Arch Razi Inst. 2024 Dec 31;79(6):1329-1335. doi: 10.32592/ARI.2024.79.6.1329. eCollection 2024 Dec.

ABSTRACT

Staphylococcus aureus is recognized for its capacity to generate biofilms, which facilitate bacterial adhesion to diverse substrates and present a significant challenge to therapeutic intervention. The process of biofilm formation is dependent on the icaABCD operon, with the icaA and icaD genes playing a pivotal role in this intricate process. The objective of this study is to investigate the role of these genes in the biofilm formation of S. aureus isolates sourced from clinical settings. A total of 100 S. aureus isolates were collected from clinical sources and subsequently subjected to DNA and RNA extraction using a commercial kit from Kiagen Co. To transcribe the RNA samples into cDNA, a commercial kit from Kiagen Co. was employed. The capacity to produce phenotypic and molecular biofilm formation was then measured using the microtiter plate method and PCR, respectively. The expression levels of the icaA and icaD genes were determined via RT-PCR (Reverse transcription polymerase chain reaction). The results indicated that 95% (95%) of the isolates were capable of producing biofilm, with 16 (16%) producing weak, 64 (64%) producing medium, and 15 (15%) producing strong biofilms. Furthermore, the icaA gene was detected in 72% of the isolates, while the icaD gene was detected in 58%. Of these isolates, 70 (97.2%) expressed the icaA gene, and 53 (73.6%) expressed the icaD gene. Conversely, four isolates (5.5%) that possessed the icaA gene but lacked the icaD gene did not form biofilm. One strain did not express either of the genes. The presence of either the icaA or icaD gene is crucial for the development of biofilm. However, further investigation is necessary to fully comprehend the intricacies of biofilm formation.

PMID:40599458 | PMC:PMC12207945 | DOI:10.32592/ARI.2024.79.6.1329

iScience. 2025 Jun 2;28(7):112808. doi: 10.1016/j.isci.2025.112808. eCollection 2025 Jul 18.

ABSTRACT

Tertiary lymphoid structures (TLSs) are associated with improved cancer immunotherapy responses. However, TLSs vary in their ability to elicit anticancer immune activity, so it is important to develop databases that allow study of variables that regulate their function. We applied single RNA molecule resolution imaging to longitudinal biopsies taken from women with TLS-enriched triple negative breast cancers prior to therapy, after pembrolizumab and after pembrolizumab plus radiation therapy. We developed a computational framework to align and analyze spatial trajectories between TLSs and tumor beds. Tumors with higher T cell infiltration rates were eradicated after pembrolizumab. In contrast, those with lower malignant cell and T cell interaction rates at baseline showed CXCL9+ macrophage infiltration after pembrolizumab, and infiltration of T cells expressing CXCL9-associated programs prior to cancer cell removal after radiation therapy. This manuscript describes single RNA molecule resolution profiling of breast tumors bearing tertiary lymphoid structures throughout an immunotherapy response.

PMID:40599321 | PMC:PMC12209978 | DOI:10.1016/j.isci.2025.112808

iScience. 2025 Jun 6;28(7):112824. doi: 10.1016/j.isci.2025.112824. eCollection 2025 Jul 18.

ABSTRACT

SARS-CoV-2 infects not only humans but also animals, posing reverse zoonotic risks. As SARS-CoV-2 rapidly evolves, JN.1 has become dominant globally. In this study, we determined the susceptibility of XBB.1.16, EG.5.1, BA.2.86, and JN.1 to 27 different animal angiotensin-converting enzyme 2 (ACE2) orthologs using pseudoviruses, and found that JN.1 displayed substantially higher overall reverse zoonotic risk potential compared to other variants except for EG.5.1. Live virus infection experiments further confirmed higher infectivity of JN.1 than BA.2.86. Mechanistic analyses revealed that L455S might be responsible for substantial increase in overall fusogenecity and infectivity by lowering S protein thermostability. Additionally, we also found that L455S mutation enhanced immune evasion of SARS-CoV-2, and XBB breakthrough infection increased levels of neutralization antibodies against JN.1. Together, our findings offer a better mechanistic understanding of CoV entry, host range, evolution, and immunogenicity and highlight the importance of surveillance of susceptible hosts to prevent potential outbreaks.

PMID:40599320 | PMC:PMC12209934 | DOI:10.1016/j.isci.2025.112824

J Med Chem. 2025 Jul 2. doi: 10.1021/acs.jmedchem.5c01204. Online ahead of print.

ABSTRACT

Selectivity for closely related isoforms of protein kinases is a major challenge in the design of drugs and chemical probes. Covalent targeting of unique cysteines is a potential strategy to achieve selectivity for highly conserved binding sites. Here, we used a pan-LIMK inhibitor to selectively probe LIMK1 over LIMK2 by targeting the LIMK1-specific cysteine C349 located in the glycine-rich loop region. Binding kinetics of both noncovalent and covalent LIMK inhibitors were investigated, and the fast on-rate and small size of type-I inhibitors were used in the design of a covalent LIMK1 inhibitor. The developed cell-active, isoform-selective LIMK1 inhibitor showed excellent proteome-wide selectivity in pull-down assays, enabling studies of LIMK1 isoform-selective functions in cellular model systems and providing a versatile chemical tool for studies of the LIMK signaling pathway.

PMID:40598933 | DOI:10.1021/acs.jmedchem.5c01204

Nucleic Acids Res. 2025 Jun 20;53(12):gkaf592. doi: 10.1093/nar/gkaf592.

ABSTRACT

DNA-transcription factor (TF) interactions are essential for gene regulation. Fully characterizing TF recognition specificities and identifying their genomic binding targets are important to understand TF function and regulatory networks. Recently, high-throughput sequencing technology HT-SELEX (high-throughput systematic evolution of ligands by exponential enrichment) has been used to measure hundreds of TFs, providing massive datasets that comprise TF binding preferences. However, there is a need to develop comprehensive computational modeling to fully extract and characterize critical TF binding preferences and fail to distinguish genome-wide binding targets. In this study, we developed a global pairwise model called DCA-Scapes trained with experimental HT-SELEX data. Our approach uncovered high-resolution TF recognition specificity landscapes, enabled the prediction of in vivo binding sequences, and was validated with ChIP-seq (ChIP sequencing) data. In addition, the DCA-Scapes model was utilized to refine the locations of binding regions and accurately identify the binding sites within the ChIP-seq enriched peaks. Moreover, we extended our model to cover the entire human genome, uncovering potential TF target sites that exhibit tissue-specific TF recognition across various cellular environments.

PMID:40598892 | DOI:10.1093/nar/gkaf592

BMC Res Notes. 2025 Jul 1;18(1):249. doi: 10.1186/s13104-025-07331-y.

ABSTRACT

OBJECTIVE: Alcohol is metabolized to acetaldehyde by alcohol dehydrogenases (ADH) and subsequently to acetate by aldehyde dehydrogenases (ALDH). Single nucleotide polymorphisms (SNPs) in ADH1B, ADH1C and ALDH2 genes lead to haplotypes encoding isozymes which influence development of alcoholism. The distribution of these haplotypes in Uganda has not been documented. The aim of this study was to determine genotype, allele, and haplotype frequencies of SNPs in ADH1B, ADH1C, and ALDH2 genes in Uganda.

RESULTS: Five SNPs: ADH1B (rs1229984 and rs2066702), ADH1C (rs1693482 and rs698) and ALDH2 (rs671) were analyzed by PCR-restriction fragment length polymorphism assays in 250 samples. The frequencies of the fast-metabolizing alleles ADH1C*1, ADH1B*3, and ADH1B*2 were 49.6%, 18.2% and 0.2% respectively. The nonprotective allele ADH1B*1 had a high frequency of 81.6% and ADH1C*2 was 10.6%. A novel allele ADH1C*new (Arg271Val349) comprising G at ADH1C rs1693482and G at ADH1C rs698 was identified with a frequency of 39.8%. Of the seven ADH1B-ADH1C haplotype combinations identified, ADH1B*1-ADH1C*1 was the most prevalent (48.4%). Notably ADH1B*1-ADH1C* new, had the second highest frequency (25.2%). Our study provides the first data on novelADH1B-ADH1C haplotypes in alcohol metabolizing genes in the Ugandan population.

PMID:40598579 | DOI:10.1186/s13104-025-07331-y

BMC Biol. 2025 Jul 1;23(1):197. doi: 10.1186/s12915-025-02306-8.

ABSTRACT

BACKGROUND: Brain-enriched miR-137 is highly associated with neuropsychiatric disorders and neural development. Although complete loss of miR-137 that leads to postnatal lethality had been addressed in mice, the underlying mechanism particularly related to growth and development remains unknown.

RESULTS: MiR-137-deficient mice (Mir137-/-) exhibited postnatal lethality, severe growth retardation, osteoporosis, fat atrophy, and hypothermia. Despite comparable serum growth hormone (GH) levels, IGF-1 levels in both liver and serum were significantly reduced, with compensatory upregulation of IGF-1 receptor expression in major organs. Reduced IGF-1 levels were not due to defects in GH secretion by the pituitary nor GH responsiveness of hepatocytes. Instead, impaired in vivo GH-induced p-STAT5 signaling suggested GH resistance in Mir137-/-. Conditional deletion of Mir137 in the nervous system, but not in the liver, showed similar results, confirming the brain-specific role of miR-137. Transcriptomic analyses revealed that differentially expressed genes in the brain were enriched in development and neurogenesis while those in the liver showed diverse and less enrichments. IGF-1 reduction caused by miR-137 deficiency emerged as a central factor impacting the cell proliferation network to systemic growth.

CONCLUSIONS: This study underscores the critical role of miR-137 in failure to thrive through regulation of the GH/IGF-1 axis and supports the use of MiR137-/- as a disease model for GH resistance. Given the conserved miR-137 sequences between mice and humans, further human studies or clinical trials may validate its potential as a biomarker and therapeutic target for growth retardation.

PMID:40598150 | DOI:10.1186/s12915-025-02306-8

BMC Nephrol. 2025 Jul 1;26(1):299. doi: 10.1186/s12882-025-04239-4.

ABSTRACT

BACKGROUND: Diabetic nephropathy is an important cause of end-stage renal disease. Arteriovenous fistula (AVF) stenosis is closely associated with hyperglycemia. However, studies exploring biomarkers linking these two diseases are lacking, which may provide insight into the mechanisms underlying Diabetic kidney disease (DKD) comorbid AVF stenosis.

OBJECTIVE: This study investigated the common pathogenesis of DKD and AVF stenosis.

METHODS: Biomarkers were screened by identifying key genes common between DKD and AVF stenosis through differential gene analysis. GO, KEGG and GSEA enrichment analysis of DEGs were performed by cluster profiler. Immuno-infiltration analysis was performed by CIBERSORT. The predictive value of HPGD to distinguish DKD comorbid AVF stenosis was determined by ROC curves. Upstream miRNAs and transcription factors (TFs) of HPGD were predicted using hTFtarget and mirtarbase databases. After specifically knockdown six upstream miRNAs of HPGD in vascular smooth muscle cells (VSMCs), the expression levels of HPGD in each group were analyzed by quantitative reverse transcription PCR (qRT-PCR), and the empty vector was used as the control group. Clinical patient samples were collected to validate HPGD expression in DKD patients with AVF stenosis via qRT-PCR and immunofluorescence. Subsequently, the proliferation ability and the release level of inflammatory cytokines of VSMCs under high glucose culture conditions were evaluated by regulating the expression of HPGD.

RESULTS: Eleven shared DEGs were identified between DKD and AVF stenosis. Diagnostic efficacy of four hub genes (INHBA, PCK1, ALB, HPGD) was validated through receiver operating characteristic (ROC) curve analysis. qRT-PCR and immunofluorescence analyses showed that HPGD expression in the veins of patients with DKD combined with AVF stenosis was significantly decreased compared to the control group. Regulatory network analysis identified 691 TFs and 72 miRNAs modulating hub gene expression. Specific knockdown of six predicted upstream miRNAs of HPGD resulted in a significant increase in HPGD expression, with the hsa-miR-486-5p knockdown group showing the most pronounced effect. Overexpression of HPGD inhibited the proliferation of VSMCs and the release of inflammatory factors under high-glucose culture conditions. Significantly reduced infiltration of memory activated CD4 T cells was observed in AVF stenosis compared to normal veins. Pearson correlation analysis indicated that HPGD is positively correlated with resting mast cells, M1 macrophages, and M2 macrophages, while it is negatively correlated with naïve B cells and resting CD4 memory T cells.

CONCLUSION: HPGD may be a biomarker of DKD comorbid AVF stenosis. The targeted therapy of HPGD may prevent the occurrence of AVF stenosis in DKD patients, which is worthy of further study.

PMID:40597829 | DOI:10.1186/s12882-025-04239-4

BMC Cancer. 2025 Jul 1;25(1):1053. doi: 10.1186/s12885-025-14033-y.

ABSTRACT

Given the prevalence of RAS mutations in various cancers, personalized therapeutic approaches, guided by molecular markers, are essential. Farnesyltransferase inhibitors (FTIs) have emerged as potential therapeutic options; however, they also face obstacles such as toxicity and limited efficacy. Alternative strategies, such as direct inhibitors combined with pathway modulators, RNA interference, and gene-editing technologies, are under clinical investigation. The targeting of RAS, complicated by its structural nuances, particularly in the G domain, has advanced with the identification of druggable pockets such as the SW-II pocket. This breakthrough has led to the development of targeted therapeutics, such as sotorasib and adagrasib, for KRAS G12C-mutated non-small cell lung cancer (NSCLC). However, these advancements face challenges, including adaptive resistance and the necessity for isoform selectivity. New inhibitors, such as LY3537982 or GDC-6036, are promising, but achieving effective and selective RAS inhibition remains a significant challenge. Additionally, clinical trials have highlighted variability in patient responses, attributing limited treatment efficacy to resistance mechanisms, including on-target mutations and off-target pathway activations. Finally, the RAS oncogene, traditionally viewed as predominantly pro-cancerous, plays a complex role in oncogenesis, with recent evidence suggesting context-dependent effects, such as inducing senescence in certain cells. This shift in understanding underscores the therapeutic potential of manipulating the interplay between RAS and TP53 mutations in cancer. In conclusion, the complexity of effectively targeting the RAS-RAF-ERK pathway is exacerbated by the diverse resistance mechanisms. Challenges such as off-target effects and delivery issues remain significant barriers in the introduction of effective therapies based on RAS inhibitors. This overview highlights the evolving nature of targeting RAS in cancer therapy.

PMID:40597785 | DOI:10.1186/s12885-025-14033-y

Int J Emerg Med. 2025 Jul 1;18(1):113. doi: 10.1186/s12245-025-00932-1.

ABSTRACT

BACKGROUND: Traumatic brain injury (TBI) is the most common type of brain injury and significantly contributes to morbidity and mortality in both adults and children. Diagnosing pediatric head trauma with precision is difficult, particularly for youngsters displaying mild symptoms. Contemporary research has investigated the capacity of biomarkers, including neuron-specific enolase (NSE), to enhance the precision of diagnosis.

OBJECTIVE: The objective of this systematic review and meta-analysis was to assess the levels of NSE in pediatrics with head trauma.

METHODS: A comprehensive literature search was performed among PubMed, Scopus, and Embase databases, from the inception to August 17th, 2024, identifying 963 articles. Any article that evaluated the levels of NSE with any source of sampling in the pediatric population was considered as a possible inclusion. The Standard Mean Difference and confidence intervals of the pooled data were calculated. Also, the robustness of the data was confirmed using sensitivity analysis, and the presence of publication bias was evaluated using funnel plots.

RESULTS: Following the screening and eligibility validation process, 12 studies were selected, which evaluated 806 participants. Meta-analyses revealed markedly elevated NSE levels in patients as compared to controls (p-value < 0.001), indicating its potential as a biomarker for head injury. Further subgroup analyses demonstrated more pronounced correlations between increased NSE levels and severe trauma (p-value < 0.001). In addition, cerebrospinal fluid samples had significantly higher NSE levels than other sample origins (p-value < 0.001). Elevated levels of NSE were also associated with unfavorable results, as assessed by the Glasgow Outcome Scale (p-value < 0.001).

CONCLUSION: The findings emphasize the capacity of NSE as a diagnostic and predictive instrument for pediatric head injury, justifying additional research into its clinical uses.

PMID:40597577 | DOI:10.1186/s12245-025-00932-1

Food Res Int. 2025 Oct;217:116357. doi: 10.1016/j.foodres.2025.116357. Epub 2025 May 29.

ABSTRACT

Flavan-3-ols are one of the most abundant dietary polyphenols, and their absorption and metabolism are vital to their healthy effect, so it is urgent to understand the metabolic characteristics of different configurations and degree of polymerizations (DPs). In this study our aim was to investigate urinary and feces excretion of flavan-3-ols to reveal their metabolism. Catechin (monomer), epicatechin-(4β-8)-catechin (B-type-dimer), epicatechin -(2β-O-7,4β-8)-catechin (A-type-dimer), and epicatechin-(4β-6)-epicatechin-(2β-O-7,4β-8)-catechin (A-type-trimer) were administered to mice. By using untargeted and targeted metabolomics it was observed that flavan-3-ols with similar DP but different linkage types were similar in metabolite recovery in urines and feces, however their constituents of metabolites were different. Phenyl-γ-valerolactones were biomarkers of catechin and B-type linkage flavan-3-ols, rather than of A-type linkage flavan-3-ols. The metabolites of A-type-dimer and A-type-trimer in urine were mainly constituted of phenolic acids. Procyanidin A1 with open C-ring was derived from A-type flavan-3-ols. In summary, phenyl-γ-valerolactones are good biomarkers for catechin and B-type linkage flavan-3-ols but not A-type linkage flavan-3-ols.

PMID:40597460 | DOI:10.1016/j.foodres.2025.116357

Microb Cell Fact. 2025 Jul 1;24(1):147. doi: 10.1186/s12934-025-02762-5.

ABSTRACT

The application of sortase-mediated surface display technology on Bacillus subtilis represents a novel approach in protein engineering. We developed and evaluated a recombinant chimeric protein (R-anz) integrating truncated forms of three Clostridium perfringens toxins (CPA, NetB, ZMP) displayed on B. subtilis. Bioinformatics analyses using docking demonstrated that the 3D structure of R-anz chimeric protein has the potential to interact with chicken Toll-like receptor 21 (TLR21). Successful expression of the chimeric antigen was confirmed through SDS-PAGE and Western blotting, revealing a 78 kDa band in lysozyme-treated, xylose-induced samples. Oral immunization of chickens with this live bacterial vaccine significantly elevated IgY antibody levels, as assessed by ELISA. Cytokine profiling demonstrated a robust immune response, with marked upregulation of IFN-γ, IL-4, IL-17, and IL-22. Post-challenge with virulent C. perfringens strains, immunized chickens exhibited significantly reduced intestinal lesion scores, indicating partial protection. This study highlights the dual activation of humoral and cellular immune pathways, evidenced by elevated IgY levels and enhanced cytokine responses, particularly IFN-γ, IL-4, and IL-22. While the results demonstrate the potential of the R-anz chimeric protein to mitigate necrotic enteritis (NE), further research is essential to refine its efficacy, explore commercial feasibility, and address industry-specific challenges. This work paves the way for advancing NE vaccines using innovative sortase-mediated surface display technology, offering a promising strategy for sustainable poultry health management.

PMID:40597270 | DOI:10.1186/s12934-025-02762-5

Cell Commun Signal. 2025 Jul 1;23(1):321. doi: 10.1186/s12964-025-02315-8.

ABSTRACT

BACKGROUND: Cellular senescence is a fundamental process leading to organismal aging and age-related diseases. Alterations accompanying cellular senescence concern, among others, nucleus architecture, chromatin structure, DNA damage and gene expression. Some changes are universal for all types of senescence, but some characteristics are typical for a given senescence inductor or cell type. The aim of the study was to analyze senescence-associated alterations in chromatin modifications and look for differences depending on senescence type (replicative, RS and stress-induced premature senescence, SIPS) in vascular smooth muscle cells (VSMCs) in vitro. The alterations were compared with those observed in VSMCs derived from atherosclerotic plaques (ex vivo) and, to assess their universality, with those in senescent fibroblasts.

METHODS: We investigated the level and distribution of HP1α and H3 modifications that are markers of hetero- and euchromatin (H3K9me3, H3K27me3, H3K4me3, H3K9Ac - WB and IF), alterations in the transcriptomic profile (DNA microarray, qPCR), H3K4me3, H3K9me3 and HP1α protein distribution in the genome (ChIP-seq), and expression of enzymes involved in histone post-translational modifications (DNA microarray, qPCR, WB, IF).

RESULTS: Our results have shown that the decline in H3K4me3 and H3K9me3 modifications and in HP1α is a universal hallmark of senescence in all tested cell and senescence types, although the extent of the change depends on the senescence inductor. The distribution of H3K4me3 and H3K9me3 in the genome of VSMCs depends on the senescence type, and the transcriptomic analysis identified genes and processes specific to each type.

CONCLUSIONS: We characterized senescence and cell type-dependent changes in chromatin-associated proteins and enzymes involved in histone H3 decoration which, in consequence, impact senescence-associated gene expression. We can conclude that certain similar alterations occur in senescent VSMCs ex vivo, although inter-individual differences usually obscure them. Our results clearly showed that differences existed not only between young and senescent cells but also between SIPS and RS ones. The subtle differences between various SIPS types suggest that various stressors activate the same cellular mechanisms. This study can serve as a starting point to search for factors that may be used to distinguish between SIPS and RS, which in turn could be helpful in defining conditions responsible for accelerated aging.

PMID:40597225 | DOI:10.1186/s12964-025-02315-8

BMC Biol. 2025 Jul 1;23(1):167. doi: 10.1186/s12915-025-02224-9.

ABSTRACT

BACKGROUND: Copy number variations (CNVs) occurring on chromosome 16p11.2 are associated with various neurodevelopmental disorders, including autism spectrum disorder (ASD), schizophrenia, and intellectual disability. Among the genes situated within the critical CNV region, DOC2A is noteworthy. We generated frameshift mutations in doc2a (double C2-like domain-containing protein a) and its paralog doc2b (double C2-like domain-containing protein b) in zebrafish via CRISPR-Cas9 respectively and obtained double-mutant doc2a-/-doc2b-/- by mating the single-mutant doc2a+/+doc2b-/- and doc2a-/-doc2b+/+ zebrafish.

RESULTS: doc2a-/-doc2b-/- mutants displayed aberrant morphology including tail bending and deformity, and morphologically normal individuals displayed aberrant behaviors, including reduced locomotion activity, impaired social interaction, and irregular movements. Whole-brain transcriptome sequencing of both wild-type and doc2a-/-doc2b-/- mutants revealed differentially expressed genes (DEGs) enriched with ASD candidate genes and synaptic signaling pathways, notably down-regulated gene npas4b (Neuronal PAS domain protein 4b). We found the downstream targets of the transcription factor Npas4b in the DEGs were mostly enriched in the synaptic signaling pathways. The npas4b knockout and knockdown zebrafish showed reduced locomotion activity and impaired social interaction similar to the behaviors observed in doc2a-/-doc2b-/- mutants.

CONCLUSIONS: This study suggests that DOC2A in the critical region of 16p11.2 may contribute to the pathogenesis of autism by interacting with other genes, such as DOC2B, and that the downregulation of NPAS4 may play an important role in autism.

PMID:40597089 | DOI:10.1186/s12915-025-02224-9

BMC Genomics. 2025 Jul 1;26(1):575. doi: 10.1186/s12864-025-11710-x.

ABSTRACT

BACKGROUND: The chemoreceptor gene families, which include gustatory, ionotropic, and odorant receptor gene families, are highly conserved across the insects yet also contain many recently duplicated, species-specific genes in particular clades. Within the Bombini (bumble bee) clade, a set of recently duplicated genes in the gustatory receptor (Gr) gene family was identified, the functions of which are unknown. Recently duplicated genes are hypothesized to first evolve to serve non-essential functions, then subsequently evolve additional functions. We tested support for this hypothesis in the common eastern bumble bee, Bombus impatiens, by identifying recently duplicated Gr genes in this lineage and examining their tissue and caste expression patterns.

RESULTS: We annotated twenty-one Gr genes in B. impatiens. Ten of these genes appear to be unique to bumble bees and more likely to be expressed in a subset of sensory organs compared to the conserved Gr genes, which were more broadly expressed across sensory organs. This finding provides support for the hypothesis that younger genes have narrower functions and subsequently become more generalized over time.

CONCLUSIONS: Recently duplicated genes can mediate behavioral and ecological shifts, making them intricately linked to evolutionary processes such as adaptation and diversification. Chemoreception mediates fundamental behaviors in bumble bees like finding mates, selecting suitable nest sites, and foraging resources. Despite this, the molecular basis of bumble bee chemoreception, and the importance of each chemoreceptor family to bumble bee behavior and ecology, are still relatively uncharacterized. This study helps to characterize how chemoreception evolves in bumble bees and provides a foundation for understanding what tissues are important for bumble bee chemoreception.

PMID:40596844 | DOI:10.1186/s12864-025-11710-x

Comput Biol Med. 2025 Jun 30;196(Pt A):110632. doi: 10.1016/j.compbiomed.2025.110632. Online ahead of print.

ABSTRACT

The inference of gene regulatory networks (GRNs) is a fundamental challenge in systems biology, aiming to decipher gene interactions from expression data. However, traditional inference techniques exhibit disparities in their results and a clear preference for specific datasets. To address this issue, we present BIO-INSIGHT (Biologically Informed Optimizer - INtegrating Software to Infer GRNs by Holistic Thinking), a parallel asynchronous many-objective evolutionary algorithm that optimizes the consensus among multiple inference methods guided by biologically relevant objectives. BIO-INSIGHT has been evaluated on an academic benchmark of 106 GRNs, comparing its performance against MO-GENECI and other consensus strategies. The results show a statistically significant improvement in AUROC and AUPR, demonstrating that biologically guided optimization outperforms primarily mathematical approaches. Additionally, BIO-INSIGHT was applied to gene expression data from patients with fibromyalgia, myalgic encephalomyelitis, and co-diagnosis of both diseases. The inferred networks revealed regulatory interactions specific to each condition, suggesting its clinical utility in biomarker identification and potential therapeutic targets. The robustness and ingenuity of BIO-INSIGHT consolidate its potential as an innovative tool for GRN inference, enabling the generation of more accurate and biologically feasible networks. The source code is hosted in a public GitHub repository under the MIT license: https://github.com/AdrianSeguraOrtiz/BIO-INSIGHT. Moreover, to facilitate its reproducibility and usage, the software associated with this implementation has been packaged into a Python library available on PyPI: https://pypi.org/project/GENECI/3.0.1/.

PMID:40596788 | DOI:10.1016/j.compbiomed.2025.110632

Alzheimers Dement. 2025 Jul;21(7):e70362. doi: 10.1002/alz.70362.

ABSTRACT

INTRODUCTION: Artificial intelligence (AI) models have been applied to differential dementia detection tasks in brain images from curated, high-quality benchmark databases, but not real-world data in hospitals.

METHODS: We describe a deep learning model specially trained for disease detection in heterogeneous clinical images from electronic health records without focusing on confounding factors. It encodes up to 14 multimodal images, alongside age and demographics, and outputs the likelihood of vascular dementia, Alzheimer's, Lewy body dementia, Pick's disease, mild cognitive impairment, and unspecified dementia. We use data from Massachusetts General Hospital (183,018 images from 11,015 patients) for training and external data (125,493 images from 6,662 patients) for testing.

RESULTS: Performance ranged between 0.82 and 0.94 area under the curve (AUC) on data from 1003 sites.

DISCUSSION: Analysis shows that the model focused on subcortical brain structures as the basis for its decisions. By detecting biomarkers in real-world data, the presented techniques will help with clinical translation of disease detection AI.

HIGHLIGHTS: Our artificial intelligence (AI) model can detect neurodegenerative disorders in brain imaging electronic health record (EHR) data. It encodes up to 14 brain images and text information from a single patient's EHR. Attention maps show that the model focuses on subcortical brain structures. Performance ranged from 0.82 to 0.94 area under the curve (AUC) on data from 1003 external sites.

PMID:40596742 | DOI:10.1002/alz.70362

Sci Rep. 2025 Jul 1;15(1):20644. doi: 10.1038/s41598-025-05645-2.

ABSTRACT

Cancer-associated fibroblasts promote tumor progression through growth facilitation, invasion, and immune evasion. This study investigated the impact of activated cancer-associated fibroblasts (aCAFs) on survival outcomes, immune response, and molecular pathways in distal bile duct (DBD) cancer. We analyzed 469 patients (418 from our cohort and 51 from The Cancer Genome Atlas) with DBD adenocarcinoma. aCAFs were evaluated using hematoxylin and eosin staining. We developed a machine learning-based survival prediction model incorporating aCAFs and clinicopathologic parameters. Additionally, we performed differential gene expression analysis, Disease Ontology analysis, gene set enrichment analysis, and in vitro drug screening of aCAFs-related genes. The presence of aCAFs significantly correlated with poor survival, advanced T and N stages, infiltrative growth pattern, lymphatic/perineural/adjacent organ invasion, and decreased tumor-infiltrating lymphocytes. aCAFs-related genes were associated with immune system functions, G protein-coupled receptor signaling, and metabolic conditions (diabetes, obesity, and abnormal C-peptide levels). In machine learning-based survival models, aCAFs emerged as a strong discriminator for survival prediction. In vitro drug screening revealed that refametinib suppressed the growth of DBD carcinoma cells expressing high levels of fibroblast activation protein-α. In conclusion, integration of machine learning and systems biology analyses identifies aCAFs as potential biomarkers for risk stratification and therapeutic targeting in DBD cancer.

PMID:40596163 | DOI:10.1038/s41598-025-05645-2

Sci Rep. 2025 Jul 1;15(1):20891. doi: 10.1038/s41598-025-05105-x.

ABSTRACT

Numerous studies have demonstrated that long non-coding RNA (lncRNA) play critical roles in regulating physiological processes and contributing to pathological diseases. This study aimed to develop lncRNA-based signatures to predict the prognostic risk of gastric cancer (GC) patients and provide therapeutic guidance. Gene expression profiles and clinical information were obtained from The Cancer Genome Atlas (TCGA) database. Differentially expressed RNAs, including lncRNA, miRNA, and mRNA, in cancerous and adjacent non-cancerous tissues were analyzed using Weighted correlation network analysis (WGCNA) and construction of a lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) network. Then, a lncRNA-based risk model was constructed by Cox regression and Lasso regression analyses. A ceRNA network comprising 235 lncRNAs, 60 miRNAs, and 52 mRNAs was identified. Based on the expression of five lncRNAs (including AC010333.1, LINC01579, AP000695.2, LINC00922 and AL121772.1) screened from the ceRNA network, a lncRNA-based risk model was developed, which effectively predict the prognosis of GC patients. The expression of AP000695.2 was significantly associated with poor prognosis and higher T stage. The knockdown of AP000695.2 inhibited the growth of GC cells both in vitro and in vivo. Transfection with miR-144-3p and miR-7-5p mimics attenuate the up-regulation of targets genes, including CDH11, COL5A2, COL12A1, and VCAN, which was induced by AP000695.2, suggesting a ceRNA mechanism. Additionally, elevated VCAN expression was correlated with poorer survival and a reduced response to anti-PD-1 immune checkpoint inhibitor treatment of GC. This study established a lncRNA-based risk model for predicting the prognosis of GC patients and identified a ceRNA mechanism involving AP000695.2-miR-144-3p-VCAN, presenting novel biomarkers and therapeutic targets for GC treatment.

PMID:40595924 | DOI:10.1038/s41598-025-05105-x

Sci Rep. 2025 Jul 2;15(1):22886. doi: 10.1038/s41598-025-04277-w.

ABSTRACT

Cancer stem cells (CSCs) are present in small quantities in tumor populations. To permit various analyses of CSCs, we attempted to enrich and expand ornithine decarboxylase (ODC) degron-transduced colorectal cancer (CRC) cells, which retain low proteasome activity. ZsGreen fluorescence-positive (ZsGreen+) cells were collected by sorting the ODC degron-transduced HCT116, DLD1, and SW480 cells, which were defined as enriched ZsGreen+ cells. ZsGreen+ cells still maintained CSC properties. These cells had higher stem cell marker expression and increased resistance to chemotherapy with 5-fluorouracil and oxaliplatin. ZsGreen+ HCT116 and DLD1 cells had greater sphere-forming ability and enhanced tumorigenicity compared to ZsGreen- control cells. Time-lapse microscopy showed that a single enriched ZsGreen+ HCT116 cell had asymmetric cell division. Thus, cancer stem model cells were acquired in sufficient quantity. Using these cells, we performed a comprehensive microRNA analysis; miR-491-3p was a candidate to suppress cancer stemness. Finally, we found that up-regulated genes in the enriched HCT116 ZsGreen+ cells correlated with those up-regulated in human clinical spheroid samples established from patient-derived xenografts (PDXs) derived from CRC tissue samples, further supporting the acquisition of enriched model CSCs. These cells with the aid of clinical spheroid samples would be useful in identifying novel CSC markers and developing medicine for anti-CSC therapy.

PMID:40595888 | DOI:10.1038/s41598-025-04277-w