Drosophila insulin and target of rapamycin (TOR) pathways regulate GSK3 beta activity to control Myc stability and determine Myc expression in vivo

<p>Abstract</p> <p>Background</p> <p>Genetic studies in <it>Drosophila melanogaster </it>reveal an important role for Myc in controlling growth. Similar studies have also shown how components of the insulin and target of rapamycin (TOR) pathways are key regulators of growth. Despite a few suggestions that Myc transcriptional activity lies downstream of these pathways, a molecular mechanism linking these signaling pathways to Myc has not been clearly described. Using biochemical and genetic approaches we tried to identify novel mechanisms that control Myc activity upon activation of insulin and TOR signaling pathways.</p> <p>Results</p> <p>Our biochemical studies show that insulin induces Myc protein accumulation in <it>Drosophila </it>S2 cells, which correlates with a decrease in the activity of glycogen synthase kinase 3-beta (GSK3<it>β </it>) a kinase that is responsible for Myc protein degradation. Induction of Myc by insulin is inhibited by the presence of the TOR inhibitor rapamycin, suggesting that insulin-induced Myc protein accumulation depends on the activation of TOR complex 1. Treatment with amino acids that directly activate the TOR pathway results in Myc protein accumulation, which also depends on the ability of S6K kinase to inhibit GSK3<it>β </it>activity. Myc upregulation by insulin and TOR pathways is a mechanism conserved in cells from the wing imaginal disc, where expression of Dp110 and Rheb also induces Myc protein accumulation, while inhibition of insulin and TOR pathways result in the opposite effect. Our functional analysis, aimed at quantifying the relative contribution of Myc to ommatidial growth downstream of insulin and TOR pathways, revealed that Myc activity is necessary to sustain the proliferation of cells from the ommatidia upon Dp110 expression, while its contribution downstream of TOR is significant to control the size of the ommatidia.</p> <p>Conclusions</p> <p>Our study presents novel evidence that Myc activity acts downstream of insulin and TOR pathways to control growth in <it>Drosophila</it>. At the biochemical level we found that both these pathways converge at GSK3<it>β </it>to control Myc protein stability, while our genetic analysis shows that insulin and TOR pathways have different requirements for Myc activity during development of the eye, suggesting that Myc might be differentially induced by these pathways during growth or proliferation of cells that make up the ommatidia.</p

Overestimate of Committed Warming

Palaeoclimate variations are an essential component in constraining future projections of climate change as a function of increasing anthropogenic greenhouse gases. The Earth System Sensitivity (ESS) describes the multi-millennial response of Earth (in terms of global mean temperature) to a doubling of CO2 concentrations. A recent study used a correlation of inferred temperatures and radiative forcing from greenhouse gases over the past 800,000 years to estimate the ESS from present day CO2 is about 9 degrees C, and to imply a long-term commitment of 3-7 degrees C even if greenhouse gas levels remain at present-day concentrations. However, we demonstrate that the methodology of ref. 2 does not reliably estimate the ESS in the presence of orbital forcing of ice age cycles and therefore conclude that the inferred present-day committed warming is considerably overestimated

Reflections on a crisis: political disenchantment, moral desolation, and political integrity

Declining levels of political trust and voter turnout, the shift towards populist politics marked by appeals to ‘the people’ and a rejection of ‘politics-as-usual’, are just some of the commonly cited manifestations of our culture of political disaffection. Democratic politics, it is argued, is in crisis. Whilst considerable energy has been expended on the task of lamenting the status of our politics and pondering over recommendations to tackle this perceived crisis, amid this raft of complaints and solutions lurks confusion. This paper seeks to explore the neglected question of what the precise nature of the crisis with which we are confronted involves, and, in so doing, to go some way towards untangling our confusion. Taking my cue from Machiavelli and his value-pluralist heirs, I argue that there is a rift between a morally admirable and a virtuous political life. Failure to appreciate this possibility causes narrations of crisis to misconstrue the moral messiness of politics in ways that lead us to misunderstand how we should respond to disenchantment. Specifically, I suggest that: (i) we think that there is a moral crisis in politics because we have an unsatisfactorily idealistic understanding of political integrity in the first place; and (ii) it is a mistake to imagine that the moral purification of politics is possible or desirable. Put simply, our crisis is not moral per se but primarily philosophical in nature: it relates to the very concepts we employ—the qualities of character and context we presuppose whilst pondering over political integrity

Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Overestimate of committed warming.

Palaeoclimate variations are an essential component in constraining future projections of climate change as a function of increasing anthropogenic greenhouse gases. The Earth System Sensitivity (ESS) describes the multi-millennial response of Earth (in terms of global mean temperature) to a doubling of CO2 concentrations. A recent study used a correlation of inferred temperatures and radiative forcing from greenhouse gases over the past 800,000 years to estimate the ESS from present day CO2 is about 9°C, and to imply a long-term commitment of 3–7°C even if greenhouse gas levels remain at present-day concentrations. However, we demonstrate that the methodology of ref. does not reliably estimate the ESS in the presence of orbital forcing of ice age cycles and therefore conclude that the inferred present-day committed warming is considerably overestimated. There is a Reply to this Comment by Snyder, C. W. Nature 547, http://dx.doi.org/10.1038/nature22804 (2017)