallelic inactivating variants in ZNF142 underlie a clinically variable neurodevelopmental disorder. ZNF142 is a zinc-finger transcription factor with potential roles on chromatin organization, implying a possible association of ZNF142 loss of function with perturbed genome-wide DNA methylation (DNAm) pattern. We performed EPIC array-based methylation profiling of peripheral blood-derived DNA samples from 27 individuals with biallelic ZNF142 inactivating variants, together with 6 heterozygous carriers and 40 controls. A DNAm signature discovery pipeline was applied by using 440 controls for discovery and validation analyses, and a machine-learning model was trained to classify 8 individuals carrying ZNF142 variants of uncertain clinical significance. Analyses directed to explore the genome-wide DNAm landscape in affected individuals revealed 88 differentially methylated probes constituting the minimal informative set specific to ZNF142 loss of function. This reproducible pattern of DNAm changes involved regulatory regions of a small number of genes. The DNAm signature derived from peripheral blood allowed us to diagnose individuals carrying biallelic inactivating ZNF142 variants when applied to fibroblasts. Our findings provide evidence that biallelic loss-of-function ZNF142 variants result in a specific and robust DNAm signature. The identified DNAm pattern suggests occurrence of a methylation disturbance involving a small number of loci that appears to be shared by different cell lineages.

PMID:40410387 | DOI:10.1038/s41431-025-01876-z

Mol Syst Biol. 2025 May 23. doi: 10.1038/s44320-025-00120-6. Online ahead of print.

ABSTRACT

Glycosaminoglycan (GAG)-binding proteins regulating essential processes such as cell growth and migration are essential for cell homeostasis. As both GAGs and the lipid A disaccharide core of Gram-negative bacteria contain negatively charged disaccharide units, we hypothesized that GAG-binding proteins could also recognize LPS and enclose cryptic antibiotic motifs. Here, we report novel antimicrobial peptides (AMPs) derived from heparin-binding proteins (HBPs), with specific activity against Gram-negative bacteria and high LPS binding. We used computational tools to locate antimicrobial regions in 82% of HBPs, most of those colocalizing with putative heparin-binding sites. To validate these results, we synthesized five candidates [HBP-1-5] that showed remarkable activity against Gram-negative bacteria, as well as a strong correlation between heparin and LPS binding. Structural characterization of these AMPs shows that heparin or LPS recognition promotes a conformational arrangement that favors binding. Among all analogs, HBP-5 displayed the highest affinity for both heparin and LPS, with antimicrobial activities against Gram-negative bacteria at the nanomolar range. These results suggest that GAG-binding proteins are involved in LPS recognition, which allows them to act also as antimicrobial proteins. Some of the peptides reported here, particularly HBP-5, constitute a new class of AMPs with specific activity against Gram-negative bacteria.

PMID:40410382 | DOI:10.1038/s44320-025-00120-6

Sci Rep. 2025 May 23;15(1):17969. doi: 10.1038/s41598-025-01912-4.

ABSTRACT

The tumorigenesis of small intestinal neuroendocrine tumors (siNETs) is not understood and comprehensive genomic and transcriptomic data sets are limited. Therefore, we performed whole genome and transcriptome analysis of 39 well differentiated siNET samples. Our genomic data revealed a lack of recurrent driver mutations and demonstrated that multifocal siNETs from individual patients can arise genetically independently. We detected germline mutations in Fanconi anemia DNA repair pathway (FANC) genes, involved in homologous recombination (HR) DNA repair, in 9% of patients and found mutational signatures of defective HR DNA repair in late-stage tumor evolution. Furthermore, transcriptomic analysis revealed low expression of the transcriptional repressor REST. Summarizing, we identify a novel common transcriptomic signature of siNETs and demonstrate that genomic alterations alone do not explain initial tumor formation, while impaired DNA repair likely contributes to tumor evolution and represents a potential pharmaceutical target in a subset of patients.

PMID:40410286 | DOI:10.1038/s41598-025-01912-4

NPJ Aging. 2025 May 23;11(1):40. doi: 10.1038/s41514-025-00237-w.

ABSTRACT

Frailty is an age-related geriatric syndrome. We performed a longitudinal study of aging female (n = 40) and male (n = 47) C57BL/6NIA mice, measured frailty index and derived metabolomics data from plasma. We identify age-related differentially abundant metabolites, determine frailty-related metabolites, and generate frailty features, both in the whole cohort and sex-stratified subgroups. Using the features, we perform an association study and build a metabolomics-based frailty clock. We find that frailty-related metabolites are enriched for amino acid metabolism and metabolism of cofactors and vitamins, include ergothioneine, tryptophan and alpha-ketoglutarate, and present sex dimorphism. We identify B vitamin metabolism related flavin-adenine dinucleotide and pyridoxate as female-specific frailty biomarkers, and lipid metabolism related sphingomyelins, glycerophosphoethanolamine and glycerophosphocholine as male-specific frailty biomarkers. These associations are confirmed in a validation cohort, with ergothioneine and perfluorooctanesulfonate identified as robust frailty biomarkers. Our results identify sex-specific metabolite frailty biomarkers, and shed light on potential mechanisms.

PMID:40410187 | DOI:10.1038/s41514-025-00237-w

Nat Commun. 2025 May 23;16(1):4790. doi: 10.1038/s41467-025-59476-w.

ABSTRACT

Malaria parasite undergoes interesting developmental transition in human and mosquito host. While it divides asynchronously in the erythrocytes, it switches to sexual forms, which is critical for disease transmission. We report a novel signalling pathway involving Protein Phosphatase PfPPM2, which regulates asexual division of Plasmodium falciparum as well as its conversion to sexual forms. PfPPM2 may regulate the phosphorylation of key proteins involved in chromatin remodelling and protein translation. One of the key PfPPM2-targets was Heterochromatin Protein 1 (HP1), a regulator of heritable gene silencing which contributes to both mitotic proliferation as well as sexual commitment of the parasite. PfPPM2 promotes sexual conversion by regulating the interaction between HP1, H3K9me3 and chromatin and it achieves this by dephosphorylating S33 of HP1. PfPPM2 also regulates protein synthesis in the parasite by repressing the phosphorylation of initiation factor eIF2α, which is likely to contribute to parasite division and possibly sexual differentiation.

PMID:40410154 | DOI:10.1038/s41467-025-59476-w

Cell Stem Cell. 2025 May 21:S1934-5909(25)00179-1. doi: 10.1016/j.stem.2025.04.012. Online ahead of print.

ABSTRACT

Isocitrate dehydrogenase 1/2 (IDH) mutations are early initiating events in acute myeloid leukemia (AML). The complex clonal architecture and cellular heterogeneity in IDH-mutant AML underlies the heterogeneous clinical presentation and outcomes. Integrating single-cell genotyping and transcriptomics, we demonstrate a stem-like and inflammatory phenotype of IDH-mutant AML and identify clone-specific programs associated with NPM1, NRAS, and SRSF2 co-mutations. Furthermore, these clones had distinct responses to treatment with combination IDH inhibitors and chemotherapy, including elimination, reconstitution of myeloid differentiation, or retention within progenitor populations. At relapse after IDH inhibitor monotherapy, we identify upregulated stemness, inflammation, mitochondrial metabolism, and anti-apoptotic factors, as well as downregulated major histocompatibility complex (MHC) class II antigen presentation. At the pre-leukemic stage, we observe upregulation of IDH2-associated pathways, including inflammation. We deliver a detailed phenotyping of IDH-mutant AML and a framework for dissecting contributions of recurrently mutated genes in AML at diagnosis and following therapy, with implications for precision medicine.

PMID:40409258 | DOI:10.1016/j.stem.2025.04.012

PLoS One. 2025 May 23;20(5):e0323708. doi: 10.1371/journal.pone.0323708. eCollection 2025.

ABSTRACT

INTRODUCTION: The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents a significant global public health threat. Concurrently, hepatitis B virus (HBV) remains a significant public health challenge. While previous studies have indicated an association between COVID-19 and chronic hepatitis B, the common underlying pathogenesis of these diseases remains incompletely understood.

METHODS: To investigate the shared molecular mechanisms between chronic HBV infection and COVID-19, a comprehensive investigation was conducted using bioinformatics and systems biology. Specifically, we utilized RNA-seq datasets (GSE196822 and GSE83148) to identify differentially expressed genes (DEGs) associated with both SARS-CoV-2 and HBV infection. Subsequently, these common DEGs were utilized to identify shared pathways, hub genes, transcriptional regulatory networks, and potential drugs. The differential expression of hub genes in both COVID-19 and HBV was verified using the GSE171110 and GSE94660 datasets, respectively.

RESULTS: From the 106 shared DEGs identified, immune-related pathways were found to play a role in the development and progression of chronic hepatitis B and COVID-19. Protein-protein interaction (PPI) network analysis revealed 8 hub genes: CDK1, E2F7, E2F8, TYMS, KIF20A, CENPE, TPX2, HMMR, CD8A, GZMA. In the validation set, the expression of hub genes was statistically significant in both the COVID-19 group and the HBV group compared with the healthy control group. Transcriptional regulatory network analysis identified 155 microRNAs (miRNAs) and 43 transcription factors (TFs) as potential regulatory signals. Notably, we identified potential therapeutic drugs for HBV chronic infection and COVID-19, including progesterone, estradiol, dasatinib, aspirin, etoposide, irinotecan hydrochloride, phorbol 12-myristate 13-acetate, lucanthone, calcitriol.

CONCLUSION: This research elucidates potential molecular targets, signaling pathways, and promising small molecule compounds that could aid in the treatment of chronic HBV infection and COVID-19.

PMID:40408617 | DOI:10.1371/journal.pone.0323708

Sci Adv. 2025 May 23;11(21):eadv2930. doi: 10.1126/sciadv.adv2930. Epub 2025 May 23.

ABSTRACT

Tumor hypoxia leads to radioresistance and markedly worse clinical outcomes for pediatric malignant rhabdoid tumors (MRTs). Our transcriptomics and bioenergetic profiling data reveal that mitochondrial oxidative phosphorylation is a metabolic vulnerability of MRT and can be exploited to overcome consumptive hypoxia by repurposing an FDA-approved antimalarial drug, atovaquone (AVO). We then establish the utility of oxygen-enhanced-multispectral optoacoustic tomography, a label-free, ionizing radiation-free imaging modality, to visualize and quantify spatiotemporal changes in tumor hypoxia in response to AVO. We show a potent but transient increase in tumor oxygenation upon AVO treatment that results in complete elimination of tumors in all tested mice when combined with 10-gray radiotherapy, a dose several times lower than the current clinic standard. Last, we use translational mathematical modeling for systematic evaluation of dosing regimens, administration timing, and therapeutic synergy in a virtual patient cohort. Together, our work establishes a framework for safe and pediatric patient-friendly image-guided metabolic radiosensitization of rhabdoid tumors.

PMID:40408469 | DOI:10.1126/sciadv.adv2930

Proc Natl Acad Sci U S A. 2025 May 27;122(21):e2411930122. doi: 10.1073/pnas.2411930122. Epub 2025 May 23.

ABSTRACT

Cancers are shaped by somatic mutations, microenvironment, and patient background, each altering gene expression and regulation in complex ways, resulting in heterogeneous cellular states and dynamics. Inferring gene regulatory networks (GRNs) from expression data can help characterize this regulation-driven heterogeneity, but network inference requires many statistical samples, limiting GRNs to cluster-level analyses that ignore intracluster heterogeneity. We propose to move beyond coarse analyses of predefined subgroups by using contextualized learning, a multitask learning paradigm that uses multiview contexts including phenotypic, molecular, and environmental information to infer personalized models. With sample-specific contexts, contextualization enables sample-specific models and even generalizes at test time to predict network models for entirely unseen contexts. We unify three network model classes (Correlation, Markov, and Neighborhood Selection) and estimate context-specific GRNs for 7,997 tumors across 25 tumor types, using copy number and driver mutation profiles, tumor microenvironment, and patient demographics as model context. Our generative modeling approach allows us to predict GRNs for unseen tumor types based on a pan-cancer model of how somatic mutations affect gene regulation. Finally, contextualized networks enable GRN-based precision oncology by providing a structured view of expression dynamics at sample-specific resolution, explaining known biomarkers in terms of network-mediated effects and leading to subtypings that improve survival prognosis. We provide a SKLearn-style Python package https://contextualized.ml for learning and analyzing contextualized models, as well as interactive plotting tools for pan-cancer data exploration at https://github.com/cnellington/CancerContextualized.

PMID:40408406 | DOI:10.1073/pnas.2411930122

Proc Natl Acad Sci U S A. 2025 May 27;122(21):e2503857122. doi: 10.1073/pnas.2503857122. Epub 2025 May 23.

ABSTRACT

A major focus of human genetics is to map severe disease mutations. Increasingly, that goal is understood as requiring huge numbers of people to be sequenced from every broadly defined genetic ancestry group, so as not to miss "ancestry-specific variants." Here, we consider whether this focus is warranted. We start from first principles considerations, based on models of mutation-drift-selection balance, which suggest that since severe disease mutations tend to be strongly deleterious, and thus evolutionarily young, they will be kept at relatively constant frequency through recurrent mutation. Therefore, highly pathogenic alleles should be shared identically by descent within extended families, not broad ancestry groups, and sequencing more people should yield similar numbers regardless of ancestry. We test the model predictions using gnomAD genetic ancestry groupings and show that they provide a good fit to the classes of variants most likely to be highly pathogenic, notably sets of loss of function alleles at strongly constrained genes. These findings clarify that strongly deleterious alleles will be found at comparable rates in people of all ancestries, and the information they provide about human biology is shared across ancestries.

PMID:40408403 | DOI:10.1073/pnas.2503857122

Integr Comp Biol. 2025 May 23:icaf052. doi: 10.1093/icb/icaf052. Online ahead of print.

ABSTRACT

Environmental pressures and temperatures around the planet are not constant, both geographically and temporally. On land, changing climates push temperatures to new highs, and in the Arctic and deepest parts of the ocean, temperatures can be below 0°C without freezing. Additionally, these temperatures can fluctuate seasonally. Pressures also have a similar extreme from land to the depth of the sea. Organisms have found ways to adapt to these extreme conditions, and sometimes, two seemingly different pressures that derive from the environment share similar physiological and biochemical problems and therefore have evolved similar adaptations to those problems. Animals that live in cold conditions, like those seen in the Arctic, face the same problems as those in the deep ocean, such as denaturing proteins, changes in membrane structure, and disruption of biological matrices such as the extracellular matrix. Given the similar problems that impact both deep-sea-adapted animals and cold-adapted animals, they have evolved similar processes to adapt to these environmental conditions. This review proposes that cold and hydrostatic pressure exert similar biological challenges. Therefore, animals have evolved related mechanisms to adapt to these conditions. Thus, the information we have learned from studying cold-adapted species could be used to understand the poorly understood mechanisms responsible for adaptation to pressure.

PMID:40408292 | DOI:10.1093/icb/icaf052

Cell Rep. 2025 May 22;44(6):115734. doi: 10.1016/j.celrep.2025.115734. Online ahead of print.

ABSTRACT

Doublecortin-like kinase 1 (Dclk1) expression identifies cells that are rare in normal pancreas but occur with an increased frequency in pancreatic neoplasia. The identity of these cells has been a matter of debate. We employed Dclk1 reporter mouse models and single-cell RNA sequencing (scRNA-seq) to define Dclk1-expressing cells. In normal pancreas, Dclk1 identifies subsets of ductal, islet, and acinar cells. In pancreatic neoplasia, Dclk1 identifies several cell populations, among which acinar-to-ductal metaplasia (ADM)-like cells and tuft-like cells are predominant. These two populations play opposing roles, with Dclk1+ ADM-like cells sustaining and Dclk1+ tuft-like cells restraining tumor progression. The generation of Dclk1+ tuft-like cells requires the transcription factor SPIB and is sustained by a paracrine loop involving type 2 innate lymphoid cells (ILC2s) and cancer-associated fibroblasts (CAFs) that provide interleukin (IL)-13 and IL-33, respectively. Dclk1+ tuft-like cells release angiotensinogen to restrain tumor progression. Overall, our study defines pancreatic Dclk1+ cells and unveils a protective tuft cell-ILC2 axis against pancreatic neoplasia.

PMID:40408246 | DOI:10.1016/j.celrep.2025.115734

Food Funct. 2025 May 23. doi: 10.1039/d5fo00499c. Online ahead of print.

ABSTRACT

Alterations in calcium homeostasis are critical for the development of type 2 diabetes (T2D), but its specific impacts on this disease are unclear. We aimed to evaluate whether the potential effect is causal. In a two-sample Mendelian randomization (TSMR) analysis, we evaluated if genetic signature predicting supplemental intake of calcium affects risks of T2D. The data on calcium supplementation (N = 461 384) were obtained from the IEU open GWAS project. The T2D GWAS dataset (N = 933 970) was provided by the DIAbetes genetics replication and meta-analysis consortium. We chose inverse variance weighting as the primary TSMR technique. Finally, we analyzed the association between calcium supplementation and T2D by mining The United States Food and Drug Administration Adverse Event Reporting System (FAERS) database (2004 Q1-2024 Q3). A disproportionality analysis was performed to evaluate calcium safety profiles using the reporting odds ratio. Our TSMR analysis showed the role of calcium supplementation in increasing the risk of T2D (OR: 3.40, 95% CI: 1.12-10.38, P = 0.031). Mining of the FAERS database showed 56 T2D side effects among 23 368 adverse events of the drug calcium, supporting the association between calcium use and a high risk of T2D (ROR: 4.27, 95% CI: 3.28-5.55, P < 0.0001). As promoting calcium intake is found to increase the risk of T2D, clinical and public health decisions should be guided accordingly.

PMID:40406923 | DOI:10.1039/d5fo00499c

JAMA Neurol. 2025 May 23. doi: 10.1001/jamaneurol.2025.1522. Online ahead of print.

ABSTRACT

IMPORTANCE: Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure.

OBJECTIVE: To estimate the worldwide burden of SAH.

DESIGN, SETTING, AND PARTICIPANTS: Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021.

EXPOSURES: SAH and 14 modifiable risk factors.

MAIN OUTCOMES AND MEASURES: Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor-specific population attributable fractions (PAFs).

RESULTS: In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution.

CONCLUSIONS AND RELEVANCE: Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

PMID:40406922 | DOI:10.1001/jamaneurol.2025.1522

Physiol Plant. 2025 May-Jun;177(3):e70274. doi: 10.1111/ppl.70274.

ABSTRACT

Magnetic fields (MF) exert a considerable influence on biological processes in various organisms, including prominent effects on plant growth and development. Plant responses to MFs are highly diverse, implying that a plethora of processes are affected, hampering their molecular characterization. In this report, we employed the well-characterized plant model Arabidopsis thaliana to determine root growth responses to both static magnetic fields (SMF) and gradient magnetic fields (Gradient MF). SMF exposure resulted in a dosage-dependent inhibition of root elongation growth and altered auxin-responsive reporter expression, whilst Gradient MF exposure interfered with root curvature and auxin signaling under conditions of minimized gravity effects. Mutants deficient in components of the Arabidopsis auxin transport machinery were less responsive to MFs than wild type, indicative of MF-induced effects on polar auxin transport. When viewing the subcellular localization of PIN-FORMED (PIN) auxin efflux transporters in root meristems, we found that MFs impact their subcellular distribution in root cap and epidermis cells. These effects on PIN localization hint at a molecular switch, linking cellular protein dynamics, auxin transport, and morphogenesis, by which MFs impact the growth of higher plants.

PMID:40405838 | DOI:10.1111/ppl.70274

Nature. 2025 May 22. doi: 10.1038/s41586-025-09124-6. Online ahead of print.

NO ABSTRACT

PMID:40404940 | DOI:10.1038/s41586-025-09124-6

Sci Rep. 2025 May 22;15(1):17813. doi: 10.1038/s41598-025-01819-0.

ABSTRACT

α-Glucosidase is a key enzyme responsible for controlling the blood glucose, making a pivotal target in the treatment of type 2 diabetes mellitus. Present work introduces1,2,4triazolo[1,5-a]pyridine as a novel, potent scaffold for α-glucosidase inhibition. A diverse scope of targeted compounds was prepared through an efficient, straightforward synthetic protocol. A series of compounds (15a-15v) were synthesized using a simple and efficient protocol, all showing notable inhibitory activity. Among them, compound 15j exhibited the best inhibition potency (IC₅₀ = 6.60 ± 0.09 µM), acting as a competitive and selective α-glucosidase inhibitor with no effect on α-amylase. Moreover, comprehensive computational studies were performed to validate the in vitro results and provide insight into compounds' binding interactions within the α-glucosidase's active site. The machine learning model, trained with the Estate fingerprint, achieved an AUC score of 0.65, demonstrating its utility in predicting α-glucosidase inhibition. Random Forest was identified as the most suitable model, and the dataset with the highest R² value was selected for further feature selection and model improvement. Molecular docking studies demonstrated that compound 15j had a strong binding affinity toward α-glucosidase, with a docking score of - 10.04 kcal/mol, and formed several remarkable interactions, particularly three key hydrogen bonds with TYR158, GLN353, and GLU411, contributing to its high inhibitory efficacy. The results of the molecular dynamics simulation demonstrated that the 15j-α-glucosidase complex exhibits high stability and effectively maintains its binding without causing significant structural changes in the enzyme, confirming the stable interaction and selective inhibition of this compound at the enzyme's active site.

PMID:40404778 | DOI:10.1038/s41598-025-01819-0

NPJ Aging. 2025 May 22;11(1):38. doi: 10.1038/s41514-025-00236-x.

ABSTRACT

DNA methylation clocks have been widely used for accurate age prediction, but most studies have been carried out on mammals. Here we present an epigenetic clock for the aquatic frog Xenopus tropicalis, a widely used model organism in developmental biology and genomics. To construct the clock, we collected DNA methylation data from 192 frogs using targeted bisulfite sequencing at genomic regions containing CpG sites previously shown to have age-associated methylation in Xenopus. We found highly positively and negatively age-correlated CpGs are enriched in heterochromatic regions marked with H4K20me3 and H3K9me3. Positively age-correlated CpGs are enriched in bivalent chromatin and gene bodies with H3K36me3, and tend to be proximal to lowly expressed genes. These epigenetic features of aging are similar to those found in mammals, suggesting evolutionary conservation of epigenetic aging mechanisms. Our clock enables future aging biology experiments that leverage the unique properties of amphibians.

PMID:40404700 | DOI:10.1038/s41514-025-00236-x