Exendin-4 stimulates autophagy in pancreatic β-cells via the RAPGEF/EPAC-Ca PPP3/calcineurin-TFEB axis

Macroautophagy/autophagy is critical for the regulation of pancreatic β-cell mass and its deregulation has been implicated in the pathogenesis of type 2 diabetes (T2D). We have previously shown that treatment of pancreatic β-cells with the GLP1R (glucagon like peptide 1 receptor) agonist exendin-4 stimulates autophagic flux in a setting of chronic nutrient excess. The aim of this study was to identify the underlying pathways contributing to enhanced autophagic flux.Pancreatic β-cells (INS-1E),mouse and human islets were treated with glucolipotoxic stress (0.5 mM palmitate and 25 mM glucose) in the presence of exendin-4. Consistent with our previous work, exendin-4 stimulated autophagic flux. Using chemical inhibitors and siRNA knockdown, we identified RAPGEF4/EPAC2 (Rap guanine nucleotide exchange factor 4) and downstream calcium signaling to be essential for regulation of autophagic flux by exendin-4. This pathway was independent of AMPK and MTOR signaling. Further analysis identified PPP3/calcineurin and its downstream regulator TFEB (transcription factor EB) as key proteins mediating exendin-4 induced autophagy. Importantly, inhibition of this pathway prevented exendin-4-mediated cell survival and overexpression of TFEB mimicked the cell protective effects of exendin-4 in INS-1E and human islets. Moreover, treatment of db/db mice with exendin-4 for 21 days increased the expression of lysosomal markers within the pancreatic islets. Collectively our data identify the RAPGEF4/EPAC2-calcium-PPP3/calcineurin-TFEB axis as a key mediator of autophagic flux, lysosomal function and cell survival in pancreatic β-cells. Pharmacological modulation of this axis may offer a novel therapeutic target for the treatment of T2D.Abbreviations: AKT1/protein kinase B: AKT serine/threonine kinase 1; AMPK: 5' AMP-activated protein kinase; CAMKK: calcium/calmodulin-dependent protein kinase kinase; cAMP: cyclic adenosine monophosphate; CASP3: caspase 3; CREB: cAMP response element-binding protein; CTSD: cathepsin D; Ex4: exendin-4(1-39); GLP-1: glucagon like peptide 1; GLP1R: glucagon like peptide 1 receptor; GLT: glucolipotoxicity; INS: insulin; MTOR: mechanistic target of rapamycin kinase; NFAT: nuclear factor of activated T-cells; PPP3/calcineurin: protein phosphatase 3; PRKA/PKA: protein kinase cAMP activated; RAPGEF3/EPAC1: Rap guanine nucleotide exchange factor 3; RAPGEF4/EPAC2: Rap guanine nucleotide exchange factor 4; SQSTM1/p62: sequestosome 1; T2D: type 2 diabetes; TFEB: transcription factor EB

The performance of the jet trigger for the ATLAS detector during 2011 data taking

The performance of the jet trigger for the ATLAS detector at the LHC during the 2011 data taking period is described. During 2011 the LHC provided proton–proton collisions with a centre-of-mass energy of 7 TeV and heavy ion collisions with a 2.76 TeV per nucleon–nucleon collision energy. The ATLAS trigger is a three level system designed to reduce the rate of events from the 40 MHz nominal maximum bunch crossing rate to the approximate 400 Hz which can be written to offline storage. The ATLAS jet trigger is the primary means for the online selection of events containing jets. Events are accepted by the trigger if they contain one or more jets above some transverse energy threshold. During 2011 data taking the jet trigger was fully efficient for jets with transverse energy above 25 GeV for triggers seeded randomly at Level 1. For triggers which require a jet to be identified at each of the three trigger levels, full efficiency is reached for offline jets with transverse energy above 60 GeV. Jets reconstructed in the final trigger level and corresponding to offline jets with transverse energy greater than 60 GeV, are reconstructed with a resolution in transverse energy with respect to offline jets, of better than 4 % in the central region and better than 2.5 % in the forward direction

Effects of antenatal betamethasone on fetal Doppler indices and short term fetal heart rate variation in early growth restricted fetuses

Purpose To investigate the effects of the antenatal administration of betamethasone on fetal Doppler and short term fetal heart rate variation (CTG-STV) in early growth restricted (FGR) fetuses.Materials and Methods Post hoc analysis of data derived from the TRUFFLE study, a prospective, multicenter, randomized management trial of severe early onset FGR. Repeat Doppler and CTG-STV measurements between the last recording within 48 hours before the first dose of betamethasone (base-line value) and for 10 days after were evaluated. Multilevel analysis was performed to analyze the longitudinal course of the umbilico-cerebral ratio (UC ratio), the ductus venosus pulsatility index (DVPIV) and CTG-STV.Results We included 115 fetuses. A significant increase from baseline in CTG-STV was found on day + 1 (p = 0.019) but no difference thereafter. The DVPIV was not significantly different from baseline in any of the 10 days following the first dose of betamethasone (p = 0.167). Multilevel analysis revealed that, over 10 days, the time elapsed from antenatal administration of betamethasone was significantly associated with a decrease in CTG-STV (p = 0.045) and an increase in the DVPIV (p = 0.001) and UC ratio (p < 0.001).Conclusion Although steroid administration in early FGR has a minimal effect on increasing CTG-STV one day afterwards, the effects on Doppler parameters were extremely slight with regression coefficients of small magnitude suggesting no clinical significance, and were most likely related to the deterioration with time in FGR. Hence, arterial and venous Doppler assessment of fetal health remains informative following antenatal steroid administration to accelerate fetal lung maturation.Developmen

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 √s = 13 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

Search for boosted diphoton resonances in the 10 to 70 GeV mass range using 138 fb−1 of 13 TeV pp collisions with the ATLAS detector

A search for diphoton resonances in the mass range between 10 and 70 GeV with the ATLAS experiment at the Large Hadron Collider (LHC) is presented. The analysis is based on pp collision data corresponding to an integrated luminosity of 138 fb−1 at a centre-of-mass energy of 13 TeV recorded from 2015 to 2018. Previous searches for diphoton resonances at the LHC have explored masses down to 65 GeV, finding no evidence of new particles. This search exploits the particular kinematics of events with pairs of closely spaced photons reconstructed in the detector, allowing examination of invariant masses down to 10 GeV. The presented strategy covers a region previously unexplored at hadron colliders because of the experimental challenges of recording low-energy photons and estimating the backgrounds. No significant excess is observed and the reported limits provide the strongest bound on promptly decaying axion-like particles coupling to gluons and photons for masses between 10 and 70 GeV

Evidence for the charge asymmetry in pp → tt¯ production at s√ = 13 TeV with the ATLAS detector

Inclusive and differential measurements of the top–antitop (tt¯) charge asymmetry Att¯C and the leptonic asymmetry Aℓℓ¯C are presented in proton–proton collisions at s√ = 13 TeV recorded by the ATLAS experiment at the CERN Large Hadron Collider. The measurement uses the complete Run 2 dataset, corresponding to an integrated luminosity of 139 fb−1, combines data in the single-lepton and dilepton channels, and employs reconstruction techniques adapted to both the resolved and boosted topologies. A Bayesian unfolding procedure is performed to correct for detector resolution and acceptance effects. The combined inclusive tt¯ charge asymmetry is measured to be Att¯C = 0.0068 ± 0.0015, which differs from zero by 4.7 standard deviations. Differential measurements are performed as a function of the invariant mass, transverse momentum and longitudinal boost of the tt¯ system. Both the inclusive and differential measurements are found to be compatible with the Standard Model predictions, at next-to-next-to-leading order in quantum chromodynamics perturbation theory with next-to-leading-order electroweak corrections. The measurements are interpreted in the framework of the Standard Model effective field theory, placing competitive bounds on several Wilson coefficients

Search for single production of vector-like T quarks decaying into Ht or Zt in pp collisions at s√ = 13 TeV with the ATLAS detector

This paper describes a search for the single production of an up-type vector-like quark (T) decaying as T → Ht or T → Zt. The search utilises a dataset of pp collisions at s√ = 13 TeV collected with the ATLAS detector during the 2015–2018 data-taking period of the Large Hadron Collider, corresponding to an integrated luminosity of 139 fb−1. Data are analysed in final states containing a single lepton with multiple jets and b-jets. The presence of boosted heavy resonances in the event is exploited to discriminate the signal from the Standard Model background. No significant excess above the Standard Model expectation is observed, and 95% CL upper limits are set on the production cross section of T quarks in different decay channels. The results are interpreted in several benchmark scenarios to set limits on the mass and universal coupling strength (κ) of the vector-like quark. For singlet T quarks, κ values above 0.53 are excluded for all masses below 2.3 TeV. At a mass of 1.6 TeV, κ values as low as 0.35 are excluded. For T quarks in the doublet scenario, where the production cross section is much lower, κ values above 0.72 are excluded for all masses below 1.7 TeV, and this exclusion is extended to κ above 0.55 for low masses around 1.0 TeV

Search for excited τ-leptons and leptoquarks in the final state with τ-leptons and jets in pp collisions at s√ = 13 TeV with the ATLAS detector

A search is reported for excited τ-leptons and leptoquarks in events with two hadronically decaying τ-leptons and two or more jets. The search uses proton-proton (pp) collision data at s√ = 13 TeV recorded by the ATLAS experiment during the Run 2 of the Large Hadron Collider in 2015–2018. The total integrated luminosity is 139 fb−1. The excited τ-lepton is assumed to be produced and to decay via a four-fermion contact interaction into an ordinary τ-lepton and a quark-antiquark pair. The leptoquarks are assumed to be produced in pairs via the strong interaction, and each leptoquark is assumed to couple to a charm or lighter quark and a τ-lepton. No excess over the background prediction is observed. Excited τ-leptons with masses below 2.8 TeV are excluded at 95% CL in scenarios with the contact interaction scale Λ set to 10 TeV. At the extreme limit of model validity where Λ is set equal to the excited τ-lepton mass, excited τ-leptons with masses below 4.6 TeV are excluded. Leptoquarks with masses below 1.3 TeV are excluded at 95% CL if their branching ratio to a charm quark and a τ-lepton equals 1. The analysis does not exploit flavour-tagging in the signal region

Measurement of the cross-sections of the electroweak and total production of a Zγ pair in association with two jets in pp collisions at √s = 13 TeV with the ATLAS detector

This Letter presents the measurement of the fiducial and differential cross-sections of the electroweak production of a Zγ pair in association with two jets. The analysis uses 140 fb−1 of LHC proton–proton collision data taken at √s = 13 TeV recorded by the ATLAS detector during the years 2015–2018. Events with a Z boson candidate decaying into either an e+e− or μ+μ− pair, a photon and two jets are selected. The electroweak component is extracted by requiring a large dijet invariant mass and by using the information about the centrality of the system and is measured with an observed and expected significance well above five standard deviations. The fiducial pp → Zγ jj cross-section for the electroweak production is measured to be 3.6 ± 0.5 fb. The total fiducial cross-section that also includes contributions where the jets arise from strong interactions is measured to be 16.8+2.0 −1.8 fb. The results are consistent with the Standard Model predictions. Differential cross-sections are also measured using the same events and are compared with parton-shower Monte Carlo simulations. Good agreement is observed between data and predictions

Search for heavy resonances decaying into a Z or W boson and a Higgs boson in final states with leptons and b-jets in 139 fb−1 of pp collisions at s√ = 13 TeV with the ATLAS detector

This article presents a search for new resonances decaying into a Z or W boson and a 125 GeV Higgs boson h, and it targets the νν¯¯¯bb¯¯, ℓ+ℓ−bb¯¯, or ℓ±νbb¯¯ final states, where ℓ = e or μ, in proton-proton collisions at s√ = 13 TeV. The data used correspond to a total integrated luminosity of 139 fb−1 collected by the ATLAS detector during Run 2 of the LHC at CERN. The search is conducted by examining the reconstructed invariant or transverse mass distributions of Zh or Wh candidates for evidence of a localised excess in the mass range from 220 GeV to 5 TeV. No significant excess is observed and 95% confidence-level upper limits between 1.3 pb and 0.3 fb are placed on the production cross section times branching fraction of neutral and charged spin-1 resonances and CP-odd scalar bosons. These limits are converted into constraints on the parameter space of the Heavy Vector Triplet model and the two-Higgs-doublet model