MicroRNAs regulate Ca2+ homeostasis in murine embryonic stem cells

MicroRNAs (miRNAs) are important regulators of embryonic stem cell (ESC) biology, and their study has identified key regulatory mechanisms. To find novel pathways regulated by miRNAs in ESCs, we undertook a bioinformatics analysis of gene pathways differently expressed in the absence of miRNAs due to the deletion of Dicer, which encodes an RNase that is essential for the synthesis of miRNAs. One pathway that stood out was Ca2+ signaling. Interestingly, we found that Dicer-/- ESCs had no difference in basal cytoplasmic Ca2+ levels but were hyperresponsive when Ca2+ import into the endoplasmic reticulum (ER) was blocked by thapsigargin. Remarkably, the increased Ca2+ response to thapsigargin in ESCs resulted in almost no increase in apoptosis and no differences in stress response pathways, despite the importance of miRNAs in the stress response of other cell types. The increased Ca2+ response in Dicer-/- ESCs was also observed during purinergic receptor activation, demonstrating a physiological role for the miRNA regulation of Ca2+ signaling pathways. In examining the mechanism of increased Ca2+ responsiveness to thapsigargin, neither store-operated Ca2+ entry nor Ca2+ clearance mechanisms from the cytoplasm appeared to be involved. Rather, it appeared to involve an increase in the expression of one isoform of the IP3 receptors (Itpr2). miRNA regulation of Itpr2 expression primarily appeared to be indirect, with transcriptional regulation playing a major role. Therefore, the miRNA regulation of Itpr2 expression offers a unique mechanism to regulate Ca2+ signaling pathways in the physiology of pluripotent stem cells

Apathy and impulsivity in frontotemporal lobar degeneration syndromes

Apathy and impulsivity are common and disabling consequences of frontotemporal lobar degeneration. They cause substantial carer distress, but their aetiology remains elusive. There are critical limitations to previous studies in this area including (i) the assessment of either apathy or impulsivity alone, despite their frequent co-existence; (ii) the assessment of behavioural changes within single diagnostic groups; and (iii) the use of limited sets of tasks or questions that relate to just one aspect of these multifactorial constructs. We proposed an alternative, dimensional approach that spans behavioural and language variants of frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome. This accommodates the commonalities of apathy and impulsivity across disorders and reveals their cognitive and anatomical bases. The ability to measure the components of apathy and impulsivity and their associated neural correlates across diagnostic groups would provide better novel targets for pharmacological manipulations, and facilitate new treatment strategies and strengthen translational models. We therefore sought to determine the neurocognitive components of apathy and impulsivity in frontotemporal lobar degeneration syndromes. The frequency and characteristics of apathy and impulsivity were determined by neuropsychological and behavioural assessments in 149 patients and 50 controls from the PIck’s disease and Progressive supranuclear palsy Prevalence and INcidence study (PiPPIN). We derived dimensions of apathy and impulsivity using principal component analysis and employed these in volumetric analyses of grey and white matter in a subset of 70 patients (progressive supranuclear palsy, n = 22; corticobasal syndrome, n = 13; behavioural variant, n = 14; primary progressive aphasias, n = 21) and 27 control subjects. Apathy and impulsivity were present across diagnostic groups, despite being criteria for behavioural variant frontotemporal dementia alone. Measures of apathy and impulsivity frequently loaded onto the same components reflecting their overlapping relationship. However, measures from objective tasks, patient-rated questionnaires and carer-rated questionnaires loaded onto separate components and revealed distinct neurobiology. Corticospinal tracts correlated with patients’ self-ratings. In contrast, carer ratings correlated with atrophy in established networks for goal-directed behaviour, social cognition, motor control and vegetative functions, including frontostriatal circuits, orbital and temporal polar cortex, and the brainstem. Components reflecting response inhibition deficits correlated with focal frontal cortical atrophy. The dimensional approach to complex behavioural changes arising from frontotemporal lobar degeneration provides new insights into apathy and impulsivity, and the need for a joint therapeutic strategy against them. The separation of objective tests from subjective questionnaires, and patient from carer ratings, has important implications for clinical trial design

Methane storms as a driver of Titan's dune orientation

Titan's equatorial regions are covered by eastward propagating linear dunes. This direction is opposite to mean surface winds simulated by Global Climate Models (GCMs), which are oriented westward at these latitudes, similar to trade winds on Earth. Different hypotheses have been proposed to address this apparent contradiction, involving Saturn's gravitational tides, large scale topography or wind statistics, but none of them can explain a global eastward dune propagation in the equatorial band. Here we analyse the impact of equinoctial tropical methane storms developing in the superrotating atmosphere (i.e. the eastward winds at high altitude) on Titan's dune orientation. Using mesoscale simulations of convective methane clouds with a GCM wind profile featuring superrotation, we show that Titan's storms should produce fast eastward gust fronts above the surface. Such gusts dominate the aeolian transport, allowing dunes to extend eastward. This analysis therefore suggests a coupling between superrotation, tropical methane storms and dune formation on Titan. Furthermore, together with GCM predictions and analogies to some terrestrial dune fields, this work provides a general framework explaining several major features of Titan's dunes: linear shape, eastward propagation and poleward divergence, and implies an equatorial origin of Titan's dune sand.Comment: Published online on Nature Geoscience on 13 April 201

Waves on the surface of the Orion molecular cloud

Massive stars influence their parental molecular cloud, and it has long been suspected that the development of hydrodynamical instabilities can compress or fragment the cloud. Identifying such instabilities has proved difficult. It has been suggested that elongated structures (such as the `pillars of creation') and other shapes arise because of instabilities, but alternative explanations are available. One key signature of an instability is a wave-like structure in the gas, which has hitherto not been seen. Here we report the presence of `waves' at the surface of the Orion molecular cloud near where massive stars are forming. The waves seem to be a Kelvin-Helmholtz instability that arises during the expansion of the nebula as gas heated and ionized by massive stars is blown over pre-existing molecular gas.Comment: Preprint of publication in Natur

Asthma Prevalence, Knowledge, and Perceptions among Secondary School Pupils in Rural and Urban Costal Districts in Tanzania.

Asthma is a common chronic disease of childhood that is associated with significant morbidity and mortality. We aimed to estimate the prevalence of asthma among secondary school pupils in urban and rural areas of coast districts of Tanzania. The study also aimed to describe pupils' perception towards asthma, and to assess their knowledge on symptoms, triggers, and treatment of asthma. A total of 610 pupils from Ilala district and 619 pupils from Bagamoyo district formed the urban and rural groups, respectively. Using a modified International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire, a history of "diagnosed" asthma or the presence of a wheeze in the previous 12 months was obtained from all the studied pupils, along with documentation of their perceptions regarding asthma. Pupils without asthma or wheeze in the prior 12 months were subsequently selected and underwent a free running exercise testing. A >= 20% decrease in the post-exercise Peak Expiratory Flow Rate (PEFR) values was the criterion for diagnosing exercise-induced asthma. The mean age of participants was 16.8 (+/-1.8) years. The prevalence of wheeze in the past 12 months was 12.1% in Bagamoyo district and 23.1% in Ilala district (p < 0.001). Self-reported asthma was found in 17.6% and 6.4% of pupils in Ilala and Bagamoyo districts, respectively (p < 0.001). The prevalence of exercise-induced asthma was 2.4% in Bagamoyo, and 26.3% in Ilala (P < 0.002). In both districts, most information on asthma came from parents, and there was variation in symptoms and triggers of asthma reported by the pupils. Non-asthmatic pupils feared sleeping, playing, and eating with their asthmatic peers. The prevalence rates of self-reported asthma, wheezing in the past 12 months, and exercise-induced asthma were significantly higher among urban than rural pupils. Although bronchial asthma is a common disease, pupils' perceptions about asthma were associated with fear of contact with their asthmatic peers in both rural and urban schools

Coffee consumption and prostate cancer risk: further evidence for inverse relationship

<p>Abstract</p> <p>Background</p> <p>Higher consumption of coffee intake has recently been linked with reduced risk of aggressive prostate cancer (PC) incidence, although meta-analysis of other studies that examine the association between coffee consumption and overall PC risk remains inconclusive. Only one recent study investigated the association between coffee intake and grade-specific incidence of PC, further evidence is required to understand the aetiology of aggressive PCs. Therefore, we conducted a prospective study to examine the relationship between coffee intake and overall as well as grade-specific PC risk.</p> <p>Methods</p> <p>We conducted a prospective cohort study of 6017 men who were enrolled in the Collaborative cohort study in the UK between 1970 and 1973 and followed up to 31st December 2007. Cox Proportional Hazards Models were used to evaluate the association between coffee consumption and overall, as well as Gleason grade-specific, PC incidence.</p> <p>Results</p> <p>Higher coffee consumption was inversely associated with risk of high grade but not with overall risk of PC. Men consuming 3 or more cups of coffee per day experienced 55% lower risk of high Gleason grade disease compared with non-coffee drinkers in analysis adjusted for age and social class (HR 0.45, 95% CI 0.23-0.90, p value for trend 0.01). This association changed a little after additional adjustment for Body Mass Index, smoking, cholesterol level, systolic blood pressure, tea intake and alcohol consumption.</p> <p>Conclusion</p> <p>Coffee consumption reduces the risk of aggressive PC but not the overall risk.</p

Reasoning deficits among illicit drug users are associated with aspects of cannabis use

Background. Deficits in deductive reasoning have been observed among ecstasy/polydrug users. The present study seeks to investigate dose-related effects of specific drugs and whether these vary with the cognitive demands of the task. Methods. One hundred and five participants (mean age 21.33, S.D. 3.14; 77 females, 28 males) attempted to generate solutions for eight one-model syllogisms and one syllogism for which there was no valid conclusion (NVC). All of the one model syllogisms generated at least one valid conclusion and six generated two valid conclusions. In these six cases one of the conclusions was classified as common and the other as non-common. Results. The number of valid common inferences was negatively associated with aspects of short term cannabis use and with measures of IQ. The outcomes observed were more than simple post intoxication effects since cannabis use in the 10 days immediately before testing was unrelated to reasoning performance. Following adjustment for multiple comparisons, the number of non-common valid inferences was not significantly associated with any of the drug use measures. Conclusions. Recent cannabis use appears to impair the processes associated with generating valid common inferences while not affecting the production of non-common inferences. It is possible, therefore, that the two types of inference may recruit different executive resources which may differ in their susceptibility to cannabis-related effects

Image informatics strategies for deciphering neuronal network connectivity

Brain function relies on an intricate network of highly dynamic neuronal connections that rewires dramatically under the impulse of various external cues and pathological conditions. Among the neuronal structures that show morphologi- cal plasticity are neurites, synapses, dendritic spines and even nuclei. This structural remodelling is directly connected with functional changes such as intercellular com- munication and the associated calcium-bursting behaviour. In vitro cultured neu- ronal networks are valuable models for studying these morpho-functional changes. Owing to the automation and standardisation of both image acquisition and image analysis, it has become possible to extract statistically relevant readout from such networks. Here, we focus on the current state-of-the-art in image informatics that enables quantitative microscopic interrogation of neuronal networks. We describe the major correlates of neuronal connectivity and present workflows for analysing them. Finally, we provide an outlook on the challenges that remain to be addressed, and discuss how imaging algorithms can be extended beyond in vitro imaging studies

Investigating the association between obesity and asthma in 6- to 8-year-old Saudi children:a matched case-control study

Background: Previous studies have demonstrated an association between obesity and asthma, but there remains considerable uncertainty about whether this reflects an underlying causal relationship. Aims: To investigate the association between obesity and asthma in pre-pubertal children and to investigate the roles of airway obstruction and atopy as possible causal mechanisms. Methods: We conducted an age- and sex-matched case–control study of 1,264 6- to 8-year-old schoolchildren with and without asthma recruited from 37 randomly selected schools in Madinah, Saudi Arabia. The body mass index (BMI), waist circumference and skin fold thickness of the 632 children with asthma were compared with those of the 632 control children without asthma. Associations between obesity and asthma, adjusted for other potential risk factors, were assessed separately in boys and girls using conditional logistic regression analysis. The possible mediating roles of atopy and airway obstruction were studied by investigating the impact of incorporating data on sensitisation to common aeroallergens and measurements of lung function. Results: BMI was associated with asthma in boys (odds ratio (OR)=1.14, 95% confidence interval (CI), 1.08–1.20; adjusted OR=1.11, 95% CI, 1.03–1.19) and girls (OR=1.37, 95% CI, 1.26–1.50; adjusted OR=1.38, 95% CI, 1.23–1.56). Adjusting for forced expiratory volume in 1 s had a negligible impact on these associations, but these were attenuated following adjustment for allergic sensitisation, particularly in girls (girls: OR=1.25; 95% CI, 0.96–1.60; boys: OR=1.09, 95% CI, 0.99–1.19). Conclusions: BMI is associated with asthma in pre-pubertal Saudi boys and girls; this effect does not appear to be mediated through respiratory obstruction, but in girls this may at least partially be mediated through increased risk of allergic sensitisation