Can Standing Long Jump Distance Be Predicted From Between-the-Legs Front Throw Distance?

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Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia

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Msh2 Blocks an Alternative Mechanism for Non-Homologous Tail Removal during Single-Strand Annealing in Saccharomyces cerevisiae

Chromosomal translocations are frequently observed in cells exposed to agents that cause DNA double-strand breaks (DSBs), such as ionizing radiation and chemotherapeutic drugs, and are often associated with tumors in mammals. Recently, translocation formation in the budding yeast, Saccharomyces cerevisiae, has been found to occur at high frequencies following the creation of multiple DSBs adjacent to repetitive sequences on non-homologous chromosomes. The genetic control of translocation formation and the chromosome complements of the clones that contain translocations suggest that translocation formation occurs by single-strand annealing (SSA). Among the factors important for translocation formation by SSA is the central mismatch repair (MMR) and homologous recombination (HR) factor, Msh2. Here we describe the effects of several msh2 missense mutations on translocation formation that suggest that Msh2 has separable functions in stabilizing annealed single strands, and removing non-homologous sequences from their ends. Additionally, interactions between the msh2 alleles and a null allele of RAD1, which encodes a subunit of a nuclease critical for the removal of non-homologous tails suggest that Msh2 blocks an alternative mechanism for removing these sequences. These results suggest that Msh2 plays multiple roles in the formation of chromosomal translocations following acute levels of DNA damage

Mammalian BTBD12 (SLX4) Protects against Genomic Instability during Mammalian Spermatogenesis

The mammalian ortholog of yeast Slx4, BTBD12, is an ATM substrate that functions as a scaffold for various DNA repair activities. Mutations of human BTBD12 have been reported in a new sub-type of Fanconi anemia patients. Recent studies have implicated the fly and worm orthologs, MUS312 and HIM-18, in the regulation of meiotic crossovers arising from double-strand break (DSB) initiating events and also in genome stability prior to meiosis. Using a Btbd12 mutant mouse, we analyzed the role of BTBD12 in mammalian gametogenesis. BTBD12 localizes to pre-meiotic spermatogonia and to meiotic spermatocytes in wildtype males. Btbd12 mutant mice have less than 15% normal spermatozoa and are subfertile. Loss of BTBD12 during embryogenesis results in impaired primordial germ cell proliferation and increased apoptosis, which reduces the spermatogonial pool in the early postnatal testis. During prophase I, DSBs initiate normally in Btbd12 mutant animals. However, DSB repair is delayed or impeded, resulting in persistent γH2AX and RAD51, and the choice of repair pathway may be altered, resulting in elevated MLH1/MLH3 focus numbers at pachynema. The result is an increase in apoptosis through prophase I and beyond. Unlike yeast Slx4, therefore, BTBD12 appears to function in meiotic prophase I, possibly during the recombination events that lead to the production of crossovers. In line with its expected regulation by ATM kinase, BTBD12 protein is reduced in the testis of Atm−/− males, and Btbd12 mutant mice exhibit increased genomic instability in the form of elevated blood cell micronucleus formation similar to that seen in Atm−/− males. Taken together, these data indicate that BTBD12 functions throughout gametogenesis to maintain genome stability, possibly by co-ordinating repair processes and/or by linking DNA repair events to the cell cycle via ATM

Patients for Patient Safety

AbstractUnsafe care results in over 2 million deaths per year and is considered one of the world's leading causes of death. In 2019, the 72nd World Health Assembly issued a call to action, The Global Action on Patient Safety, that called for Member States to democratize healthcare by engaging with the very users of the healthcare system—patients, families, and community members—along with other partners—in the "co-production" of safer healthcare.The WHO's Patients for Patient Safety (PFPS) Programme, guided by the London Declaration, addresses this global concern by advancing co-production efforts that demonstrate the powerful and important role that civil society, patients, families, and communities play in building harm reduction strategies that result in safer care in developing and developed countries. The real-world examples from the PFPS Programme and Member States illustrate how civil society as well as patients, families, and communities who have experienced harm from unsafe care have harnessed their wisdom and courageously partnered with passionate and forward-thinking leaders in healthcare including clinicians, researchers, policy makers, medical educators, and quality improvement experts to co-produce sustainable patient safety initiatives. Although each example is different in scope, structure, and purpose and engage different stakeholders at different levels, each highlights the necessary building blocks to transform our healthcare systems into learning environments through co-production of patient safety initiatives, and each responds to the call made in the London Declaration, the WHO PFPS Programme, and the World Health Assembly to place patients, families, communities, and civil society at the center of efforts to improve patient safety

Caenorhabditis elegans HIM-18/SLX-4 Interacts with SLX-1 and XPF-1 and Maintains Genomic Integrity in the Germline by Processing Recombination Intermediates

Homologous recombination (HR) is essential for the repair of blocked or collapsed replication forks and for the production of crossovers between homologs that promote accurate meiotic chromosome segregation. Here, we identify HIM-18, an ortholog of MUS312/Slx4, as a critical player required in vivo for processing late HR intermediates in Caenorhabditis elegans. DNA damage sensitivity and an accumulation of HR intermediates (RAD-51 foci) during premeiotic entry suggest that HIM-18 is required for HR–mediated repair at stalled replication forks. A reduction in crossover recombination frequencies—accompanied by an increase in HR intermediates during meiosis, germ cell apoptosis, unstable bivalent attachments, and subsequent chromosome nondisjunction—support a role for HIM-18 in converting HR intermediates into crossover products. Such a role is suggested by physical interaction of HIM-18 with the nucleases SLX-1 and XPF-1 and by the synthetic lethality of him-18 with him-6, the C. elegans BLM homolog. We propose that HIM-18 facilitates processing of HR intermediates resulting from replication fork collapse and programmed meiotic DSBs in the C. elegans germline

Determinants of burnout and other aspects of psychological well-being in healthcare workers during the Covid-19 pandemic: A multinational cross-sectional study

The Covid-19 pandemic has placed unprecedented pressure on healthcare systems and workers around the world. Such pressures may impact on working conditions, psychological wellbeing and perception of safety. In spite of this, no study has assessed the relationship between safety attitudes and psychological outcomes. Moreover, only limited studies have examined the relationship between personal characteristics and psychological outcomes during Covid-19. From 22nd March 2020 to 18th June 2020, healthcare workers from the United Kingdom, Poland, and Singapore were invited to participate using a self-administered questionnaire comprising the Safety Attitudes Questionnaire (SAQ), Oldenburg Burnout Inventory (OLBI) and Hospital Anxiety and Depression Scale (HADS) to evaluate safety culture, burnout and anxiety/depression. Multivariate logistic regression was used to determine predictors of burnout, anxiety and depression. Of 3,537 healthcare workers who participated in the study, 2,364 (67%) screened positive for burnout, 701 (20%) for anxiety, and 389 (11%) for depression. Significant predictors of burnout included patient-facing roles: doctor (OR 2.10; 95% CI 1.49–2.95), nurse (OR 1.38; 95% CI 1.04–1.84), and ‘other clinical’ (OR 2.02; 95% CI 1.45–2.82); being redeployed (OR 1.27; 95% CI 1.02–1.58), bottom quartile SAQ score (OR 2.43; 95% CI 1.98–2.99), anxiety (OR 4.87; 95% CI 3.92–6.06) and depression (OR 4.06; 95% CI 3.04–5.42). Significant factors inversely correlated with burnout included being tested for SARS-CoV-2 (OR 0.64; 95% CI 0.51–0.82) and top quartile SAQ score (OR 0.30; 95% CI 0.22–0.40). Significant factors associated with anxiety and depression, included burnout, gender, safety attitudes and job role. Our findings demonstrate a significant burden of burnout, anxiety, and depression amongst healthcare workers. A strong association was seen between SARS-CoV-2 testing, safety attitudes, gender, job role, redeployment and psychological state. These findings highlight the importance of targeted support services for at risk groups and proactive SARS-CoV-2 testing of healthcare workers

Processing of joint molecule intermediates by structure-selective endonucleases during homologous recombination in eukaryotes

Homologous recombination is required for maintaining genomic integrity by functioning in high-fidelity repair of DNA double-strand breaks and other complex lesions, replication fork support, and meiotic chromosome segregation. Joint DNA molecules are key intermediates in recombination and their differential processing determines whether the genetic outcome is a crossover or non-crossover event. The Holliday model of recombination highlights the resolution of four-way DNA joint molecules, termed Holliday junctions, and the bacterial Holliday junction resolvase RuvC set the paradigm for the mechanism of crossover formation. In eukaryotes, much effort has been invested in identifying the eukaryotic equivalent of bacterial RuvC, leading to the discovery of a number of DNA endonucleases, including Mus81–Mms4/EME1, Slx1–Slx4/BTBD12/MUS312, XPF–ERCC1, and Yen1/GEN1. These nucleases exert different selectivity for various DNA joint molecules, including Holliday junctions. Their mutant phenotypes and distinct species-specific characteristics expose a surprisingly complex system of joint molecule processing. In an attempt to reconcile the biochemical and genetic data, we propose that nicked junctions constitute important in vivo recombination intermediates whose processing determines the efficiency and outcome (crossover/non-crossover) of homologous recombination