Science. 2025 May 15;388(6748):703-704. doi: 10.1126/science.adx8689. Epub 2025 May 15.

ABSTRACT

Certain fungal plant pathogens maintain varying chromosome distributions across multiple nuclei.

PMID:40373126 | DOI:10.1126/science.adx8689

Science. 2025 May 15:eadp0535. doi: 10.1126/science.adp0535. Online ahead of print.

ABSTRACT

Within the intestine, peripherally-induced regulatory T (pTreg) cells play an essential role in suppressing inflammatory responses to food proteins. However, the identity of antigen-presenting cells (APC) that instruct food-specific pTreg cells is poorly understood. Here, we found that a subset of Thetis cells, TC IV, is required for food-specific pTreg cell differentiation. TC IV were almost exclusively present within mesenteric lymph nodes suggesting that the presence of TC IV underlies the phenomenon of oral tolerance. A wave of TC IV differentiation in the peri-weaning period was associated with a window of opportunity for enhanced pTreg generation in response to food antigens. Our findings indicate that TC IV may represent a therapeutic target for the treatment of food-associated allergic and inflammatory diseases.

PMID:40373113 | DOI:10.1126/science.adp0535

G3 (Bethesda). 2025 May 15:jkaf109. doi: 10.1093/g3journal/jkaf109. Online ahead of print.

ABSTRACT

The Mountain bongo (Tragelaphus eurycerus isaaci), a critically endangered tragelaphine antelope native to the montane forests of Kenya, faces significant threats from habitat loss and hunting. Although the Mountain bongo is a flagship species in Kenya, the majority are found in small, isolated populations of less than 100 animals total, making it a species of high conservation concern. In this report, we present a chromosome-length draft genome assembly for the Mountain bongo, generated using a combination of linked-read and proximity ligation (Hi-C) sequencing techniques. The assembly resulted in a 2.96 Gb sized genome with a contig N50 of 79.5 kb and a scaffold N50 of 192 Mb. Assembly completeness was 95.1% based on 12,234 Benchmarking Universal Single-Copy Orthologs (BUSCO) and annotation revealed 29,820 protein coding genes, of which 27,761 were functionally annotated, and a repetitive content of 47.31%. Synteny analysis against the domestic cattle (Bos taurus) genome assembly revealed numerous chromosomal rearrangements between the two species. Our analysis also revealed insights into the evolutionary and demographic history of the Mountain bongo, offering valuable information for conservation management. We also assembled and annotated the mitochondrial genome which showed <1% differences from the Lowland bongo subspecies, T. e. eurycerus. By integrating genomic data with traditional conservation methods, this reference lays the foundation to evaluate and preserve genetic diversity of both in-situ and ex-situ populations of the Mountain bongo amidst growing environmental pressures.

PMID:40373072 | DOI:10.1093/g3journal/jkaf109

PLoS One. 2025 May 15;20(5):e0321756. doi: 10.1371/journal.pone.0321756. eCollection 2025.

ABSTRACT

Lung cancer remains the leading cause of malignant tumors worldwide in terms of the incidence and mortality, posing a significant threat to human health. Given that distant metastases typically occur at the time of initial diagnosis, leading to a poor 5-year survival rate among patients, it is crucial to identify markers for diagnosis, prognosis, and therapeutic efficacy monitoring. Abnormal glycosylation is a hallmark of cancer cells, characterized by the disruption of core fucosylation, which is predominantly driven by the enzyme fucosyltransferase 8 (FUT8). Evidence indicates that FUT8 is a pivotal enzyme in cancer onset and progression, influencing cellular glycosylation pathways. Utilizing bioinformatics approaches, we have investigated FUT8 in lung cancer, resulting in a more systematic and comprehensive understanding of its role in the disease's pathogenesis. In this study, we employed bioinformatics to analyze the differential expression of FUT8 between LUAD and LUSC. We observed upregulation of FUT8 in both LUAD and LUSC, associated with unfavorable prognosis, and higher diagnostic utility in LUAD. GO/KEGG analysis revealed a primary association between LUAD and the spliceosome. Immunologically, FUT8 expression was significantly associated with immune cell infiltration and immune checkpoint activity, with a notable positive correlation with M2 macrophage infiltration. Our analysis of FUT8 indicates that it may serve as a potential biomarker for lung cancer diagnosis and prognosis, and could represent a therapeutic target for LUAD and LUSC immunotherapy.

PMID:40373023 | DOI:10.1371/journal.pone.0321756

Elife. 2025 May 15;13:RP99005. doi: 10.7554/eLife.99005.

ABSTRACT

Walking animals must maintain stability in the presence of external perturbations, despite significant temporal delays in neural signaling and muscle actuation. Here, we develop a 3D kinematic model with a layered control architecture to investigate how sensorimotor delays constrain the robustness of walking behavior in the fruit fly, Drosophila. Motivated by the anatomical architecture of insect locomotor control circuits, our model consists of three component layers: a neural network that generates realistic 3D joint kinematics for each leg, an optimal controller that executes the joint kinematics while accounting for delays, and an inter-leg coordinator. The model generates realistic simulated walking that resembles real fly walking kinematics and sustains walking even when subjected to unexpected perturbations, generalizing beyond its training data. However, we found that the model's robustness to perturbations deteriorates when sensorimotor delay parameters exceed the physiological range. These results suggest that fly sensorimotor control circuits operate close to the temporal limit at which they can detect and respond to external perturbations. More broadly, we show how a modular, layered model architecture can be used to investigate physiological constraints on animal behavior.

PMID:40372779 | DOI:10.7554/eLife.99005

Mol Biol Cell. 2025 May 15:mbcE24110511. doi: 10.1091/mbc.E24-11-0511. Online ahead of print.

ABSTRACT

Inflammasomes are nucleated by receptors that become activated upon cellular stresses including ionic dyshomeostasis. Rather than forming in the cytosol, recent evidence suggests that inflammasomes are nucleated at specific sites in the cell including on cytoskeletal polymers and the membrane surfaces of organelles. The NLRP3 inflammasome, which is formed upon the loss of cytosolic K+, had been proposed to form on intermediate filaments as well as on vesicles along the endocytic pathway. To determine the necessary requirement of either mechanism, we used vimentin knockout macrophages which do not have intermediate filaments and compared the formation and function of NLRP3 inflammasomes. We report that vimentin was dispensable for the activation of caspase-1, IL-1β cleavage and release, and inflammatory responses in mice attributed to the inflammasome. Instead, NLRP3 was recruited to PI(3,5)P2, PI(4)P- and LAMP1-positive compartments undergoing osmotic swelling. Swelling of these compartments was dependent on the V-ATPase, the inhibition of which curtailed NLRP3 recruitment and inflammasome activation. Similarly, decreasing the hydrostatic pressure on these vesicles prevented NLRP3 recruitment, IL-1β release and pyroptosis. The results suggest that NLRP3 is activated by biophysical features of acidic organelles in the endocytic pathway. [Media: see text].

PMID:40372734 | DOI:10.1091/mbc.E24-11-0511

Development. 2025 May 15;152(10):dev204870. doi: 10.1242/dev.204870. Epub 2025 May 15.

NO ABSTRACT

PMID:40371902 | DOI:10.1242/dev.204870

Evolution. 2025 May 15:qpaf068. doi: 10.1093/evolut/qpaf068. Online ahead of print.

ABSTRACT

Regulatory mutations, coding sequence variations, and gene deletions and duplica- tions are generally expected to have qualitatively different effects on fitness during adaptation. We aim to ground this expectation within a theoretical framework using evolutionary simulations of gene regulatory networks (GRNs) controlling the expression of fitness-related genes. We examined the distribution of fitness effects as a function of the type of mutation and the topology of the gene network. Contrary to our expectation, the GRN topology had more influence on the effect of mutations than the type of mutation itself. In particular, the topology conditioned (i) the speed of adaptation, (ii) the distribution of fitness effects, and (iii) the degree of pleiotropy which acts as explanatory factor for all mutation types. All mutations had the potential to participate in adaptation, although their propensity to generate beneficial variants differed according to the net- work topology. In scale-free networks, arguably the most common topology for biological networks, coding mutations were more pleiotropic and overrepresented in both beneficial and deleterious mu- tations, while regulatory mutations were more often neutral. However, this observation was not general, as this pattern was reversed in the other network topologies. These results highlight the critical role of gene interactions in defining mutations' contributions to adaptation.

PMID:40371760 | DOI:10.1093/evolut/qpaf068

Protein Sci. 2025 Jun;34(6):e70156. doi: 10.1002/pro.70156.

ABSTRACT

Since the emergence of SARS-CoV-2 at the end of 2019, the virus has caused significant global health and economic disruptions. Despite the rapid development of antiviral vaccines and some approved treatments such as remdesivir and paxlovid, effective antiviral pharmacological treatments for COVID-19 patients remain limited. This study explores Nsp15, a 3'-uridylate-specific RNA endonuclease, which has a critical role in immune system evasion and hence in escaping the innate immune sensors. We conducted a comprehensive drug repurposing screen and identified 44 compounds that showed more than 55% inhibition of Nsp15 activity in a real-time fluorescence assay. A validation pipeline was employed to exclude unspecific interactions, and dose-response assays confirmed 29 compounds with an IC50 below 10 μM. Structural studies, including molecular docking and x-ray crystallography, revealed key interactions of identified inhibitors, such as TAS-103 and YM-155, with the Nsp15 active site and other critical regions. Our findings show that the identified compounds, particularly those retaining potency under different assay conditions, could serve as promising hits for developing Nsp15 inhibitors. Additionally, the study emphasizes the potential of combination therapies targeting multiple viral processes to enhance treatment efficacy and reduce the risk of drug resistance. This research contributes to the ongoing efforts to develop effective antiviral therapies for SARS-CoV-2 and possibly other coronaviruses.

PMID:40371758 | DOI:10.1002/pro.70156

Alzheimers Dement. 2025 May;21(5):e70282. doi: 10.1002/alz.70282.

ABSTRACT

INTRODUCTION: Neurodegenerative diseases (NDDs) are chronic diseases caused by brain neuron degeneration, requiring systematic integration of risk factors to address their heterogeneity. Established in 2021, Knowledgebase of Risk Factors for Neurodegenerative Diseases (NDDRF) was the first knowledge base to consolidate NDD risk factors. NDDRF 2.0 expands focus to modifiable lifestyle-related factors, enhancing utility for NDD prevention.

METHODS: Data from the past 4 years were comprehensively updated, while lifestyle factors were manually collected and filtered from 1975 to 2024. Each factor was embedded with International Classification of Diseases codes and clinical stage annotations, and then re-standardized, classified, and annotated in accordance with the Unified Medical Language System Semantic Network.

RESULTS: NDDRF 2.0 encompasses 1971 risk factors classified under 151 subcategories across 20 NDDs, including 536 lifestyle-related factors covering six major categories and is freely accessible at http://sysbio.org.cn/NDDRF/.

DISCUSSION: As the first lifestyle-specific and holistic knowledge base for NDDs, NDDRF 2.0 offers structured and deep phenotype information, enabling personalized prevention strategies and clinical decision support.

HIGHLIGHTS: An enhanced lifestyle-specific and holistic knowledge base (Knowledgebase of Risk Factors for Neurodegenerative Diseases [NDDRF] 2.0) was built for neurodegenerative diseases (NDDs). NDDRF 2.0 provides detailed categorization and deep phenotypes to support targeted NDD prevention. NDDRF 2.0 provides a knowledge-driven resource that facilitates personalized risk assessment and proactive health management. NDDRF 2.0 provides clinicians, researchers, and at-risk populations with knowledge to develop and implement effective risk prevention strategies. NDDRF 2.0 can be used to build chatbots by enhancing large language models in the future.

PMID:40371632 | DOI:10.1002/alz.70282

J Am Heart Assoc. 2025 May 15:e039098. doi: 10.1161/JAHA.124.039098. Online ahead of print.

ABSTRACT

BACKGROUND: Most human disease definitions, except for rare and communicable diseases, are based on symptoms in specific organs, not on causal molecular mechanisms. This limits treatments to imprecise symptomatic approaches with high numbers needed to treat. Systems medicine, instead, has a holistic approach and defines diseases in an organ-agnostic manner on the basis of associated risk genes, their encoded proteins, and protein-protein interactions. Dysregulation of such disease modules is best corrected by multitarget, synergistic network pharmacology. Here we test this principle in acute ischemic stroke, a highly unmet medical indication without any approved neuroprotective drug so far.

METHODS: We extend 3 validated risk genes, neuronal nitric oxide synthase (NOS1), NADPH oxidase 5 (NOX5), and soluble guanylate cyclase (sGC), to a single disease module. For preclinical validation, we used C57/Bl6 mice and humanized NOX5-knock-in mice because NOX5 is not present in the mouse genome despite playing a key role in early stroke. Because up to 70% of patients with stroke have diabetes or prediabetes as an aggravating comorbidity, we also induced diabetes in these mice to model the increased clinical risk for hemorrhagic transformation.

RESULTS: We found that a triple-drug combination of a NOX inhibitor, a nitric oxide synthase inhibitor, and an sGC activator reduced infarct size and, in diabetic animals, also prevented hemorrhagic transformation. Reducing each individual compound dose to subthreshold levels still resulted in full protection when combined, typical for supra-additive network pharmacology. To examine clinical safety, 3 drugs, either marketed for sGC or repurposed for nitric oxide synthase and NADPH oxidase, were administered to healthy volunteers in a phase I trial.

CONCLUSIONS: Our data establish that a mechanism-based network pharmacology approach is effective and clinically safe, warranting a currently ongoing first-in-class neuroprotective phase II interventional trial.

REGISTRATION: URL: https://clinicaltrials.gov/study/NCT05762146?term=repo-stroke&rank=1; Unique Identifier: NCT05762146.

PMID:40371623 | DOI:10.1161/JAHA.124.039098

PNAS Nexus. 2025 May 2;4(5):pgaf139. doi: 10.1093/pnasnexus/pgaf139. eCollection 2025 May.

ABSTRACT

Topological signals are variables or features associated with both nodes and edges of a network. Recently, in the context of topological machine learning, great attention has been devoted to signal processing of such topological signals. Most of the previous topological signal processing algorithms treat node and edge signals separately and work under the hypothesis that the true signal is smooth and/or well approximated by a harmonic eigenvector of the higher-order Laplacian, which may be violated in practice. Here, we propose Dirac-equation signal processing, a framework for efficiently reconstructing true signals on nodes and edges, also if they are not smooth or harmonic, by processing them jointly. The proposed physics-inspired algorithm is based on the spectral properties of the topological Dirac operator. It leverages the mathematical structure of the topological Dirac equation to boost the performance of the signal processing algorithm. We discuss how the relativistic dispersion relation obeyed by the topological Dirac equation can be used to assess the quality of the signal reconstruction. Finally, we demonstrate the improved performance of the algorithm with respect to previous algorithms. Specifically, we show that Dirac-equation signal processing can also be used efficiently if the true signal is a nontrivial linear combination of more than one eigenstate of the Dirac equation, as it generally occurs for real signals.

PMID:40371396 | PMC:PMC12076202 | DOI:10.1093/pnasnexus/pgaf139

Plant Commun. 2025 May 13:101376. doi: 10.1016/j.xplc.2025.101376. Online ahead of print.

ABSTRACT

Cis-regulatory elements (CREs) are non-coding DNA sequences that modulate gene expression. Their identification is critical to study the transcriptional regulation of genes controlling key traits that govern plant growth and development. They are also crucial components for the delineation of gene regulatory networks, which represent regulatory interactions between transcription factors (TFs) and target genes. In maize, CREs have been profiled using different computational and experimental methods, but the extent to which these methods complement each other in identifying functional CREs is unclear. Here, we report the data-driven integration of different maize CRE profiling methods to optimize the capture of experimentally-confirmed TF binding sites, resulting in maps of integrated CREs (iCREs) showing increased levels of completeness and precision. We combined the iCREs with a wide diversity of gene expression data under drought conditions to perform motif enrichment and infer drought-specific GRNs. Mining these organ-specific GRNs revealed known and novel candidate regulators of maize drought response, and showed these networks significantly overlap with drought eQTL regulatory interactions. Furthermore, by studying the transposable elements (TEs) overlapping with iCREs, we identified few TE superfamilies displaying typical epigenetic features of regulatory DNA that are potentially involved in wiring specific TF-target gene regulatory interactions. Overall, our study showcases the integration of different omics data sources to generate a high-quality collection of CREs, together with their applicability to better characterize gene regulation in the complex maize genome.

PMID:40369872 | DOI:10.1016/j.xplc.2025.101376

Nature. 2025 May 14. doi: 10.1038/s41586-025-09012-z. Online ahead of print.

ABSTRACT

Metastasis to the cerebrospinal-fluid-filled leptomeninges, or leptomeningeal metastasis, represents a fatal complication of solid tumours1. Multimodal analyses of clinical specimens reveal substantial inflammatory infiltrate in leptomeningeal metastases with enrichment of IFNγ and resulting downstream signalling. Here, to investigate and overcome this futile anti-tumour response within the leptomeninges, we developed syngeneic lung cancer, breast cancer and melanoma leptomeningeal-metastasis mouse models. We show that transgenic host mice lacking IFNγ or its receptor fail to control the growth of leptomeningeal metastases growth. Leptomeningeal overexpression of Ifng through a targeted adeno-associated-virus-based system controls cancer cell growth independent of adaptive immunity. Using a suite of transgenic hosts, we demonstrate that leptomeningeal T cells generate IFNγ to actively recruit and activate peripheral myeloid cells, generating a diverse spectrum of dendritic cell subsets. Independent of antigen presentation, migratory CCR7+ dendritic cells orchestrate the influx, proliferation and cytotoxic action of natural killer cells to control cancer cell growth in the leptomeninges. This study identifies unique, leptomeninges-specific IFNγ signalling and suggests an immune-therapeutic approach against tumours within this space.

PMID:40369076 | DOI:10.1038/s41586-025-09012-z

Nat Commun. 2025 May 14;16(1):4428. doi: 10.1038/s41467-025-59059-9.

ABSTRACT

Embryonic macrophages emerge before the onset of definitive hematopoiesis, seed into discrete tissues and contribute to specialized resident macrophages throughout life. Presence of embryonic macrophages in the bone marrow and functional impact on hematopoietic stem cells (HSC) or the niche remains unclear. Here we show that bone marrow macrophages consist of two ontogenetically distinct cell populations from embryonic and adult origin. Newborn mice lacking embryonic macrophages have decreased HSC numbers in the bone marrow suggesting an important function for embryo-derived macrophages in orchestrating HSC trafficking around birth. The establishment of a normal cellular niche space in the bone marrow critically depends on embryonic macrophages that are important for the development of mesenchymal stromal cells, but not other non-hematopoietic niche cells, providing evidence for a specific role for embryo-derived macrophages in the establishment of the niche environment pivotal for the establishment of a normally sized HSC pool.

PMID:40368907 | DOI:10.1038/s41467-025-59059-9

Trends Plant Sci. 2025 May 13:S1360-1385(25)00085-8. doi: 10.1016/j.tplants.2025.03.011. Online ahead of print.

ABSTRACT

The mathematics of mass screening is crucial for understanding results from imperfect detection methods in large datasets. Although this framework is well-established, it is not commonly applied in plant biology. Here, we view the identification of messenger RNAs that travel over long distances in plants (mobile mRNAs) through the lens of mass screening statistics. RNA-Seq analyses have identified thousands of mobile mRNAs. Consideration of the detection accuracy and prevalence, however, cast doubt on these numbers. The presented methodology is relevant to all areas of research where detection tests with less than 100% accuracy are applied to find rare events in large datasets.

PMID:40368680 | DOI:10.1016/j.tplants.2025.03.011

Antiviral Res. 2025 May 12:106187. doi: 10.1016/j.antiviral.2025.106187. Online ahead of print.

ABSTRACT

Lipovirtide, originally designated as LP-80, is a stearic acid-modified lipopeptide HIV fusion inhibitor with highly potent and long-lasting anti-HIV activity, and it has already progressed to phase II clinical trials. In this report, we investigated the pharmacokinetics and safety profile of LP-80 in Sprague Dawley (SD) rats. LP-80 was absorbed rapidly following subcutaneous injection, exhibiting high absolute bioavailability (F): 92.32% in male and 84.74% in female. The time to reach maximum plasma concentration (Tmax) ranged from 5.5 to 8 hours (h), and the elimination half-life (T1/2) was between 6.26 and 7.47 h, indicating a relatively long-lasting presence in the bloodstream. LP-80 was widely distributed across various tissues, with the highest concentration observed in serum, suggesting effective systemic delivery and potential for targeting HIV in different compartments. Only a minimal amount of the parent drug was excreted in feces and urine, which indicates that LP-80 is metabolically stable and not rapidly cleared from the body. Acute, subchronic, and chronic toxicity studies demonstrated that LP-80 was well tolerated in animals, with no significant adverse effects observed. No anti-drug antibodies (ADA) were detected, suggesting low immunogenicity. Furthermore, LP-80 showed no toxic effects on fertility, embryo-fetal development, or offspring development. Collectively, our studies demonstrate that LP-80 is metabolically stable and exhibits a favorable safety profile, supporting its advancement into clinical trials for HIV treatment.

PMID:40368113 | DOI:10.1016/j.antiviral.2025.106187

Int J Antimicrob Agents. 2025 May 12:107538. doi: 10.1016/j.ijantimicag.2025.107538. Online ahead of print.

NO ABSTRACT

PMID:40368009 | DOI:10.1016/j.ijantimicag.2025.107538

JACC CardioOncol. 2025 May 5:S2666-0873(25)00141-3. doi: 10.1016/j.jaccao.2025.03.007. Online ahead of print.

ABSTRACT

BACKGROUND: Cardiomyocyte loss occurs in acute and chronic cardiac injury, including cardiotoxicity due to chemotherapeutics like doxorubicin, and contributes to heart failure development. There is a pressing need for cardiac-specific therapeutics that target cardiomyocyte loss, preventing chemotherapy complications without compromising chemotherapeutic efficacy.

OBJECTIVES: The authors employed massively parallel combinatorial genetic screening to find microRNA (miRNA) combinations that promote cardiomyocyte survival.

METHODS: CombiGEM (combinatorial genetics en masse) screening in a cardiomyocyte cell line was followed by validation in the original cell type and screening in primary cardiomyocytes. The top combination was tested in mouse and developing zebrafish models of doxorubicin cardiotoxicity. RNA sequencing provided insight into possible mechanisms.

RESULTS: Multiple miRNA combinations protected cardiomyocytes from doxorubicin in vitro. The most effective (miR-222+miR-455) appeared to act synergistically, and mitigated doxorubicin cardiotoxicity phenotypes in murine and zebrafish in vivo models. RNA sequencing revealed overlapping and synergistic regulation of relevant genes and biological processes in cardiomyocytes, including mitochondrial homeostasis, oxidative stress, muscle contraction, and others.

CONCLUSIONS: We identified miR-222 and miR-455 as a combination with potential therapeutic applications for cardioprotection. This study furthers our knowledge of the cardiac effects of miRNAs and their combinations and demonstrates the potential of CombiGEM for cardioprotective combinatorial therapeutic discovery.

PMID:40366325 | DOI:10.1016/j.jaccao.2025.03.007

Plant Cell. 2025 May 14:koaf093. doi: 10.1093/plcell/koaf093. Online ahead of print.

ABSTRACT

Systems biology aims to uncover gene regulatory networks (GRNs) for agricultural traits, but validating them in crops is challenging. We addressed this challenge by learning and validating model-to-crop GRN regulons governing nitrogen use efficiency (NUE). First, a fine-scale time-course nitrogen (N) response transcriptome analysis revealed a conserved temporal N response cascade in maize (Zea mays) and Arabidopsis (Arabidopsis thaliana). This data was used to infer time-based causal transcription factor (TF) target edges in N-regulated GRNs (N-GRNs). By validating 23 maize TFs in a cell-based TF-perturbation assay (TARGET), precision/recall analysis enabled us to prune high-confidence edges between ∼200 TFs/700 maize target genes. We next learned gene-to-NUE trait scores using XGBoost machine learning models trained on conserved N-responsive genes across maize and Arabidopsis accessions. By integrating NUE gene scores within our N-GRN, we ranked maize TFs based on a cumulative NUE regulon score. Regulons for top-ranked TFs were validated using the cell-based TARGET assay in maize (e.g. ZmMYB34/R3→24 targets) and the Arabidopsis ZmMYB34/R3 ortholog (e.g. AtDIV1→23 targets). The genes in this NUE regulon significantly enhanced the ability of XGBoost models to predict NUE traits in both maize and Arabidopsis. Thus, our pipeline for identifying NUE regulons that combines GRN inference, machine learning, and orthologous network regulons offers a strategic framework for crop trait improvement.

PMID:40365911 | DOI:10.1093/plcell/koaf093