P682Preserved contractile function of unloaded cardiomyocytes despite diminished sarcomere size is associated with troponin I activation

Objective: Myocardial unloading with ventricular assist devices in patients with severe heart failure (HF) can lead to reversal of certain aspects of pathological remodeling. However, these effects do not translate into recovery of myocardial function in the human heart, possibly due to detrimental atrophic processes also elicited through unloading. We have studied the effects of long-term unloading on sarcomeric morphology and function in a small animal model of ventricular unloading, heterotopic heart transplantation (HTX) in rats. Methods: Native rat hearts were unloaded via HTX for 30 days, CMs from control and unloaded hearts were isolated (n=8 hearts/>250 individual cells/group). CM overall size was determined, sarcomere length/contractility assessed and Calcium transients as well as E-C coupling gain analyzed in patch-clamped CMs. Additionally, phosphorylation of Troponin I, indicative of sarcomere activation, was measured with western blotting. Results: CM cross-sectional area was diminished in unloaded cells by about one third (2787±345 vs 1993±230 μm2) as was cell capacitance in patched cells. Accordingly, baseline sarcomere length was significantly reduced by ~0.2μm (Figure). However, this reduction did not diminish contractile function: fractional shortening was significantly higher in unloaded CMs (8.0 ± 3 % vs 6.6 ± 2.5 % in CTR, p = 0.01). Departure velocity of the transients was similar (-135.2 ± 48 vs -119.4 ± 40 dL/dt), and return velocity was slightly increased in unloaded cells (120.7 ± 54 vs 94.0 ± 46 dL/dt, p < 0.05), indicating preserved relaxation. Calcium transient amplitudes and current-voltage relationship under basal condition and isoproterenol stimulation was not changed. Troponin I phosphorylation was elevated and may contribute to the maintenance of sarcomeric function in long-term unloaded CMs. Conclusion: Although there are limitations regarding assessment of contractility in isolated cells, we may conclude that the considerable size reduction in CMs induced by unloading does not translate into diminished contractile function or E-C couplin

Maternal corticotropin-releasing hormone is associated with LEP DNA methylation at birth and in childhood: an epigenome-wide study in Project Viva

BackgroundCorticotropin-releasing hormone (CRH) plays a central role in regulating the secretion of cortisol which controls a wide range of biological processes. Fetuses overexposed to cortisol have increased risks of disease in later life. DNA methylation may be the underlying association between prenatal cortisol exposure and health effects. We investigated associations between maternal CRH levels and epigenome-wide DNA methylation of cord blood in offsprings and evaluated whether these associations persisted into mid-childhood.MethodsWe investigated mother-child pairs enrolled in the prospective Project Viva pre-birth cohort. We measured DNA methylation in 257 umbilical cord blood samples using the HumanMethylation450 Bead Chip. We tested associations of maternal CRH concentration with cord blood cells DNA methylation, adjusting the model for maternal age at enrollment, education, maternal race/ethnicity, maternal smoking status, pre-pregnancy body mass index, parity, gestational age at delivery, child sex, and cell-type composition in cord blood. We further examined the persistence of associations between maternal CRH levels and DNA methylation in children's blood cells collected at mid-childhood (n = 239, age: 6.7-10.3 years) additionally adjusting for the children's age at blood drawn.ResultsMaternal CRH levels are associated with DNA methylation variability in cord blood cells at 96 individual CpG sites (False Discovery Rate &lt;0.05). Among the 96 CpG sites, we identified 3 CpGs located near the LEP gene. Regional analyses confirmed the association between maternal CRH and DNA methylation near LEP. Moreover, higher maternal CRH levels were associated with higher blood-cell DNA methylation of the promoter region of LEP in mid-childhood (P &lt; 0.05, β = 0.64, SE = 0.30).ConclusionIn our cohort, maternal CRH was associated with DNA methylation levels in newborns at multiple loci, notably in the LEP gene promoter. The association between maternal CRH and LEP DNA methylation levels persisted into mid-childhood

Circulating FGF21 Levels Are Progressively Increased from the Early to End Stages of Chronic Kidney Diseases and Are Associated with Renal Function in Chinese

Fibroblast growth factor 21 (FGF21) is a hepatic hormone involved in the regulation of lipid and carbohydrate metabolism. This study aims to test the hypothesis that elevated FGF21 concentrations are associated with the change of renal function and the presence of left ventricular hypertrophy (LVH) in the different stages of chronic kidney disease (CKD) progression.0.05).Plasma FGF21 levels are significantly increased with the development of early- to end-stage CKD and are independently associated with renal function and adverse lipid profiles in Chinese population. Understanding whether increased FGF21 is associated with myocardial hypertrophy in CKD requires further study

The pharmacological regulation of cellular mitophagy

Small molecules are pharmacological tools of considerable value for dissecting complex biological processes and identifying potential therapeutic interventions. Recently, the cellular quality-control process of mitophagy has attracted considerable research interest; however, the limited availability of suitable chemical probes has restricted our understanding of the molecular mechanisms involved. Current approaches to initiate mitophagy include acute dissipation of the mitochondrial membrane potential (ΔΨm) by mitochondrial uncouplers (for example, FCCP/CCCP) and the use of antimycin A and oligomycin to impair respiration. Both approaches impair mitochondrial homeostasis and therefore limit the scope for dissection of subtle, bioenergy-related regulatory phenomena. Recently, novel mitophagy activators acting independently of the respiration collapse have been reported, offering new opportunities to understand the process and potential for therapeutic exploitation. We have summarized the current status of mitophagy modulators and analyzed the available chemical tools, commenting on their advantages, limitations and current applications

Mechanics Regulates Fate Decisions of Human Embryonic Stem Cells

Research on human embryonic stem cells (hESCs) has attracted much attention given their great potential for tissue regenerative therapy and fundamental developmental biology studies. Yet, there is still limited understanding of how mechanical signals in the local cellular microenvironment of hESCs regulate their fate decisions. Here, we applied a microfabricated micromechanical platform to investigate the mechanoresponsive behaviors of hESCs. We demonstrated that hESCs are mechanosensitive, and they could increase their cytoskeleton contractility with matrix rigidity. Furthermore, rigid substrates supported maintenance of pluripotency of hESCs. Matrix mechanics-mediated cytoskeleton contractility might be functionally correlated with E-cadherin expressions in cell-cell contacts and thus involved in fate decisions of hESCs. Our results highlighted the important functional link between matrix rigidity, cellular mechanics, and pluripotency of hESCs and provided a novel approach to characterize and understand mechanotransduction and its involvement in hESC function

An investigation of cognitive 'branching' processes in major depression

<p>Abstract</p> <p>Background</p> <p>Patients with depression demonstrate cognitive impairment on a wide range of cognitive tasks, particularly putative tasks of frontal lobe function. Recent models of frontal lobe function have argued that the frontal pole region is involved in cognitive branching, a process requiring holding in mind one goal while performing sub-goal processes. Evidence for this model comes from functional neuroimaging and frontal-pole lesion patients. We have utilised these new concepts to investigate the possibility that patients with depression are impaired at cognitive 'branching'.</p> <p>Methods</p> <p>11 non-medicated patients with major depression were compared to 11 matched controls in a behavioural study on a task of cognitive 'branching'. In the version employed here, we recorded participant's performance as they learnt to perform the task. This involved participants completing a control condition, followed by a working memory condition, a dual-task condition and finally the branching condition, which integrates processes in the working memory and dual-task conditions. We also measured participants on a number of other cognitive tasks as well as mood-state before and after the branching experiment.</p> <p>Results</p> <p>Patients took longer to learn the first condition, but performed comparably to controls after six runs of the task. Overall, reaction times decreased with repeated exposure on the task conditions in controls, with this effect attenuated in patients. Importantly, no differences were found between patients and controls on the branching condition. There was, however, a significant change in mood-state with patients increasing in positive affect and decreasing in negative affect after the experiment.</p> <p>Conclusion</p> <p>We found no clear evidence of a fundamental impairment in anterior prefrontal 'branching processes' in patients with depression. Rather our data argue for a contextual learning impairment underlying cognitive dysfunction in this disorder. Our data suggest that MDD patients are able to perform high-level cognitive control tasks comparably to controls provided they are well trained. Future work should replicate these preliminary findings in a larger sample of MDD patients.</p

Low prevalence of H. pylori Infection in HIV-Positive Patients in the Northeast of Brazil

<p>Abstract</p> <p>Background</p> <p>This study conducted in Northeastern Brazil, evaluated the prevalence of <it>H. pylori </it>infection and the presence of gastritis in HIV-infected patients.</p> <p>Methods</p> <p>There were included 113 HIV-positive and 141 age-matched HIV-negative patients, who underwent upper gastrointestinal endoscopy for dyspeptic symptoms. <it>H. pylori </it>status was evaluated by urease test and histology.</p> <p>Results</p> <p>The prevalence of <it>H. pylori </it>infection was significantly lower (p < 0.001) in HIV-infected (37.2%) than in uninfected (75.2%) patients. There were no significant differences between <it>H. pylori </it>status and gender, age, HIV viral load, antiretroviral therapy and the use of antibiotics. A lower prevalence of <it>H. pylori </it>was observed among patients with T CD4 cell count below 200/mm³; however, it was not significant. Chronic active antral gastritis was observed in 87.6% of the HIV-infected patients and in 780.4% of the control group (p = 0.11). <it>H. pylori </it>infection was significantly associated with chronic active gastritis in the antrum in both groups, but it was not associated with corpus chronic active gastritis in the HIV-infected patients.</p> <p>Conclusion</p> <p>We demonstrated that the prevalence of <it>H. pylori </it>was significantly lower in HIV-positive patients compared with HIV-negative ones. However, corpus gastritis was frequently observed in the HIV-positive patients, pointing to different mechanisms than <it>H. pylori </it>infection in the genesis of the lesion.</p

Discovery and Annotation of Functional Chromatin Signatures in the Human Genome

Transcriptional regulation in human cells is a complex process involving a multitude of regulatory elements encoded by the genome. Recent studies have shown that distinct chromatin signatures mark a variety of functional genomic elements and that subtle variations of these signatures mark elements with different functions. To identify novel chromatin signatures in the human genome, we apply a de novo pattern-finding algorithm to genome-wide maps of histone modifications. We recover previously known chromatin signatures associated with promoters and enhancers. We also observe several chromatin signatures with strong enrichment of H3K36me3 marking exons. Closer examination reveals that H3K36me3 is found on well-positioned nucleosomes at exon 5′ ends, and that this modification is a global mark of exon expression that also correlates with alternative splicing. Additionally, we observe strong enrichment of H2BK5me1 and H4K20me1 at highly expressed exons near the 5′ end, in contrast to the opposite distribution of H3K36me3-marked exons. Finally, we also recover frequently occurring chromatin signatures displaying enrichment of repressive histone modifications. These signatures mark distinct repeat sequences and are associated with distinct modes of gene repression. Together, these results highlight the rich information embedded in the human epigenome and underscore its value in studying gene regulation

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT