TLR3 Mediates Repair and Regeneration of Damaged Neonatal Heart through Glycolysis Dependent YAP1 Regulated miR-152 Expression

The present study investigated whether TLR3 is required for neonatal heart repair and regeneration following myocardial infarction (MI). TLR3 deficient neonatal mice exhibited impaired cardiac functional recovery and a larger infarct size, while wild type neonatal mice showed cardiac functional recovery and small infarct size after MI. The data suggest that TLR3 is essential for the regeneration and repair of damaged neonatal myocardium. In vitro treatment of neonatal cardiomyocytes with a TLR3 ligand, Poly (I:C), significantly enhances glycolytic metabolism, YAP1 activation and proliferation of cardiomyocytes which were prevented by a glycolysis inhibitor, 2-deoxyglucose (2-DG). Administration of 2-DG to neonatal mice abolished cardiac functional recovery and YAP activation after MI, suggesting that TLR3-mediated regeneration and repair of the damaged neonatal myocardium is through glycolytic-dependent YAP1 activation. Inhibition of YAP1 activation abolished Poly (I:C) induced proliferation of neonatal cardiomyocytes. Interestingly, activation of YAP1 increases the expression of miR-152 which represses the expression of cell cycle inhibitory proteins, P27kip1 and DNMT1, leading to cardiomyocyte proliferation. We conclude that TLR3 is required for neonatal heart regeneration and repair after MI. The mechanisms involve glycolytic-dependent YAP1 activation, resulting in miR-152 expression which targets DNMT1/p27kip1

Association of Short Tandem Repeat Polymorphism in the Promoter of Prostate Cancer Antigen 3 Gene with the Risk of Prostate Cancer

BACKGROUND: PCA3 (prostate cancer antigen 3) gene is one of the most prostate cancer-specific genes at present. Consequently, the prostate-specific expression and the sharp up-regulation of PCA3 mRNA in prostate cancer suggest a unique transcriptional regulation, which possibly can be attributed to promoter polymorphism. In our study, we evaluated whether there is polymorphism in PCA3 promoter region and also assess the association of the polymorphism with prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS: We designed a specific primer set to screen the promoter of PCA3 gene by polymerase chain reaction (PCR)-based cloning and sequencing with the DNA extracted from peripheral blood samples of prostate cancer (PCa) cases (n = 186) and healthy control cases (n = 135). Genotype-specific risks were estimated as odds ratios (ORs) with associated 95% confidence intervals (CIs) by chi-square test. Possible deviation of the genotype frequencies from controls and PCa cases expected under Hardy-Weinberg equilibrium was assessed by the chi-square test. Short tandem repeat polymorphism of TAAA was found in the promoter region of PCA3 gene, five polymorphisms and eight genotypes were identified. The eight genotypes were divided into three groups: ≤10TAAA, 11TAAA, ≥12TAAA. The group 11TAAA and ≥12TAAA were associated with higher relative risk for prostate cancer than group ≤10TAAA (OR = 1.76, 95%CI = 1.07-2.89[for group 11TAAA]; OR = 5.28, 95%CI = 1.76-15.89[for group ≥12TAAA]). CONCLUSIONS/SIGNIFICANCE: The presence of the (TAAA)n short tandem repeat polymorphisms in the PCA3 promoter region may be a risk factor for prostate cancer in the Chinese population

MicroRNA-214 Protects Against Hypoxia/Reoxygenation Induced Cell Damage and Myocardial Ischemia/Reperfusion Injury via Suppression of PTEN and Bim1 Expression

Background: Myocardial apoptosis plays an important role in myocardial ischemia/reperfusion (I/R) injury. Activation of PI3K/Akt signaling protects the myocardium from I/R injury. This study investigated the role of miR-214 in hypoxia/ reoxygenation (H/R)-induced cell damage in vitro and myocardial I/R injury in vivo. Methods and Results: H9C2 cardiomyoblasts were transfected with lentivirus expressing miR-214 (LmiR-214) or lentivirus expressing scrambled miR-control (LmiR-control) respectively, to establish cell lines of LmiR-214 and LmiR-control. The cells were subjected to hypoxia for 4 h followed by reoxygenation for 24 h. Transfection of LmiR-214 suppresses PTEN expression, significantly increases the levels of Akt phosphorylation, markedly attenuates LDH release, and enhances the viability of the cells subjected to H/R. In vivo transfection of mouse hearts with LmiR-214 significantly attenuates I/R induced cardiac dysfunction and reduces I/Rinduced myocardial infarct size. LmiR-214 transfection significantly attenuates I/Rinduced myocardial apoptosis and caspase-3/7 and caspase-8 activity. Increased expression of miR-214 by transfection of LmiR-214 suppresses PTEN expression, increases the levels of phosphorylated Akt, represses Bim1 expression and induces Bad phosphorylation in the myocardium. In addition, in vitro data shows transfection of miR-214 mimics to H9C2 cells suppresses the expression and translocation of Bim1 from cytosol to mitochondria and induces Bad phosphorylation. Conclusions: Our in vitro and in vivo data suggests that miR-214 protects cells from H/R induced damage and attenuates I/R induced myocardial injury. The mechanisms involve activation of PI3K/Akt signaling by targeting PTEN expression, induction of Bad phosphorylation, and suppression of Bim1 expression, resulting in decreases in I/R-induced myocardial apoptosis

Bottom-up growth of n-type monolayer molecular crystals on polymeric substrate for optoelectronic device applications.

Self-assembly of monolayers of functional molecules on dielectric surfaces is a promising approach for the development of molecular devices proposed in the 1970s. Substrate chemically bonded self-assembled monolayers of semiconducting conjugated molecules exhibit low mobility. And self-assembled monolayer molecular crystals are difficult to scale up and limited to growth on substrates terminated by hydroxyl groups, which makes it difficult to realize sophisticated device functions, particularly for those relying on n-type electron transport, as electrons suffer severe charge trapping on hydroxyl terminated surfaces. Here we report a gravity-assisted, two-dimensional spatial confinement method for bottom-up growth of high-quality n-type single-crystalline monolayers over large, centimeter-sized areas. We demonstrate that by this method, n-type monolayer molecular crystals with high field-effect mobility of 1.24 cm2 V-1 s-1 and band-like transport characteristics can be grown on hydroxyl-free polymer surface. Furthermore, we used these monolayer molecular crystals to realize high-performance crystalline, gate-/light-tunable lateral organic p-n diodes

TIR/BB-Loop Mimetic AS-1 Attenuates Cardiac Ischemia/Reperfusion Injury via a Caveolae and Caveolin-3-Dependent Mechanism

AS-1, the TIR/BB loop mimetic, plays a protective role in cardiac ischemia/reperfusion (I/R) but the molecular mechanism remains unclear. The muscle specific caveolin3 (Cav-3) and the caveolae have been found to be critical for cardioprotection. This study aimed to evaluate our hypothesis that caveolae and Cav-3 are essential for AS-1-induced cardioprotection against myocardial I/R injury. To address these issues, we analyzed the involvement of Cav-3 in AS-1 mediated cardioprotection both in vivo and in vitro. We demonstrate that AS-1 administration significantly decreased infarct size, improved cardiac function after myocardial I/R and modulated membrane caveolae and Cav-3 expression in the myocardium. For in vitro studies, AS-1 treatment prevented Cav-3 re-distribution induced by H/R injury. In contrast, disruption of caveolae by MCD treatment or Cav-3 knockdown abolished the protection against H/R-induced myocytes injury by AS-1. Our findings reveal that AS-1 attenuates myocardial I/R injury through caveolae and Cav-3 dependent mechanism

Mitochondrial Calcium Transporters Mediate Sensitivity to Noise-Induced Losses of Hair Cells and Cochlear Synapses

Mitochondria modulate cellular calcium homeostasis by the combined action of the mitochondrial calcium uniporter (MCU), a selective calcium entry channel, and the sodium calcium exchanger (NCLX), which extrudes calcium from mitochondria. In this study, we investigated MCU and NCLX in noise-induced hearing loss (NIHL) using adult CBA/J mice and noise-induced alterations of inner hair cell (IHC) synapses in MCU knockout mice. Following noise exposure, immunoreactivity of MCU increased in cochlear sensory hair cells of the basal turn, while immunoreactivity of NCLX decreased in a time- and exposure-dependent manner. Inhibition of MCU activity via MCU siRNA pretreatment or the specific pharmacological inhibitor Ru360 attenuated noise-induced loss of sensory hair cells and synaptic ribbons, wave I amplitudes, and NIHL in CBA/J mice. This protection was afforded, at least in part, through reduced cleavage of caspase 9 (CC9). Furthermore, MCU knockout mice on a hybrid genetic CD1 and C57/B6 background showed resistance to noise-induced seizures compared to wild-type littermates. Owing to the CD1 background, MCU knockouts and littermates suffer genetic high frequency hearing loss, but their IHCs remain intact. Noise-induced loss of IHC synaptic connections and reduction of auditory brainstem response (ABR) wave I amplitude were recovered in MCU knockout mice. These results suggest that cellular calcium influx during noise exposure leads to mitochondrial calcium overload via MCU and NCLX. Mitochondrial calcium overload, in turn, initiates cell death pathways and subsequent loss of hair cells and synaptic connections, resulting in NIHL

Sub-5 nm single crystalline organic p-n heterojunctions.

The cornerstones of emerging high-performance organic photovoltaic devices are bulk heterojunctions, which usually contain both structure disorders and bicontinuous interpenetrating grain boundaries with interfacial defects. This feature complicates fundamental understanding of their working mechanism. Highly-ordered crystalline organic p-n heterojunctions with well-defined interface and tailored layer thickness, are highly desirable to understand the nature of organic heterojunctions. However, direct growth of such a crystalline organic p-n heterojunction remains a huge challenge. In this work, we report a design rationale to fabricate monolayer molecular crystals based p-n heterojunctions. In an organic field-effect transistor configuration, we achieved a well-balanced ambipolar charge transport, comparable to single component monolayer molecular crystals devices, demonstrating the high-quality interface in the heterojunctions. In an organic solar cell device based on the p-n junction, we show the device exhibits gate-tunable open-circuit voltage up to 1.04 V, a record-high value in organic single crystalline photovoltaics

Cyclohexyl-Substituted Anthracene Derivatives for High Thermal Stability Organic Semiconductors

A novel p-type organic semiconductor with high thermal stability is developed by simply incorporating cyclohexyl substituted aryl groups into the 2,6-position of anthracene, namely 2,6-di(4-cyclohexylphenyl)anthracene (DcHPA), and a similar compound with linear alkyl chain, 2,6-di(4-n-hexylphenyl)anthracene (DnHPA), is also studied for comparison. DcHPA shows sublimation temperature around 360°C, and thin film field-effect transistors of DcHPA could maintain half of the original mobility value when heated up to 150°C. Corresponding DnHPA has sublimation temperature of 310°C and the performance of its thin film devices decreases by about 50% when heated to 80°C. The impressing thermal stability of the cyclohexyl substitution compounds might provide guidelines for developing organic electronic materials with high thermal stability

Peregrine and saker falcon genome sequences provide insights into evolution of a predatory lifestyle

As top predators, falcons possess unique morphological, physiological and behavioral adaptations that allow them to be successful hunters: for example, the peregrine is renowned as the world's fastest animal. To examine the evolutionary basis of predatory adaptations, we sequenced the genomes of both the peregrine (Falco peregrinus) and saker falcon (Falco cherrug), and we present parallel, genome-wide evidence for evolutionary innovation and selection for a predatory lifestyle. The genomes, assembled using Illumina deep sequencing with greater than 100-fold coverage, are both approximately 1.2 Gb in length, with transcriptome-assisted prediction of approximately 16,200 genes for both species. Analysis of 8,424 orthologs in both falcons, chicken, zebra finch and turkey identified consistent evidence for genome-wide rapid evolution in these raptors. SNP-based inference showed contrasting recent demographic trajectories for the two falcons, and gene-based analysis highlighted falcon-specific evolutionary novelties for beak development and olfaction and specifically for homeostasis-related genes in the arid environment–adapted saker