Search Results (9,906)

Human adenovirus (HAdV), a double-stranded DNA virus, targets terminally differentiated cells in the upper respiratory tract. As a key platform for gene therapy vectors, elucidating HAdV’s virulence factors is vital for optimizing therapeutic applications and mitigating risks. To achieve productive replication, HAdV strategically neutralizes host immune defenses and induces S-phase pathways essential for viral propagation. This review synthesizes the latest insights into the key pathways through which HAdVs harness these early proteins to enhance virulence, skilfully evading and counteracting host defense mechanisms while propelling viral replication. As foundational platforms for gene therapy vectors (e.g., in oncology and rare disease treatments) and vaccine backbones (e.g., COVID-19 vaccines like ChAdOx1), understanding HAdV’s immunoshadowing—the multifaceted strategies used to cloak innate and adaptive immunity—is crucial for enhancing vector safety and efficacy. Recent insights unveil how early viral proteins—including E1A, E1B-55K, E4orf1, E4orf3, E4orf6, and the E3 complex—participate in these processes. This review critically synthesizes these pathways, evaluating study limitations such as reliance on immortalized cell lines that underestimate the role of these proteins in immunological competent cells, and addresses unresolved controversies, including differential immunoshadowing efficacy across HAdV species that impacts vaccine design. Full article

Elastic fibers are key components of the skin extracellular matrix and are essential for maintaining skin integrity and elasticity. During skin aging, particularly photoaging, elastic fiber integrity is progressively compromised by increased elastase activity and the downregulation of elastin and scaffold-related gene expression. Therefore, effective strategies to preserve elastic fiber function should address not only elastin synthesis but also enzymatic degradation and scaffold integrity. In this study, we investigated a multitarget approach to restoring the elastic fiber network by modulating elastin production, elastase activity, and scaffold protein expression. We found that Copper Tripeptide-1 enhanced elastin expression and secretion, ethyl ferulate inhibited elastase activity, and cedrol promoted scaffold-related gene expression and microfibrillar protein restoration in dermal fibroblasts. To assess the biological relevance of this approach, the combined treatment was evaluated using UV-damaged human skin biopsy samples. This combination effectively mitigated UV-induced elastic fiber disruption and significantly improved fiber architecture, as confirmed by immunofluorescence staining and scanning electron microscopy. These findings indicate that coordinated modulation of elastin production, proteolytic protection, and scaffold reinforcement is essential for maintaining elastic fiber integrity and represents a promising approach for preserving skin elasticity during aging. Full article

The hERG potassium channel is critical for cardiac ventricular repolarization and a core target in pre-clinical drug safety screening. A robust, stable cell line with uniform, high hERG expression is essential for high-throughput assessments. In this study, we established a functional stable HEK293T cell line with high hERG expression. The hERG gene was subcloned into Lenti-HA-hERG-P2A-EGFP plasmid, in which GFP serves as a selection marker via a P2A self-cleaving peptide. GFP-positive monoclonal cells were isolated by fluorescence-activated cell sorting (FACS). Confocal imaging confirmed that hERG localized predominantly to the cell membrane, consistent with its physiological role. Manual patch-clamp revealed canonical hERG current properties: a small, stable current during depolarization to 20 mV, followed by a large outward tail current upon repolarization to −40 mV-a hallmark of hERG channel gating. Automated patch-clamp (APC)-based current profiling showed 93.5% of stable hERG cells exhibited peak tail currents >50 pA (87% > 100 pA, with 49.5% > 400 pA), whereas 100% of blank HEK293T cells showed peak tail currents < 50 pA. Pharmacological validation with E-4031 demonstrated concentration-dependent inhibition of hERG currents, with an IC₅₀ of 29.8 nM, which is consistent with literature-reported values. The stable hERG-expressing HEK293T cell line developed here exhibits consistent hERG expression, canonical channel function, and physiological sensitivity to hERG blockers. When paired with high-throughput APC systems, this cell model provides a robust, standardized platform for pre-clinical drug-induced hERG inhibition evaluation, aiding early detection of long QT syndrome risks and safer drug development. Full article

Background/Objectives: Regulated cell death (RCD), a process that relies on a series of molecular mechanisms, can be targeted to eliminate superfluous, irreversibly damaged, and potentially harmful cells. In this research, we want to better understand how the cell death pathway contributes to cancer therapy. Methods: We studied 1150 cancer cells in the Dependency Map (DepMap) database for 12 distinct cell death pathways and assessed their gene essentialities. Genes which are essential in 90% or more of cancer cell lines are called always essential, or partial essential if falling into (10%, 90%), or rare essential if they are essential in less than 10% of cancer cell lines. Results: Overall, among these 12 cell death pathways, 23, 47, and 549 genes were classified as always essential, partial essential, and rare essential, respectively. In two cell death pathways, Parthanatos, and Pyroptosis, all genes were rare essential. Among the other ten cell death pathways, Apoptosis, Autosis, Necroptosis, Efferocytosis, Ferroptosis, Mitotic cell death, Autophagy, Lysosome-dependent cell death, MPT-driven necrosis and Immunogenic, there are (10, 1, 13, 6, 3, 9, 11, 1, 1, 0) partial essential genes, and (2, 0, 3, 1, 1, 13, 4, 0, 0, 1) always essential genes. Conclusions: These cell death pathway essential genes could be viable targets for therapeutic drug development for cancer therapies. Full article

The development of rice flowers and panicles critically affects grain yield and quality. LEAFY HULL STERILE1/OsMADS1, a grass-specific SEPALLATA-like MADS-box transcription factor, is essential for rice floral development and floral meristem activity maintenance. However, the mechanism through which OsMADS1 interacts with other genes to regulate floral organ identity and meristem determinacy remains unclear. In this study, we first generated OsMADS1 knockout mutants using CRISPR/Cas9. The mutant florets exhibited obvious morphological defects, which were categorized into five phenotypic classes. Yeast two-hybrid screening identified two OsMADS1-interacting proteins: OsMADS22, an STMADS11-like protein, and OsYABBY5, a YABBY transcription factor. Their physical interactions were validated both in vitro and in vivo, and were important for floral organ specification and meristem maintenance. Transcriptomic analysis revealed that OsMADS1 regulates numerous genes involved in hormone signaling and panicle/flower development. Furthermore, OsMADS1 acts together with OsMADS22 and OsYABBY5 to modulate the expression of the downstream target OsMADS55, thereby controlling rice spikelet development. Together, our results reveal that OsMADS1 executes diverse regulatory functions in floral organ specification and meristem identity by interacting with multiple developmental regulators, providing new insights into the molecular mechanisms of plant flower development. Full article

Apoptosis, or programmed cell death, is a fundamental process essential for tissue homeostasis, development, and the elimination of damaged or potentially cancerous cells. Here, we identify the E3/E4 ubiquitin ligase UBE4B as a critical suppressor of apoptosis in p53-proficient tumor cells, functioning through a previously uncharacterized dual mechanism. Initially, an orthogonal ubiquitin transfer screening approach identified CCAR2 as a UBE4B substrate. We demonstrate that UBE4B interacts with and ubiquitinates CCAR2, promoting its proteasomal degradation. Furthermore, we found that UBE4B concurrently targets p53 itself for ubiquitin-dependent degradation. Functionally, UBE4B overexpression suppresses apoptosis, whereas rescue experiments indicate that restoring p53 expression reverses this suppression more effectively than restoring CCAR2, highlighting the dominance of the direct p53 degradation pathway. Mechanistically, UBE4B deficiency leads to CCAR2 accumulation, which inhibits SIRT1 activity, thereby enhancing p53 acetylation and stability; this effect is reversed upon CCAR2 co-depletion. Consistently, transcriptional profiling confirms that UBE4B downregulates key p53 target genes (e.g., BAX, PUMA) through this dual-pathway regulation. In summary, our study establishes that UBE4B acts as a key apoptosis suppressor by coordinately degrading both p53 and its positive regulator CCAR2, revealing a targetable vulnerability in p53-wild-type tumors. Full article

Deoxynivalenol (DON), a Group III carcinogenic mycotoxin frequently detected in cereals and animal-derived food products, poses serious health risks to animals and humans. In this study, we developed a genetically engineered Saccharomyces cerevisiae strain as a proof-of-concept platform for DON detoxification. The yeast was engineered to co-express two detoxification genes, YTDepA and YTDepB (homologs of DepA and DepB from Devosia mutans 17-2-E-8) originally identified in Youhaiella tibetensis. Concurrently, the pyrroloquinoline quinone (PQQ) biosynthesis gene cluster from Klebsiella pneumoniae was integrated to supply the essential cofactor. Gene expression was verified by qRT-PCR and Western blot. The recombinant strain demonstrated a significant 13.98% detoxification of DON after 72 h of fermentation (p < 0.05), as confirmed by HPLC–MS, while the strain expressing only the PQQ cluster showed no detoxification activity. This study establishes an integrated yeast cell factory for DON detoxification and highlights key limitations to guide future optimization efforts. Full article

Fusarium oxysporum f. sp. lycopersici (FOL) is one of the most destructive soil-borne pathogens affecting tomato production worldwide, causing substantial yield losses and persisting in soil for extended periods. The increasing regulatory restrictions on chemical fungicides and the emergence of resistant pathogen strains have intensified the search for sustainable and environmentally friendly alternatives. This systematic review synthesizes studies published between 2000 and 2025 that evaluated the antifungal efficacy of essential oils (EOs), their bioactive constituents, and EO-based nanoformulations against FOL in tomato. A total of 40 studies were included, following the PRISMA 2020 guidelines, encompassing in vitro, greenhouse, and limited field evaluations. Many EOs rich in phenolic compounds and oxygenated monoterpenes, such as thymol, carvacrol, eugenol, citral, and menthol, consistently inhibited FOL growth and spore germination, with reported mycelial growth inhibition ranging from 60 to 100% and minimum inhibitory concentrations (MICs) between 0.05 and 1.5 µL ml⁻¹. However, the use of EOs is often limited because they evaporate quickly, do not mix well with water, can harm plants, and do not persist under field conditions. Nano-delivery systems, including nanoemulsions, polymeric nanoparticles, chitosan-based carriers, and lipid-based nanostructures, have been shown to enhance the stability, bioavailability, and antifungal efficacy of EOs. This has led to improved disease management and reduced pesticide application rates. In addition, several EO-based treatments have been reported to activate plant defense responses, including the induction of defense-related genes, antioxidant enzymes, and epigenetic modifications. Overall, EO-based nanoformulations show promise as next-generation biopesticides for the sustainable management of tomato Fusarium wilt. Nevertheless, large-scale field validation, standardized formulation protocols, and regulatory assessments are required before these technologies can be widely implemented in agriculture. Full article

Juniperus communis is the juniper with the widest geographical distribution, owing to its high ecological valence. Nevertheless, there is only a limited number of studies of its phenotypic and molecular variability. In this study, we coupled leaf essential oil (EO) composition with molecular and environmental data to better understand this species’ distribution and variability in the central Balkans. EOs were obtained by simultaneous hydrodistillation and extraction, and analysed using GC coupled with MS and FID detectors. For molecular analysis, inter-simple sequence repeats (ISSR) using five primers were analysed. Three chemotypes were most abundant in the study area: sabinene, an intermediate chemotype, and α-pinene. Several additional chemotypes were also identified. In total, 118 compounds present above 0.05% were detected and identified. Monoterpene hydrocarbons dominated the EO composition (43.8–79.1%). Multivariate analyses showed separation of populations from north to south. ISSRs yielded 78 polymorphic bands. Three genetic pools could also be identified that roughly correspond to this distribution, though data is not completely congruent with chemophenetic. Results indicate high genetic diversity, with high gene flow between populations, but also certain differentiation of populations. Full article

Antimicrobial resistance (AMR) represents a global health crisis, driven largely by the mobility of resistance determinants through mobile genetic elements (MGEs). These include plasmids, integrons, insertion sequences, transposons, integrative and conjugative elements (ICEs), and prophages, which together facilitate horizontal gene transfer (HGT) across bacterial species and ecosystems. This review aims to provide a comprehensive synthesis of current knowledge on the types, mechanisms, ecological drivers, and impacts of MGEs in the dissemination of antibiotic resistance genes (ARGs). Methods involved critical evaluation of recent genomic, epidemiological, and ecological studies, alongside case studies of clinically significant resistance outbreaks. Findings highlight how MGEs function as hubs for ARG capture, recombination, and stabilization, enabling the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) pathogens. We also explored their interactions with ecological pressures such as antibiotics, heavy metals, and biocides, as well as their role in One Health transmission pathways. The significance of this study lies in linking molecular insights with applied strategies, including genomic surveillance, MGE-targeted inhibitors, phage therapy, and CRISPR-based interventions. Understanding MGEs is essential for designing effective interventions to mitigate AMR and protect global health. Full article

Background/Objectives: Essential oils (EOs) have multi-target antifungal activity, but their translation is limited by volatility and poor aqueous dispersibility. Randomly methylated β-cyclodextrin (RAMEB) inclusion may enhance effective exposure and thereby alter susceptibility, stress responses, and biofilm outcomes in a species-dependent manner. This study quantified species-specific planktonic and biofilm susceptibility to four EOs and their RAMEB complexes across clinically relevant Candida species. Methods: Lavender (L), lemon balm (B), peppermint (P), and thyme (T) oils and their RAMEB complexes (RL, RB, RP, and RT) were tested against C. albicans and non-albicans Candida. Susceptibility thresholds were used to derive phase plasticity metrics. Functional inhibition was assessed via planktonic metabolism/viability and established biofilm metabolism/viability/biomass. Mechanistic signatures were captured by ROS/RNS measurements and a qPCR analysis of antioxidant genes (CAT1, GPX1, and SOD1) was performed. Mixed-effects models and multivariate/unsupervised and interpretable classification approaches (k-means, PCA, and CRT) were used to integrate endpoints and stratify response phenotypes. Results: Susceptibility thresholds were strongly species-structured (lowest MIC₉₀/EC₁₀ for C. albicans; higher thresholds and broader sublethal windows in non-albicans species). RAMEB complexation produced formulation-dependent shifts in efficacy, with RT emerging as the most consistent broad-spectrum inhibitory condition across compartments. Biofilm biomass was comparatively insensitive even when viability was suppressed, indicating a decoupling of structural biomass from biocidal activity. Mechanistic signatures were broadly conserved across species and linked to antioxidant-program engagement, with CAT1-related rules contributing to responder/tolerant classification. Conclusions: Integrating MIC/EC plasticity with functional and mechanistic markers supports the rational selection of EO formulations; RAMEB complexation, particularly RT, prioritizes candidates for further pharmaceutical optimization while highlighting species-specific vulnerabilities. Full article

The MADS-box family is a multifunctional family of transcription factors characterized by the presence of a unique MADS domain, which plays an important part in regulating essential biological processes, including metabolic synthesis and the stress response. In this review, we analyze the structural features and classification of MADS-box proteins, then summarize the functions of the MADS-box family in the stress response. The MADS-box family can directly regulate downstream functional genes by binding to the CArG-box in the promoters of target genes, thereby influencing growth, development, and stress responses. Also, MADS-box transcription factors can form protein complexes with both MADS-box proteins and other types of transcription factors and chromatin regulatory proteins to modulate the chromatin state or transcriptional activation. Furthermore, they can regulate plant physiological responses by facilitating the synthesis of essential signaling molecules, including hormones and non-coding RNA. Finally, we discuss the potential of the MADS-box family in crop molecular breeding, offering a novel approach for developing high-yield and stress-resistant cultivars for solving global food security and climate change challenges. Full article

Docosahexaenoic acid (DHA) is an essential ω-3 polyunsaturated fatty acid (PUFA) with high nutritional and pharmaceutical value. The marine protist Aurantiochytrium is a promising industrial DHA producer; however, its DHA biosynthesis via the PUFA synthase pathway co-produces ω-6 docosapentaenoic acid (DPA), limiting DHA purity. Here, we introduced an ω-3 desaturase from Phytophthora infestans (Pin-O3D) into Aurantiochytrium sp. SD116. Functional validation in an Escherichia coli system co-expressing the native PUFA synthase confirmed that Pin-O3D converts DPA to DHA, shifting the DHA/DPA ratio from 1:1 to 2:1. Pin-O3D was then integrated into the fatty acid synthase (FAS) locus, simultaneously attenuating FAS activity and enabling heterologous gene expression. The engineered strain ΔFAS-Pin-O3D exhibited significantly (p < 0.0001 in t-test) increased DHA content (55.2% of total fatty acids) and DHA/DPA ratio (5.91) in shake flasks, with no negative impact on biomass or lipid accumulation. Fed-batch fermentation confirmed the scalability of this strategy, achieving a >20% increase in DHA/DPA ratio. This study demonstrates that combining heterologous ω-3 desaturase expression with FAS attenuation is an effective approach for optimizing PUFA profiles in Aurantiochytrium. Full article

Background/Objectives: Population-specific genomic data are essential for understanding hepatocellular carcinoma (HCC) biology, particularly in underrepresented regions. This study aimed to perform exploratory single-nucleotide polymorphism (SNP)-array-based profiling of HCC tumor samples from Indonesian patients and to prioritize candidate functional variants using a systematic in silico framework. Methods: This retrospective cross-sectional study included 15 resected HCC cases with available formalin-fixed paraffin-embedded (FFPE) tumor tissue. Genome-wide SNP genotyping was performed using the Illumina Asian Screening Array. Following quality control and filtering, variants were annotated using the Ensembl Variant Effect Predictor. A case-only functional prioritization approach incorporating multiple in silico prediction tools was applied, followed by gene-level burden aggregation. Results: After multistep filtering, 11 samples and 104 prioritized variants were retained for analysis. Variants consisted predominantly of splice-region, missense, and regulatory changes. Gene-level burden analysis identified Nuclear Autoantigenic Sperm Protein (NASP, rs775916096) as the highest-ranked candidate gene, while G protein-coupled receptor 78 (GPR78, rs558447540) emerged as a secondary candidate with predicted functional annotations but currently limited biological evidence in HCC. Given the tumor-only design without matched normal tissue, the prioritized variants cannot be distinguished from rare germline variants. Conclusions: This exploratory SNP-array study provides a hypothesis-generating framework for functional variant prioritization in Indonesian HCC. NASP and GPR78 represent preliminary candidates that require validation in larger cohorts with matched normal tissue and sequencing-based confirmation. Full article

The increase in multidrug resistance in microorganisms and the rise of emergent infectious diseases worldwide is a threat to human and animal health. Therefore, research on new molecules with antibiotic potential is a priority. Lichens have a unique secondary metabolism with relatively untapped potential, yet their essential oils (EOs) and volatile organic compounds (VOCs) remain a relatively untapped resource. This systematic review was conducted following PRISMA 2020 guidelines, with a comprehensive search performed in the Web of Science database for studies published up to 2023. From 254 identified records, six studies involving nine lichen species (Evernia prunastri, Evernia divaricata, Cladonia rangiformis, Cladonia furcata, Parmotrema perlatum, Lichina pygmaea, Parmelia perlata, Hypogymnia physodes, and Parmelia sulcata) met the eligibility criteria. The synthesized data show that these volatile fractions possess significant antimicrobial potential, with minimum inhibitory concentrations (MICs) generally lower than 1 mg/mL. Major bioactive constituents identified include atraric acid, orsellinates, and various sesquiterpenes. While the current evidence highlights a strong potential of lichen volatiles against pathogens, research is limited to a small fraction of known species. This review identifies a critical gap in testing these compounds directly against MDR clinical isolates and suggests that future research should focus on high-biomass species and the heterologous expression of lichen biosynthetic genes to develop sustainable antimicrobial applications. Full article