J Hum Hypertens. 2025 May 20. doi: 10.1038/s41371-025-01027-3. Online ahead of print.

ABSTRACT

Hypertension is a prevalent disease that substantially elevates the risk of neurological disorders such as dementia, stroke and Parkinson's disease. MicroRNAs (miRNAs) play a critical role in the regulation of gene expression related to brain function and disorders. Understanding the involvement of miRNAs in these conditions could provide new insights into potential therapeutic targets. The main objective of this study is to target and investigate microRNAs (miRNAs) associated with neurological disorders in patients suffering from hypertension. The genes involved in hypertension were identified from various databases including GeneCard, MalaCard, DisGeNet, OMIM & GEO2R. The key gene for hypertension was identified using a systems biology approach. Also, potent phytochemical for hypertension was determined by computer-aided drug-designing approach. Functional miRNAs were determined for the key target gene using miRNet analytics platform by hypergeometric tests. Further, the gene-miRNA interaction was determined and enrichment analysis was done. RPS27A was identified as a key target gene for hypertension. Naringenin showed effective molecular interaction with RPS27A with a binding energy score (-6.28). Further, a list of miRNAs which were targeting brain disorders was determined from miRNet. A gene-miRNA network was constructed using the PSRR tool for Parkinson's Disease, Autism Spectrum Disorder, Acute Cerebral Infarction, ACTH-Secreting Pituitary Adenoma, & Ependymoma. Further, miRNA 21 & miRNA 16 were found to be associated with four of the neurological disorders. The study identifies specific miRNAs that may serve as potential biomarkers for brain disorders in hypertensive patients. Targeting these miRNAs could open new avenues for therapeutic strategies aimed at mitigating neurological damage in this patient population.

PMID:40389629 | DOI:10.1038/s41371-025-01027-3

Nat Commun. 2025 May 20;16(1):4666. doi: 10.1038/s41467-025-59844-6.

ABSTRACT

Computer-aided design has become common practice in DNA nanotechnology, and many programs are available that make the sophisticated design processes accessible to both the core research community and curious scientists in other fields. However, most of the design tools are committed to the scaffolded DNA origami method. Here we present an automated design pipeline for creating DNA wireframe nanostructures based on a scaffold-free molecular self-assembly approach. Unlike in the DNA origami method, scaffold-free designs are not built around a global backbone strand but are constituted entirely of short, locally intertwined oligonucleotides. This overcomes many limitations inherent in scaffolded nanostructure designs, most notably the size constraints imposed by the length of available scaffold strands, and the topological and algorithmic challenges of finding feasible scaffold-strand routings. In practice, this leads to simpler design flows and opens up new design possibilities. To demonstrate the flexibility and capability of our approach, we generate a variety of complex DNA wireframe designs automatically from 2D and 3D mesh models and successfully realise the respective molecular nanostructures experimentally.

PMID:40389428 | DOI:10.1038/s41467-025-59844-6

Pain. 2025 May 20. doi: 10.1097/j.pain.0000000000003656. Online ahead of print.

ABSTRACT

The peripheral nervous system (PNS) plays a critical role in pathological conditions, including chronic pain disorders, that manifest differently in men and women. To investigate this sexual dimorphism at the molecular level, we integrated quantitative proteomic profiling of human dorsal root ganglia (hDRG) and peripheral nerve tissue into the expanding omics framework of the PNS. Using data-independent acquisition (DIA) mass spectrometry, we characterized a comprehensive proteomic profile, validating tissue-specific differences between the hDRG and peripheral nerve. Through multi-omic analyses and in vitro functional assays, we identified sex-specific molecular differences, with TNFα signalling emerging as a key sexually dimorphic pathway with higher prominence in men. Genetic evidence from genome-wide association studies further supports the functional relevance of TNFα signalling in the periphery, while clinical trial data and meta-analyses indicate a sex-dependent response to TNFα inhibitors. Collectively, these findings underscore a functionally sexual dimorphism in the PNS, with direct implications for sensory and pain-related clinical translation.

PMID:40388638 | DOI:10.1097/j.pain.0000000000003656

Syst Biol. 2025 May 19:syaf037. doi: 10.1093/sysbio/syaf037. Online ahead of print.

ABSTRACT

Batesian mimicry is an impressive example of convergent evolution driven by predation. However, the observation that many mimics only superficially resemble their models despite strong selective pressures is an apparent paradox. Here, we tested the 'perfecting hypothesis', that posits that inaccurate mimicry may represent a transitional stage at the macro-evolutionary scale by performing the hereto largest phylogenetic analysis (in terms of the number of taxa and genetic data) of ant-mimicking spiders across two speciose but independent clades, the jumping spider tribe Myrmarachnini (Salticidae) and the sac spider sub-family Castianeirinae (Corinnidae). We found that accurate ant mimicry evolved in a gradual process in both clades, by an integration of compound traits contributing to the ant-like habitus with each trait evolving at different speeds. Accurate states were highly unstable at the macro-evolutionary scale likely because strong expression of some of these traits comes with high fitness costs. Instead, the inferred global optimum of mimicry expression was at an inaccurate state. This result reverses the onus of explanation from inaccurate mimicry to explaining the exceptional evolution and maintenance of accurate mimicry and highlights that the evolution of Batesian mimicry is ruled by multiple conflicting selective pressures.

PMID:40388318 | DOI:10.1093/sysbio/syaf037

Physiol Genomics. 2025 May 19. doi: 10.1152/physiolgenomics.00183.2024. Online ahead of print.

ABSTRACT

Background: Risk factors for cardiac arrhythmias that can cause sudden death and heart failure include genetics, age, lifestyle, and other environmental factors. Objectives: The study assessed electrocardiography (ECG) traits in BXD mice and explored associated quantitative trait loci (QTLs). Methods: Five-minute electrocardiograms were recorded in 44 BXD strains at 4-5 months of age (n≥5 mice/sex/strain). ECG and arrhythmia traits were associated with echocardiography, blood pressure, genome and heart transcriptome data followed by expression QTL mapping. Results: A significant variability in ECG parameters and arrhythmias were recorded among BXDs. Among male BXDs, QRS duration was significantly associated with increased left ventricular internal diameter (LVID) and reduced ejection fraction and fractional shortening, while premature ventricular contractions (PVCs) were correlated with LVID, LV volumes and pulmonary vein peak pressure. In female BXDs, PVCs and premature atrial contractions (PACs) significantly related with right ventricular ID and cardiac output. One significant QTL associated with QTc and JT durations was identified on Chromosome (Chr) 3 in male BXDs, while Chr 9 locus was suggestive for association with QTc and QT intervals in female mice. Gon4l was predicted as a strong candidate gene associated with repolarization abnormalities including short or long QT syndromes in humans. Conclusions: Study results suggested an influence of genetic background on expression of ECG parameters and arrhythmias based on significant variations of those traits between mouse strains of the BXD family. We conclude that murine BXD family can serve as a valuable reference for systems biology and comparative predictions of arrhythmia disorders.

PMID:40388294 | DOI:10.1152/physiolgenomics.00183.2024

Expert Opin Drug Discov. 2025 May 19. doi: 10.1080/17460441.2025.2508866. Online ahead of print.

ABSTRACT

INTRODUCTION: Artificial intelligence (AI) has emerged as a transformative tool in drug discovery, particularly in virtual screening (VS), which is a crucial initial step in identifying potential drug candidates. This article highlights the significance of AI in revolutionizing both ligand-based virtual screening (LBVS) and structure-based virtual screening (SBVS) approaches, streamlining and enhancing the drug discovery process.

AREAS COVERED: The authors provide an overview of AI applications in drug discovery, with a focus on LBVS and SBVS approaches utilized in prospective cases where new bioactive molecules were identified and experimentally validated. Discussion includes the use of AI in quantitative structure-activity relationship (QSAR) modeling for LBVS, as well as its role in enhancing SBVS techniques such as molecular docking and molecular dynamics simulations. The article is based on literature searches on all studies published up to March 2025.

EXPERT OPINION: AI is rapidly transforming VS in drug discovery, by leveraging increasing amounts of experimental data and expanding its scalability. These innovations promise to enhance efficiency and precision across both LBVS and SBVS approaches, yet challenges such as data curation, rigorous and prospective validation of new models, and efficient integration with experimental methods remain critical for realizing AI's full potential in drug discovery.

PMID:40388244 | DOI:10.1080/17460441.2025.2508866

Acta Neuropathol. 2025 May 19;149(1):49. doi: 10.1007/s00401-025-02889-0.

ABSTRACT

Trisomy of chromosome 21, the cause of Down syndrome (DS), is the most commonly occurring genetic cause of Alzheimer's disease (AD). Here, we compare the frontal cortex proteome of people with Down syndrome-Alzheimer's disease (DSAD) to demographically matched cases of early onset AD and healthy ageing controls. We find dysregulation of the proteome, beyond proteins encoded by chromosome 21, including an increase in the abundance of the key AD-associated protein, APOE, in people with DSAD compared to matched cases of AD. To understand the cell types that may contribute to changes in protein abundance, we undertook a matched single-nuclei RNA-sequencing study, which demonstrated that APOE expression was elevated in subtypes of astrocytes, endothelial cells, and pericytes in DSAD. We further investigate how trisomy 21 may cause increased APOE. Increased abundance of APOE may impact the development of, or response to, AD pathology in the brain of people with DSAD, altering disease mechanisms with clinical implications. Overall, these data highlight that trisomy 21 alters both the transcriptome and proteome of people with DS in the context of AD, and that these differences should be considered when selecting therapeutic strategies for this vulnerable group of individuals who have high risk of early onset dementia.

PMID:40387921 | DOI:10.1007/s00401-025-02889-0

J Exp Med. 2025 Aug 4;222(8):e20242078. doi: 10.1084/jem.20242078. Epub 2025 May 19.

ABSTRACT

Latent viral infections rely on a precise coordination of the immune response to control sporadic viral reactivation. CD8+ T cells play a crucial role in controlling viral latency by generating diverse memory responses in an epitope-specific manner. Among these distinct responses, conventional and inflationary memory responses have been described during herpesvirus infections. Using a newly generated TCR transgenic mouse strain, we investigated the transcriptomic and epigenetic remodeling of distinct epitope-specific CD8+ T cells during CMV infection across tissues at both population and single-cell levels. Our findings reveal that whereas the transcriptomic and epigenetic landscapes of conventional and inflationary memory responses diverge in the spleen and liver, these molecular programs converge in the salivary gland, a site of CMV persistence. Thus, we provide evidence that the dynamics of memory CD8+ T cell responses are distinct between tissues.

PMID:40387857 | DOI:10.1084/jem.20242078

Elife. 2025 May 19;13:RP101630. doi: 10.7554/eLife.101630.

ABSTRACT

Microglia exhibit diverse morphologies reflecting environmental conditions, maturity, or functional states. Thus, morphological characterization provides important information to understand microglial roles and functions. Most recent morphological analysis relies on classifying cells based on morphological parameters. However, this classification may lack biological relevance, as microglial morphologies represent a continuum rather than distinct, separate groups, and do not correspond to mathematically defined clusters irrelevant of microglial cells function. Instead, we propose a new open-source tool, MorphoCellSorter, which assesses microglial morphology by automatically computing morphological criteria, using principal component analysis and Andrews plots to score cells. MorphoCellSorter properly ranked cells from various microglia datasets in mice and rats of different ages, from in vivo, in vitro, and ex vivo models, that were acquired using diverse imaging techniques. This approach allowed for the discrimination of cell populations in various pathophysiological conditions. Finally, MorphoCellSorter offers a versatile, easy, and ready-to-use method to evaluate microglial morphological diversity that could easily be generalized to standardize practices across laboratories.

PMID:40387080 | DOI:10.7554/eLife.101630

NPJ Womens Health. 2025;3(1):31. doi: 10.1038/s44294-025-00077-9. Epub 2025 May 15.

ABSTRACT

This study employed physiologically based pharmacokinetic (PBPK) modelling to compare the extent of foetal exposure between oral and long-acting injectable (LAI) aripiprazole and olanzapine. Adult and pregnancy PBPK models were developed and validated with relevant clinical data. Relevant indices of foetal exposure during pregnancy were predicted from concentration-time data at steady-state dosing for both oral and LAI formulations. Foetal Cmax for aripiprazole was 59-78% higher with LAI than oral, and 68-181% higher with LAI olanzapine than the oral formulation. Predicted cord:maternal ratios (range) were 0.59-0.69 for oral aripiprazole and 0.61-0.66 for LAI aripiprazole, 0.34-0.64 for oral olanzapine and 0.89-0.96 for LAI olanzapine. Also, cumulative foetal exposure over 28 days from oral formulations were generally predicted to be lower compared with their therapeutic-equivalent LAI. As in utero foetal exposure to maternal drugs does not necessarily translate to risk, these data should be interpreted in a broader context that includes benefit-risk assessments.

PMID:40386696 | PMC:PMC12081286 | DOI:10.1038/s44294-025-00077-9

Front Genet. 2025 May 2;16:1569290. doi: 10.3389/fgene.2025.1569290. eCollection 2025.

ABSTRACT

The Cancer Genome Atlas (TCGA) provides comprehensive genomic data across various cancer types. However, complex file naming conventions and the necessity of linking disparate data types to individual case IDs can be challenging for first-time users. While other tools have been introduced to facilitate TCGA data handling, they lack a straightforward combination of all required steps. To address this, we developed a streamlined pipeline using the Genomic Data Commons (GDC) portal's cart system for file selection and the GDC Data Transfer Tool for data downloads. We use the Sample Sheet provided by the GDC portal to replace the default 36-character opaque file IDs and filenames with human-readable case IDs. We developed a pipeline integrating customizable Python scripts in a Jupyter Notebook and a Snakemake pipeline for ID mapping along with automating data preprocessing tasks (https://github.com/alex-baumann-ur/TCGADownloadHelper). Our pipeline simplifies the data download process by modifying manifest files to focus on specific subsets, facilitating the handling of multimodal data sets related to single patients. The pipeline essentially reduced the effort required to preprocess data. Overall, this pipeline enables researchers to efficiently navigate the complexities of TCGA data extraction and preprocessing. By establishing a clear step-by-step approach, we provide a streamlined methodology that minimizes errors, enhances data usability, and supports the broader utilization of TCGA data in cancer research. It is particularly beneficial for researchers new to genomic data analysis, offering them a practical framework prior to conducting their TCGA studies.

PMID:40385985 | PMC:PMC12081331 | DOI:10.3389/fgene.2025.1569290

EMI Anim Environ. 2025 May 8:1-37. doi: 10.1080/29986990.2025.2503155. Online ahead of print.

ABSTRACT

Sapovirus (SaV) infections have been linked with moderate-to-severe acute gastroenteritis (AGE) in animals and humans and represent a significant risk to public health. SaVs from animals including pigs, chimpanzees, and rodents have been reported to be closely related with human SaVs, indicating the possibility of cross-species transmission. Divergent SaVs have been reported in various bat species across various continents including Asia, Europe, Oceania and Africa. However, little is known about the evolutionary history of SaVs across various bat species and their zoonotic potential. In this report, we describe the findings of a surveillance study across various bat species in Nigeria. Samples were pooled and subjected to metagenomics sequencing and analyses. Nine of 57 sample pools (containing 223 rectal swabs from five bat species) had SaV reads from which we assembled a total of four complete and three near-complete (having complete coding sequences) genomes. The bat SaV (BtSaV) strains from this study formed five distinct lineages of which four represented novel genogroups. BtSaV lineages clustered mainly according to bat families, which might suggest a likely virus-host-specific evolution. The BtSaV VP1 capsid protein structure prediction confirmed three main domains (S, P1, and P2) as reported for Human SaV (HuSaV). We found that the P2 subdomain of the VP1 protein contains a degree of homology to known immunoreactive epitopes suggesting these conserved regions may be valuable for diagnostics or medical countermeasure development. This study expands our understanding of reservoir hosts, provides information on the genetic diversity and continuous evolution of SaVs in bats.

PMID:40385501 | PMC:PMC12080456 | DOI:10.1080/29986990.2025.2503155

iScience. 2025 Apr 16;28(5):112446. doi: 10.1016/j.isci.2025.112446. eCollection 2025 May 16.

ABSTRACT

Focusing on the early stages of Alzheimer's disease (AD) holds great promise. However, the specific events in neural cells preceding AD onset remain elusive. To address this, we utilized human-induced pluripotent stem cells carrying APPswe mutation to explore the initial changes associated with AD progression. We observed enhanced neural activity and early neuronal differentiation in APPswe cerebral organoids cultured for one month. This phenomenon was also evident when neural progenitor cells (NPCs) were differentiated into neurons. Furthermore, transcriptomic analyses of NPCs and neurons confirmed altered expression of neurogenesis-related genes in APPswe NPCs. We also found that the upregulation of reactive oxygen species (ROS) is crucial for early neuronal differentiation in these cells. In addition, APPswe neurons remained immature after initial differentiation with increased susceptibility to toxicity, providing valuable insights into the premature exit from the neural progenitor state and the increased vulnerability of neural cells in AD.

PMID:40384927 | PMC:PMC12084003 | DOI:10.1016/j.isci.2025.112446

Plant J. 2025 May;122(4):e70139. doi: 10.1111/tpj.70139.

ABSTRACT

We examined the nature and evolution of three-dimensional (3D) genome conformation, including topologically associating domains (TADs), in five genomes within the genus Oryza. These included three varieties from subspecies within domesticated Asian rice O. sativa as well as their closely related wild relatives O. rufipogon and O. meridionalis. We used the high-resolution chromosome conformation capture technique Micro-C, which we modified for use in rice. Our analysis of rice TADs shows that TAD boundaries have high transcriptional activity, low methylation levels, low transposable element (TE) content, and increased gene density. We also find a significant correlation of expression levels for genes within TADs, suggesting that they do function as genomic domains with shared regulatory features. Our findings indicate that animal and plant TADs may share more commonalities than were initially thought, as evidenced by similar genetic and epigenetic signatures associated with TADs and boundaries. To examine 3D genome divergence, we employed a computer vision-based algorithm for the comparison of chromatin contact maps and complemented this analysis by assessing the evolutionary conservation of individual TADs and their boundaries. We conclude that overall chromatin organization is conserved in rice, and 3D structural divergence correlates with evolutionary distance between genomes. We also note that individual TADs are not well conserved, even at short evolutionary timescales.

PMID:40384625 | DOI:10.1111/tpj.70139

Protein Sci. 2025 Jun;34(6):e70155. doi: 10.1002/pro.70155.

ABSTRACT

The complex genotype-to-phenotype relationships in Mendelian diseases can be elucidated by mutation-induced disturbances to the networks of molecular interactions (interactomes) in human cells. Missense and nonsense mutations cause distinct perturbations within the human protein interactome, leading to functional and phenotypic effects with varying degrees of severity. Here, we structurally resolve the human protein interactome at atomic-level resolutions and perform structural and thermodynamic calculations to assess the biophysical implications of these mutations. We focus on a specific type of missense mutation, known as "quasi-null" mutations, which destabilize proteins and cause similar functional consequences (node removal) to nonsense mutations. We propose a "fold difference" quantification of deleteriousness, which measures the ratio between the fractions of node-removal mutations in datasets of Mendelian disease-causing and non-pathogenic mutations. We estimate the fold differences of node-removal mutations to range from 3 (for quasi-null mutations with folding ΔΔG ≥2 kcal/mol) to 20 (for nonsense mutations). We observe a strong positive correlation between biophysical destabilization and phenotypic deleteriousness, demonstrating that the deleteriousness of quasi-null mutations spans a continuous spectrum, with nonsense mutations at the extreme (highly deleterious) end. Our findings substantiate the disparity in phenotypic severity between missense and nonsense mutations and suggest that mutation-induced protein destabilization is indicative of the phenotypic outcomes of missense mutations. Our analyses of node-removal mutations allow for the potential identification of proteins whose removal or destabilization lead to harmful phenotypes, enabling the development of targeted therapeutic approaches, and enhancing comprehension of the intricate mechanisms governing genotype-to-phenotype relationships in clinically relevant diseases.

PMID:40384578 | DOI:10.1002/pro.70155

Nucleic Acids Res. 2025 May 19:gkaf406. doi: 10.1093/nar/gkaf406. Online ahead of print.

ABSTRACT

Base editing enables the high-throughput screening of genetic variants for phenotypic effects. Base editing screens require the design of single guide RNA (sgRNA) libraries to enable either gene- or variant-centric approaches. While computational tools supporting the design of sgRNAs exist, no solution offers versatile and scalable library design enabling all major use cases. Here, we introduce BEscreen, a comprehensive base editing guide design tool provided as a web server (bescreen.ostendorflab.org) and as a command line tool. BEscreen provides variant-, gene-, and region-centric modes to accommodate various screening approaches. The variant mode accepts genomic coordinates, amino acid changes, or rsIDs as input. The gene mode designs near-saturation libraries covering the entire coding sequence of given genes or transcripts, and the region mode designs all possible guides for given genomic regions. BEscreen enables selection of guides by biological consequence, it features comprehensive customization of base editor characteristics, and it offers optional annotation using Ensembl's Variant Effect Predictor. In sum, BEscreen is a highly versatile tool to design base editing screens for a wide range of use cases with seamless scalability from individual variants to large, near-saturation libraries.

PMID:40384567 | DOI:10.1093/nar/gkaf406

ACS Synth Biol. 2025 May 19. doi: 10.1021/acssynbio.5c00142. Online ahead of print.

ABSTRACT

Optogenetic systems offer precise control over gene expression, but leaky activity in the dark limits their dynamic range and, consequently, their applicability. Here, we enhanced an optogenetic system based on a split T7 RNA polymerase fused to blue-light-inducible Magnets by incorporating a tet-controlled riboregulatory module. This module exploits the photosensitivity of anhydrotetracycline and the designability of synthetic small RNAs to digitize light-controlled gene expression, implementing a repressive action over the translation of a polymerase fragment gene that is relieved with blue light. Our engineered system exhibited 13-fold improvement in dynamic range upon blue light exposure, which even raised to 23-fold improvement when using cells preadapted to chemical induction. As a functional demonstration, we implemented light-controlled antibiotic resistance in bacteria. Such integration of regulatory layers represents a suitable strategy for engineering better circuits for light-based biotechnological applications.

PMID:40384364 | DOI:10.1021/acssynbio.5c00142

Nat Commun. 2025 May 17;16(1):4607. doi: 10.1038/s41467-025-59780-5.

ABSTRACT

Cis-regulatory elements (CREs), including enhancers, silencers, promoters and insulators, play pivotal roles in orchestrating gene regulatory mechanisms that drive complex biological traits. However, current approaches for CRE identification are predominantly sequence-based and typically focus on individual CRE types, limiting insights into their cell-type-specific functions and regulatory dynamics. Here, we present CREATE, a multimodal deep learning framework based on Vector Quantized Variational AutoEncoder, tailored for comprehensive CRE identification and characterization. CREATE integrates genomic sequences, chromatin accessibility, and chromatin interaction data to generate discrete CRE embeddings, enabling accurate multi-class classification and robust characterization of CREs. CREATE excels in identifying cell-type-specific CREs, and provides quantitative and interpretable insights into CRE-specific features, uncovering the underlying regulatory codes. By facilitating large-scale prediction of CREs in specific cell types, CREATE enhances the recognition of disease- or phenotype-associated biological variabilities of CREs, thus advancing our understanding of gene regulatory landscapes and their roles in health and disease.

PMID:40382355 | DOI:10.1038/s41467-025-59780-5

Trends Genet. 2025 May 16:S0168-9525(25)00103-9. doi: 10.1016/j.tig.2025.04.011. Online ahead of print.

ABSTRACT

LINE-1 (long interspersed nuclear element 1, L1) retrotransposons constitute ~17% of human DNA (~0.5 million genomic L1 copies) and exhibit context-dependent expression in different cell lines. Recent studies reveal that L1 is under multilayered control by diverse factors that either collaborate or compete with each other to ensure precise L1 activity. Remarkably, L1s have been co-opted as various transcription-dependent regulatory elements, such as promoters, enhancers, and topologically associating domain (TAD) boundaries, that regulate gene expression in zygotic genome activation, aging, cancer, and other disorders. This review highlights the regulation of L1 and its regulatory functions that influence disease and development.

PMID:40382218 | DOI:10.1016/j.tig.2025.04.011

Int J Radiat Oncol Biol Phys. 2025 Jun 1;122(2):524. doi: 10.1016/j.ijrobp.2025.03.057.

NO ABSTRACT

PMID:40382175 | DOI:10.1016/j.ijrobp.2025.03.057