PKG oxidation at Cys42 amplifies mTORC1 activation to worsen hypertrophic heart disease

Rationale Protein kinase G-1a (PKG1a) phosphorylation of tuberous sclerosis complex 2 (TSC2, or tuberin) at serine 1365 (S1365) potently suppresses mTORC1 activation. This results in greater autophagy and limits pathological hypertrophy myocytes and the heart. Cardiac stress also induce oxidation of PKG1a between cysteine 42 residues in homo-monomers, which reduces cardioprotection. Objective We tested the hypothesis that pathological mTORC1 activation is potently amplified by concomitant PKG1a C42-oxidation, and that this is countered by stimulating soluble guanylyl cyclase-1 (GC-1). Methods and results In mice expressing only C42-redox inhibited PKG1a (PKG1aCS), pressure-overload (PO) induces markedly less mTORC1 activation, increasing autophagic flux and reducing protein aggregation, hypertrophy, and dysfunction compared to PO in PKG1aWT mice. Similar results were obtained in cardiomyocytes exposed to endothelin-1. Protection against PO in PKG1aCS mice was similar to PKG1aWT co-treated with the mTORC1-inhibitor everolimus. TSC2 S1365 phosphorylation increased more in PKG1aCS than PKG1aWT myocardium after PO. Knock-in mice with TSC2 S1365A and PKG1aCS mutations, to prevent TSC2 phosphorylation by PKG1a displayed amplified mTORC1, cardiodepression, and mortality after PO as compared to PKG1aCS. Lastly, the marked disparity between PKG1aWT and PKG1aCS PO phenotype for TSC2 S1365 phosphorylation, mTORC1 activation, and cardiac dysfunction is overcome by BAY-602770, a direct stimulator of GC-1. Conclusion Oxidant-induced PKG1a C42 dimerization blunts its attenuation of mTORC1 activity by reducing TSC2 S1365 phosphorylation, thereby contributing to inadequate autophagy and worsened hypertrophic dysfunction. This is ameliorated by direct GC-1 stimulation. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): DFG

Conclusion

Previous works, notably by David Fitzpatrick, have stressed the concept of a ‘collective sacrifice’ in Ireland during the First World War. However, it is clear that, in Ireland, there was a marked disparity of sacrifice. Disparities are clear between Ulster and the South and West of Ireland, urban and rural Ireland and between Ireland and Great Britain. Much of the recruitment in Ireland was heavily politicised, especially in the opening months of the war, relying on the Irish National Volunteers and Ulster Volunteer Force. While in GB ‘Pals’ units mobilised skilled working class and middle class recruits, remarkably few of these were formed in Ireland. British Dominion Forces contained many of those who could be considered Irish; however, very few, if any, of these men were recruited in Ireland itself. British recruiting propaganda remained amateurish until the Summer of 1918.

Reassessment of the Triassic archosauriform Scleromochlus taylori: neither runner nor biped, but hopper

The six known specimens of Scleromochlus taylori and casts made from their negative impressions were examined to reassess the osteological evidence that has been used to interpret Scleromochlus’s locomotion and phylogenetic relationships. It was found that the trunk was dorsoventrally compressed. The upper temporal fenestra was on the lateral surface of skull and two-thirds the size of the lower, the jaw joint posteriorly placed with short retroarticular process, and teeth short and subconical, but no evidence of external nares or antorbital fossae was found. The posterior trunk was covered with ~20 rows of closely spaced transversely elongate dorsal osteoderms. The coracoid was robust and elongate. The acetabulum was imperforate and the femoral head hemispherical and only weakly inturned such that the hip joint was unsuited to swinging in a parasagittal plane. The presence of four distal tarsals is confirmed. The marked disparity of tibial and fibular shaft diameters and of proximal tarsal dimensions indicates that the larger proximal tarsal is the astragalus and the significantly smaller tarsal is the calcaneum. The astragalus and calcaneum bear little resemblance to those of Lagosuchus, and the prominent calcaneal tuber confirms that the ankle was crurotarsal. There is no evidence that preserved body and limb postures are unnatural, and most specimens are preserved in what is interpreted as a typical sprawling resting pose. A principal component analysis of skeletal measurements of Scleromochlus and other vertebrates of known locomotor type found Scleromochlus to plot with frogs, and that finding combined with skeletal morphology suggests Scleromochlus was a sprawling quadrupedal hopper. Phylogenetic analyses found that Scleromochlus was not an ornithodiran, but was either within the Doswelliidae or outside the clade consisting of the most recent common ancestor of the Erythrosuchidae and Archosauria and all its descendants.

Labor market and management of gender based decision making

Improving gender equality in decision-making is a very important issue in a country's economic development. The main purpose of the research is to analyze the level of central level decision making and the alignment of the labor market at Kosovo level on gender basis. Also, this paper presents a theoretical focus on the role of decision making for a better service and the possible management of gender equality counseling programs in the economic, political and social spheres. Kosovo continues to face challenges as well as a marked disparity in women's disadvantage in regards to managing the gender-based decision-making process at both the central and the local level. Although there are laws that stimulate gender equality, the position of women in decision-making in public life in terms of contributing to economic, political and social development endeavors are lacking their increase in participation and decision-making at both central and local levels.

1950s vibe, 21st century audience: Australia’s dearth of on-screen diversity

The difference between how multicultural Australia is ‘in real life’ and ‘in broadcasting’ can be seen through data from the Census, and from Screen Australia’s most recent research into on screen diversity. In 2016, these sources of data coincided with the Census, which takes place every five years. Conducted by the Australian Bureau of Statistics, this presents a ‘snapshot’ of Australian life. From the newest Census figures in 2016, it appears that nearly half of the population in Australia (49 percent) had either been born overseas (identifying as first generation Australian) or had one or both parents born overseas (identifying as second generation Australian). Nearly a third, or 32 percent, of Australians identified as having come from non-Anglo Celtic backgrounds, and 2.8 percent of Australians identify as Indigenous (Aboriginal or Torres Strait Islander). Nearly a fifth, or 18 percent, of Australians identify as having a disability. Screen Australia is the government agency that oversees film and TV funding and research. Conducted in 2016, Screen Australia’s study looked at 199 television dramas (fiction, excluding animation) that aired between 2011 and 2015. The comparison between these two sources of data reveals that with one exception, there is a marked disparity between diversity as depicted in the lived experiences of Australians and recorded by the Census, and diversity as depicted on screen and recorded by the Screen Australia survey.

Dispute Settlement Mechanisms in U.S. FTAs with Korea, Panama, Peru and Colombia: Basic Designs, Key Characteristics and Implications

The United States concluded free trade agreements (FTAs) with Korea, Peru, Panama and Colombia in late 2000s. Since the four FTAs were negotiated and concluded largely contemporaneously, key traits and characteristics of the agreements are similarly formulated. In light of this, dispute settlement mechanisms (state-to-state dispute settlement proceedings, investor-state dispute settlement proceedings, and Joint Committees) of the four FTAs also share commonalities. At the same time, new ideas and suggestions are explored in the four FTAs. While issues and disputes under the four FTAs have arguably not been ripe for the constitution of dispute settlement proceedings under the FTAs at the moment, sooner or later they are likely to end up in the dockets of the respective proceedings. The key elements of the four FTAs’ dispute settlement mechanisms are also adopted in other FTAs that the United States have concluded afterwards including most recently the Trans-Pacific Partnership, since these elements are reflective of the general scheme of the United States in their FTAs. What remains to be seen is how the general scheme of dispute settlement proceedings can be applied and implemented in actual settings when the FTAs produce increasing numbers of disputes in the future. In particular, marked disparity in human and financial resources between the United States and the four FTA’s parties may bring about disparate impacts and consequences among contracting parties. Continued attention needs to be paid to the development concerning implementation of the four FTAs, in particular their dispute settlement proceedings.

Differential toxicity of Pb & Hg on the development of modular traits, photosynthetic and biochemical attributes in two varieties of a forage crop species Trifolium alexandrinum L.

Heavy metal stress as result of natural and anthropogenic activities is main environmental problem. Pb and Hg are among non-biodegradable metals thus remaining persistent in soil and water. The present study was carried out to assess growth and biochemical responses of two varieties (Desi and Misri) of Trifolium alexandrinum L. after application of varying levels (25mg/kg, 50mg/kg and 100mg/kg) of Pb and Hg in soil along with control. Seed germination, biomass of above and below ground tissues, number of flowers and leaves, leaf area and nodulation was observed. For biochemical attributes, green pigments, protein and amino acids, were determined. Both varieties (Desi and Misri) showed variable responses in relation to both Pb and Hg. Similarly, the pattern of character expression was independent for metal levels and types. Misri performed consistently better as it showed best threshold for most of the attributes studied. Hg was found to be more toxic as compared to the Pb as it induced more drastic decline in parameters studied. The study showed that biometric traits can be used as good predictors and the biochemical parameters cannot be used as useful biochemical markers as they showed no marked disparity.