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关键词： children   diabetes mellitus type 1   psychosocial   qualitative interviews   screening   surveys and questionnaires  

摘要： Aims: Research and policy initiatives for type 1 diabetes (T1D) across European countries demonstrate an emergent, critical shift towards universal paediatric screening. National adaptations of screening, however, remain under-researched. The current study, as part of the EU-funded EDENT1FI programme, aimed to examine the psychosocial impact and acceptability of screening according to local contexts and regions. Methods: The EDENT1FI screening research programme includes 27 partners involved in implementing screening across eight European countries-four countries already implementing national or local research screening programmes and four countries that are new adopters. The study consists of four sub-studies with assessments performed at five timepoints, from screening baseline to insulin-requiring T1D: (1) we examine the screening-specific psychological impact on families using a novel questionnaire for parents of screened children;(2) we further measure the psychological wellbeing of parents by administering validated questionnaires;(3) we explore parental acceptability through semi-structured interviews and (4) we explore professional stakeholder acceptability via semi-structured interviews. Data analysis will integrate questionnaire responses and thematic analysis for the interviews. Results: Findings should provide a deeper understanding of the psychosocial aspects of universal paediatric screening measured longitudinally. The experience of implementation context across countries will be harmonised with the attitudes towards and practices of screening to inform best practice for scaling up universal screening. Conclusions: The study will provide essential insights into how best a general population screening program for T1D can be integrated into existing European health systems.

关键词： Genetic causes of cancer   Breast cancer   Prostate cancer   Small interfering RNA   Transfection   DNA repair   Cancer treatment   Ovarian cancer  

摘要： Microcephalin-1 (MCPH1) is a tumour suppressor protein that regulates homologous recombination repair (HRR) and is down-regulated in several tumour types. Given that HRR-defective cancer cells can be killed via synthetic lethal approaches, MCPH1 thus represents an attractive target in cancer therapy. Functionally, cells lacking MCPH1 have reported defects in the recruitment and retention of BRCA2 and RAD51 to DNA double strand breaks (DSBs) during HRR, though the magnitude of this defect in human cells is not entirely clear. Multiple studies have demonstrated that HRR-defective cells, particularly those lacking BRCA1 and BRCA2, can be specifically killed by inhibitors of the base excision repair enzyme, poly(ADP-ribose) polymerase-1 (PARP-1). Mechanistically, PARP-1 inhibition can cause (i) elevated DNA single strand breaks (SSBs) and (ii) 'PARP-1 trapping' on damaged DNA, both of which can lead to the formation of DSBs during DNA replication, which would normally be repaired by HRR. Given the functional link between MCPH1 and BRCA2, this study aimed to compare HRR-deficiency in cells lacking either protein and correlate this with PARP-1 inhibitor sensitivity. Our data shows that MCPH1-deficient cells are defective in HRR but still retain similar to 50% activity and this results in little to no sensitivity to two clinically-relevant PARP-1 inhibitors. In contrast, BRCA2-deficient cells showed a far greater defect in HRR and consistent sensitivity to both PARP-1 inhibitors, which was not enhanced by co-depletion of MCPH1. These data suggest that the magnitude of HRR defect in cancer cells influences PARP-1 inhibitor sensitivity and BRCA2 retains significant functionality in the absence of MCPH1.

摘要： Herein, we develop a photocatalytic [4 + 1] annulation of vinyl aziridines with alkyl halides. The reaction appears to experience radical trigger kinetically favored β-scission of the vinyl aziridine C–N bond, generating transient nitrogen-centered radical, followed by sequential single electron oxidation, 5-exo-trig cyclization, and protonation. Significantly, an unprecedented annulation mode in which vinyl aziridines serve as four-atom synthons has been disclosed.

摘要： Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian life span and protects against a range of age-related diseases. Unexpectedly, we found that reduced IGF-1 signaling fails to extend the life span of mitochondrial mutator mice. Most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the prolongevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome, revealing an unexpected hierarchy in the pathways that control mammalian aging. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.

关键词： 1-absorbing prime ideals   rho-ideals   (1, rho)-absorbing ideals   (1, P)-absorbing ideals   1, P-& lowast   )-absorbing ideals  

摘要： This paper introduces and investigates new generalizations of both 1-absorbing prime and rho-ideals in the setting of noncommutative rings with identity, using special radicals rho. We define the notions of (1, rho)-absorbing and (1, rho*)-absorbing ideals for a given special radical rho, and we study the relationships between these new classes of ideals and previously known ideal classes. Several structural results are obtained, characterizing when these ideals coincide or differ, especially in the existence or absence of the identity. We provide characterizations in product rings, under homomorphic images, and for constructions such as idealizations. A portion of the study is devoted to the case when rho = P, the prime radical, where we establish specific properties in various classes of rings, including C I-rings.

摘要： Glycolysis is critical for NLRP3 inflammasome activation, yet the link between lactic acid metabolism and inflammasome signaling remains unclear. Here, we show that stimulation of macrophages with the NLRP3 activators nigericin or ATP induces lactic acid production and efflux via a lactate dehydrogenase–dependent pathway. Accumulation of intracellular lactic acid leads to cytoplasmic acidification, which promotes NLRP3 inflammasome activation. Concurrently, elevated extracellular lactic acid impairs lactate efflux, exacerbating intracellular acidification and amplifying ASC speck formation, caspase-1 activation, and IL-1β secretion. Alkalinization of the extracellular milieu prevents intracellular acidification and abolishes inflammasome activation. Mechanistically, intracellular lactic acidification promoted mitochondrial dysfunction and reactive oxygen species production, and concurrently induced phosphorylation of the stress kinase PKR, which facilitated PKR–NLRP3 interaction and inflammasome assembly through parallel pathways. Independently of inflammasome signaling, lactic acid also directly cleaves pro-IL-1β and pro-IL-18 into mature forms through a mechanism requiring its carboxyl group and mimicking caspase-1 substrate specificity. Mass spectrometry analysis revealed lactic acid–mediated cleavage of pro-IL-1β at Asp116, the canonical caspase-1 site. In a murine model of polymicrobial sepsis induced by cecal ligation and puncture, systemic lactate administration exacerbated inflammation, increased IL-1β levels and neutrophil infiltration, induced hypothermia, and worsened survival. Together, these findings identify intracellular lactic acidification as a metabolic signal that promotes inflammation predominantly through NLRP3 inflammasome activation, while also revealing a potential inflammasome-independent cytokine processing mechanism under conditions of severe metabolic stress.