Hirschsprung's disease (HSCR), or aganglionic megacolon, is a congenital disorder characterized by the absence of enteric ganglia in variable portions of the distal intestine. RET is a well-established susceptibility locus, although existing evidence strongly suggests additional loci contributing to sporadic HSCR. To identify these additional genetic loci, we carried out a genome-wide association study using the Affymetrix 500K marker set. We successfully genotyped 293,836 SNPs in 181 Chinese subjects with sporadic HSCR and 346 ethnically matched control subjects. The SNPs most associated with HSCR were genotyped in an independent set of 190 HSCR and 510 control subjects. Aside from SNPs in RET, the strongest overall associations in plausible candidate genes were found for 2 SNPs located in intron 1 of the neuregulin1 gene (NRG1) on 8p12, with rs16879552 and rs7835688 yielding odds ratios of 1.68 [CI 95%:(1.40, 2.00), P ‫؍‬ 1.80 ؋ 10 ؊8 ] and 1.98 [CI95%:(1.59, 2.47), P ‫؍‬ 1.12 ؋ 10 ؊9 ], respectively, for the heterozygous risk genotypes under an additive model. There was also a significant interaction between RET and NRG1 (P ‫؍‬ 0.0095), increasing the odds ratio 2.3-fold to 19.53 for the RET rs2435357 risk genotype (TT) in the presence of the NRG1 rs7835688 heterozygote, indicating that NRG1 is a modifier of HSRC penetrance. Our highly significant association findings are backed-up by the important role of NRG1 as regulator of the development of the enteric ganglia precursors. The identification of NRG1 as an additional HSCR susceptibility locus not only opens unique fields of investigation into the mechanisms underlying the HSCR pathology, but also the mechanisms by which a discrete number of loci interact with each other to cause disease.GWA ͉ RET

A fluorescent probe, HKOCl-1, has been successfully developed for the detection of hypochlorous acid on the basis of a specific reaction with p-methoxyphenol. The formation of HOCl has been successfully detected not only in an abiotic system but also in an enzymatic system (myeloperoxidase/H2O2/Cl(-) system) and in living macrophage cells upon stimulation. This new probe might be used as an efficient tool for probing the roles HOCl plays in biological systems.

The aim of this study was to observe the impact of dexmedetomidine on postoperative myocardial injury in patients undergoing off-pump coronary artery bypass (OPCAB) grafting. One hundred and sixty-two patients who were undergoing OPCAB surgery were randomly divided into control and dexmedetomidine groups (groups C and Dex, respectively). Following the first vascular anastomosis grafting, the patients in group Dex received a continuous intravenous infusion of 0.2–0.5 μg/kg/h dexmedetomidine, until they were transferred to the Cardiac Surgery intensive care unit (ICU) for 12 h. Patients in group C received physiological saline intraoperatively and an intravenous infusion of 2–4 mg/kg/h isopropylphenol for postoperative sedation. Invasive arterial pressure and heart rate were continuously monitored for 5 min subsequent to entry into the operating theatre (T0), immediately following surgery (T1), 12 h post-surgery (T2), 24 h post-surgery(T3), 48 h post-surgery(T4) and 72 h post-surgery (T5). Blood samples were taken to determine the plasma levels of cardiac troponin I (cTnI) and creatine kinase-MB (CK-MB) at each time point. At 72 h post-surgery, a dynamic electrocardiogram was monitored. The blood pressure, heart rate, levels of cTnI, CK-MB, norepinephrine and cortisol, and postoperative arrhythmic events in the patients in group Dex all decreased compared with those in group C. The duration of mechanical ventilation and ICU residence time were also shorter than those in the control group (P<0.05). Dexmedetomidine reduced post-surgical myocardial injury in patients who had undergone OPCAB surgery.

A fluorescent probe, HKGreen-2, has been developed based on a specific reaction between ketone and peroxynitrite (ONOO(-)). This probe is highly sensitive and selective for the detection of peroxynitrite not only in abiotic but also in biological systems. With this probe, we successfully detected peroxynitrite generated in murine macrophage cells activated by phorbol 12-myristate 13-acetate (PMA), interferon-gamma (IFN-gamma), and lipopolysaccharide (LPS). This new probe will be a useful tool for studying the roles of peroxynitrite in biological processes.

The present study examined the processing of the Mandarin Chinese long-distance reflexive ziji to evaluate the role that syntactic structure plays in the memory retrieval operations that support sentence comprehension. Using the multiple-response speed-accuracy tradeoff (MR-SAT) paradigm, we measured the speed with which comprehenders retrieve an antecedent for ziji. Our experimental materials contrasted sentences where ziji's antecedent was in the local clause with sentences where ziji's antecedent was in a distant clause. Time course results from MR-SAT suggest that ziji dependencies with syntactically distant antecedents are slower to process than syntactically local dependencies. To aid in interpreting the SAT data, we present a formal model of the antecedent retrieval process, and derive quantitative predictions about the time course of antecedent retrieval. The modeling results support the Local Search hypothesis: during syntactic retrieval, comprehenders initially limit memory search to the local syntactic domain. We argue that Local Search hypothesis has important implications for theories of locality effects in sentence comprehension. In particular, our results suggest that not all locality effects may be reduced to the effects of temporal decay and retrieval interference.

No abstract

Non‑small cell lung cancer (NSCLC) represents one of the most important causes of cancer mortality in the world, and leads to the largest number of deaths in all kinds of lung cancer. Hypoxia has been confirmed to be a characteristic feature of NSCLC and has been shown to decrease the therapeutic efficacy of radiotherapy and some forms of chemotherapy. Previous studies revealed that many miRNAs have been proven to be involved in the molecular regulation of hypoxia and to affect the protein expression level of HIF‑1α. Here, we demonstrated that miR‑199a‑5p downregulated HIF‑1α expression and was involved in regulating the proliferation of NLSCS cell under hypoxia through downregulation of HIF‑1α. Recently, PVT1 has been proposed to function as a molecular sponge by competitively binding miR‑199a‑5p using miRcode. In this study, we confirmed that PVT1 was overexpressed in the hypoxic lung cancer cells, and then we further demonstrated that PVT1 functioned as competing endogenous (ce)RNA for miR‑199a‑5p, upregulated expression of its endogenous targets HIF‑1α and inhibited its function. Collectively, our study suggested that PVT1 promotes expression of HIF‑1α in NSCLC by functioning as ceRNA of miR‑199a‑5p. These findings support the hypothesis that PVT1 is a vital potential target for hypoxia therapy.

Stress-induced neural injuries are closely linked to the pathogenesis of various neuropsychiatric disorders and psychosomatic diseases. We and others have previously demonstrated certain protective effects of epigallocatechin-3-gallate (EGCG) in stress-induced cerebral impairments, but the underlying protective mechanisms still remain poorly elucidated. Here we provide evidence to support the possible involvement of PKCα and ERK1/2 signaling pathways in EGCG-mediated protection against restraint stress-induced neural injuries in rats. In both open-field and step-through behavioral tests, the restraint stress-induced neuronal impairments were significantly ameliorated by administration of EGCG or green tea polyphenols (GTPs), which was associated with a partial restoration of normal plasma glucocorticoid, dopamine and serotonin levels. Furthermore, the stress-induced decrease of PKCα and ERK1/2 expression and phosphorylation was significantly attenuated by EGCG and to a less extent by GTP administration. Additionally, EGCG supplementation restored the production of ATP and the expression of a key regulator of cellular energy metabolism, the peroxisome proliferators-activated receptor-γ coactivator-1α (PGC-1α), in stressed animals. In conclusion, PKCα and ERK1/2 signaling pathways as well as PGC-1α-mediated ATP production might be involved in EGCG-mediated protection against stress-induced neural injuries.