Search Results (34,804)

Rheumatoid arthritis (RA) has traditionally been managed after the onset of clinically apparent synovitis; however, accumulating evidence indicates that disease-related immune abnormalities precede clinical diagnosis by several years. This preclinical phase is characterized by systemic autoimmunity, early musculoskeletal symptoms, and subclinical inflammation in genetically and environmentally susceptible individuals. In this review, we summarize current concepts regarding the pathogenesis, risk stratification, and therapeutic interception of preclinical RA. Particular attention is given to the mucosal origin hypothesis and to the roles of immunosenescence, peripheral helper T cells, and fibroblast-like synoviocytes in early disease evolution. Recent advances in clinical, serological, and imaging-based risk stratification have improved the identification of individuals at high risk of progression to clinical RA, and emerging intervention trials have shown that selected therapies may delay disease onset or reduce early inflammatory burden. Although complete prevention of RA has not yet been achieved, these findings support a paradigm shift from the treatment of established RA toward earlier, risk-adapted intervention before irreversible joint damage occurs. Future efforts should focus on refining predictive biomarkers, optimizing the timing and intensity of intervention, and establishing safe, individualized preventive strategies. Full article

Wheat is a globally important food crop, and its yield is crucial for ensuring food security. Lunxuan 13 is an elite wheat variety developed by the Institute of Crop Sciences, Chinese Academy of Agricultural Sciences. It has high yield potential and outstanding agronomic traits, such as excellent seed setting rate, plump kernels, and good lodging resistance. However, this variety is highly susceptible to pre-harvest sprouting (PHS) when exposed to rain during the maturation period, leading to premature grain germination on the spike, which causes yield losses and quality deterioration, severely restricting its popularization. This study focused on addressing the PHS susceptibility of Lunxuan 13 by employing CRISPR/Cas9 technology for the targeted knockout of the three homoeologous copies (A, B, and D subgenomes) of TaQsd1, a key gene regulating seed dormancy. A total of 41 transgenic plants were obtained, achieving a transformation efficiency of 52.6%, among which 27 plants exhibited edits at the target sites, resulting in an editing efficiency of 65.9%. Phenotypic analysis of homozygous T₂ edited lines revealed significant functional redundancy among the three TaQsd1 homoeologs: a significant extension of the seed dormancy period and a substantial increase in PHS resistance were achieved only when all three A, B, and D copies underwent loss-of-function mutation (aabbdd genotype). After-ripened seeds from these mutants showed normal germination ability, indicating enhanced dormancy rather than loss of germination capacity. Importantly, all of the edited lines exhibited no significant differences compared to the wild type in key agronomic traits such as plant height, spike length, and grains per spike, thus retaining the excellent characteristics of Lunxuan 13. This study successfully optimized Lunxuan 13 for significantly enhanced PHS resistance while retaining its superior agronomic traits. This work provides an effective approach for improving PHS resistance in white-grained wheat and removes a key barrier to the potential commercialization of this variety. Full article

This case-control study investigated the association between polymorphisms in the dedicator of cytokinesis 2 (DOCK2) gene and susceptibility to COVID-19 in a Mexican population. Methods: Genotyping of five single-nucleotide polymorphisms (SNPs) in the DOCK2 gene (rs9307 A/G, rs1045176 G/T, rs1045168 C/T, rs2112703 A/C, and rs2287727 A/C) was performed using TaqMan assays in 248 COVID-19 patients and 288 healthy controls. Results: No significant differences were observed in the allelic or genotypic distributions of rs1045176 G/T and rs2287727 A/C between cases and controls. However, under multiple genetic inheritance models (co-dominant, dominant, recessive, heterozygous, and additive), the rs9307 A, rs1045168 C, and rs2112703 A alleles were significantly associated with a reduced risk of COVID-19 (p < 0.05). Furthermore, sub-analyses stratified by genotype in COVID-19 patients revealed that the rs9307 AA, rs1045168 CC, and rs2112703 AA genotypes correlated with altered plasma concentrations of lactic acid dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and ferritin. Conclusions: The DOCK2 SNPs rs9307 A/G, rs1045168 C/T, and rs2112703 A/C are associated with decreased susceptibility to COVID-19 in this population and influence plasma levels of LDH, ALT, AST, and ferritin, suggesting a potential role in disease pathogenesis and severity. Full article

The global demand for Salvia miltiorrhiza Bunge in the botanical medicine market is steadily increasing. However, its production has long relied on asexual root propagation, making it highly susceptible to germplasm degradation. Transitioning to seed reproduction offers the advantage of genetic renewal, yet it is constrained by unstable seed vigor and slow seedling growth. In the present study, comprehensive physiological and microbiome analyses of S. miltiorrhiza seeds from 14 regions across 7 provinces in China were conducted to elucidate the association between the seed microbiome and vigor, and to identify plant growth-promoting (PGP) strains. The results demonstrated: (1) Seed physical traits and germination characteristics varied significantly across geographic origins. Seed vigor, exhibiting the highest coefficient of variation, served as a key parameter reflecting germination quality. (2) High-vigor seeds harbored distinct microbial communities characterized by higher diversity indices, greater network complexity, and the significant enrichment of potentially beneficial bacteria (e.g., Pseudomonas). (3) Through correlation-directed screening of isolated pure cultures, Pseudomonas mendocina P-6 and Enterobacter ludwigii BM-12 were identified as exhibiting robust, multi-trait PGP capacity. In planta validation showed that these two strains significantly promoted the growth of 1-month-old S. miltiorrhiza seedlings, increasing total fresh weight by 33.9–71.3%. This study reveals the microecological drivers of seed vigor and provides candidate strains for inoculant development, thereby supporting the sustainable, seed-based propagation of S. miltiorrhiza. Full article

Ceratitis capitata (Diptera: Tephritidae), or medfly, is an invasive pest widespread in Argentina, where standardized management methods, such as cultural and chemical controls, are commonly implemented. The success in controlling medfly populations depends on implementing preventive, sustainable, long-term, and eco-friendly eradication/control strategies across all invaded environments. One strategy may involve augmentative biological control using parasitoids adapted to local conditions, such as Ganaspis pelleranoi (Brèthes) (Hymenoptera: Figitidae), a Neotropical-native parasitoid that mostly forages on tephritid larvae in a broad range of fallen fruit. Two hypotheses were tested in the current study: (1) G. pelleranoi females are more efficient in controlling medfly larvae infesting different fruits as the density of released females progressively increases, and (2) such parasitoid-induced host mortality capacity remains when host density is increased. Parasitism (reproductive effects) and additional host mortality (non-reproductive effects) were the indicator variables of parasitoid-induced host ability. Trials were performed in field cages (semi-field conditions) using two medfly-multiplier host fruit species, namely sour orange and peach, and with variations in both parasitoid release and host larval densities. Three major findings were highlighted: (1) G. pelleranoi females successfully parasitized host larvae on peach and sour orange, regardless of their strongly differing physical features, although medfly larvae in peaches were significantly more susceptible to the parasitoid; (2) medfly mortality significantly increased in both peach and sour orange relative to the gradual increase in released G. pelleranoi females, regardless of the increase in host density offered to parasitoids; and (3) G. pelleranoi females induced a substantially high host die-off rate when the additional mortality was added to the analysis, which was not revealed when parasitism alone was regarded as a medfly mortality variable. Such outcomes may provide relevant information for implementing an augmentative biological control against medfly using indigenous parasitoid species within an eco-friendly fruit fly pest management approach. Full article

Large, shallow lakes lacking rooted aquatic vegetation are susceptible to wind-induced wave action that results in increased shear stress on the lake bottom, sediment resuspension and poor water clarity. The relationship between meteorological, hydrographical and sediment characteristics, and sediment dynamics has implications for internal phosphorus cycling and bioavailability, the frequency and duration of harmful cyanobacterial blooms, lake level management and restoration potential. In this study, a multi-parameter water quality sonde was deployed at various sites at the bottom of Utah Lake to measure water quality variables. Sediment cores were collected at each of the deployment sites and analyzed for common physical and chemical properties. Several machine learning regression techniques, including polynomial, decision tree, artificial neural network, and support vector machine, were applied to predict turbidity, a measure of water clarity and surrogate for sediment dynamics, using the observed explanatory variables wind speed and direction, fetch, water depth, sediment properties, algae, and cyanobacteria. The decision tree estimators, random forest and histogram-based gradient boosting had the best model performance, explaining 86–89% of the variability in turbidity when including all the explanatory variables. The artificial neural network estimator multi-layer perceptron and the polynomial regression models also performed well (81%), whereas the support vector machine estimator exhibited poor performance. Chlorophyll and phycocyanin, components of turbidity, were amongst the most important variables to the decision tree and artificial neural network models. Wind speed and water depth were also of high importance, which conforms with mechanistic explanations of sediment mobility caused by wave action and shear stress. Carbonate content was consistently a good predictor due to the calcareous nature of Utah Lake, whereas the importance of the other sediment properties was dependent on the machine learning technique applied. This case study demonstrated the potential for machine learning models to predict water clarity and has promise for more general applications to other shallow lakes and serves as a useful tool for lake management and restoration. Full article

Landslides are one of the most common natural hazards in China, and the efficient screening of important factors is crucial for landslide susceptibility mapping. Taking the Zigui–Badong section of the Three Gorges Reservoir Area (TGRA) as the study area, this research initially selected 25 evaluation factors based on topography, geology, hydrology, remote sensing images, and previous studies. Thirteen key factors were obtained through analysis. Three machine learning models—RF, DT, and XGBoost—were then used for landslide susceptibility mapping, with SHAP and LIME employed to interpret the models. Finally, a scoring method was used to rank the six sets of results and compare them with those from the traditional AUC-based Recursive Feature Elimination (AUC-RFE) method. The results showed that the core factor sets screened by interpretable methods outperformed those from AUC-RFE. To further obtain accurate core factor sets, two additional interpretable methods—PI and Explainable Boosting Machine (EBM)—were integrated, ultimately identifying a core factor set consisting of eight factors including Elevation, Slope Height, and Aspect. This set achieved an AUC value of 0.931, only 0.003 lower than that of the 13 filtered factors. The screening method proposed in this paper can significantly improve the efficiency of factor acquisition, reduce the difficulty of factor acquisition, and provide a new approach for the selection of key factors in landslide susceptibility assessment. Full article

Background: COVID-19 is primarily a respiratory disease, but increasing evidence suggests possible oral and maxillofacial complications. This study presents a case series of post-COVID maxillary osteonecrosis (PC-RONJ) cases from western Romania and explores the possible association between SARS-CoV-2 infection, its treatment, and this complication. Methods: We conducted a multicenter retrospective case series of two patients with recent PCR-confirmed SARS-CoV-2 infection who subsequently developed maxillary osteonecrosis (ONC) between 2021 and 2023. Clinical examination, CT imaging (including 3D reconstructions), and ENT assessment were used to assess the severity of the disease. All medical records were reviewed to identify comorbidities, details of COVID-19 treatment, and the appearance of maxillofacial symptoms. Results: Both patients had been hospitalized for severe COVID-19 and treated according to the national protocol with systemic corticosteroids, oxygen therapy, anticoagulation, and antivirals. CT scans revealed marked osteolytic destruction of the maxilla and maxillary sinus walls, with extension toward adjacent facial bones. Microbiological analysis revealed a complex polymicrobial profile, including Gram-positive and Gram-negative bacteria as well as opportunistic fungal species, consistent with a chronic biofilm-associated infectious process. Patients received surgical treatment, followed by local care and, in both cases, prosthetic rehabilitation with maxillary obturators, which improved speech, chewing, and oral function. Conclusions: This case series suggests a possible association between severe COVID-19, its treatment, and subsequent maxillary osteonecrosis in susceptible patients; however, the small number of cases precludes causal inference. To our knowledge, this is the first Romanian report describing such cases in patients without prior antiresorptive therapy. These findings highlight the need for careful use of systemic corticosteroids and vigilant post-recovery monitoring of maxillofacial complications. Further studies are required to clarify the underlying mechanisms and risk factors. Full article

Lolium rigidum is among the most prevalent and noxious weeds in cereal and perennial cropping systems worldwide and has developed resistance to several herbicide modes of action. This study employed a sensor-based smart farming method for the early screening of herbicide resistance across three L. rigidum accessions in Greece, followed by dose–response experiments with clodinafop-propargyl, glyphosate, and mesosulfuron-methyl + iodosulfuron-methyl. In the preliminary screening, herbicides were applied at their highest recommended rates, whereas the dose–response experiments included five application rates (0, 1/4X, X, 2X, and 4X). The EM2 accession exhibited confirmed resistance to mesosulfuron-methyl + iodosulfuron-methyl, with a resistance index of 5.31 and a five-fold increase in the herbicide rate required compared to the susceptible EM1 accession. For clodinafop-propargyl, the GR50 value of the resistant EM3 accession (147.97 g a.i. ha⁻¹) was approximately 2.5-fold higher than that of the susceptible EM2 accession (60.28 g a.i. ha⁻¹). Glyphosate application provided only partial biomass reduction in resistant accessions, indicating reduced susceptibility. In parallel, TaqMan assays were developed and validated to detect target-site mutations linked to resistance against EPSPS-, ACCase-, and ALS-inhibiting herbicides, supporting the molecular interpretation of the observed resistance patterns. Overall, the results demonstrate that sensor-based smart farming approaches can provide a rapid and reliable tool for the early screening of herbicide resistance, enabling more informed crop protection strategies and supporting sustainable weed management. Further research across diverse soil types and climatic conditions is warranted to validate and extend the applicability of these approaches. Full article

Background/Objectives: Cytokine-mediated immune dysregulation contributes to the heterogeneity of multiple sclerosis (MS). Interleukin-18 (IL-18) and interleukin-8 (IL-8) are involved in distinct inflammatory pathways; however, their genetic contributions to disease susceptibility and radiological activity remain incompletely defined. Methods: In this study, 98 relapsing–remitting MS (RRMS) patients and 98 healthy controls were genotyped for IL-18 and IL-8 variations using PCR-based methods. Clinical data and MRI findings were analyzed in the MS cohort. Associations with disease susceptibility, clinical severity (EDSS), and MRI activity were evaluated using regression analyses. Results: IL-18 (−137 G/C) and IL-8 variations were significantly associated with MS susceptibility. The G allele of IL-18 (−137), the T allele of IL-8 (−251), and the C allele of IL-8 (+781) were more frequent in MS patients. No significant associations were observed between cytokine variations and clinical severity measures. However, IL-18 (−137) variation was significantly associated with higher baseline MRI lesion burden, with C allele carriers showing increased lesion counts. In addition, IL-8 (−251 AA genotype) was independently associated with increased annual lesion development. These findings were confirmed in multivariable regression analyses. Conclusions: IL-18 and IL-8 gene variations contribute to MS through distinct but complementary mechanisms. IL-18 appears to be primarily involved in disease susceptibility and baseline inflammatory burden, whereas IL-8 is more closely associated with ongoing radiological activity. These results highlight the importance of integrating genetic and imaging biomarkers to better understand disease heterogeneity in MS. Full article

Background/Objectives: Staphylococcus aureus, particularly methicillin-resistant strains, is a leading cause of severe pneumonia. Understanding local molecular epidemiology, including virulence gene profiles and antimicrobial resistance (AMR) mechanisms, is crucial for effective infection control. This pilot study aimed to characterize S. aureus isolates from pneumonia patients in Karaganda, Kazakhstan. Methods: We collected 48 respiratory samples from patients with pneumonia across three medical institutions. Bacterial identification was performed using MALDI-TOF MS. Antimicrobial susceptibility testing (AST) was carried out using European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. Whole-genome sequencing of S. aureus isolates was conducted on an Ion Torrent S5 platform. Genomic analysis included multilocus sequence typing (MLST), identification of virulence and AMR genes, and phylogenetic reconstruction. Results: S. aureus was identified in 14.6% (n = 7) of pneumonia cases included in this study. All isolates (100%, n = 7) were phenotypically resistant to benzylpenicillin. The mecA gene was detected in 57.1% of isolates (n = 4), while phenotypic resistance to methicillin was observed in 28.6% (n = 2) of the isolates. Resistance to azithromycin (57.1%, n = 4) and levofloxacin (42.9%, n = 3) was observed among the isolates. Two isolates (28.6%) were multidrug-resistant (MDR). Genomic analysis revealed the prevalence of the ST22 clone (57.1%, n = 4) in the studied cohort. Other sequence types were ST97, ST8, and ST45 (14.3% each). Phylogenetic analysis showed clustering consistent with MLST profiles. All isolates carried a conserved core virulence arsenal, including hemolysin (hla, hlg), biofilm-forming genes (icaADBC), immune evasion genes (sak, scn), and iron acquisition genes (isd). The Panton–Valentine leukocidin (PVL) genes were detected in three isolates. AMR gene analysis revealed the ubiquitous presence of mepA and tetracycline efflux pump genes, along with regulatory genes (arlRS, mepR, mgrA). The blaZ and ermA genes were not detected despite high phenotypic resistance to penicillin and macrolides. Conclusions: This study reports the identification of the virulent and resistant ST22 S. aureus clone in pneumonia cases in Karaganda, Kazakhstan. The discordance between phenotypic and genotypic AMR profiles underscores the necessity for integrated diagnostic approaches. Full article

Background: Vancomycin-resistant Enterococcus (VRE) bacteremia represents a major therapeutic and epidemiological challenge, particularly in regions with high antimicrobial resistance rates such as Southern Europe. Longitudinal local data are essential to guide infection control and antimicrobial stewardship strategies. This study aimed to evaluate temporal trends in incidence, management, and mortality of VRE bacteremia in a tertiary care center in Greece over a six-year period, including comparison before and after the coronavirus disease 2019 (COVID-19) pandemic. Methods: This retrospective observational study included adult patients with VRE bacteremia at the University Hospital of Heraklion, Greece, from 2018 to 2023. Demographic and clinical data, such as the Pitt Bacteremia Index (PBI), as well as microbiological, and treatment data were collected from patient records. Incidence was calculated per 10,000 patient-days. Comparisons were performed between survivors and non-survivors and between pre- and post-COVID-19 eras. Multivariate regression analysis was used to identify predictors of in-hospital mortality. Results: A total of 96 patients were included (mean age 68.6 ± 14.5 years; 56.3% male). The incidence of VRE bacteremia increased more than five-fold during the study period, from 0.242 cases per 10,000 patient-days in 2018 to a peak of 1.344 per 10,000 patient-days in 2022, remaining elevated in 2023 (1.001 per 10,000 patient-days). The overall in-hospital mortality was 54.2%. Non-survivors had significantly higher PBI scores compared to survivors (median 2.5 vs. 0, p = 0.005). In the multivariate analysis, higher PBI was independently associated with in-hospital mortality [odds ratio: 1.449 (95% confidence intervals: 1.166–1.801)]. Appropriate empirical therapy was administered in 41.7% of cases and was not significantly associated with survival. Post-COVID-19 patients were older (69.9 vs. 61.4 years, p = 0.0365), and antimicrobial regimens were more frequently adjusted according to susceptibility testing (55.7% vs. 18.2%, p = 0.0141), but mortality did not significantly differ between periods. Conclusion: VRE bacteremia incidence increased dramatically over the six-year study period in our tertiary center, with persistently high mortality exceeding 50%. Severity of illness at the diagnosis of bacteremia, as measured by the PBI, was an independent predictor of in-hospital mortality. Strengthened infection prevention measures, optimized antimicrobial stewardship, and early aggressive management are urgently needed to mitigate the growing burden of VRE bacteremia. Full article

Background: Gestation is a period of significant biological plasticity where the intrauterine environment influences fetal development via “fetal programming”. This study systematically reviews and meta-analyzes the association between genetic determinants—specifically the NR3C1, FKBP5, and CRHR1 genes, chosen for their pivotal role in the functional regulation and feedback sensitivity of the hypothalamic–pituitary–adrenal (HPA) axis—and stress reactivity during pregnancy. Methods: Following PRISMA guidelines, a systematic search was conducted across PubMed, Scopus, and Web of Science, yielding an initial total of 1430 records. After removing duplicates and screening 669 studies, a total of 34 primary observational studies were included in the systematic review and qualitative synthesis. For the quantitative synthesis, 27 articles provided sufficient data, resulting in k = 39 independent effect sizes analyzed via a mixed-effects model to account for tissue-specific and cohort-specific outcomes. Results: Systematic analysis reveals that maternal psychosocial stress significantly correlates with NR3C1 hypermethylation, acting as a biological mediator for neonatal cortisol dysregulation and hippocampal volume reduction. The FKBP5 rs1360780 polymorphism emerged as a key moderator of structural vulnerability, showing a “double-hit” effect when combined with epigenetic alterations. Furthermore, the study identifies sex-specific susceptibility, with divergent placental trajectories for male and female fetuses. Meta-analytic estimates confirmed the robustness of these associations (Rosenthal Fail-Safe N = 431,000), despite a general trend toward statistical significance (p = 0.079) in heterogeneous cohorts. Conclusions: The findings underscore a stable link between genetic determinants and prenatal stress reactivity. The interaction between molecular predisposition and environmental factors defines the health of the mother–infant dyad. These results advocate for a transition toward Precision Prenatal Medicine, integrating polygenic risk scores and epigenetic monitoring to implement early, targeted preventive interventions. Full article

Background: Chronic stress is a major contributing factor to mood disorders, including depression and anxiety; however, the molecular mechanisms underlying individual differences in susceptibility to such disorders remain poorly understood. DNA methyltransferase 3a (Dnmt3a), a key epigenetic regulator, has been increasingly implicated in stress-related neurobiological adaptations. In this study, we employed a well-established mouse model of chronic social defeat stress (CSDS) to investigate the functional role of Dnmt3a in modulating individual susceptibility to social stress. Methods: Male C57BL/6J mice were exposed to chronic/submaximal social defeat stress (CSDS/SSDS). AAV vectors were used to achieve Dnmt3a overexpression or global and oligodendrocyte-specific knockdown in the nucleus accumbens (NAc). Behavioral tests, including social interaction, open field, and elevated zero maze, were conducted alongside Western blotting and immunofluorescence assays. Results: CSDS selectively increased Dnmt3a expression in NAc oligodendrocytes of stress-susceptible mice. Overexpression of Dnmt3a in the NAc enhanced susceptibility to stress, whereas its knockdown conferred resilience, without affecting baseline behaviors. Dnmt3a negatively regulated myelin basic protein (MBP) and dopamine D1 receptor expression. Stress-susceptible mice exhibited shortened myelinated segments and reduced D1 receptor levels, while D2 receptor expression remained unchanged. Conclusions: Dnmt3a in NAc oligodendrocytes modulates susceptibility to social stress through a Dnmt3a-MBP/D1 receptor-NAc pathway, highlighting a critical glia-neuron interaction. This mechanism extends our understanding of the neurobiological basis of stress-related disorders and positions Dnmt3a as a promising therapeutic target for developing precision interventions or biomarkers. Full article

Large language models (LLMs) have revolutionized natural language processing, but their susceptibility to biases poses significant challenges. This comprehensive review examines the landscape of bias in LLMs, from its origins to current mitigation strategies. We categorize biases as intrinsic and extrinsic, analyzing their manifestations in various natural language processing (NLP) tasks. The review critically assesses a range of bias evaluation methods, including data-level, model-level, and output-level approaches, providing researchers with a robust toolkit for bias detection. We further explore mitigation strategies, categorizing them into pre-model, intra-model, and post-model techniques, highlighting their effectiveness and limitations. Ethical and legal implications of biased LLMs are discussed, emphasizing potential harms in real-world applications such as healthcare and criminal justice. By synthesizing current knowledge on bias in LLMs, this review contributes to the ongoing effort to develop fair and responsible artificial intelligence (AI) systems. Our work serves as a comprehensive resource for researchers and practitioners working towards understanding, evaluating, and mitigating bias in LLMs, fostering the development of more equitable AI technologies. Full article