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SLC25A51 is a member of the mitochondrial carrier family (MCF) but lacks key residues that contribute to the mechanism of other nucleotide MCF transporters. Thus, how SLC25A51 transports NAD+ across the inner mitochondrial membrane remains unclear. To elucidate its mechanism, we use Molecular Dynamics simulations to reconstitute SLC25A51 homology models into lipid bilayers and to generate hypotheses to test. We observe spontaneous binding of cardiolipin phospholipids to three distinct sites on the exterior of SLC25A51's central pore and find that mutation of these sites impairs cardiolipin binding and transporter activity. We also observe that stable formation of the required matrix gate is controlled by a single salt bridge. We identify binding sites in SLC25A51 for NAD+ and show that its selectivity for NAD+ is guided by an electrostatic interaction between the charged nicotinamide ring in the ligand and a negatively charged patch in the pore. In turn, interaction of NAD+ with interior residue E132 guides the ligand to dynamically engage and weaken the salt bridge gate, representing a ligand‐induced initiation of transport. Synopsis: This study reveals how human mitochondrial transporter SLC25A51 distinguishes its cognate ligand, oxidized NAD+, and identifies a requirement for bound membrane phospholipid cardiolipin. Inaugural description of an NAD+ binding site among mitochondrial carriers.Evidence for a ligand‐led gate opening mechanism.Requirement of bound cardiolipin for activity.Potential for uniport activity in specific contexts. [ABSTRACT FROM AUTHOR]

Cancer treatments targeting DNA repair deficiencies often encounter drug resistance, possibly due to alternative metabolic pathways that counteract the most damaging effects. To identify such alternative pathways, we screened for metabolic pathways exhibiting synthetic lethality with inhibition of the DNA damage response kinase Ataxia-telangiectasia-mutated (ATM) using a metabolism-centered Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 library. Our data revealed Kelch-like ECH-associated protein 1 (KEAP1) as a key factor involved in desensitizing cancer cells to ATM inhibition both in vitro and in vivo. Cells depleted of KEAP1 exhibited an aberrant overexpression of the cystine transporter SLC7A11, robustly accumulated cystine inducing disulfide stress, and became hypersensitive to ATM inhibition. These hallmarks were reversed in a reducing cellular environment indicating that disulfide stress was a crucial factor. In The Cancer Genome Atlas (TCGA) pan-cancer datasets, we found that ATM levels negatively correlated with KEAP1 levels across multiple solid malignancies. Together, our results unveil ATM and KEAP1 as new targetable vulnerabilities in solid tumors. [ABSTRACT FROM AUTHOR]

Heightened concerns about school violence in recent years have amplified the need for implementation of effective prevention and intervention programs in our educational systems. This paper describes an intervention designed to accomplish three goals: 1) to educate school personnel about the effects of violence and evidence-based programs for school safety; 2) to assess perceptions of school personnel about school safety, barriers to violence prevention and systemic response to crisis; and 3) to develop a model for strategic planning that can be disseminated into the community. To address these aims, participants (N = 32) of a one-day summer educational workshop on violence and posttraumatic stress disorder for K-12 school personnel attended didactic sessions and participated in focus groups. They completed post-course surveys rating their knowledge and understanding of the topic areas discussed. In addition, they completed baseline and 9-month follow-up surveys rating their schools on the characteristics of safe schools identified in the literature on school violence. The follow-up surveys also assessed whether or not new programs to improve safety or prevent violence had been implemented in their schools. The study demonstrated that educational interventions can be used effectively to enhance school personnel's knowledge about violence and create safer school environments., Violence in the United States has been increasing among children and adolescents at alarming rates and is now considered a significant public health concern (Thornton, Craft, Dahlberg, Lynch, & Baer, [...]

New models of health care delivery, managed care oversight and government regulation have increased the need for highly skilled care coordinators. Hospitals, health systems and insurers recognize the importance of care coordination as a valuable strategy to achieve the triple aim of improving health outcomes, quality of care and lowering costs. It is critical that employers, service providers and educators work together to ensure nurses are prepared for the demands of the current healthcare environment. Although care coordination is not a new practice, the emphasis on interprofessional practice, the use of data and technology, and outcomes-driven-care are driving the need for nurses who have a strong understanding of the care coordination process. Schools of nursing, in collaboration with healthcare organizations and other key stakeholders, are well positioned to prepare nursing students for the care coordinator role. [ABSTRACT FROM AUTHOR]

Introduction: Inflammatory and protein mediators (cytokine, chemokine, acute phase proteins) play an important, but still not completely understood, role in the morbidity and mortality of intra-abdominal sepsis/injury. We therefore systematically reviewed preclinical and clinical studies of mediators in intra-abdominal sepsis/injury in order to evaluate their ability to: (1) function as diagnostic/prognostic biomarkers; (2) serve as therapeutic targets; and (3) illuminate the pathogenesis mechanisms of sepsis or injury-related organ dysfunction.Methods: We searched MEDLINE, PubMed, EMBASE and the Cochrane Library. Two investigators independently reviewed all identified abstracts and selected articles for full-text review. We included original studies assessing mediators in intra-abdominal sepsis/injury.Results: Among 2437 citations, we selected 182 studies in the scoping review, including 79 preclinical and 103 clinical studies. Serum procalcitonin and C-reactive protein appear to be useful to rule out infection or monitor therapy; however, the diagnostic and prognostic value of mediators for complications/outcomes of sepsis or injury remains to be established. Peritoneal mediator levels are substantially higher than systemic levels after intra-abdominal infection/trauma. Common limitations of current studies included small sample sizes and lack of uniformity in study design and outcome measures. To date, targeted therapies against mediators remain experimental.Conclusions: Whereas preclinical data suggests mediators play a critical role in intra-abdominal sepsis or injury, there is no consensus on the clinical use of mediators in diagnosing or managing intra-abdominal sepsis or injury. Measurement of peritoneal mediators should be further investigated as a more sensitive determinant of intra-abdominal inflammatory response. High-quality clinical trials are needed to better understand the role of inflammatory mediators. [ABSTRACT FROM AUTHOR]