Coupling of Smoothened to inhibitory G proteins reduces voltage-gated K

SMO (Smoothened), the central transducer of Hedgehog signaling, is coupled to heterotrimeric Gi proteins in many cell types, including cardiomyocytes. In this study, we report that activation of SMO with SHH (Sonic Hedgehog) or a small agonist, purmorphamine, rapidly causes a prolongation of the action potential duration that is sensitive to a SMO inhibitor. In contrast, neither of the SMO agonists prolonged the action potential in cardiomyocytes from transgenic GiCT/TTA mice, in which Gi signaling is impaired, suggesting that the effect of SMO is mediated by Gi proteins. Investigation of the mechanism underlying the change in action potential kinetics revealed that activation of SMO selectively reduces outward voltage-gated K+ repolarizing (Kv) currents in isolated cardiomyocytes and that it induces a down-regulation of membrane levels of Kv4.3 in cardiomyocytes and intact hearts from WT but not from GiCT/TTA mice. Moreover, perfusion of intact hearts with Shh or purmorphamine increased the ventricular repolarization time (QT interval) and induced ventricular arrhythmias. Our data constitute the first report that acute, noncanonical Hh signaling mediated by Gi proteins regulates K+ currents density in cardiomyocytes and sensitizes the heart to the development of ventricular arrhythmias. © 2018 Cheng et al

Low admission triglyceride and mortality in acute coronary syndrome patients

Background: The relationship between admission triglyceride (TG) levels and long-term outcomes has not been established in patients with acute coronary syndrome. We tested the hypothesis that patients who develop non-ST segment elevation myocardial infarction (NSTEMI) despite low TG have a worse cardiovascular outcome in the long term. Methods: Patients admitted with NSTEMI between 1 January 1997 and 31 December 2000 and with fasting lipid profiles measured within 24 hours of admission were included for analysis. Baseline characteristics and three-year all-cause mortality were compared between the patients with TG above and below the median. Multivariate analysis was used to determine the predictors of all-cause mortality and adjusted survival was analyzed using the Cox proportional hazard model. Results: Of 517 patients, 395 had TG £ 200 mg/dL and 124 had TG > 200 mg/dL. Patients with low TG were more often Caucasian, with no significant differences in gender or severity of coronary artery disease between the two groups. There was a trend for increased all-cause mortality at six months (9% vs 3%, p = 0.045) and three years (13.4% vs 5.6%, p = 0.016) in patients with low TG. In multivariate analysis, low TG level at admission was an independent predictor of increased mortality at three years (adjusted OR 2.5, 95% CI = 1.04–5.9, p = 0.04). Conclusions: In our cohort, lower TG at admission is associated with increased three-year mortality in patients with NSTEMI. Whether this is a result of current therapy, or a marker for worse baseline characteristics, needs to be studied further. (Cardiol J 2011; 18, 3: 297–303

The Degree of Achieving Organizational Rigidity at Umm Al-Qura and Ajloun National Universities: Faculty Members’ Perspective

The paper pinpoints the degree of achieving organizational rigidity at Umm Al-Qura University and Ajloun National University from the faculty members’ viewpoint in line with the faculty, academic rank, and number of years of experience. The nature of the research necessitates using the descriptive survey research approach. A questionnaire adopted as a research instrument is applied to a 410-member sample of (410) randomly designated from the two universities. It is found that the organizational rigidity achievement is of a medium degree with a mean of (3.48). The results also show no statistically significant differences thanks to the variables of the number of years of experience and academic rank. However, it is found that there are differences caused by the faculty variable in favor of scientific faculties. The research recommends activating the methods of evaluating job performance, activating accountability and accounting systems, dividing work at the university according to the competence and experience of workers, and defining the tasks and duties of employees

Genome-wide association mapping in a diverse spring barley collection reveals the presence of QTL hotspots and candidate genes for root and shoot architecture traits at seedling stage

Figure S1. Examples of scanned root images from individual plants. Figure S2. Concatenated split network tree for the collection of 233 accessions based on 6019 SNP markers. Figure S3. LD pattern along the individual chromosomes of barley. Figure S4. Schematic representation of the eight re-sequenced candidate genes models. (DOCX 3427 kb

The Impact of Psychosocial Factors of Physical Health Outcomes: A Review of the Biopsychosocial Model in Family Medicine

Discontent with the biological model of illness—which is still the predominant healthcare model—led to the development of the biopsychosocial model, which was described in Engel's seminal Science paper forty years ago. It is the foundation of the International Classification of Functioning (WHO ICF) developed by the World Health Organization Clinical outcomes for functional disorders and chronic diseases treated in family medicine may be improved by the biopsychosocial approach. Since clinical performance metrics and standards are biomedically focused, family medicine doctors have no financial incentive to implement the biopsychosocial paradigm in their practices. Implementing the biopsychosocial approach in family medicine may be hampered by workload and incompetence

The N–Terminal Tail of hERG Contains an Amphipathic α–Helix That Regulates Channel Deactivation

The cytoplasmic N–terminal domain of the human ether–a–go–go related gene (hERG) K+ channel is critical for the slow deactivation kinetics of the channel. However, the mechanism(s) by which the N–terminal domain regulates deactivation remains to be determined. Here we show that the solution NMR structure of the N–terminal 135 residues of hERG contains a previously described Per–Arnt–Sim (PAS) domain (residues 26–135) as well as an amphipathic α–helix (residues 13–23) and an initial unstructured segment (residues 2–9). Deletion of residues 2–25, only the unstructured segment (residues 2–9) or replacement of the α–helix with a flexible linker all result in enhanced rates of deactivation. Thus, both the initial flexible segment and the α–helix are required but neither is sufficient to confer slow deactivation kinetics. Alanine scanning mutagenesis identified R5 and G6 in the initial flexible segment as critical for slow deactivation. Alanine mutants in the helical region had less dramatic phenotypes. We propose that the PAS domain is bound close to the central core of the channel and that the N–terminal α–helix ensures that the flexible tail is correctly orientated for interaction with the activation gating machinery to stabilize the open state of the channel

Seroprevalence and correlates of HIV, syphilis, and hepatitis B and C virus among intrapartum patients in Kabul, Afghanistan

BackgroundLittle current information is available for prevalence of vertically-transmitted infections among the Afghan population. The purpose of this study is to determine prevalence and correlates of human immunodeficiency virus (HIV), syphilis, and hepatitis B and C infection among obstetric patients and model hepatitis B vaccination approaches in Kabul, Afghanistan.MethodsThis cross-sectional study was conducted at three government maternity hospitals in Kabul, Afghanistan from June through September, 2006. Consecutively-enrolled participants completed an interviewer-administered survey and whole blood rapid testing with serum confirmation for antibodies to HIV, T. pallidum, and HCV, and HBsAg. Descriptive data and prevalence of infection were calculated, with logistic regression used to identify correlates of HBV infection. Modeling was performed to determine impact of current and birth dose vaccination strategies on HBV morbidity and mortality.ResultsAmong 4452 women, prevalence of HBsAg was 1.53% (95% CI: 1.18 - 1.94) and anti-HCV was 0.31% (95% CI: 0.17 - 0.53). No cases of HIV or syphilis were detected. In univariate analysis, HBsAg was associated with husband's level of education (OR = 1.13, 95% CI: 1.01 - 1.26). Modeling indicated that introduction of birth dose vaccination would not significantly reduce hepatitis-related morbidity or mortality for the measured HBsAg prevalence.ConclusionIntrapartum whole blood rapid testing for HIV, syphilis, HBV, and HCV was acceptable to patients in Afghanistan. Though HBsAg prevalence is relatively low, periodic assessments should be performed to determine birth dose vaccination recommendations for this setting

The S4–S5 Linker Acts as a Signal Integrator for hERG K+ Channel Activation and Deactivation Gating

Human ether-à-go-go-related gene (hERG) K+ channels have unusual gating kinetics. Characterised by slow activation/deactivation but rapid inactivation/recovery from inactivation, the unique gating kinetics underlie the central role hERG channels play in cardiac repolarisation. The slow activation and deactivation kinetics are regulated in part by the S4–S5 linker, which couples movement of the voltage sensor domain to opening of the activation gate at the distal end of the inner helix of the pore domain. It has also been suggested that cytosolic domains may interact with the S4–S5 linker to regulate activation and deactivation kinetics. Here, we show that the solution structure of a peptide corresponding to the S4–S5 linker of hERG contains an amphipathic helix. The effects of mutations at the majority of residues in the S4–S5 linker of hERG were consistent with the previously identified role in coupling voltage sensor movement to the activation gate. However, mutations to Ser543, Tyr545, Gly546 and Ala548 had more complex phenotypes indicating that these residues are involved in additional interactions. We propose a model in which the S4–S5 linker, in addition to coupling VSD movement to the activation gate, also contributes to interactions that stabilise the closed state and a separate set of interactions that stabilise the open state. The S4–S5 linker therefore acts as a signal integrator and plays a crucial role in the slow deactivation kinetics of the channel

Heme oxygenase-1 derived carbon monoxide suppresses Aβ1-42 toxicity in astrocytes

Neurodegeneration in Alzheimer’s disease (AD) is extensively studied, and the involvement of astrocytes and other cell types in this process has been described. However, the responses of astrocytes themselves to amyloid β peptides ((Aβ; the widely accepted major toxic factor in AD) is less well understood. Here, we show that Aβ(1-42) is toxic to primary cultures of astrocytes. Toxicity does not involve disruption of astrocyte Ca2+ homeostasis, but instead occurs via formation of the toxic reactive species, peroxynitrite. Thus, Aβ(1-42) raises peroxynitrite levels in astrocytes, and Aβ(1-42) toxicity can be inhibited by antioxidants, or by inhibition of nitric oxide (NO) formation (reactive oxygen species (ROS) and NO combine to form peroxynitrite), or by a scavenger of peroxynitrite. Increased ROS levels observed following Aβ(1-42) application were derived from NADPH oxidase. Induction of heme oxygenase-1 (HO-1) protected astrocytes from Aβ(1-42) toxicity, and this protective effect was mimicked by application of the carbon monoxide (CO) releasing molecule CORM-2, suggesting HO-1 protection was attributable to its formation of CO. CO suppressed the rise of NADPH oxidase-derived ROS caused by Aβ(1-42). Under hypoxic conditions (0.5% O2, 48h) HO-1 was induced in astrocytes and Aβ(1-42) toxicity was significantly reduced, an effect which was reversed by the specific HO-1 inhibitor, QC-15. Our data suggest that Aβ(1-42) is toxic to astrocytes, but that induction of HO-1 affords protection against this toxicity due to formation of CO. HO-1 induction, or CO donors, would appear to present attractive possible approaches to provide protection of both neuronal and non-neuronal cell types from the degenerative effects of AD in the central nervous system

Heme oxygenase-1 derived carbon monoxide suppresses Aβ1-42 toxicity in astrocytes

Neurodegeneration in Alzheimer’s disease (AD) is extensively studied, and the involvement of astrocytes and other cell types in this process has been described. However, the responses of astrocytes themselves to amyloid peptides ((A; the widely accepted major toxic factor in AD) is less well understood. Here, we show that A(1-42) is toxic to primary cultures of astrocytes. Toxicity does not involve disruption of astrocyte Ca2+ homeostasis, but instead occurs via formation of the toxic reactive species, peroxynitrite. Thus, A(1-42) raises peroxynitrite levels in astrocytes, and A(1-42) toxicity can be inhibited by antioxidants, or by inhibition of nitric oxide (NO) formation (reactive oxygen species (ROS) and NO combine to form peroxynitrite), or by a scavenger of peroxynitrite. Increased ROS levels observed following A(1-42) application were derived from NADPH oxidase. Induction of heme oxygenase-1 (HO-1) protected astrocytes from A(1-42) toxicity, and this protective effect was mimicked by application of the carbon monoxide (CO) releasing molecule CORM-2, suggesting HO-1 protection was attributable to its formation of CO. CO suppressed the rise of NADPH oxidase-derived ROS caused by A(1-42). Under hypoxic conditions (0.5% O2, 48h) HO-1 was induced in astrocytes and A(1-42) toxicity was significantly reduced, an effect which was reversed by the specific HO-1 inhibitor, QC-15. Our data suggest that A(1-42) is toxic to astrocytes, but that induction of HO-1 affords protection against this toxicity due to formation of CO. HO-1 induction, or CO donors, would appear to present attractive possible approaches to provide protection of both neuronal and non-neuronal cell types from the degenerative effects of AD in the central nervous system