J Biomol Struct Dyn. 2025 Feb 3:1-14. doi: 10.1080/07391102.2025.2460069. Online ahead of print.

ABSTRACT

Lung squamous cell carcinoma (LUSC) is a type of non-small cell lung cancer that is the most common and deadly type of lung cancer, originating from the cells lining the bronchi. The progression of LUSC is influenced by various factors, such as genetic, viral, environmental and hormonal factors, immune system response, and smoking history. Despite extensive studies aimed at improving patient survival, the role of gender-specific molecular variants in LUSC progression remains unclear. Using a systems biology approach, combining differential gene expression, network analysis, and machine learning, aberrant mRNA and ncRNAs implicated in LUSC have been identified to improve patient survival, stratify patients and develop novel prognostic strategies. Furthermore, a systematic analysis of the prognostic implications and functional annotations of the molecular variants results in the filtering of key protein-coding genes and non-coding RNAs that are involved in tumor progression. We found several common molecular variants in both genders, including 4 mRNA, 4 miRNAs, and 27 lncRNAs. Among the shared lncRNAs, 5 were novel for both genders. These were found to have a poor prognostic performance in patients with lung cancer. The key players are involved in DNA replication, nucleotide excision repair, complement and coagulation cascades, and estrogen signaling pathways. In this study, we report lncRNAs (PVT1, FAM13A-AS1, LINC00461, NAV2-AS5, PRICKLE2-AS1, and VCAN-AS1) that may function as oncogenes or tumor suppressors by regulating the expression of coding genes, such as RAB24, HECW2, LGR4, and FKBP5. These lncRNAs and coding genes may play important roles in LUSC development and progression.

PMID:39895519 | DOI:10.1080/07391102.2025.2460069

Ann Rheum Dis. 2025 Feb 1:S0003-4967(25)00078-0. doi: 10.1016/j.ard.2025.01.022. Online ahead of print.

ABSTRACT

OBJECTIVES: To analyse the immune mechanisms of diffuse cutaneous systemic sclerosis (dcSSc) skin disease focusing on CD8+ T-cell responses in the affected skin of patients because chronic inflammation, vasculopathy, and extensive cutaneous fibrosis are prominent features of dcSSc skin disease, causing pain and disability in patients, with no effective therapy.

METHODS: Single-cell transcriptomics and epigenomics were applied to well-characterised patient skin samples to identify transcriptomes and key regulators of skin-resident CD8+ T-cell subsets. Multicolor immunofluorescence miscoscopy was used to validate molecular findings. Ex vivo skin explant assays were used to functionally characterise dysfunctional CD8+ T-cell subsets on nonlesional autologous skin.

RESULTS: We identified 2 major developmentally connected CD8+ T-cell subpopulations that were expanded in SSc skin lesions compared with healthy control skin. The first was a heterogeneous subset of effector-memory CD8+KLRB1+IL7R+ cells characterised by increased cytolytic and Tc2/Tc17 effector functions that appear to induce tissue damage and fibrosis in early-stage dcSSc skin lesions. The second, found primarily in patients with late-stage disease, was an exhausted CD8+KLRG1+IL7R- subset that exhibited transcriptional features of long-lived effector cells, likely contributing to chronic inflammation. Significantly, both subsets were also expanded in other benign dermatoses, implicating these cell populations in the pathogenesis of chronic human skin inflammation.

CONCLUSIONS: This study provides new insight into core regulatory programmes modulating skin-resident CD8+ T-cell plasticity and identifies distinct CD8+ T-cell subpopulations that contribute to initiation and chronicity of inflammatory responses in systemic sclerosis skin lesions. These findings reveal prospective molecular targets for new therapeutic strategies against this incurable disease.

PMID:39894688 | DOI:10.1016/j.ard.2025.01.022

J Adv Res. 2025 Jan 31:S2090-1232(25)00071-2. doi: 10.1016/j.jare.2025.01.052. Online ahead of print.

ABSTRACT

BACKGROUND: The development of pangenomes has revolutionized genomic studies by capturing the complete genetic diversity within a species. Pangenome assembly integrates data from multiple individuals to construct a comprehensive genomic landscape, revealing both core and accessory genomic elements. This approach enables the identification of novel genes, structural variations, and gene presence-absence variations, providing insights into species evolution, adaptation, and trait variation. Representing pangenomes requires innovative visualization formats that effectively convey the complex genomic structures and variations.

AIM: This review delves into contemporary methodologies and recent advancements in constructing pangenomes, particularly in plant genomes. It examines the structure of pangenome representation, including format comparison, conversion, visualization techniques, and their implications for enhancing crop improvement strategies.

KEY SCIENTIFIC CONCEPTS OF REVIEW: Earlier comparative studies have illuminated novel gene sequences, copy number variations, and presence-absence variations across diverse crop species. The concept of a pan-genome, which captures multiple genetic variations from a broad spectrum of genotypes, offers a holistic perspective of a species' genetic makeup. However, constructing a pan-genome for plants with larger genomes poses challenges, including managing vast genome sequence data and comprehending the genetic variations within the germplasm. To address these challenges, researchers have explored cost-effective alternatives to encapsulate species diversity in a single assembly known as a pangenome. This involves reducing the volume of genome sequences while focusing on genetic variations. With the growing prominence of the pan-genome concept in plant genomics, several software tools have emerged to facilitate pangenome construction. This review sheds light on developing and utilizing software tools tailored for constructing pan-genomes in plants. It also discusses representation formats suitable for downstream analyses, offering valuable insights into the genetic landscape and evolutionary dynamics of plant species. In summary, this review underscores the significance of pan-genome construction and representation formats in resolving the genetic architecture of plants, particularly those with complex genomes. It provides a comprehensive overview of recent advancements, aiding in exploring and understanding plant genetic diversity.

PMID:39894347 | DOI:10.1016/j.jare.2025.01.052

Int J Biol Macromol. 2025 Jan 31:140567. doi: 10.1016/j.ijbiomac.2025.140567. Online ahead of print.

ABSTRACT

BACKGROUND: Staphylococcus aureus (S. aureus) is a globally prevalent foodborne pathogen responsible for significant public health concerns. Staphylococcal food poisoning (SFP) results from staphylococcal enterotoxins (SEs) produced by specific strains of S. aureus. Rapid and effective detection of SEs remains a significant challenge for public health authorities. Aptamers, short single-stranded DNA(ssDNA), RNA, or synthetic xeno nucleic acid (XNA) molecules, exhibit high affinity for binding to their specific targets. Due to their unique properties, including low production costs, ease of chemical modification, high thermal stability, and reproducibility, aptamers present a viable alternative to antibodies for diagnostic and therapeutic applications.

OBJECTIVES: This research aimed to isolate high-affinity ssDNA aptamers with specificity for staphylococcal enterotoxin D (SED).

METHODS: The systematic evolution of ligands by the exponential enrichment (SELEX) method was utilized to identify specific aptamers. These aptamers were then validated using enzyme-linked apta-sorbent assay (ELASA) and surface plasmon resonance (SPR) to assess their binding characteristics and affinity.

RESULTS: SELEX successfully identified aptamers with strong binding affinity to SED. Among the identified candidates, one aptamer, Aptamer 1, exhibited the highest specificity for SED with a dissociation constant (KD) of 4.4 ± 2.26 nM. The limit of detection (LOD) for SED using this aptamer was determined to be 45 nM.

CONCLUSIONS: The findings indicate that the ELASA system designed using the aptamer developed in this study demonstrates higher specificity, sensitivity, and reproducibility in detecting enterotoxin D. This novel aptamer offers significant potential for applications in diagnostic platforms targeting S. aureus enterotoxins.

PMID:39894103 | DOI:10.1016/j.ijbiomac.2025.140567

SLAS Discov. 2025 Jan 31:100220. doi: 10.1016/j.slasd.2025.100220. Online ahead of print.

ABSTRACT

Protein-nucleic acid phase separation has been implicated in many diseases such as viral infections, neurodegeneration, and cancer. There is great interest in identifying condensate modulators (CMODs), which are small molecules that alter the dynamics and functions of phase-separated condensates, as a potential therapeutic modality. Most CMODs were identified in cellular high-content screens (HCS) where micron-scale condensates were characterized by fluorescence microscopy. These approaches lack information on protein dynamics, are limited by microscope resolution, and are insensitive to subtle condensation phenotypes missed by overfit analysis pipelines. Here, we evaluate two alternative cell-based assays: high-throughput single molecule tracking (htSMT) and proximity-based condensate biosensors using NanoBIT (split luciferase) and NanoBRET (bioluminescence resonance energy transfer) technologies. We applied these methods to evaluate condensation of the SARS-CoV-2 nucleocapsid (N) protein under GSK3 inhibitor treatment, which we had previously identified in our HCS campaign to induce condensation with well-defined structure-activity relationships (SAR). Using htSMT, we observed robust changes in N protein diffusion as early as 3 hours post GSK3 inhibition. Proximity-based N biosensors also reliably reported on condensation, enabling the rapid assaying of large compound libraries with a readout independent of imaging. Both htSMT and proximity-based biosensors performed well in a screening format and provided information on CMOD activity that was complementary to HCS. We expect that this expanded toolkit for interrogating phase-separated proteins will accelerate the identification of CMODs for important therapeutic targets.

PMID:39894078 | DOI:10.1016/j.slasd.2025.100220

Cell Rep. 2025 Feb 1;44(2):115240. doi: 10.1016/j.celrep.2025.115240. Online ahead of print.

ABSTRACT

Despite the broad use of single-cell/nucleus RNA sequencing in plant research, accurate cluster annotation in less-studied plant species remains a major challenge due to the lack of validated marker genes. Here, we generated a single-cell RNA sequencing atlas of soil-grown wheat roots and annotated cluster identities by transferring annotations from publicly available datasets in wheat, rice, maize, and Arabidopsis. The predictions from our orthology-based annotation approach were next validated using untargeted spatial transcriptomics. These results allowed us to predict evolutionarily conserved tissue-specific markers and generate cell type-specific gene regulatory networks for root tissues of wheat and the other species used in our analysis. In summary, we generated a single-cell and spatial transcriptomics resource for wheat root apical meristems, including numerous known and uncharacterized cell type-specific marker genes and developmental regulators. These data and analyses will facilitate future cell type annotation in non-model plant species.

PMID:39893633 | DOI:10.1016/j.celrep.2025.115240

ISME J. 2025 Feb 2:wraf018. doi: 10.1093/ismejo/wraf018. Online ahead of print.

ABSTRACT

Microbes transform their environments using diverse enzymatic reactions. However, it remains challenging to measure microbial reaction rates in natural environments. Despite advances in global quantification of enzyme abundances, the individual relationships between enzyme abundances and their reaction rates have not been systematically examined. Using matched proteomic and reaction rate data from microbial cultures, we show that enzyme abundance is often insufficient to predict its corresponding reaction rate. However, we discovered that global proteomic measurements can be used to make accurate rate predictions of individual reaction rates (median R2 = 0.78). Accurate rate predictions required only a small number of proteins and they did not need explicit prior mechanistic knowledge or environmental context. These results indicate that proteomes are encoders of cellular reaction rates, potentially enabling proteomic measurements in situ to estimate the rates of microbially mediated reactions in natural systems.

PMID:39893571 | DOI:10.1093/ismejo/wraf018

Nat Commun. 2025 Feb 1;16(1):1247. doi: 10.1038/s41467-025-56535-0.

ABSTRACT

Recent advances in spatial epigenomic techniques have given rise to spatial assay for transposase-accessible chromatin using sequencing (spATAC-seq) data, enabling the characterization of epigenomic heterogeneity and spatial information simultaneously. Integrative analysis of multiple spATAC-seq samples, for which no method has been developed, allows for effective identification and elimination of unwanted non-biological factors within the data, enabling comprehensive exploration of tissue structures and providing a holistic epigenomic landscape, thereby facilitating the discovery of biological implications and the study of regulatory processes. In this article, we present INSTINCT, a method for multi-sample INtegration of Spatial chromaTIN accessibility sequencing data via stochastiC domain Translation. INSTINCT can efficiently handle the high dimensionality of spATAC-seq data and eliminate the complex noise and batch effects of samples through a stochastic domain translation procedure. We demonstrate the superiority and robustness of INSTINCT in integrating spATAC-seq data across multiple simulated scenarios and real datasets. Additionally, we highlight the advantages of INSTINCT in spatial domain identification, visualization, spot-type annotation, and various downstream analyses, including motif enrichment analysis, expression enrichment analysis, and partitioned heritability analysis.

PMID:39893190 | DOI:10.1038/s41467-025-56535-0

Nat Commun. 2025 Feb 1;16(1):1253. doi: 10.1038/s41467-025-56383-y.

ABSTRACT

We reported that an acquired miR-142 deficit transforms chronic phase (CP) chronic myeloid leukemia (CML) leukemic stem cells (LSCs) into blast crisis (BC) LSCs. Given the role of miR-142 in the development and activity of the immune system, we postulated that this deficit also promotes LSC immune escape. Herein, we report on IL-6-driven miR-142 deficit occurring in T cells during BC transformation. In CML murine models, miR-142 deficit impairs thymic differentiation of lymphoid-primed multipotent progenitors (LMPP) into T cells and prevents T cells' metabolic reprogramming, thereby leading to loss of T cells and leukemia immune escape. Correcting miR-142 deficit with a miR-142 mimic compound (M-miR-142), alone or in combination with immune checkpoint antibodies, restores T cell number and immune activity, leading to LSC elimination and prolonged survival of BC CML murine and patient-derived xenograft models. These observations may open new therapeutic opportunities for BC CML and other myeloid malignancies.

PMID:39893171 | DOI:10.1038/s41467-025-56383-y

J Genet Genomics. 2025 Jan 30:S1673-8527(25)00032-3. doi: 10.1016/j.jgg.2025.01.017. Online ahead of print.

ABSTRACT

The liver performs several vital functions such as metabolism, toxin removal, and glucose storage through the coordination of various cell types. With the recent breakthrough of the single-cell/single-nucleus RNA-seq (sc/snRNA-seq) techniques, there is a great opportunity to establish a reference cell map of the liver at single-cell resolution with transcriptome-wise features. In this study, we build a unified liver cell atlas uniLIVER (http://lifeome.net/database/uniliver) by integrative analysis of a large-scale sc/snRNA-seq data collection of normal human liver with 331,125 cells and 79 samples from 6 datasets. Moreover, we introduce LiverCT, a novel machine learning based method for mapping any query dataset to the liver reference map by introducing the definition of "variant" cellular states analogy to the sequence variants in genomic analysis. Applying LiverCT on liver cancer datasets, we find that the "deviated" states of T cells are highly correlated with the stress pathway activities in hepatocellular carcinoma, and the enrichments of tumor cells with the hepatocyte-cholangiocyte "intermediate" states significantly indicate poor prognosis. Besides, we find the tumor cells of different patients have different zonation tendencies and this zonation tendency is also significantly associated with the prognosis. This reference atlas mapping framework can also be extended to any other tissues.

PMID:39892777 | DOI:10.1016/j.jgg.2025.01.017

Protein Expr Purif. 2025 Jan 30:106678. doi: 10.1016/j.pep.2025.106678. Online ahead of print.

ABSTRACT

SOG1, a transcription factor consisting of a folded NAC (NAM-ATAF-CUC2) domain and an intrinsically disordered C-terminal domain (CTD), co-ordinates the DNA damage response in plants. Here we compare different methods to express and purify recombinant full length Arabidopsis thaliana SOG1. Expression in Sf9 insect cells results in a protein that contains a phosphorylated site that is possibly located on the T423 site in the CTD. This site is reported to be phosphorylated in planta upon aluminium toxicity stress and may affect the transcriptional activity of SOG1 in an yet undetermined way. Expression of SOG1 in E. coli BL21 (DE3) leads to the formation of inclusion bodies, a problem that is resolved by using a cleavable SUMO solubility tag. The resulting protein is not phosphorylated and represents the transcriptional inactive state of SOG1. Both protein preparations show similar CD spectra and melting temperatures. SEC-MALS determined that the proteins, like other NAC transcription factors, form a dimer in solution. Both proteins are also highly non-globular as determined by analytical SEC and are likely stretched out due to their disordered CTD. In electromobility shift assays, both insect and E. coli purified SOG1 proteins bind to a DNA fragment from the promoter region of SMR5, a well established target gene of SOG1, showing the functionality of both purified proteins.

PMID:39892530 | DOI:10.1016/j.pep.2025.106678

Mol Cell. 2025 Jan 28:S1097-2765(25)00003-6. doi: 10.1016/j.molcel.2025.01.003. Online ahead of print.

ABSTRACT

Amplification of chromosomal material derived from 12q13-15 is common in human cancer and believed to result in overexpression of multiple collaborating oncogenes. To define the oncogenes involved, we overexpressed genes recurrently amplified in human liposarcoma using a zebrafish model of the disease. We found several genes whose overexpression collaborated with AKT in sarcomagenesis, including the tRNA methyltransferase METTL1. This was surprising, because AKT phosphorylates METTL1 to inactivate its enzymatic activity. Indeed, phosphomimetic S27D or catalytically dead alleles phenocopied the oncogenic activity of wild-type METTL1. We found that METTL1 binds the multi-tRNA synthetase complex, which contains many of the cellular aminoacyl-tRNA synthetases and promotes tRNA aminoacylation, polysome formation, and protein synthesis independent of its methyltransferase activity. METTL1-amplified liposarcomas were hypersensitive to actinomycin D, a clinical inhibitor of ribosome biogenesis. We propose that METTL1 overexpression promotes sarcomagenesis by stimulating tRNA aminoacylation, protein synthesis, and tumor cell growth independent of its methyltransferase activity.

PMID:39892392 | DOI:10.1016/j.molcel.2025.01.003

Cell Genom. 2025 Jan 30:100764. doi: 10.1016/j.xgen.2025.100764. Online ahead of print.

ABSTRACT

Tumor hypoxia drives metabolic shifts, cancer progression, and therapeutic resistance. Challenges in quantifying hypoxia have hindered the exploitation of this potential "Achilles' heel." While gene expression signatures have shown promise as surrogate measures of hypoxia, signature usage is heterogeneous and debated. Here, we present a systematic pan-cancer evaluation of 70 hypoxia signatures and 14 summary scores in 104 cell lines and 5,407 tumor samples using 472 million length-matched random gene signatures. Signature and score choice strongly influenced the prediction of hypoxia in vitro and in vivo. In cell lines, the Tardon signature was highly accurate in both bulk and single-cell data (94% accuracy, interquartile mean). In tumors, the Buffa and Ragnum signatures demonstrated superior performance, with Buffa/mean and Ragnum/interquartile mean emerging as the most promising for prospective clinical trials. This work delivers recommendations for experimental hypoxia detection and patient stratification for hypoxia-targeting therapies, alongside a generalizable framework for signature evaluation.

PMID:39892389 | DOI:10.1016/j.xgen.2025.100764

Microbiol Res. 2025 Jan 30;293:128087. doi: 10.1016/j.micres.2025.128087. Online ahead of print.

ABSTRACT

Erwinia amylovora (Ea) is a devastating bacterial pathogen that causes fire blight disease in Rosaceae family plants, including apples and pears. The use of bacteriophages is an alternative strategy to antibiotics for managing bacterial pathogens. In this study, the Ea-specific virulent phiEaSP1 phage was characterized, and its biocontrol efficacy against Ea was evaluated in apple seedlings. Genomic analyses revealed that phiEaSP1 belongs to the family Chaseviridae, subfamily Cleopatravirinae, and genus Loessnervirus. Most phiEaSP1 particles bound to the host cell surface within 5 min, and one virion made 68 progenies within 20 min of infection. The phage rapidly lysed Ea cells in vitro and maintained its lytic activity after incubation under different environmental conditions, including temperature, pH, and UV-A, as well as in the soil, with surfactants, and on apple seedlings. Receptor analysis using the Tn5 random mutant library of Ea TS3128 demonstrated that phiEaSP1 recognizes lipopolysaccharide as a receptor, whereas phiEaP-8 and phiEaP-21 recognize cellulose as a receptor. Protective efficacy against fire blight was tested on apple seedlings pretreated with the single phiEaSP1 or a phage cocktail containing phiEaSP1, phiEaP-8, and phiEaP-21. No or only weak symptoms were observed in the phage-treated seedlings. The application of a phage cocktail showed better control efficacy, indicating the potential of the phage cocktail, including phiEaSP1, as a preventive agent. Taken together, these results suggest that the use of a phage cocktail containing phiEaSP1 could be a potential strategy for the biocontrol of fire blight disease in apples.

PMID:39892321 | DOI:10.1016/j.micres.2025.128087

Eur J Med Chem. 2025 Jan 2;287:117234. doi: 10.1016/j.ejmech.2024.117234. Online ahead of print.

ABSTRACT

Despite the significant roles of solute carrier (SLC) and ATP-binding cassette (ABC) transporters in human health and disease, most remain poorly characterized as intrinsic and/or xenobiotic ligands are unknown, rendering them as 'undruggable'. Polypharmacology, defined as the simultaneous engagement of multiple targets by a single ligand, offers a promising avenue for discovering novel lead compounds addressing these emerging pharmacological challenges - a major focus in contemporary medicinal chemistry. While common structural motifs among phylogenetically diverse proteins have been proposed to underlie polypharmacology through the concept of 'multitarget binding sites', a comprehensive analysis of these functional and structural aspects from a medicinal chemistry perspective has yet to be undertaken. In our study, we synthesized 65 distinct indazole derivatives and evaluated their activity across a broad biological assessment platform encompassing 17 specific and polyspecific SLC and ABC transporters. Notably, ten indazoles exhibited cross-target activity against challenging transporter targets associated with neurodegeneration (ABCA1), metabolic reprogramming (MCT4), and cancer multidrug resistance (ABCC10). Furthermore, molecular blind docking experiments and advanced binding site analyses revealed, for the first time, conserved binding motifs across monocarboxylate transporters (MCTs), organic anion transporting polypeptides (OATPs), organic cation transporters (OCTs), and ABC transporters, characterized by specific and recurring residues of tyrosine, phenylalanine, serine, and threonine. These findings highlight not only the potential of polypharmacology in drug discovery but also provide insights into the structural underpinnings of ligand binding across membrane transporters.

PMID:39892094 | DOI:10.1016/j.ejmech.2024.117234

J Thromb Thrombolysis. 2025 Feb 1. doi: 10.1007/s11239-025-03072-8. Online ahead of print.

ABSTRACT

Chronic thromboembolic pulmonary hypertension (CTEPH) and COVID-19 share molecular pathways yet remain poorly understood in their interrelation. Using RNA-seq datasets (GSE130391 and GSE169687), we identified 645, 206, and 1,543 differentially expressed genes (DEGs) for long-COVID (16 and 24 weeks post-infection) and CTEPH, respectively. Weighted Gene Co-Expression Network Analysis (WGCNA) pinpointed 234 intersecting key module genes. Three hub genes-DNAJA1, NDUFA5, and SLC2A14-were identified with robust discriminatory capabilities (AUC ≥ 0.7). Enrichment analyses revealed shared pathways linked to immune modulation, oxidative stress, and metabolic dysfunction. Immune analysis highlighted activated CD8 T cells as critical regulators. Regulatory networks implicated TFs and miRNAs, including STAT1 and hsa-mir-23a-3p. Drug prediction identified potential therapeutic compounds with strong molecular docking interactions. These findings unravel critical molecular linkages, emphasizing shared pathogeneses and guiding experimental validations for improved diagnostic and therapeutic strategies in COVID-19 and CTEPH.

PMID:39891865 | DOI:10.1007/s11239-025-03072-8

Eur J Nutr. 2025 Feb 1;64(2):75. doi: 10.1007/s00394-025-03589-x.

ABSTRACT

PURPOSE: During pregnancy, extracellular vesicle and particle microRNAs (EVP miRNA) in maternal circulation have the capacity to cross the placenta and facilitate maternal-fetal communication. Both dysregulation of circulating EVP miRNA during pregnancy and maternal diet quality have been previously associated with pregnancy complications and adverse birth outcomes. However, little is known about how maternal diet influences circulating EVP miRNA during pregnancy. This study assesses associations between maternal diet quality, as measured by the Alternative Healthy Eating Index (2010; AHEI-2010), and EVP miRNA levels in maternal circulation during pregnancy.

METHODS: In a pilot study of 53 pregnant participants in the New Hampshire Birth Cohort Study, maternal diet quality was assessed using AHEI-2010 and plasma (mean gestational age at blood collection: 28.8 weeks) EVP miRNA were profiled using the NanoString nCounter platform which interrogates 798 miRNA transcripts.

RESULTS: In covariate-adjusted models, the AHEI-2010 adherence score was negatively associated (P < 0.05) with the number of unique miRNA transcripts detectable in each sample. In post hoc analyses, greater consumption of red and processed meats was positively associated with levels of 7 miRNA (Q < 0.05), including hsa-miR-512-5p (PBonf < 0.01), a member of the placenta-specific chromosome 19 miRNA cluster.

CONCLUSION: We identified associations between the consumption of red and processed meat and levels of circulating select EVP miRNA during pregnancy, including placenta-specific miRNA and miRNA with target genes overrepresented in pathways involved in placental development. Additional research is needed to assess whether alterations in maternal circulating EVP miRNA may mediate maternal diet quality's impacts on pregnancy and birth outcomes.

PMID:39891736 | DOI:10.1007/s00394-025-03589-x

BMC Cancer. 2025 Jan 31;25(1):182. doi: 10.1186/s12885-025-13580-8.

ABSTRACT

BACKGROUND: Small-molecule compounds that even partially restore the GTPase activity of RASG12V can be used in anticancer therapy. Until now, attempts to obtain such compounds have failed. Compounds with this ability have been defined in our research.

METHODS: The compounds were initially identified through virtual screening, and their optimal binding conformation in the RAS SW-II pocket was determined using the flexible docking technique. Efficacy was verified based on the IC50 determination, GTPase activity, as well as the AKT and ERK phospho WB assays.

RESULTS: The IC50 of the tested compounds was significantly lower against cells with the RASG12V mutation than against selected types of normal cells. The molecular mechanism of action of these compounds was proposed - minimization of the negative impact of the V12 sidechain on GTP hydrolysis of RASG12V. The work also indicates that the model of action of RAS mutants in cell lines is incomplete. The analysed cell line (SW-480) with RAS mutations does not always show increased ERK and AKT activity.

CONCLUSIONS: We have demonstrated molecules that partially restore the GTPase activity of RASG12V. Their mechanism of action is well explained based on current RAS mutant conformation and mechanistic models. These molecules inhibit the RAS-AKT pathway and show higher cytotoxicity against cancer cells with the RASG12V mutation (SW-480 cell line). However, SW-480 cells can switch into the subline proliferating independently of AKT phosphorylation and show partial resistance to the molecules described in this article.

PMID:39891136 | DOI:10.1186/s12885-025-13580-8

Sci Rep. 2025 Jan 31;15(1):3946. doi: 10.1038/s41598-025-87867-y.

ABSTRACT

This paper focuses on the elective surgical scheduling problem with multi-resource constraints, including material resources, such as operating rooms (ORs) and non-operating room (NOR) beds, and human resources (i.e., surgeons, anesthesiologists, and nurses). The objective of multi-resource constrained elective surgical scheduling (MESS) is to simultaneously minimize the average recovery completion time for all patients, the average overtime for medical staffs, and the total medical cost. This problem can be formulated as a mixed integer linear multi-objective optimization model, and the honey badger algorithm based on the Nash equilibrium (HBA-NE) is developed for the MESS. Experimental studies were carried out to test the performance of the proposed approach, and the performance of the proposed surgical scheduling scheme was validated. Finally, to narrow the gap between the optimal surgical scheduling solution and actual hospital operations, digital twin (DT) technology is adopted to build a physical-virtual hospital surgery simulation model. The experimental results show that by introducing a digital twin, the physical and virtual spaces of the smart hospital can be integrated to visually simulate and verify surgical processes.

PMID:39890977 | DOI:10.1038/s41598-025-87867-y

Inflamm Res. 2025 Jan 31;74(1):31. doi: 10.1007/s00011-025-01996-8.

ABSTRACT

OBJECTIVE AND DESIGN: Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of inflammatory muscle disorders of unknown etiology. It is postulated that mitochondrial dysfunction and protein aggregation in skeletal muscle contribute to myofiber degeneration. However, molecular pathways that lead to protein aggregation in skeletal muscle are not well defined.

SUBJECTS: Here we have isolated membrane-bound organelles (e.g., nuclei, mitochondria, sarcoplasmic/endoplasmic reticulum, Golgi apparatus, and plasma membrane) from muscle biopsies of normal (n = 3) and muscle disease patients (n = 11). Of the myopathy group, 10 patients displayed mitochondrial abnormalities (IIM (n = 9); mitochondrial myopathy (n = 1)), and one IIM patient did not show mitochondrial abnormalities (polymyositis).

METHODS: Global proteomic analysis was performed using an Orbitrap Fusion mass spectrometer. Upon unsupervised clustering, normal and mitochondrial myopathy muscle samples clustered separately from IIM samples.

RESULTS: We have confirmed previously known protein alterations in IIM and identified several new ones. For example, we found differential expression of (i) nuclear proteins that control cell division, transcription, RNA regulation, and stability, (ii) ER and Golgi proteins involved in protein folding, degradation, and protein trafficking in the cytosol, and (iii) mitochondrial proteins involved in energy production/metabolism and alterations in cytoskeletal and contractile machinery of the muscle.

CONCLUSIONS: Our data demonstrates that molecular alterations are not limited to protein aggregations in the cytosol (inclusions) and occur in nuclear, mitochondrial, and membrane compartments of IIM skeletal muscle.

PMID:39890639 | DOI:10.1007/s00011-025-01996-8