Lett Appl Microbiol. 2025 Mar 20:ovaf043. doi: 10.1093/lambio/ovaf043. Online ahead of print.

ABSTRACT

Sleep is an essential homeostatic process that undergoes dynamic changes throughout the lifespan, with distinct life stages predisposed to specific sleep pathologies. Similarly, the gut microbiome also varies with age, with different signatures associated with health and disease in the latest decades of life. Emerging research has shown significant cross-talk between the gut microbiota and the brain through several pathways, suggesting the microbiota may influence sleep, though the specific mechanisms remain to be elucidated. Here, we critically examine the existing literature on the potential impacts of the gut microbiome on sleep and how this relationship varies across adulthood. We suggest that age-related shifts in gut microbiome composition and immune function may, in part, drive age-related changes in sleep. We conclude with an outlook on the therapeutic potential of microbiome-targeted interventions aimed at improving sleep across adulthood, particularly for individuals experiencing high stress or with sleep complaints.

PMID:40113228 | DOI:10.1093/lambio/ovaf043

Plant Physiol. 2025 Mar 21:kiaf112. doi: 10.1093/plphys/kiaf112. Online ahead of print.

ABSTRACT

Late blight caused by Phytophthora infestans is a major threat to global potato and tomato production. Sustainable management of late blight requires the development of resistant crop cultivars. This process can be facilitated by high-throughput identification of functional genes involved in late blight pathogenesis. In this study, we generated a high-quality transcriptomic time-course dataset focusing on the initial twenty-four hours of contact between P. infestans and three solanaceous plant species, tobacco(Nicotiana benthamiana), tomato (Solanum lycopersicum), and potato (Solanum tuberosum). Our results demonstrate species-specific transcriptional regulation in early stages of the infection. Transient silencing of putative RIBOSE-5-PHOSPHATE ISOMERASE and HMG-CoA REDUCTASE genes in N. benthamiana lowered plant resistance against P. infestans. Furthermore, heterologous expression of a putative tomato Golgi-localized nucleosugar transporter-encoding gene exacerbated P. infestans infection of N. benthamiana. In comparison, bioassays using transgenic tomato lines showed that the quantitative disease resistance genes were required but insufficient for late blight resistance; genetic knock-out of the susceptibility gene enhanced resistance. The same RNA-seq dataset was exploited to examine the transcriptional landscape of P. infestans and revealed host-specific gene expression patterns in the pathogen. This temporal transcriptomic diversity, in combination with genomic distribution features, identified the P. infestans IPI-B family GLYCINE-RICH PROTEINs as putative virulence factors that promoted disease severity or induced plant tissue necrosis when transiently expressed in N. benthamiana. These functional genes underline the effectiveness of functional gene-mining through a time-course dual RNA-seq approach and provide insight into the molecular interactions between solanaceous plants and P. infestans.

PMID:40112880 | DOI:10.1093/plphys/kiaf112

Cell. 2025 Mar 18:S0092-8674(25)00202-8. doi: 10.1016/j.cell.2025.02.017. Online ahead of print.

ABSTRACT

The relationships of human diversity with biomedical phenotypes are pervasive yet remain understudied, particularly in a single-cell genomics context. Here, we present the Asian Immune Diversity Atlas (AIDA), a multi-national single-cell RNA sequencing (scRNA-seq) healthy reference atlas of human immune cells. AIDA comprises 1,265,624 circulating immune cells from 619 donors, spanning 7 population groups across 5 Asian countries, and 6 controls. Though population groups are frequently compared at the continental level, we found that sub-continental diversity, age, and sex pervasively impacted cellular and molecular properties of immune cells. These included differential abundance of cell neighborhoods as well as cell populations and genes relevant to disease risk, pathogenesis, and diagnostics. We discovered functional genetic variants influencing cell-type-specific gene expression, which were under-represented in non-Asian populations, and helped contextualize disease-associated variants. AIDA enables analyses of multi-ancestry disease datasets and facilitates the development of precision medicine efforts in Asia and beyond.

PMID:40112801 | DOI:10.1016/j.cell.2025.02.017

Plant Physiol. 2025 Mar 20:kiaf109. doi: 10.1093/plphys/kiaf109. Online ahead of print.

ABSTRACT

Herbivores sharing host plants are often temporally and spatially separated, limiting direct interactions between them. Nevertheless, as observed in numerous aboveground study systems, they can reciprocally influence each other via systemically induced plant responses. In contrast, examples of such plant-mediated interactions between belowground herbivores are scarce; however, we postulated that they similarly occur, given the large diversity of root-interacting soil organisms. To test this hypothesis, we analyzed the performance of cabbage root fly (Delia radicum) larvae feeding on the main roots of field mustard (Brassica rapa) plants whose fine roots were infected by the root-knot nematode (Meloidogyne incognita). Simultaneously, we studied the effects of M. incognita on D. radicum-induced defense responses and the accumulation of primary metabolites in the main root. We observed that almost 1.5 times as many D. radicum adults emerged from nematode-infected plants, indicating a facilitation effect of M. incognita infection. Although we observed increases in the accumulation of proteins and two essential amino acids, the strongest effect of nematode infection was visible in the defense response to D. radicum. We observed a 1.5 times higher accumulation of the defense-related phytohormone JA-Ile in response to D. radicum on nematode-infected plants, coinciding with a 75% increase in indole glucosinolate concentrations. Contrastingly, concentrations of aliphatic glucosinolates, secondary metabolites negatively affecting D. radicum, were 10-25% lower in nematode-infected plants. We hypothesize that the attenuated aliphatic glucosinolate concentrations result from antagonistic interactions between biosynthetic pathways of both glucosinolate classes, which was reflected in the expression of key biosynthesis genes. Our results provide explicit evidence of plant-mediated interactions between belowground organisms, likely via systemically induced responses in roots.

PMID:40112263 | DOI:10.1093/plphys/kiaf109

Plant Physiol. 2025 Mar 20:kiaf105. doi: 10.1093/plphys/kiaf105. Online ahead of print.

ABSTRACT

Abiotic and biotic stresses pose serious threats to plant productivity. Elucidating the gene regulatory networks involved in plant stress responses is essential for developing future breeding programs and innovative agricultural products. Here, we introduce the AtSRGA (Arabidopsis thaliana Stress Responsive Gene Atlas), a user-friendly application facilitating the retrieval of stress-responsive genes in Arabidopsis (Arabidopsis thaliana). The application was developed using 1,131 microarray and 1,050 RNA sequencing datasets obtained from public databases. These datasets correspond to 11 stress-related conditions, namely abscisic acid, cold, drought, heat, high light, hypoxia, osmotic stress, oxidative stress, salt, wounding, and Pseudomonas syringae pv. tomato DC3000. Using a modified meta-analysis technique known as the vote-counting method, we computed integrated scores to evaluate stress responsiveness for each condition across multiple studies. AtSRGA visualizes gene behavior under 11 stress conditions and offers an interactive, user-friendly interface accessible to all researchers. It presents a comprehensive heatmap of stress-responsive genes, facilitating the comparative analysis of individual stress responses and groups of genes responding to multiple stresses. We validated the expression patterns of several high-scoring genes of unknown function under cold and heat stress using RT-qPCR, thus demonstrating that our application helps select targets to understand stress-responsive gene networks in Arabidopsis. AtSRGA will improve the screening of stress-responsive genes in Arabidopsis, thereby supporting the advancement of plant science toward a sustainable society.

PMID:40112239 | DOI:10.1093/plphys/kiaf105

J Proteome Res. 2025 Mar 20. doi: 10.1021/acs.jproteome.5c00092. Online ahead of print.

ABSTRACT

Proteomics data-dependent acquisition data sets collected with high-resolution mass-spectrometry (MS) can achieve very high-quality results, but nearly every analysis yields results that are thresholded at some accepted false discovery rate, meaning that a substantial number of results are incorrect. For study conclusions that rely on a small number of peptide-spectrum matches being correct, it is thus important to examine at least some crucial spectra to ensure that they are not one of the incorrect identifications. We present Quetzal, a peptide fragment ion spectrum annotation tool to assist researchers in annotating and examining such spectra to ensure that they correctly support study conclusions. We describe how Quetzal annotates spectra using the new Human Proteome Organization (HUPO) Proteomics Standards Initiative (PSI) mzPAF standard for fragment ion peak annotation, including the Python-based code, a web-service end point that provides annotation services, and a web-based application for annotating spectra and producing publication-quality figures. We illustrate its functionality with several annotated spectra of varying complexity. Quetzal provides easily accessible functionality that can assist in the effort to ensure and demonstrate that crucial spectra support study conclusions. Quetzal is publicly available at https://proteomecentral.proteomexchange.org/quetzal/.

PMID:40111914 | DOI:10.1021/acs.jproteome.5c00092

J Comp Physiol B. 2025 Mar 20. doi: 10.1007/s00360-025-01608-1. Online ahead of print.

ABSTRACT

Widespread species often display traits of generalists, yet local adaptations may limit their ability to cope with diverse environmental conditions. With climate change being a pressing issue, distinguishing between the general ecological and physiological capacities of a species and those of individual populations is vital for assessing the capability to adapt rapidly to changing habitats. Despite its importance, physiological variation across broad range distributions, particularly among free-ranging bats in natural environments, has rarely been assessed. Studies focusing on physiological variation among different populations across seasons are even more limited. We investigated physiological variation in the Malagasy Trident Bat Triaenops menamena across three different roost types in Madagascar during the wet and dry season, examining aspects such as energy regimes, body temperature, and roost microclimates. We focused on patterns of torpor in relation to roosting conditions. We hypothesized that torpor occurrence would be higher during the colder, more demanding dry season. We predicted that populations roosting in more variable microclimates would expend less energy than those in mores stable ones due to more frequent use of torpor and greater metabolic rate reductions. Our findings highlight complex thermoregulatory strategies, with varying torpor expression across seasons and roosts. We observed an overall higher energy expenditure during the wet season but also greater energy savings during torpor in that season, regardless of roost type. We found that reductions in metabolic rate were positively correlated with greater fluctuations in ambient conditions, demonstrating these bats' adaptability to dynamic environments. Notably, we observed diverse torpor patterns, indicating the species' ability to use prolonged torpor under extreme conditions. This individual-level variation is crucial for adaptation to changing environmental conditions. Moreover, the flexibility in body temperature during torpor suggests caution in relying solely on it as an indicator for torpor use. Our study emphasizes the necessity to investigate thermoregulatory responses across different populations in their respective habitats to fully understand a species' adaptive potential.

PMID:40111435 | DOI:10.1007/s00360-025-01608-1

Tree Physiol. 2025 Mar 3;45(3):tpaf016. doi: 10.1093/treephys/tpaf016.

ABSTRACT

Ink disease caused by the hemibiotrophic root pathogen Phytophthora cinnamomi (Pc) is devastating for the European chestnut (Castanea sativa), unlike Asian chestnuts and interspecific hybrids, which are resistant to Pc. The role that hormone responses play for Pc resistance remains little understood, especially regarding the temporal regulation of hormone responses. We explored the relationship between changes in tree health and physiology and alterations in leaf and root phytohormones and primary and secondary metabolites during compatible and incompatible Castanea spp.-Pc interactions. Susceptible (S) C. sativa and resistant (R) C. sativa × C. crenata ramets were inoculated with Pc in roots and assessed for disease progression, leaf physiology and biochemistry at 1, 3, 5 and 8 days after inoculation (d.a.i.). In S chestnuts, Pc increasingly deteriorated the leaf physiological functioning by decreasing leaf CO2 assimilation, stomatal conductance, transpiration rate, chlorophylls content and the maximum quantum yield of the photosystem II over time, triggering aerial symptoms (leaf wilting and chlorosis) 8 d.a.i. Pc had little impact on the leaf physiological functioning of R chestnuts, which remained asymptomatic. In roots of S chestnuts, Pc transiently induced jasmonates signaling (5 d.a.i.) while impairing root carbohydrates metabolism over time. In leaves, a transient antioxidant burst (5 d.a.i.) followed by abscisic acid (ABA) accumulation (8 d.a.i.) was observed. R chestnuts responded to Pc by up-regulating root salicylic acid (SA) at early (1 d.a.i.) and late (8 d.a.i.) infection stages, in an antagonistic crosstalk with root ABA. Overall, the results pinpoint an important role of SA in mediating the resistant response of chestnuts to Pc, but also show that the specific hormone pathways induced by Pc are genotype dependent. The study also highlights that the dynamic nature of hormone responses over time must be considered when elucidating hormone-regulated responses to Pc.

PMID:40111229 | DOI:10.1093/treephys/tpaf016

Eur J Immunol. 2025 Mar;55(3):e202451388. doi: 10.1002/eji.202451388.

ABSTRACT

Epigenetic modification plays a crucial role in establishing the transcriptional program that governs the differentiation of CD8+ effector T cells. However, the mechanisms by which this process is regulated at an early stage, prior to the expression of master transcription factors, are not yet fully understood. In this study, we have identified PDCD5 as an activation-induced molecule that is necessary for the proper differentiation and expansion of antigen-specific CD8+ effector T cells in a mouse model of chronic viral infection. The genetic deletion of Pdcd5 resulted in impaired differentiation and function of effector T cells, while T-cell activation, metabolic reprogramming, and the differentiation of memory/exhausted T cells were largely unaffected. At the molecular level, we observed reduced chromatin accessibility and transcriptional activity of Tbx21 and its regulated genes in Pdcd5-/- CD8+ T cells. We further identified that PRDM9 facilitates the H3K4me3 modification of genes associated with the effector phenotype in CD8+ T cells. The interaction between PDCD5 and PRDM9 promotes the nuclear translocation and lysine methyltransferase activity of PRDM9. Collectively, these findings highlight the crucial role of the PDCD5/PRDM9 axis in epigenetic reprogramming during the early stages of fate determination for effector CD8+ T cell fate.

PMID:40111008 | DOI:10.1002/eji.202451388

Appl Environ Microbiol. 2025 Mar 20:e0212324. doi: 10.1128/aem.02123-24. Online ahead of print.

ABSTRACT

Lignocellulose is a renewable resource for the production of a diverse array of platform chemicals, including the biofuel isoprenol. Although this carbon stream provides a rich source of sugars, other organic compounds, such as acetate, can be used by microbial hosts. Here, we examined the growth and isoprenol production in a Pseudomonas putida strain pre-tolerized ("PT") background where its native isoprenol catabolism pathway is deleted, using glucose and acetate as carbon sources. We found that PT displays impaired growth in minimal medium containing acetate and often fails to grow in glucose-acetate medium. Using a mutant recovery-based approach, we generated tolerized strains that overcame these limitations, achieving fast growth and isoprenol production in the mixed carbon feed. Changes in the glucose and acetate assimilation routes, including an upregulation in PP_0154 (SpcC, succinyl-CoA:acetate CoA-transferase) and differential expression of the gluconate assimilation pathways, were key for higher isoprenol titers in the tolerized strains, whereas a different set of mechanisms were likely enabling tolerance phenotypes in media containing acetate. Among these, a coproporphyrinogen-III oxidase (HemN) was upregulated across all tolerized strains and in one isolate required for acetate tolerance. Utilizing a defined glucose and acetate mixture ratio reflective of lignocellulosic feedstocks for isoprenol production in P. putida allowed us to obtain insights into the dynamics and challenges unique to dual carbon source utilization that are obscured when studied separately. Together, this enabled the development of a P. putida bioconversion chassis able to use a more complex carbon stream to produce isoprenol.IMPORTANCEAcetate is a relatively abundant component of many lignocellulosic carbon streams and has the potential to be used together with sugars, especially in microbes with versatile catabolism such as P. putida. However, the use of mixed carbon streams necessitates additional optimization. Furthermore, the use of P. putida for the production of the biofuel target, isoprenol, requires the use of engineered strains that have additional growth and production constraints when cultivated in acetate and glucose mixtures. In this study, we generate acetate-tolerant P. putida strains that overcome these challenges and examine their ability to produce isoprenol. We show that acetate tolerance and isoprenol production, although independent phenotypes, can both be optimized in a given P. putida strain. Using proteomics and whole genome sequencing, we examine the molecular basis of both phenotypes and show that tolerance to acetate can occur via alternate routes and result in different impacts on isoprenol production.

PMID:40110994 | DOI:10.1128/aem.02123-24

Ecol Evol. 2025 Mar 18;15(3):e71119. doi: 10.1002/ece3.71119. eCollection 2025 Mar.

ABSTRACT

Sexual differences in physiology are widely regarded as potential proximate mechanisms that underlie sex differences in mortality, life history and disease risk of vertebrates. However, little is known about the causes of sex-specific variation in physiology. Sexual selection and parental workload are two key components suggested to play a role. Theory predicts that, within males, species with stronger male sexual selection (greater sexual dichromatism and more frequent social polygyny) and higher male parental effort should have lower immune capacity and stronger oxidative imbalance. Within females, a weak or no direct effect of male sexual selection on physiology is expected, but species where females invest more in parental care should have lower immune capacity and higher oxidative imbalance. We tested these predictions by phylogenetic comparative analyses conducted separately for the two sexes and based on 11,586 physiological measurements of samples collected in the field from 2048 individuals of 116 and 106 European bird species for males and females, respectively. For males, we found that the degree of dichromatism, polygyny and male parental effort correlated negatively with multiple immune indices, and the level of antioxidant glutathione correlated positively with polygyny score. In contrast, female immune and oxidative variables were unrelated or weakly related to both male sexual selection and female parental effort. We conclude that sex roles can drive inter-specific variation in immune function (primarily in male birds), but less so in oxidative physiology. These findings support earlier claims that males pay higher physiological costs of sexual selection than females, but apparently also of caregiving. We discuss how females might avoid such costs.

PMID:40109553 | PMC:PMC11919744 | DOI:10.1002/ece3.71119

Comput Struct Biotechnol J. 2025 Feb 27;27:804-812. doi: 10.1016/j.csbj.2025.02.029. eCollection 2025.

ABSTRACT

N7-methylguanosine (m7G) modifications play a pivotal role in RNA stability, mRNA export, and protein translation. They are closely associated with ribosome function and the regulation of gene expression. Dysregulation of m7G has been implicated in various diseases, including cancers and neurodegenerative disorders, where the loss of m7G can lead to genomic instability and uncontrolled cell proliferation. Accurate identification of m7G sites is thus essential for elucidating these mechanisms. Due to the high cost of experimentally validating m7G sites, several artificial intelligence models have been developed to predict these sites. However, the performance of these models is not yet optimal, and a user-friendly web server is still needed. To address these issues, we developed CAP-m7G, an innovative model that integrates Chaos Game Representation, Capsule Networks, and reconstruction layers. CAP-m7G achieved an accuracy of 96.63%, a specificity of 95.07%, and a Matthews correlation coefficient (MCC) of 0.933 on independent test data. Our results demonstrate that the integration of Chaos Game Representation with Capsule Network can effectively capture the crucial sequence information associated with m7G sites. The web server can be accessed at https://awi.cuhk.edu.cn/~biosequence/CAP-m7G/index.php.

PMID:40109445 | PMC:PMC11919597 | DOI:10.1016/j.csbj.2025.02.029

Lab Chip. 2025 Mar 20. doi: 10.1039/d5lc00015g. Online ahead of print.

ABSTRACT

Glioblastoma is one of the most malignant tumors in the world, but the development of its therapies remains limited. Herein, a microfluidic chip that mimics the cerebrospinal fluid (CSF) circulation microenvironment is proposed to study the migration characteristics of glioblastoma U87-MG cells and U251 cells in complex environments where glioblastoma coexists with diseases that elevate CSF levels. In the presence of interstitial flow (IF), changing both cell densities and the cellular environment results in increased cell motility, including an increase in the number of migrating cells, the mean displacement of the top 30% fastest-moving cells, and the overall mean displacement. Then, through dynamic migration characterization analysis, it was found that IF enhances cell velocity and speed. Importantly, cells exposed to IF tend to migrate in directions with smaller angles of deviation from the opposite direction of IF. Finally, cytoskeleton inhibitors and decreased expressions of focal adhesion proteins, such as cytochalasin D, FAK inhibitors (VS-6063 and PF-573228), and FAK siRNA, were both proved to decrease the cells' response to IF. This work not only demonstrates the effect of IF on glioblastoma cell migration, but also indicates the reliability of microfluidic chips for modeling complex physiological environments, which is expected to be further developed for drug screening.

PMID:40109161 | DOI:10.1039/d5lc00015g

J Phys Chem B. 2025 Mar 20. doi: 10.1021/acs.jpcb.4c07325. Online ahead of print.

ABSTRACT

Insulin fibrillation inflicts both economic and clinical challenges by causing bioactivity loss, inflammation, and adverse effects during storage, transport, and injection. The present study explores antiamyloidogenic and fibril-disaggregating effects of a gut microbiota-derived indole metabolite, indole-3-acetic acid (IAA) on insulin fibrillation. According to Thioflavin T (ThT) fluorescence assays and transmission electron microscopy (TEM), IAA significantly inhibited both primary and seed-induced fibrillation of insulin. We note that IAA reduced insulin aggregate sizes as evident from the scattering profiles, while circular dichroism studies confirmed that IAA preserves native α-helical structure possibly minimizing the exposed surface hydrophobicity of insulin. Additionally, IAA showed effectiveness in breaking apart preformed fibrils, indicated by a time-dependent decrease in ThT fluorescence and further confirmed by TEM. Our biolayer interferometry interaction studies revealed a moderate 2:1 binding affinity between IAA and insulin. Two key binding sites on insulin were identified via machine-learning-based-docking and hybrid QM/MM studies, where IAA interacts. Site I (Leu13A, Tyr14A, Glu17A, Phe1B) showed more favorable interaction energetics than site II (Tyr19A, Phe25B, Thr27B) based on SAPT0 residue-wise interaction energy analysis. IAA also protected cells from fibril-induced cytotoxicity and hemolysis, thereby offering a promising therapeutic option for amyloid-related disorders, with dual action in preventing fibril formation and promoting fibril disaggregation.

PMID:40109067 | DOI:10.1021/acs.jpcb.4c07325

Plant Cell Environ. 2025 Mar 19. doi: 10.1111/pce.15456. Online ahead of print.

ABSTRACT

Bacteriophages impact soil bacteria through lysis, altering the availability of organic carbon and plant nutrients. However, the magnitude of nutrient uptake by plants from lysed bacteria remains unknown, partly because this process is challenging to investigate in the field. In this study, we extend ecosystem fabrication (EcoFAB 2.0) approaches to study plant-bacteria-phage interactions by comparing the impact of virocell (phage-lysed) and uninfected 15N-labelled bacterial necromass on plant nitrogen acquisition and rhizosphere exometabolites composition. We show that grass Brachypodium distachyon derives some nitrogen from amino acids in uninfected Pseudomonas putida necromass lysed by sonication but not from virocell necromass. Additionally, the bacterial necromass elicits the formation of rhizosphere exometabolites, some of which (guanosine), alongside tested aromatic acids (p-coumaric and benzoic acid), show bacterium-specific effects on bacteriophage-induced lysis when tested in vitro. The study highlights the dynamic feedback between virocell necromass and plants and suggests that root exudate metabolites can impact bacteriophage infection dynamics.

PMID:40108761 | DOI:10.1111/pce.15456

Microbiome. 2025 Mar 19;13(1):76. doi: 10.1186/s40168-025-02066-1.

ABSTRACT

BACKGROUND: Female genital tract (FGT) diseases such as bacterial vaginosis (BV) and sexually transmitted infections are prevalent in South Africa, with young women being at an increased risk. Since imbalances in the FGT microbiome are associated with FGT diseases, it is vital to investigate the factors that influence FGT health. The mycobiome plays an important role in regulating mucosal health, especially when the bacterial component is disturbed. However, we have a limited understanding of the FGT mycobiome since many studies have focused on bacterial communities and have neglected low-abundance taxonomic groups, such as fungi. To reduce this knowledge deficit, we present the first large-scale metaproteomic study to define the taxonomic composition and potential functional processes of the FGT mycobiome in South African reproductive-age women.

RESULTS: We examined FGT fungal communities present in 123 women by collecting lateral vaginal wall swabs for liquid chromatography-tandem mass spectrometry. From this, 39 different fungal genera were identified, with Candida dominating the mycobiome (53.2% relative abundance). We observed changes in relative abundance at the protein, genus, and functional (gene ontology biological processes) level between BV states. In women with BV, Malassezia and Conidiobolus proteins were more abundant, while Candida proteins were less abundant compared to BV-negative women. Correspondingly, Nugent scores were negatively associated with total fungal protein abundance. The clinical variables, Nugent score, pro-inflammatory cytokines, chemokines, vaginal pH, Chlamydia trachomatis, and the presence of clue cells were associated with fungal community composition.

CONCLUSIONS: The results of this study revealed the diversity of FGT fungal communities, setting the groundwork for understanding the FGT mycobiome. Video Abstract.

PMID:40108637 | DOI:10.1186/s40168-025-02066-1

Cell Death Differ. 2025 Mar 19. doi: 10.1038/s41418-025-01476-w. Online ahead of print.

ABSTRACT

Mammalian mitochondria undergo Ca2+-induced and cyclosporinA (CsA)-regulated permeability transition (mPT) by activating the mitochondrial permeability transition pore (mPTP) situated in mitochondrial inner membranes. Ca2+-induced prolonged openings of mPTP under certain pathological conditions result in mitochondrial swelling and rupture of the outer membrane, leading to mitochondrial dysfunction and cell death. While the exact molecular composition and structure of mPTP remain unknown, mammalian ATP synthase was reported to form voltage and Ca2+-activated leak channels involved in mPT. Unlike in mammals, mitochondria of the crustacean Artemia franciscana have the ability to accumulate large amounts of Ca2+ without undergoing the mPT. Here, we performed structural and functional analysis of A. franciscana ATP synthase to study the molecular mechanism of mPTP inhibition in this organism. We found that the channel formed by the A. franciscana ATP synthase dwells predominantly in its inactive state and is insensitive to Ca2+, in contrast to porcine heart ATP synthase. Single-particle cryo-electron microscopy (cryo-EM) analysis revealed distinct structural features in A. franciscana ATP synthase compared with mammals. The stronger density of the e-subunit C-terminal region and its enhanced interaction with the c-ring were found in A. franciscana ATP synthase. These data suggest an inactivation mechanism of the ATP synthase leak channel and its possible contribution to the lack of mPT in this organism.

PMID:40108410 | DOI:10.1038/s41418-025-01476-w

EMBO Rep. 2025 Mar 19. doi: 10.1038/s44319-025-00400-0. Online ahead of print.

ABSTRACT

Small open-reading frame-encoded micropeptides within long noncoding RNAs (lncRNAs) are often overlooked due to their small size and low abundance. However, emerging evidence links these micropeptides to various biological pathways, though their roles in neural development and neurodegeneration remain unclear. Here, we investigate the function of murine micropeptide Sertm2, encoded by the lncRNA A730046J19Rik, during spinal motor neuron (MN) development. Sertm2 is predicted to be a conserved transmembrane protein found in both mouse and human, with subcellular analysis revealing that it is enriched in the cytoplasm and neurites. By generating C terminally Flag-tagged Sertm2 and expressing it from the A730046J19Rik locus, we demonstrate that the Sertm2 micropeptide localizes in spinal MNs in mice. The GDNF signaling-induced Etv4+ motor pool is impaired in Sertm2 knockout mice, which display motor nerve arborization defects that culminate in impaired motor coordination and muscle weakness. Similarly, human SERTM2 knockout iPSC-derived MNs also display reduced ETV4+ motor pools, highlighting that Sertm2 is a novel, evolutionarily conserved micropeptide essential for maintaining GDNF-induced MN subtype identity.

PMID:40108406 | DOI:10.1038/s44319-025-00400-0

Sci Rep. 2025 Mar 19;15(1):9415. doi: 10.1038/s41598-025-94362-x.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers known to humans. However, not all patients fare equally poor survival, and a minority of patients even survives advanced disease for months or years. Thus, there is a clinical need to search corresponding prognostic biomarkers which forecast survival on an individual basis. To dig more information and identify potential biomarkers from PDAC pathological slides, we trained a deep learning (DL) model based U-net-shaped backbone. This DL model can automatically detect tumor, stroma and lymphocytes on whole slide images (WSIs) of PDAC patients. We performed an analysis of 800 PDAC scans, categorizing stroma in percentage (SIP) and lymphocytes in percentage (LIP) into two and three categories, respectively. The presented model achieved remarkable accuracy results with a total accuracy of 94.72%, a mean intersection of union rate of 78.66%, and a mean dice coefficient of 87.74%. Survival analysis revealed that SIP-mediate and LIP-high groups correlated with enhanced median overall survival (OS) across all cohorts. These findings underscore the potential of SIP and LIP as prognostic biomarkers for PDAC and highlight the utility of DL as a tool for PDAC biomarkers detecting on WSIs.

PMID:40108402 | DOI:10.1038/s41598-025-94362-x

Sci Rep. 2025 Mar 19;15(1):9486. doi: 10.1038/s41598-025-93695-x.

ABSTRACT

Cutaneous melanoma (CM) is an aggressive skin cancer with high metastatic potential and poor prognosis. Splicing factors, which regulate pre-mRNA alternative splicing (AS) events, have been suggested as potential therapeutic targets in CM. The objective of this study was to identify candidate splicing factors involved in CM through a systems biology approach and to elucidate their roles in CM progression. 390 AS events associated with patient survival were identified using bivariate Cox regression and receiver operating characteristic (ROC) analyses. 121 splicing factors significantly associated with patient prognosis were screened by univariate Cox regression analysis. A bipartite association network between AS events and splicing factors was constructed using Spearman correlation analysis. Based on the network topology, five candidate splice factors were identified. Among them, U2SURP, a poorly characterized serine/arginine-rich protein family member, was selected for further analysis in CM. Results indicated that U2SURP gene expression was significantly negatively correlated with the Immune Infiltration Score, the infiltration levels of dendritic cells, gamma-delta T cells, natural killer (NK) cells, and cytotoxic cells, as well as the expression of the immune checkpoint gene PD-1, suggesting that U2SURP may serve as a potential target for CM immunotherapy. Experimental validation showed that U2SURP mRNA and protein were overexpressed in CM cells, and silencing of U2SURP using siRNA significantly reduced CM cell survival, proliferation and migration. Furthermore, single-cell functional analysis showed that U2SURP gene expression was positively correlated with CM cell proliferation and differentiation. This study systematically identified candidate splicing factors involved in CM and provided new insights into the role of U2SURP in CM progression. These findings contribute to a deeper understanding of the pathogenesis of CM and establish new approaches for identifying splicing-related cancer therapeutic targets.

PMID:40108329 | DOI:10.1038/s41598-025-93695-x