Pulmonary vasoconstrictor action of KCNQ potassium channel blockers

KCNQ channels have been widely studied in the nervous system, heart and inner ear, where they have important physiological functions. Recent reports indicate that KCNQ channels may also be expressed in portal vein where they are suggested to influence spontaneous contractile activity. The biophysical properties of K+ currents mediated by KCNQ channels resemble a current underlying the resting K+ conductance and resting potential of pulmonary artery smooth muscle cells. We therefore investigated a possible role of KCNQ channels in regulating the function of pulmonary arteries by determining the ability of the selective KCNQ channel blockers, linopirdine and XE991, to promote pulmonary vasoconstriction. Linopirdine and XE991 both contracted rat and mouse pulmonary arteries but had little effect on mesenteric arteries. In each case the maximum contraction was almost as large as the response to 50 mM K+. Linopirdine had an EC50 of around 1 μM and XE991 was almost 10-fold more potent. Neither removal of the endothelium nor exposure to phentolamine or α,β-methylene ATP, to block α1-adrenoceptors or P2X receptors, respectively, affected the contraction. Contraction was abolished in Ca2+-free solution and in the presence of 1 μM nifedipine or 10 μM levcromakalim

Gray matter correlates of cognitive ability tests used for vocational guidance

<p>Abstract</p> <p>Background</p> <p>Individual differences in cognitive abilities provide information that is valuable for vocational guidance, but there is an ongoing debate about the role of ability factors, including general intelligence (<it>g</it>), compared to individual tests. Neuroimaging can help identify brain parameters that may account for individual differences in both factors and tests. Here we investigate how eight tests used in vocational guidance correlate to regional gray matter. We compare brain networks identified by using scores for ability factors (general and specific) to those identified by using individual tests to determine whether these relatively broad and narrow approaches yield similar results.</p> <p>Findings</p> <p>Using MRI and voxel-based morphometry (VBM), we correlated gray matter with independent ability factors (general intelligence, speed of reasoning, numerical, spatial, memory) and individual test scores from a battery of cognitive tests completed by 40 individuals seeking vocational guidance. Patterns of gray matter correlations differed between group ability factors and individual tests. Moreover, tests within the same factor showed qualitatively different brain correlates to some degree.</p> <p>Conclusions</p> <p>The psychometric factor structure of cognitive tests can help identify brain networks related to cognitive abilities beyond a general intelligence factor (<it>g</it>). Correlates of individual ability tests with gray matter, however, appear to have some differences from the correlates for group factors.</p

State of the California current 2012-13: No such thing as an “average” year

This report reviews the state of the California Current System (CCS) between winter 2012 and spring 2013, and includes observations from Washington State to Baja California. During 2012, large-scale climate modes indicated the CCS remained in a cool, productive phase present since 2007. The upwelling season was delayed north of 42°N, but regions to the south, especially 33° to 36°N, experienced average to above average upwelling that persisted throughout the summer. Contrary to the indication of high production suggested by the climate indices, chlorophyll observed from surveys and remote sensing was below average along much of the coast. As well, some members of the forage assemblages along the coast experienced low abundances in 2012 surveys. Specifically, the concentrations of all lifestages observed directly or from egg densities of Pacific sardine, Sardinops sagax, and northern anchovy, Engraulis mordax, were less than previous years’ survey estimates. However, 2013 surveys and observations indicate an increase in abundance of northern anchovy. During winter 2011/2012, the increased presence of northern copepod species off northern California was consistent with stronger southward transport. Krill and small-fraction zooplankton abundances, where examined, were generally above average. North of 42°N, salps returned to typical abundances in 2012 after greater observed concentrations in 2010 and 2011. In contrast, salp abundance off central and southern California increased after a period of southward transport during winter 2011/2012. Reproductive success of piscivorous Brandt’s cormorant, Phalacrocorax penicillatus, was reduced while planktivorous Cassin’s auklet, Ptychoramphus aleuticus was elevated. Differences between the productivity of these two seabirds may be related to the available forage assemblage observed in the surveys. California sea lion pups from San Miguel Island were undernourished resulting in a pup mortality event perhaps in response to changes in forage availability. Limited biological data were available for spring 2013, but strong winter upwelling coastwide indicated an early spring transition, with the strong upwelling persisting into early summer

Association between respiratory tract diseases and secondhand smoke exposure among never smoking flight attendants: a cross-sectional survey

<p>Abstract</p> <p>Background</p> <p>Little is known about long-term adverse health consequences experienced by flight attendants exposed to secondhand smoke (SHS) during the time smoking was allowed on airplanes. We undertook this study to evaluate the association between accumulated flight time in smoky airplane cabins and respiratory tract diseases in a cohort of never smoking flight attendants.</p> <p>Methods</p> <p>We conducted a mailed survey in a cohort of flight attendants. Of 15,000 mailed questionnaires, 2053 (14%) were completed and returned. We excluded respondents with a personal history of smoking (n = 748) and non smokers with a history of respiratory tract diseases before the age of 18 years (n = 298). The remaining 1007 respondents form the study sample.</p> <p>Results</p> <p>The overall study sample was predominantly white (86%) and female (89%), with a mean age of 54 years. Overall, 69.7% of the respondents were diagnosed with at least one respiratory tract disease. Among these respondents, 43.4% reported a diagnosis of sinusitis, 40.3% allergies, 30.8% bronchitis, 23.2% middle ear infections, 13.6% asthma, 13.4% hay fever, 12.5% pneumonia, and 2.0% chronic obstructive pulmonary disease. More hours in a smoky cabin were observed to be significantly associated with sinusitis (OR = 1.21; p = 0.024), middle ear infections (OR = 1.30; p = 0.006), and asthma (OR = 1.26; p = 0.042).</p> <p>Conclusion</p> <p>We observed a significant association between hours of smoky cabin exposure and self-reported reported sinusitis, middle ear infections, and asthma. Our findings suggest a dose-response between duration of SHS exposure and diseases of the respiratory tract. Our findings add additional evidence to the growing body of knowledge supporting the need for widespread implementation of clean indoor air policies to decrease the risk of adverse health consequences experienced by never smokers exposed to SHS.</p

Impact of RNA degradation on gene expression profiling

<p>Abstract</p> <p>Background</p> <p>Gene expression profiling is a highly sensitive technique which is used for profiling tumor samples for medical prognosis. RNA quality and degradation influence the analysis results of gene expression profiles. The impact of this influence on the profiles and its medical impact is not fully understood. As patient samples are very valuable for clinical studies, it is necessary to establish criteria for the RNA quality to be able to use these samples in later analysis.</p> <p>Methods</p> <p>To investigate the effects of RNA integrity on gene expression profiling, whole genome expression arrays were used. We used tumor biopsies from patients diagnosed with locally advanced rectal cancer. To simulate degradation, the isolated total RNA of all patients was subjected to heat-induced degradation in a time-dependent manner. Expression profiling was then performed and data were analyzed bioinformatically to assess the differences.</p> <p>Results</p> <p>The differences introduced by RNA degradation were largely outweighed by the biological differences between the patients. Only a relatively small number of probes (275 out of 41,000) show a significant effect due to degradation. The genes that show the strongest effect due to RNA degradation were, especially, those with short mRNAs and probe positions near the 5' end.</p> <p>Conclusions</p> <p>Degraded RNA from tumor samples (RIN > 5) can still be used to perform gene expression analysis. A much higher biological variance between patients is observed compared to the effect that is imposed by degradation of RNA. Nevertheless there are genes, very short ones and those with the probe binding side close to the 5' end that should be excluded from gene expression analysis when working with degraded RNA. These results are limited to the Agilent 44 k microarray platform and should be carefully interpreted when transferring to other settings.</p

Cold-Induced Changes in the Protein Ubiquitin

Conformational changes are essential for protein-protein and protein-ligand recognition. Here we probed changes in the structure of the protein ubiquitin at low temperatures in supercooled water using NMR spectroscopy. We demonstrate that ubiquitin is well folded down to 263 K, although slight rearrangements in the hydrophobic core occur. However, amide proton chemical shifts show non-linear temperature dependence in supercooled solution and backbone hydrogen bonds become weaker in the region that is most prone to cold-denaturation. Our data suggest that the weakening of the hydrogen bonds in the β-sheet of ubiquitin might be one of the first events that occur during cold-denaturation of ubiquitin. Interestingly, the same region is strongly involved in ubiquitin-protein complexes suggesting that this part of ubiquitin more easily adjusts to conformational changes required for complex formation

Missed opportunities for tobacco use screening and brief cessation advice in South African primary health care: a cross-sectional study

BACKGROUND: Primary health care (PHC) settings offer opportunities for tobacco use screening and brief cessation advice, but data on such activities in South Africa are limited. The aim of this study was to determine the extent to which participants were screened for and advised against tobacco use during consultations. METHODS: This cross-sectional study involved 500 participants, 18 years and older, attended by doctors or PHC nurses. Using an exit-interview questionnaire, information was obtained on participants' tobacco use status, reason(s) for seeking medical care, whether participants had been screened for and advised about their tobacco use and patients' level of comfort about being asked about and advised to quit tobacco use. Main outcome measures included patients' self-reports on having been screened and advised about tobacco use during their current clinic visit and/or any other visit within the last year. Data analysis included the use of chi-square statistics, t-tests and multiple logistic regression analysis. RESULTS: Of the 500 participants, 14.9% were current smokers and 12.1% were smokeless tobacco users. Only 12.9% of the participants were screened for tobacco use during their current visit, indicating the vast majority were not screened. Among the 134 tobacco users, 11.9% reported being advised against tobacco use during the current visit and 35.1% during any other visit within the last year. Of the participants not screened, 88% indicated they would be 'very comfortable' with being screened. A pregnancy-related clinic visit was the single most significant predictor for being screened during the current clinic visit (OR = 4.59; 95%CI = 2.13-9.88). CONCLUSION: Opportunities for tobacco use screening and brief cessation advice were largely missed by clinicians. Incorporating tobacco use status into the clinical vital signs as is done for pregnant patients during antenatal care visits in South Africa has the potential to improve tobacco use screening rates and subsequent cessation

Dual-functioning transcription factors in the developmental gene network of Drosophila melanogaster

Quantitative models for transcriptional regulation have shown great promise for advancing our understanding of the biological mechanisms underlying gene regulation. However, all of the models to date assume a transcription factor (TF) to have either activating or repressing function towards all the genes it is regulating.In this paper we demonstrate, on the example of the developmental gene network in D. melanogaster, that the data-fit can be improved by up to 40% if the model is allowing certain TFs to have dual function, that is, acting as activator for some genes and as repressor for others. We demonstrate that the improvement is not due to additional flexibility in the model but rather derived from the data itself. We also found no evidence for the involvement of other known site-specific TFs in regulating this network. Finally, we propose SUMOylation as a candidate biological mechanism allowing TFs to switch their role when a small ubiquitin-like modifier (SUMO) is covalently attached to the TF. We strengthen this hypothesis by demonstrating that the TFs predicted to have dual function also contain the known SUMO consensus motif, while TFs predicted to have only one role lack this motif.We argue that a SUMOylation-dependent mechanism allowing TFs to have dual function represents a promising area for further research and might be another step towards uncovering the biological mechanisms underlying transcriptional regulation

E. coli Nissle 1917 Affects Salmonella Adhesion to Porcine Intestinal Epithelial Cells

BACKGROUND: The probiotic Escherichia coli strain Nissle 1917 (EcN) has been shown to interfere in a human in vitro model with the invasion of several bacterial pathogens into epithelial cells, but the underlying molecular mechanisms are not known. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated the inhibitory effects of EcN on Salmonella Typhimurium invasion of porcine intestinal epithelial cells, focusing on EcN effects on the various stages of Salmonella infection including intracellular and extracellular Salmonella growth rates, virulence gene regulation, and adhesion. We show that EcN affects the initial Salmonella invasion steps by modulating Salmonella virulence gene regulation and Salmonella SiiE-mediated adhesion, but not extra- and intracellular Salmonella growth. However, the inhibitory activity of EcN against Salmonella invasion always correlated with EcN adhesion capacities. EcN mutants defective in the expression of F1C fimbriae and flagellae were less adherent and less inhibitory toward Salmonella invasion. Another E. coli strain expressing F1C fimbriae was also adherent to IPEC-J2 cells, and was similarly inhibitory against Salmonella invasion like EcN. CONCLUSIONS: We propose that EcN affects Salmonella adhesion through secretory components. This mechanism appears to be common to many E. coli strains, with strong adherence being a prerequisite for an effective reduction of SiiE-mediated Salmonella adhesion

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO