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IsoDGR-Induced Endothelial Cytoskeletal Disruption Drives Age-Related Blood-Brain Barrier Breakdown
No full text3867 Improving frailty education for undergraduate medical students at a UK teaching hospital
No full textSpatial disaggregation for relative risks, with an application to drug-related problems in North East England
No full textGene body methylation buffers noise in gene expression in plants
No full textAbstract Non-genetic variability in gene expression is an inevitable consequence of the stochastic nature of processes driving transcription and translation. While previous studies demonstrated that gene expression noise is negatively correlated with gene body methylation, the function of this correlation remains poorly understood in multicellular systems. Here, we provide a first functional link between gene body methylation and transcription noise in plants. We investigated a mutant with partial loss of CG methylation (met1-1) and 10 epigenetic recombinant inbred lines (epiRILs) generated by a cross between Col-0 and met1-3 plants, and observed an increase in gene expression noise, but this was not the case in met1-3 with complete loss of CG methylation. Loss of CG methylation in met1-3 could be compensated by a low but significant gain of non-CG methylation that buffers the noise in gene expression. Overall, our results show that gene body methylation has a functional role in reducing variability in transcription in a large subset of housekeeping genes, which require precise expression patterns to meet metabolic requirements. Genes lacking this noise-buffering effect are mainly enriched in stress response, where variability in gene expression can be seen as highly beneficial.</jats:p
Partitioned polygenic scores show mechanistic heterogeneity in type 2 diabetes and hypertension comorbidity.
No full textType 2 diabetes and hypertension are common health conditions that often occur together, suggesting shared biological mechanisms. To explore this relationship, we analyse large-scale multiomic data to uncover genetic factors underlying type 2 diabetes and blood pressure comorbidity. We curate 1304 independent single-nucleotide variants associated with type 2 diabetes and blood pressure, grouping them into five clusters related to metabolic syndrome, inverse type 2 diabetes/blood pressure risk, impaired pancreatic beta-cell function, higher adiposity, and vascular dysfunction. Colocalization with tissue-specific gene expression highlights significant enrichment in pathways related to thyroid function and fetal development. Partitioned polygenic scores derived from these clusters improve risk prediction for type 2 diabetes/hypertension comorbidity, identifying individuals with more than twice the usual susceptibility. These results reveal a mechanistically heterogeneous genetic architecture shared between type 2 diabetes and blood pressure, enhancing comorbidity risk prediction. Partitioned polygenic risk scores offer a promising approach for early risk stratification, personalised prevention, and improved management of these interconnected conditions
Clasificación, preferencia y percepción de los asuntos de correos electrónicos de estudiantes universitarios chinos y españoles
No full textEl asunto es una categoría textual que mantiene una estrecha relación con el cuerpo del mensaje y combinada con otros datos de la cabecera, como la fecha y el emisor, permite resumir el contenido del mensaje de forma objetiva. Numerosas investigaciones han investigado su contenido, longitud e impacto en el receptor, no obstante, estos resultados son mixtos. El presente trabajo analiza la preferencia de uso, la función y el efecto que este posee en la comunicación mediada por ordenador (CMO) en un contexto académico. Para ello, primero se observaron y clasificaron 262 asuntos en búsqueda de los usos y las preferencias de los estudiantes universitarios españoles (n = 38) y chinos (n = 224) al comunicarse con un miembro de la facultad y después se contrastaron con la percepción de un grupo de docentes (n = 14) en cuanto a su adecuación y relevancia al contexto. Los resultados muestran una tendencia hacia la omisión del asunto en ambos grupos. En aquellos casos en los que sí se utilizó, tanto españoles como chinos prefirieron hacer referencias al contenido del mensaje. La percepción de los docentes mostró la necesidad de instruir a los alumnos en una correcta redacción de correos electrónicos.</jats:p
The impact of adverse childhood experiences on DNA methylation age: a systematic review and meta-analysis.
No full textAdverse childhood experiences (ACEs), such as abuse and neglect, are associated with poor health in adulthood. One proposed biological mechanism linking early adversity to health outcomes is epigenetic age acceleration (EAA), a measure of biological aging derived from DNA methylation. Understanding whether ACEs contribute to EAA might identify pathways linking early life stress to increased risk of morbidity and mortality.This systematic review and meta-analysis examined the relationship between cumulative ACE exposure and EAA in adults across 27 eligible observational studies from 1036 identified by comprehensive screening of the literature. Studies involved more female participants (median 56.6%) and employed a range of epigenetic clocks, most frequently Horvath, GrimAge, and PhenoAge. Risk of bias was assessed using the ROBINS-E tool, with most studies rated as having some concerns, primarily due to a lack of adjustment for key covariates. Meta-analyses of 6 studies using cumulative ACE exposure and standardised regression coefficients revealed no significant associations with EAA for first-generation clocks (Horvath: β = - 0.03, 95% CI - 0.15 to 0.09; Hannum: β = - 0.09, 95% CI - 0.41 to 0.23) or second-generation clocks (PhenoAge and GrimAge: both β = 0.21, 95% CIs spanning zero). Narrative synthesis of studies, including those that could not be considered in the meta-analyses, highlighted heterogeneous methodologies and mixed findings, particularly for individual ACEs and third generation clocks such as DunedinPACE. These findings suggest that while ACEs may influence biological aging, current evidence does not support a robust or consistent association with EAA. The study identifies the need for more consistent methodologies in future research
Toward AI Autonomous Navigation for Mechanical Thrombectomy Using Hierarchical Modular Multi-Agent Reinforcement Learning (HM-MARL)
No full textTurn CAR T against TAMs.
No full textThe diversity of tumor-associated macrophages presents a major challenge to the clinical translation of myeloid cell-targeting strategies. In this issue of Cancer Cell, Yagel et al. and Mateus-Tique et al. demonstrate that IL-12 armored CAR T cells effectively target tumor-promoting macrophage populations and reset the microenvironment toward an anti-cancer mode
Risk of ovarian cancer in women with a pathogenic or likely pathogenic variant in NBN: a systematic review and meta-analysis.
Get PDFOBJECTIVE: NBN is a putative ovarian cancer susceptibility gene. The association between a pathogenic variant in NBN and ovarian cancer is not well-established. We aimed to estimate the ovarian cancer risk in unselected women with an NBN pathogenic variant. DATA SOURCES: PubMed, EMBASE searched from inception to January 2026. ELIGIBILITY-CRITERIA: Population: Women diagnosed with ovarian cancer undergoing germline sequencing of NBN (Intervention). STUDY APPRAISAL AND SYNTHESIS METHODS: We followed a prospective protocol as per PRISMA guidelines (PROSPERO: CRD42024567791). The number of NBN pathogenic variants in ovarian cancer cases in included studies were pooled and an estimated odds calculated. This was compared to the odds of an NBN loss-of-function variant in gnomAD-v4.1 controls of matched ethnicities to obtain the odds-ratio of ovarian cancer with an NBN pathogenic variant. We performed prespecified subgroup analyses for high-grade serous carcinoma and non-high-grade serous-carcinoma, and those with a family-history of ovarian cancer. RESULTS: Searches yielded 9,025 studies; 57 studies (n=40,537) were included in our initial analysis: 36 in majority White-cohorts (n=33,822) and 21 in non-White cohorts (n=6,715). In the White-cohorts, the odds-ratio of ovarian cancer with an NBN pathogenic variant was 1.68 (95% confidence-interval:1.37-2.07, p<0.001), and the derived relative risk and lifetime-risk of ovarian cancer 1.66 and 3.32% respectively. For the commonest pathogenic variant c.657_661del, the odds-ratio was 2.69 (95% confidence-interval:1.58-4.57, p<0.001), and the relative risk and lifetime-risk of OC 2.60 and 5.2% respectively. The odds-ratio of high-grade serous carcinoma and non-high-grade serous carcinoma is 1.58 (95% confidence-interval:1.02-2.45, p=0.039), and 2.43 (95% confidence-interval:1.56-3.81, p<0.001) respectively. Data in non-White cohorts and in ovarian cancer cases with family history was insufficient for any meaningful inference. CONCLUSIONS: There is a clear association between an NBN pathogenic variant and ovarian cancer in the White-population, and this may be stronger with non-high-grade serous carcinoma compared to high-grade serous carcinoma. Further data is required to confirm the association with family history or establish any association in the non-White population. NBN pathogenic variants could be combined with other non-genetic and genetic (polygenic-risk-score) ovarian cancer risk factors using complex ovarian cancer risk-prediction models going forward, to identify several NBN-positive women at an ovarian cancer risk level for offering surgical prevention