Familial co-occurrence of congenital heart defects follows distinct patterns

Aims Congenital heart defects (CHD) affect almost 1% of all live born children and the number of adults with CHD is increasing. In families where CHD has occurred previously, estimates of recurrence risk, and the type of recurring malformation are important for counselling and clinical decision-making, but the recurrence patterns in families are poorly understood. We aimed to determine recurrence patterns, by investigating the co-occurrences of CHD in 1163 families with known malformations, comprising 3080 individuals with clinically confirmed diagnosis. Methods and results We calculated rates of concordance and discordance for 41 specific types of malformations, observing a high variability in the rates of concordance and discordance. By calculating odds ratios for each of 1640 pairs of discordant lesions observed between affected family members, we were able to identify 178 pairs of malformations that co-occurred significantly more or less often than expected in families. The data show that distinct groups of cardiac malformations co-occur in families, suggesting influence from underlying developmental mechanisms. Analysis of human and mouse susceptibility genes showed that they were shared in 19% and 20% of pairs of co-occurring discordant malformations, respectively, but none of malformations that rarely co-occur, suggesting that a significant proportion of co-occurring lesions in families is caused by overlapping susceptibility genes. Conclusion Familial CHD follow specific patterns of recurrence, suggesting a strong influence from genetically regulated developmental mechanisms. Co-occurrence of malformations in families is caused by shared susceptibility genes

Peri-adolescent alcohol consumption increases sensitivity and dopaminergic response to nicotine during adulthood in female alcohol-preferring (P) rats: alterations to α7 nicotinic acetylcholine receptor expression

Adolescent alcohol drinking has been linked to increased risk for drug abuse during adulthood. Nicotine microinjected directly into the posterior ventral tegmental area (pVTA) stimulates dopamine (DA) release in the nucleus accumbens (NAc) shell. The α7 nicotinic acetylcholine receptor (nAChR) is a potent regulator of dopaminergic activity in the pVTA. The current experiments examined the effects of peri-adolescent ethanol (EtOH) drinking on the ability of intra-pVTA nicotine to stimulate DA release during adulthood and alterations in α7 nAChR expression within the pVTA. Alcohol-preferring (P) female rats consumed EtOH and/or water during adolescence (post-natal day [PND] 30–60) or adulthood (PND 90–120). Thirty days following removal of EtOH, subjects received microinjections of 1 μM, 10 μM, or 50 μM nicotine into the pVTA concurrently with microdialysis for extracellular DA in the NAc shell. Brains were harvested from an additional cohort after PND 90 for quantification of α7 nAChR within the pVTA. The results indicated that only adolescent EtOH consumption produced a leftward and upward shift in the dose response curve for nicotine to stimulate DA release in the NAc shell. Investigation of α7 nAChR expression within the pVTA revealed a significant increase in animals that consumed EtOH during adolescence compared to naïve animals. The data suggests that peri-adolescent EtOH consumption produced cross-sensitization to the effects of nicotine during adulthood. The interaction between adolescent EtOH consumption and inflated adult risk for drug dependency could be predicated, at least in part, upon alterations in α7 nAChR expression within the mesolimbic reward pathway

Native-state stability determines the extent of degradation relative to secretion of protein variants from Pichia pastoris.

We have investigated the relationship between the stability and secreted yield of a series of mutational variants of human lysozyme (HuL) in Pichia pastoris. We show that genes directly involved in the unfolded protein response (UPR), ER-associated degradation (ERAD) and ER-phagy are transcriptionally up-regulated more quickly and to higher levels in response to expression of more highly-destabilised HuL variants and those variants are secreted to lower yield. We also show that the less stable variants are retained within the cell and may also be targeted for degradation. To explore the relationship between stability and secretion further, two different single-chain-variable-fragment (scFv) antibodies were also expressed in P. pastoris, but only one of the scFvs gave rise to secreted protein. The non-secreted scFv was detected within the cell and the UPR indicators were pronounced, as they were for the poorly-secreted HuL variants. The non-secreted scFv was modified by changing either the framework regions or the linker to improve the predicted stability of the scFv and secretion was then achieved and the levels of UPR indicators were lowered Our data support the hypothesis that less stable proteins are targeted for degradation over secretion and that this accounts for the decrease in the yields observed. We discuss the secretion of proteins in relation to lysozyme amyloidosis, in particular, and optimised protein secretion, in general

Runx1 deficiency protects against adverse cardiac remodeling following myocardial infarction

Background: Myocardial infarction (MI) is a leading cause of heart failure and death worldwide. Preservation of contractile function and protection against adverse changes in ventricular architecture (cardiac remodeling) are key factors to limiting progression of this condition to heart failure. Consequently, new therapeutic targets are urgently required to achieve this aim. Expression of the Runx1 transcription factor is increased in adult cardiomyocytes after MI; however, the functional role of Runx1 in the heart is unknown. Methods: To address this question, we have generated a novel tamoxifen-inducible cardiomyocyte-specific Runx1-deficient mouse. Mice were subjected to MI by means of coronary artery ligation. Cardiac remodeling and contractile function were assessed extensively at the whole-heart, cardiomyocyte, and molecular levels. Results: Runx1-deficient mice were protected against adverse cardiac remodeling after MI, maintaining ventricular wall thickness and contractile function. Furthermore, these mice lacked eccentric hypertrophy, and their cardiomyocytes exhibited markedly improved calcium handling. At the mechanistic level, these effects were achieved through increased phosphorylation of phospholamban by protein kinase A and relief of sarco/endoplasmic reticulum Ca2+-ATPase inhibition. Enhanced sarco/endoplasmic reticulum Ca2+-ATPase activity in Runx1-deficient mice increased sarcoplasmic reticulum calcium content and sarcoplasmic reticulum–mediated calcium release, preserving cardiomyocyte contraction after MI. Conclusions: Our data identified Runx1 as a novel therapeutic target with translational potential to counteract the effects of adverse cardiac remodeling, thereby improving survival and quality of life among patients with MI

SSWAP: A Simple Semantic Web Architecture and Protocol for semantic web services

<p>Abstract</p> <p>Background</p> <p>SSWAP (<b>S</b>imple <b>S</b>emantic <b>W</b>eb <b>A</b>rchitecture and <b>P</b>rotocol; pronounced "swap") is an architecture, protocol, and platform for using reasoning to semantically integrate heterogeneous disparate data and services on the web. SSWAP was developed as a hybrid semantic web services technology to overcome limitations found in both pure web service technologies and pure semantic web technologies.</p> <p>Results</p> <p>There are currently over 2400 resources published in SSWAP. Approximately two dozen are custom-written services for QTL (Quantitative Trait Loci) and mapping data for legumes and grasses (grains). The remaining are wrappers to Nucleic Acids Research Database and Web Server entries. As an architecture, SSWAP establishes how clients (users of data, services, and ontologies), providers (suppliers of data, services, and ontologies), and discovery servers (semantic search engines) interact to allow for the description, querying, discovery, invocation, and response of semantic web services. As a protocol, SSWAP provides the vocabulary and semantics to allow clients, providers, and discovery servers to engage in semantic web services. The protocol is based on the W3C-sanctioned first-order description logic language OWL DL. As an open source platform, a discovery server running at <url>http://sswap.info</url> (as in to "swap info") uses the description logic reasoner Pellet to integrate semantic resources. The platform hosts an interactive guide to the protocol at <url>http://sswap.info/protocol.jsp</url>, developer tools at <url>http://sswap.info/developer.jsp</url>, and a portal to third-party ontologies at <url>http://sswapmeet.sswap.info</url> (a "swap meet").</p> <p>Conclusion</p> <p>SSWAP addresses the three basic requirements of a semantic web services architecture (<it>i.e</it>., a common syntax, shared semantic, and semantic discovery) while addressing three technology limitations common in distributed service systems: <it>i.e</it>., <it>i</it>) the fatal mutability of traditional interfaces, <it>ii</it>) the rigidity and fragility of static subsumption hierarchies, and <it>iii</it>) the confounding of content, structure, and presentation. SSWAP is novel by establishing the concept of a canonical yet mutable OWL DL graph that allows data and service providers to describe their resources, to allow discovery servers to offer semantically rich search engines, to allow clients to discover and invoke those resources, and to allow providers to respond with semantically tagged data. SSWAP allows for a mix-and-match of terms from both new and legacy third-party ontologies in these graphs.</p

The Speed of Sound in Methane under Conditions of the Thermal Boundary Layer of Uranus

We present the first direct observations of acoustic waves in warm dense matter. We analyze wavenumber- and energy-resolved X-ray spectra taken from warm dense methane created by laser-heating a cryogenic liquid jet. X-ray diffraction and inelastic free electron scattering yield sample conditions of 0.3$\pm$0.1 eV and 0.8$\pm$0.1 g/cm$^3$, corresponding to a pressure of $\sim$13 GPa and matching the conditions predicted in the thermal boundary layer between the inner and outer envelope of Uranus. Inelastic X-ray scattering was used to observe the collective oscillations of the ions. With a highly improved energy resolution of $\sim$50 meV, we could clearly distinguish the Brillouin peaks from the quasi-elastic Rayleigh feature. Data at different wavenumbers were used to obtain a sound speed of 5.9$\pm$0.5 km/s, which enabled us to validate the use of Birch's law in this new parameter regime.Comment: 7 pages, 4 figures with supplementary informatio

The WiggleZ Dark Energy Survey: constraining galaxy bias and cosmic growth with three-point correlation functions

Higher order statistics are a useful and complementary tool for measuring the clustering of galaxies, containing information on the non-Gaussian evolution and morphology of large-scale structure in the Universe. In this work we present measurements of the three-point correlation function (3PCF) for 187 000 galaxies in theWiggleZ spectroscopic galaxy survey.We explore the WiggleZ 3PCF scale and shape dependence at three different epochs z = 0.35, 0.55 and 0.68, the highest redshifts where these measurements have been made to date. Using N-body simulations to predict the clustering of dark matter, we constrain the linear and non-linear bias parameters of WiggleZ galaxies with respect to dark matter, and marginalize over them to obtain constraints on σ 8 (z), the variance of perturbations on a scale of 8 h-1 Mpc and its evolution with redshift. These measurements of σ 8 (z), which have 10-20 per cent accuracies, are consistent with the predictions of the δ cold dark matter concordance cosmology and test this model in a new way. © 2013 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society

Reduced Complexity Model Intercomparison Project Phase 1: introduction and evaluation of global-mean temperature response

Reduced-complexity climate models (RCMs) are critical in the policy and decision making space, and are directly used within multiple Intergovernmental Panel on Climate Change (IPCC) reports to complement the results of more comprehensive Earth system models. To date, evaluation of RCMs has been limited to a few independent studies. Here we introduce a systematic evaluation of RCMs in the form of the Reduced Complexity Model Intercomparison Project (RCMIP). We expect RCMIP will extend over multiple phases, with Phase 1 being the first. In Phase 1, we focus on the RCMs' global-mean temperature responses, comparing them to observations, exploring the extent to which they emulate more complex models and considering how the relationship between temperature and cumulative emissions of CO2 varies across the RCMs. Our work uses experiments which mirror those found in the Coupled Model Intercomparison Project (CMIP), which focuses on complex Earth system and atmosphere–ocean general circulation models. Using both scenario-based and idealised experiments, we examine RCMs' global-mean temperature response under a range of forcings. We find that the RCMs can all reproduce the approximately 1 ∘C of warming since pre-industrial times, with varying representations of natural variability, volcanic eruptions and aerosols. We also find that RCMs can emulate the global-mean temperature response of CMIP models to within a root-mean-square error of 0.2 ∘C over a range of experiments. Furthermore, we find that, for the Representative Concentration Pathway (RCP) and Shared Socioeconomic Pathway (SSP)-based scenario pairs that share the same IPCC Fifth Assessment Report (AR5)-consistent stratospheric-adjusted radiative forcing, the RCMs indicate higher effective radiative forcings for the SSP-based scenarios and correspondingly higher temperatures when run with the same climate settings. In our idealised setup of RCMs with a climate sensitivity of 3 ∘C, the difference for the ssp585–rcp85 pair by 2100 is around 0.23∘C(±0.12 ∘C) due to a difference in effective radiative forcings between the two scenarios. Phase 1 demonstrates the utility of RCMIP's open-source infrastructure, paving the way for further phases of RCMIP to build on the research presented here and deepen our understanding of RCMs

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Compressed representation of a partially defined integer function over multiple arguments

In OLAP (OnLine Analitical Processing) data are analysed in an n-dimensional cube. The cube may be represented as a partially defined function over n arguments. Considering that often the function is not defined everywhere, we ask: is there a known way of representing the function or the points in which it is defined, in a more compact manner than the trivial one