Laforin, a dual specificity protein phosphatase involved in Lafora disease, is phosphorylated at Ser25 by AMP-activated protein kinase

Carlos Romá-Mateo et alt.Lafora progressive myoclonus epilepsy [LD (Lafora disease)] is a fatal autosomal recessive neurodegenerative disorder caused by loss-of-function mutations in either the EPM2A gene, encoding the dual-specificity phosphatase laforin, or the EPM2B gene, encoding the E3-ubiquitin ligase malin. Previously, we and others showed that laforin and malin form a functional complex that regulates multiple aspects of glycogen metabolism, and that the interaction between laforin and malin is enhanced by conditions activating AMPK (AMP-activated protein kinase). In the present study, we demonstrate that laforin is a phosphoprotein, as indicated by two-dimensional electrophoresis, and we identify Ser25 as the residue involved in this modification. We also show that Ser25 is phosphorylated both in vitro and in vivo by AMPK. Lastly, we demonstrate that this residue plays a critical role for both the phosphatase activity and the ability of laforin to interact with itself and with previously established binding partners. The results of the present study suggest that phosphorylation of laforin-Ser25 by AMPK provides a mechanism to modulate the interaction between laforin and malin. Regulation of this complex is necessary to maintain normal glycogen metabolism. Importantly, Ser25 is mutated in some LD patients (S25P), and our results begin to elucidate the mechanism of disease in these patientsThis work was supported the Spanish Ministry of Education and Science [grant number SAF2008-01907 (to P.S.)]; the Generalitat Valenciana [grant number Prometeo 2009/051 (to P.S.)]; the National Institutes of Health [grant numbers R00NS061803, P20RR020171, R01NS070899 (to M.S.G.)]; and the University of Kentucky College of Medicine startup funds (to M.S.G.)Peer reviewe

Predictors and prognosis of paroxysmal atrial fibrillation in general practice in the UK

BACKGROUND: Natural history of paroxysmal atrial fibrillation (AF) is not very well documented. Clinical experience suggests that paroxysmal AF could progress to chronic AF with estimates ranging between 15 and 30% over a period of 1–3 years. We performed an epidemiologic study to elucidate the natural history of paroxysmal AF, this study estimated its incidence in a general practice setting, identified associated factors and analyzed the progression into chronic AF as well as the mortality rate. METHODS: Using the UK General Practice Research Database (GPRD), we identified patients aged 40–89 years with a first-recorded episode of paroxysmal AF during 1996. Risk factors were assessed using 525 incident paroxysmal AF cases confirmed by the general practitioner (GP) and a random sample of controls. We follow-up paroxysmal AF patients and estimated their mortality rate and progression to chronic AF. RESULTS: The incidence of paroxysmal AF was 1.0 per 1,000 person-years. Major risk factors for paroxysmal AF were age and prior valvular heart disease, ischaemic heart disease, heart failure and hyperthyroidism. During a mean follow-up of 2.7 years, 70 of 418 paroxysmal AF patients with complete information progressed to chronic AF. Risk factors associated with progression were valvular heart disease (OR 2.7, 95% CI 1.2–6.0) and moderate to high alcohol consumption (OR 3.0, 95% CI 1.1–8.0). Paroxysmal AF patients did not carry an increased risk of mortality, compared to an age and sex matched sample of the general population. There was a suggestion of a small increased risk among patients progressing to chronic AF (RR 1.5, 96% CI 0.8–2.9). CONCLUSION: Paroxysmal AF is a common arrhythmia in the general practice setting, increasing with age and commonly associated with other heart diseases. It sometimes is the initial presentation and then progress to chronic AF. A history of valvular heart disease and alcohol consumption are associated with this progression

Endoscopic Intragastric Injection of Botulinum Toxin A in Obese Patients Accelerates Weight Loss after Bariatric Surgery: Follow-Up of a Randomised Controlled Trial (IntraTox Study)

Intragastric injection of botulinum toxin A (BT-A) has been shown to be effective for weight loss up to six months after administration, according to previous studies. Our objective was to determine, in patients on bariatric surgery waiting lists, the effect of BT-A on weight loss in the pre- and postoperative period and to analyse if there are different responses based on Body Mass Index (BMI). Methods: We performed a follow-up analysis of the IntraTox study, which included 46 patients on bariatric surgery waiting lists in a single-centre, randomised, double-blind, placebo-controlled clinical trial. The treatment group received intragastric BT-A, whereas the control group received physiological saline solution. The one-time procedure was performed at the time of diagnostic endoscopy 7–8 months before surgery. Weight loss was evaluated at admission and after 4 and 12 weeks from the bariatric surgery. Our analysis was stratified by BMI at randomisation. Results: weight loss percentage on the day of surgery, with respect to the initial visit, was −4.5 ± 3.9% for the control group vs. −7.6 ± 4.2%, for the treatment group (p = 0.013). Weight loss percentage tended to remain greater in the treatment group one month after the intervention (−12.7 ± 4.7% vs. −15.2 ± 4.6%, p = 0.07) and become similar three months after (−21.6 ± 4.7% vs. −21.6 ± 4.6%). After stratifying by BMI, only patients with BMI over 50 kg/m2 allocated to the treatment group obtained a greater weight loss at the end of the trial, the day of surgery, and one month after, compared with the placebo group (−4.9 ± 4.9%, −10.8 ± 5.3% and −17.1 ± 3.8% vs. −0.1 ± 2.6%, −4.3 ± 3.2% and −12.8 ± 4.1%, respectively (p < 0.05). Conclusions: intragastric injection of BT-A is effective to achieve significant weight loss, especially in extreme obesity. Its use before bariatric surgery enhances perioperative weight loss.Merz Pharma (Frankfurt am Main, Germany) collaborated with a non-restricted grant. The study was co-funded by the Sociedad Andaluza de Endocrinología, Diabetes y Nutrición (SAEDYN) and the Sociedad Andaluza de Nutrición, Clínica y Dietética (SANCYD). This research was supported by the Plataforma Española de Investigación Clínica y Ensayos Clínicos, SCReN (Spanish Clinical Research Network), funded by ISCIII-Subdirección General de Evaluación y Fomento de la Investigación, through the projects PT13/0002/0020 and PT17/0020, integrated in the Plan Estatal de I+D+I 2013-2016 and co-funded by the European Regional Development Fund (ERDF). Partial funding for open access charge: Universidad de Málag

A search for an unexpected asymmetry in the production of e(+)mu(-) and e(-)mu(+) pairs in proton-proton collisions recorded by the ATLAS detector at root s=13 TeV

This search, a type not previously performed at ATLAS, uses a comparison of the production cross sections for e(+)mu(-) and e(-)mu(+) pairs to constrain physics processes beyond the Standard Model. It uses 139 fb(-1) of proton-proton collision data recorded at root s = 13 TeV at the LHC. Targeting sources of new physics which prefer final states containing e(+)mu(-) and e(-)mu(+), the search contains two broad signal regions which are used to provide model-independent constraints on the ratio of cross sections at the 2% level. The search also has two special selections targeting supersymmetric models and leptoquark signatures. Observations using one of these selections are able to exclude, at 95% confidence level, singly produced smuons with masses up to 640 GeV in a model in which the only other light sparticle is a neutralino when the R-parity-violating coupling lambda(23)(1)' is close to unity. Observations using the other selection exclude scalar leptoquarks with masses below 1880 GeV when g(1R)(eu) = g(1R)(mu c) = 1, at 95% confidence level. The limit on the coupling reduces to g(1R)(eu) = g(1R)(mu c) = 0.46 for a mass of 1420 GeV

Search for tt¯ resonances in fully hadronic final states in pp collisions at √s = 13 TeV with the ATLAS detector

This paper presents a search for new heavy particles decaying into a pair of top quarks using 139 fb of proton-proton collision data recorded at a centre-of-mass energy of s = 13 TeV with the ATLAS detector at the Large Hadron Collider. The search is performed using events consistent with pair production of high-transverse-momentum top quarks and their subsequent decays into the fully hadronic final states. The analysis is optimized for resonances decaying into a tt¯ pair with mass above 1.4 TeV, exploiting a dedicated multivariate technique with jet substructure to identify hadronically decaying top quarks using large-radius jets and evaluating the background expectation from data. No significant deviation from the background prediction is observed. Limits are set on the production cross-section times branching fraction for the new Z′ boson in a topcolor-assisted-technicolor model. The Z′ boson masses below 3.9 and 4.7 TeV are excluded at 95% confidence level for the decay widths of 1% and 3%, respectively. [Figure not available: see fulltext.

ATLAS search for a heavy gauge boson decaying to a charged lepton and a neutrino in pp collisions at root s=7 TeV

The ATLAS detector at the LHC is used to search for high-mass states, such as heavy charged gauge bosons (W'), decaying to a charged lepton (electron or muon) and a neutrino. Results are presented based on the analysis of pp collisions at a center-of-mass energy of 7 TeV corresponding to an integrated luminosity of 4.7 fb(-1). No excess beyond Standard Model expectations is observed. A W' with Sequential Standard Model couplings is excluded at the 95 % credibility level for masses up to 2.55 TeV. Excited chiral bosons (W*) with equivalent coupling strength are excluded for masses up to 2.42 TeV

Evidence for the production of three massive vector bosons with the ATLAS detector

A search for the production of three massive vector bosons in proton–proton collisions is performed using data at s=13 TeV recorded with the ATLAS detector at the Large Hadron Collider in the years 2015–2017, corresponding to an integrated luminosity of 79.8 fb. Events with two same-sign leptons ℓ (electrons or muons) and at least two reconstructed jets are selected to search for WWW→ℓνℓνqq. Events with three leptons without any same-flavour opposite-sign lepton pairs are used to search for WWW→ℓνℓνℓν, while events with three leptons and at least one same-flavour opposite-sign lepton pair and one or more reconstructed jets are used to search for WWZ→ℓνqqℓℓ. Finally, events with four leptons are analysed to search for WWZ→ℓνℓνℓℓ and WZZ→qqℓℓℓℓ. Evidence for the joint production of three massive vector bosons is observed with a significance of 4.1 standard deviations, where the expectation is 3.1 standard deviations.Peer Reviewe

Measurement of isolated-photon plus two-jet production in pp collisions at √s = 13 TeV with the ATLAS detector

The dynamics of isolated-photon plus two-jet production in pp collisions at a centre-of-mass energy of 13 TeV are studied with the ATLAS detector at the LHC using a dataset corresponding to an integrated luminosity of 36.1 fb. Cross sections are measured as functions of a variety of observables, including angular correlations and invariant masses of the objects in the final state, γ + jet + jet. Measurements are also performed in phase-space regions enriched in each of the two underlying physical mechanisms, namely direct and fragmentation processes. The measurements cover the range of photon (jet) transverse momenta from 150 GeV (100 GeV) to 2 TeV. The tree-level plus parton-shower predictions from Sherpa and Pythia as well as the next-to-leading-order QCD predictions from Sherpa are compared with the measurements. The next-to-leading-order QCD predictions describe the data adequately in shape and normalisation except for regions of phase space such as those with high values of the invariant mass or rapidity separation of the two jets, where the predictions overestimate the data. [Figure not available: see fulltext.

Measurement of the Z(-> l(+)l(-))gamma production cross-section in pp collisions at root s=13 TeV with the ATLAS detector

The production of a prompt photon in association with a Z boson is studied in proton-proton collisions at a centre-of-mass energy s = 13 TeV. The analysis uses a data sample with an integrated luminosity of 139 fb collected by the ATLAS detector at the LHC from 2015 to 2018. The production cross-section for the process pp → ℓℓγ + X (ℓ = e, μ) is measured within a fiducial phase-space region defined by kinematic requirements on the photon and the leptons, and by isolation requirements on the photon. An experimental precision of 2.9% is achieved for the fiducial cross-section. Differential cross-sections are measured as a function of each of six kinematic variables characterising the ℓℓγ system. The data are compared with theoretical predictions based on next-to-leading-order and next-to-next-to-leading-order perturbative QCD calculations. The impact of next-to-leading-order electroweak corrections is also considered. [Figure not available: see fulltext.]