Search Results (184,341)

Background: The emergence of pan-drug-resistant (PDR) Klebsiella pneumoniae has compromised the efficacy of last-line agents, leaving few therapeutic options. Repurposing zidovudine, an FDA-approved thymidine analog with antibacterial activity, may enhance existing therapies, but pharmacodynamic data under clinically relevant conditions are scarce. This study addresses this gap using static and dynamic in vitro models. Materials/methods: A PDR strain of Klebsiella pneumoniae harboring bla_NDM-1, bla_CMY-6, bla_CTX-M-15, bla_SHV-2, and disrupted mgrB was used in this study. Minimum inhibitory concentrations (MICs) followed by static time-kills were performed to investigate the synergistic interplay between zidovudine and last-line antibiotics (ceftazidime/avibactam, polymyxin B). To simulate human pharmacokinetics, a hollow-fiber infection model (HFIM) was employed using steady-state concentrations of zidovudine (4 mg/L), polymyxin B (4 mg/L), and avibactam (22 mg/L). Structural and morphological effects on bacterial cells were examined via fluorescence microscopy following glutaraldehyde fixation. Results: In this study, the PDR K. pneumoniae showed a ~5-fold reduction in polymyxin MIC when combined with zidovudine (from >4 µg/mL to 0.25 µg/mL). Time-kill assays demonstrated ≥2.5 log₁₀ CFU/mL bacterial reduction with zidovudine-based combinations, whereas monotherapies failed to inhibit bacterial growth. In the HFIM, the triple combination achieved rapid bactericidal activity (>3 log₁₀ CFU/mL reduction within 4 h) and sustained killing (>5–6 log₁₀ reduction maintained through 216 h), with bacterial counts remaining below 1 CFU/mL. In contrast, dual combinations initially reduced bacterial burden (1–3 log₁₀ reduction) but failed to maintain suppression, with significant regrowth (>10¹⁰ CFU/mL) observed by 168 h. Microscopy corroborated these findings, revealing extensive cellular damage in the zidovudine-containing treatment arms. These HFIM results underscore the potential of zidovudine-based triple therapy in overcoming resistance to last-line antibiotics in K. pneumoniae. Conclusions: Our results provide promising unprecedented insight into novel zidovudine-based combination therapies against difficult-to-treat MBL Gram-negatives. The observed synergy in MIC reduction, rapid killing in time-kill assays, and near-complete eradication in the HFIM underscore the therapeutic potential of this triple combination. Future studies will focus on broadening the application of these novel combinations to other ‘superbugs’, such as highly resistant strains of Acinetobacter baumannii and Pseudomonas aeruginosa. Full article

Background/Objectives: Selenoproteins play indispensable roles in embryonic development, with their dysregulation linked to various metabolic and neurological disorders. This study aims to systematically quantify the mRNA expression levels of all 24 selenoprotein genes in murine heart, brain, liver, and kidney tissues across embryonic (E8.5, E12.5, E18.5) and postnatal (P7, P30, P90) developmental stages, in order to elucidate the regulatory landscape of selenium metabolism during development. Methods: We collected tissues from mice at six developmental stages and performed RNA extraction followed by quantitative real-time PCR (qPCR) to measure the expression of all 24 selenoprotein genes. Data were normalized using the geometric mean of ActB and Gapdh, and statistical analyses were conducted using one-way ANOVA with Duncan’s post hoc test. Results: Our analysis reveals three principal findings: (1) Distinct expression patterns emerge among selenoprotein families—deiodinases (Dio1-3) and thioredoxin reductases (Txnrd1-3) exhibit limited embryonic expression (<20-fold changes), while glutathione peroxidases (Gpx1, Gpx3, Gpx4) and biosynthesis-related genes (Selenop, Msrb1) show substantial postnatal upregulation (up to 600-fold increases); (2) Selenoproteins essential for embryonic survival (Gpx4, Txnrd1, Txnrd2, Selenoi, Selenot) display expression profiles concordant with their essential developmental functions; (3) Selenop and Msrb1, involved in selenium transport and redox regulation, demonstrate early embryonic upregulation with further increases during postnatal development. Conclusions: These spatiotemporal expression patterns elucidate the regulatory landscape of selenium metabolism during development and provide mechanistic insights into the phenotypes associated with selenium deficiency. The findings offer valuable implications for human nutritional interventions and developmental health. Full article

Sepsis represents a life-threatening organ dysfunction caused by a dysregulated host response to infection, and is considered a medical emergency. Therefore, quick diagnosis and treatment are required in order to improve survivability. Currently, patient evaluation in sepsis is based on the Sequential Organ Failure Assessment (SOFA) score to determine the severity of the disease; however, novel biomarkers are also actively researched with the aim to develop quicker diagnostic tools and better therapy. Endothelin-1 is one of the most potent vasoconstrictors found in the human body and is involved in the pathophysiology of both sepsis and other conditions involving organs that make up the SOFA score. In this narrative review, we aimed to gather information of this peptide’s multiple effects and to help determine whether or not it could prove a valuable biomarker in the evaluation of patients with multi-organ dysfunction in sepsis. Full article

This study presents a comprehensive Quantitative Microbial Risk Assessment (QMRA) for Escherichia coli in northeastern Greece’s riverine and deltaic aquatic systems, evaluating potential human health risks from recreational water exposure. The analysis integrates seasonal microbiological monitoring data—E. coli, total coliforms, enterococci, Salmonella spp., Clostridium perfringens (spores and vegetative forms), and physicochemical parameters (e.g., pH, temperature, BOD₅)—across multiple sites. A beta-Poisson dose–response model within a Monte Carlo simulation framework (10,000 iterations) was applied to five exposure scenarios, simulating varying ingestion volumes for different population groups. Median annual infection risks ranged from negligible to high, with several locations (e.g., Mandra River, Konsynthos South, and Delta Evros) surpassing the World Health Organization (WHO)’s benchmark of 10⁻⁴ infections per person per year. A Gradient Boosting Regressor (GBR) model was developed to enhance predictive capacity, demonstrating superior accuracy metrics. Permutation Importance analysis identified enterococci, total coliforms, BOD₅, temperature, pH, and seasons as critical predictors of E. coli concentrations. Additionally, sensitivity analysis highlighted the dominant role of ingestion volume and E. coli levels across all scenarios and sites. These findings support the integration of ML-based tools and probabilistic modelling in water quality risk governance, enabling proactive public health strategies in vulnerable or high-use recreational zones. Full article

Ixodid ticks are blood-sucking ectoparasites of vertebrates. They constitute an integral part of natural foci and are responsible for the worldwide transmission of infections to humans, which can result in severe symptoms. For instance, the Tomsk region, where three abundant tick species (Dermacentor reticulatus, Ixodes pavlovskyi, I. persulcatus) occur, is an endemic area for tick-borne encephalitis virus (TBEV). An increasing number of novel infectious agents carried by ticks have been identified using metagenomic sequencing. A notable example is the Yezo virus (Orthonairovirus yezoense, YEZV), which was discovered in patients with fever after tick bites in Japan and China between 2014 and 2025. For the first time, we have performed metagenomic sequencing of the virome of ticks collected in the Tomsk region. In a sample obtained from a pool of I. pavlovskyi ticks, all three segments of the YEZV genome were detected. The phylogenetic analysis showed that the newly identified isolate formed a sister group to previously described virus isolates, indicating the presence of a new genetic variant. This study presents the first report of YEZV detection in I. pavlovskyi ticks in the Tomsk region, thereby expanding the geographical range and number of vector species for YEZV and highlighting the importance of monitoring viral agents circulating among ticks in Western Siberia. Full article

Focal cortical dysplasia (FCD) is a major cause of drug-resistant epilepsy, yet its molecular basis remains poorly understood. Numerous studies have analyzed RNA, protein, and microRNA alterations, but results are often inconsistent across subtypes and methodologies. To address this gap, we conducted a systematic review integrating transcriptomic, proteomic, and microRNA data from 117 human studies of FCD subtypes I–III. Differentially expressed factors were extracted, categorized by subtype, and analyzed using pathway enrichment and network approaches. Our integrative analysis revealed convergent dysregulation of neuroinflammatory, synaptic, cytoskeletal, and metabolic pathways across FCD subtypes. Consistently altered genes, including IL1B, TLR4, BDNF, HMGCR, and ROCK2, together with dysregulated microRNAs such as hsa-miR-21-5p, hsa-miR-155-5p, and hsa-miR-132-3p, were linked to PI3K–Akt–mTOR, Toll-like receptor, and GABAergic signaling, emphasizing shared pathogenic mechanisms. Importantly, we identified overlapping transcript–protein patterns and subtype-specific molecular profiles that may refine diagnosis and inform therapeutic strategies. This review provides the first cross-omics molecular framework of FCD, demonstrating how convergent pathways unify heterogeneous findings and offering a roadmap for biomarker discovery and targeted interventions. Full article

Environmental stressors during the crucial period of fetal development can have a substantial impact on long-term health outcomes. A major concern is dietary exposure to endocrine-disrupting chemicals (EDCs), which can readily cross the placenta and disrupt fetal hormonal signaling and developmental programming. Examples of these chemicals include bisphenols, phthalates, pesticides, and persistent organic pollutants (POPs). Prenatal exposure to EDC has been associated with long-term effects in children, including immune disruption, metabolic dysregulation, impaired neurodevelopment, and reproductive alterations, as evidenced by human cohort studies and experimental models. Epigenetic reprogramming, direct interference with endocrine signaling, and oxidative stress (OS) are hypothesized pathways for these adverse consequences, which often combine to produce long-lasting physiological changes. This narrative review summarizes current research on maternal dietary exposure to EDCs during pregnancy, highlighting associations with adverse child health outcomes. It also discusses the growing evidence of transgenerational effects, the potential mechanisms linking prenatal exposure to long-term outcomes, and the importance of understanding the roles of timing, dosage, and chemical type. By highlighting the necessity of focused interventions to lower maternal EDC exposure and lessen threats to the health of offspring, the review concludes by discussing implications for future research, preventive measures, and public health policy. Full article

To explore the potential of Large Language Models (LLMs) as AI Annotators in the domain of sustainability reporting, this study establishes a systematic evaluation methodology. We use the specific case of European football clubs, quantifying their sustainability reports based on the sport Positive matrix as a benchmark to compare the performance of three state-of-the-art models (i.e., GPT-4o, Qwen-2-72b-instruct, and Llama-3-70b-instruct) against human expert scores. The evaluation is benchmarked on dimensions including accuracy, mean absolute error (MAE), and hallucination rates. The results indicate that GPT-4o is the top performer, yet its average accuracy of approximately 56% shows it cannot fully replace human experts at present. The study also reveals significant issues with overconfidence and factual hallucinations in models like Qwen-2-72b-instructon. Critically, we find that by implementing further data processing, specifically a Chain-of-Verification (CoVe) self-correction method, GPT-4o’s initial hallucination rate is successfully reduced from 16% to 10%, while accuracy improved to 58%. In conclusion, while LLMs demonstrate immense potential to streamline and democratize sustainability ratings, inherent risks like hallucinations remain a primary obstacle. Adopting verification strategies such as CoVe is a crucial pathway to enhancing model reliability and advancing their effective application in this field. Full article

Methicillin-resistant Staphylococcus spp. are microorganisms found in dairy products, bovine mastitis, and human infections. The prevalence of resistant strains from this genus in the food chain is increasing, drawing attention to transmission in the community and highlighting the importance of One Health studies. Thus, the aim of this study was to determine the MIC of oxacillin (OXA) and the sanitizers benzalkonium chloride (BAC) and sodium hypochlorite (HP) against isolates of methicillin-resistant Staphylococcus spp., and to evaluate the possible influence of sub-MIC application of these compounds on bacterial cells, in order to observe possible microbial resistance. Ten isolates of methicillin-resistant Staphylococcus spp. (S. epidermidis and S. chromogenes) were used. Among the sanitizers, BAC showed greater efficiency during the pre-inhibition test. Increased resistance to OXA was found in isolates of S. chromogenes and S. epidermidis after sub-MICs of 50% and 90% of OXA, while sub-inhibition of HP favored resistance to OXA. The application of HP and OXA, even at low concentrations, induced a reduction in biofilm production. This study shows that sub-inhibitory sanitizer exposure in Staphylococcus spp. induces antimicrobial resistance phenotypes linked to mutations in regulatory, mobile, and DNA repair genes. These findings suggest that selective pressure promotes resistant variants through genomic plasticity and regulatory activation, supporting the hypothesis that sanitizer residues may drive multidrug resistance emergence, although further functional validation is required. Full article

Background/Objectives: Nasal biopharmaceutics is the scientific understanding of product and patient factors that determine the rate and extent of drug exposure following nasal administration. The authors considered whether current biopharmaceutics tools are fit for the current and future needs of nasal product development and regulation. Methods: The limitations of current methods were critically assessed, unmet needs were highlighted, and key questions were posed to guide future directions in biopharmaceutics research. Results: The emergence of physiologically based biopharmaceutics models for nasal delivery has the potential to drive the scientific understanding of nasal delivery. Simulations can guide formulation and device development, inform dose selection and generate mechanistic insights. Developments in modeling need to be complemented by advances in experimental systems, including the use of realistic or idealized nasal casts to estimate the regional deposition of nasal sprays and refined in vitro cell culture models to study nasal drug absorption and the influence of mucus. Similarly, improvements are needed to address the practicalities of using animals in non-clinical studies of nasal drug delivery, and greater clinical use of gamma scintigraphy/magnetic resonance imaging is recommended to measure the delivery and nasal retention of different formulations in humans. Conclusions: Nasal drug delivery is a rapidly growing field and requires advances in nasal biopharmaceutics to support product innovation. Key needs are (i) validated clinically relevant critical product attributes for product performance and (ii) established links between how patients administer the product and where in the nose it deposits and dissolves in order to act or be absorbed, leading to its desired clinical effect. Full article

Sleep bruxism (SB) is a masticatory muscle activity during sleep which can be categorized as primary, when it remains unclear whether the phenomenon is directly linked to a specific disorder, or if it only coexists, and secondary, when it is proven to be associated with a particular disorder, treatment or lifestyle and bruxism that is part of the signs of a disorder. In this way, SB is associated with various factors, including obstructive sleep apnea and gastroesophageal reflux (GER), where evidence suggests SB has a protective role in airway patency, potentially triggered by microarousals and autonomic instability, especially under hypoxia conditions. Since hypobaric hypoxia exposition—generated by high-altitude exposure—produces a decrease in the partial pressure of oxygen, it triggers alterations in cardiac rhythm and gastric function, which could be associated with physiological alterations mentioned in SB. Therefore, the aim of this review is to determine the effect of hypobaric hypoxia exposure on the physiological and molecular alterations during sleep bruxism. Method: The SANRA-guided narrative review synthesized recent human and animal studies on hypoxia’s physiological and molecular effects in sleep bruxism. In conclusion, SB is associated with GER and autonomic dysregulation, which are present in hypobaric hypoxia conditions, where respiratory disturbances, microarousals, and increased muscle activity are associated with SB. High-altitude exposure triggers oxidative stress, genetics, and sleep alteration, which exacerbate its severity. Moreover, neurophysiological and molecular mechanisms, including TRPV1 and HIF-1α activation, are implicated. Finally, polysomnography remains the gold standard for diagnosis; however, studies at high altitude are needed to confirm this association. Full article

Microplastic pollution represents a significant environmental challenge, as microplastics accumulate in effluents and soils, causing serious risks to ecosystems and human health. Efficient removal of these contaminants is essential to mitigate their potential adverse effects. This review summarizes and critically analyses current methods for the removal of microplastics from effluents and soils, focusing on their effectiveness, advantages, and limitations. Conventional techniques—including filtration, flotation, chemical coagulation, flocculation, and adsorption—are discussed in the context of wastewater treatment and soil remediation. Emerging approaches, such as flocculation processes with special focus on the application of bio-based flocculants, are also highlighted as promising solutions. Key challenges in microplastic removal, including the diversity of microplastic types, their small size, and the complexity of environmental matrices, are addressed. This work intends to contribute to the urgent need for further research to develop more efficient and sustainable strategies for microplastic removal from environmental systems. Full article

In parallel with technical training on knowledge and skills of task-specific medical or surgical procedures, wide arrays of soft skills training would contribute to obstetric safety in the contemporary healthcare setting. This article, as a service evaluation, explored the effect of a specialty-based Crew Resource Management (CRM) training series that transforms the concept of human factors into sustainable measures in fostering clinical safety culture of the Department of Obstetrics and Gynaecology (O&G) in the Queen Elizabeth Hospital. Within the last decade, a tri-phasic programme has been implemented by an inter-professional workgroup which consists of a consultant anaesthesiologist, medical specialists and departmental operations manager from O&G, a nurse simulation specialist, hospital administrators, and a research psychologist. (1) Phase I identified different patterns of attitudinal changes (in assertiveness, communication, leadership, and situational awareness, also known as “ACLS”) between doctors and nurses and between generic and specialty-based sessions for curriculum planning. (2) Phase II evaluated how these specific behaviours changed over 3 months following CRM training tailored for frontline professionals in O&G. (3) Phase III examined the coping style in conflict management and the level of sustainability in self-efficacy over 3 months following specialty-based CRM training. The findings showed the positive impacts of O&G CRM training on healthcare professionals’ increased attitude and behaviour in “ACLS” by 22.7% at a p < 0.05 level, character strengths in conflict management, and non-inferior or sustained level of self-efficacy under tough conditions in the clinical setting up to 3 months after training. As a way forward, incorporating a scenario-based O&G CRM programme into existing skills-based training is expected to change service framework with an innovative approach. In addition, exploring actual clinical outcomes representing a higher level of organisational impacts can be a strategic direction for further studies on the effect of this practical and educational approach on obstetric safety culture. Full article

Corneal fibrosis, a significant source of visual impairment, can result from keratocyte-to-myofibroblast transdifferentiation during wound healing. This study investigated the antifibrotic role of 1,25-dihydroxyvitamin D₃ (1,25 Vit D) and the lesser-known vitamin D, 24,25-dihydroxyvitamin D₃ (24,25 Vit D), in human and mouse corneal stromal cells (HSCs and MSCs) and in a Vit D receptor knockout (VDR KO) mouse model. Cells were treated with TGF-β1 ± Vit D metabolites and the expression of fibrotic and antifibrotic genes and proteins was evaluated. Both metabolites significantly reduced α-smooth muscle actin levels in HSCs, MSCs and organ-cultured mouse corneas (p < 0.05). They also upregulated the mRNA expression of BMP2, BMP6, BMPR2, and TGF-β3, as well as the protein expression of BMP6 and TGF-β3. VDR KO corneas subjected to alkali injury exhibited increased fibrotic responses and reduced CD45+ immune cell infiltration compared to wild-type controls. Notably, 24,25 Vit D exerted antifibrotic effects even in VDR KO cells, and the alternative 24,25 Vit D receptor FAM57B was expressed in all corneal cell layers. These results reveal consistent antifibrotic effects of both 1,25 and 24,25 Vit D across species, support the existence of VDR-independent mechanisms in the cornea, and offer new insights into potential therapeutic strategies for preventing corneal fibrosis. Full article

The rise in the number of cancer cases and the dissemination of strains with multiple drug resistance in the world pose a serious threat to public health care and human well-being. The design and study of new chemotherapeutic agents for cancer and infectious diseases are hot topics in science. Hydrazones, a versatile and diverse class of chemical compounds, gained a lot of attention as a promising base for future drugs. In this paper, we report on the synthesis of eight new gold(III) complexes with hydrazones derived from pyridoxal-5′-phosphate and pyridoxal. The complexes are thoroughly characterized using IR, ¹H, ³¹P NMR, and mass spectroscopy. The cytotoxic effect of twelve various hydrazones derived from pyridoxal 5′-phosphate on both immortalized (HEK293T) and tumor (HCT116) human cell lines was estimated using the MTT assay. In addition, this contribution describes the antibacterial action of complexes of gold(III) and pyridoxal and pyridoxal 5′-phosphate-derived hydrazones, as well as the mixtures of the solutions containing tetrachloroaurate(III) and hydrazones, using the zone of inhibition test. Gold(III) complexes exhibit moderate antibacterial activity against both Gram-positive and Gram-negative bacteria, while free hydrazones show low cytotoxicity and thus could be considered relatively safe for humans. Full article