Wnt11/Fzd7 signaling compartmentalizes AKAP2/PKA to regulate L-type Ca2+ channel

Calcium influx through the voltage-gated L-type calcium channels (LTCC) mediates a wide range of physiological processes from contraction to secretion. Despite extensive research on regulation of LTCC conductance by PKA phosphorylation in response to β-adrenergic stimulation, the science remains incomplete. Here, we show that Wnt11, a non-canonical Wnt ligand, through its G protein-coupled receptor (GPCR) Fzd7 attenuates the LTCC conductance by preventing the proteolytic processing of its C terminus. This is mediated across species by protein kinase A (PKA), which is compartmentalized by A-kinase anchoring proteins (AKAP). Systematic analysis of all AKAP family members revealed AKAP2 anchoring of PKA is central to the Wnt11-dependent regulation of the channel. The identified Wnt11/AKAP2/PKA signalosome is required for heart development, controlling the intercellular electrical coupling in the developing zebrafish heart. Altogether, our data revealed Wnt11/Fzd7 signaling via AKAP2/PKA as a conserved alternative GPCR system regulating Ca(2+) homeostasis

Income redistribution in the European Union

We explore the redistributive effects of taxes and benefits in the 27 member states of the European Union (EU) using EUROMOD, the tax-benefit microsimulation model for the EU. As well as describing redistributive effects in aggregate, we assess and compare the effectiveness of eight individual types of policy in reducing income disparities. We derive results for the 27 members of the EU using policies in effect in 2010 and present them for each country separately as well as for the EU as a whole

Understanding and meeting the needs of those using growth hormone injection devices

BACKGROUND: Recombinant human growth hormone (r-hGH) is used to treat: growth hormone deficiency in children and adults; children born small for gestational age; Turner's syndrome; and chronic renal failure. r-hGH is administered by daily subcutaneous injection and may be given using a number of different administration devices. The aim of this survey was, firstly, to identify which attributes of an r-hGH administration device are considered most important to physicians, teenage patients, parents of young children requiring GH and nurses who have experience of r-hGH administration, and, secondly, to determine how they rate existing devices in each of these key attributes. METHODS: The opinions of 67 individuals with experience in r-hGH administration were captured in discussion sessions. Parents, physicians and nurses were asked to rate 19 device attributes by completing a questionnaire, and to rank four different r-hGH administration devices (including a conceptual electronic device) in order of preference. RESULTS: Reliability, ease of use, lack of pain during injection, safety in use, storage, and number of steps in preparation before use, during use and after were considered to be the five most desirable attributes of an r-hGH administration device. An electronic device was preferred to an automatic, multi-dose injection device, a needle-free injection device or a manual, ready-to-use, disposable injection device. CONCLUSION: In the opinion of physicians, nurses and parents using r-hGH injection devices, an ideal device must combine reliability with simplicity, while delivering treatment with minimal pain. An electronic device, which combines many of the most useful features of existing devices with novel functions, was the preferred option for r-hGH administration

The Alvarez impact theory of mass extinction; limits to its applicability and the „great expectations syndrome”

For the past three decades, the Alvarez impact theory of mass extinction, causally related to catastrophic meteorite impacts, has been recurrently applied to multiple extinction boundaries. However, these multidisciplinary research efforts across the globe have been largely unsuccessful to date, with one outstanding exception: the Cretaceous-Paleogene boundary. The unicausal impact scenario as a leading explanation, when applied to the complex fossil record, has resulted in force-fitting of data and interpretations ("great expectations syndrome". The misunderstandings can be grouped at three successive levels of the testing process, and involve the unreflective application of the impact paradigm: (i) factual misidentification, i.e., an erroneous or indefinite recognition of the extraterrestrial record in sedimentological, physical and geochemical contexts, (ii) correlative misinterpretation of the adequately documented impact signals due to their incorrect dating, and (iii) causal overestimation when the proved impact characteristics are doubtful as a sufficient trigger of a contemporaneous global cosmic catastrophe. Examples of uncritical belief in the simple cause-effect scenario for the Frasnian-Famennian, Permian-Triassic, and Triassic-Jurassic (and the Eifelian-Givetian and Paleocene-Eocene as well) global events include mostly item-1 pitfalls (factual misidentification), with Ir enrichments and shocked minerals frequently misidentified. Therefore, these mass extinctions are still at the first test level, and only the F-F extinction is potentially seen in the context of item-2, the interpretative step, because of the possible causative link with the Siljan Ring crater (53 km in diameter). The erratically recognized cratering signature is often marked by large timing and size uncertainties, and item-3, the advanced causal inference, is in fact limited to clustered impacts that clearly predate major mass extinctions. The multi-impact lag-time pattern is particularly clear in the Late Triassic, when the largest (100 km diameter) Manicouagan crater was possibly concurrent with the end-Carnian extinction (or with the late Norian tetrapod turnover on an alternative time scale). The relatively small crater sizes and cratonic (crystalline rock basement) setting of these two craters further suggest the strongly insufficient extraterrestrial trigger of worldwide environmental traumas. However, to discuss the kill potential of impact events in a more robust fashion, their location and timing, vulnerability factors, especially target geology and palaeogeography in the context of associated climate-active volatile fluxes, should to be rigorously assessed. The current lack of conclusive impact evidence synchronous with most mass extinctions may still be somewhat misleading due to the predicted large set of undiscovered craters, particularly in light of the obscured record of oceanic impact events

SHIRAZ: an automated histology image annotation system for zebrafish phenomics

Histological characterization is used in clinical and research contexts as a highly sensitive method for detecting the morphological features of disease and abnormal gene function. Histology has recently been accepted as a phenotyping method for the forthcoming Zebrafish Phenome Project, a large-scale community effort to characterize the morphological, physiological, and behavioral phenotypes resulting from the mutations in all known genes in the zebrafish genome. In support of this project, we present a novel content-based image retrieval system for the automated annotation of images containing histological abnormalities in the developing eye of the larval zebrafish

The X-inactivation trans-activator Rnf12 is negatively regulated by pluripotency factors in embryonic stem cells

X-inactivation, the molecular mechanism enabling dosage compensation in mammals, is tightly controlled during mouse early embryogenesis. In the morula, X-inactivation is imprinted with exclusive silencing of the paternally inherited X-chromosome. In contrast, in the post-implantation epiblast, X-inactivation affects randomly either the paternal or the maternal X-chromosome. The transition from imprinted to random X-inactivation takes place in the inner cell mass (ICM) of the blastocyst from which embryonic stem (ES) cells are derived. The trigger of X-inactivation, Xist, is specifically downregulated in the pluripotent cells of the ICM, thereby ensuring the reactivation of the inactive paternal X-chromosome and the transient presence of two active X-chromosomes. Moreover, Tsix, a critical cis-repressor of Xist, is upregulated in the ICM and in ES cells where it imposes a particular chromatin state at the Xist promoter that ensures the establishment of random X-inactivation upon differentiation. Recently, we have shown that key transcription factors supporting pluripotency directly repress Xist and activate Tsix and thus couple Xist/Tsix control to pluripotency. In this manuscript, we report that Rnf12, a third X-linked gene critical for the regulation of X-inactivation, is under the control of Nanog, Oct4 and Sox2, the three factors lying at the heart of the pluripotency network. We conclude that in mouse ES cells the pluripotency-associated machinery exerts an exhaustive control of X-inactivation by taking over the regulation of all three major regulators of X-inactivation: Xist, Tsix, and Rnf12

ACE Inhibition and Endothelial Function: Main Findings of PERFECT, a Sub-Study of the EUROPA Trial

Background: ACE inhibition results in secondary prevention of coronary artery disease (CAD) through different mechanisms including improvement of endothelial dysfunction. The Perindopril-Function of the Endothelium in Coronary artery disease Trial (PERFECT) evaluated whether long-term administration of perindopril improves endothelial dysfunction. Methods: PERFECT is a 3-year double blind randomised placebo controlled trial to determine the effect of perindopril 8 mg once daily on brachial artery endothelial function in patients with stable CAD without clinical heart failure. Endothelial function in response to ischaemia was assessed using ultrasound. Primary endpoint was difference in flow-mediated vasodilatation (FMD) assessed at 36 months. Results: In 20 centers, 333 patients randomly received perindopril or matching placebo. Ischemia-induced FMD was 2.7% (SD 2.6). In the perindopril group FMD went from 2.6% at baseline to 3.3% at 36 months and in the placebo group from 2.8 to 3.0%. Change in FMD after 36 month treatment was 0.55% (95% confidence interval −0.36, 1.47; p = 0.23) higher in perindopril than in placebo group. The rate of change in FMD per 6 months was 0.14% (SE 0.05, p = 0.02) in perindopril and 0.02% (SE 0.05, p = 0.74) in placebo group (0.12% difference in rate of change p = 0.07). Conclusion: Perindopril resulted in a modest, albeit not statistically significant, improvement in FMD