Characterization and regulation of wild‐type and mutant TASK‐1 two pore domain potassium channels indicated in pulmonary arterial hypertension

Key points The TASK-1 channel gene (KCNK3) has been identified as a possible disease-causing gene in heritable pulmonary arterial hypertension (PAH). In the present study, we show that novel mutated TASK-1 channels, seen in PAH patients, have a substantially reduced current compared to wild-type TASK-1 channels. These mutated TASK-1 channels are located at the plasma membrane to the same degree as wild-type TASK-1 channels. ONO-RS-082 and alkaline pH 8.4 both activate TASK-1 channels but do not recover current through mutant TASK-1 channels. We show that the guanylate cyclase activator, riociguat, a novel treatment for PAH, enhances current through TASK-1 channels but does not recover current through mutant TASK-1 channels. Pulmonary arterial hypertension (PAH) affects ∼15–50 people per million. KCNK3, the gene that encodes the two pore domain potassium channel TASK-1 (K2P3.1), has been identified as a possible disease-causing gene in heritable PAH. Recently, two new mutations have been identified in KCNK3 in PAH patients: G106R and L214R. The present study aimed to characterize the functional properties and regulation of wild-type (WT) and mutated TASK-1 channels and determine how these might contribute to PAH and its treatment. Currents through WT and mutated human TASK-1 channels transiently expressed in tsA201 cells were measured using whole-cell patch clamp electrophysiology. Localization of fluorescence-tagged channels was visualized using confocal microscopy and quantified with in-cell and on-cell westerns. G106R or L214R mutated channels were located at the plasma membrane to the same degree as WT channels; however, their current was markedly reduced compared to WT TASK-1 channels. Functional current through these mutated channels could not be restored using activators of WT TASK-1 channels (pH 8.4, ONO-RS-082). The guanylate cyclase activator, riociguat, enhanced current through WT TASK-1 channels; however, similar to the other activators investigated, riociguat did not have any effect on current through mutated TASK-1 channels. Thus, novel mutations in TASK-1 seen in PAH substantially alter the functional properties of these channels. Current through these channels could not be restored by activators of TASK-1 channels. Riociguat enhancement of current through TASK-1 channels could contribute to its therapeutic benefit in the treatment of PAH

Impact of negative and positive CO2 emissions on global warming metrics using an ensemble of Earth system model simulations

The benefits of implementing negative emission technologies in the global warming response to cumulative carbon emissions until the year 2420 are assessed following the shared socioeconomic pathway (SSP) 1-2.6, the sustainable development scenario, with a comprehensive set of intermediate-complexity Earth system model integrations. Model integrations include 86 different model realisations covering a wide range of plausible climate states. The global warming response is assessed in terms of two key climate metrics: the effective transient climate response to cumulative CO2 emissions (eTCRE), measuring the surface warming response to cumulative carbon emissions and associated non-CO2 forcing, and the effective zero emissions commitment (eZEC), measuring the extent of any continued warming after net-zero CO2 emissions are reached. The transient climate response to cumulative CO2 emissions (TCRE) is estimated as 2.2 K EgC−1 (median value) with a 10 %–90 % range of 1.75 to 3.13 K EgC−1 in 2100, approximated from the eTCRE by removing the contribution of non-CO2 forcing. During the positive emission phase, the eTCRE decreases from 2.71 (2.0 to 3.65) to 2.61 (1.91 to 3.62) K EgC−1 due to a weakening in the dependence of radiative forcing on atmospheric carbon, which is partly opposed by an increasing fraction of the radiative forcing warming the surface as the ocean stratifies. During the net negative and zero emission phases, a progressive reduction in the eTCRE to 2.0 (1.39 to 2.96) K EgC−1 is driven by the reducing airborne fraction as atmospheric CO2 is drawn down mainly by the ocean. The model uncertainty in the slopes of warming versus cumulative CO2 emissions varies from being controlled by the radiative feedback parameter during positive emissions to being affected by carbon-cycle parameters during net negative emissions, consistent with the drivers of uncertainty diagnosed from the coefficient of variation of the contributions in the eTCRE framework. The continued warming after CO2 emissions cease and remain at zero gives a model mean eZEC of −0.03 K after 25 years, which decreases in time to −0.21 K at 90 years after emissions cease. However, there is a spread in the ensemble with a temperature overshoot occurring in 20 % of the ensemble members at 25 years after cessation of emissions. If net negative emissions are included, there is a reduction in atmospheric CO2 and there is a decrease in temperature overshoot so that the eZEC is positive in only 5 % of the ensemble members. Hence, incorporating negative emissions enhances the ability to meet climate targets and avoid risk of continued warming after net zero is reached

Characterisation and regulation of wild type and mutant TASK-1 two pore domain potassium channels indicated in pulmonary arterial hypertension

KEY POINTS SUMMARY The TASK-1 channel gene (KCNK3) has been identified as a possible disease-causing gene in heritable pulmonary arterial hypertension (PAH). In this study we show that novel mutated TASK-1 channels, seen in PAH patients, have a substantially reduced current compared to wild type TASK-1 channels. These mutated TASK-1 channels are located at the plasma membrane to the same degree as wild type TASK-1 channels. ONO-RS-082 and alkaline pH 8.4 both activate TASK-1 channels but do not recover current through mutant TASK-1 channels. We show that the guanylate cyclase activator, riociguat, a novel treatment for PAH, enhances current through TASK-1 channels but does not recover current through mutant TASK-1 channels. ABSTRACT Pulmonary arterial hypertension (PAH) affects approximately 15-50 people per million. KCNK3, the gene that encodes the two pore domain potassium channel TASK-1 (K2P3.1), has been identified as a possible disease-causing gene in heritable PAH. Recently two new mutations have been identified in KCNK3, G106R and L214R, in PAH patients. The aim of this study is to characterise the functional properties and regulation of wildtype (WT) and mutated TASK-1 channels and understand how these might contribute to PAH and its treatment. Currents through WT and mutated human TASK-1 channels transiently expressed in tsA201 cells were measured using whole-cell patch-clamp electrophysiology. Localisation of fluorescently-tagged channels was visualised using confocal microscopy and quantified with in-cell and on-cell Westerns. G106R or L214R mutated channels were located at the plasma membrane to the same degree as WT channels, however their current was markedly reduced compared to WT TASK-1 channels. Functional current through these mutated channels could not be restored using activators of WT TASK-1 channels (pH 8.4, ONO-RS-082). The guanylate cyclase activator, riociguat, enhanced current through WT TASK-1 channels, however, like the other activators investigated, riociguat did not have any effect on current through mutated TASK-1 channels. Thus, novel mutations in TASK-1 seen in PAH, substantially alter the functional properties of these channels. Current through these channels could not be restored by activators of TASK-1 channels. Riociguat enhancement of current through TASK-1 channels could contribute to its therapeutic benefit in the treatment of PAH

The global atmospheric electrical circuit and climate

Evidence is emerging for physical links among clouds, global temperatures, the global atmospheric electrical circuit and cosmic ray ionisation. The global circuit extends throughout the atmosphere from the planetary surface to the lower layers of the ionosphere. Cosmic rays are the principal source of atmospheric ions away from the continental boundary layer: the ions formed permit a vertical conduction current to flow in the fair weather part of the global circuit. Through the (inverse) solar modulation of cosmic rays, the resulting columnar ionisation changes may allow the global circuit to convey a solar influence to meteorological phenomena of the lower atmosphere. Electrical effects on non-thunderstorm clouds have been proposed to occur via the ion-assisted formation of ultra-fine aerosol, which can grow to sizes able to act as cloud condensation nuclei, or through the increased ice nucleation capability of charged aerosols. Even small atmospheric electrical modulations on the aerosol size distribution can affect cloud properties and modify the radiative balance of the atmosphere, through changes communicated globally by the atmospheric electrical circuit. Despite a long history of work in related areas of geophysics, the direct and inverse relationships between the global circuit and global climate remain largely quantitatively unexplored. From reviewing atmospheric electrical measurements made over two centuries and possible paleoclimate proxies, global atmospheric electrical circuit variability should be expected on many timescale

Improved constraints on the expansion rate of the Universe up to z~1.1 from the spectroscopic evolution of cosmic chronometers

We present new improved constraints on the Hubble parameter H(z) in the redshift range 0.15 < z < 1.1, obtained from the differential spectroscopic evolution of early-type galaxies as a function of redshift. We extract a large sample of early-type galaxies (\sim11000) from several spectroscopic surveys, spanning almost 8 billion years of cosmic lookback time (0.15 < z < 1.42). We select the most massive, red elliptical galaxies, passively evolving and without signature of ongoing star formation. Those galaxies can be used as standard cosmic chronometers, as firstly proposed by Jimenez & Loeb (2002), whose differential age evolution as a function of cosmic time directly probes H(z). We analyze the 4000 {\AA} break (D4000) as a function of redshift, use stellar population synthesis models to theoretically calibrate the dependence of the differential age evolution on the differential D4000, and estimate the Hubble parameter taking into account both statistical and systematical errors. We provide 8 new measurements of H(z) (see Tab. 4), and determine its change in H(z) to a precision of 5-12% mapping homogeneously the redshift range up to z \sim 1.1; for the first time, we place a constraint on H(z) at z \neq 0 with a precision comparable with the one achieved for the Hubble constant (about 5-6% at z \sim 0.2), and covered a redshift range (0.5 < z < 0.8) which is crucial to distinguish many different quintessence cosmologies. These measurements have been tested to best match a \Lambda CDM model, clearly providing a statistically robust indication that the Universe is undergoing an accelerated expansion. This method shows the potentiality to open a new avenue in constrain a variety of alternative cosmologies, especially when future surveys (e.g. Euclid) will open the possibility to extend it up to z \sim 2.Comment: 34 pages, 15 figures, 6 tables, published in JCAP. It is a companion to Moresco et al. (2012b, http://arxiv.org/abs/1201.6658) and Jimenez et al. (2012, http://arxiv.org/abs/1201.3608). The H(z) data can be downloaded at http://www.physics-astronomy.unibo.it/en/research/areas/astrophysics/cosmology-with-cosmic-chronometer

Cosmology with clusters of galaxies

In this Chapter I review the role that galaxy clusters play as tools to constrain cosmological parameters. I will concentrate mostly on the application of the mass function of galaxy clusters, while other methods, such as that based on the baryon fraction, are covered by other Chapters of the book. Since most of the cosmological applications of galaxy clusters rely on precise measurements of their masses, a substantial part of my Lectures concentrates on the different methods that have been applied so far to weight galaxy clusters. I provide in Section 2 a short introduction to the basics of cosmic structure formation. In Section 3 I describe the Press--Schechter (PS) formalism to derive the cosmological mass function, then discussing extensions of the PS approach and the most recent calibrations from N--body simulations. In Section 4 I review the methods to build samples of galaxy clusters at different wavelengths. Section 5 is devoted to the discussion of different methods to derive cluster masses. In Section 6 I describe the cosmological constraints, which have been obtained so far by tracing the cluster mass function with a variety of methods. Finally, I describe in Section 7 the future perspectives for cosmology with galaxy clusters and the challenges for clusters to keep playing an important role in the era of precision cosmology.Comment: 49 pages, 19 figures, Lectures for 2005 Guillermo Haro Summer School on Clusters, to appear in "Lecture notes in Physics" (Springer

Statistical Mechanics of Horizontal Gene Transfer in Evolutionary Ecology

The biological world, especially its majority microbial component, is strongly interacting and may be dominated by collective effects. In this review, we provide a brief introduction for statistical physicists of the way in which living cells communicate genetically through transferred genes, as well as the ways in which they can reorganize their genomes in response to environmental pressure. We discuss how genome evolution can be thought of as related to the physical phenomenon of annealing, and describe the sense in which genomes can be said to exhibit an analogue of information entropy. As a direct application of these ideas, we analyze the variation with ocean depth of transposons in marine microbial genomes, predicting trends that are consistent with recent observations using metagenomic surveys.Comment: Accepted by Journal of Statistical Physic

Relatively lower body mass index is associated with an excess of severe truncal asymmetry in healthy adolescents: Do white adipose tissue, leptin, hypothalamus and sympathetic nervous system influence truncal growth asymmetry?

<p>Abstract</p> <p>Background</p> <p>In healthy adolescents normal back shape asymmetry, here termed truncal asymmetry (TA), is evaluated by higher and lower subsets of BMI. The study was initiated after research on girls with adolescent idiopathic scoliosis (AIS) showed that higher and lower BMI subsets discriminated patterns of skeletal maturation and asymmetry unexplained by existing theories of pathogenesis leading to a new interpretation which has therapeutic implications <it>(double neuro-osseous theory)</it>.</p> <p>Methods</p> <p>5953 adolescents age 11–17 years (boys 2939, girls 3014) were examined in a school screening program in two standard positions, standing forward bending (FB) and sitting FB. The sitting FB position is thought to reveal intrinsic TA free from back humps induced by any leg-length inequality. TA was measured in both positions using a Pruijs scoliometer as angle of trunk inclinations (ATIs) across the back at each of three spinal regions, thoracic, thoracolumbar and lumbar. Abnormality of ATIs was defined as being outside 2 standard deviations for each age group, gender, position and spinal region, and termed <it>severe </it>TA.</p> <p>Results</p> <p>In the sitting FB position after correcting for age,<it>relatively lower BMIs </it>are statistically associated with a greater number of severe TAs than with relatively higher BMIs in both girls (thoracolumbar region) and boys (thoracolumbar and lumbar regions).</p> <p>The relative frequency of severe TAs is significantly higher in girls than boys for each of the right thoracic (56.76%) and thoracolumbar (58.82%) regions (p = 0.006, 0.006, respectively). After correcting for age, smaller BMIs are associated with more <it>severe TAs </it>in boys and girls.</p> <p>Discussion</p> <p>BMI is a surrogate measure for body fat and circulating leptin levels. The finding that girls with relatively lower BMI have significantly later menarche, and a significant excess of TAs, suggests a relation to energy homeostasis through the hypothalamus. The hypothesis we suggest for the pathogenesis of severe TA in girls and boys has the same mechanism as that proposed recently for AIS girls, namely: severe TAs are initiated by a <it>genetically-determined selectively </it>increased hypothalamic sensitivity (up-regulation, i.e. increased sensitivity) to leptin with asymmetry as an adverse response to stress (hormesis), mediated bilaterally mainly to the growing trunk via the sympathetic nervous system <it>(leptin-hypothalamic-sympathetic nervous system (LHS) concept)</it>. The putative autonomic dysfunction is thought to be increased by any lower circulating leptin levels associated with relatively lower BMIs. Sympathetic nervous system activation with asymmetry leads to asymmetries in ribs and/or vertebrae producing severe TA when beyond the capacity of postural mechanisms of the somatic nervous system to control the shape distortion of the trunk. A test of this hypothesis testing skin sympathetic responses, as in the Rett syndrome, is suggested.</p

Macrosocial determinants of population health in the context of globalization

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55738/1/florey_globalization_2007.pd