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Oxidative-Stress-Mediated Epigenetic Dysregulation in Spermatogenesis: Implications for Male Infertility and Offspring Health
No full textMale reproductive health is governed by an intricate interplay of genetic, epigenetic, and environmental factors. Epigenetic mechanisms-encompassing DNA methylation, histone modifications, and non-coding RNA activity-are crucial both for spermatogenesis and sperm maturation. However, oxidative stress, driven by excessive reactive oxygen species, disrupts these processes, leading to impaired sperm function and male infertility. This disruption extends to epigenetic modifications, resulting in abnormal gene expression and chromatin remodeling that compromise genomic integrity and fertilization potential. Importantly, oxidative-stress-induced epigenetic alterations can be inherited, affecting the health and fertility of offspring and future generations. This review investigates how oxidative stress influences epigenetic regulation in male reproduction by modifying DNA methylation, histone modifications, and non-coding RNAs, ultimately compromising spermatogenesis. Additionally, it discusses the transgenerational implications of these epigenetic disruptions and their potential role in hereditary infertility and disease predisposition. Understanding these mechanisms is vital for developing therapeutic strategies that mitigate oxidative damage and restore epigenetic homeostasis in the male germline. By integrating insights from molecular, clinical, and transgenerational research, this work emphasizes the need for targeted interventions to enhance male reproductive health and prevent adverse outcomes in progeny. Furthermore, elucidating the dose-response relationships between oxidative stress and epigenetic changes remains a critical research priority, informing personalized diagnostics and therapeutic interventions. In this context, future studies should adopt standardized markers of oxidative damage, robust clinical trials, and multi-omic approaches to capture the complexity of epigenetic regulation in spermatogenesis. Such rigorous investigations will ultimately reduce the risk of transgenerational disorders and optimize reproductive health outcomes.Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Improving environmental sustainability in urology as a resident
No full textRDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
COA5 has an essential role in the early stage of mitochondrial complex IV assembly
No full textPathogenic variants in cytochrome c oxidase assembly factor 5 (COA5), a proposed complex IV (CIV) assembly factor, have been shown to cause clinical mitochondrial disease with two siblings affected by neonatal hypertrophic cardiomyopathy manifesting a rare, homozygous COA5 missense variant (NM_001008215.3: c.157G>C, p.Ala53Pro). The most striking observation in the affected individuals was an isolated impairment in the early stage of mitochondrial CIV assembly. In this study, we report an unrelated family in whom we have identified the same COA5 variant with patient-derived fibroblasts and skeletal muscle biopsies replicating an isolated CIV deficiency. A CRISPR/Cas9-edited homozygous COA5 knockout U2OS cell line with a similar biochemical profile was generated to interrogate the functional role of the human COA5 protein. Mitochondrial complexome profiling pinpointed a role of COA5 in early CIV assembly, more specifically, its involvement in the stage between MTCO1 maturation and the incorporation of MTCO2. We therefore propose that the COA5 protein plays an essential role in the biogenesis of MTCO2 and its integration into the early CIV assembly intermediate for downstream assembly of the functional holocomplex.This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Delayed diagnosis of axial spondyloarthritis: the crucial role of primary care - how you can make a difference
No full textThis article is Open Access: CC BY 4.0 licence (http://creativecommons.org/licences/by/4.0/).Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Optimising outcomes for adults with cystic fibrosis taking CFTR modulators by individualising care: Personalised data linkage to understand treatment optimisation (PLUTO), a novel clinical framework
No full textJournal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Assessing artificial intelligence in breast screening with stratified results on 306 839 mammograms across geographic regions, age, breast density and ethnicity: A Retrospective Investigation Evaluating Screening (ARIES) study
No full textOBJECTIVES: Evaluate an Artificial Intelligence (AI) system in breast screening through stratified results across age, breast density, ethnicity and screening centres, from different UK regions. METHODS: A large-scale retrospective study evaluating two variations of using AI as an independent second reader in double reading was executed. Stratifications were conducted for clinical and operational metrics. Data from 306 839 mammography cases screened between 2017 and 2021 were used and included three different UK regions.The impact on safety and effectiveness was assessed using clinical metrics: cancer detection rate and positive predictive value, stratified according to age, breast density and ethnicity. Operational impact was assessed through reading workload and recall rate, measured overall and per centre.Non-inferiority was tested for AI workflows compared with human double reading, and when passed, superiority was tested. AI interval cancer (IC) flag rate was assessed to estimate additional cancer detection opportunity with AI that cannot be assessed retrospectively. RESULTS: The AI workflows passed non-inferiority or superiority tests for every metric across all subgroups, with workload savings between 38.3% and 43.7%. The AI standalone flagged 41.2% of ICs overall, ranging between 33.3% and 46.8% across subgroups, with the highest detection rate for dense breasts. DISCUSSION: Human double reading and AI workflows showed the same performance disparities across subgroups. The AI integrations maintained or improved performance at all metrics for all subgroups while achieving significant workload reduction. Moreover, complementing these integrations with AI as an additional reader can improve cancer detection. CONCLUSION: The granularity of assessment showed that screening with the AI-system integrations was as safe as standard double reading across heterogeneous populations.CC BY 4.0 (Creative Commons Attribution
Standardized Measurement of Type 1 Diabetes Polygenic Risk Across Multiancestry Population Cohorts
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Usability testing a web application to support evidence-based commissioning decisions for implementing mobile stroke units
No full textCommissioning of innovations in healthcare is a complex socio-technical process, ideally informed by high quality evidence. However, evidence is not always prepared and presented in a format usable for commissioning decisions. Agile methodology, combined with qualitative co-design, were used to develop a digital web application incorporating machine learning models of stroke outcomes to inform commissioning decisions for the implementation of mobile stroke units (MSUs) in England, followed by usability testing using think aloud methodology. Sixteen stakeholders involved in developing consensus on model parameters and pathways participated with data thematically analysed. Required improvements to the web application were identified and novel insights into the complexity of context-specific commissioning decisions were generated, which also informed participants' views on the viability of MSUs. This study provides empirical evidence in support of developing innovative and accessible digital dissemination methods to engage with commissioning processes and prospectively understand commissioning challenges.CC BY 4.0 (Creative Commons Attribution
The role of molecular pathology in soft tissue tumor diagnosis: what the radiologist needs to know
No full textFor both general radiologists and those specializing in soft tissue sarcoma imaging, understanding the importance and basic concepts of molecular pathology is becoming increasingly relevant to current clinical practice. As molecular research identifies the most fundamental causes and markers of disease, diagnostic testing is increasingly focused on the cell nucleus and its genetic material. Identifying molecular abnormalities, such as mutations, deletions, and amplifications, has advanced our ability to diagnose genetic diseases, including a variety of cancers. Over the past two decades, molecular pathology has rapidly evolved, enhancing our understanding of sarcoma pathogenesis, diagnosis, and classification. This progress forms the foundation of the 2020 WHO classification of soft tissue and bone tumors. This article will highlight cases where molecular diagnostics are crucial for the definitive classification and diagnosis of select soft tissue tumors, with MRI correlation and key teaching points.All rights reserve
