Aging and aerobic fitness affect the contribution of noradrenergic sympathetic nerves to the rapid cutaneous vasodilator response to local heating

Sedentary aging results in a diminished rapid cutaneous vasodilator response to local heating. We investigated whether this diminished response was due to altered contributions of noradrenergic sympathetic nerves; assessing 1) the age-related decline and, 2) the effect of aerobic fitness. We measured skin blood flow (SkBF)(laser-Doppler flowmetry) in young (24±1 yr) and older (64±1 yr) endurance-trained and sedentary men (n=7 per group) at baseline and during 35 min of local skin heating to 42 °C at three forearm sites: 1) untreated; 2) bretylium tosylate (BT), preventing neurotransmitter release from noradrenergic sympathetic nerves; and 3) yohimbine and propranolol (YP), antagonising α- and β-adrenergic receptors. SkBF was converted to cutaneous vascular conductance (CVC) (SkBF/mean arterial pressure) and normalized to maximal CVC (%CVCmax) achieved by skin heating to 44 °C. Pharmacological agents were administered using microdialysis. In the young trained, the rapid vasodilator response was reduced at the BT and YP sites (P0.05) but treatment with BT did (P>0.05). Neither BT nor YP treatments affected the rapid vasodilator response in the older sedentary group (P>0.05). These data suggest that the age-related reduction in the rapid vasodilator response is due to an impairment of sympathetic-dependent mechanisms, which can be partly attenuated with habitual aerobic exercise. Rapid vasodilation involves noradrenergic neurotransmitters in young trained men, and non-adrenergic sympathetic cotransmitters (e.g., neuropeptide Y) in young sedentary and older trained men, possibly as a compensatory mechanism. Finally, in older sedentary men, the rapid vasodilation appears not to involve the sympathetic system

Learning to laugh : children and being human in early modern thought

This essay explores the construction of the human in early modern English thought, and uses discussions of the nature and use of laughter as a distinguishing feature of humanity from classical arguments as well as early modern ones. Using these classical, reformed English discussions of education and of the nature of children reveals an anxiety about the status of the child. Laughing appropriately - using tile mind and not merely the body - is a key feature of being human, and as such, the child's lack of "true' laughter reveals that child's status to be never always-already human. "Human' is a created rather than merely a natural status

Multi-site phosphorylation controls the neurogenic and myogenic activity of E47.

The superfamily of basic-Helix-Loop-Helix (bHLH) transcription factors influence cell fate in all three embryonic germ layers, and the tissue-specific class II factors have received prominent attention for their potent ability to direct differentiation during development and in cellular reprogramming. The activity of many class II bHLH proteins driving differentiation, and the inhibitory class VI bHLH factor Hes1, is controlled by phosphorylation on multiple sites by Cyclin-dependent kinases (Cdks). As class II proteins are generally thought to be active through hetero-dimerisation with the ubiquitously expressed class I E proteins, regulation of class I transcription factors such as E47 may influence the activity of multiple tissue-specific bHLH proteins. Using differentiation of nerve and muscle in Xenopus frog embryos as a model system, we set out to explore whether with the ubiquitously expressed class I E protein E47 that hetero-dimerises with Class II bHLHs to control their activity, is also regulated by multi-site phosphorylation. We demonstrate that E47 can be readily phosphorylated by Cdks on multiple sites in vitro, while ectopically-expressed E47 exists in multiple phosphorylated forms in Xenopus embryos. Preventing multi-site phosphorylation using a phospho-mutant version of E47 enhances the neurogenic and myogenic activity of three different class II bHLH reprogramming factors, and also when E47 acts in hetero-dimerisation with endogenous proteins. Mechanistically, unlike phospho-regulation of class II bHLH factors, we find that preventing phosphorylation of E47 increases the amount of chromatin-bound E47 protein but without affecting its overall protein stability. Thus, multi-site phosphorylation is a conserved regulatory mechanism across the bHLH superfamily that can be manipulated to enhance cellular differentiation.This work was supported by Medical Research Council Research Grants MR/L021129/1 and MR/K018329 and AP receives core funding from Wellcome and MRC at the Wellcome-MRC Cambridge Stem Cell Institute. LH is supported by a Peterhouse Research Fellowship

Study protocol: a randomised controlled trial investigating the effect of exercise training on peripheral blood gene expression in patients with stable angina

Background: Exercise training has been shown to reduce angina and promote collateral vessel development in patients with coronary artery disease. However, the mechanism whereby exercise exerts these beneficial effects is unclear. There has been increasing interest in the use of whole genome peripheral blood gene expression in a wide range of conditions to attempt to identify both novel mechanisms of disease and transcriptional biomarkers. This protocol describes a study in which we will assess the effect of a structured exercise programme on peripheral blood gene expression in patients with stable angina, and correlate this with changes in angina level, anxiety, depression, and exercise capacity. Methods/Design: Sixty patients with stable angina will be recruited and randomised 1: 1 to exercise training or conventional care. Patients randomised to exercise training will attend an exercise physiology laboratory up to three times weekly for supervised aerobic interval training sessions of one hour in total duration. Patients will undergo assessments of angina, anxiety, depression, and peripheral blood gene expression at baseline, after six and twelve weeks of training, and twelve weeks after formal exercise training ceases. Discussion: This study will provide comprehensive data on the effect of exercise training on peripheral blood gene expression in patients with angina. By correlating this with improvement in angina status we will identify candidate peripheral blood transcriptional markers predictive of improvements in angina level in response to exercise training

Sedative properties of Mitracarpus villosus leaves in mice

The leaves of Mitracarpus villosus (Sw.) DC. (Rubiaceae) have several therapeutic applications in the West African folk medicine for the management of a plethora of stress-related diseases including headaches. This study was designed to evaluate the sedative properties of the ethylacetate extract of Mitracarpus villosus on open field (OFT), diazepam-induced sleep, staircase climbing, head-dips in the hole-board test and rota rod test in mice. Graded doses (100 – 400 mg/kg) of the extract significantly and dose-dependently prolonged the duration of diazepam-induced sleep (P<0.05), decreased the number of squares crossed in the OFT (P<0.0001), decreased number of head-dips in the hole-board test (P<0.05) and reduced steps climbing (P<0.05) in mice. The extract at the doses tested had no effect on motor coordination as observed in the rota-rod treadmill assay in mice. Our results revealed that the ethylacetate extract of Mitracarpus villosus leaves may contain psychoactive principles that are sedative in nature, thus supporting further development of the psychoactive components of this plant for management of stress-related diseases.Keywords: Mitracarpus villosus, sedation, diazepam, locomotion

Completeness and Incompleteness of Synchronous Kleene Algebra

Synchronous Kleene algebra (SKA), an extension of Kleene algebra (KA), was proposed by Prisacariu as a tool for reasoning about programs that may execute synchronously, i.e., in lock-step. We provide a countermodel witnessing that the axioms of SKA are incomplete w.r.t. its language semantics, by exploiting a lack of interaction between the synchronous product operator and the Kleene star. We then propose an alternative set of axioms for SKA, based on Salomaa's axiomatisation of regular languages, and show that these provide a sound and complete characterisation w.r.t. the original language semantics.Comment: Accepted at MPC 201

Etiology of Severe Non-malaria Febrile Illness in Northern Tanzania: A Prospective Cohort Study.

The syndrome of fever is a commonly presenting complaint among persons seeking healthcare in low-resource areas, yet the public health community has not approached fever in a comprehensive manner. In many areas, malaria is over-diagnosed, and patients without malaria have poor outcomes. We prospectively studied a cohort of 870 pediatric and adult febrile admissions to two hospitals in northern Tanzania over the period of one year using conventional standard diagnostic tests to establish fever etiology. Malaria was the clinical diagnosis for 528 (60.7%), but was the actual cause of fever in only 14 (1.6%). By contrast, bacterial, mycobacterial, and fungal bloodstream infections accounted for 85 (9.8%), 14 (1.6%), and 25 (2.9%) febrile admissions, respectively. Acute bacterial zoonoses were identified among 118 (26.2%) of febrile admissions; 16 (13.6%) had brucellosis, 40 (33.9%) leptospirosis, 24 (20.3%) had Q fever, 36 (30.5%) had spotted fever group rickettsioses, and 2 (1.8%) had typhus group rickettsioses. In addition, 55 (7.9%) participants had a confirmed acute arbovirus infection, all due to chikungunya. No patient had a bacterial zoonosis or an arbovirus infection included in the admission differential diagnosis. Malaria was uncommon and over-diagnosed, whereas invasive infections were underappreciated. Bacterial zoonoses and arbovirus infections were highly prevalent yet overlooked. An integrated approach to the syndrome of fever in resource-limited areas is needed to improve patient outcomes and to rationally target disease control efforts

Conscientiousness, extraversion, and field sales performance: Combining narrow personality, social skill, emotional stability, and nonlinearity

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordAlthough prior research indicated that extraversion and conscientiousness are uniformly beneficial to sales performance, recent evidence suggests that scholars should consider nonlinearity, narrow personality, social skill, and the research context in the personality-performance relation. Further, scholars have found conscientiousness to have inverted U-shaped relationships with performance. Taking these into account, the present study examines the nonlinear relation that the combined conscientiousness facets of discipline and achievement motivation (i.e., disciplined achievement motivation) have with objective sales performance in a predictive study with a nine month time interval. We argue that stable social potency, composed of the activity facet of extraversion, social skill, and emotional stability, will moderate this nonlinear relation in the context of insurance field sales, such that the greatest sales performance will be from those high on both constructs. Our findings support our hypotheses, demonstrating that a relevant social-related trait (i.e., stable social potency) can offset the potential downsides of high disciplined achievement motivation (e.g., perfectionism, and workaholism), helping such individuals to achieve high objective sales. Implications for theory and future research directions are discussed