Generation of the first human in vitro model for McArdle disease based on iPSC Technology

McArdle disease is a rare autosomal recessive disorder caused by mutations in the PYGM gene. This gene encodes for the skeletal muscle isoform of glycogen phosphorylase (myophosphorylase), the first enzyme in glycogenolysis. Patients with this disorder are unable to obtain energy from their glycogen stored in skeletal muscle, prompting an exercise intolerance. Currently, there is no treatment for this disease, and the lack of suitable in vitro human models has prevented the search for therapies against it. In this article, we have established the first human iPSC-based model for McArdle disease. For the generation of this model, induced pluripotent stem cells (iPSCs) from a patient with McArdle disease (harbouring the homozygous mutation c.148C>T; p.R50* in the PYGM gene) were differentiated into myogenic cells able to contract spontaneously in the presence of motor neurons and generate calcium transients, a proof of their maturity and functionality. Additionally, an isogenic skeletal muscle model of McArdle disease was created. As a proof-of-concept, we have tested in this model the rescue of PYGM expression by two different read-through compounds (PTC124 and RTC13). The developed model will be very useful as a platform for testing drugs or compounds with potential pharmacological activity.This work has been funded by grants from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III (ISCIII): PI15/00484, CP16/00046 and PI18/00151 to MEG and PI17/02052 to JA (co-funded by European Regional Development Fund “A way to make Europe”); PI21/00162 and CPII21/00011 co-funded by the European Union to MEG. MdCOC receives grant support from the ‘Ministerio de Educación, Cultura y Deporte’ (FPU16/03895), ‘Fundación para la Investigación Biomédica Hospital 12 de Octubre’ (2022/0065, i+12-AY20220114-1) and EMBO Grant 8917. CL and MD were recipient of a fellowship from the French Ministry of Education. The work in FM’s laboratory was funded by “Association Française contre les Myopathies” (AFM; TRIM-RD and MoThARD) and from the Excellence Initiative of Aix-Marseille University-A*Midex, a French “investissement d’avenir programme” AMX-19-IET-007 through the Marseille Maladies Rares (MarMaRa) Institute (phD fellowship to CL)

Criterios de ordenación temporal de las intervenciones quirúrgicas en patología cardiovascular y endovascular adquirida. Versión 2022

Waiting list management of cardiac surgical procedures is a main concern for all the Spanish autonomic health systems and for our scientific Society. The first statement for optimal timing of patients waiting for cardiac surgery was published in 2000. Since then, after significant changes in the management of some pathologies, new normative frameworks and the current healthcare situation, a review of the timing criteria to offer an adequate and updated standard of care is needed. In this document we aim to review the available literature in the field and stablish a consensus within a working group of the Spanish Society of Cardiovascular and Endovascular Surgery to optimize the priority recommendations in cardiac surgical waiting lists in our country. (c) 2022 Sociedad Espanola de Cirugia Cardiovascular y Endovascular. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ riccuses/by-nc-nri/4.0/)

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.

Prediction of poor outcome in clostridioides difficile infection: A multicentre external validation of the toxin B amplification cycle

Producción CientíficaClassification of patients according to their risk of poor outcomes in Clostridioides difficile infection (CDI) would enable implementation of costly new treatment options in a subset of patients at higher risk of poor outcome. In a previous study, we found that low toxin B amplification cycle thresholds (Ct) were independently associated with poor outcome CDI. Our objective was to perform a multicentre external validation of a PCR-toxin B Ct as a marker of poor outcome CDI. We carried out a multicentre study (14 hospitals) in which the characteristics and outcome of patients with CDI were evaluated. A subanalysis of the results of the amplification curve of real-time PCR gene toxin B (XpertTM C. difficile) was performed. A total of 223 patients were included. The median age was 73.0 years, 50.2% were female, and the median Charlson index was 3.0. The comparison of poor outcome and non–poor outcome CDI episodes revealed, respectively, the following results: median age (years), 77.0 vs 72.0 (p = 0.009); patients from nursing homes, 24.4% vs 10.8% (p = 0.039); median leukocytes (cells/μl), 10,740.0 vs 8795.0 (p = 0.026); and median PCR-toxin B Ct, 23.3 vs 25.4 (p = 0.004). Multivariate analysis showed that a PCR-toxin B Ct cut-off <23.5 was significantly and independently associated with poor outcome CDI (p = 0.002; OR, 3.371; 95%CI, 1.565–7.264). This variable correctly classified 68.5% of patients. The use of this microbiological marker could facilitate early selection of patients who are at higher risk of poor outcome and are more likely to benefit from newer and more costly therapeutic options

Measurement of the production of a W boson in association with a charmed hadron in pp collisions at √s=13 TeV with the ATLAS detector

Álvarez Piqueras, D.; Amos, K.R. ; Aparisi, Pozo, J.A.; Bailey, A.J.; Barranco, Laura; Bouchhar, Naseem; Cabrera, Susana; Cantero, Josu; Cardillo, Fabio Castillo, F.L.; Castillo Mª Victoria; Chitishvili, Mariam Cerda Alberich, L.; Costa, María José; Didenko, Mariia , Escobar, Carlos; Estrada, Oscar; Ferrer, Antonio; Fiorini, L.; Fullana, Esteban; Fuster, Juan; García García, Carmen; García Navarro, José Enrique; Gomez Delegido, A.J.; González de la Hoz, Santiago; Gonzalvo Rodríguez, Galo Rafael; Guerrero Rojas, J.G.R.; Higón, Emilio; Jimenez Pena, Javier; Lacasta Llácer, Carlos; Lozano Bahilo, José J.; Madaffari, Daniele; Mamuzic, Judita; Martí García, Salvador; Martinez Agullo, Pablo;; Melini, Davide; Miñano Moya, M.; Mitsou, Vasiliki A.; Miralles López, Marcos; Monsonis Romero, Luis; Moreno Llácer, María; Muñoz Perez, David; Navarro Gonzalez, Josep; Poveda, Joaquín; Prades Ibañez, Alberto; Rodriguez Bosca, S.; Rodriguez Rodriguez, D.; Rubio Jiménez, Adrián ; Ruiz Martínez, Arantxa; Sabatini, Paolo , Salt, José; Sanchez Sebastian, Victoria Santra, A.; Sánchez Martínez, Javier; Sayago Galvan, Ivan; Senthilkumar, Varsha ; Soldevila, Urmila; Torró Pastor, Emma; Valero, Alberto; Valls Ferrer, Juan Antonio; Valiente Moreno, Enrique ; Villaplana Pérez, Miguel , Varriale, Lorenzo; Vos, Marcel; ATLAS CollaborationThe production of a W boson in association with a single charm quark is studied using 140 fb - 1 of s = 13 TeV proton-proton collision data collected with the ATLAS detector at the Large Hadron Collider. The charm quark is tagged by the presence of a charmed hadron reconstructed with a secondary-vertex fit. The W boson is reconstructed from the decay to either an electron or a muon and the missing transverse momentum present in the event. The charmed mesons reconstructed are D + → K - π + π + and D * + → D 0 π + → ( K - π + ) π + and the charge conjugate decays in the fiducial regions where p T ( e , μ ) > 30 GeV , | η ( e , μ ) | 8 GeV , and | η ( D ( * ) ) | < 2.2 . The integrated and normalized differential cross sections as a function of the pseudorapidity of the lepton from the W boson decay, and of the transverse momentum of the charmed hadron, are extracted from the data using a profile likelihood fit. The measured total fiducial cross sections are σ fid OS - SS ( W - + D + ) = 50.2 ± 0.2 ( stat ) - 2.3 + 2.4 ( syst ) pb , σ fid OS - SS ( W + + D - ) = 48.5 ± 0.2 ( stat ) - 2.2 + 2.3 ( syst ) pb , σ fid OS - SS ( W - + D * + ) = 51.1 ± 0.4 ( stat ) - 1.8 + 1.9 ( syst ) pb , and σ fid OS - SS ( W + + D * - ) = 50.0 ± 0.4 ( stat ) - 1.8 + 1.9 ( syst ) pb . Results are compared with the predictions of next-to-leading-order quantum chromodynamics calculations performed using state-of-the-art parton distribution functions. Additionally, the ratio of charm to anticharm production cross sections is studied to probe the s - s ¯ quark asymmetry. The ratio is found to be R c ± = 0.971 ± 0.006 ( stat ) ± 0.011 ( syst ) . The ratio and cross-section measurements are consistent with the predictions obtained with parton distribution function sets that have a symmetric s - s ¯ sea, indicating that any s - s ¯ asymmetry in the Bjorken- x region relevant for this measurement is small

Heteroatom-tagged proteomics of lung cancer and chronic obstructive pulmonary disease human serum reveal alterations in selenoproteins

Heteroatom-tagged proteomics allows the absolute quantification of selenoproteins using the heteroatom as a "tag" into a selective and sensitive atomic detector instead of a molecular one. Using this analytical method, about 90% of total selenium in human serum/plasma can be measured as selenoproteins and total selenometabolites and thus, the status of selenium can be determined. Herein, we determined the absolute concentration of selenoproteins in human serum patients with lung cancer (LC) and chronic obstructive pulmonary disease (COPD), a competing cause of morbidity and mortality in smokers as well as an independent risk factor for LC. We conducted an observational study of 154 human serum samples obtained from LC and COPD patients with varying severity of disease, including COPD patients who developed LC during follow-up and healthy controls (HC). Using heteroatom-tagged proteomics, we determined extracellular glutathione peroxidase (eGPx), selenoprotein P (SELENOP), and selenoalbumin (SeAlb). Associations between selenoproteins were also studied as potential biomarkers of disease. The concentration of eGPx was significantly higher in the all-inclusive COPD cohort compared to HC, COPD patients with LC, or those with mild obstructive lung disease, while SELENOP concentration was significantly decreased in LC patients compared to HC and COPD. We found an inverse correlation between SELENOP and SeAlb in HC, but also in LC patients, and especially in patients with COPD and LC. Moreover, we found that eGPx and selenometabolite concentrations were positively associated with LC human serum. Selenoprotein concentrations were altered in COPD and LC when compared to healthy controls suggesting a potential role of the selenoproteome in the diagnosis and/or treatment of these tobacco-related diseases.Funding: This work has been supported by the project “Heteroatom-tagged proteomics and metabolomics to study lung cancer. Influence of gut microbiota” (Ref.: PY20_00366). Project of Excellence. Regional Ministry of Economy, Knowledge, Business and University, Andalusia, Spain. The authors also thank the grants Ref. 651/2018 and 115/2020 from the Spanish Society of Pneumology and Surgery (SEPAR) and 08/2018 from the Association of Pneumology and Thoracic Surgery (Neumosur) that supported samples recruitment at the hospitals and biobank registration. The authors also thank Instituto de Salud Carlos III (AES16/01783) and unrestricted funding from Menarini Group and AstraZeneca“. Funding for open access charge: Universidad de Huelva / CBUA. Acknowledgements: We thank all the patients who have volunteered and donated their biomaterials for the study

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.