ATM Dependent Silencing Links Nucleolar Chromatin Reorganization to DNA Damage Recognition

SummaryResolution of DNA double-strand breaks (DSBs) is essential for the suppression of genome instability. DSB repair in transcriptionally active genomic regions represents a unique challenge that is associated with ataxia telangiectasia mutated (ATM) kinase-mediated transcriptional silencing. Despite emerging insights into the underlying mechanisms, how DSB silencing connects to DNA repair remains undefined. We observe that silencing within the rDNA depends on persistent DSBs. Non-homologous end-joining was the predominant mode of DSB repair allowing transcription to resume. ATM-dependent rDNA silencing in the presence of persistent DSBs led to the large-scale reorganization of nucleolar architecture, with movement of damaged chromatin to nucleolar cap regions. These findings identify ATM-dependent temporal and spatial control of DNA repair and provide insights into how communication between DSB signaling and ongoing transcription promotes genome integrity

Anharmonicity-induced isostructural phase transition of Zirconium under pressure

We have performed a detailed x-ray diffraction structural study of Zr under pressure and unambiguously identify the existence of a first-order isostructural bcc-to-bcc phase transition near 58 GPa. First-principles quantum molecular dynamics lattice dynamics calculations support the existence of this phase transition, in excellent agreement with experimental results, triggered by anharmonic effects. Our results highlight the potential ubiquity of anharmonically driven isostructural transitions within the periodic table under pressure and calls for follow-up experimental and theoretical studies

Communication is Key: State-level Organizational Correlates of Readiness for Evidence-based Programming within the Cooperative Extension System

The necessity to implement evidence-based programs to support the healthy development of youth and families is becoming part of national policy. Organizations that are not “ready” to do so will likely lose resources, disallowing them to serve as they have set out to do. Consequently, the current survey study draws from a national sample of Cooperative Extension personnel in 2009 to examine characteristics within their organizational context that facilitate successful change related to youth/family programming. Data were collected from 946 4-H/youth development or Family and Consumer Sciences employees at all levels. Self-reported indices of each state organization’s openness to change, leadership, morale, communication, and resources were constructed to assess the organizational context. Dependent variables included indicators of readiness to implement prevention and evidence-based programming. Results suggest that the organizational context was strongly associated with indicators of readiness for evidence-based prevention programming, and specifically, the clarity of communication was most important

The Drosophila Forkhead Transcription Factor FOXO Mediates the Reduction in Cell Number Associated with Reduced Insulin Signaling

Background: Forkhead transcription factors belonging to the FOXO subfamily are negatively regulated by protein kinase B (PKB) in response to signaling by insulin and insulin-like growth factor in Caenorhabditis elegans and mammals. In Drosophila, the insulin-signaling pathway regulates the size of cells, organs, and the entire body in response to nutrient availability, by controlling both cell size and cell number. In this study, we present a genetic characterization of dFOXO, the only Drosophila FOXO ortholog. Results: Ectopic expression of dFOXO and human FOXO3a induced organ-size reduction and cell death in a manner dependent on phosphoinositide (PI) 3-kinase and nutrient levels. Surprisingly, flies homozygous for dFOXO null alleles are viable and of normal size. They are, however, more sensitive to oxidative stress. Furthermore, dFOXO function is required for growth inhibition associated with reduced insulin signaling. Loss of dFOXO suppresses the reduction in cell number but not the cell-size reduction elicited by mutations in the insulin-signaling pathway. By microarray analysis and subsequent genetic validation, we have identified d4E-BP, which encodes a translation inhibitor, as a relevant dFOXO target gene. Conclusion: Our results show that dFOXO is a crucial mediator of insulin signaling in Drosophila, mediating the reduction in cell number in insulin-signaling mutants. We propose that in response to cellular stresses, such as nutrient deprivation or increased levels of reactive oxygen species, dFOXO is activated and inhibits growth through the action of target genes such as d4E-BP

Development of a Mind Body Program for Obese Knee Osteoarthritis Patients with Comorbid Depression

Knee osteoarthritis (OA) is the most common joint disorder in the U.S. and a leading cause of disability. Depression and obesity are highly comorbid among knee OA patients, and the combination of obesity and depression is associated with decreased physical activity, higher pain and disability, and more rapid cartilage degradation. Depression, obesity and OA exacerbate one another and share a common pathophysiology involving systemic inflammation and pro-inflammatory cytokines, reflecting a complex mind-body interaction. Current treatments for knee OA offer little to no benefit over placebo, and do not emphasize mind-body practices or physical activity to target the underlying pathophysiology. Mind-body interventions to lessen depressive symptoms and increase physical activity offer the ability to target biological, mechanical and psychological mechanisms of OA progression. Our long-term goals are to evaluate the mechanisms by which the Relaxation Response Resiliency Program (3RP) delivered via secure telehealth, and adapted for patients with depression, obesity and knee OA (GetActive-OA) promotes increases in physical activity and improved knee health. We hypothesize that the synergistic interaction between mindfulness, adaptive thinking, positive psychology and healthy living skills of the GetActive-OA will slow the progression of symptomatic knee OA by reducing pro-inflammatory cytokine expression and promoting optimal mechanical loading of the cartilage. Here we present the protocol for a mixed methods study that will adapt the 3RP for the needs of knee OA patients with depression and obesity with a focus on increasing physical activity (GetActive-OA), and iteratively maximize the feasibility, credibility and acceptability of the programs and research procedures

Results of a Feasibility Randomized Controlled Trial (RCT) of the Toolkit for Optimal Recovery (TOR): A Live Video Program to Prevent Chronic Pain in At-Risk Adults with Orthopedic Injuries

Background: Orthopedic injuries are the leading cause of hospital admissions in the USA, and many of these patients transition into chronic pain. Currently, there are no evidence-based interventions targeting prevention of chronic pain in patients with orthopedic injuries. We iteratively developed a four-session intervention “The Toolkit for Optimal Recovery” (TOR) which we plan to subsequently test for efficacy in a phase III hybrid efficacy-effectiveness multi-site clinical trial. In order to prevent methodological weaknesses in the subsequent trial, we conducted a feasibility pilot to evaluate the TOR delivered via secure live video versus usual care (UC) in patients with orthopedic injuries from an urban, level I trauma clinic, who screen in as at risk for chronic pain and disability. We tested the feasibility of recruitment, acceptability of screening, and randomization methods; acceptability of the intervention, treatment adherence, and treatment fidelity; satisfaction with the intervention; feasibility of the assessment process at all time points; acceptability of outcome measures for the definitive trial; and within-treatment effect sizes. Methods: We aimed to recruit 50–60 participants, randomize, and retain them for ~ 4 months. Assessments were done electronically via REDCap at baseline, post-intervention (approximately 5 weeks after baseline), and 3 months later. We followed procedures we intend to implement in the full-scale hybrid efficacy-effectiveness trial. Results: We recruited 54 participants and found that randomization and data collection procedures were generally acceptable. The majority of participants were white, educated, and employed. Warm hand-off referrals were more effective than research assistants directly approaching patients for participation without their providers’ engagement. Feasibility of recruitment, acceptability of screening, and randomization were good. Satisfaction with the program, adherence to treatment sessions, and treatment fidelity were all high. There were no technical issues associated with the live video delivery of the TOR. There was minimal missing data and outcome measures were deemed appropriate. Effect sizes for improvement after participation in TOR were moderate to large. There were many lessons learned for future trials. Conclusions: This study provided evidence of the feasibility of the planned hybrid efficacy-effectiveness trial design when implemented at our home institution. Establishing feasibility of the intervention and study procedures at other trauma centers with more diverse patient populations and different clinical practices is required before a multi-site phase III efficacy-effectiveness trial. Trial registration: ClinicalTrials.gov ID: NCT03405610. Registered on January 28, 2018—retrospectively registered

Endothelial cell-surface tissue transglutaminase inhibits neutrophil adhesion by binding and releasing nitric oxide

Nitric oxide (NO) produced by endothelial cells in response to cytokines displays anti-inflammatory activity by preventing the adherence, migration and activation of neutrophils. The molecular mechanism by which NO operates at the blood-endothelium interface to exert anti-inflammatory properties is largely unknown. Here we show that on endothelial surfaces, NO is associated with the sulfhydryl-rich protein tissue transglutaminase (TG2), thereby endowing the membrane surfaces with anti-inflammatory properties. We find that tumor necrosis factor-α-stimulated neutrophil adherence is opposed by TG2 molecules that are bound to the endothelial surface. Alkylation of cysteine residues in TG2 or inhibition of endothelial NO synthesis renders the surface-bound TG2 inactive, whereas specific, high affinity binding of S-nitrosylated TG2 (SNO-TG2) to endothelial surfaces restores the anti-inflammatory properties of the endothelium, and reconstitutes the activity of endothelial-derived NO. We also show that SNO-TG2 is present in healthy tissues and that it forms on the membranes of shear-activated endothelial cells. Thus, the anti-inflammatory mechanism that prevents neutrophils from adhering to endothelial cells is identified with TG2 S-nitrosylation at the endothelial cell-blood interface

Single Versus Multi-Center Surgeons\u27 Risk-Adjusted Mitral Valve Repair Procedural Outcomes

The purpose of this study is to explore strategies to improve mitral valve repair (MVr) outcomes. This research explores postoperative outcomes of patients undergoing MVr surgery by single center surgeons versus patients of multicenter surgeons. Specific outcomes of interest include 30-day operative mortality, major operative complications (e.g., deep sternal wound infection, permanent stroke, renal dysfunction requiring dialysis, reoperation, and prolonged ventilation), length of stay, and 30-day readmissions. In brief, the serisk-adjusted outcome rates for surgeons that perform mitral valve repair procedures will be compared for surgeons that operate at a single center [i.e. SC surgeons] versus multiple centers [i.e. MC surgeons]. The overarching study hypothesis is: H(0) There will be no difference in the risk-adjusted outcome rates between surgeons that operate at a single center [i.e. SC surgeons] versus multiple centers [i.e. MC surgeons]. Based on prior research, however, it is anticipated that single center surgeons may have superior outcomes compared to multi-center surgeons