Search Results (2,569)

Hearing loss is often caused by genetic and environmental factors, with inherited mutations responsible for 50–60% of cases. The GJB2 gene, encoding connexin 26, is a major contributor to nonsyndromic sensorineural hearing loss (NSHL) due to its role in cellular communication critical for auditory function. In Taiwan, common deafness-associated genes include GJB2, SLC26A4, OTOF, MYO15A, and MTRNR1, which were similar to those found in other populations. The most common pathogenic genes is GJB2 mutations and the hearing level in children with GJB2 p.V37I/p.V37I or p.V37I/c.235delC was estimated to deteriorate at approximately 1 decibel hearing level (dB HL)/year. We found another common mutation in Taiwan Biobank, GJB2 p.I203T, which were identified in our data and individuals carrying this mutation experienced more severe hearing loss, suggesting a synergistic effect of these mutations on auditory impairment. We suggest GJB2 whole genetic screening is recommended for clinical management and prevention strategies in Taiwan. This study used data from the Taiwan Biobank to analyze allele frequencies of GJB2 gene variants. Predictive software (PolyPhen-2 version 2.2, SIFT for missense variants 6.2.1, MutationTaster Ensembl 112 and Alphamissense CC BY-NC-SA 4.0) assessed the pathogenicity of specific mutations. Additionally, 82 unrelated NSHL patients were screened for mutations in these genes using PCR and DNA sequencing. The study explored the correlation between genetic mutations and the severity of hearing loss in patients. Several common GJB2 mutation sites were identified from the Taiwan Biobank, including GJB2 p.V37I (7.7%), GJB2 p.I203T (6%), GJB2 p.V27I (31%), and GJB2 p.E114G (22%). Bioinformatics analysis classified GJB2 p.I203T as pathogenic, while GJB2 p.V27I and GJB2 p.E114G were considered polymorphisms. Patients with GJB2 p.I203T mutation experienced more severe hearing loss, emphasizing the potential interaction between the gene in auditory impairment. The mutation patterns of GJB2 in the Taiwanese population are similar to other East Asian regions. Although GJB2 mutations represent the predominant genetic cause of hereditary hearing loss, the corresponding mutant proteins exhibit detectable aggregation, particularly at cell–cell junctions, suggesting at least partial trafficking to the plasma membrane. Genetic screening for these mutations—especially GJB2 p.I203T (6%), GJB2 p.V27I (31%), and GJB2 p.E114G (22%)—is essential for the effective diagnosis and management of non-syndromic hearing loss (NSHL) in Taiwan. We found GJB2 p.I203T which were identified in our data and individuals carrying this mutation experienced more severe hearing loss, suggesting a synergistic effect of these mutations on auditory impairment. We suggest whole GJB2 gene sequencing in genetic screening is recommended for clinical management and prevention strategies in Taiwan. These findings have significant clinical and public health implications for the development of preventive and therapeutic strategies. Full article

Worldwide, 13.3% of food was wasted in 2020. Ethylene biosynthesis, responsible for fruit ripening, regulates key processes in plant growth and aging. Aptamers are DNA or RNA molecules with the capacity to bind with high affinity and specificity to proteins due to their three-dimensional structure. Therefore, conventional aptamer selection methods are often costly, inefficient, and time-consuming. In this context, in silico molecular docking offers an efficient alternative, enabling the evaluation of binding potential prior to experimental assays. This research identified aptamers with high predicted affinity for the 1-aminocyclopropane-1-carboxylate synthase (ACC synthase) and 1-aminocyclopropane-1-carboxylate oxidase (ACC oxidase) enzymes, essential in ethylene biosynthesis. Using ZDOCK for preliminary screening and HDOCK for refined analysis, aptamer-enzyme interactions were modeled. Aptamers AB451 and ABR6P.1 showed promising binding to ACC synthase, while RO33828 and O0O6O1 were optimal for ACC oxidase. These results represent a computational foundation for the development of aptamer-based inhibitors to potentially delay ripening and reduce postharvest losses. Experimental validation will be required to confirm their inhibitory function. Full article

With the recent development of accurate protein structure prediction tools, virtually all protein sequences now have an experimental or a modeled structure. It has therefore become essential to develop fast algorithms capable of detecting non-covalent interactions not only within proteins but also in protein-protein, protein-DNA, protein-RNA, and protein-ligand complexes. Interactions involving aromatic compounds, particularly their $\pi$ molecular orbitals, hold unique significance among molecular interactions due to the electron delocalization, which is known to play a key role in processes such as protein aggregation. In this paper, we present PInteract, an algorithm that detects $\pi$-involving interactions in input structures based on geometric criteria, including $\pi$-$\pi$, cation-$\pi$, amino-$\pi$, His-$\pi$, and sulfur-$\pi$ interactions. In addition, it is capable of detecting chains and clusters of $\pi$ interactions as well as particular recurrent motifs at protein-DNA and protein-RNA interfaces, called stair motifs, consisting of a particular combination of $\pi$-$\pi$ stacking, cation/amino/His-$\pi$ and H-bond interactions. Full article

The rapid development of the nuclear industry and mining has increased environmental radioactive contamination, posing potentially ecological risks and health threats to humans. Uranium compounds are known to exhibit selective nephrotoxicity, but their toxicological processes and mechanisms still remain poorly understood and controversial. In this study, the uranyl-induced toxicity in human renal tubular epithelial cells (HK-2) were explored using flow cytometry, DAPI staining, and comet assays. Our results demonstrate that uranium exposure primarily triggers apoptosis. Kyoto Encyclopedia of Genes and Genomes pathway enrichment and protein–protein interaction (PPI) analyses revealed significant associations with DNA damage. Moreover, aberrant expression of ABC transporters (e.g., ABCB7) and mitochondrial-related proteins confirms uranium-induced mitochondrial dysfunction. Gene Ontology functional annotation implicated extrinsic apoptotic signaling pathways in uranium-induced cell death. The downregulation of the UBL5 protein also pointed to endoplasmic reticulum stress-mediated apoptosis. In summary, uranium exposure can induce the apoptosis of HK-2 cells through intrinsic pathways by damaging DNA and mitochondria and disrupting protein synthesis, with secondary contributions from endoplasmic reticulum stress and extrinsic apoptotic signaling. Full article

Integrase is a key protein during HIV-1 replication as it catalyzes the integration of viral DNA into the host DNA. After several decades of research, highly potent and selective active site inhibitors have emerged. The new challenge is now to develop molecules with an original mode of action, targeting integrase out of its catalytic site. During a previous study, we developed an in vitro assay to monitor the interaction between HIV-1 integrase and one of its cellular partners, GCN2. This AlphaLISA-based assay was validated as a platform for chemical modulator screening. In the present study, we used a library of natural products from the Developmental Therapeutics Program (NIH) to identify novel chemical leads. The best modulators were characterized and a structure–activity relationship study was initiated with a limited number of derivatives. We found that most inhibitors were tricylic or tetraclyclic molecules, with the most potent belonging to the anthracyclines/anthraquinones. Of note, several molecules exhibited interesting cellular activities and may be suitable for further optimization. Full article

PR/SET domain 2 (PRDM2)/RIZ is a member of the histone/protein methyltransferases (PRDMs) superfamily. Discovered to have the ability to bind retinoblastoma in the mid-1990s, PRDM2 was assumed to play a role in neuronal development. Like other family members characterized by a conserved N-terminal PR structural domain and a classical C2H2 zinc-finger array at the C-terminus, PRDM2 encodes two major protein types, the RIZ1 and RIZ2 isoforms. The two subtypes differ in the presence or absence of the PR domain: the RIZ1 subtype has the PR domain, whereas the RIZ2 subtype lacks it. The PR domain exhibits varying conservation levels across species and shares structural and functional similarities with the catalytic SET domain, defining histone methyltransferases. Functioning as an SET domain, the PR domain possesses protein-binding interfaces and acts as a lysine methyltransferase. The variable number of classic C2H2 zinc fingers at the C-terminus may mediate protein–protein, protein–RNA, or protein–DNA interactions. An imbalance in the RIZ1/RIZ2 mechanism may be an essential cause of malignant tumors, where PR-positive isoforms are usually lost or downregulated. Conversely, PR-negative isoforms are always present at higher levels in cancer cells. RIZ1 isoforms are also important targets for estradiol interaction with hormone receptors. PRDM2 can regulate gene transcription and expression combined with transcription factors and plays a role in the development of several systemic diseases through mRNA expression deletion, code-shift mutation, chromosomal deletion, and missense mutation occurrence. Thus, PRDM2 is a key indicator for disease diagnosis, but it lacks systematic summaries to serve as a reference for study. Therefore, this paper describes the structure and biological function of PRDM2 from the perspective of its role in various systemic diseases. It also organizes and categorizes its latest research progress to provide a systematic theoretical basis for a more in-depth investigation of the molecular mechanism of PRDM2’s involvement in disease progression and clinical practice. Full article

COVID affects around 400 million individuals today with a strong economic impact on the global economy. The list of long COVID symptoms is extremely broad because it is derived from neurological, cardiovascular, respiratory, immune, and renal dysfunctions and damages. We review here these pathophysiological manifestations and the predictors of this multi-organ pathology like the persistence of the virus, altered endothelial function, unrepaired tissue damage, immune dysregulation, and gut dysbiosis. We also discuss the similarities between long COVID and vaccine side effects together with possible common immuno-inflammatory pathways. Since the spike protein is present in SARS-CoV-2 (and its variants) but also produced by the COVID vaccines, its toxicity may also apply to all mRNA or adenoviral DNA vaccines as they are based on the production of a very similar spike protein to the virus. After COVID infection or vaccination, the spike protein can last for months in the body and may interact with ACE2 receptors and mannan-binding lectin (MBL)/mannan-binding lectin serine protease 2 (MASP-2), which are present almost everywhere in the organism. As a result, the spike protein may be able to trigger inflammation in a lot of organs and systems similar to COVID infection. We suggest that three immuno-inflammatory pathways are particularly key and responsible for long COVID and COVID vaccine side effects, as it has been shown for COVID, which may explain in large part their strong similarities: the renin–angiotensin–aldosterone system (RAAS), the kininogen–kinin–kallikrein system (KKS), and the lectin complement pathway. We propose that therapeutic studies should focus on these pathways to propose better cures for both long COVID as well as for COVID vaccine side effects. Full article

Knots are ubiquitous in polymers and biological macromolecules such as DNA and proteins, yet their behavior and functionality are still not sufficiently explored. Here we investigate the impact of Poiseuille flow on simple knots in flexible polymers placed in a quasi-rectangular micro-channel by systematically varying the flow strength for different chain lengths. Hydrodynamic interactions are accounted for by means of Multi-Particle Collision Dynamics (MPCD). We find that initially loosely localized knots in polymer coils typically tighten under shear to several segments beyond a certain body force threshold. At higher shear rates, intermittent transition from chain stretching to tumbling is observed which correlates with strong fluctuations in the knot size. Somewhat unexpectedly, our results indicate that the influence of channel width on tightening steadily increases with growing width even at equal mean shear rate $\overline{\dot{\gamma }}$. Full article

Dental caries is now recognised as a multifactorial disease shaped by complex interactions among genetic, epigenetic, microbiological, environmental, and social factors. This narrative review synthesises recent findings on the influence of genetic and epigenetic factors on caries susceptibility, exploring implications for personalised prevention strategies, including novel vaccine approaches. Numerous gene polymorphisms in pathways related to enamel formation, saliva composition, immune response, and taste perception have been linked to increased caries risk, with some effects modulated by sex and tooth-specific factors. Early-life environmental exposures (diet, tobacco, and antibiotic use) have been demonstrated to further alter risk through epigenetic modifications such as DNA methylation, microRNA regulation, and histone changes. The recognition of this landscape of inherited and acquired vulnerabilities has given rise to interest in innovative preventive measures. In particular, anti-caries vaccines targeting Streptococcus mutans are being developed using protein subunits, DNA constructs, and even plant-based antigen production. Notwithstanding the challenges that still need to be overcome—chiefly the achievement of robust mucosal immunity, the assurance of safety, and the enhancement of production—these vaccines are proving to be a promising addition to traditional oral hygiene and fluoride measures. The integration of genetic and epigenetic insights with immunological advances has the potential to facilitate the development of more effective, personalised interventions to prevent dental caries. Full article

Oxidative stress plays a central role in numerous conditions, including cancer, cardiovascular and neurodegenerative diseases, diabetes, chronic inflammation, and organ transplantation. In transplantation, oxidative stress leads to mitochondrial dysfunction, DNA and protein damage, lipid peroxidation, and activation of pro-inflammatory pathways such as NF-κB, ultimately impairing cell viability and organ function. A Kinase-Interacting Protein 1 (AKIP1) has been linked to oxidative stress regulation in transgenic mouse models. To investigate this further in a livestock setting, we generated AKIP1 transgenic pigs and assessed AKIP1’s protective role against oxidative-stress-induced cell death, including apoptosis, necrosis, and ferroptosis in vitro. Our cellular analyses revealed reduced apoptosis (caspase-3/7 activity), suppressed MPTP-mediated necrosis, and decreased lipid peroxidation, suggesting protection from ferroptosis. Additionally, we observed lower mitochondrial superoxide production and enhanced mitochondrial respiration and recovery following H₂O₂-induced oxidative challenge. This is the first study to examine AKIP1 in porcine cells, providing a unique and translational platform for studying oxidative injury in a physiologically relevant species. Our in vitro data reveal that AKIP1 overexpression enhances antioxidant defenses and mitochondrial stability, offering future potential for improving graft survival in xenotransplantation. Full article

In response to abiotic stress, plants utilize hub protein-mediated signaling networks, with members of the SIMILAR TO RCD ONE (SRO) protein family playing a pivotal role in regulating stress resistance pathways. This study investigates the functional role of the soybean GmRCD1 protein and its interaction mechanisms to elucidate its molecular regulatory network in stress resistance responses. By employing yeast two-hybrid technology to screen a soybean cDNA library under high-salt stress conditions, 17 potential interacting proteins were identified, which include NAC transcription factors (e.g., GmNAC058), ubiquitin–proteasome proteins, and ribosomal proteins. Subsequent validation using GST pull-down and bimolecular fluorescence complementation assays confirmed the direct interaction between GmRCD1 and GmNAC058, which is mediated by the RST domain of GmRCD1 and the C-terminal disordered region (amino acids 288–323) of GmNAC058. Subcellular localization studies revealed that both proteins are nuclear-localized, aligning with their roles in transcriptional regulation. Furthermore, PAR binding assays demonstrated that both GmRCD1 and AtRCD1 can bind to PAR polymers; however, PARP activity analysis revealed that neither protein exhibits catalytic activity, indicating their participation in stress responses via non-enzymatic mechanisms. This study represents the first to elucidate the interaction network and structural basis between soybean GmRCD1 and GmNAC058, providing crucial theoretical support for understanding the multifunctional roles of plant hub proteins in stress resistance regulation and for molecular breeding in soybean. Full article

Bacteriophages of the order Crassvirales are highly abundant and near-universal members of the human gut microbiome worldwide. Zeta crAss-like phages comprise a separate group in the order Crassvirales, and their genomes exhibit greater variability than genomes of crAss-like phages from other families within the order. Zeta crAss-like phages employ multiple adaptation mechanisms, ensuring their survival despite host defenses and environmental pressure. Some Zeta crAss-like phages use alternative genetic coding and exploit diversity-generating retroelements (DGRs). These features suggest complex evolutionary relationships with their bacterial hosts, sustaining parasitic coexistence. Mutations in tail fiber proteins introduced by DGR can contribute to their adaptation to changes in the host cell surface and even expand the range of their hosts. In addition, the exchange of DNA polymerases via recombination makes it possible to overcome the bacterial anti-phage protection directed at these enzymes. Zeta crAss-like phages continuously adapt due to genetic diversification, host interaction tweaks, and counter-defense innovations, driving an evolutionary arms race with hosts. Based on the genome characteristics of the Zeta crAss-like phages, we propose to separate them into the Echekviridae family (“эчәк”—“intestines” in Tatar) following the tradition of using the word “intestines” in different languages, suggested previously. Full article

Tooth development (odontogenesis) is regulated by interactions between epithelial and mesenchymal tissues through signaling pathways such as Bone Morphogenetic Protein (BMP), Wingless-related integration site (Wnt), Sonic Hedgehog (SHH), and Fibroblast Growth Factor (FGF). Mesenchymal stem cells (MSCs) derived from dental tissues—including dental pulp stem cells (DPSCs), periodontal ligament stem cells (PDLSCs), and dental follicle progenitor cells (DFPCs)—show promise for regenerative dentistry due to their multilineage differentiation potential. Epigenetic regulation, particularly DNA methylation, is hypothesized to underpin their distinct regenerative capacities. This study reanalyzed publicly available DNA methylation data generated with Illumina Infinium HumanMethylation450 BeadChip arrays (450K arrays) from DPSCs, PDLSCs, and DFPCs. High-confidence CpG sites were selected based on detection p-values, probe variance, and genomic annotation. Principal Component Analysis (PCA) and hierarchical clustering identified distinct methylation profiles. Functional enrichment analyses highlighted biological processes and pathways associated with specific methylation clusters. Noncoding RNA analysis was integrated to construct regulatory networks linking DNA methylation patterns with key developmental genes. Distinct epigenetic signatures were identified for DPSCs, PDLSCs, and DFPCs, characterized by differential methylation across specific genomic contexts. Functional enrichment revealed pathways involved in odontogenesis, osteogenesis, and neurodevelopment. Network analysis identified central regulatory nodes—including genes, such as PAX6, FOXC2, NR2F2, SALL1, BMP7, and JAG1—highlighting their roles in tooth development. Several noncoding RNAs were also identified, sharing promoter methylation patterns with developmental genes and being implicated in regulatory networks associated with stem cell differentiation and tissue-specific function. Altogether, DNA methylation profiling revealed that distinct epigenetic landscapes underlie the developmental identity and differentiation potential of dental-derived mesenchymal stem cells. This integrative analysis highlights the relevance of noncoding RNAs and regulatory networks, suggesting novel biomarkers and potential therapeutic targets in regenerative dentistry and orthodontics. Full article

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

Background/Objectives: The breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene whose mutations are associated with increased susceptibility to develop breast or ovarian cancer. BRCA1 mainly exerts its protective effects through DNA double-strand break repair. Although not itself a transcriptional factor, BRCA1, through its multiple protein interaction domains, exerts transcriptional coregulation. In addition, BRCA1 expression alters cellular metabolism including inhibition of de novo fatty acid synthesis, changes in cellular bioenergetics, and activation of antioxidant defenses. Some of these actions may contribute to its global oncosuppressive effects. However, the breadth of metabolic pathways reprogrammed by BRCA1 is not fully elucidated. Methods: Breast cancer cells expressing BRCA1 were investigated by multiplatform metabolomics, metabolism-related transcriptomics, and joint metabolomics/transcriptomics data processing techniques, namely two-way orthogonal partial least squares and pathway analysis. Results: Joint analyses revealed the most important metabolites, genes, and pathways of metabolic reprogramming in BRCA1-expressing breast cancer cells. The breadth of metabolic reprogramming included fatty acid synthesis, bioenergetics, HIF-1 signaling pathway, antioxidation, nucleic acid synthesis, and other pathways. Among them, rewiring of glycerophospholipid (including phosphatidylcholine, -serine and -inositol) metabolism and increased arginine metabolism have not been reported yet. Conclusions: Rewired glycerophospholipid and arginine metabolism were identified as components of BRCA1-induced metabolic reprogramming in breast cancer cells. The study helps to identify metabolites that are candidate biomarkers of the BRCA1 genotype and metabolic pathways that can be exploited in targeted therapies. Full article