mTOR signaling in proteostasis and its relevance to autism spectrum disorders

Proteins are extremely labile cellular components, especially at physiological temperatures. The appropriate regulation of protein levels, or proteostasis, is essential for all cells. In the case of highly polarized cells like neurons, proteostasis is also crucial at synapses, where quick confined changes in protein composition occur to support synaptic activity and plasticity. The accurate regulation of those cellular processes controlling protein synthesis and degradation is necessary for proteostasis, and its deregulation has deleterious consequences in brain function. Alterations in those cellular mechanisms supporting synaptic protein homeostasis have been pinpointed in autism spectrum disorders such as tuberous sclerosis, neurofibromatosis 1, PTEN-related disorders, fragile X syndrome, MECP2 disorders and Angelman syndrome. Proteostasis alterations in these disorders share the alterations in mechanistic/mammalian target of rapamycin (mTOR) signaling pathway, an intracellular pathway with key synaptic roles. The aim of the present review is to describe the recent literature on the major cellular mechanisms involved in proteostasis regulation in the synaptic context, and its association with mTOR signaling deregulations in various autism spectrum disorders. Altogether, the cellular and molecular mechanisms in synaptic proteostasis could be the foundation for novel shared therapeutic strategies that would take advantage of targeting common disorder mechanisms.This review was supported by grant BFU2015-68568-P (MINECO/FEDER, EU) to AO

Redox regulation of immunometabolism

Metabolic pathways and redox reactions are at the core of life. In the past decade(s), numerous discoveries have shed light on how metabolic pathways determine the cellular fate and function of lymphoid and myeloid cells, giving rise to an area of research referred to as immunometabolism. Upon activation, however, immune cells not only engage specific metabolic pathways but also rearrange their oxidation–reduction (redox) system, which in turn supports metabolic reprogramming. In fact, studies addressing the redox metabolism of immune cells are an emerging field in immunology. Here, we summarize recent insights revealing the role of reactive oxygen species (ROS) and the differential requirement of the main cellular antioxidant pathways, including the components of the thioredoxin (TRX) and glutathione (GSH) pathways, as well as their transcriptional regulator NF-E2-related factor 2 (NRF2), for proliferation, survival and function of T cells, B cells and macrophages. © Springer Nature Limited 2020.ISSN:1474-1733ISSN:1471-173

Search for heavy long-lived multi-charged particles in the full LHC Run 2 pp collision data at s = 13 TeV using the ATLAS detector

A search for heavy long-lived multi-charged particles is performed using the ATLAS detector at the LHC. Data collected in 2015–2018 at √s = 13 TeV from pp collisions corresponding to an integrated luminosity of 139 fb−1 are examined. Particles producing anomalously high ionization, consistent with long-lived spin-½ massive particles with electric charges from |q| = 2e to |q| = 7e are searched for. No statistically significant evidence of such particles is observed, and 95% confidence level cross-section upper limits are calculated and interpreted as the lower mass limits for a Drell–Yan plus photon-fusion production mode. The least stringent limit, 1060 GeV, is obtained for |q| = 2e particles, and the most stringent one, 1600 GeV, is for |q| = 6e particles

Anomaly detection search for new resonances decaying into a Higgs boson and a generic new particle X in hadronic final states using s=13 TeV pp collisions with the ATLAS detector

A search is presented for a heavy resonance Y decaying into a Standard Model Higgs boson H and a new particle X in a fully hadronic final state. The full Large Hadron Collider run 2 dataset of proton-proton collisions at..

Search for the Zγ decay mode of new high-mass resonances in pp collisions at s = 13 TeV with the ATLAS detector

This letter presents a search for narrow, high-mass resonances in the Zγ final state with the Z boson decaying into a pair of electrons or muons. The TeV pp collision data were recorded by the ATLAS detector at the CERN Large Hadron Collider and have an integrated luminosity of 140 fb−1. The data are found to be in agreement with the Standard Model background expectation. Upper limits are set on the resonance production cross section times the decay branching ratio into Zγ. For spin-0 resonances produced via gluon–gluon fusion, the observed limits at 95% confidence level vary between 65.5 fb and 0.6 fb, while for spin-2 resonances produced via gluon–gluon fusion (or quark–antiquark initial states) limits vary between 77.4 (76.1) fb and 0.6 (0.5) fb, for the mass range from 220 GeV to 3400 GeV

Tools for estimating fake/non-prompt lepton backgrounds with the ATLAS detector at the LHC

International audienceMeasurements and searches performed with the ATLAS detector at the CERN LHC often involve signatures with one or more prompt leptons. Such analysesare subject to `fake/non-prompt' lepton backgrounds, where either a hadron or a lepton from a hadron decay or an electron from a photon conversion satisfies the prompt-leptonselection criteria. These backgrounds often arise within a hadronic jet because of particle decays in the showering process, particle misidentification or particleinteractions with the detector material. As it is challenging to model these processes with high accuracy in simulation, their estimation typically uses data-driven methods.Three methods for carrying out this estimation are described, along with their implementation in ATLAS and their performance