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

Personal Inner Values – A Key to Effective Face-to-Face Business Communication

Effective face-to-face oral communication is crucial for organizational performance. Managers must communicate effectively with their subordinates, their peers and superiors to link organizational direction to those at all levels of the organization. In addition, face-to-face oral communications are fundamental to the messaging process between business entities, whether a person is acting for oneself or representing his/her company. Face-to-face oral communication that builds empathic trust and mutual confidence is essential in business, especially in light of the recent “crisis in trust” caused by the 2008 financial market “meltdown” and the widely publicized ethical failures in business that have occurred in the past decade. This need is now being successfully addressed and taught to business executives using the neuro-scientifically based technique of compassionate communication, in which two or more people speak slowly and briefly as they remain in a deep state of relaxation and nonjudgmental attentiveness. The twelve components of compassionate communication are reviewed along with the supporting research of earlier studies, with emphasis on a unique inner values exercise that appears to be a key to its successful use in business situations

The Sudden Death of the Nearest Quasar

Galaxy formation is significantly modulated by energy output from supermassive black holes at the centers of galaxies which grow in highly efficient luminous quasar phases. The timescale on which black holes transition into and out of such phases is, however, unknown. We present the first measurement of the shutdown timescale for an individual quasar using X-ray observations of the nearby galaxy IC 2497, which hosted a luminous quasar no more than 70,000 years ago that is still seen as a light echo in `Hanny's Voorwerp', but whose present-day radiative output is lower by at least 2 and more likely by over 4 orders of magnitude. This extremely rapid shutdown provides new insights into the physics of accretion in supermassive black holes, and may signal a transition of the accretion disk to a radiatively inefficient state.Comment: 4 pages, 2 figures. Astrophysical Journal Letters, in pres

Transcutaneous vagus nerve stimulation (t-VNS): A novel effective treatment for temper outbursts in adults with Prader-Willi Syndrome indicated by results from a non-blind study.

Temper outbursts are a severe problem for people with Prader-Willi Syndrome (PWS). Previous reports indicate that vagus nerve stimulation (VNS) may reduce maladaptive behaviour in neurodevelopmental disorders, including PWS. We systematically investigated the effectiveness of transcutaneous VNS (t-VNS) in PWS. Using a non-blind single case repeat measures modified ABA design, with participants as their own controls, t-VNS was evaluated in five individuals with PWS [three males; age 22-41 (M = 26.8)]. After a baseline phase, participants received four-hours of t-VNS daily for 12 months, followed by one month of daily t-VNS for two-hours. The primary outcome measure was the mean number of behavioural outbursts per day. Secondary outcomes included findings from behavioural questionnaires and both qualitative and goal attainment interviews. Four of the five participants who completed the study exhibited a statistically significant reduction in number and severity of temper outbursts after approximately nine months of daily four-hour t-VNS. Subsequent two-hour daily t-VNS was associated with increased outbursts for all participants, two reaching significance. Questionnaire and interview data supported these findings, the latter indicating potential mechanisms of action. No serious safety issues were reported. t-VNS is an effective, novel and safe intervention for chronic temper outbursts in PWS. We propose these changes are mediated through vagal projections and their effects both centrally and on the functioning of the parasympathetic nervous system. These findings challenge our present biopsychosocial understanding of such behaviours suggesting that there is a single major mechanism that is modifiable using t-VNS. This intervention is potentially generalizable across other clinical groups. Future research should address the lack of a sham condition in this study along with the prevalence of high drop out rates, and the potential effects of different stimulation intensities, frequencies and pulse widths

Generation of folk song melodies using Bayes transforms

The paper introduces the `Bayes transform', a mathematical procedure for putting data into a hierarchical representation. Applicable to any type of data, the procedure yields interesting results when applied to sequences. In this case, the representation obtained implicitly models the repetition hierarchy of the source. There are then natural applications to music. Derivation of Bayes transforms can be the means of determining the repetition hierarchy of note sequences (melodies) in an empirical and domain-general way. The paper investigates application of this approach to Folk Song, examining the results that can be obtained by treating such transforms as generative models

Society for Cardiovascular Magnetic Resonance (SCMR) guidance for the practice of cardiovascular magnetic resonance during the COVID-19 pandemic

The aim of this document is to provide general guidance and specific recommendations on the practice of cardiovascular magnetic resonance (CMR) in the era of the COVID-19 pandemic. There are two major considerations. First, continued urgent and semi-urgent care for the patients who have no known active COVID-19 should be provided in a safe manner for both patients and staff. Second, when necessary, CMR on patients with confirmed or suspected active COVID-19 should focus on the specific clinical question with an emphasis on myocardial function and tissue characterization while optimizing patient and staff safety

Abundance and Isotopic Composition of Gases in the Martian Atmosphere: First Results from the Mars Curiosity Rover

Repeated measurements of the composition of the Mars atmosphere from Curiosity Rover yield a (40)Ar/N2 ratio 1.7 times greater and the (40)Ar/(36)Ar ratio 1.6 times smaller than the Viking Lander values in 1976. The unexpected change in (40)Ar/N2 ratio probably results from different instrument characteristics although we cannot yet rule out some unknown atmospheric process. The new (40)Ar/(36)Ar ratio is more aligned with Martian meteoritic values. Besides Ar and N2 the Sample Analysis at Mars instrument suite on the Curiosity Rover has measured the other principal components of the atmosphere and the isotopes. The resulting volume mixing ratios are: CO2 0.960(+/- 0.007); (40)Ar 0.0193(+/- 0.0001); N2 0.0189(+/- 0.0003); O2 1.45(+/- 0.09) x 10(exp -3); and CO 5.45(+/- 3.62) x 10(exp 4); and the isotopes (40)Ar/(36)Ar 1.9(+/- 0.3) x 10(exp 3), and delta (13)C and delta (18)O from CO2 that are both several tens of per mil more positive than the terrestrial averages. Heavy isotope enrichments support the hypothesis of large atmospheric loss. Moreover, the data are consistent with values measured in Martian meteorites, providing additional strong support for a Martian origin for these rocks

Clinical effectiveness and cost-effectiveness of collaborative care for depression in UK primary care (CADET): a cluster randomised controlled trial.

BACKGROUND: Collaborative care is effective for depression management in the USA. There is little UK evidence on its clinical effectiveness and cost-effectiveness. OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of collaborative care compared with usual care in the management of patients with moderate to severe depression. DESIGN: Cluster randomised controlled trial. SETTING: UK primary care practices (n = 51) in three UK primary care districts. PARTICIPANTS: A total of 581 adults aged ≥ 18 years in general practice with a current International Classification of Diseases, Tenth Edition depressive episode, excluding acutely suicidal people, those with psychosis, bipolar disorder or low mood associated with bereavement, those whose primary presentation was substance abuse and those receiving psychological treatment. INTERVENTIONS: Collaborative care: 14 weeks of 6-12 telephone contacts by care managers; mental health specialist supervision, including depression education, medication management, behavioural activation, relapse prevention and primary care liaison. Usual care was general practitioner standard practice. MAIN OUTCOME MEASURES: Blinded researchers collected depression [Patient Health Questionnaire-9 (PHQ-9)], anxiety (General Anxiety Disorder-7) and quality of life (European Quality of Life-5 Dimensions three-level version), Short Form questionnaire-36 items) outcomes at 4, 12 and 36 months, satisfaction (Client Satisfaction Questionnaire-8) outcomes at 4 months and treatment and service use costs at 12 months. RESULTS: In total, 276 and 305 participants were randomised to collaborative care and usual care respectively. Collaborative care participants had a mean depression score that was 1.33 PHQ-9 points lower [n = 230; 95% confidence interval (CI) 0.35 to 2.31; p = 0.009] than that of participants in usual care at 4 months and 1.36 PHQ-9 points lower (n = 275; 95% CI 0.07 to 2.64; p = 0.04) at 12 months after adjustment for baseline depression (effect size 0.28, 95% CI 0.01 to 0.52; odds ratio for recovery 1.88, 95% CI 1.28 to 2.75; number needed to treat 6.5). Quality of mental health but not physical health was significantly better for collaborative care at 4 months but not at 12 months. There was no difference for anxiety. Participants receiving collaborative care were significantly more satisfied with treatment. Differences between groups had disappeared at 36 months. Collaborative care had a mean cost of £272.50 per participant with similar health and social care service use between collaborative care and usual care. Collaborative care offered a mean incremental gain of 0.02 (95% CI -0.02 to 0.06) quality-adjusted life-years (QALYs) over 12 months at a mean incremental cost of £270.72 (95% CI -£202.98 to £886.04) and had an estimated mean cost per QALY of £14,248, which is below current UK willingness-to-pay thresholds. Sensitivity analyses including informal care costs indicated that collaborative care is expected to be less costly and more effective. The amount of participant behavioural activation was the only effect mediator. CONCLUSIONS: Collaborative care improves depression up to 12 months after initiation of the intervention, is preferred by patients over usual care, offers health gains at a relatively low cost, is cost-effective compared with usual care and is mediated by patient activation. Supervision was by expert clinicians and of short duration and more intensive therapy may have improved outcomes. In addition, one participant requiring inpatient treatment incurred very significant costs and substantially inflated our cost per QALY estimate. Future work should test enhanced intervention content not collaborative care per se. TRIAL REGISTRATION: Current Controlled Trials ISRCTN32829227. FUNDING: This project was funded by the Medical Research Council (MRC) (G0701013) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership

Barriers, facilitators, and survival strategies for GPs seeking treatment for distress:a qualitative study

BACKGROUND: GPs are under increasing pressure due to a lack of resources, a diminishing workforce, and rising patient demand. As a result, they may feel stressed, burnt out, anxious, or depressed. AIM: To establish what might help or hinder GPs experiencing mental distress as they consider seeking help for their symptoms, and to explore potential survival strategies. DESIGN AND SETTING: The authors recruited 47 GP participants via e-mails to doctors attending a specialist service, adverts to local medical committees (LMCs) nationally and in GP publications, social media, and snowballing. Participants self-identified as either currently living with mental distress, returning to work following treatment, off sick or retired early as a result of mental distress, or without experience of mental distress. Interviews were conducted face to face or over the telephone. METHOD: Transcripts were uploaded to NVivo 11 and analysed using thematic analysis. RESULTS: Barriers and facilitators were related to work, stigma, and symptoms. Specifically, GPs discussed feeling a need to attend work, the stigma surrounding mental ill health, and issues around time, confidentiality, and privacy. Participants also reported difficulties accessing good-quality treatment. GPs also talked about cutting down or varying work content, or asserting boundaries to protect themselves. CONCLUSION: Systemic changes, such as further information about specialist services designed to help GPs, are needed to support individual GPs and protect the profession from further damage