Search Results (2,770)

The core perturbome is defined as a central response to multiple disturbances, functioning as a complex molecular network to overcome the disruption of homeostasis under stress conditions, thereby promoting tolerance and survival under stress conditions. Based on the biological and clinical relevance of Escherichia coli and Staphylococcus aureus, we characterized their molecular responses to multiple perturbations. Gene expression data from E. coli (8815 target genes—based on a pangenome—across 132 samples) and S. aureus (3312 target genes across 156 samples) were used. Accordingly, this study aimed to identify and describe the functionality of the core perturbome of these two prokaryotic models using a machine learning approach. For this purpose, feature selection and classification algorithms (KNN, RF and SVM) were implemented to identify a subset of genes as core molecular signatures, distinguishing control and perturbation conditions. After verifying effective dimensional reduction (with median accuracies of 82.6% and 85.1% for E. coli and S. aureus, respectively), a model of molecular interactions and functional enrichment analyses was performed to characterize the selected genes. The core perturbome was composed of 55 genes (including nine hubs) for E. coli and 46 (eight hubs) for S. aureus. Well-defined interactomes were predicted for each model, which are jointly associated with enriched pathways, including energy and macromolecule metabolism, DNA/RNA and protein synthesis and degradation, transcription regulation, virulence factors, and other signaling processes. Taken together, these results may support the identification of potential therapeutic targets and biomarkers of stress responses in future studies. Full article

Chronic infection with the hepatitis B virus (HBV) results in over 1 million deaths annually. Although currently licensed treatments, including pegylated interferon-α and nucleoside/nucleotide analogs, can inhibit viral replication, they rarely eradicate covalently closed circular DNA (cccDNA) reservoirs. Moreover, vaccination does not offer therapeutic benefit to already infected individuals or non-responders. Consequently, chronic infection is maintained by the persistence of cccDNA in infected hepatocytes. For this reason, novel therapeutic strategies that permanently inactivate cccDNA are a priority. Obligate heterodimeric transcription activator-like effector nucleases (TALENs) provide the precise gene-editing needed to disable cccDNA. To develop this strategy using a therapeutically relevant approach, TALEN-encoding mRNA targeting viral core and surface genes was synthesized using in vitro transcription with co-transcriptional capping. TALENs reduced hepatitis B surface antigen (HBsAg) by 80% in a liver-derived mammalian cell culture model of infection. In a stringent HBV transgenic murine model, a single dose of hepatotropic lipid nanoparticle-encapsulated TALEN mRNA lowered HBsAg by 63% and reduced viral particle equivalents by more than 99%, without evidence of toxicity. A surveyor assay demonstrated mean in vivo HBV DNA mutation rates of approximately 16% and 15% for Core and Surface TALENs, respectively. This study presents the first evidence of the therapeutic potential of TALEN-encoding mRNA to inactivate HBV replication permanently. Full article

Background: Thyroid eye disease (TED) is a rare autoimmune orbital disorder predominantly associated with Graves’ disease. It is characterized by orbital inflammation, tissue remodeling, and potential visual morbidity. Conventional therapies, particularly systemic glucocorticoids, offer only partial symptomatic relief, failing to reverse chronic structural changes such as proptosis and diplopia, and are associated with substantial adverse effects. This review aims to synthesize recent developments in understandings of TED pathogenesis and to critically evaluate emerging therapeutic strategies. Methods: A systematic literature review was conducted using MEDLINE, Embase, and international clinical trial registries focusing on pivotal clinical trials and investigational therapies targeting core molecular pathways involved in TED. Results: Current evidence suggests that TED pathogenesis is primarily driven by the autoimmune activation of orbital fibroblasts (OFs) through thyrotropin receptor (TSH-R) and insulin-like growth factor-1 receptor (IGF-1R) signaling. Teprotumumab, a monoclonal IGF-1R inhibitor and the first therapy approved by the U.S. Food and Drug Administration for TED, has demonstrated substantial clinical benefit, including improvements in proptosis, diplopia, and quality of life. However, concerns remain regarding relapse rates and treatment-associated adverse events, particularly hearing impairment. Investigational therapies, including next-generation IGF-1R inhibitors, small-molecule antagonists, TSH-R inhibitors, neonatal Fc receptor (FcRn) blockers, cytokine-targeting agents, and gene-based interventions, are under development. These novel approaches aim to address both inflammatory and fibrotic components of TED. Conclusions: Teprotumumab has changed TED management but sustained control and toxicity reduction remain challenges. Future therapies should focus on targeted, mechanism-based, personalized approaches to improve long-term outcomes and patient quality of life. Full article

This study explores how aristolochic acid I (AAI) drives hepatocellular carcinoma (HCC). We first employ network toxicology and machine learning to map the key molecular target genes. Next, our research utilizes molecular docking to evaluate how AAI binds to these targets, and finally confirms the stability and dynamics of the resulting complexes through molecular dynamics simulations. We identified 193 overlapping target genes between AAI and HCC through databases such as PubChem, OMIM, and ChEMBL. Machine learning algorithms (SVM-RFE, random forest, and LASSO regression) were employed to screen 11 core genes. LASSO serves as a rapid dimension-reduction tool, SVM-RFE recursively eliminates the features with the smallest weights, and Random Forest achieves ensemble learning through decision trees. Protein–protein interaction networks were constructed using Cytoscape 3.9.1, and key genes were validated through GO and KEGG enrichment analyses, an immune infiltration analysis, a drug sensitivity analysis, and a survival analysis. Molecular-docking experiments showed that AAI binds to each of the core targets with a binding affinity stronger than −5 kcal mol⁻¹, and subsequent molecular dynamics simulations verified that these complexes remain stable over time. This study determined the potential molecular mechanisms underlying AAI-induced HCC and identified key genes (CYP1A2, ESR1, and AURKA) as potential therapeutic targets, providing valuable insights for developing targeted strategies to mitigate the health risks associated with AAI exposure. Full article

Freshwater salinization, an escalating global environmental stressor, poses a significant threat to freshwater biodiversity, including fish communities. This study investigates the grass carp (Ctenopharyngodon idellus), a species with the highest aquaculture output in China, to elucidate the molecular underpinnings of its physiological adaptations to fluctuating salinity gradients. We used high-throughput mRNA sequencing and differential gene expression profiling to analyze transcriptional dynamics in intestinal and kidney tissues of grass carp exposed to heterogeneous salinity stressors. Concurrent serum biochemical analyses showed salinity stress significantly increased Na⁺, Cl⁻, and osmolarity, while decreasing lactate and glucose. Salinity stress exerted a profound impact on the global transcriptomic landscape of grass carp. A substantial number of co-regulated differentially expressed genes (DEGs) in kidney and intestinal tissues were enriched in immune and metabolic pathways. Specifically, genes associated with antigen processing and presentation (e.g., cd4-1, calr3b) and apoptosis (e.g., caspase17, pik3ca) exhibited upregulated expression, whereas genes involved in gluconeogenesis/glycolysis (e.g., hk2, pck2) were downregulated. KEGG pathway enrichment analyses revealed that metabolic and cellular structural pathways were predominantly enriched in intestinal tissues, while kidney tissues showed preferential enrichment of immune and apoptotic pathways. Rigorous validation of RNA-seq data via qPCR confirmed the robustness and cross-platform consistency of the findings. This study investigated the core transcriptional and physiological mechanisms regulating grass carp’s response to salinity stress, providing a theoretical foundation for research into grass carp’s resistance to salinity stress and the development of salt-tolerant varieties. Full article

Background/Objectives: Enterococci, particularly Enterococcus faecalis and Enterococcus faecium, are Gram-positive cocci that can cause severe infections in hospitalized patients. The rise of vancomycin-resistant enterococci (VRE) and vancomycin-variable enterococci (VVE) poses significant challenges in healthcare settings due to their resistance to multiple antibiotics. Methods: We conducted a point prevalence survey (PPS) to assess the prevalence of VRE and VVE colonization in hospitalized patients. Rectal swabs were collected from 160 patients and analyzed using molecular assays (MAs) and culture. Whole-genome sequencing (WGS) and core-genome multilocus sequence typing (cgMLST) were performed to identify the genetic diversity. Results: Of the 160 rectal swabs collected, 54 (33.7%) tested positive for the vanA and/or vanB genes. Culture-based methods identified 47 positive samples (29.3%); of these, 44 isolates were identified as E. faecium and 3 as E. faecalis. Based on the resistance profiles, 35 isolates (74.5%) were classified as VRE, while 12 (25.5%) were classified as VVE. WGS and cgMLST analyses identified seven clusters of E. faecium, with sequence type (ST) 80 being the most prevalent. Various resistance genes and virulence factors were identified, and this study also highlighted intra- and inter-ward transmission of VRE strains. Conclusions: Our findings underscore the potential for virulence and resistance of both the VRE and VVE strains, and they highlight the importance of effective infection control measures to prevent their spread. VVE in particular should be carefully monitored as they often escape detection. Integrating molecular data with clinical information will hopefully enhance our ability to predict and prevent future VRE infections. Full article

Soil salinization is a major constraint to global crop productivity, highlighting the need to identify salt tolerance genes and their molecular mechanisms. Here, we integrated mRNA and miRNA profile analyses to investigate the molecular basis of salt tolerance of an elite Brassica napus cultivar S268. Time-course RNA-seq analysis revealed dynamic transcriptional reprogramming under 215 mM NaCl stress, with 212 core genes significantly enriched in organic acid degradation and glyoxylate/dicarboxylate metabolism pathways. Combined with weighted gene co-expression network analysis (WGCNA) and RT-qPCR validation, five candidate genes (WRKY6, WRKY70, NHX1, AVP1, and NAC072) were identified as the regulators of salt tolerance in rapeseed. Haplotype analysis based on association mapping showed that NAC072, ABI5, and NHX1 exhibited two major haplotypes that were significantly associated with salt tolerance variation under salt stress in rapeseed. Integrated miRNA-mRNA analysis and RT-qPCR identified three regulatory miRNA-mRNA pairs (bna-miR160a/BnaA03.BAG1, novel-miR-126/BnaA08.TPS9, and novel-miR-70/BnaA07.AHA1) that might be involved in S268 salt tolerance. These results provide novel insights into the post-transcriptional regulation of salt tolerance in B. napus, offering potential targets for genetic improvement. Full article

As typical environmental hormones, endocrine-disrupting chemicals (EDCs) have become a global environmental health issue of high concern due to their property of interfering with the endocrine systems of organisms. As a commonly used substitute for bisphenol A (BPA), bisphenol E (BPE) has been frequently detected in environmental matrices such as soil and water in recent years. Existing research has unveiled the developmental and reproductive toxicity of BPE; however, only one in vitro cellular experiment has preliminarily indicated potential neurotoxic risks, with its underlying mechanisms remaining largely unelucidated in the current literature. Potential toxic mechanisms and action targets of BPE were predicted using the zebrafish model via network toxicology and molecular docking, with RT-qPCRs being simultaneously applied to uncover neurotoxic effects and associated mechanisms of BPE. A significant decrease (p < 0.05) in the frequency of embryonic spontaneous movements was observed in zebrafish at exposure concentrations ≥ 0.01 mg/L. At 72 hpf and 144 hpf, the larval body length began to shorten significantly from 0.1 mg/L to 1 mg/L, respectively (p < 0.01), accompanied by a reduced neuronal fluorescence intensity and a shortened neural axon length (p < 0.01). By 144 hpf, the motor behavior in zebrafish larvae was inhibited. Through network toxicology and molecular docking, HSP90AB1 was identified as the core target, with the cGMP/PKG signaling pathway determined to be the primary route through which BPE induces neurotoxicity in zebrafish larvae. BPE induces neuronal apoptosis and disrupts neurodevelopment by inhibiting the cGMP/PKG signaling pathway, ultimately suppressing the larval motor behavior. To further validate the experimental outcomes, we measured the expression levels of genes associated with neurodevelopment (elavl3, mbp, gap43, syn2a), serotonergic synaptic signaling (5-ht1ar, 5-ht2ar), the cGMP/PKG pathway (nos3), and apoptosis (caspase-3, caspase-9). These results offer crucial theoretical underpinnings for evaluating the ecological risks of BPE and developing environmental management plans, as well as crucial evidence for a thorough comprehension of the toxic effects and mechanisms of BPE on neurodevelopment in zebrafish larvae. Full article

Honeybees (Apis mellifera) are pollinators for most crops in nature and a core species for the production of bee products. Body size and body weight are crucial breeding traits, as colonies possessing individuals with large body weight tend to be healthier and exhibit high productivity. In this study, small interfering RNA (siRNA) targeting 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) was incorporated into the feed for feeding worker bee larvae, thereby achieving the silencing of this gene’s expression. The research further analyzed the impact of the RNA expression level of the 15-PGDH gene on the juvenile hormone (JH) titer and its subsequent effects on the body weight and size of worker bees. The results show that inhibiting the expression of 15-PGDH in larvae could significantly increase JH titer, which in turn led to an increase in the body weight of worker bees (1.13-fold higher than that of the control group reared under normal conditions (CK group); p < 0.01; SE: 7.85) and a significant extension in femur (1.08-fold longer than that of the CK group; p < 0.01; SE: 0.18). This study confirms that 15-PGDH can serve as a molecular marker related to body weight and size in honey bees, providing an important basis for molecular marker-assisted selection in honey bee breeding. Full article

Triatoma pallidipennis, the main vector of Chagas disease in central Mexico, hosts a diverse and complex gut bacterial community shaped by environmental and physiological factors. To gain insight into these microbes’ dynamics, we characterised the gut bacterial communities of wild and insectary insects under different feeding and Trypanosoma cruzi infection conditions, using 16S rRNA gene sequencing. We identified 91 bacterial genera across 8 phyla, with Proteobacteria dominating most samples. Wild insects showed greater bacterial diversity, led by Acinetobacter and Pseudomonas, while insectary insects exhibited lower diversity and were dominated by Arsenophonus. The origin of the insects, whether they were reared in the insectary (laboratory) or collected from wild populations, was the principal factor structuring the gut microbiota, followed by feeding and T. cruzi infection. A stable core microbiota of 12 bacterial genera was present across all conditions, suggesting key functional roles in host physiology. Co-occurrence and functional enrichment analyses revealed that feeding and infection induced condition-specific microbial interactions and metabolic pathways. Our findings highlight the ecological plasticity of the triatomine gut microbiota and its potential role in modulating vector competence, providing a foundation for future microbiota-based control strategies. Full article

The tufted deer (Elaphodus cephalophus), a Near-Threatened (NT) species endemic to China and Myanmar, requires robust genetic data for effective conservation. However, the genetic landscape of key populations, such as those in Chongqing, remains poorly understood. This study aimed to comprehensively evaluate the genetic diversity, population structure, gene flow, and demographic history of tufted deer across this critical region. We analyzed mitochondrial DNA (mtDNA) from 46 non-invasively collected fecal samples from three distinct populations: Jinfo Mountain (JF, n = 13), Simian Mountain (SM, n = 21), and the Northeastern Mountainous region (NEM, n = 12). Genetic variation was assessed using the cytochrome b (Cyt b) and D-loop regions, with analyses including F_st, gene flow (N_m), neutrality tests, and Bayesian Skyline Plots (BSP). Our results revealed the highest genetic diversity in the SM population, establishing it as a genetic hub. In contrast, the JF population exhibited the lowest diversity and significant genetic differentiation (>0.23) from the SM and NEM populations, indicating profound isolation. Gene flow was substantial between SM and NEM but severely restricted for the JF population. Demographic analyses, including BSP, indicated a long history of demographic stability followed by a significant expansion beginning in the Middle to Late Pleistocene. We conclude that the SM/NEM metapopulation serves as the genetic core for the species in this region, while the highly isolated JF population constitutes a distinct and vulnerable Management Unit (MU). This historical demographic expansion is likely linked to climatic and environmental changes during the Pleistocene, rather than recent anthropogenic factors. These findings underscore the urgent need for a dual conservation strategy: targeted management for the isolated JF population and the establishment of ecological corridors to connect the Jinfo Mountain and Simian Mountain populations, ensuring the long-term persistence of this unique species. Full article

The gut microbiota plays an essential role in the host’s metabolism. Its composition and structure depend on biological and environmental factors. This work was designed to identify the composition and structure of the wild and captive red grouper (Epinephelus morio) microbiota and make predictions regarding its metabolic functions. Our hypothesis stated that wild and captive individuals would share the most abundant taxonomic groups, forming a core microbiota, and individuals in captivity might have exclusive taxonomic groups. Metagenomic DNA was extracted from the intestinal contents of wild and captive individuals. The 16S rRNA gene was amplified and sequenced using Illumina pair-end technology. QIIME2 pipeline was used for sequence analysis and alpha and beta diversity assessment. PICRUSt was used to infer metabolic functions. Twenty-nine phyla were identified; the most abundant were Pseudomonadota, Bacillota, Fusobacteriota, and Actinomycetota. The dominant genera were Photobacterium, Vibrio, Cetobacterium, and Escherichia-Shigella. The metabolic prediction analysis suggested that the Epinephelus morio gut microbiota is related to food digestion, the immune system, antioxidant enzymes, antibiotic resistance, and vitamin B12 transport. We concluded that the microbiota of E. morio established in captivity is sensitive to environmental changes such as water pollution, which can cause a decrease in diversity. Full article

Background/Objectives: An important new consideration when studying autism spectrum disorder (ASD) is the bioenergetic mechanisms underlying the relatively recent rapid evolutionary expansion of the human brain, which pose fundamental risks for mitochondrial dysfunction and calcium signaling abnormalities and their potential role in ASD, as recently highlighted by insights from the BTBR mouse model of ASD. The rapid brain expansion taking place as Homo sapiens evolved, particularly in the parietal lobe, led to increased energy demands, making the brain vulnerable to such metabolic disruptions as are seen in ASD. Methods: Mitochondrial dysfunction in ASD is characterized by impaired oxidative phosphorylation, elevated lactate and alanine levels, carnitine deficiency, abnormal reactive oxygen species (ROS), and altered calcium homeostasis. These dysfunctions are primarily functional, rather than being due to mitochondrial DNA mutations. Calcium signaling plays a crucial role in neuronal ATP production, with disruptions in inositol 1,4,5-trisphosphate receptor (ITPR)-mediated endoplasmic reticulum (ER) calcium release being observed in ASD patient-derived cells. Results: This impaired signaling affects the ER–mitochondrial calcium axis, leading to mitochondrial energy deficiency, particularly in high-energy regions of the developing brain. The BTBR mouse model, with its unique Itpr3 gene mutation, exhibits core autism-like behaviors and metabolic syndromes, providing valuable insights into ASD pathophysiology. Conclusions: Various interventions have been tested in BTBR mice, as in ASD, but none have directly targeted the Itpr3 mutation or its calcium signaling pathway. This review presents current genetic, biochemical, and neurological findings in ASD and its model systems, highlighting the need for further research into metabolic resilience and calcium signaling as potential diagnostic and therapeutic targets for ASD. Full article

Background: Despite distinct etiologies, type 1 diabetes (T1D) and type 2 diabetes (T2D) share chronic inflammation as a core feature. Interleukins, key immune mediators, play important yet still not fully understood roles in the development and complications of both conditions. Objective: This narrative review aims to provide a comprehensive and critical synthesis of current evidence on the role of key interleukins in T1D and T2D, highlighting their immunological functions, genetic associations, clinical correlations, and translational potential. Methods: A targeted literature search was conducted in PubMed, Google Scholar, and ScienceDirect up to January 2025, focusing on English-language clinical and experimental studies involving interleukins and their relevance to T1D and T2D. Reference lists were manually screened for additional sources. Interleukins (ILs) were reviewed individually to assess their immunobiology, disease specificity, and biomarker or therapeutic value. Findings: Pro-inflammatory cytokines such as IL-1β, IL-6, and IL-17 contribute to islet inflammation, insulin resistance, and microvascular damage in both T1D and T2D. Anti-inflammatory mediators including IL-4, IL-10, and IL-13 exhibit protective effects but vary in expression across disease stages. Less-characterized interleukins such as IL-3, IL-5, IL-9, and IL-27 demonstrate dual or context-dependent roles, particularly in shaping immune tolerance and tissue-specific complications such as nephropathy and neuropathy. Polymorphisms in IL-10 and IL-6 genes further suggest genetic contributions to interleukin dysregulation and metabolic dysfunction. Despite promising insights, translational gaps persist due to overreliance on preclinical models and limited longitudinal clinical data. Conclusions: Interleukins represent a mechanistic bridge linking immune dysregulation to metabolic derangements in both T1D and T2D. While their diagnostic and therapeutic potential is increasingly recognized, future research must address current limitations through isoform-specific targeting, context-aware interventions, and validation in large-scale, human cohorts. A unified interleukin-based framework may ultimately advance personalized strategies for diabetes prevention and treatment. Full article

This study describes the first complete genomic sequence of an NDM-19 and QnrS11-producing multidrug-resistant (MDR) Escherichia coli isolate collected from a fecal swab from a poultry farm in 2019 in Egypt. The bla_NDM-19 was identified by PCR screening and DNA sequencing. The isolate was then subjected to antimicrobial susceptibility testing, conjugation and transformation experiments, and complete genome sequencing. The chromosome of strain M2-13-1 measures 4,738,278 bp and encodes 4557 predicted genes, with an average G + C content of 50.8%. M2-13-1 is classified under ST167, serotype O101:H5, phylogroup A, and shows an MDR phenotype, having minimum inhibitory concentrations (MICs) of 64 mg/L for both meropenem and doripenem. The genes bla_NDM-19 and qnrS11 are present on 49,816 bp IncX3 and 113,285 bp IncFII: IncFIB plasmids, respectively. M2-13-1 harbors genes that impart resistance to sulfonamides (sul1), trimethoprim (dfrA14), β-lactams (bla_TEM-1B), aminoglycosides (aph(6)-Id, aph(3′)-Ia, aph(3″)-Ib, aac(3)-IV, and aph(4)-Ia), tetracycline (tet(A)), and chloramphenicol (floR). It was susceptible to aztreonam, colistin, fosfomycin, and tigecycline. The genetic context surrounding bla_NDM-19 includes ISAba125-IS5-bla_NDM-19-ble_MBL-trpF-hp1-hp2-IS26. Hierarchical clustering of the core genome MLST (HierCC) indicated M2-13-1 clusters with global ST167 E. coli lineages, showing HC levels of 100 (HC100) core genome allelic differences. Plasmids of the IncX3 group and the insertion sequence (ISAba125) are critical vehicles for the dissemination of bla_NDM and its related variants. To our knowledge, this is the first genomic report of a bla_NDM-19/IncX3-carrying E. coli isolate of animal origin globally. Full article