Sci Adv. 2025 May 16;11(20):eadu2079. doi: 10.1126/sciadv.adu2079. Epub 2025 May 16.

ABSTRACT

The impact of SARS-CoV-2 in the lung has been extensively studied, yet the molecular regulators of host-cell programs hijacked by the virus in distinct human airway epithelial cell populations remain poorly understood. Some of the reasons include overreliance on transcriptomic profiling and use of nonprimary cell systems. Here we report a network-based analysis of single-cell transcriptomic profiles able to identify master regulator (MR) proteins controlling SARS-CoV-2-mediated reprogramming in pathophysiologically relevant human ciliated, secretory, and basal cells. This underscored chromatin remodeling, endosomal sorting, ubiquitin pathways, as well as proviral factors identified by CRISPR assays as components of the viral-host response in these cells. Large-scale drug perturbation screens revealed 11 candidate drugs able to invert the entire MR signature activated by SARS-CoV-2. Leveraging MR analysis and perturbational profiles of human primary cells represents an innovative approach to investigate pathogen-host interactions in multiple airway conditions for drug prioritization.

PMID:40378209 | DOI:10.1126/sciadv.adu2079

Function (Oxf). 2025 May 16:zqaf020. doi: 10.1093/function/zqaf020. Online ahead of print.

ABSTRACT

Previous studies reported that opioids depress breathing by inhibiting respiratory neural networks in the brainstem. The effects of opioids on sensory inputs regulating breathing are less studied. This study examined the effects of fentanyl and sufentanil on carotid body neural activity, a crucial sensory regulator of breathing. Both opioids stimulated carotid body afferent nerve activity and increased glomus cell [Ca2+]i levels. RNA sequencing and immunohistochemistry revealed a high abundance of κ opioid receptors (KORs) in carotid bodies, but no µ or δ opioid receptors. A KOR agonist, like fentanyl, stimulated carotid body afferents, while a KOR antagonist blocked carotid body activation by fentanyl and KOR agonist. In unanesthetized rats, fentanyl initially stimulated breathing, followed by respiratory depression. A KOR agonist stimulated breathing without respiratory inhibition, and this effect was absent in carotid body-denervated rats. Combining fentanyl with a KOR agonist attenuated respiratory depression in rats with intact carotid body but not in carotid body denervated rats. These findings highlight previously uncharacterized activation of carotid body afferents by fentanyl via KORs as opposed to depression of brainstem respiratory neurons by µ opioid receptors and suggest that KOR agonists might counteract the central depressive effects of opioids on breathing.

PMID:40378144 | DOI:10.1093/function/zqaf020

J Chem Inf Model. 2025 May 16. doi: 10.1021/acs.jcim.5c00462. Online ahead of print.

ABSTRACT

Although there are over 100,000 distinct human metabolites, their biological significance is often not fully appreciated. Metabolites can reshape the protein pockets to which they bind by COLIG formation, thereby influencing enzyme kinetics and altering the monomer-multimer equilibrium in protein complexes. Binding a common metabolite to a set of protein monomers or multimers results in metabolic entanglements that couple the conformational states and functions of nonhomologous, nonphysically interacting proteins that bind the same metabolite. These shared metabolites might provide the collective behavior responsible for protein pathway formation. Proteins whose binding and functional behavior is modified by a set of metabolites are termed an "entabolon"─a portmanteau of metabolic entanglement and metabolon. 55%-60% (22%-24%) of pairs of nonenzymatic proteins that likely bind the same metabolite have a p-value that they are in the same pathway, which is <0.05 (0.0005). Interestingly, the most populated pairs of proteins common to multiple pathways bind ancient metabolites. Similarly, we suggest how metabolites can possibly activate, terminate, or preclude transcription and other nucleic acid functions and may facilitate or inhibit the binding of nucleic acids to proteins, thereby influencing transcription and translation processes. Consequently, metabolites likely play a critical role in the organization and function of biological systems.

PMID:40378093 | DOI:10.1021/acs.jcim.5c00462

Cell Rep. 2025 May 14;44(5):115703. doi: 10.1016/j.celrep.2025.115703. Online ahead of print.

ABSTRACT

Radiotherapy is a pillar of breast cancer treatment; however, it remains unclear how radiotherapy modulates the tumor microenvironment. We investigated this question in a cohort of 20 patients with estrogen-receptor positive (ER+) breast tumors who received neoadjuvant radiotherapy. Tumor biopsies were collected before and 7 days postradiation. Single-cell DNA sequencing (scDNA-seq) and scRNA-seq were conducted on 8 and 11 patients, respectively, at these two time points. The scRNA data showed increased infiltration of naive-like CD4 T cells and an early, activated CD8 T cell population following radiotherapy. Radiotherapy also eliminated existing cytotoxic T cells and resulted in myeloid cell increases. In tumor cells, the scDNA-seq data showed a high genomic selection of subclones in half of the patients with high ER expression, while the remaining number had low genomic selection and an interferon response. Collectively, these data provide insight into the impact of radiotherapy in ER+ breast cancer patients.

PMID:40378044 | DOI:10.1016/j.celrep.2025.115703

Proc Natl Acad Sci U S A. 2025 May 20;122(20):e2420132122. doi: 10.1073/pnas.2420132122. Epub 2025 May 16.

ABSTRACT

Anther dehiscence is the process that facilitates pollen release from mature anthers in flowering plants. Despite its crucial importance to reproduction, the underlying developmental mechanism and its integration with environmental cues remain poorly understood. Establishing noninvasive, controlled humidity treatments of Arabidopsis thaliana flowers, we show here that high humidity prevents anthers from opening. Manipulation of stomatal densities alters dehiscence dynamics, suggesting a contribution of controlled transpiration. Furthermore, analyses of subcellular markers revealed the occurrence of a developmentally prepared and environmentally triggered programmed cell death (PCD) process in specific anther tissues, epidermis and endothecium. Notably, genetic inhibition of PCD delays anther dehiscence, whereas precocious PCD induction promotes it. Our data reveal a rapid PCD execution process modulated by ambient humidity as instrumental for timely pollen release in the flowering plant Arabidopsis.

PMID:40377996 | DOI:10.1073/pnas.2420132122

Proc Natl Acad Sci U S A. 2025 May 20;122(20):e2418279122. doi: 10.1073/pnas.2418279122. Epub 2025 May 16.

ABSTRACT

The switch from precursor cell proliferation to onset of differentiation in adult stem cell lineages must be carefully regulated to produce sufficient progeny to maintain and repair tissues, yet prevent overproliferation that may enable oncogenesis. In the Drosophila male germ cell lineage, spermatogonia produced by germ line stem cells undergo a limited number of transit amplifying mitotic divisions before switching to the spermatocyte program that sets up meiosis and eventual spermatid differentiation. The number of transit amplifying divisions is set by accumulation of the bag-of-marbles (Bam) protein to a critical threshold. In bam mutants, spermatogonia proliferate through several extra rounds of mitosis and then die without becoming spermatocytes. Here, we show that a key role of Bam for the mitosis to differentiation switch is repressing expression of Held Out Wings (how), homolog of mammalian Quaking. Knockdown of how in germ cells was sufficient to allow spermatogonia mutant for bam or its partner benign gonial cell neoplasm to differentiate, while forced expression of nuclear-targeted How protein in spermatogonia wild-type for bam resulted in continued proliferation at the expense of differentiation. Our findings suggest that Bam targets how RNA for degradation by acting as an adapter to recruit the CCR4-NOT deadenylation complex via binding its subunit, Caf40. As How is itself an RNA-binding protein with roles in RNA processing, our findings reveal that the switch from proliferation to meiosis and differentiation in the Drosophila male germ line adult stem cell lineage is regulated by a cascade of RNA-binding proteins.

PMID:40377994 | DOI:10.1073/pnas.2418279122

J Chem Phys. 2025 May 21;162(19):194104. doi: 10.1063/5.0256659.

ABSTRACT

Reaction-diffusion equations are commonly used to model a diverse array of complex systems, including biological, chemical, and physical processes. Typically, these models are phenomenological, requiring the fitting of parameters to experimental data. In the present work, we introduce a novel formalism to construct reaction-diffusion models that is grounded in the principle of maximum entropy. This new formalism aims to incorporate various types of experimental data, including ensemble currents, distributions at different points in time, or moments of such. To this end, we expand the framework of Schrödinger bridges and maximum caliber problems to nonlinear interacting systems. We illustrate the usefulness of the proposed approach by modeling the evolution of (i) a morphogen across the fin of a zebrafish and (ii) the population of two varieties of toads in Poland, so as to match the experimental data.

PMID:40377200 | DOI:10.1063/5.0256659

Elife. 2025 May 16;12:RP89862. doi: 10.7554/eLife.89862.

ABSTRACT

A wide variety of human diseases are associated with loss of microbial diversity in the human gut, inspiring a great interest in the diagnostic or therapeutic potential of the microbiota. However, the ecological forces that drive diversity reduction in disease states remain unclear, rendering it difficult to ascertain the role of the microbiota in disease emergence or severity. One hypothesis to explain this phenomenon is that microbial diversity is diminished as disease states select for microbial populations that are more fit to survive environmental stress caused by inflammation or other host factors. Here, we tested this hypothesis on a large scale, by developing a software framework to quantify the enrichment of microbial metabolisms in complex metagenomes as a function of microbial diversity. We applied this framework to over 400 gut metagenomes from individuals who are healthy or diagnosed with inflammatory bowel disease (IBD). We found that high metabolic independence (HMI) is a distinguishing characteristic of microbial communities associated with individuals diagnosed with IBD. A classifier we trained using the normalized copy numbers of 33 HMI-associated metabolic modules not only distinguished states of health vs IBD, but also tracked the recovery of the gut microbiome following antibiotic treatment, suggesting that HMI is a hallmark of microbial communities in stressed gut environments.

PMID:40377187 | DOI:10.7554/eLife.89862

Ann N Y Acad Sci. 2025 May 16. doi: 10.1111/nyas.15373. Online ahead of print.

ABSTRACT

Recursion, the neuro-computational operation of nesting a signal or pattern within itself, lies at the structural basis of language. Classically considered absent in the vocal repertoires of nonhuman animals, whether recursion evolved step-by-step or saltationally in humans is among the most fervent debates in cognitive science since Chomsky's seminal work on syntax in the 1950s. The recent discovery of self-embedded vocal motifs in wild (nonhuman) great apes-Bornean male orangutans' long calls-lends initial but important support to the notion that recursion, or at least temporal recursion, is not uniquely human among hominids and that its evolution was based on shared ancestry. Building on these findings, we test four necessary predictions for a gradual evolutionary scenario in wild Sumatran female orangutans' alarm calls, the longest known combinations of consonant-like and vowel-like calls among great apes (excepting humans). From the data, we propose third-order self-embedded isochrony: three hierarchical levels of nested isochronous combinatoric units, with each level exhibiting unique variation dynamics and information content relative to context. Our findings confirm that recursive operations underpin great ape call combinatorics, operations that likely evolved gradually in the human lineage as vocal sequences became longer and more intricate.

PMID:40376956 | DOI:10.1111/nyas.15373

Biophys Rev. 2025 Mar 4;17(2):667-685. doi: 10.1007/s12551-025-01290-1. eCollection 2025 Apr.

ABSTRACT

Bacterial communication is essential for survival, adaptation, and collective behavior. While chemical signaling, such as quorum sensing, has been extensively studied, physical cues play a significant role in bacterial interactions. This review explores the diverse range of physical stimuli, including mechanical forces, electromagnetic fields, temperature, acoustic vibrations, and light that bacteria may experience with their environment and within a community. By integrating these diverse communication pathways, bacteria can coordinate their activities and adapt to changing environmental conditions. Furthermore, we discuss how these physical stimuli modulate bacterial growth, lifestyle, motility, and biofilm formation. By understanding the underlying mechanisms, we can develop innovative strategies to combat bacterial infections and optimize industrial processes.

PMID:40376406 | PMC:PMC12075086 | DOI:10.1007/s12551-025-01290-1

Plant Biol (Stuttg). 2025 May 16. doi: 10.1111/plb.70035. Online ahead of print.

ABSTRACT

Sulphur (S) deficiency is known to hinder iron (Fe) uptake and distribution in wheat, mainly by reducing phytosiderophores (PS) synthesis and release. This study investigated the impact of S supply on Fe accumulation in four tetraploid wheat genotypes with different genetic backgrounds: a modern genotype, Svevo (Triticum turgidum subsp. durum), two ancient Khorasan wheats, Turanicum_21 and Etrusco (T. turgidum subsp. turanicum) and an ancient Polish wheat, Polonicum_2 (T. turgidum subsp. polonicum). Plants were grown hydroponically for 20 days under adequate (S = 1.2 mM) or limiting (L = 0.06 mM) sulfate levels, while receiving sufficient Fe (80 μM). Most genotypes exhibited reduced Fe accumulation under low S conditions, as expected. However, Polonicum_2 showed a unique response, accumulating significantly more Fe in both shoots and roots. This increased Fe accumulation was associated with a higher rate of PS release and upregulation of both TdYSL15 and TdIRO2 in roots of Polonicum_2, suggesting altered regulation of Fe deficiency responses. However, the expression pattern of TdIDEF1 was not correlated with TdYSL15 expression in this plant, suggesting the involvement of additional regulatory pathways beyond Fe supply. Finally, there was a strong correlation between O-acetylserine(thiol)lyase activity in shoot tissues and PS release rate across all genotypes. There is increased interest in Khorasan and Polish wheats as alternative crops for marginal areas, hence, these findings are noteworthy from a biofortification perspective and could potentially lead to innovations in agriculture that benefit food security.

PMID:40375730 | DOI:10.1111/plb.70035

Scand J Med Sci Sports. 2025 May;35(5):e70074. doi: 10.1111/sms.70074.

ABSTRACT

Scarce evidence exists on the demands needed to attain the highest positions during Grand Tours (Giro d'Italia, Tour de France, Vuelta a España). Using power output (PO) and heart rate (HR) data, we aimed to compare the racing demands of successful (at least top-5) and less successful (at least top-15) cyclists during Grand Tours. We identified Grand Tours in which we could compare cyclists who had attained a top-5 position (Top) with riders who also competed for the General Classification in the same race but attained a worse position (Non-Top, at least top 15). Different race-derived measures of physical demands (e.g., PO, kJ spent, training stress score, durability and repeatability measures, time in different PO/HR zones) were analyzed. Data from 9 Grand Tours, including 9 Top (average position 3rd, range 1st-5th) and 9 Non-Top cyclists (average position 9th, range 4th-12th) were available. Despite significant between-group differences in finishing time (86.2 ± 6.3 vs. 86.3 ± 6.3 h, p < 0.001), no differences were found for any of the analyzed outcomes, except for a slightly higher proportion of time spent at low PO levels (zone 1 (≤ 55% of functional threshold power)) in Top compared to Non-Top cyclists (60.9% ± 1.8% vs. 58.4% ± 2.5%, respectively, p = 0.011). In summary, achieving a top position during a Grand Tour does not necessarily imply overall higher physical demands compared to those cases in which cyclists attain a slightly lower position, which suggests that other factors (e.g., individual or team tactics) or metrics might have a greater influence.

PMID:40375449 | DOI:10.1111/sms.70074

Comput Biol Med. 2025 May 14;192(Pt B):110296. doi: 10.1016/j.compbiomed.2025.110296. Online ahead of print.

ABSTRACT

We present an easy-to-use, nonlinear filter for effective background identification in fluorescence microscopy images with dense and low-contrast foreground. The pixel-wise filtering is based on comparison of the pixel intensity with the mean intensity of pixels in its local neighborhood. The pixel is given a background or foreground label depending on whether its intensity is less than or greater than the mean respectively. Multiple labels are generated for the same pixel by computing mean expression values by varying neighborhood size. These labels are accumulated to decide the final pixel label. We demonstrate that the performance of our filter favorably compares with state-of-the-art image processing, machine learning, and deep learning methods. We present three use cases that demonstrate its effectiveness, and also show how it can be used in multiplexed fluorescence imaging contexts and as a pre-processing step in image segmentation. A fast implementation of the filter is available in Python 3 on GitHub.

PMID:40375425 | DOI:10.1016/j.compbiomed.2025.110296

BMC Med Inform Decis Mak. 2025 May 15;25(Suppl 2):188. doi: 10.1186/s12911-025-03012-9.

ABSTRACT

BACKGROUND: Colorectal cancer is the fourth most deadly cancer, with a high mortality rate and a high probability of recurrence and metastasis. Since continuous examinations and disease monitoring for patients after surgery are currently difficult to perform, it is necessary for us to develop a predictive model for colorectal cancer metastasis and recurrence to improve the survival rate of patients.

RESULTS: Previous studies mostly used only clinical or radiological data, which are not sufficient to explain the in-depth mechanism of colorectal cancer recurrence and metastasis. Therefore, this study proposes such a multiomics data-based predictive model for the recurrence and metastasis of colorectal cancer. LR, SVM, Naïve-bayes and ensemble learning models are used to build this predictive model.

CONCLUSIONS: The experimental results indicate that our proposed multiomics data-based ensemble learning model effectively predicts the recurrence and metastasis of colorectal cancer.

PMID:40375082 | DOI:10.1186/s12911-025-03012-9

BMC Med Genomics. 2025 May 15;18(1):87. doi: 10.1186/s12920-025-02154-z.

ABSTRACT

BACKGROUND: Recent decades have witnessed a steady decrease in the use of race categories in genomic studies. While studies that still include race categories vary in goal and type, these categories already build on a history during which racial color lines have been enforced and adjusted in the service of social and political systems of power and disenfranchisement. For early modern classification systems, data collection was also considerably arbitrary and limited. Fixed, discrete classifications have limited the study of human genomic variation and disrupted widely spread genetic and phenotypic continuums across geographic scales. Relatedly, the use of broad and predefined classification schemes-e.g. continent-based-across traits can risk missing important trait-specific genomic signals.

METHODS: To address these issues, we introduce a dynamic approach to clustering human genomics cohorts based on genomic variation in trait-specific loci and without using a set of predefined categories. We tested the approach on whole-exome sequencing datasets in ten cancer types and partitioned them based on germline variants in cancer-relevant genes that could confer cancer type-specific disease predisposition.

RESULTS: Results demonstrate clustering patterns that transcend discrete continent-based categories across cancer types. Functional analysis based on cancer type-specific clusterings also captures the fundamental biological processes underlying cancer, differentiates between dynamic clusters on a functional level, and identifies novel potential drivers overlooked by a predefined continent-based clustering.

CONCLUSIONS: Through a trait-based lens, the dynamic clustering approach reveals genomic patterns that transcend predefined classification categories. We propose that coupled with diverse data collection, new clustering approaches have the potential to draw a more complete portrait of genomic variation and to address, in parallel, technical and social aspects of its study.

PMID:40375077 | DOI:10.1186/s12920-025-02154-z

Nat Commun. 2025 May 15;16(1):4534. doi: 10.1038/s41467-025-58841-z.

ABSTRACT

Suppressing immune responses promotes allograft survival but also favours tumour progression and recurrence. Selectively suppressing allograft rejection while maintaining or even enhancing antitumor immunity is challenging. Here, we show loss of allograft-related rejection in mice deficient in Setdb1, an H3K9 methyltransferase, while antitumor immunity remains intact. RNA sequencing shows that Setdb1-deficiency does not affect T-cell activation or cytokine production but induces an increase in Treg-cell-associated gene expression. Depletion of Treg cells impairs graft acceptance in Setdb1-deficient mice, indicating that the Treg cells promote allograft survival. Surprisingly, Treg cell-specific Setdb1 deficiency does not prolong allograft survival, suggesting that Setdb1 may function prior to Foxp3 induction. Using single-cell RNA sequencing, we find that Setdb1 deficiency induces a new Treg population in the thymus. This subset of Treg cells expresses less IL-1R2 and IL-18R1. Mechanistically, during Treg cell induction, Setdb1 is recruited by transcription factor ATF and altered histone methylation. Our data thus define Setdb1 in T cells as a hub for Treg cell differentiation, in the absence of which suppressing allograft rejection is uncoupled from maintaining antitumor immunity.

PMID:40374612 | DOI:10.1038/s41467-025-58841-z

Nat Commun. 2025 May 15;16(1):4529. doi: 10.1038/s41467-025-59578-5.

ABSTRACT

Latent HIV-1 presents a formidable challenge for viral eradication. HIV-1 transcription and latency reversal require interactions between the viral promoter and host proteins. Here, we perform the dCas9-targeted locus-specific protein analysis and discover the interaction of human arginine methyltransferase 3 (PRMT3) with the HIV-1 promoter. This interaction reverses latency in cell line models and primary cells from latently infected persons by increasing the levels of H4R3Me2a and transcription factor P-TEFb at the viral promoter. PRMT3 is found to promote chromatin accessibility and transcription of HIV-1 and a small subset of host genes in regions harboring the classical recognition motif for another transcription factor TEAD4. This motif attracts TEAD4 and PRMT3 to the viral promoter to synergistically activate transcription. Physical interactions among PRMT3, P-TEFb, and TEAD4 exist, which may help form a transcriptional hub at the viral promoter. Our study reveals the potential of targeting these hub proteins to eradicate latent HIV-1.

PMID:40374607 | DOI:10.1038/s41467-025-59578-5

Int J Sports Med. 2025 May 15. doi: 10.1055/a-2555-8961. Online ahead of print.

ABSTRACT

Durability is increasingly recognized as a determinant of cycling performance. However, its reliability remains unknown. In this study, we assessed the repeatability of durability (determined as the decline in power output after accumulated work). We recorded the highest power output values (maximum mean power values) attained by 18 professional cyclists (27±4 y) during training and competition for different effort durations (10 s and 1, 5, 10, and 20 min) after different levels of accumulated work (0-40 kJ/kg) during a cycling season. Repeatability was examined through the standard error of measurement and the intra-class correlation coefficient calculated from the two highest maximum mean power values obtained by each cyclist for each duration and level of accumulated work. A progressive decline of maximum mean power values compared to the non-fatigued state was observed after higher levels of accumulated work, particularly after 20 kJ/kg (p<0.001). All maximum mean power values showed high repeatability under fatigue states (all standard error of measurement<5% and intra-class correlation coefficient>0.90), with the lowest repeatability observed for the shortest efforts (10-s maximum mean power). These findings were confirmed separately for training sessions and competitions, albeit with lower repeatability (standard error of measurement<8% and intra-class correlation coefficient>0.80). The measure of durability appears therefore reliable, which might support its validity for monitoring field-based performance in professional cyclists.

PMID:40373793 | DOI:10.1055/a-2555-8961

Cell Stem Cell. 2025 May 7:S1934-5909(25)00178-X. doi: 10.1016/j.stem.2025.04.011. Online ahead of print.

ABSTRACT

Precise dorsal-ventral (D-V) patterning of the neural tube (NT) is essential for the development and function of the central nervous system. However, existing models for studying NT D-V patterning and related human diseases remain inadequate. Here, we present organizers derived from pluripotent stem cell aggregate fusion ("ORDER"), a method that establishes opposing BMP and SHH gradients within neural ectodermal cell aggregates. Using this approach, we generated NT organoids with ordered D-V patterning from both zebrafish and human pluripotent stem cells (hPSCs). Single-cell transcriptomic analysis revealed that the synthetic human NT organoids (hNTOs) closely resemble the human embryonic spinal cord at Carnegie stage 12 (CS12) and exhibit greater similarity to human NT than to mouse models. Furthermore, using the hNTO model, we demonstrated the critical role of WNT signaling in regulating intermediate progenitors, modeled TCTN2-related D-V patterning defects, and identified a rescue strategy.

PMID:40373768 | DOI:10.1016/j.stem.2025.04.011

Cell Genom. 2025 May 14;5(5):100875. doi: 10.1016/j.xgen.2025.100875.

ABSTRACT

Transcriptome-wide association studies (TWASs) help identify disease-causing genes but often fail to pinpoint disease mechanisms at the cellular level because of the limited sample sizes and sparsity of cell-type-specific expression data. Here, we propose scPrediXcan, which integrates state-of-the-art deep learning approaches that predict epigenetic features from DNA sequences with the canonical TWAS framework. Our prediction approach, ctPred, predicts cell-type-specific expression with high accuracy and captures complex gene-regulatory grammar that linear models overlook. Applied to type 2 diabetes (T2D) and systemic lupus erythematosus (SLE), scPrediXcan outperformed the canonical TWAS framework by identifying more candidate causal genes, explaining more genome-wide association study (GWAS) loci and providing insights into the cellular specificity of TWAS hits. Overall, our results demonstrate that scPrediXcan represents a significant advance, promising to deepen our understanding of the cellular mechanisms underlying complex diseases.

PMID:40373737 | DOI:10.1016/j.xgen.2025.100875