Neural Regen Res. 2025 Apr 29. doi: 10.4103/NRR.NRR-D-24-00794. Online ahead of print.

ABSTRACT

Retinal ganglion cells, a crucial component of the central nervous system, are often affected by irreversible visual impairment due to various conditions, including trauma, tumors, ischemia, and glaucoma. Studies have shown that the optic nerve crush model and glaucoma model are commonly used to study retinal ganglion cell injury. While these models differ in their mechanisms, both ultimately result in retinal ganglion cell injury. With advancements in high-throughput technologies, techniques such as microarray analysis, RNA sequencing, and single-cell RNA sequencing have been widely applied to characterize the transcriptomic profiles of retinal ganglion cell injury, revealing underlying molecular mechanisms. This review focuses on optic nerve crush and glaucoma models, elucidating the mechanisms of optic nerve injury and neuron degeneration induced by glaucoma through single-cell transcriptomics, transcriptome analysis, and chip analysis. Research using the optic nerve crush model has shown that different retinal ganglion cell subtypes exhibit varying survival and regenerative capacities following injury. Single-cell RNA sequencing has identified multiple genes associated with retinal ganglion cell protection and regeneration, such as Gal, Ucn, and Anxa2. In glaucoma models, high-throughput sequencing has revealed transcriptomic changes in retinal ganglion cells under elevated intraocular pressure, identifying genes related to immune response, oxidative stress, and apoptosis. These genes are significantly upregulated early after optic nerve injury and may play key roles in neuroprotection and axon regeneration. Additionally, CRISPR-Cas9 screening and ATAC-seq analysis have identified key transcription factors that regulate retinal ganglion cell survival and axon regeneration, offering new potential targets for neurorepair strategies in glaucoma. In summary, single-cell transcriptomic technologies provide unprecedented insights into the molecular mechanisms underlying optic nerve injury, aiding in the identification of novel therapeutic targets. Future researchers should integrate advanced single-cell sequencing with multi-omics approaches to investigate cell-specific responses in retinal ganglion cell injury and regeneration. Furthermore, computational models and systems biology methods could help predict molecular pathways interactions, providing valuable guidance for clinical research on optic nerve regeneration and repair.

PMID:40313107 | DOI:10.4103/NRR.NRR-D-24-00794

Nat Methods. 2025 May 1. doi: 10.1038/s41592-025-02659-6. Online ahead of print.

ABSTRACT

Structural biology offers a window into the functionality of molecular machines in health and disease. A fundamental challenge lies in capturing both the high-resolution structural details and dynamic changes that are essential for function. The high-resolution methods of X-ray crystallography and electron cryo-microscopy (cryo-EM) are mainly used to study ensembles of static conformations but can also capture crucial dynamic transition states. Here, we review the latest strategies and advancements in time-resolved structural biology with a focus on capturing dynamic changes. We describe recent technology developments for time-resolved sample preparation and delivery in the cryo-EM and X-ray fields and explore how these technologies could mutually benefit each other to advance our understanding of biology at the molecular and atomic scales.

PMID:40312512 | DOI:10.1038/s41592-025-02659-6

Sci Rep. 2025 May 1;15(1):15298. doi: 10.1038/s41598-025-98923-y.

NO ABSTRACT

PMID:40312492 | DOI:10.1038/s41598-025-98923-y

Eur Urol Oncol. 2025 Apr 30:S2588-9311(25)00094-X. doi: 10.1016/j.euo.2025.03.016. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: The interplay between prostate cancer and the tumor microenvironment is well documented and of primary importance in disease evolution. Herein, we investigated the prognostic value of tissue and urinary collagen-related molecular signatures in predicting biochemical recurrence (BCR) after radical prostatectomy (RP).

METHODS: A comprehensive analysis of 55 collagen-related features was conducted using transcriptomic datasets (n = 1393), with further validation at the proteomic level (n = 69). Additionally, a distinct cohort (n = 73) underwent a urine-based peptidomic analysis, culminating in the validation of a urine-derived prognostic model. Independent prognostic significance was assessed using Cox proportional hazards modeling, while the model's predictive performance was benchmarked against established clinical metrics.

KEY FINDINGS AND LIMITATIONS: An expression analysis of 55 collagen-related transcripts identified 11 transcripts significantly associated with BCR (C-index: 0.55-0.72, p < 0.002). Multivariable models incorporating these transcripts enhanced prognostic accuracy, surpassing clinical variables (C-index: 0.66-0.89, p < 0.002). Proteomic validation confirmed five key collagen proteins, while a urine-based collagen model (C-index: 0.73, 95% confidence interval: 0.62-0.85) demonstrated a strong prognostic potential, although limited by small patient numbers. Additionally, tissue collagen-based models predicted overall survival with a significant prognostic value (C-index: 0.59-0.70, p < 0.01).

CONCLUSIONS AND CLINICAL IMPLICATIONS: Collagen-based molecular signatures in both tissue and urine emerge as robust prognostic biomarkers for predicting BCR following RP.

PMID:40312179 | DOI:10.1016/j.euo.2025.03.016

Acta Biomater. 2025 Apr 29:S1742-7061(25)00304-6. doi: 10.1016/j.actbio.2025.04.051. Online ahead of print.

ABSTRACT

This study investigates the material composition of the keratinous teeth and jaw sheaths of Anuran tadpoles, for the first time. Using scanning electron microscopy (SEM), confocal laser scanning microscopy (CSLM), and energy dispersive X-ray spectroscopy (EDX), the oral discs of eight species were analysed. SEM analysis revealed structural diversity, including different tooth microstructures, which may reflect functional adaptations to different mechanical loads. CSLM imagining documented consistent autofluorescence patterns across species, with notable interspecific differences in tooth composition. EDX analysis identified a wide variety of elemental compositions, suggesting possible correlations with ecological or/and dietary factors. This study is the first on the composition of tadpole mouth parts and provides a foundation for future research on the functional morphology and biomechanics of these structures and their interplay with feeding ecology. STATEMENT OF SIGNIFICANCE: This study marks the first detailed exploration of the material composition of keratinous teeth and jaw sheaths in Anuran tadpoles, unveiling significant structural and compositional diversity. Using SEM, CSLM, and EDX analyses, it highlights interspecific differences in microstructure, autofluorescence, and elemental composition, with potential links to ecological and dietary adaptations. Notably, SEM revealed multi-layered tooth structures likely reducing abrasion, while CSLM indicated species-specific autofluorescence variations possibly linked to element distribution. Elemental analysis identified differences in sulphur, aluminium, and silicon content across species. These findings provide a critical foundation for advancing research into the functional morphology, biomechanics, and ecological roles of tadpole oral structures, paving the way for deeper understanding of their evolution and adaptive mechanisms.

PMID:40311990 | DOI:10.1016/j.actbio.2025.04.051

Lancet Microbe. 2025 Apr 28:101098. doi: 10.1016/j.lanmic.2025.101098. Online ahead of print.

ABSTRACT

BACKGROUND: Cross-reactive immune memory responses to orthopoxviruses in humans remain poorly characterised despite their relevance for vaccine design and outbreak control. We aimed to assess the magnitude, specificity, and durability of cross-reactive immune responses elicited by smallpox vaccines and mpox virus infection.

METHODS: We did a multicohort observational study involving participants from the USA, Brazil, and Portugal across four groups: Dryvax (first-generation smallpox vaccine) recipients vaccinated 40-80 years ago, JYNNEOS (third-generation smallpox vaccine) recipients vaccinated within the past year, a cohort receiving both vaccines, and patients infected with clade IIb mpox. Samples were analysed for systemic and mucosal humoral responses, neutralising antibody titres, viral antigen structural analysis, and T-cell cross-reactivity to vaccina virus, cowpox virus, and mpox virus. Statistical analyses included correlation assessments and comparisons across cohorts to determine the magnitude, longevity, and breadth of immune responses.

FINDINGS: Between July 7, 2022, and Aug 3, 2023, 262 participants were recruited, resulting in analysis of 378 samples. Both first-generation and third-generation smallpox vaccines elicited vaccinia virus-reactive and mpox virus-reactive antibodies, with the strongest responses targeting the less conserved extracellular virion antigens B5 and A33. Despite high concentrations of anti-mpox virus antibodies in the plasma, cross-neutralisation activity correlated with viral antigenic distance. Higher neutralisation was observed for cowpox virus than for mpox virus, which has lower antigenic conservation with vaccina virus. Complement-mediated neutralisation enhanced mpox virus neutralisation, overcoming the limitations of antigenic distance. Dryvax recipients sustained vaccina virus neutralisation titres for over 80 years, whereas cross-reactive responses did not show this durability. JYNNEOS-induced responses waned within a year. T-cell cross-reactivity was long-lasting, detected up to 70 years after vaccination. Booster vaccinations augmented the magnitude, breadth, and longevity of cross-neutralising responses.

INTERPRETATION: Our findings highlight the potential combined role of antibody effector functions and T-cell memory in cross-protection against orthopoxviruses. Complement-mediated neutralisation enhances cross-protection, overcoming antigenic distance. These Fc-mediated functions, along with T-cell responses, contribute to effective and long-lasting immunity conferred by smallpox vaccines against other orthopoxviruses.

FUNDING: Yale University and Stavros Niarchos Foundation Institute for Global Infectious Disease.

PMID:40311645 | DOI:10.1016/j.lanmic.2025.101098

Cell Rep Med. 2025 Apr 25:102100. doi: 10.1016/j.xcrm.2025.102100. Online ahead of print.

ABSTRACT

Head and neck squamous cell carcinoma (HNSCC) shows variable response to anti-programmed cell death protein 1 (PD-1) therapy, which can be partially explained by a combined positive score (CPS) of tumor and immune cell expression of programmed death-ligand 1 (PD-L1) within the local tumor microenvironment (TME). To better define TME immune determinants associated with treatment efficacy, we conduct a study of n = 48 HNSCC tumors from patients prior to pembrolizumab therapy. Our investigation combines a rapid bioorthogonal multiplex staining method with computational analysis of whole-slide imaging to capture the single-cell spatial heterogeneity and complexity of the TME. Analyzing 6,316 fields of view (FOVs), we provide comprehensive PD-L1 phenotyping and cell proximity assays across the entirety of tissue sections. While none of the PD-L1 metrics adequately predict response, we find that the spatial organization of CCR7+ dendritic cells (DCs) in niches better predicts overall patient survival than CPS alone. This study highlights the importance of understanding the spatial context of immune networks for immunotherapy.

PMID:40311615 | DOI:10.1016/j.xcrm.2025.102100

Nutr Res. 2025 Apr 5;138:55-67. doi: 10.1016/j.nutres.2025.04.004. Online ahead of print.

ABSTRACT

Although the human gut microbiome, and its role in health and disease, have been extensively studied in different populations, a comprehensive assessment of gut microbiome composition has not been performed in vulnerable refugee populations. In this study, we hypothesized that overall nutritional status, as indicated by serum micronutrients concentrations, is an important driver of variations in gut microbiome composition. Therefore, gut-microbiome diversity and associated demographic, health and nutritional factors were assessed in adolescent Afghan refugees (n=206). Blood and faecal samples were collected and analysed for nutrition status markers and 16S rRNA gene amplicon-based community profiling, respectively. Bioinformatics and statistical analysis were performed using SPSS, QIIME and R. Overall, 56 distinct phyla, 117 families and 252 genera were identified in the faecal samples. Bacterial diversity (alpha and beta diversity) and the Firmicutes:Bacteroidetes (F/B) ratio were significantly higher in the 15 to 19 year old age group (cf. the 10-14 age group) but were lower in the underweight and vitamin D deficient groups. Furthermore, LEfSe analysis identified significant differences in the relative abundance of bacterial genera based on age, BMI and micronutrient (vitamins and minerals) status. These results were further scrutinised by correlation analysis which confirmed that age, BMI and micronutrient status show significant correlations with F/B ratio and the relative abundance of specific bacterial taxa. Collectively, our study provides the first indication of how the gut-microbiota profile of adolescent Afghan refugees is associated with a range of nutrition-status factors. These findings can thus provide a basis for translational microbiota research aimed at improving the health of such understudied and vulnerable populations.

PMID:40311534 | DOI:10.1016/j.nutres.2025.04.004

Semin Cell Dev Biol. 2025 Apr 30;171:103616. doi: 10.1016/j.semcdb.2025.103616. Online ahead of print.

ABSTRACT

Biological systems inherently perform computations, inspiring synthetic biologists to engineer biological systems capable of executing predefined computational functions for diverse applications. Typically, this involves applying principles from the design of conventional silicon-based computers to create novel biological systems, such as genetic Boolean gates and circuits. However, the natural evolution of biological computation has not adhered to these principles, and this distinction warrants careful consideration. Here, we explore several concepts connecting computational theory, living cells, and computers, which may offer insights into the development of increasingly sophisticated biological computations. While conventional computers approach theoretical limits, solving nearly all problems that are computationally solvable, biological computers have the opportunity to outperform them in specific niches and problem domains. Crucially, biocomputation does not necessarily need to scale to rival or replicate the capabilities of electronic computation. Rather, efforts to re-engineer biology must recognise that life has evolved and optimised itself to solve specific problems using its own principles. Consequently, intelligently designed cellular computations will diverge from traditional computing in both implementation and application.

PMID:40311248 | DOI:10.1016/j.semcdb.2025.103616

Hepatology. 2025 May 1. doi: 10.1097/HEP.0000000000001346. Online ahead of print.

ABSTRACT

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than 30% of the world's population and is associated with multisystemic comorbidities. We combined multidimensional OMICs approaches to explore the feasibility of using high-throughput targeted circulating proteomics to track systemic organ damage and infer the underlying molecular mechanisms.

METHODS: We evaluated a 92-plex panel of prioritized proteins with pathophysiological relevance to organ damage in serum samples of patients using in-depth phenotyping. We included proteomic data from 60,042 individuals in the discovery and replication stages using diverse study designs and cross-proteomic platforms. We used deconvolution strategies to investigate whether the affected liver participated in the expression of biomarkers of organ damage. To assess cell type-specific transcriptional changes in the selected target, we used liver organoid data.

FINDINGS: The implicated proteins, including ADGRG1 (GPR56), are deregulated in patients who are at-risk of progressive disease and significant fibrosis. ADGRG1 was validated as a surrogate for organ damage, as it was associated with increased risk of end-stage liver disease, moderate but clinically significant risk of death, chronic obstructive pulmonary disease and ischaemic heart disease over a 16-year follow-up, regardless of the subject's MASLD status. ADGRG1 liver expression mirrors the circulation pattern. Mechanistic insights show that ADGRG1 shifts its transcriptional profile from low expression to upregulation in cells of the fibrotic and inflammatory niche in response to injury.

CONCLUSIONS: Our study provides a framework for potential mechanisms associated with systemic diseases that facilitates holistic management by stratifying patients with MASLD into subclasses at-risk of extrahepatic manifestations.

PMID:40310655 | DOI:10.1097/HEP.0000000000001346

mBio. 2025 May 1:e0201924. doi: 10.1128/mbio.02019-24. Online ahead of print.

ABSTRACT

Sponge-associated microbes play fundamental roles in regulating their hosts' physiology, yet their contribution to sexual reproduction has been largely overlooked. Most studies have concentrated on the proportion of the microbiome transmitted from parents to offspring, providing little evidence of the putative microbial role during gametogenesis in sponges. Here, we use 16S rRNA gene analysis to assess whether the microbial composition of five gonochoristic sponge species differs between reproductive and non-reproductive individuals and correlate these changes with their gametogenic stages. In sponges with mature oocytes, reproductive status did not influence either beta or alpha microbial diversity. However, in two of the studied species, Geodia macandrewii and Petrosia ficiformis, which presented oocytes at the previtellogenic stage, significant microbial composition changes were detected between reproductive and non-reproductive individuals. These disparities were primarily driven by differentially abundant taxa affiliated with the Nitrososphaeria archaeal class in both species. We speculate that the previtellogenic stages are more energetically demanding, leading to microbial changes due to the phagocytosis of microbes to meet nutritional demands during this period. Supporting our hypothesis, we observed significant transcriptomic differences in G. macandrewii, mainly associated with the immune system, indicating potential changes in the sponge's recognition system. Overall, we provide new insights into the possible roles of sponge microbiomes during reproductive periods, potentially uncovering critical interactions that support reproductive success.

IMPORTANCE: Our research explores the fascinating relationship between sponges and their resident microbes, focusing specifically on how these microbes might influence sponge reproduction. Sponges are marine animals known for their complex and beneficial partnerships with various microbes. While previous studies have mainly looked at how these microbes are passed from parent sponges to their offspring, our study is among the first to examine how microbial communities change during the different stages of sponge reproduction. By analyzing the microbial composition in five sponge species, we discovered that significant changes occur in species with premature oocytes, suggesting that microbes may play a crucial role in providing the necessary nutrients during early egg development. This work not only enhances our understanding of sponge biology but also opens up new avenues for studying how microbes support the reproductive success of their hosts in marine environments.

PMID:40310091 | DOI:10.1128/mbio.02019-24

Physiol Plant. 2025 May-Jun;177(3):e70245. doi: 10.1111/ppl.70245.

ABSTRACT

The rising frequency of extreme climate events requires sustainable strategies to secure food production. Environmental stress impacts seed germination and seedling development, posing a significant agricultural challenge. To address this, we developed and applied iron-based nanoparticles (Bio-NPs) synthesized through green biosynthesis from Haematococcus pluvialis, a microalga rich in antioxidants like astaxanthin. These Bio-NPs, approximately 21 nm in diameter and characterized by a negative surface charge, were used as priming agents for maize seeds. Their effects on physiological traits were analyzed with multispectral imaging, showing enhanced normalized difference vegetation index (NDVI) and chlorophyll levels in maize seedlings, highlighting Bio-NPs as effective biostimulants. Among the tested concentrations, 6 mM Bio-NPs yielded the most substantial improvements in seedling health compared to unprimed and hydro-primed groups. Importantly, in vitro studies confirmed that Bio-NPs had no harmful effects on beneficial bacteria and fungi of agronomic importance, underscoring their safety. Although the exact biological pathways responsible for these enhancements are yet to be fully understood, further research into plant responses to Bio-NPs could yield new insights into plant biostimulation. Bio-NPs thus hold promises for strengthening seedling resilience under extreme environmental scenarios, currently observed due to global climate change, offering a safe, sustainable approach to agricultural enhancement. By leveraging microalgae-based biostimulants, this work advances seed priming technology, fostering crop resilience and supporting environmentally friendly agricultural practices.

PMID:40309930 | DOI:10.1111/ppl.70245

R Soc Open Sci. 2025 Apr 30;12(4):241025. doi: 10.1098/rsos.241025. eCollection 2025 Apr.

ABSTRACT

Different isogenic cells exhibit different responses to the same extracellular signals. Several authors assumed that this variation arose from stochastic signalling noise with the implication that single eukaryotic cells could not detect their surroundings accurately, but work by us and others has shown that the variation is dominated instead by persistent cell-to-cell differences. Here, we analysed previously published data to quantify the sources of variation in pheromone-induced gene expression in Saccharomyces cerevisiae. We found that 91% of response variation was due to stable cell-to-cell differences, 8% from experimental measurement error, and 1% from signalling noise and expression noise. Low noise enabled precise signalling; individual cells could transmit over 3 bits of information through the pheromone response system and so respond differently to eight different pheromone concentrations. Additionally, if individual cells could reference their responses against constitutively expressed proteins, then cells could determine absolute pheromone concentrations with 2 bits of accuracy. These results help explain how individual yeast cells can accurately sense and respond to different extracellular pheromone concentrations.

PMID:40309186 | PMC:PMC12040454 | DOI:10.1098/rsos.241025

R Soc Open Sci. 2025 Apr 30;12(4):241791. doi: 10.1098/rsos.241791. eCollection 2025 Apr.

ABSTRACT

The bond graph approach has been recognized as a useful conceptual basis for understanding the behaviour of living entities modelled as a system with hierarchical interacting parts exchanging energy. One such behaviour is oscillation, which underpins many essential biological functions. In this paper, energy-based modelling of biochemical systems using the bond graph approach is combined with classical feedback control theory to give a novel approach to the analysis, and potentially synthesis, of biochemical oscillators. It is shown that oscillation is dependent on the interplay between active and passive feedback and this interplay is formalized using classical frequency-response analysis of feedback systems. In particular, the phase margin is suggested as a simple scalar indicator of the presence or absence of oscillations; it is shown how this indicator can be used to investigate the effect of both the structure and parameters of biochemical system on oscillation. It follows that the combination of classical feedback control theory and the bond graph approach to systems biology gives a novel analysis and design methodology for biochemical oscillators. The approach is illustrated using an introductory example similar to the Goodwin oscillator, the Sel'kov model of glycolytic oscillations and the repressilator.

PMID:40309185 | PMC:PMC12040473 | DOI:10.1098/rsos.241791

Biophys Rep. 2025 Apr 30;11(2):129-142. doi: 10.52601/bpr.2024.240045.

ABSTRACT

In this study, we conducted a comprehensive proteomic analysis of B cells from the spleen, mesenteric lymph nodes (mLN), and peripheral blood mononuclear cells (PBMC) in a time-course model of systemic lupus erythematosus (SLE) using female MRL/lpr mice. By combining fluorescence-activated cell sorting (FACS) and 4D-Data-Independent Acquisition (4D-DIA) mass spectrometry, we quantified nearly 8000 proteins, identifying significant temporal and tissue-specific proteomic changes during SLE progression. PBMC-derived B cells exhibited early proteomic alterations by Week 9, while spleen-derived B cells showed similar changes by Week 12. We identified key regulatory proteins, including BAFF, BAFFR, and NFKB2, involved in B cell survival and activation, as well as novel markers such as CD11c and CD117, which have previously been associated with other immune cells. The study highlights the dynamic reprogramming of B cell proteomes across different tissues, with distinct contributions to SLE pathogenesis, providing valuable insights into the molecular mechanisms underlying B cell dysregulation in lupus. These findings offer potential therapeutic targets and biomarkers for SLE.

PMID:40308935 | PMC:PMC12035744 | DOI:10.52601/bpr.2024.240045

Virus Evol. 2025 Mar 11;11(1):veaf015. doi: 10.1093/ve/veaf015. eCollection 2025.

ABSTRACT

Mutations within the N-terminal domain (NTD) of the spike (S) protein are critical for the emergence of successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral lineages. The NTD has been repeatedly impacted by deletions, often exhibiting complex and dynamic patterns, such as the recurrent emergence and disappearance of deletions in dominant variants. This study investigates the influence of repair of NTD lineage-defining deletions found in the BA.1 lineage (Omicron variant) on viral success. We performed comparative genomic analyses of >10 million SARS-CoV-2 genomes from the Global Initiative on Sharing All Influenza Data (GISAID) EpiCov database to evaluate the detection of viruses lacking S:ΔH69/V70, S:ΔV143/Y145, or both. These findings were contrasted against a screening of publicly available raw sequencing data, revealing substantial discrepancies between data repositories, suggesting that spurious deletion repair observations in GISAID may result from systematic artifacts. Specifically, deletion repair events were approximately an order of magnitude less frequent in the read-run survey. Our results suggest that deletion repair events are rare, isolated events with limited direct influence on SARS-CoV-2 evolution or transmission. Nevertheless, such events could facilitate the emergence of fitness-enhancing mutations. To explore potential drivers of NTD deletion repair patterns, we characterized the viral phenotype of such markers in a surrogate in vitro system. Repair of the S:ΔH69/V70 deletion reduced viral infectivity, while simultaneous repair with S:ΔV143/Y145 led to lower fusogenicity. In contrast, individual S:ΔV143/Y145 repair enhanced both fusogenicity and susceptibility to neutralization by sera from vaccinated individuals. This work underscores the complex genotype-phenotype landscape of the spike NTD in SARS-CoV-2, which impacts viral biology, transmission efficiency, and immune escape potential, offering insights with direct relevance to public health, viral surveillance, and the adaptive mechanisms driving emerging variants.

PMID:40308784 | PMC:PMC12041916 | DOI:10.1093/ve/veaf015

J Anim Sci Biotechnol. 2025 May 1;16(1):62. doi: 10.1186/s40104-025-01181-1.

ABSTRACT

BACKGROUND: Lactate is a classical byproduct of glucose metabolism, and the main lactate production pathway depends on glycolysis. Lactate stabilized HIF1α by inhibiting PHD activity, leading to hypoxic stress response and exacerbating glycolysis in multiple tissues. However, the redox induction mechanism of lactate in mammary gland has not been understood yet. Herein, we describe a lactate-responsive HIF1α/circadian control mechanism in oxidative stress in the mammary glands of dairy cows.

RESULTS: The in vivo study showed that dairy cows with high lactate concentrations are associated with reduced milk yield and more ROS accumulation in mammary gland. Western blot results in MAC-T cells showed positive correlation between lactate concentrations, expression of HIF1α and oxidative stress indicators, but not circadian core components. To test how lactate-mediated HIF1α dysfunction leads to cell protection process, we investigated altered expression of circadian core related genes following HIF1α stabilization. We found that stabilized HIF1α by lactate inhibited stimulated expression of circadian core components due to the similarity of HRE and E-box transcription elements. Furthermore, we found that lactate treatment strengthened the binding of HIF1α with BMAL1, HMOX1 and FOXO3 in MAC-T cells. Moreover, HIF1α knockdown altered expression of circadian rhythm related genes and reduced oxidative stress state.

CONCLUSION: In summary, our study highlights the central role of competitive transcriptional element occupancy in lactate-mediated oxidative stress of mammary gland, which is caused by HIF1α stabilization and circadian rhythm dysfunction. Our findings introduce a novel nutritional strategy with potential applications in dairy farming for optimizing milk production and maintaining mammary gland health.

PMID:40307878 | DOI:10.1186/s40104-025-01181-1

BMC Cancer. 2025 May 1;25(Suppl 1):733. doi: 10.1186/s12885-025-14089-w.

ABSTRACT

Accurately resolving the composition of tumor-infiltrating leukocytes is pivotal for advancing cancer immunotherapy strategies. Despite the success of some clinical trials, applying these strategies remains limited due to the challenges in deciphering the immune microenvironment. In this study, we developed a streamlined, two-step workflow to address the complexity of bioinformatics processes involved in analyzing immune cell composition from transcriptomics data. Our dockerized toolkit, DOCexpress_fastqc, integrates the hisat2-stringtie pipeline with customized scripts within Galaxy/Docker environments, facilitating RNA sequencing (RNA-seq) gene expression profiling. The output from DOCexpress_fastqc is seamlessly formatted with mySORT, a web application that employs a deconvolution algorithm to determine the immune content across 21 cell subclasses. We validated mySORT using synthetic pseudo-bulk data derived from single-cell RNA sequencing (scRNA-seq) datasets. Our predictions exhibit strong concordance with the ground-truth immune cell composition, achieving Pearson's correlation coefficients of 0.871 in melanoma patients and 0.775 in head and neck cancer patients. Additionally, mySORT outperforms existing methods like CIBERSORT in accuracy and provides a wide range of data visualization features, such as hierarchical clustering and cell complexity plots. The toolkit and web application are freely available for the research community, providing enhanced resolution for conventional bulk RNA sequencing data and facilitating the analysis of immune microenvironment responses in immunotherapy. The mySORT demo website and Docker image are free at https://mysort.iis.sinica.edu.tw and https://hub.docker.com/r/lsbnb/mysort_2022 .

PMID:40307726 | DOI:10.1186/s12885-025-14089-w

Nature. 2025 Apr 30. doi: 10.1038/s41586-025-08941-z. Online ahead of print.

ABSTRACT

Land plants thrive in soils showing vastly different properties and environmental stresses1. Root systems can adapt to contrasting soil conditions and stresses, yet how their responses are programmed at the individual cell scale remains unclear. Using single-cell RNA sequencing and spatial transcriptomic approaches, we showed major expression changes in outer root cell types when comparing the single-cell transcriptomes of rice roots grown in gel versus soil conditions. These tissue-specific transcriptional responses are related to nutrient homeostasis, cell wall integrity and defence in response to heterogeneous soil versus homogeneous gel growth conditions. We also demonstrate how the model soil stress, termed compaction, triggers expression changes in cell wall remodelling and barrier formation in outer and inner root tissues, regulated by abscisic acid released from phloem cells. Our study reveals how root tissues communicate and adapt to contrasting soil conditions at single-cell resolution.

PMID:40307555 | DOI:10.1038/s41586-025-08941-z

Nature. 2025 Apr 30. doi: 10.1038/s41586-025-08937-9. Online ahead of print.

ABSTRACT

A high-fat, low-fibre Western-style diet (WD) induces microbiome dysbiosis characterized by reduced taxonomic diversity and metabolic breadth1,2, which in turn increases risk for a wide array of metabolic3-5, immune6 and systemic pathologies. Recent work has established that WD can impair microbiome resilience to acute perturbations such as antibiotic treatment7,8, although little is known about the mechanism of impairment and the specific consequences for the host of prolonged post-antibiotic dysbiosis. Here we characterize the trajectory by which the gut microbiome recovers its taxonomic and functional profile after antibiotic treatment in mice on regular chow (RC) or WD, and find that only mice on RC undergo a rapid successional process of recovery. Metabolic modelling indicates that a RC diet promotes the development of syntrophic cross-feeding interactions, whereas in mice on WD, a dominant taxon monopolizes readily available resources without releasing syntrophic byproducts. Intervention experiments reveal that an appropriate dietary resource environment is both necessary and sufficient for rapid and robust microbiome recovery, whereas microbial transplant is neither. Furthermore, prolonged post-antibiotic dysbiosis in mice on WD renders them susceptible to infection by the intestinal pathogen Salmonella enterica serovar Typhimurium. Our data challenge widespread enthusiasm for faecal microbiota transplant (FMT) as a strategy to address dysbiosis, and demonstrate that specific dietary interventions are, at a minimum, an essential prerequisite for effective FMT, and may afford a safer, more natural and less invasive alternative.

PMID:40307551 | DOI:10.1038/s41586-025-08937-9