Homeostasis of neural firing properties is important in stabilizing neuronal circuitry, but how such plasticity might depend on alternative splicing is not known. Here we report that chronic inactivity homeostatically increases action potential duration by changing alternative splicing of BK channels; this requires nuclear export of the splicing factor Nova-2. Inactivity and Nova-2 relocation were connected by a novel synapto-nuclear signaling pathway that surprisingly invoked mechanisms akin to Hebbian plasticity Ca2+-permeable AMPA receptor upregulation, L-type Ca2+ channel activation, enhanced spine Ca2+ transients, nuclear translocation of a CaM shuttle, and nuclear CaMKIV activation. These findings not only uncover commonalities between homeostatic and Hebbian plasticity but also connect homeostatic regulation of synaptic transmission and neuronal excitability. The signaling cascade provides a full-loop mechanism for a classic autoregulatory feedback loop proposed ∼25 years ago. Each element of the loop has been implicated previously in neuropsychiatric disease.The discovery of the 2,000-year-old Dead Sea Scrolls had an incomparable impact on the historical understanding of Judaism and Christianity. "Piecing together" scroll fragments is like solving jigsaw puzzles with an unknown number of missing parts. We used the fact that most scrolls are made from animal skins to "fingerprint" pieces based on DNA sequences. Genetic sorting of the scrolls illuminates their textual relationship and historical significance. Disambiguating the contested relationship between Jeremiah fragments supplies evidence that some scrolls were brought to the Qumran caves from elsewhere; significantly, they demonstrate that divergent versions of Jeremiah circulated in parallel throughout Israel (ancient Judea). Similarly, patterns discovered in non-biblical scrolls, particularly the Songs of the Sabbath Sacrifice, suggest that the Qumran scrolls represent the broader cultural milieu of the period. Finally, genetic analysis divorces debated fragments from the Qumran scrolls. Our study demonstrates that interdisciplinary approaches enrich the scholar's toolkit.Background Pulmonary artery wedge pressure (PAWP) is often elevated in patients with right-sided congenital heart disease (CHD), raising the possibility of coexisting left-heart disease, but pressure-volume relationships in the left and right sides of the heart influence one another through interdependence, which may be amplified in patients with CHD. Methods We hypothesized that increases in PAWP in patients with CHD would be more strongly related to ventricular interdependence compared with patients who have isolated left-heart disease such as heart failure with preserved ejection fraction (HFpEF). Ventricular interdependence was assessed by the relationship between PAWP and right-atrial pressure (RAP), RAP/PAWP ratio, and the left-ventricular (LV) eccentricity index. Results PAWP was elevated (≥15 mm Hg) in 49% of patients with CHD (n = 449). There was a very strong correlation between RAP and PAWP in CHD (r = 0.81, P less then 0.001) that greatly exceeded the respective correlation in HFpEF (n = 160; r = 0.58, P less then 0.001; P less then 0.001 between groups). RAP/PAWP ratio and LV eccentricity index were higher in CHD than HFpEF (1.26 ± 0.18 vs 1.05 ± 0.14, P = 0.007) and (0.80 ± 0.21 vs 0.59 ± 0.19, P less then 0.001), respectively. RAP (but not PAWP) was an independent predictor of death/transplant (hazard ratio 1.86 per 5 mm Hg, 95% confidence interval, 1.39-2.45, P = 0.002). Conclusions Left-heart filling pressures are commonly elevated in right-sided CHD, but this is related predominantly to right-heart failure and enhanced ventricular interdependence rather than left-heart disease. https://www.selleckchem.com/products/gdc-0068.html These data provide new insight into the basis of abnormal left-heart hemodynamics in patients with CHD and reinforce the importance of therapeutic interventions targeted to the right heart.Background Evidence of clinical outcomes for oral anticoagulants and antiplatelet treatment (APT) in patients with atrial fibrillation (AF) and critical limb ischemia (CLI) is very limited. Methods In this nationwide retrospective cohort study collected from Taiwan National Health Insurance Research Database, 1223 patients with AF and CLI taking direct-acting oral coagulants (DOACs), warfarin, or APT were identified from June 1, 2012, to December 31, 2017. We used propensity score stabilized weighting (PSSW) to balance covariates across study groups. Results After PSSW, DOAC (n = 446) was associated with lower risks of ischemic stroke/systemic embolism (IS/SE), all major adverse limb events, and all major bleeding events compared with warfarin (n = 237). DOAC was associated with lower risks of IS/SE, acute myocardial infarction (AMI), and all major adverse limb events and a comparable risk of major bleeding events compared with APT (n = 540). DOAC has a lower risk of composite net-clinical-benefit outcome (IS/SE, AMI, all major adverse limb events, plus all major bleeding events) compared with warfarin (hazard ratio [HR] 0.48; 95% confidence interval [CI] 0.35-0.65; P 75 years, presence of diabetes mellitus, or chronic kidney disease. Conclusions DOAC was associated with a significantly lower risk of composite net-clinical-benefit outcome than either warfarin or APT in patients with AF and concomitant CLI. Further prospective study is necessary to validate the findings in the future.Health policy is an important component of prevention of cardiovascular disease (CVD) and promotion of health in childhood and adolescence, when major health behaviours are formed. Development of CVD-related health policy begins with continuous systematic collection, analysis, and interpretation of health-related data to establish the baseline prevalence of CV risk factors and behaviours. These findings allow identification of problems, initiation of focused research, and development of evidence-based interventions. Ultimately, these results inform development and implementation of population-level policies. This review focuses on CVD health-promotion policies in North American youth, for whom health surveillance is an ongoing part of public health policy, providing direct, objective, measurements of growth, lipids, blood pressure, physical activity and tobacco exposure for development of CV health research and policy. When national surveillance data identified significant risk of CVD in youth in the 1970s, major pediatric epidemiologic studies established the strong association between these risk factors and behaviours in childhood and the initiation and progression of atherosclerosis.