Linker histones bind to nucleosomes and modify chromatin structure and dynamics as a means of epigenetic regulation. Biophysical studies have shown that chromatin fibers can adopt a plethora of conformations with varying levels of compaction. Linker histone condensation, and its specific binding disposition, has been associated with directly tuning this ensemble of states. However, the atomistic dynamics and quantification of this mechanism remains poorly understood. Here, we present molecular dynamics simulations of octa-nucleosome arrays, based on a cryo-EM structure of the 30-nm chromatin fiber, with and without the globular domains of the H1 linker histone to determine how they influence fiber structures and dynamics. Results show that when bound, linker histones inhibit DNA flexibility and stabilize repeating tetra-nucleosomal units, giving rise to increased chromatin compaction. Furthermore, upon the removal of H1, there is a significant destabilization of this compact structure as the fiber adopts less strained and untwisted states. Interestingly, linker DNA sampling in the octa-nucleosome is exaggerated compared to its mono-nucleosome counterparts, suggesting that chromatin architecture plays a significant role in DNA strain even in the absence of linker histones. Moreover, H1-bound states are shown to have increased stiffness within tetra-nucleosomes, but not between them. This increased stiffness leads to stronger long-range correlations within the fiber, which may result in the propagation of epigenetic signals over longer spatial ranges. These simulations highlight the effects of linker histone binding on the internal dynamics and global structure of poly-nucleosome arrays, while providing physical insight into a mechanism of chromatin compaction.N-Ethylpentylone (NEP) is one of the most recent novel stimulants, and there is limited understanding of its toxicity. Here we employed zebrafish model for analyzing the effects of NEP on early embryos and cardiovascular and nervous systems at late developmental stages. We first observed multi-malformations in early embryos and larvae after NEP administration, together with significant deregulations of brain and heart development-associated genes (neurog1, her6, elavl3, nkx2.5, nppa, nppb, tnnt2a) at transcriptional level. Low-dosed NEP treatment induced an anxiety-like phenotype in zebrafish larvae, while higher doses of NEP exerted an inhibitory effect on locomotion and heart rate. Besides, the expression of th (tyrosine hydroxylase) and th2 (tyrosine hydroxylase 2), identifying dopamine (DA) release, were significantly increased during one-hour free swimming after effective low-dosed NEP administration, along with the upregulation of gene fosab and fosb related to stress and anxiety response. D1R antagonist SCH23390 and D2R antagonist sulpiride partially alleviated the aberrances of locomotion and heart rate, indicating dopaminergic receptors were involved in the bidirectional dosage-dependent pattern of NEP-induced performance. Meanwhile, sulpiride offset the upregulated expression of th, th2 and fosab in the group of 1.5 μM NEP, which highlighted the significant role of D2R in NEP-induced locomotive effects. This study systematically described the developmental, neuronal and cardiac toxicity of NEP in zebrafish, and identified the dopaminergic receptors as one of the downstream effectors of NEP administration.
  To identify the risk factors for early mortality and morbidity in a population with distal esophageal atresia (EA)-tracheoesophageal fistula.
 
  Cohort study from a national register.  https://www.selleckchem.com/screening/natural-product-library.html  Main outcomes and measures included early mortality, hospital length of stay (LoS), need for nutritional support at 1year of age as a proxy measure of morbidity, and complications during the first year of life.
 
  In total, 1008 patients with a lower esophageal fistula were included from January 1, 2008, to December 31, 2014. The survival rate at 3months was 94.9%. The cumulative hospital LoS was 31.0 (17.0-64.0) days. Multivariate analysis showed that intrahospital mortality at 3months was associated with low birth weight (OR 0.52, 95% CI [0.38-0.72], P<.001), associated cardiac abnormalities (OR 6.09 [1.96-18.89], P = .002), and prenatal diagnosis (OR 2.96 [1.08-8.08], P = .034). LoS was associated with low birth weight (-0.225±0.035, P<.001), associated malformations (0.082±0.118, P<.001), surgical difficulties (0.270±0.107, P<.001), and complications (0.535±0.099, P<.001) during the first year of life. Predictive factors for dependency on nutrition support at 1year of age were complications before 1year (OR 3.28 [1.23-8.76], P<.02) and initial hospital LoS (OR 1.96 [1.15-3.33], P<.01).
 
  EA has a low rate of early mortality, but morbidity is high during the first year of life. Identifying factors associated with morbidity may help to improve neonatal care of this population.
 EA has a low rate of early mortality, but morbidity is high during the first year of life. Identifying factors associated with morbidity may help to improve neonatal care of this population.
  To analyze the long-term outcomes in pediatric liver transplant recipients after they have transferred to an adult provider and assess for racial disparities in health outcomes.
 
  This is a single-center, retrospective review of pediatric patients who underwent liver transplantation between July 1990 and August 2015 at a tertiary healthcare system with a large transplant center. Patient mortality and retransplantation were assessed after transfer to adult care.
 
  There were 120 patients who were transferred, of whom 19 did not meet the inclusion criteria. Of the remaining 101 patients, 64 (63%) transferred care to a nearby affiliated tertiary adult facility, 29 (29%) were followed by other healthcare systems, and 8 (8%) were lost to follow-up. Of the patients followed at our affiliated adult center, 18 of the 64 (28%) died. Of those 18 deaths, 4 (22%) occurred within the first 2years after transfer, and 10 (55%) within 5years of transfer. Four patients were retransplanted by an adult provider, of whom 2 eventually received a third transplant.