Pharmacological Effect of Histone Deacetylase Inhibitors on Pulmonary Arterial Hypertension

Pulmonary hypertension (PH) is characterized by structural remodelling of pulmonary arteries and arterioles, the result, at least in part, of excessive cell proliferation, resistance to cell death and hyperactive inflammatory reactions. Currently available treatments targeting the hyper-proliferative and pro-inflammatory pathology are limited. Epigenetic programming, dynamically regulated by histone acetylation, is an important mechanism for cell proliferation and survival. Aberrant changes of histone acetylation, modulated by histone deacetylase (HDAC), are shown in many proliferative and inflammatory disorders, especially cancer, and may contribute to the phenotypical changes in remodelling and overall to the development of PH. Hypothetically, HDAC inhibitors have therapeutic potential by reversing the imbalance of acetylation. I examined the correlations between HDAC expression and PH development, followed by evaluation of the pharmacological effects and possible mechanisms of two HDAC inhibitors, class I inhibitor valproic acid (VPA) and pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), on animal models and cellular systems. Altered HDAC expression, specifically increased HDAC1 and HDAC5 along with elevation of anti-apoptotic marker Bcl-2, were found in lungs from patients with idiopathic pulmonary arterial hypertension and chronically hypoxic rats. In in vivo studies, VPA and SAHA ameliorated the established PH in both hypoxia- and monocrotalineinduced PH rat models, by reducing pulmonary arterial pressure, right ventricular hypertrophy and pulmonary vascular muscularization, in parallel with increasing histone acetylation. In in vitro studies, VPA and SAHA inhibited stimulated cell growth of pulmonary artery smooth muscle cells and cytokine release from endothelial cells. Biochemical analysis indicated these two inhibitors exert anti-proliferative effects comprising cell cycle arrest by upregulation of p21 and apoptotic induction by downregulation of Bcl-2. Collectively, this study shows the contribution of abnormal HDAC activity to vascular pathology of PH and provides a preclinical basis to further explore the therapeutic potential of HDAC inhibitors in human PH

Baseband Transceiver Design of a High Definition Radio FM System Using Joint Theoretical Analysis and FPGA Implementation

Advances in wireless communications have enabled various technologies for wireless digital communication. In the field of digital radio broadcasting, several specifications have been proposed, such as Eureka-147 and digital radio mondiale (DRM). These systems require a new spectrum assignment, which incurs heavy cost due to the depletion of the available spectrum. Therefore, the in-band on-channel (IBOC) system has been developed to work in the same band with the conventional analog radio and to provide digital broadcasting services. This paper discusses the function and algorithm of the high definition (HD) radio frequency modulation (FM) digital radio broadcasting system. Content includes data format allocation, constellation mapping, orthogonal frequency division multiplexing (OFDM) modulation of the transmitter, timing synchronization, OFDM demodulation, integer and fraction carrier frequency (integer carrier frequency offset (ICFO) and fractional CFO (FCFO)) estimation, and channel estimation of the receiver. When we implement this system to the field programmable gate array (FPGA) based on a hardware platform, both theoretical and practical aspects have been considered to accommodate the available hardware resources

Integrative network analysis reveals active microRNAs and their functions in gastric cancer

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) are a class of endogenous, small and highly conserved noncoding RNAs that control gene expression either by degradation of target mRNAs or by inhibition of protein translation. They play important roles in cancer progression. A single miRNA can provoke a chain reaction and further affect protein interaction network (PIN). Therefore, we developed a novel integrative approach to identify the functional roles and the regulated PIN of oncomirs.</p> <p>Results</p> <p>We integrated the expression profiles of miRNA and mRNA with the human PIN to reveal miRNA-regulated PIN in specific biological conditions. The potential functions of miRNAs were determined by functional enrichment analysis and the activities of miRNA-regulated PINs were evaluated by the co-expression of protein-protein interactions (PPIs). The function of a specific miRNA, miR-148a, was further examined by clinical data analysis and cell-based experiments. We uncovered several miRNA-regulated networks which were enriched with functions related to cancer progression. One miRNA, miR-148a, was identified and its function is to decrease tumor proliferation and metastasis through its regulated PIN. Furthermore, we found that miR-148a could reduce the invasiveness, migratory and adhesive activities of gastric tumor cells. Most importantly, elevated miR-148a level in gastric cancer tissues was strongly correlated with distant metastasis, organ and peritoneal invasion and reduced survival rate.</p> <p>Conclusions</p> <p>This study provides a novel method to identify active oncomirs and their potential functions in gastric cancer progression. The present data suggest that miR-148a could be a potential prognostic biomarker of gastric cancer and function as a tumor suppressor through repressing the activity of its regulated PIN.</p

Extracorporeal membrane oxygenation for neonatal congenital diaphragmatic hernia: The initial single-center experience in Taiwan

Background/Purpose Extracorporeal membrane oxygenation (ECMO) is a treatment option for stabilizing neonates with congenital diaphragmatic hernia (CDH) in a critical condition when standard therapy fails. However, the use of this approach in Taiwan has not been previously reported. Methods The charts of all neonates with CDH treated in our institute during the period 2007–2014 were reviewed. After 2010, patients who could not be stabilized with conventional treatment were candidates for ECMO. We compared the demographic data of patients with and without ECMO support. The clinical course and complications of ECMO were also reviewed. Results We identified 39 neonates with CDH with a median birth weight of 2696 g (range, 1526–3280 g). Seven (18%) of these patients required ECMO support. The APGAR score at 5 minutes differed significantly between the ECMO and non-ECMO groups. The survival rate was 84.6% (33/39) for all CDH patients and 57.1% (4/7) for the ECMO group. The total ECMO bypass times in the survivors was in the range of 5–36 days, whereas all nonsurvivors received ECMO for at least 36 days (mean duration, 68 days). Surgical bleeding occurred in four of seven patients in the ECMO group. Conclusion The introduction of ECMO rescued some CDH patients who could not have survived by conventional management. Prolonged (i.e., > 36 days) ECMO support had no benefit for survival

Pengembangan Suplemen Pembelajaran Fisika Gelombang Elektromagnetik Cahaya Sebagai Partikel Memanfaatkan Virtual Laboratorium

This research has been done to make a supplement for physics learning about light electromagnetic wave as a particle using virtual laboratory. The population of this research was the second year science-students at SMA Muhammadiyah 1 Metro. This development is begun by needs analysis, then identification of resource which is the background of this developmental research. The next step is, identifying the product specification then developing products which contained a tutorial book for teacher and a work sheet for student (LKS). The material and design expert test result is that those products were approved. The external test resulted by users show that the LKS was attractive, very easy to use, and useful. It also was effective to be used as a learning resource because 80% of students reached the passing grade.Telah dilakukan penelitian untuk mengembangkan suplemen pembelajaran fisika gelombang elektromagnetik cahaya sebagai partikel dengan memanfaatkan virtual laboratorium. Populasi penelitian pengembangan ini adalah siswa kelas XI IPA di SMA Muhammadiyah 1 Metro. Pengembangan ini diawali dengan analisis kebutuhan, kemudian identifikasi sumber daya yang melatar belakangi pengembangan. Langkah selanjutnya identifikasi spesifikasi produk yang dilanjutkan dengan mengembangkan produk berupa LKS untuk siswa dan buku panduan untuk guru. Hasil uji internal oleh ahli materi dan ahli desain menyatakan produk yang dikembangkan layak digunakan sebagai media pembelajaran. Hasil uji eksternal oleh pengguna menunjukkan kualitas media pembelajaran menarik, sangat mudah digunakan, dan bermanfaat serta efektif digunakan sebagai media pembelajaran dengan presentase hasil belajar sebesar 80% siswa telah memenuhi KKM

SOX17 Enhancer Variants Disrupt Transcription Factor Binding And Enhancer Inactivity Drives Pulmonary Hypertension

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease characterized by remodeling of the pulmonary arteries, increased vascular resistance, and right-sided heart failure. Genome-wide association studies of idiopathic/heritable PAH established novel genetic risk variants, including conserved enhancers upstream of transcription factor (TF) SOX17 containing 2 independent signals. SOX17 is an important TF in embryonic development and in the homeostasis of pulmonary artery endothelial cells (hPAEC) in the adult. Rare pathogenic mutations in SOX17 cause heritable PAH. We hypothesized that PAH risk alleles in an enhancer region impair TF-binding upstream of SOX17, which in turn reduces SOX17 expression and contributes to disturbed endothelial cell function and PAH development. METHODS: CRISPR manipulation and siRNA were used to modulate SOX17 expression. Electromobility shift assays were used to confirm in silico–predicted TF differential binding to the SOX17 variants. Functional assays in hPAECs were used to establish the biological consequences of SOX17 loss. In silico analysis with the connectivity map was used to predict compounds that rescue disturbed SOX17 signaling. Mice with deletion of the SOX17 signal 1 enhancer region (SOX17-4593/enhKO) were phenotyped in response to chronic hypoxia and SU5416/hypoxia. RESULTS: CRISPR inhibition of SOX17-signal 2 and deletion of SOX17signal 1 specifically decreased SOX17 expression. Electromobility shift assays demonstrated differential binding of hPAEC nuclear proteins to the risk and nonrisk alleles from both SOX17 signals. Candidate TFs HOXA5 and ROR-α were identified through in silico analysis and antibody electromobility shift assays. Analysis of the hPAEC transcriptomes revealed alteration of PAH-relevant pathways on SOX17 silencing, including extracellular matrix regulation. SOX17 silencing in hPAECs resulted in increased apoptosis, proliferation, and disturbance of barrier function. With the use of the connectivity map, compounds were identified that reversed the SOX17-dysfunction transcriptomic signatures in hPAECs. SOX17 enhancer knockout in mice reduced lung SOX17 expression, resulting in more severe pulmonary vascular leak and hypoxia or SU5416/hypoxia-induced pulmonary hypertension. CONCLUSIONS: Common PAH risk variants upstream of the SOX17 promoter reduce endothelial SOX17 expression, at least in part, through differential binding of HOXA5 and ROR-α. Reduced SOX17 expression results in disturbed hPAEC function and PAH. Existing drug compounds can reverse the disturbed SOX17 pulmonary endothelial transcriptomic signature