Search Results (1,874)

Background/Objectives: CDH1 gene is widely studied, as pathogenic variants are involved in diffuse gastric cancers and lobular breast cancers. CDH1 genotype contributes to the management of clinical practice recommendations for cancer prevention. We proposed a qualitative and quantitative description of CDH1 alternative splicing profile on lymphoblastoid cell lines (LCLs). The aim of this description was to allow a comprehensive interpretation of the effect of variants of uncertain significance (VUS) on CDH1 splicing. Methods: We studied, using RNAseq, the splicing profile of 22 LCLs (untreated and treated with puromycin) with no pathogenic variant on CDH1 and evaluated the effect on CDH1 splicing of four VUS. Results: We highlighted a total of eleven alternative splicing events including four junctions starting from intron 2, defining novel isoforms of CDH1. We also identified an isoform causing the skip of exon 11 and leading to a disruption of the reading frame with high levels of expression on negative CDH1 control LCLs, confirmed by ddPCR. Splicing RNAseq results for CDH1 VUS: c.1008+1G>A and c.1936+5G>A showed complex splicing patterns but allowed their classification as pathogenic. We studied CDH1 VUS exon 4 to exon 11 duplication with RNA analysis combined with Bionano optical genome mapping. Depending on alternative splicing of proximal and distal exons 11 within the duplication, we identified four distinct transcripts, leading to truncated proteins, classifying the duplication as pathogenic. Conclusions:CDH1 has a complex alternative splicing profile characterized by a dynamic splicing of intron 2 making CDH1 a good candidate for a study using long-read RNAseq. Full article

The study of attack–defense game decision making in critical infrastructure systems confronting intelligent adversaries, grounded in complex network theory, has emerged as a prominent topic in the field of network security. Most existing research centers on game-theoretic analysis under conditions of complete information and assumes that the attacker and defender share congruent criteria for evaluating target values. However, in reality, asymmetric value perception may lead to different evaluation criteria for both the offensive and defensive sides. This paper examines the game problem wherein the attacker and defender possess distinct target value evaluation criteria. The research findings reveal that both the attacker and defender have their own “advantage ranges” for value assessment, and topological heterogeneity is the reason for this phenomenon. Within their respective advantage ranges, the attacker or defender can adopt clear-cut strategies to secure optimal benefits—without needing to consider their opponents’ decisions. Outside these ranges, we explore how the attacker can leverage small-sample detection outcomes to probabilistically infer defenders’ strategies, and we further analyze the attackers’ preference strategy selections under varying acceptable security thresholds and penalty coefficients. The research results deliver more practical solutions for games involving uncertain value criteria. Full article

Background/Objectives: Cerebral small vessel disease (CSVD) is a leading cause of cognitive decline and dementia. The comparative prognostic value of MRI-based neuroimaging markers and genetic risk factors such as the APOE ε4 allele for cognitive outcomes remains uncertain. The objectives of this study were to estimate the pooled prevalence of cognitive impairment in CSVD, evaluate the associations of key neuroimaging markers (white matter hyperintensities [WMHs], cerebral microbleeds [CMBs], lacunes) and APOE ε4 with cognitive outcomes, and assess their diagnostic performance. Methods: This study included a systematic review and meta-analysis in accordance with PRISMA and MOOSE guidelines, searching five databases (2005–2025). Eligible studies included adults with CSVD and MRI-visible markers reporting cognitive outcomes (mild cognitive impairment [MCI], global cognitive impairment [GCI], all-cause dementia [ACD], vascular dementia [VaD], and Alzheimer’s disease [AD]). Thirty-nine studies comprising 18,425 participants were included. Pooled prevalence and associations were estimated using random-effects models, and diagnostic accuracy was evaluated. Certainty of evidence was assessed using the GRADE framework. Results: The pooled prevalence of GCI in CSVD was 57% (95% CI: 51–62%), while MCI prevalence was 46% (95% CI: 42–51%). WMHs were strongly associated with VaD (OR 10.35, 95% CI: 7.32–14.64), lacunes with ACD (OR 3.18, 95% CI: 1.24–8.20), and CMBs with AD (OR 1.52, 95% CI: 1.04–2.24). APOE ε4 carriage increased the risk of GCI (OR 1.80, 95% CI: 1.41–2.29). Across markers, diagnostic sensitivity was low, specificity was moderate-to-high, and AUROC values were modest. GRADE certainty ranged from low to moderate, with the highest confidence for WMHs and VaD. Conclusions: CSVD-related MRI markers and APOE ε4 are significantly associated with both early and late cognitive outcomes, supporting the integrated vascular–neurodegenerative continuum. The limited diagnostic sensitivity and variable certainty of evidence highlight the need for harmonized definitions, lesion quantification, and multimodal imaging–genetic approaches to improve early detection and risk stratification of CSVD-related cognitive impairment. Full article

Wearable devices are increasingly used for health and stress monitoring, yet their accuracy under dynamic, real-world conditions remains uncertain. This study validated the heart rate measurement accuracy of one chest-worn device (Zephyr BioHarness 3.0), a research-grade wrist-worn device (EmbracePlus), and five commercial wrist-worn wearable devices (Fitbit Charge 5, Fitbit Sense 2, Garmin Vivosmart 4, WHOOP 4.0, and Withings Scanwatch) against a 12-lead ECG using a 20 min protocol simulating real-life dynamics, including rest and varied-intensity walking. Device performance was evaluated across the full protocol and during transient states, defined as periods of rapid heart rate change. Accuracy and agreement were evaluated across per-second, 10 s, and 60 s resolutions. The Zephyr device showed a strong performance during all dynamic conditions. Among the wrist-worn devices, the Fitbit Charge 5 and Sense 2 showed the highest accuracy overall, while the Garmin Vivosmart 4 demonstrated greater stability during transitions. The WHOOP 4.0, Withings Scanwatch, and EmbracePlus devices performed acceptably during steady-state conditions, but were less accurate during transitions. Performance notably declined across all wrist-worn devices during transient states, with motion onset and large step changes in heart rate exacerbating measurement errors. Larger averaging windows improved accuracy by smoothing variability. The findings underscore that wrist-worn wearable devices may be better suited for average and trend heart rate monitoring rather than capturing acute dynamics. However, the Garmin and Fitbit devices showed suitable when requiring moderate accuracy during dynamic conditions. These results highlight the importance of context-specific validation and informed device selection to ensure effective use in health and stress-related applications. Full article

Background: The gut microbiome is crucial in sustaining intestinal balance and general health. Following rectal cancer surgery, the creation of a diverting stoma to protect the anastomosis results in a defunctioned colon, leading to dysbiosis. The effect of probiotic intake on gut dysbiosis following ileostomy repair remains uncertain. Thus, this study aims to determine the changes in gut microbiota based on the intake of probiotics after diverting stoma repair. Methods: This single-center, parallel, prospective pilot study will include patients with primary rectal cancer planning to undergo a diverting stoma during rectal cancer surgery. The study will comprise 20 patients, with 10 patients receiving synbiotics after stoma repair and 10 patients not receiving probiotics. The primary endpoint is the change in the gut microbiota of the resting colon based on the intake of probiotics, assessed through fecal testing at the following time points: before bowel resection, immediately after diverting stoma repair, and 3 weeks after diverting stoma repair. Changes in gut microbiota will be evaluated using alpha- and beta-diversity analyses based on 16S rRNA sequencing of fecal samples. Discussion: This study is the first prospective cohort trial investigating changes in the gut microbiota of the resting colon based on oral probiotic administration in patients undergoing diverting stoma repair. This trial is anticipated to clarify the impact of probiotic intake in these patients. Trial registration: Clinical Research Information Service (CRIS) of the Republic of Korea, KCT0008392, Registered on 27 April 2023. Full article

Background: Sarcopenia is linked with high rates of adverse surgical outcomes, and computed tomography angiography (CTA)-based psoas measurements are used as imaging sarcopenia surrogates. Their prognostic value in patients with chronic limb-threatening ischemia (CLTI) undergoing revascularization remains uncertain. Objectives: To evaluate whether CTA-derived psoas muscle indices predict complications and mortality after lower-limb revascularization for CLTI. Methods: We performed a retrospective cohort study of consecutive adults who underwent open, hybrid, or endovascular revascularization for CLTI at a single tertiary center (March 2018–December 2021). Psoas muscle area (PMA) and density (PMD) were measured preoperatively on CTA at the mid-L3 vertebral level. Psoas muscle index (PMI) was calculated as PMA/height². Patients were stratified by tertiles for each index (lowest tertile = “sarcopenic” vs. upper two tertiles). Outcomes included early in-hospital complications, late complications, overall complications, late mortality, and overall mortality. Group comparisons used χ²/Fisher tests with false discovery rate (FDR) adjustment; multivariable logistic regression with AIC-guided selection assessed independent predictors. Results: A total of 234 patients were included (median age 68 years; 65.4% men). Early complications occurred in 15.8%; late complications in 70.3%; overall mortality during follow-up was 26.6% (38/143 within follow-up data). In tertile analyses, none of the psoas-derived measures were significantly associated with early complications, late complications, overall complications, or mortality after FDR correction. Lower PMD showed consistent but non-significant trends toward higher late complications (84% vs. 64%), overall complications (87% vs. 72%), overall mortality (38% vs. 21%), and late mortality (37% vs. 20%) (all p < 0.05 unadjusted; all p_adj ≥ 0.139). In multivariable models, PMA, PMD, and PMI were not independent predictors of any outcome. Conclusions: In this retrospective cohort study, preoperative CTA-derived psoas indices were not independent predictors of early, late, or overall complications, nor of in-hospital or follow-up mortality after revascularization for chronic limb-threatening ischemia. Although lower psoas muscle density showed consistent trends toward higher risk, these associations did not reach statistical significance after adjustment. Taken together, our findings suggest that psoas-based measures have limited prognostic value in this setting and should be interpreted cautiously, while their potential role warrants confirmation in larger, prospective studies. Full article

Background: Parkinson’s disease (PD) is characterized not only by motor dysfunction but also by widespread degeneration across cortico-striatal, limbic, and cortical circuits. Mounting evidence suggests that tau and α-synuclein pathology underlie these processes, though how these proteinopathies translate into affective and cognitive outcomes remains uncertain. Depression and anxiety are highly prevalent in PD, yet the biological correlates of these affective disturbances are poorly defined. Methods: This is a retrospective analysis of existing data from the Parkinson’s Progression Markers Initiative (PPMI). Montreal Cognitive Assessment (MoCA), geriatric depression scale (GDS), and State-Trait Anxiety Inventory (STAI) were used to assess cognition, depression, and anxiety in PD, respectively. The CSF biomarkers evaluated were Aβ42, t-tau, and p-tau181, using Elecsys electro-chemiluminescence immunoassays on the cobas e601 platform (Roche Diagnostics). Results: From the 4380 patients who had GDS information, the MoCA test was collected from 438 patients, and 445 from the GDS test for depression, and the STAI screening for anxiety. There were no significant differences in biomarker levels between patients with depression (GDS ≥ 5) and those without (GDS < 5), nor between patients with anxiety (STAI > 40) and those with lower anxiety scores (STAI ≤ 40). In contrast, cognitive outcomes showed clear associations. Patients with cognitive impairment (MoCA < 26) demonstrated higher levels of pTau (p = 0.02) and tTau (p = 0.01), as well as elevated pTau/Aβ42 (p = 0.003) and tTau/Aβ42 (p = 0.002) ratios compared to those with MoCA ≥ 26. In multivariate analysis, both pTau/Aβ42 > 0.022 (OR 4.64, 95% CI 1.67–13.8) and tTau/Aβ42 > 0.26 (OR 4.18, 95% CI 1.6–11.5) remained significantly associated with cognitive decline. In a longitudinal analysis in the first 3 years of follow-up, cognition in PD remained lower than in controls, while CSF p-tau and Aβ42 remained higher in controls. Conclusions: In our cohort, no associations were found between CSF biomarkers and depression or anxiety, underscoring that mood disturbances in PD are likely mediated by alternative mechanisms such as monoaminergic dysregulation, neuroinflammation, and psychosocial factors. By contrast, cognitive performance (MoCA) was clearly linked to tau-related pathology, rather than α-synuclein or Aβ42 alone. While Aβ42 and α-synuclein remain useful for staging and assessing global disease risk, our findings highlight the specificity of tau-related pathology for cognitive outcomes in PD. Full article

Background and objectives: Large language models (LLMs) show promise in automating open-ended evaluation tasks, yet their reliability in rubric-based assessment remains uncertain. Variability in scoring, feedback, and rubric adherence raises concerns about transparency and pedagogical validity in educational contexts. This study introduces CourseEvalAI, a framework designed to enhance consistency and fidelity in rubric-guided evaluation by fine-tuning a general-purpose LLM with authentic university-level instructional content. Methods: The framework employs supervised fine-tuning with Low-Rank Adaptation (LoRA) on rubric-annotated answers and explanations drawn from undergraduate computer science exams. Responses generated by both the base and fine-tuned models were independently evaluated by two human raters and two LLM judges, applying dual-layer rubrics for answers (technical or argumentative) and explanations. Inter-rater reliability was reported as intraclass correlation coefficient (ICC(2,1)), Krippendorff’s α, and quadratic-weighted Cohen’s κ (QWK), and statistical analyses included Welch’s t tests with Holm–Bonferroni correction, Hedges’ g with bootstrap confidence intervals, and Levene’s tests. All responses, scores, feedback, and metadata were stored in a Neo4j graph database for structured exploration. Results: The fine-tuned model consistently outperformed the base version across all rubric dimensions, achieving higher scores for both answers and explanations. After multiple-testing correction, only the Generative Pre-trained Transformer (GPT-4)—judged Technical Answer contrast remains statistically significant; other contrasts show positive trends without passing the adjusted threshold, and no additional significance is claimed for explanation-level results. Variance in scoring decreased, inter-model agreement increased, and evaluator feedback for fine-tuned outputs contained fewer vague or critical remarks, indicating stronger rubric alignment and greater pedagogical coherence. Inter-rater reliability analyses indicated moderate human–human agreement and weaker alignment of LLM judges to the human mean. Originality: CourseEvalAI integrates rubric-guided fine-tuning, dual-layer evaluation, and graph-based storage into a unified framework. This combination provides a replicable and interpretable methodology that enhances the consistency, transparency, and pedagogical value of LLM-based evaluators in higher education and beyond. Full article

Soil mineral nutrient heterogeneity is a distinctive characteristic of coastal habitats, yet its impact on plant growth and development remains uncertain. The objective of the present study was to establish an experimental system for evaluating the influence of mineral nutrient availability on the development of three distinct short-lived wild coastal plant species: Phleum arenarium, Plantago coronopus, and Ranunculus sceleratus. These plants were cultivated in containers of different volumes employing an inert substrate with varying proportions of commercial garden soil in controlled conditions. Low mineral nutrient concentration served as a factor inhibiting plant vegetative growth for both P. arenarium and R. sceleratus plants, albeit with a substrate volume-dependent effect. In contrast, P. coronopus exhibited relatively low root biomass and exhibited minimal susceptibility to alterations in mineral nutrient concentration. Conversely, proportional allocation to roots decreased with increasing mineral nutrient concentration, mirroring the pattern observed for P. arenarium. Notably, for R. sceleratus, this effect was pronounced only at a high substrate volume. Furthermore, allocation to roots decreased with increasing substrate volume, but this occurred only at a high mineral nutrient concentration. The substrate, similar to that in coastal habitats, incorporated quartz sand with varying proportions of mineral-rich organic matter, providing comparable plant-available mineral concentrations for analyzing the effects of nutrient concentration, substrate volume, and genetic variability on plant growth and development. For future experiments, a wider range of mineral concentrations and more individual concentrations should be used to assess mineral availability more realistically. Full article

Sertraline, a selective serotonin reuptake inhibitor (SSRI), has emerged as a candidate for therapeutic repurposing due to its reported antifungal activity. We systematically reviewed in vitro, in vivo, and clinical evidence up to July 2025 (PubMed, Scopus, Web of Science). As a result, 322 records were screened and 63 studies were found to meet the inclusion criteria (PRISMA 2020). We close a critical gap by consolidating relevant evidence on Candida auris, including preclinical in vivo models, which have been under-represented in previous summaries. Outcomes included minimum inhibitory and fungicidal concentrations (MIC/MFC), biofilm inhibition, fungal burden, survival, and pharmacokinetic/pharmacodynamic parameters. Preclinical data indicate its activity against clinically relevant fungi—particularly Cryptococcus neoformans and Candida spp., including C. auris—as well as consistent anti-biofilm effects and synergy with amphotericin B, fluconazole, micafungin, or voriconazole. Mechanistic evidence implicates mitochondrial dysfunction, membrane perturbation, impaired protein synthesis, and calcium homeostasis disruption. However, its potential for clinical translation remains uncertain: in cryptococcal meningitis, small phase II studies suggested improved early fungicidal activity, whereas a phase III randomized trial did not demonstrate a benefit regarding survival. Pharmacokinetic constraints at conventional doses, the absence of an intravenous formulation, and safety considerations at higher doses further limit its immediate applicability. Overall, the available evidence supports sertraline as a promising adjuvant candidate, rather than a stand-alone antifungal. Future research should define PK/PD targets, optimize doses and formulations, and evaluate rational combinations through rigorously designed trials, particularly for multidrug-resistant and biofilm-associated infections. Full article

Understanding the climate change impacts on the geographical distribution of plant species is vital for biodiversity conservation. Lycium ruthenicum, a second-grade protected plant in China, holds considerable medicinal and ecological value; however, its potential habitat distribution under climate change remains uncertain. By utilizing occurrence records and geographical and environmental data, we optimized a maximum entropy model and evaluated the current and future potential habitat suitability of L. ruthenicum in China. The main results were as follows: (1) The distribution of L. ruthenicum was primarily influenced by the precipitation of the warmest quarter, topsoil base saturation, precipitation seasonality, precipitation of the coldest quarter, and minimum temperature of the coldest month. (2) Under the current conditions, the potential suitable area of L. ruthenicum was approximately 2.25 × 10⁶ km² in China, predominantly distributed in Xinjiang, Qinghai, Gansu, Ningxia, and Inner Mongolia. (3) An obvious reduction in the predicted suitable area of L. ruthenicum was found under future climate scenarios, with the centroid primarily shifting northeastward. These findings highlight the potential vulnerability of this medicinally and ecologically important species and underscore the urgent need for targeted conservation strategies to ensure its long-term survival. Full article

Background/Objectives: Persistent human papillomavirus (HPV) infection is the leading cause of cervical intraepithelial neoplasia (CIN), a known precursor to cervical squamous carcinoma. While progesterone receptor membrane component 1 (PGRMC1) has been implicated in various cancers, its specific role in cervical carcinogenesis has remained uncertain. This study aimed to elucidate the function of PGRMC1 in the progression of CIN. Methods: Bioinformatics techniques were employed to assess the expression levels of PGRMC1 in cervical cancer tissues and to investigate its correlation with patient prognosis. To explore the functional role of PGRMC1, we manipulated its expression in the cervical cancer cell line HeLa using siRNA. Subsequently, we evaluated cell migration via the scratch assay, and invasion through the Transwell assay. We employed mass spectrometry to identify proteins interacting with PGRMC1 and confirmed these interactions using co-immunoprecipitation (co-IP). Further co-IP experiments were conducted to pinpoint the specific binding sites of these protein interactions, and immunofluorescence staining was utilized to observe the spatial distribution of interacting proteins within the cells. The phosphorylation status of VIM was further confirmed by WB. At the clinical level, we collected cervical biopsy specimens from HPV-positive patients and verified the expression patterns of PGRMC1 and VIM using immunohistochemical staining in cervical squamous cell carcinoma (CSCC) tissues. Results: We discovered a correlation between progressively increasing PGRMC1 expression and the severity of CIN as well as a poor prognosis. Knockdown of PGRMC1 resulted in the inhibition of migration and invasion capabilities in cervical cancer cells. Furthermore, PGRMC1 was found to physically interact and colocalize with Vimentin (VIM). Notably, PGRMC1 knockdown specifically increased phosphorylation at the Ser-39 residue of VIM. Conclusions: Our findings suggest that PGRMC1 facilitates CIN progression by binding to VIM and suppressing Ser-39 phosphorylation, thereby promoting the migration and invasion of cervical carcinoma cells. This study enhances our understanding of PGRMC1’s role in CIN progression and lays an experimental foundation for targeted therapeutic approaches to cervical squamous carcinoma. Full article

DNA binding proteins play a crucial role in regulating gene expression, DNA replication, and chromatin organization. While many DNA-binding proteins have been identified, many unique DNA-binding proteins in non-model organisms and recently evolved lineage- or species-specific proteins remain uncharacterized or often lack experimental validation. In addition, genetic variants may alter previously known DNA-binding proteins, leading to loss of binding ability. To address this gap, various computational tools have been developed to predict DNA-binding proteins from protein sequences or structures. Yet, their real-world utility in biological research remains uncertain. To evaluate their effectiveness, we assessed the availability and predictive performance of existing tools using five real-world case studies. We found that most tools were web-based, offering accessibility to researchers without computational expertise. However, many suffered from poor maintenance, including frequent server connection problems, input errors, and long processing times. Among the ten tools that were functional and practical, we found that prediction scores often failed to reflect incorrect outputs, and multiple methods frequently produced the same erroneous predictions. Overall, even a small number of misclassifications can significantly distort biological interpretation, indicating that current DNA-binding prediction tools are not yet sufficiently reliable for empirical research. Full article

Background: Anterior shoulder dislocations are common in athletes, particularly in contact sports. Surgical stabilization reduces recurrence, but the optimal timing—early versus delayed—remains uncertain, especially for in-season athletes. Methods: A systematic search of PubMed, Embase, and Cochrane (2013–2023) yielded 945 articles; 15 met the inclusion criteria. Data were charted on procedure type, outcomes, follow-up, patient group, and timing of surgery. Search terms, e.g., ‘shoulder’, ‘athlete’, ‘anterior’ and ‘shoulder dislocation’, were used in a broad search protocol casting a wide net to maximize the likelihood of capturing all available data. Results: Surgery was superior to conservative care in lowering recurrence and enabling return-to-play, with arthroscopic and combined procedures most effective in high-contact sports. Conservative management carried higher instability risk. Evidence directly comparing early versus delayed surgery was scarce, and therefore inconclusive. Conclusions: Surgical stabilization remains the treatment with better outcomes compared to conservative treatment for young athletes. Still, athletes opt to delay surgery until postseason, with the impact of delaying surgery being unclear. Further research is needed to evaluate early versus delayed surgery regarding recurrence, joint damage, and return to sport. Full article

Background: Rare pediatric neurological diseases (RPND) often remain undiagnosed for years, creating prolonged and costly diagnostic odysseys. Combining Human Phenotype Ontology (HPO)-based deep phenotyping with exome sequencing (ES) and reverse phenotyping offers the potential to improve diagnostic yield, accelerate diagnosis, and support sustainable healthcare in resource-limited settings. Objectives: To evaluate the diagnostic yield and clinical impact of an integrated approach combining deep phenotyping, ES, and reverse phenotyping in children with suspected RPNDs. Methods: In this multicenter observational study, eighty-one children from eleven hospitals in South Kazakhstan were recruited via the Central Asian and Transcaucasian Rare Pediatric Neurological Diseases Consortium. All patients underwent standardized HPO-based phenotyping and ES, with variant interpretation following ACMG guidelines. Reverse phenotyping and interdisciplinary discussions were used to refine clinical interpretation. Results: A molecular diagnosis was established in 34 of 81 patients (42%) based on pathogenic or likely pathogenic variants. Variants of uncertain significance (VUS) were identified in an additional 9 patients (11%), but were reported separately and not included in the diagnostic yield. Reverse phenotyping clarified or expanded clinical features in one-third of genetically diagnosed cases and provided supportive evidence in most VUS cases, although their classification remained unchanged. Conclusions: Integrating deep phenotyping, ES, and reverse phenotyping substantially improved diagnostic outcomes and shortened the diagnostic odyssey. This model reduces unnecessary procedures, minimizes delays, and provides a scalable framework for advancing equitable access to genomic diagnostics in resource-constrained healthcare systems. Full article