A Computational Investigation of Cardiac Caveolae as a Source of Persistent Sodium Current

Recent studies of cholesterol-rich membrane microdomains, called caveolae, reveal that caveolae are reservoirs of “recruitable” sodium ion channels. Caveolar channels constitute a substantial and previously unrecognized source of sodium current in cardiac cells. In this paper we model for the first time caveolar sodium currents and their contributions to cardiac action potential morphology. We show that the β-agonist-induced opening of caveolae may have substantial impacts on peak overshoot, maximum upstroke velocity, and ultimately conduction velocity. Additionally, we show that prolonged action potentials and the formation of potentially arrhythmogenic afterdepolarizations, can arise if caveolae open intermittently throughout the action potential. Our simulations suggest that caveolar sodium current may constitute a route, which is independent of channelopathies, to delayed repolarization and the arrhythmias associated with such delays

The Beaker phenomenon and the genomic transformation of northwest Europe

From around 2750 to 2500 bc, Bell Beaker pottery became widespread across western and central Europe, before it disappeared between 2200 and 1800 bc. The forces that propelled its expansion are a matter of long-standing debate, and there is support for both cultural diffusion and migration having a role in this process. Here we present genome-wide data from 400 Neolithic, Copper Age and Bronze Age Europeans, including 226 individuals associated with Beaker-complex artefacts. We detected limited genetic affinity between Beaker-complex-associated individuals from Iberia and central Europe, and thus exclude migration as an important mechanism of spread between these two regions. However, migration had a key role in the further dissemination of the Beaker complex. We document this phenomenon most clearly in Britain, where the spread of the Beaker complex introduced high levels of steppe-related ancestry and was associated with the replacement of approximately 90% of Britain’s gene pool within a few hundred years, continuing the east-to-west expansion that had brought steppe-related ancestry into central and northern Europe over the previous centuries

Variegation of active regions on comet 67P/Churyumov-Gerasimenko

Since Rosetta spacecraft\u2019s arrival to the comet 67P, the OSIRIS scientific imager (Optical, Spectroscopic, and Infrared Remote Imaging System, Keller et al. 2007) is successfully observing the nucleus with high spatial resolution in the 250-1000 nm range thanks to set of 26 dedicated filters.While 67P has a typical red spectral slope, the active areas tend to display bluer spectra (Sierks et al. 2015, Fornasier et al. 2015). We performed a spectral analysis of the active areas and derived spectral characteristics of them, possibly indicating the presence of material enriched in volatiles.The \u2018activity thresholds\u2019 spectral method (Oklay et al, 2015) is used for the identification of the active areas. In most cases, areas detected with this technique have been later on confirmed as active sources (Lara et al. 2015, Lin et al. 2015, Vincent et al. 2015) by direct detection of dust jets. This technique is therefore able to identify currently active areas, but also predicts which regions of the surface are likely to become activated once they receive enough insolation.Acknowledgements: OSIRIS was built by a consortium led by the Max-Planck-Institut f\ufcr Sonnensystemforschung, G\uf6ttingen, Germany, in collaboration with CISAS, University of Padova, Italy, the Laboratoire d'Astrophysique de Marseille, France, the Instituto de Astrofi\uadsica de Andalucia, CSIC, Granada, Spain, the Scientific Support Office of the European Space Agency, Noordwijk, The Netherlands, the Instituto Nacional de Tecnica Aeroespacial, Madrid, Spain, the Universidad Politechnica de Madrid, Spain, the Department of Physics and Astronomy of Uppsala University, Sweden, and the Institut f\ufcr Datentechnik und Kommunikationsnetze der Technischen Universit\ue4t Braunschweig, Germany. We thank the Rosetta Science Ground Segment at ESAC, the Rosetta Mission Operations Centre at ESOC and the Rosetta Project at ESTEC for their outstanding work enabling the science return of the Rosetta Mission.Keller, et al. 2007, Space Sci. Rev., 128, 433Sierks et al. 2015, Science, 347,1Fornasier et al. 2015, A&A, published onlineLara et al. 2015, A&A, published onlineLin et al. 2015, A&A, published onlineVincent et al. 2015, A&A, submittedOklay et al. 2015, in preparatio

The Rima Bode Region -Absolute Model Ages of a Candidate Future Lunar Landing Site

International audienc

The Rima Bode Region -Absolute Model Ages of a Candidate Future Lunar Landing Site

International audienc

Isolation of the protein and RNA content of active sites of transcription from mammalian cells.

Mammalian cell nuclei contain three RNA polymerases (RNAP I, RNAP II and RNAP III), which transcribe different gene subsets, and whose active forms are contained in supramolecular complexes known as 'transcription factories.' These complexes are difficult to isolate because they are embedded in the 3D structure of the nucleus. Factories exchange components with the soluble nucleoplasmic pool over time as gene expression programs change during development or disease. Analysis of their content can provide information on the nascent transcriptome and its regulators. Here we describe a protocol for the isolation of large factory fragments under isotonic salt concentrations in <72 h. It relies on DNase I-mediated detachment of chromatin from the nuclear substructure of freshly isolated, unfixed cells, followed by caspase treatment to release multi-megadalton factory complexes. These complexes retain transcriptional activity, and isolation of their contents is compatible with downstream analyses by mass spectrometry (MS) or RNA-sequencing (RNA-seq) to catalog the proteins and RNA associated with sites of active transcription

A Large-Scale, Consortium-Based Genomewide Association Study of Asthma

BACKGROUND Susceptibility to asthma is influenced by genes and environment; implicated genes may indicate pathways for therapeutic intervention. Genetic risk factors may be useful in identifying subtypes of asthma and determining whether intermediate phenotypes, such as elevation of the total serum IgE level, are causally linked to disease. METHODS We carried out a genomewide association study by genotyping 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. We used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma. RESULTS We observed associations of genomewide significance between asthma and the following single-nucleotide polymorphisms: rs3771166 on chromosome 2, implicating IL1RL1/IL18R1 (P = 3x10(-9)); rs9273349 on chromosome 6, implicating HLA-DQ (P = 7x10(-14)); rs1342326 on chromosome 9, flanking IL33 (P = 9x10(-10)); rs744910 on chromosome 15 in SMAD3 (P = 4x10(-9)); and rs2284033 on chromosome 22 in IL2RB (P = 1.1x10(-8)). Association with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to childhood-onset disease (rs2305480, P = 6x10(-23)). Only HLA-DR showed a significant genomewide association with the total serum IgE concentration, and loci strongly associated with IgE levels were not associated with asthma. CONCLUSIONS Asthma is genetically heterogeneous. A few common alleles are associated with disease risk at all ages. Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Variants at the ORMDL3/GSDMB locus are associated only with childhood-onset disease. Elevation of total serum IgE levels has a minor role in the development of asthma