Cloning of the cDNA encoding the urotensin II precursor in frog and human reveals intense expression of the urotensin II gene in motoneurons of the spinal cord

Urotensin II (UII) is a cyclic peptide initially isolated from the caudal neurosecretory system of teleost fish. Subsequently, UII has been characterized from a frog brain extract, indicating that a gene encoding a UII precursor is also present in the genome of a tetrapod. Here, we report the characterization of the cDNAs encoding frog and human UII precursors and the localization of the corresponding mRNAs. In both frog and human, the UII sequence is located at the C-terminal position of the precursor. Human UII is composed of only 11 amino acid residues, while fish and frog UII possess 12 and 13 amino acid residues, respectively. The cyclic region of UII, which is responsible for the biological activity of the peptide, has been fully conserved from fish to human. Northern blot and dot blot analysis revealed that UII precursor mRNAs are found predominantly in the frog and human spinal cord. In situ hybridization studies showed that the UII precursor gene is actively expressed in motoneurons. The present study demonstrates that UII, which has long been regarded as a peptide exclusively produced by the urophysis of teleost fish, is actually present in the brain of amphibians and mammals. The fact that evolutionary pressure has acted to conserve fully the biologically active sequence of UII suggests that the peptide may exert important physiological functions in humans.     

Effects of pinacidil,verapamil, and heart rate on afterdepolarizations in the guinea-pig heart in vivo

Summary Recently, ionic current simulation in the Luo-Rudy model has elucidated putative mechanisms of afterdepolarizations under various experimental conditions. The present study was aimed at gaining insight into the differential mechanism of different types of afterdepolarizations in the guinea-pig heart in vivo. The effects of pharmacological and heart rate perturbations on early (EADs) and delayed (DADs) afterdepolarizations, induced by either digoxin, CsCl, or BayK 8644 were studied, using mid-myocardial left ventricular monophasic action potential (MAP) recordings. Digoxin insignificantly shortened sinus cycle length (SCL) and CsCl and BayK 8644 differentially prolonged SCL and MAP duration. Digoxin induced phase 3-EADs and DADs and CsCl or BayK 8644 induced phase 2- and phase 3-EADs. Pinacidil shortened MAP duration, suppressed almost all the phase 2-EADs and some of the phase 3-EADs, but not the DADs. In a few cases, DADs were manifested following the abolishment of phase 2-EADs by pinacidil, but this phenomenon did not occur in the presence of hexamethonium. Verapamil prolonged SCL, did not significantly affect phase 2-EADs, but suppressed almost all of the DADs, including those which appeared after pinacidil, and all but one of the phase 3-EADs. The effects of pinacidil and verapamil were independent of the mode of afterdepolarization induction. A pacing-induced heart rate increase, which shortened MAP duration, and vagal stimulation, which prolonged MAP duration, attenuated and enhanced phase 2-EADs, respectively. The amplitude of phase 3-EADs was inversely related to the heart rate. These data, taken together, are consistent with those obtained previously by others in a computer model and recent observations on CsCl-induced EADs in the guinea-pig Purkinje fibers in vitro which have indicated that the mechanism of phase 2-EADs is different from that of DADs and that late phase 3-EADs generated under conditions of Ca²⁺ overload and DADs share similar properties.     

Trends of lipoprotein variables from childhood to adulthood in offspring of parents with coronary heart disease: The Bogalusa heart study

Although dyslipidemia among offspring of parents with coronary heart disease (CHD) has been known, the development of this adverse relationship with respect to specific lipoprotein variables from childhood to young adulthood has not been elucidated. This aspect was examined in a young adult cohort with (n = 271) and without (n = 805) a parental history of CHD followed longitudinally since childhood by repeated surveys from 1973 to 1991. Trends in fasting lipoprotein variables by parental CHD status were assessed by Lowess smoothing curve and Generalized Estimating Equations (GEE). In multivariate analyses adjusted for race and sex, parental CHD associated positively with low-density lipoprotein cholesterol (LDL-C, P <.01) and triglycerides (P <.05) mainly at the young adulthood age, whereas a positive association was noted with very-low-density lipoprotein cholesterol (VLDL-C) during both childhood and young adulthood (P <.05). The positive association between parental CHD and LDL-C in young adulthood persisted independently of body mass index (BMI) and fasting insulin, but disappeared when fasting glucose was added to the model. With respect to triglycerides and VLDL-C, inclusion of BMI, insulin, and/or glucose eliminated the adverse association with parental CHD. These observations suggest that parental CHD is just one more explanatory variable that loses its partial contribution to lipoprotein profiles in their offspring when other strongly interrelated contributory variables such as age, body fatness, and measures of glucose homeostasis are taken into account. Information on these risk variables in conjunction with parental or family history of CHD may enhance the potential of CHD risk assessment in youth.     

Association between serotonin transporter genotype,brain structure and adolescent-onset major depressive disorder: a longitudinal prospective study

The extent to which brain structural abnormalities might serve as neurobiological endophenotypes that mediate the link between the variation in the promoter of the serotonin transporter gene (5-HTTLPR) and depression is currently unknown. We therefore investigated whether variation in hippocampus, amygdala, orbitofrontal cortex (OFC) and anterior cingulate cortex volumes at age 12 years mediated a putative association between 5-HTTLPR genotype and first onset of major depressive disorder (MDD) between age 13–19 years, in a longitudinal study of 174 adolescents (48% males). Increasing copies of S-alleles were found to predict smaller left hippocampal volume, which in turn was associated with increased risk of experiencing a first onset of MDD. Increasing copies of S-alleles also predicted both smaller left and right medial OFC volumes, although neither left nor right medial OFC volumes were prospectively associated with a first episode of MDD during adolescence. The findings therefore suggest that structural abnormalities in the left hippocampus may be present prior to the onset of depression during adolescence and may be partly responsible for an indirect association between 5-HTTLPR genotype and depressive illness. 5-HTTLPR genotype may also impact upon other regions of the brain, such as the OFC, but structural differences in these regions in early adolescence may not necessarily alter the risk for onset of depression during later adolescence.     

Synthesis,characterization and cytotoxic activity of naturally isolated naringin-metal complexes

High-purity naringin was isolated from the fruit peels of Citrus maxima and characterized by various spectroscopic methods like UV and NMR. The isolated compound ligand (HL) was used as ligand-metal complexes synthesis after using Ag (I), Y (III) and Ru (III) metals. These ligand-metal complexes were characterized by elemental analysis, FT-IR, UV–VIS, TGA, molar conductance and magnetic properties. Cytotoxic activity of the isolated naringin and its metal complexes were investigated against two human cancer cell lines namely, white breast Adenocarcinoma (MCF7) and Lung carcinoma (A549) using cell viability assay. Transition metal increased the cytotoxic activity of naringin when they were conjugated. LC50 of Ag ligand complex demonstrated strong cytotoxicity against MCF-7 and A549 cell line that was found higher active more than three and four times the strength, respectively when compared to LC50 of Adriamycin. While LC50 of Adriamycin compound was slightly more active only about 30% and twice the strength of the Ru ligand complex against MCF-7 and A549 cell line, respectively.     

Polychlorinated Biphenyl Exposures and Cognition in Older U.S. Adults: NHANES (1999–2002)

Background: Polychlorinated biphenyls (PCBs) are ubiquitously present in humans because of their resistance to degradation and accumulation in fatty tissues. Data on neurotoxic effects in older adults are limited.Objective: We examined the cross-sectional association between serum PCB concentrations and cognitive function in older adults from the general U.S. population.Methods: We analyzed data from 708 respondents, 60–84 years of age, participating in the National Health and Nutrition Examination Survey (1999–2002). We used the summed concentrations of 12 lipid-standardized PCB congeners as the measure of exposure and assessed cognitive function with the Digit-Symbol Coding test. We adjusted analyses for age, education, race/ethnicity, and poverty/income ratio.Results: The median concentration of lipid-standardized PCBs in serum was 271 ng/g (interquartile range, 193–399 ng/g). We found a significant interaction between dioxin-like PCB concentration and age in association with cognitive score (p = 0.04). Among older individuals (70–84 years of age), a 100-ng/g increase in serum concentrations of dioxin-like PCBs was associated with a significantly lower cognitive score (–2.7 points; 95% CI: –5.1, –0.2; p = 0.04); however, in younger individuals (60–69 years of age), there was a nonsignificant positive association (2.9 points; 95% CI: –1.8, 7.7; p = 0.32). Among the older participants, the negative association was more pronounced in women than in men.Conclusion: Our findings support the hypothesis that PCB exposure has adverse cognitive effects even at levels generally considered to pose low or no risk, perhaps affecting mainly those of advanced age.Citation: Bouchard MF, Oulhote Y, Sagiv SK, Saint-Amour D, Weuve J. 2014. Polychlorinated biphenyl exposures and cognition in older U.S. adults: NHANES (1999–2002). Environ Health Perspect 122:73–78; http://dx.doi.org/10.1289/ehp.1306532     

Collapsin response‐mediator protein 5 (CRMP5) phosphorylation at threonine 516 regulates neurite outgrowth inhibition

The collapsin response‐mediator proteins (CRMPs) are multifunctional proteins highly expressed during brain development but down‐regulated in the adult brain. They are involved in axon guidance and neurite outgrowth signalling. Among these, the intensively studied CRMP2 has been identified as an important actor in axon outgrowth, this activity being correlated with the reorganisation of cytoskeletal proteins via the phosphorylation state of CRMP2. Another member, CRMP5, restricts the growth‐promotional effects of CRMP2 by inhibiting dendrite outgrowth at early developmental stages. This inhibition occurs when CRMP5 binds to tubulin and the microtubule‐associated protein MAP2, but the role of CRMP5 phosphorylation is still unknown. Here, we have studied the role of CRMP5 phosphorylation by mutational analysis. Using non‐phosphorylatable truncated constructs of CRMP5 we have demonstrated that, among the four previously identified CRMP5 phosphorylation sites (T509, T514, T516 and S534), only the phosphorylation at T516 residue was needed for neurite outgrowth inhibition in PC12 cells and in cultured C57BL/6J mouse hippocampal neurons. Indeed, the expression of the CRMP5 non‐phosphorylated form induced a loss of function of CRMP5 and the mutant mimicking the phosphorylated form induced the growth inhibition function seen in wildtype CRMP5. The T516 phosphorylation was achieved by the glycogen synthase kinase‐3β (GSK‐3β), which can phosphorylate the wildtype protein but not the non‐phosphorylatable mutant. Furthermore, we have shown that T516 phosphorylation is essential for the tubulin‐binding property of CRMP5. Therefore, CRMP5‐induced growth inhibition is dependent on T516 phosphorylation through the GSK‐3β pathway. The findings provide new insights into the mechanisms underlying neurite outgrowth.     

Preoperative Prediction of Failure Following Two-Stage Revision for Knee Prosthetic Joint Infections

While two-stage revision is the gold standard for treatment of knee prosthetic joint infection (PJI), it is not without risk. The purpose of this study was to develop a tool to preoperatively predict the probability that a two-stage revision would fail to eradicate knee PJI. 3,809 surgical cases were retrospectively reviewed and data were collected from 314 charts. Overall, 105 (33.4%) cases failed to eradicate PJI using this procedure. Univariate analysis identified multiple variables independently associated with reinfection. Logistic regression was used to generate a model (bootstrap-corrected concordance index of 0.773) predicting failure of infection eradication. Preoperative knowledge of a high probability of failure may improve risk assessment, lead to more aggressive management, and allow for time to consider alternative therapies.     

Discovery of Thienoimidazole-Based HCV NS5A Genotype 1a and 1b Inhibitors

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