J Nucl Med. 2025 May 8:jnumed.124.267660. doi: 10.2967/jnumed.124.267660. Online ahead of print.

ABSTRACT

The study of the human phenome is essential for understanding the complexities of wellness and disease and their transitions, with molecular imaging being a vital tool in this exploration. Molecular imaging embodies the 4 principles of human phenomics: precise measurement, accurate calculation or analysis, well-controlled manipulation or intervention, and innovative invention or creation. Its application has significantly enhanced the precision, individualization, and effectiveness of medical interventions. This article provides an overview of molecular imaging's technologic advancements and presents the potential use of molecular imaging in human phenomics and precision medicine. The integration of molecular imaging with multiomics data and artificial intelligence has the potential to transform health care, promoting proactive and preventive strategies. This evolving approach promises to deepen our understanding of the human phenome, lead to preclinical diagnostics and treatments, and establish quantitative frameworks for precision health management.

PMID:40341093 | DOI:10.2967/jnumed.124.267660

Genome Biol. 2025 May 8;26(1):119. doi: 10.1186/s13059-025-03590-x.

ABSTRACT

BACKGROUND: Cell-free RNAs (cfRNAs) can be detected in biofluids and have emerged as valuable disease biomarkers. Accurate identification of the fragmented cfRNA signals, especially those originating from pathological cells, is crucial for understanding their biological functions and clinical value. However, many challenges still need to be addressed for their application, including developing specific analysis methods and translating cfRNA fragments with biological support into clinical applications.

RESULTS: We present cfPeak, a novel method combining statistics and machine learning models to detect the fragmented cfRNA signals effectively. When test in real and artificial cfRNA sequencing (cfRNA-seq) data, cfPeak shows an improved performance compared with other applicable methods. We reveal that narrow cfRNA peaks preferentially overlap with protein binding sites, vesicle-sorting sites, structural sites, and novel small non-coding RNAs (sncRNAs). When applied in clinical cohorts, cfPeak identified cfRNA peaks in patients' plasma that enable cancer detection and are informative of cancer types and metastasis.

CONCLUSIONS: Our study fills the gap in the current small cfRNA-seq analysis at fragment-scale and builds a bridge to the scientific discovery in cfRNA fragmentomics. We demonstrate the significance of finding low abundant tissue-derived signals in small cfRNA and prove the feasibility for application in liquid biopsy.

PMID:40340952 | DOI:10.1186/s13059-025-03590-x

BMC Plant Biol. 2025 May 8;25(1):604. doi: 10.1186/s12870-025-06595-7.

ABSTRACT

BACKGROUND: Rice is a critical global food source, but it faces challenges due to nutritional deficiencies and the pressures of a growing population. Understanding the molecular mechanisms and protein functions in rice seed development is essential to improve yield and grain quality. However, there is still a significant knowledge gap regarding the key proteins and their interactions that govern rice seed development. Protein-protein interaction (PPI) analysis is a powerful tool for studying developmental processes like seed development, though its potential in rice research is yet to be fully realized. With the aim of unraveling the protein interaction landscape associated with rice seed development, this systems biology study conducted a PPI network-based analysis. Using a list of known seed development proteins from the Gene Ontology (GO) knowledgebase and literature, novel candidate proteins for seed development were predicted using an ensemble of network-based algorithms, including Majority Voting, Hishigaki Algorithm, Functional Flow, and Random Walk with Restart, which were selected based on their popularity and usability. The predictions were validated using enrichment analysis and cross-checked with independent transcriptomic analysis results. The rice seed development sub-network was further analyzed for community and hub detection.

RESULTS: The study predicted 196 new proteins linked to rice seed development and identified 14 sub-modules within the network, each representing different developmental pathways, such as endosperm development and seed growth regulation. Of these, 17 proteins were identified as intra-modular hubs and 6 as inter-modular hubs. Notably, the protein SDH1 emerged as a dual hub, acting as both an intra-modular and inter-modular hub, highlighting its importance in seed development PPI network stability.

CONCLUSIONS: These findings, including the identified hub proteins and sub-modules, provide a better understanding of the PPI interaction landscape governing seed development in rice. This information is useful for achieving a systems biology understanding of seed development. This study implements an ensemble of algorithms for the analysis and showcases how systems biology techniques can be applied in developmental biology.

PMID:40340735 | DOI:10.1186/s12870-025-06595-7

J Biotechnol. 2025 May 6:S0168-1656(25)00109-9. doi: 10.1016/j.jbiotec.2025.04.024. Online ahead of print.

ABSTRACT

The single-step biotransformation of the natural compound piperine into a known dual inhibitor of monoamine oxidase B (MAO-B) and catechol-O-methyltransferase (COMT), was achieved by cytochrome P450 BM3 wild-type and the D251G/Q307H double mutant. This compound is used for research in neurodegenerative disorders, such as Parkinson's disease, and its value in the market is ~14,000 €/g. Currently, it is produced by chemical synthesis requiring incubation of piperine with boron tribromide (BBr3) in dichloromethane with yield of product not exceeding 55% and using tedious and long procedure for its production and isolation. The P450 D251G/Q307H double mutant exhibited a 3-fold increase in catalytic efficiency compared to the wild-type enzyme, achieving high conversion (51.6% of conversion in 15minutes) under mild, environmentally friendly conditions. The yield of production was 0.01mg of the inhibitor in 1mL of reaction in 15minutes at 28°C using the purified enzyme. Moreover, biological assays demonstrated that the resulting compound has a novel and stronger antioxidant and antimicrobial activities, respectively, when compared to piperine. The data further demonstrates the broader potential of engineered enzymes as versatile and sustainable tools in industrial biotechnology, offering an efficient platform for the modification of natural compounds to produce bioactive molecules.

PMID:40339650 | DOI:10.1016/j.jbiotec.2025.04.024

Cell. 2025 May 5:S0092-8674(25)00353-8. doi: 10.1016/j.cell.2025.03.035. Online ahead of print.

ABSTRACT

The emergence of SARS-CoV in 2002 and SARS-CoV-2 in 2019 led to increased sampling of sarbecoviruses circulating in horseshoe bats. Employing phylogenetic inference while accounting for recombination of bat sarbecoviruses, we find that the closest-inferred bat virus ancestors of SARS-CoV and SARS-CoV-2 existed less than a decade prior to their emergence in humans. Phylogeographic analyses show bat sarbecoviruses traveled at rates approximating their horseshoe bat hosts and circulated in Asia for millennia. We find that the direct ancestors of SARS-CoV and SARS-CoV-2 are unlikely to have reached their respective sites of emergence via dispersal in the bat reservoir alone, supporting interactions with intermediate hosts through wildlife trade playing a role in zoonotic spillover. These results can guide future sampling efforts and demonstrate that viral genomic regions extremely closely related to SARS-CoV and SARS-CoV-2 were circulating in horseshoe bats, confirming their importance as the reservoir species for SARS viruses.

PMID:40339581 | DOI:10.1016/j.cell.2025.03.035

Cell Syst. 2025 May 5:101292. doi: 10.1016/j.cels.2025.101292. Online ahead of print.

ABSTRACT

The arginine dihydrolase pathway (arc operon) provides a metabolic niche by transforming arginine into metabolic byproducts. We investigate the role of the arc operon in probiotic Escherichia coli Nissle 1917 on human gut community assembly and health-relevant metabolite profiles. By stabilizing environmental pH, the arc operon reduces variability in community composition in response to pH perturbations and frequently enhances butyrate production in synthetic communities. We use a tailored machine learning model for microbiomes to predict community assembly in response to variation in initial media pH and arc operon activity. This model uncovers the pH- and arc operon-dependent interactions shaping community assembly. Human gut species display altered colonization dynamics in response to the arc operon in the murine gut. In sum, our framework to quantify the contribution of a specific pathway to microbial community assembly and metabolite production can reveal new engineering strategies. A record of this paper's transparent peer review process is included in the supplemental information.

PMID:40339579 | DOI:10.1016/j.cels.2025.101292

Dev Cell. 2025 May 2:S1534-5807(25)00250-3. doi: 10.1016/j.devcel.2025.04.012. Online ahead of print.

ABSTRACT

The lymphatic vasculature comprises lymphatic capillaries and collecting vessels. To support lymphatic development, lymphatic endothelial cells (LECs) utilize nutrients to fuel lymphangiogenic processes. Meanwhile, LECs maintain constant prospero homeobox 1 (PROX1) expression critical for lymphatic specification. However, molecular mechanisms orchestrating nutrient metabolism while sustaining PROX1 levels in LECs remain unclear. Here, we show that loss of RAPTOR, an indispensable mechanistic target of rapamycin complex 1 (mTORC1) component, downregulates PROX1 and impairs lymphatic capillary growth and differentiation of collecting lymphatics in mice. Mechanistically, mTORC1 inhibition in mouse and human LECs causes Myc reduction, which decreases hexokinase 2 (HK2) and glutaminase (GLS), inhibiting glycolysis and glutaminolysis. Myc or HK2/GLS ablation impedes lymphatic capillary and collecting vessel formation. Interestingly, mTORC1 regulation of PROX1 is independent of Myc-HK2/GLS signaling. Moreover, genetic interaction analysis indicates that Myc and PROX1 play crucial roles in mTORC1-regulated lymphatic development. Collectively, our findings identify mTORC1 as a key regulator of metabolic programs and PROX1 expression during lymphangiogenesis.

PMID:40339577 | DOI:10.1016/j.devcel.2025.04.012

Proc Natl Acad Sci U S A. 2025 May 13;122(19):e2502368122. doi: 10.1073/pnas.2502368122. Epub 2025 May 8.

ABSTRACT

Single-cell organisms and various cell types use a range of motility modes when following a chemical gradient, but it is unclear which mode is best suited for different gradients. Here, we model directional decision-making in chemotactic amoeboid cells as a stimulus-dependent actin recruitment contest. Pseudopods extending from the cell body compete for a finite actin pool to push the cell in their direction until one pseudopod wins and determines the direction of movement. Our minimal model provides a quantitative understanding of the strategies cells use to reach the physical limit of accurate chemotaxis, aligning with data without explicit gradient sensing or cellular memory for persistence. To generalize our model, we employ reinforcement learning optimization to study the effect of pseudopod suppression, a simple but effective cellular algorithm by which cells can suppress possible directions of movement. Different pseudopod-based chemotaxis strategies emerge naturally depending on the environment and its dynamics. For instance, in static gradients, cells can react faster at the cost of pseudopod accuracy, which is particularly useful in noisy, shallow gradients where it paradoxically increases chemotactic accuracy. In contrast, in dynamics gradients, cells form de novo pseudopods. Overall, our work demonstrates mechanical intelligence for high chemotaxis performance with minimal cellular regulation.

PMID:40339116 | DOI:10.1073/pnas.2502368122

Theor Appl Genet. 2025 May 8;138(6):111. doi: 10.1007/s00122-025-04892-1.

ABSTRACT

Finger millet (Eleusine coracana subsp. coracana) (2n = 4x = 36) remains one of the most important millets in East Africa (EA), where it was most likely domesticated along the highlands of Ethiopia and Uganda. The goal of the current study was to understand the population structure of the Ethiopian finger millet landraces and identify quantitative trait nucleotides (QTNs) and haplotypes associated with agronomic and nutritional traits. In a field evaluation across three environments, 448 genotypes were assessed for days to flowering (DTF), days to maturity (DTM), thousand seed weight (TSW), grain yield (GY), stay-green score (STG), and drought score (DrtSc). The harvested grain was analyzed for Fe and Zn contents. A subset of 391 genotypes was skim-sequenced, generating 24,112 high-quality SNPs that were employed for population structure, association mapping, and haplotype analysis. Seventy marker-trait associations were detected including 15 major QTNs with more than 30% phenotypic variance explained (PVE) for all traits except STG and GY. Pleiotropic major QTNs were identified for DTM/DTF and Fe/Zn on chromosomes 9B and 2B, respectively. Haplotype analysis of major QTNs identified 54 significant haplotype blocks and 2 additional haplotypes for a multidrug ABC transporter gene family like protein on chromosome 4A that was associated with PTH. Favorable haplotypes from pleiotropic DTM/DTF and Fe/Zn QTNs were present in 13 and 12 genotypes respectively, majority from Tigray region. Two genotypes from Tigray and one from Amhara harbored favorable haplotypes for DTM/DTF and Fe/Zn. These findings provide invaluable insights for targeted breeding to enhance finger millet resilience, nutritional profile, and yield.

PMID:40338316 | DOI:10.1007/s00122-025-04892-1

Genome. 2025 Jan 1;68:1-12. doi: 10.1139/gen-2024-0106.

ABSTRACT

Soybean seeds are rich in oil and protein; however, the seed composition is influenced by genotype and environment. For years, it has been observed that soybeans grown in western Canada have lower seed protein concentration (by ∼1%-5% total seed weight) than those grown in eastern Canada. In this study, soybean seeds harvested from five varieties were grown in four different locations in Canada (east and west growing regions) and analyzed using RNA-sequencing. Using gene ontology and biological pathway mapping, we identified a difference in cysteine and methionine metabolism between soybeans grown in eastern and western Canada that may attribute to the difference in seed protein concentration. Further, we identified differential gene expression within the oil biosynthesis pathway, specifically upregulation of lipoxygenases in western-grown soybeans, which may also influence seed composition and/or membrane fluidity. The information gained in this study is useful for marker assisted selection in soybean breeding programs across Canada and globally.

PMID:40338102 | DOI:10.1139/gen-2024-0106

J Diabetes Sci Technol. 2025 May 8:19322968251338865. doi: 10.1177/19322968251338865. Online ahead of print.

ABSTRACT

BACKGROUND: Continuous glucose monitors (CGMs) are increasingly being used to guide glucose management in the hospital. However, uncertainty regarding their accuracy in this setting remains.

METHODS: We conducted a nonrandomized, open-label, clinically blinded prospective trial of the Dexcom G6 Pro (G6P) and FreeStyle Libre Pro (FLP) in the inpatient setting among critically ill hospitalized patients (n = 40) requiring continuous intravenous insulin infusion. In parallel with CGM data, reference serum (Lab) glucose and point-of-care (POC) glucose values were obtained. On completion of the study, CGM and reference values were analyzed to assess CGM accuracy.

RESULTS: A total of 1015 matched G6P-Lab pairs had a mean absolute relative difference (MARD) of 22.7%, 2369 G6P-POC pairs had an MARD of 22.9%, 1006 matched FLP-Lab pairs had an MARD of 25.2%, and 2353 FLP-POC pairs had an MARD of 27.0%. Both CGM systems demonstrated considerable inter-patient variability in sensor accuracy and tended to underestimate glucose in comparison with the reference values. Rarely were low reference values overestimated by either sensor.

CONCLUSIONS: Factory-calibrated continuous glucose monitors may require accuracy validation and per-patient calibration for inpatient use in critically ill patients.

PMID:40337990 | DOI:10.1177/19322968251338865

Nucleic Acids Res. 2025 May 8:gkaf384. doi: 10.1093/nar/gkaf384. Online ahead of print.

ABSTRACT

Changes in alternative splicing between groups or conditions contribute to protein-protein interaction rewiring, a consequence often neglected in data analysis. The web server and database DIGGER overcomes this limitation by augmenting a protein-protein interaction network with domain-domain interactions and splicing information. Here, we present DIGGER 2.0, which now features both experimental and newly added predicted domain-domain interactions. In addition to the human interactome, DIGGER 2.0 adds support for mouse as an important model organism. Additionally, we integrated the splicing analysis tool NEASE, which allows users to perform online splicing- and interactome-informed enrichment analysis on RNA-seq data. In two application cases (multiple sclerosis and mice models of cardiac diseases), we show the utility of DIGGER 2.0 for deeper exploration and functional interpretation of changes in alternative splicing in human and mouse disorders. DIGGER 2.0 is available at https://exbio.wzw.tum.de/digger/.

PMID:40337913 | DOI:10.1093/nar/gkaf384

Ann Bot. 2025 May 4:mcaf079. doi: 10.1093/aob/mcaf079. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Dry dehiscent fruits have independently evolved multiple times during angiosperm diversification. A striking example is the convergent evolution of Brassicaceae siliques and Papaveraceae pods, both formed by two fused carpels forming valves, that meet at a replum or replum-like structure. In both cases, valve separation occurs through a dehiscence zone at the valve margins in contact with the replum. In Arabidopsis, fruit development is regulated by transcription factors: FRUITFULL (FUL) ensures proper valve cell division, REPLUMLESS (RPL) specifies replum identity, and SHATTERPROOF (SHP1/2) genes pattern the dehiscence zone. SHP1/2 also regulate INDEHISCENT (IND) for lignified layer formation and ALCATRAZ (ALC) and SPATULA (SPT) for the non-lignified layer, with the network antagonized by APETALA2 (AP2), which influences replum formation and valve margin growth.

METHODS: Using previously published and new In situ RNA hybridization expression data, we evaluated how this network applies to basal eudicots.

KEY RESULTS: In Bocconia frutescens, homolog expression suggests conserved roles for FUL and AP2 in fruit wall proliferation, acting antagonistically to ALC and RPL homologs localized to the dehiscence zone. A role for STK homologs in dehiscence zone formation cannot be excluded, while the role of AG-like genes, the closest homologs of SHP during fruit development is unlikely.

CONCLUSIONS: Our findings indicate significant rewiring of the fruit developmental network between basal and core eudicots, underscoring the need for functional studies in non-eudicot species to validate this framework.

PMID:40337869 | DOI:10.1093/aob/mcaf079

Philos Trans A Math Phys Eng Sci. 2025 May 8;383(2296):20230384. doi: 10.1098/rsta.2023.0384. Epub 2025 May 8.

ABSTRACT

Since the turn of the millennium, computational modelling of biological systems has evolved remarkably and sees matured use spanning basic and clinical research. While the topic of the peri-millennial debate about the virtues and limitations of 'reductionism and integrationism' seems less controversial today, a new apparent dichotomy dominates discussions: mechanistic versus data-driven modelling. In light of this distinction, we provide an overview of recent achievements and new challenges with a focus on the cardiovascular system. Attention has shifted from generating a universal model of the human to either models of individual humans (digital twins) or entire cohorts of models representative of clinical populations to enable in silico clinical trials. Disease-specific parametrization, inter-individual and intra-individual variability, uncertainty quantification as well as interoperable, standardized and quality-controlled data are important issues today, which call for open tools, data and metadata standards, as well as strong community interactions. The quantitative, biophysical and highly controlled approach provided by in silico methods has become an integral part of physiological and medical research. In silico methods have the potential to accelerate future progress also in the fields of integrated multi-physics modelling, multi-scale models, virtual cohort studies and machine learning beyond what is feasible today. In fact, mechanistic and data-driven modelling can complement each other synergistically and fuel tomorrow's artificial intelligence applications to further our understanding of physiology and disease mechanisms, to generate new hypotheses and assess their plausibility, and thus to contribute to the evolution of preventive, diagnostic and therapeutic approaches.This article is part of the theme issue 'Science into the next millennium: 25 years on'.

PMID:40336283 | DOI:10.1098/rsta.2023.0384

Development. 2025 May 1;152(9):dev204890. doi: 10.1242/dev.204890. Epub 2025 May 8.

NO ABSTRACT

PMID:40337795 | DOI:10.1242/dev.204890

Front Microbiol. 2025 Apr 23;16:1551123. doi: 10.3389/fmicb.2025.1551123. eCollection 2025.

ABSTRACT

Plant viruses participate as biotrophic parasites in complex interactions with their hosts, resulting in the regulation of a diverse range of chloroplast/mitochondria-related genes that are essential for mediating immune responses. In this study, integrative systems biology approaches were applied to identify chloroplast/mitochondrial genes during viral infections caused by a wide number of viruses in Arabidopsis thaliana, tobacco (Nicotiana tabacum L.), and rice (Oryza sativa L.). These findings indicated that 1.5% of the DEGs were common between Arabidopsis/tobacco and Arabidopsis/rice, whereas 0.1% of the DEGs were shared among all species. Approximately 90% of common DEGs are uniquely associated with chloroplasts and mitochondria in the host defense against viral infection and replication. The functions of WRKY, NAC, and MYB transcription factors in imparting resistance to viral infections can be established. Promoter analysis revealed that AP2/EREBP, DOF, and C2H2 zinc finger factors included the most frequent binding sites and played a more important role in plant-viral interactions. Comparative analysis revealed several miRNAs with defensive functions including miRNA156, miRNA160, and miRNA169. The PPI network revealed several key hub genes mostly related to chloroplasts/mitochondria, including ZAT6, CML37, CHLI, DREB, F27B13.20, and ASP2 with upregulation, also PLGG1, PSBY, APO2, POR, ERF, and CSP with downregulation. Moreover, novel hub genes with unknown functions, such as AT2G41640 and AT3G57380 have been identified. This study represents the first preliminary systems biology approach to elucidate the roles of chloroplast/mitochondria-related genes in Arabidopsis, tobacco, and rice against viral challenges by introducing valuable candidate genes for enhanced genetic engineering programs to develop virus-resistant crop varieties.

PMID:40336839 | PMC:PMC12055828 | DOI:10.3389/fmicb.2025.1551123

Brief Bioinform. 2025 May 1;26(3):bbaf201. doi: 10.1093/bib/bbaf201.

ABSTRACT

Despite the significant progress in accuracy and reliability in mass spectrometry technology, as well as the development of strategies based on isotopic labeling or internal standards in recent decades, systematic biases originating from non-biological factors remain a significant challenge in data analysis. In addition, the wide range of available normalization methods renders the choice of a suitable normalization method challenging. We systematically evaluated 17 normalization and 2 batch effect correction methods, originally developed for preprocessing DNA microarray data but widely applied in proteomics, on 6 publicly available spike-in and 3 label-free and tandem mass tag datasets. Opposed to state-of-the-art normalization practice, we found that a reduction in intragroup variation is not directly related to the effectiveness of the normalization methods. Furthermore, our results demonstrated that the methods RobNorm and Normics, specifically developed for proteomics data, in line with LoessF performed consistently well across the spike-in datasets, while EigenMS exhibited a high false-positive rate. Finally, based on experimental data, we show that normalization substantially impacts downstream analyses, and the impact is highly dataset-specific, emphasizing the importance of use-case-specific evaluations for novel proteomics datasets. For this, we developed the PROteomics Normalization Evaluator (PRONE), a unifying R package enabling comparative evaluation of normalization methods, including their impact on downstream analyses, while offering considerable flexibility, acknowledging the lack of universally accepted standards. PRONE is available on Bioconductor with a web application accessible at https://exbio.wzw.tum.de/prone/.

PMID:40336172 | DOI:10.1093/bib/bbaf201

Nature. 2025 May 7. doi: 10.1038/s41586-025-08973-5. Online ahead of print.

ABSTRACT

Despite recent advances in understanding disease biology, treatment of group 3/4 medulloblastoma remains a therapeutic challenge in paediatric neuro-oncology1. Bulk-omics approaches have identified considerable intertumoural heterogeneity in group 3/4 medulloblastoma, including the presence of clear single-gene oncogenic drivers in only a subset of cases, whereas in most cases, large-scale copy number aberrations prevail2,3. However, intratumoural heterogeneity, the role of oncogene aberrations, and broad copy number variation in tumour evolution and treatment resistance remain poorly understood. To dissect this interplay, we used single-cell technologies (single-nucleus RNA sequencing (snRNA-seq), single-nucleus assay for transposase-accessible chromatin with high-throughput sequencing (snATAC-seq) and spatial transcriptomics) on a cohort of group 3/4 medulloblastoma with known alterations in the oncogenes MYC, MYCN and PRDM6. We show that large-scale chromosomal aberrations are early tumour-initiating events, whereas the single-gene oncogenic events arise late and are typically subclonal, but MYC can become clonal upon disease progression to drive further tumour development and therapy resistance. Spatial transcriptomics shows that the subclones are mostly interspersed across tumour tissue, but clear segregation is also present. Using a population genetics model, we estimate medulloblastoma initiation in the cerebellar unipolar brush cell lineage starting from the first gestational trimester. Our findings demonstrate how single-cell technologies can be applied for early detection and diagnosis of this fatal disease.

PMID:40335697 | DOI:10.1038/s41586-025-08973-5

Nature. 2025 May 7. doi: 10.1038/s41586-025-08971-7. Online ahead of print.

ABSTRACT

The eukaryotic genome is packed into nucleosomes of 147 base pairs around a histone core and is organized into euchromatin and heterochromatin, corresponding to the A and B compartments, respectively1,2. Here we investigated whether individual nucleosomes contain sufficient information for 3D genomic organization into compartments, for example, in their biophysical properties. We purified native mononucleosomes to high monodispersity and used physiological concentrations of polyamines to determine their condensability. The chromosomal regions known to partition into A compartments have low condensability and those for B compartments have high condensability. Chromatin polymer simulations using condensability as the only input, without any trans factors, reproduced the A/B compartments. Condensability is also strongly anticorrelated with gene expression, particularly near the promoters and in a cell type-dependent manner. Therefore, mononucleosomes have biophysical properties associated with genes being on or off. Comparisons with genetic and epigenetic features indicate that nucleosome condensability is an emergent property, providing a natural axis on which to project the high-dimensional cellular chromatin state. Analysis using various condensing agents or histone modifications and mutations indicates that the genome organization principle encoded into nucleosomes is mostly electrostatic in nature. Polyamine depletion in mouse T cells, resulting from either knocking out or inhibiting ornithine decarboxylase, results in hyperpolarized condensability, indicating that when cells cannot rely on polyamines to translate the biophysical properties of nucleosomes to 3D genome organization, they accentuate condensability contrast, which may explain the dysfunction observed with polyamine deficiency3-5.

PMID:40335690 | DOI:10.1038/s41586-025-08971-7

Sci Rep. 2025 May 7;15(1):15886. doi: 10.1038/s41598-025-00817-6.

ABSTRACT

Isoform switching in cancer is a prevalent phenomenon with significant implications for immunotherapy, as actionable neoantigens derived from these cancer-specific events would be applicable to broad categories of patients, reducing the necessity for personalized treatments. By integrating five large-scale transcriptomic datasets comprising over 19,500 samples across 29 cancer and 54 normal tissue types, we identified cancer-associated isoform switching events common to multiple cancer types, several of which involve genes with established mechanistic roles in oncogenesis. The presence of neoantigen-containing peptides derived from these transcripts was confirmed in broad cancer and normal tissue proteome datasets and the binding affinity of predicted neoantigens to the human leukocyte antigen (HLA) complex via molecular dynamics simulations. The study presents strong evidence that isoform switching in cancer is a significant source of actionable neoantigens that have the capability to trigger an immune response. These findings suggest that isoform switching events could potentially be leveraged for broad immunotherapeutic strategies across various cancer types.

PMID:40335513 | DOI:10.1038/s41598-025-00817-6