809 research outputs found

    Determinants of the voltage dependence of G protein modulation within calcium channel β subunits

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    CaVβ subunits of voltage-gated calcium channels contain two conserved domains, a src-homology-3 (SH3) domain and a guanylate kinase-like (GK) domain with an intervening HOOK domain. We have shown in a previous study that, although Gβγ-mediated inhibitory modulation of CaV2.2 channels did not require the interaction of a CaVβ subunit with the CaVα1 subunit, when such interaction was prevented by a mutation in the α1 subunit, G protein modulation could not be removed by a large depolarization and showed voltage-independent properties (Leroy et al., J Neurosci 25:6984–6996, 2005). In this study, we have investigated the ability of mutant and truncated CaVβ subunits to support voltage-dependent G protein modulation in order to determine the minimal domain of the CaVβ subunit that is required for this process. We have coexpressed the CaVβ subunit constructs with CaV2.2 and α2δ-2, studied modulation by the activation of the dopamine D2 receptor, and also examined basal tonic modulation. Our main finding is that the CaVβ subunit GK domains, from either β1b or β2, are sufficient to restore voltage dependence to G protein modulation. We also found that the removal of the variable HOOK region from β2a promotes tonic voltage-dependent G protein modulation. We propose that the absence of the HOOK region enhances Gβγ binding affinity, leading to greater tonic modulation by basal levels of Gβγ. This tonic modulation requires the presence of an SH3 domain, as tonic modulation is not supported by any of the CaVβ subunit GK domains alone

    Rapidly rotating second-generation progenitors for the blue hook stars of {\omega} Cen

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    Horizontal Branch stars belong to an advanced stage in the evolution of the oldest stellar galactic population, occurring either as field halo stars or grouped in globular clusters. The discovery of multiple populations in these clusters, that were previously believed to have single populations gave rise to the currently accepted theory that the hottest horizontal branch members (the blue hook stars, which had late helium-core flash ignition, followed by deep mixing) are the progeny of a helium-rich "second generation" of stars. It is not known why such a supposedly rare event (a late flash followed by mixing) is so common that the blue hook of {\omega} Cen contains \sim 30% of horizontal branch stars 10 , or why the blue hook luminosity range in this massive cluster cannot be reproduced by models. Here we report that the presence of helium core masses up to \sim 0.04 solar masses larger than the core mass resulting from evolution is required to solve the luminosity range problem. We model this by taking into account the dispersion in rotation rates achieved by the progenitors, whose premain sequence accretion disc suffered an early disruption in the dense environment of the cluster's central regions where second-generation stars form. Rotation may also account for frequent late-flash-mixing events in massive globular clusters.Comment: 44 pages, 8 figures, 2 tables in Nature, online june 22, 201

    The hOGG1 Ser326Cys polymorphism and prostate cancer risk: a meta-analysis of 2584 cases and 3234 controls

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    <p>Abstract</p> <p>Background</p> <p>Genetic polymorphism of human 8-oxoguanine glycosylase 1 (hOGG1) Ser326Cys (rs1052133) has been implicated to alter the risk of prostate cancer, but the results are controversial.</p> <p>Methods</p> <p>Two investigators independently searched the Medline, and Cochrane Library up to June 7, 2011. Summary odds ratios (OR) and 95% confidence interval (CI) for Ser326Cys polymorphism and prostate cancer were calculated. Statistical analysis was performed with the software program Review Manage, version 5.0 and Stata 10.0.</p> <p>Results</p> <p>A total of 8 independent studies, including 2584 cases and 3234 controls, were identified. Our analysis suggested that Ser326Cys was not associated with prostate cancer risk in overall population. In the subgroup analysis, we detected the significant association between Ser326Cys polymorphism and decreased prostate risk in mixed population under additive model (OR = 0.67, 95% CI = 0.50-0.90, P = 0.007), recessive model (OR = 0.68, 95% CI = 0.51-0.91, P = 0.008), and Cys allele versus Ser allele (OR = 0.88, 95% CI = 0.78-0.98, P = 0.02). Subanalysis on Caucasian subjects demonstrated that Ser326Cys was not associated with prostate cancer risk.</p> <p>Conclusion</p> <p>This meta-analysis showed the evidence that hOGG1 Ser326Cys polymorphism was associated with a decreased risk of prostate cancer development in mixed populations.</p

    Standard values and relationship-specific validity of the Bielefeld Relationship Expectations Questionnaire (BFPE)

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    <p>Abstract</p> <p>Background</p> <p>The Bielefeld Partnership Expectations Questionnaire (BFPE) is a tool to assess attachment in the romantic relationships of adults. The attachment styles are operationalized as configuration patterns of scale scores. While convergent validity has already been investigated, discriminant validity is still lacking confirmation.</p> <p>Methods</p> <p>The present sample (n = 1509) is representative for the German population aged 18 to 50. The mean age was 34.6 years. Most of the participants lived in a relationship (77.3 %). Discriminant validity was analyzed using a marital quality questionnaire (PFB), a social support questionnaire (F-Soz-U K-14), and a life satisfaction questionnaire (FLZ).</p> <p>Results</p> <p>All the BFPE scales have a satisfying internal consistency between r = .79 and .86. Those individuals who showed a secure pattern, i.e. increased "Readiness for Self-Disclosure" and "Conscious Need for Care" as well as reduced "Fear of Rejection" experienced their partner as socially supportive, reported higher marital quality in all of its facets, and were more satisfied within the life-domains "family/children" and "relationship/sexuality". Standard values for each scale are presented.</p> <p>Conclusions</p> <p>The BFPE has repeatedly been verified as a short, reliable, and valid instrument applicable to research practice with healthy individuals as well as within clinical contexts.</p

    Diurnal Variation in Urodynamics of Rat

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    In humans, the storage and voiding functions of the urinary bladder have a characteristic diurnal variation, with increased voiding during the day and urine storage during the night. However, in animal models, the daily functional differences in urodynamics have not been well-studied. The goal of this study was to identify key urodynamic parameters that vary between day and night. Rats were chronically instrumented with an intravesical catheter, and bladder pressure, voided volumes, and micturition frequency were measured by continuous filling cystometry during the light (inactive) or dark (active) phases of the circadian cycle. Cage activity was recorded by video during the experiment. We hypothesized that nocturnal rats entrained to a standard 12:12 light:dark cycle would show greater ambulatory activity and more frequent, smaller volume micturitions in the dark compared to the light. Rats studied during the light phase had a bladder capacity of 1.44±0.21 mL and voided every 8.2±1.2 min. Ambulatory activity was lower in the light phase, and rats slept during the recording period, awakening only to urinate. In contrast, rats studied during the dark were more active, had a lower bladder capacities (0.65±0.18 mL), and urinated more often (every 3.7±0.9 min). Average bladder pressures were not significantly different between the light and dark (13.40±2.49 and 12.19±2.85 mmHg, respectively). These results identify a day-night difference in bladder capacity and micturition frequency in chronically-instrumented nocturnal rodents that is phase-locked to the normal circadian locomotor activity rhythm of the animal. Furthermore, since it has generally been assumed that the daily hormonal regulation of renal function is a major driver of the circadian rhythm in urination, and few studies have addressed the involvement of the lower urinary tract, these results establish the bladder itself as a target for circadian regulation

    A change in the transportation needs today, a better future for tomorrow – climate change review

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    No sooner than later, the world will be living hell as a result of the transportation effects on our climate now escalating. The pressure is now growing towards their resultant effects to be totally eradicated in order to save our planet otherwise, the stabilisation of these effects; global warming, greenhouse gas (GHG) emission and degradation will need to be sought after. The world all over is at it now in an effort to restore our climate, to save it from the effects of these catastrophes/disasters. On the proposition of the Kyoto Protocol in1997, the main focus was to decrease greenhouse emissions of mainly six gases – Carbon dioxide, methane, nitrous oxide, sulphur hexafluoride, Hydro fluorocarbons (HFCs) and Per fluorinated Compounds (PFCs). And transport alone, accounts for over 26% of global CO2 and has been regarded as one of the few industrial sectors wherein emissions are still on the increase, on this basis, researchers and policy makers are all at it to tackle the menace of climate changes through provision of sustainable transport. This paper focuses on the new and developed technologies like the renewable energy source [RES], which will be an alternative to transport fuels to avoid the dependence on petroleum which after effects are damaging to the world climate, and may probably not be there forever to continue serving the world ever increasing population. While the long term solutions are being sought, these alternatives will make do for now

    Glycan Structures Contain Information for the Spatial Arrangement of Glycoproteins in the Plasma Membrane

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    Glycoconjugates at the cell surface are crucial for cells to communicate with each other and the extracellular microenvironment. While it is generally accepted that glycans are vectorial biopolymers, their information content is unclear. This report provides evidence that distinct N-glycan structures influence the spatial arrangement of two integral membrane glycoproteins, Kv3.1 and E-cadherin, at the adherent membrane which in turn alter cellular properties. Distinct N-glycan structures were generated by heterologous expression of these glycoproteins in parental and glycosylation mutant Chinese hamster ovary cell lines. Unlike the N-linked glycans, the O-linked glycans of the mutant cell lines are similar to those of the parental cell line. Western and lectin blots of total membranes and GFP immunopurified samples, combined with glycosidase digestion reactions, were employed to verify the glycoproteins had predominantly complex, oligomannose, and bisecting type N-glycans from Pro(-)5, Lec1, and Lec10B cell lines, respectively. Based on total internal reflection fluorescence and differential interference contrast microscopy techniques, and cellular assays of live parental and glycosylation mutant CHO cells, we propose that glycoproteins with complex, oligomannose or bisecting type N-glycans relay information for localization of glycoproteins to various regions of the plasma membrane in both a glycan-specific and protein-specific manner, and furthermore cell-cell interactions are required for deciphering much of this information. These distinct spatial arrangements also impact cell adhesion and migration. Our findings provide direct evidence that N-glycan structures of glycoproteins contribute significantly to the information content of cells

    Chromosome 15q25 (CHRNA3-CHRNA5) Variation Impacts Indirectly on Lung Cancer Risk

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    Genetic variants at the 15q25 CHRNA5-CHRNA3 locus have been shown to influence lung cancer risk however there is controversy as to whether variants have a direct carcinogenic effect on lung cancer risk or impact indirectly through smoking behavior. We have performed a detailed analysis of the 15q25 risk variants rs12914385 and rs8042374 with smoking behavior and lung cancer risk in 4,343 lung cancer cases and 1,479 controls from the Genetic Lung Cancer Predisposition Study (GELCAPS). A strong association between rs12914385 and rs8042374, and lung cancer risk was shown, odds ratios (OR) were 1.44, (95% confidence interval (CI): 1.29–1.62, P = 3.69×10−10) and 1.35 (95% CI: 1.18–1.55, P = 9.99×10−6) respectively. Each copy of risk alleles at rs12914385 and rs8042374 was associated with increased cigarette consumption of 1.0 and 0.9 cigarettes per day (CPD) (P = 5.18×10−5 and P = 5.65×10−3). These genetically determined modest differences in smoking behavior can be shown to be sufficient to account for the 15q25 association with lung cancer risk. To further verify the indirect effect of 15q25 on the risk, we restricted our analysis of lung cancer risk to never-smokers and conducted a meta-analysis of previously published studies of lung cancer risk in never-smokers. Never-smoker studies published in English were ascertained from PubMed stipulating - lung cancer, risk, genome-wide association, candidate genes. Our study and five previously published studies provided data on 2,405 never-smoker lung cancer cases and 7,622 controls. In the pooled analysis no association has been found between the 15q25 variation and lung cancer risk (OR = 1.09, 95% CI: 0.94–1.28). This study affirms the 15q25 association with smoking and is consistent with an indirect link between genotype and lung cancer risk
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