Kontracepcija

<div><p>Aims</p><p>To determine the mechanisms by which the α_1A-adrenergic receptor (AR) regulates cardiac contractility.</p><p>Background</p><p>We reported previously that transgenic mice with cardiac-restricted α_1A-AR overexpression (α_1A-TG) exhibit enhanced contractility but not hypertrophy, despite evidence implicating this Gα_q/11-coupled receptor in hypertrophy.</p><p>Methods</p><p>Contractility, calcium (Ca²⁺) kinetics and sensitivity, and contractile proteins were examined in cardiomyocytes, isolated hearts and skinned fibers from α_1A-TG mice (170-fold overexpression) and their non-TG littermates (NTL) before and after α_1A-AR agonist stimulation and blockade, angiotensin II (AngII), and Rho kinase (ROCK) inhibition.</p><p>Results</p><p>Hypercontractility without hypertrophy with α_1A-AR overexpression is shown to result from increased intracellular Ca²⁺ release in response to agonist, augmenting the systolic amplitude of the intracellular Ca²⁺ concentration [Ca²⁺]_i transient without changing resting [Ca²⁺]_i. In the <i>absence</i> of agonist, however, α_1A-AR overexpression <i>reduced</i> contractility despite unchanged [Ca²⁺]_i. This hypocontractility is not due to heterologous desensitization: the contractile response to AngII, acting via its Gα_q/11-coupled receptor, was unaltered. Rather, the hypocontractility is a pleiotropic signaling effect of the α_1A-AR in the absence of agonist, inhibiting RhoA/ROCK activity, resulting in hypophosphorylation of both myosin phosphatase targeting subunit 1 (MYPT1) and cardiac myosin light chain 2 (cMLC2), reducing the Ca²⁺ sensitivity of the contractile machinery: all these effects were rapidly reversed by selective α_1A-AR blockade. Critically, ROCK inhibition in normal hearts of NTLs without α_1A-AR overexpression caused hypophosphorylation of both MYPT1 and cMLC2, and rapidly reduced basal contractility.</p><p>Conclusions</p><p>We report for the first time pleiotropic α_1A-AR signaling and the physiological role of RhoA/ROCK signaling in maintaining contractility in the normal heart.</p></div

Attributing Atmospheric Methane to Anthropogenic Emission Sources

Methane is a greenhouse gas, and increases in atmospheric methane concentration over the past 250 years have driven increased radiative forcing of the atmosphere. Increases in atmospheric methane concentration since 1750 account for approximately 17% of increases in radiative forcing of the atmosphere, and that percentage increases by approximately a factor of 2 if the effects of the greenhouse gases produced by the atmospheric reactions of methane are included in the assessment. Because of the role of methane emissions in radiative forcing of the atmosphere, the identification and quantification of sources of methane emissions is receiving increased scientific attention. Methane emission sources include biogenic, geogenic, and anthropogenic sources; the largest anthropogenic sources are natural gas and petroleum systems, enteric fermentation (livestock), landfills, coal mining, and manure management. While these source categories are well-known, there is significant uncertainty in the relative magnitudes of methane emissions from the various source categories. Further, the overall magnitude of methane emissions from all anthropogenic sources is actively debated, with estimates based on source sampling extrapolated to regional or national scale (“bottom-up analyses”) differing from estimates that infer emissions based on ambient data (“top-down analyses”) by 50% or more.To address the important problem of attribution of methane to specific sources, a variety of new analytical methods are being employed, including high time resolution and highly sensitive measurements of methane, methane isotopes, and other chemical species frequently associated with methane emissions, such as ethane. This Account describes the use of some of these emerging measurements, in both top-down and bottom-up methane emission studies. In addition, this Account describes how data from these new analytical methods can be used in conjunction with chemical mass balance (CMB) methods for source attribution. CMB methods have been developed over the past several decades to quantify sources of volatile organic compound (VOC) emissions and atmospheric particulate matter. These emerging capabilities for making measurements of methane and species coemitted with methane, rapidly, precisely, and at relatively low cost, used together with CMB methods of source attribution can lead to a better understanding of methane emission sources. Application of the CMB approach to source attribution in the Barnett Shale oil and gas production region in Texas demonstrates both the importance of extensive and simultaneous source testing in the region being analyzed and the potential of CMB method to quantify the relative strengths of methane emission sources

Strategic financial management

The aim of the CIMA/Loughborough project is to encourage management accountants to "so complement their experience with research that they are able to encapsulate their knowledge into a thesis for the future benefit of the profession, and have the standard of the work and its importance recognised by the granting of a higher degree". This particular thesis opens with a recognition of the rapid rate of environmental change, and the consequent shift of emphasis towards the strategic level of management. It poses the question of the role of the finance function at this level, and demonstrates the inadequacies of the traditional accounting model in this context. Various techniques of adjusting accounts for the effect of changing price levels are looked at, but are all seen to be irrelevant in terms of decision-making and performance-monitoring. [Continues.

Appendix-Final – Supplemental material for Cognate frequency and assessment of second language lexical knowledge

<p>Supplemental material, Appendix-Final for Cognate frequency and assessment of second language lexical knowledge by David Allen in International Journal of Bilingualism</p

Example of digital photograph-based estimate of <i>C. viridis</i> population parameters.

<p>(A) The area of census includes the leaf area and all veins, starting from the pedicel till the 5^th secondary vein for the top and bottom of the abaxial surface of the leaf. (B) Close up of dashed rectangular area of leaf on day 7, where a crawler (c), nymph (n), adult (a), and ant are marked.</p

Estimated parameter values for Lefkovitch transitions and predation rates.

<p>P-values were calculated using the likelihood ratio test. Graphical examples are indicated for the two significantly different parameters in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0043510#pone-0043510-g003" target="_blank">Fig. 3</a>.</p

Dynamic Management of NO_<i>x</i> and SO₂ Emissions in the Texas and Mid-Atlantic Electric Power Systems and Implications for Air Quality

Cap and trade programs have historically been designed to achieve annual or seasonal reductions in emissions of nitrogen oxides and sulfur dioxide from power plants. Emissions reductions may not be temporally coincident with meteorological conditions conducive to the formation of peak ozone and fine particulate matter concentrations. Integrated power system and air quality modeling methods were developed to evaluate time-differentiated emissions price signals on high ozone days in the Mid-Atlantic portion of the Pennsylvania–New Jersey–Maryland (PJM) Interconnection and Electric Reliability Council of Texas (ERCOT) grids. Sufficient flexibility exists in the two grids with marked differences in demand and fuel generation mix to accommodate time-differentiated emissions pricing alone or in combination with a season-wide program. System-wide emissions reductions and production costs from time-differentiated pricing are shown to be competitive with those of a season-wide program on high ozone days and would be more cost-effective if the primary policy goal was to target emissions reductions on these days. Time-differentiated pricing layered as a complement to the Cross-State Air Pollution Rule had particularly pronounced benefits for the Mid-Atlantic PJM system that relies heavily on coal-fired generation. Time-differentiated pricing aimed at reducing ozone concentrations had particulate matter reduction co-benefits, but if particulate matter reductions are the primary objective, other approaches to time-differentiated pricing may lead to greater benefits

Proposed Requirements-driven User-scenario Development Protocol for the Belmont Forum E-Infrastructure and Data Management Cooperative Research Agreement

<p>The Belmont Forum E-Infrastructure and Data Management Cooperative Research Agreement (CRA) is designed to foster a global community to collaborate on e-infrastructure challenges. One of the deliverables is an implementation plan to address global data infrastructure interoperability challenges and align existing domestic and international capabilities. Work package three (WP3) of the CRA focuses on the harmonization of global data infrastructure for sharing environmental data. One of the subtasks under WP3 is the development of user scenarios that guide the development of applicable deliverables.</p> <p>This paper describes the proposed protocol for user scenario development. It enables the solicitation of user scenarios from a broad constituency, and exposes the mechanisms by which those solicitations are evaluated against requirements that map to the Belmont Challenge. The underlying principle of traceability forms the basis for a structured, requirements-driven approach resulting in work products amenable to trade-off analyses and objective prioritization.</p> <p>The protocol adopts the ISO Reference Model for Open Distributed Processing (RM-ODP) as a top level framework. User scenarios are developed within RM-ODP’s “Enterprise Viewpoint”. To harmonize with existing frameworks, the protocol utilizes the conceptual constructs of “scenarios”, “use cases”, “use case categories”, and use case templates as adopted by recent GEOSS Architecture Implementation Project (AIP) deliverables and CSIRO’s eReefs project. These constructs are encapsulated under the larger construct of “user scenarios”.</p> <p>Once user scenarios are ranked by goodness-of-fit to the Belmont Challenge, secondary scoring metrics may be generated, like goodness-of-fit to FutureEarth science themes. The protocol also facilitates an assessment of the ease of implementing given user scenario using existing GEOSS AIP deliverables.</p> <p>In summary, the protocol results in a traceability graph that can be extended to coordinate across research programmes. If implemented using appropriate technologies and harmonized with existing ontologies, this approach enables queries, sensitivity analyses, and visualization of complex relationships.</p

Development and Validation of a Computational Model for Androgen Receptor Activity

Testing thousands of chemicals to identify potential androgen receptor (AR) agonists or antagonists would cost millions of dollars and take decades to complete using current validated methods. High-throughput in vitro screening (HTS) and computational toxicology approaches can more rapidly and inexpensively identify potential androgen-active chemicals. We integrated 11 HTS ToxCast/Tox21 in vitro assays into a computational network model to distinguish true AR pathway activity from technology-specific assay interference. The in vitro HTS assays probed perturbations of the AR pathway at multiple points (receptor binding, coregulator recruitment, gene transcription, and protein production) and multiple cell types. Confirmatory in vitro antagonist assay data and cytotoxicity information were used as additional flags for potential nonspecific activity. Validating such alternative testing strategies requires high-quality reference data. We compiled 158 putative androgen-active and -inactive chemicals from a combination of international test method validation efforts and semiautomated systematic literature reviews. Detailed in vitro assay information and results were compiled into a single database using a standardized ontology. Reference chemical concentrations that activated or inhibited AR pathway activity were identified to establish a range of potencies with reproducible reference chemical results. Comparison with existing Tier 1 AR binding data from the U.S. EPA Endocrine Disruptor Screening Program revealed that the model identified binders at relevant test concentrations (<100 μM) and was more sensitive to antagonist activity. The AR pathway model based on the ToxCast/Tox21 assays had balanced accuracies of 95.2% for agonist (<i>n</i> = 29) and 97.5% for antagonist (<i>n</i> = 28) reference chemicals. Out of 1855 chemicals screened in the AR pathway model, 220 chemicals demonstrated AR agonist or antagonist activity and an additional 174 chemicals were predicted to have potential weak AR pathway activity