Adenosine closes the K+ channel KCa3.1 in human lung mast cells and inhibits their migration via the adenosine A2A receptor

Human lung mast cells (HLMC) express the Ca2+-activated K+ channel KCa3.1, which opens following IgE-dependent activation. This hyperpolarises the cell membrane and potentiates both Ca2+ influx and degranulation. In addition, blockade of KCa3.1 profoundly inhibits HLMC migration to a variety of diverse chemotactic stimuli. KCa3.1 activation is attenuated by the β2adrenoceptor through a Gαs-coupled mechanism independent of cyclic AMP. Adenosine is an important mediator that both attenuates and enhances HLMC mediator release through the Gαs-coupled A2A and A2B adenosine receptors, respectively. We show that at concentrations that inhibit HLMC degranulation (10–5–10–3 M), adenosine closes KCa3.1 both dose-dependently and reversibly. KCa3.1 suppression by adenosine was reversed partially by the selective adenosine A2A receptor antagonist ZM241385 but not by the A2B receptor antagonist MRS1754, and the effects of adenosine were mimicked by the selective A2A receptor agonist CGS21680. Adenosine also opened a depolarising current carried by non-selective cations. As predicted from the role of KCa3.1 in HLMC migration, adenosine abolished HLMC chemotaxis to asthmatic airway smooth muscle-conditioned medium. In summary, the Gαs-coupled adenosine A2A receptor closes KCa3.1, providing a clearly defined mechanism by which adenosine inhibits HLMC migration and degranulation. A2A receptor agonists with channel-modulating function may be useful for the treatment of mast cell-mediated disease

Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes.

In the peripheral sensory nervous system the neuronal expression of voltage-gated sodium channels (Navs) is very important for the transmission of nociceptive information since they give rise to the upstroke of the action potential (AP). Navs are composed of nine different isoforms with distinct biophysical properties. Studying the mutations associated with the increase or absence of pain sensitivity in humans, as well as other expression studies, have highlighted Nav1.7, Nav1.8, and Nav1.9 as being the most important contributors to the control of nociceptive neuronal electrogenesis. Modulating their expression and/or function can impact the shape of the AP and consequently modify nociceptive transmission, a process that is observed in persistent pain conditions. Post-translational modification (PTM) of Navs is a well-known process that modifies their expression and function. In chronic pain syndromes, the release of inflammatory molecules into the direct environment of dorsal root ganglia (DRG) sensory neurons leads to an abnormal activation of enzymes that induce Navs PTM. The addition of small molecules, i.e., peptides, phosphoryl groups, ubiquitin moieties and/or carbohydrates, can modify the function of Navs in two different ways: via direct physical interference with Nav gating, or via the control of Nav trafficking. Both mechanisms have a profound impact on neuronal excitability. In this review we will discuss the role of Protein Kinase A, B, and C, Mitogen Activated Protein Kinases and Ca++/Calmodulin-dependent Kinase II in peripheral chronic pain syndromes. We will also discuss more recent findings that the ubiquitination of Nav1.7 by Nedd4-2 and the effect of methylglyoxal on Nav1.8 are also implicated in the development of experimental neuropathic pain. We will address the potential roles of other PTMs in chronic pain and highlight the need for further investigation of PTMs of Navs in order to develop new pharmacological tools to alleviate pain

A General Definition and Nomenclature for Alternative Splicing Events

Understanding the molecular mechanisms responsible for the regulation of the transcriptome present in eukaryotic cells is one of the most challenging tasks in the postgenomic era. In this regard, alternative splicing (AS) is a key phenomenon contributing to the production of different mature transcripts from the same primary RNA sequence. As a plethora of different transcript forms is available in databases, a first step to uncover the biology that drives AS is to identify the different types of reflected splicing variation. In this work, we present a general definition of the AS event along with a notation system that involves the relative positions of the splice sites. This nomenclature univocally and dynamically assigns a specific “AS code” to every possible pattern of splicing variation. On the basis of this definition and the corresponding codes, we have developed a computational tool (AStalavista) that automatically characterizes the complete landscape of AS events in a given transcript annotation of a genome, thus providing a platform to investigate the transcriptome diversity across genes, chromosomes, and species. Our analysis reveals that a substantial part—in human more than a quarter—of the observed splicing variations are ignored in common classification pipelines. We have used AStalavista to investigate and to compare the AS landscape of different reference annotation sets in human and in other metazoan species and found that proportions of AS events change substantially depending on the annotation protocol, species-specific attributes, and coding constraints acting on the transcripts. The AStalavista system therefore provides a general framework to conduct specific studies investigating the occurrence, impact, and regulation of AS

A Micro RNA Processing Defect in Rapidly Progressing Idiopathic Pulmonary Fibrosis

BACKGROUND: Idiopathic pulmonary fibrosis exhibits differential progression from the time of diagnosis but the molecular basis for varying progression rates is poorly understood. The aim of the present study was to ascertain whether differential miRNA expression might provide one explanation for rapidly versus slowly progressing forms of IPF. METHODOLOGY AND PRINCIPAL FINDINGS: miRNA and mRNA were isolated from surgical lung biopsies from IPF patients with a clinically documented rapid or slow course of disease over the first year after diagnosis. A quantitative PCR miRNA array containing 88 of the most abundant miRNA in the human genome was used to profile lung biopsies from 9 patients with rapidly progressing IPF, 6 patients with slowly progressing IPF, and 10 normal lung biopsies. Using this approach, 11 miRNA were significantly increased and 36 were significantly decreased in rapid biopsies compared with normal biopsies. Slowly progressive biopsies exhibited 4 significantly increased miRNA and 36 significantly decreased miRNA compared with normal lung. Among the miRNA present in IPF with validated mRNA targets were those with regulatory effects on epithelial-mesenchymal transition (EMT). Five miRNA (miR-302c, miR-423-5p, miR-210, miR-376c, and miR-185) were significantly increased in rapid compared with slow IPF lung biopsies. Additional analyses of rapid biopsies and fibroblasts grown from the same biopsies revealed that the expression of AGO1 and AGO2 (essential components of the miRNA processing RISC complex) were lower compared with either slow or normal lung biopsies and fibroblasts. CONCLUSION: These findings suggest that the development and/or clinical progression of IPF might be the consequence of aberrant miRNA processing

Rationale, design and methods for a randomised and controlled trial to investigate whether home access to electronic games decreases children's physical activity

Background. Many children are reported to have insufficient physical activity (PA) placing them at greater risk of poor health outcomes. Participating in sedentary activities such as playing electronic games is widely believed to contribute to less PA. However there is no experimental evidence that playing electronic games reduces PA. There is also no evidence regarding the effect of different types of electronic games (traditional sedentary electronic games versus new active input electronic games) on PA. Further, there is a poor understanding about how characteristics of children may moderate the impact of electronic game access on PA and about what leisure activities are displaced when children play electronic games. Given that many children play electronic games, a better understanding of the effect of electronic game use on PA is critical to inform child health policy and intervention. Methods. This randomised and controlled trial will examine whether PA is decreased by access to electronic games and whether any effect is dependent on the type of game input or the child's characteristics. Children aged 1012 years (N = 72, 36 females) will be recruited and randomised to a balanced ordering of 'no electronic games', 'traditional' electronic games and 'active' electronic games. Each child will participate in each condition for 8 weeks, and be assessed prior to participation and at the end of each condition. The primary outcome is PA, assessed by Actical accelerometers worn for 7 days on the wrist and hip. Energy expenditure will be assessed by the doubly labelled water technique and motor coordination, adiposity, self-confidence, attitudes to technology and PA and leisure activities will also be assessed. A sample of 72 will provide a power of > 0.9 for detecting a 15 mins difference in PA (sd = 30 mins). Discussion. This is the first such trial and will provide critical information to understand whether access to electronic games affects children's PA. Given the vital importance of adequate PA to a healthy start to life and establishing patterns which may track into adulthood, this project can inform interventions which could have a profound impact on the long term health of children. Trial registration. This trial is registered in the Australia and New Zealand Clinical Trials Registry (ACTRN 12609000279224)

Improved upper limits on the stochastic gravitational-wave background from 2009-2010 LIGO and Virgo data

Paper producido por "The LIGO Scientific Collaboration and the Virgo Collaboration". (En el registro se mencionan solo algunos autores de las decenas de personas que participan).Gravitational waves from a variety of sources are predicted to superpose to create a stochastic background. This background is expected to contain unique information from throughout the history of the Universe that is unavailable through standard electromagnetic observations, making its study of fundamental importance to understanding the evolution of the Universe. We carry out a search for the stochastic background with the latest data from the LIGO and Virgo detectors. Consistent with predictions from most stochastic gravitational-wave background models, the data display no evidence of a stochastic gravitational-wave signal. Assuming a gravitational-wave spectrum of ΩGWðfÞ ¼ Ωαðf=frefÞα, we place 95% confidence level upper limits on the energy density of the background in each of four frequency bands spanning 41.5–1726 Hz. In the frequency band of 41.5–169.25 Hz for a spectral index of α¼ 0, we constrain the energy density of the stochastic background to be ΩGWðfÞ <5.6 × 10−6. For the 600–1000 Hz band, ΩGWðfÞ <0.14ðf=900 HzÞ3, a factor of 2.5 lower than the best previously reported upper limits. We find ΩGWðfÞ <1.8 × 10−4 using a spectral index of zero for 170–600 Hz and ΩGWðfÞ < 1.0ðf=1300 HzÞ3 for 1000–1726 Hz, bands in which no previous direct limits have been placed. The limits in these four bands are the lowest direct measurements to date on the stochastic background. We discuss the implications of these results in light of the recent claim by the BICEP2 experiment of the possible evidence for inflationary gravitational waves.http://journals.aps.org/prl/abstract/10.1103/PhysRevLett.113.231101publishedVersionFil: Aasi, J. LIGO. California Institute of Technology; Estados Unidos de América.Fil: Maglione, C. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina.Fil: Maglione, C. Argentinian Gravitational Wave Group; Argentina.Fil: Quiroga, G. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina.Fil: Quiroga, G. Argentinian Gravitational Wave Group; Argentina.Física de Partículas y Campo

Searches for continuous gravitational waves from nine young supernova remnants

We describe directed searches for continuous gravitational waves in data from the sixth LIGO science data run. The targets were nine young supernova remnants not associated with pulsars; eight of the remnants are associated with non-pulsing suspected neutron stars. One target's parameters are uncertain enough to warrant two searches, for a total of ten. Each search covered a broad band of frequencies and first and second frequency derivatives for a fixed sky direction. The searches coherently integrated data from the two LIGO interferometers over time spans from 5.3-25.3 days using the matched-filtering F-statistic. We found no credible gravitational-wave signals. We set 95% confidence upper limits as strong (low) as $4\times10^{-25}$ on intrinsic strain, $2\times10^{-7}$ on fiducial ellipticity, and $4\times10^{-5}$ on r-mode amplitude. These beat the indirect limits from energy conservation and are within the range of theoretical predictions for neutron-star ellipticities and r-mode amplitudes.Comment: Science summary available at http://www.ligo.org/science/Publication-S6DirectedSNR/index.ph

First all-sky search for continuous gravitational waves from unknown sources in binary systems

We present the first results of an all-sky search for continuous gravitational waves from unknown spinning neutron stars in binary systems using LIGO and Virgo data. Using a specially developed analysis program, the TwoSpect algorithm, the search was carried out on data from the sixth LIGO Science Run and the second and third Virgo Science Runs. The search covers a range of frequencies from 20 Hz to 520 Hz, a range of orbital periods from 2 to ~2,254 h and a frequency- and period-dependent range of frequency modulation depths from 0.277 to 100 mHz. This corresponds to a range of projected semi-major axes of the orbit from ~0.6e-3 ls to ~6,500 ls assuming the orbit of the binary is circular. While no plausible candidate gravitational wave events survive the pipeline, upper limits are set on the analyzed data. The most sensitive 95% confidence upper limit obtained on gravitational wave strain is 2.3e-24 at 217 Hz, assuming the source waves are circularly polarized. Although this search has been optimized for circular binary orbits, the upper limits obtained remain valid for orbital eccentricities as large as 0.9. In addition, upper limits are placed on continuous gravitational wave emission from the low-mass x-ray binary Scorpius X-1 between 20 Hz and 57.25 Hz.Comment: 16 pages, 6 figure