Search Results (1,579)

The ubiquitous co-contamination of traditional and novel brominated flame retardants (TBFRs and NBFRs) in anaerobic environments necessitates a comprehensive understanding of their combined environmental fate. This study investigated the anaerobic biotransformation of BDE 99 (a legacy aromatic TBFR) and β-TBCO (a cycloaliphatic NBFR) using a Dehalogenimonas-containing mixed culture (QY2-S1) under single- and co-exposure conditions. In a single-exposure system, QY2-S1 achieved efficient transformation of both substrates, with the observed first-order kinetic constants (k_obs) of 1.31 ± 0.09 d⁻¹ and 2.35 ± 0.13 d⁻¹ for BDE 99 and β-TBCO, respectively. However, the corresponding k_obs values decreased by approximately 3- to 5-fold in a co-exposure system, demonstrating pronounced reciprocal kinetic inhibition. Notably, while culture QY2-S1 maintained a unique ortho-regioselectivity for BDE 99, its stepwise debromination was truncated at the tetra-BDE stage during co-exposure. Absolute quantitative 16S rRNA sequencing identified Dehalogenimonas as the sole organohalide-respiring bacterium, with its abundance initially increasing in tandem with substrate transformation. However, the dehalogenation-coupled cell growth of Dehalogenimonas was significantly modulated by substrate type and combination, with its absolute biomass following the order of: single β-TBCO > co-exposure > single BDE 99. Collectively, these results suggest that the reciprocal kinetic inhibition and the truncation of the BDE 99 debromination pathway under co-exposure are collectively driven by the suppressed growth and substrate preference of Dehalogenimonas. This study provides critical insights for predicting ecological risks and developing bioremediation strategies for co-occurring BFRs in real-world scenarios. Full article

Introduction: Long-term real-world data on bictegravir/emtricitabine/tenofovir alafenamide (BIC-STR), particularly in key subgroups, remain limited. The primary endpoints of the study were changes in CD4+ cell count and viral load after BIC-STR introduction. The secondary endpoints were the impact of the therapy on metabolic profile and body mass index. Methods: Retrospective observational cohort study including people living with HIV (PLWH) receiving BIC-STR with more than 6 months of follow-up at a tertiary Infectious Diseases clinic (Perugia, Italy). Immunovirological outcomes (HIV-RNA, CD4 count, CD4/CD8 ratio) and metabolic parameters were assessed up to 48 months, with subgroup analyses (treatment-naïve/experienced, >60 years, women, and foreign nationals). Results: 425 patients were included (median follow-up 37.7 months, IQR, 22.1–55.8 months). Most were treatment-experienced (367/425, 86.4%) and viral suppression improved after switching, reaching 90.7% with HIV-RNA < 50 cp/mL; HIV-RNA declined mainly within the first 6 months and then remained stable. CD4 count and CD4/CD8 ratio increased significantly over time, with similar immunovirological trends in older patients (>60 years; 138/425, 32.3%), women (94/425, 22.1%), and foreign nationals (143/425, 33.7%). In treatment-experienced patients not on statins, HDL and LDL did not change significantly, while triglycerides decreased (median from 110 mg/dL, IQR 78.0–164.0, to 103 mg/dL, IQR 70.3–147.8; p = 0.007). In ART-naïve patients (58/425, 13.6%), HDL (median from 41, IQR, 33.0–47.0 to 47, IQR 39.0–54.7, p = 0.0003) and BMI (median from 23.2, IQR 21.7–26.3 to 25.7, IQR 23.4–29.0, p < 0.0001) increased, whereas other lipid changes were not significant. BMI increased only in underweight and normal-weight naïve patients, not in overweight/obese individuals. Conclusions: BIC-STR showed sustained effectiveness, immunological benefit, and favourable metabolic outcomes in routine practice, including, PLWH > 60 years, women, and foreign nationals subgroups. Full article

Background/Objectives: The increasing prevalence of antimicrobial resistance has become a major challenge in the management of Helicobacter pylori infection and is a leading cause of eradication failure. Resistance to clarithromycin and fluoroquinolones is primarily mediated by mutations in the 23S rRNA and gyrA genes, respectively. This study aimed to evaluate the prevalence of resistance-associated mutations in the 23S rRNA and gyrA genes, investigate their relationship with phenotypic antimicrobial resistance, assess their impact on eradication outcomes, and develop a prediction model for treatment failure. Methods: This retrospective real-world cohort study included 294 adult patients with confirmed H. pylori infection evaluated at the Oradea County Emergency Clinical Hospital, Romania, between November 2022 and November 2025. Clinical, endoscopic, histopathological, microbiological, molecular, and treatment outcome data were collected from medical records. Resistance-associated mutations in the 23S rRNA (A2143G, A2142G, and A2142C) and gyrA (N87K, D91G, and D91N) genes were analyzed and correlated with phenotypic antimicrobial resistance and eradication outcomes. Independent predictors of eradication failure were identified using multivariable logistic regression, and a prediction model was subsequently developed. Results: Overall, 101 patients (34.4%) harbored 23S rRNA mutations and 64 (21.8%) carried gyrA mutations, while 27 patients (9.2%) exhibited mutations in both genes. A2143G was the most frequent mutation (25.2%). Resistance-associated mutations showed strong concordance with phenotypic antimicrobial resistance. Patients with wild-type strains achieved eradication rates exceeding 90%, whereas significantly lower success rates were observed among patients carrying A2143G, A2142G, or gyrA mutations. Multivariable analysis identified previous eradication attempts (aOR 3.12, 95% CI 1.71–5.68), A2143G mutation (aOR 4.86, 95% CI 2.43–9.72), gyrA mutation (aOR 2.91, 95% CI 1.45–5.84), increasing age (aOR 1.03, 95% CI 1.01–1.05), and treatment with clarithromycin-based triple therapy (aOR 2.18, 95% CI 1.02–4.63) as independent predictors of eradication failure. The prediction model demonstrated excellent discriminatory performance (AUC 0.88, 95% CI 0.84–0.92), with a sensitivity of 82.5%, specificity of 80.1%, and satisfactory calibration (Hosmer–Lemeshow p = 0.68). Conclusions: Resistance-associated mutations in the 23S rRNA and gyrA genes are strongly associated with phenotypic antimicrobial resistance and reduced H. pylori eradication success. Molecular resistance testing may facilitate individualized treatment selection and improve clinical outcomes. The proposed prediction model, integrating clinical characteristics, treatment regimen, and molecular resistance markers, demonstrated excellent performance and may represent a useful tool for identifying patients at increased risk of eradication failure. Full article

Viral hemorrhagic fevers (VHFs) are severe infectious diseases caused by RNA viruses of the families Arenaviridae, Filoviridae, Flaviviridae, and Hantaviridae, characterized by high morbidity, significant case fatality rates, and frequent diagnostic uncertainty in early disease stages. For military medical services, timely clinical recognition and laboratory confirmation are essential to guide patient management, prevent nosocomial transmission, and maintain operational continuity, particularly in endemic or resource-limited deployment settings. This review critically examines current diagnostic approaches to VHF-causative agents, emphasizing their use in clinical and field medical settings. The diagnostic process, from exposure through specimen collection, laboratory testing, and result interpretation is analyzed, including the use of molecular, serological, and antigen-based assays. Particular attention is given to deployable diagnostic platforms and their role in bridging the gap between frontline clinical suspicion and definitive laboratory confirmation. Biosafety requirements and infection prevention measures are discussed as integral components of clinical diagnostic workflows, aligned with guidance from the World Health Organization and the Centers for Disease Control and Prevention. Comparative analyses of virus-specific diagnostic timelines and laboratory requirements are presented to support differential diagnosis and clinical decision-making. Emerging technologies, including rapid molecular assays and genomic methods, are evaluated for their potential to improve early diagnosis and patient outcomes. This review highlights the central role of diagnostic readiness in clinical management of the VHFs and provides evidence-based considerations to support military clinicians facing high-risk febrile illnesses in operational environments. Full article

Freshwater amphipods of the genus Gammarus are important trophic components of aquatic ecosystems and are increasingly considered a potential bioresource for aquaculture. However, their role in the maintenance and transmission of infectious agents remains poorly understood. This study evaluated the presence of major crustacean and fish pathogens in Gammarus lacustris populations from Kazakhstan and characterized associated viral communities using metagenomic sequencing. Six pooled samples collected from freshwater ecosystems across Kazakhstan were screened using PCR and RT-PCR assays targeting World Organisation for Animal Health (WOAH)-listed pathogens, including White Spot Syndrome Virus, Taura Syndrome Virus, Infectious Myonecrosis Virus, Aphanomyces astaci, and Aphanomyces invadans. In parallel, high-throughput sequencing (Illumina NovaSeq) was performed to assess virome composition and structure. No WOAH-listed pathogens were detected, suggesting a low detectable occurrence of major notifiable agents under the conditions of the present study. Metagenomic analysis revealed a virome dominated by RNA viruses, particularly picorna-like viruses (Picornaviridae), Dicistroviridae, and Marnaviridae. Phylogenetic and genome organization analyses identified potentially novel or highly divergent viral lineages within Picornavirales. Collectively, these findings suggest a favorable epizootiological profile of G. lacustris populations while highlighting freshwater amphipods as hosts of diverse and partially uncharacterized viral communities relevant to aquatic disease surveillance and aquaculture biosecurity. Full article

The second most prevalent neurodegenerative illness in the world, Parkinson’s disease (PD), currently has no viable treatments. Although it is yet unknown if mitochondrial dysfunction is an initial event or evolves as a result of neurodegeneration, it is thought to be a crucial component of Parkinson’s disease etiology. From the perspective of mitochondrial quality control (MQC), which includes PINK1/Parkin-mediated mitophagy, mitochondrial dynamics, and mitochondrial proteostasis, this article examines mitochondrial dysfunction. Together, these processes preserve mitochondrial homeostasis and prevent the buildup of damaged mitochondria. Dysfunctional mitochondria gradually build up and cause oxidative stress and aberrant cellular signaling when mitochondrial quality control is compromised. According to available data, mitochondrial reactive oxygen species (mtROS) primarily worsen pre-existing mitochondrial damage by encouraging α-synuclein aggregation, cardiolipin remodeling, and dopamine oxidation. In addition, innate immune pathways like cGAS–STING and TLR9 signaling can be triggered by mitochondrial damage-associated molecular patterns (mtDAMPs), especially mitochondrial DNA, which can lead to long-term neuroinflammatory reactions in PD. While new research suggests that m⁶A RNA modification may be involved in the regulation of mitochondrial stress, the PINK1/Parkin pathway is crucial for maintaining mitochondrial homeostasis. Therapeutic approaches that target mitophagy augmentation, neuroinflammatory signaling, and mitochondrial protection have garnered increasing attention. In an attempt to improve mitochondrial function and lessen persistent neuroinflammatory activation, future research will probably need to concentrate on combination treatment techniques. Full article

Generative artificial intelligence (AI) is transforming biological and medical research and data analysis. Beyond analyzing existing information, these models can learn complex patterns and generate new data such as realistic protein sequences, genetic variants, or clinical notes. In molecular biology, language-like sequence models can read and generate DNA, RNA, and amino acid sequences to predict genetic variant effects, design new proteins, and explore molecular functions. In medicine, large language models (LLMs) trained on biomedical literature and electronic health records (EHRs) can summarize clinical findings, identify patterns, and provide decision support for clinicians and healthcare providers. Additionally, synthetic data generation can help protect patient privacy and augment existing disease datasets. While these advances make tasks that were previously impractical possible at scale, they also carry major risks, including producing convincing but incorrect results, reflecting hidden biases in the training data, and underperforming when real-world conditions change. Full article

Streptococcus pneumoniae remains a major global health threat and is listed by the World Health Organization as a pathogen in urgent need of new antimicrobial strategies. While primarily considered an extracellular pathogen, S. pneumoniae can persist within splenic macrophages in severe disease, creating a protected intracellular niche that may contribute to fulminant sepsis. We recently demonstrated the concept of an mRNA-based therapeutic approach in which host cells produce the pneumococcal bacteriophage endolysin Cpl-1. Here, we investigated whether expression of Cpl-1 in macrophages can target S. pneumoniae residing within host cells. Using the human THP-1 macrophage line, we demonstrated successful translation and intracellular accumulation of bioactive Cpl-1 following IVT-mRNA transfection. Lysates from Cpl-1 mRNA-transfected cells exhibited bacteriolytic activity, and Western blotting as well as immunofluorescent staining confirmed cytosolic endolysin production. Phagocytosis assays using an encapsulated and unencapsulated pneumococcal strain showed a reduction in intracellular bacterial burden in Cpl-1 mRNA-transfected macrophages compared with control and inactive-mutant Cpl-1 mRNA groups, and a flow cytometry-based assay further corroborated a decreased intracellular bacterial signal. Together, these findings suggest that mRNA-encoded Cpl-1 enhances intracellular killing of S. pneumoniae and supports the feasibility of mRNA-based endolysin therapies to target intracellular pneumococcal reservoirs. Full article

As liver cancer is a leading cause of death all over the world, there is a need to explore new therapeutic strategies. This study presents an in silico analysis of the genes Caspase₃ (CASP₃), Caspase₉ (CASP₉), and BCL-2-associated X protein (BAX) in liver cancer cells to evaluate the apoptosis profile following exposure to green-synthesized plant extract. We assessed the modulatory effects of phytochemicals on the apoptotic pathway by means of bioinformatics tools and a publicly available gene expression dataset. Our findings revealed the possible mechanistic basis of the pro-apoptotic activity observed in vitro, utilizing a structure-based molecular docking method. The biologically synthesized AgNPs at a concentration of 50 µg/mL induced an approximately 4-fold increase in the mRNA expression levels of CASP3, CASP9, and BAX compared with chemically synthesized AgNPs, as determined by qPCR. Rutin was the compound with the highest binding affinities toward all three proteins, with ΔG values of −9.3 kcal/mol (Caspase₃), −9.1 kcal/mol (Caspase₉), and −9.0 kcal/mol (BAX). These findings offer new insights about the molecular mechanisms that support the cytotoxicity of phytochemicals, and simultaneously highlight the potential of green nanotechnology for the development of therapeutic strategies for liver cancer. Full article

Background: mRNA vaccines, first approved in December 2020, have been used globally to prevent infectious diseases, and those for treating cancers are being developed. Safety-related labelling changes of Comirnaty and Spikevax were made in June 2025; however, concerns remain. This study assessed the potential risks associated with mRNA vaccines on the indications previously approved, utilizing Real-World Data (RWD) of Adverse Events Following Immunization (AEFIs) derived from the Vaccine Adverse Event Reporting System (VAERS) and Academic Literature Databases (ALD). Methods: A Disproportionality Analysis (DPA) was performed using the Reporting Odds Ratio (ROR) and the Bayesian Confidence Propagation Neural Network (BCPNN) algorithm on spontaneous case reports from VAERS. Statistical positive signals were cross-validated with literature case reports from ALD to provide more comprehensive medical descriptions and clearer causal assessments, and compared with safety information documented in clinical trials and on vaccine labelling. Time-to-onset, stratified, and immunization schedule analyses were conducted to characterize the safety profiles of mRNA vaccines. Results: In total, 5,040,725 spontaneous case reports and 4,387 literature case reports were analyzed. In both VAERS and ALD, new signals involving blood and lymphatic system disorders (e.g., thrombotic thrombocytopenic purpura) and ear and labyrinth disorders (e.g., deafness) were detected from Comirnaty as Designated Medical Events (DMEs), while blood and lymphatic system disorders (e.g., thrombotic thrombocytopenic purpura) from Spikevax in ALD only. No new signals were detected from other vaccines on the DMEs list. In VAERS, Serious Adverse Events (SAEs) were more common in females, while death risk was higher in males. In ALD, SAEs were more common in males for most mRNA vaccines, except Comirnaty. Medical history emerged as a key risk factor for SAEs, particularly among older adults. Conclusions: Statistically significant safety signals were detected across all mRNA vaccines based on five-year cumulative RWD, indicating the need of intensified monitoring of specific populations, including older adults and individuals with medical histories, alongside further optimization of vaccination strategies. Full article

Global agricultural production faces unprecedented challenges due to climate crisis, biodiversity loss, and increasing population pressure, while there is a growing demand for sustainable and eco-conscious food production systems. Traditional methods of crop protection like the use of synthetic chemical pesticides are becoming less effective due to the high resistance development in major insect pests. Moreover, their overuse has raised numerous environmental concerns. In this context, RNA interference (RNAi) has emerged as a promising and environmentally friendly alternative to traditional pesticides, with a more sustainable way of managing pests. This review systematically identifies promising RNAi target gene families for insect pest control, particularly key developmental genes. The selected genes were chosen based on demonstrated RNAi efficacy in at least three different insect species, emphasizing their broad applicability and potential impact. It also discusses the translation of RNAi technologies from laboratory research to field applications. It underscores the importance of moving beyond functional gene characterization to improving the efficiency and scalability of RNAi in real-world agricultural systems. This review systematically lists RNAi target genes and delivery methods in insect pests, identifies research gaps, and supports the development of RNAi-based biopesticides. Full article

HER2DX is a 27-gene genomic assay generating three complementary scores: a pCR score predicting the likelihood of achieving pathological complete response (pCR, defined as absence of residual invasive disease after neoadjuvant therapy), a Risk score estimating long-term recurrence risk, and an ERBB2 mRNA score quantifying HER2 transcriptional activation. Together, these scores may guide treatment escalation or de-escalation strategies in routine practice. We performed a single-center observational study at 12 de Octubre University Hospital (Madrid, Spain), including patients with early-stage HER2-positive breast cancer who underwent HER2DX testing (2023–2025), and analyzed clinicopathologic features, treatment decisions, and pathological outcomes. Forty-five patients were included (median age 57 years). Stage II accounted for 71.1% of cases; 66.7% were hormone receptor-positive, and 31.3% were node-positive. HER2DX modified clinical management in 51.1% of patients. The pCR score changed the initial strategy (neoadjuvant therapy versus upfront surgery) in 17.8% of cases and, independently, favored de-escalation to taxane plus dual HER2 blockade, with 90% of high-score tumors achieving a pathological complete response. The Risk score informed chemotherapy backbone selection within stage II disease. The ERBB2 score correlated with HER2 immunohistochemical intensity. In this exploratory real-world cohort, HER2DX provided biologically distinct information beyond traditional immunohistochemistry and was associated with modifications in multidisciplinary treatment decision-making in early-stage HER2-positive breast cancer, warranting prospective validation in larger cohorts. Full article

The global expansion of highly pathogenic avian influenza A (H5N1), particularly the clade 2.3.4.4b lineage, has renewed urgent concerns about its pandemic potential in the context of its ongoing panzootic expansion and increasing cross-species transmission. Despite decades of preparedness initiatives, critical technological and structural gaps persist, especially in low- and middle-income countries (LMICs), where both vaccine access and sustainable manufacturing capacity remain limited. In this perspective, we examine key lessons from past influenza pandemics and global preparedness strategies, including the Global Action Plan for Influenza Vaccines, highlighting persistent challenges related to sustainable manufacturing capacity and equitable vaccine access. Additionally, we examine the potential of messenger RNA (mRNA) vaccine platforms to address these limitations, given their rapid design, scalable manufacturing, and adaptability to emerging pathogens. Moreover, we examine the role of neuraminidase (NA) as a complementary antigen capable of broadening immune protection and reducing viral transmission. Finally, we describe recent advances in Latin America, focusing on Argentina’s participation in the mRNA Technology Transfer Programme co-led by the World Health Organization (WHO) and the Medicines Patent Pool (MPP), as a model for strengthening regional manufacturing capacity and contributing to global pandemic preparedness. Together, these elements indicate that effective H5N1 pandemic preparedness will require the integration of improved antigen design, flexible mRNA platforms, and sustainable regional manufacturing systems aligned with global procurement strategies. Full article

The effect of periodic temperature variation on short and partially matching interacting RNA strands is demonstrated using three pairs of competing RNA duplexes as simplified model systems. They represent random base-pairing interactions between short RNA chains at very early stages of RNA evolution. The molecular interaction kinetics are simulated based on the experimental thermodynamic data obtained by M. E. Christiansen et al. and on the Eyring theory. The simulated time developments demonstrate the impact of shifting reaction kinetics and a state of continuous non-equilibrium. The product mix that develops slowly at low temperatures releases chemical (free) energy quickly at high temperatures, and the product mix that develops quickly at high temperatures releases chemical (free) energy slowly at low temperatures. Regarding heat flow and energy storage, the chosen model system represents a generalized Carnot engine, similar to most comparable reactions during RNA evolution. Its action provides a perpetual driving force for selection processes, creating ideal conditions for an ongoing molecular evolution. Full article

Background: Adenovirus-vectored vaccines played an important role in the global response to SARS-CoV-2. Adenovirus platforms have many advantages including a simple and readily transferred manufacturing process, low cost, and thermostability. Speed of production of an initial Good Manufacturing Practice (GMP)-compliant batch has, however, been viewed as a limitation of adenovirus vectors relative to mRNA platforms. Production of the initial viral starting material and release testing are key rate-limiting steps. Methods: Production of viral starting material from DNA, and release testing in accordance with regulatory expectations, for first-in-human trials of adenovirus-vectored vaccines. Results: We describe experience of these stages in the production of the first GMP batches for multiple adenovirus-vectored candidates and the adaptations made for ChAdOx1 nCoV-19 (the Oxford COVID-19 vaccine) in early 2020. We also report development of a streamlined approach to starting material generation, enabling initial GMP batch availability within c. 60 days of publication of a new pathogen sequence. Using a New World arenavirus vaccine construct as a proof of concept, we demonstrate reproducible execution of this pipeline, maintaining acceptable infectivity and other quality attributes. Conclusions: We discuss opportunities for additional time savings in the future. This work demonstrates suitability of an adenovirus platform to contribute to the “100 Days Mission” for vaccines against “Disease X”. Full article