Fast and slow-twitching muscles are differentially affected by reduced cholinergic transmission in mice deficient for VAChT: A mouse model for congenital myasthenia

Congenital myasthenic syndromes (CMS) result from reduced cholinergic transmission at neuromuscular junctions (NMJs). While the etiology of CMS varies, the disease is characterized by muscle weakness. To date, it remains unknown if CMS causes long-term and irreversible changes to skeletal muscles. In this study, we examined skeletal muscles in a mouse line with reduced expression of Vesicular Acetylcholine Transporter (VAChT, mouse line herein called VAChT-KDHOM). We examined this mouse line for several reasons. First, VAChT plays a central function in loading acetylcholine (ACh) into synaptic vesicles and releasing it at NMJs, in addition to other cholinergic nerve endings. Second, loss of function mutations in VAChT causes myasthenia in humans. Importantly, VAChT-KDHOM present with reduced ACh and muscle weakness, resembling CMS. We evaluated the morphology, fiber type (myosin heavy chain isoforms), and expression of muscle-related genes in the extensor digitorum longus (EDL) and soleus muscles. This analysis revealed that while muscle fibers atrophy in the EDL, they hypertrophy in the soleus muscle of VAChT-KDHOM mice. Along with these cellular changes, skeletal muscles exhibit altered levels of markers for myogenesis (Pax-7, Myogenin, and MyoD), oxidative metabolism (PGC1-alpha and MTND1), and protein degradation (Atrogin1 and MuRF1) in VAChT-KDHOM mice. Importantly, we demonstrate that deleterious changes in skeletal muscles and motor deficits can be partially reversed following the administration of the cholinesterase inhibitor, pyridostigmine in VAChT-KDHOM mice. These findings reveal that fast and slow type muscles differentially respond to cholinergic deficits. Additionally, this study shows that the adverse effects of cholinergic transmission, as in the case of CMS, on fast and slow type skeletal muscles are reversible

Antitumor Activity and Reductive Stress by Platinum(II) N-Heterocyclic Carbenes based on Guanosine**

Funding Information: We thank Fernanda Murtinheira for the support on the autophagy measurements. This work was supported by FCT – Fundação para a Ciência e a Tecnologia, I.P., through MOSTMICRO‐ITQB R&D Unit (UIDB/04612/2020, UIDP/04612/2020) and LS4FUTURE Associated Laboratory (LA/P/0087/2020). M.I.P.S.L. was supported by fellowships PD/BD/135483/2018 and COVID/BD/152502/2022 from FCT. A.P. acknowledges the contract CEECINST/00102/2018. The NMR spectra were acquired at CERMAX–ITQB, supported by Infrastructure Project No. 022161 (co‐financed by FEDER through COMPETE 2020, POCI, PORL and FCT through PIDDAC). C.S.B. Gomes acknowledges the XTAL – Macromolecular Crystallography group for granting access to the X‐ray diffractometer. X‐ray infrastructure financed by FCT‐MCTES through project RECI/BBBBEP/0124/2012. FH was supported by Centre grants from FCT to the BioISI Research Unit (Refs. UIDB/04046/2020 and UIDP/04046/2020) and the Microscopy facility at FCUL (as a node of the Portuguese Platform of BioImaging, reference PPBI‐POCI‐01‐0145‐FEDER‐022122), and by individual grants through FCT (Ref. PTDC/FIS‐MAC/2741/2021) and the ARSACS Foundation (Canada). Maria Turos‐Cabal was supported by fellowship from the Spanish Association Against Cancer (AECC, SV‐19‐AECC‐FPI) and the Consejería de Economía y Empleo del Principado de Asturias (FICYT, Severo‐Ochoa BP20‐073). Publisher Copyright: © 2023 Wiley-VCH GmbH.Platinum(II) complexes bearing N-heterocyclic carbenes based guanosine and caffeine have been synthesized by unassisted C−H oxidative addition, leading to the corresponding trans-hydride complexes. Platinum guanosine derivatives bearing triflate as counterion or bromide instead of hydride as co-ligand were also synthesized to facilitate correlation between structure and activity. The hydride compounds show high antiproliferative activity against all cell lines (TC-71, MV-4-11, U-937 and A-172). Methyl Guanosine complex 3, bearing a hydride ligand, is up to 30 times more active than compound 4, with a bromide in the same position. Changing the counterion has no significant effect in antiproliferative activity. Increasing bulkiness at N7, with an isopropyl group (compound 6), allows to maintain the antiproliferative activity while decreasing toxicity for non-cancer cells. Compound 6 leads to an increase in endoplasmic reticulum and autophagy markers on TC71 and MV-4-11 cancer cells, induces reductive stress and increases glutathione levels in cancer cells but not in non-cancer cell line HEK-293.preprintinpres

First exposure to Arduino through peer-coaching: Impact on students' attitudes towards programming

In this paper we report the work that jeKnowledge (Júnior Empresa da Faculdade de Ciências e Tecnologias da Universidade de Coimbra), a student-led initiative, has done in the ‘jeKnowledge academy’ courses to actively engage Portuguese high-school students in STEM education through hands-on projects based on the low-cost Arduino platform. F2F activities, based on a peer-assisted learning strategy, were complemented with tutorials and more advanced project suggestions in a blog. Pre and post surveys on students'' attitudes towards programming and peer-coaching were administered to pre-university and first year college participants, finding an overall increase in the Likert scale for all the programming-related constructs under study (confidence, interest, gender, usefulness and professional) after the introductory course. As regards the peer-based learning approach, younger students seemed to be more eager to be taught in a less formal way than their older counterparts. The course resulted in high degrees of satisfaction for both the student tutors and their tutees

The Relativistic Factor in the Orbital Dynamics of Point Masses

There is a growing population of relativistically relevant minor bodies in the Solar System and a growing population of massive extrasolar planets with orbits very close to the central star where relativistic effects should have some signature. Our purpose is to review how general relativity affects the orbital dynamics of the planetary systems and to define a suitable relativistic correction for Solar System orbital studies when only point masses are considered. Using relativistic formulae for the N body problem suited for a planetary system given in the literature we present a series of numerical orbital integrations designed to test the relevance of the effects due to the general theory of relativity in the case of our Solar System. Comparison between different algorithms for accounting for the relativistic corrections are performed. Relativistic effects generated by the Sun or by the central star are the most relevant ones and produce evident modifications in the secular dynamics of the inner Solar System. The Kozai mechanism, for example, is modified due to the relativistic effects on the argument of the perihelion. Relativistic effects generated by planets instead are of very low relevance but detectable in numerical simulations

Automatic diagnosis of the 12-lead ECG using a deep neural network

The role of automatic electrocardiogram (ECG) analysis in clinical practice is limited by the accuracy of existing models. Deep Neural Networks (DNNs) are models composed of stacked transformations that learn tasks by examples. This technology has recently achieved striking success in a variety of task and there are great expectations on how it might improve clinical practice. Here we present a DNN model trained in a dataset with more than 2 million labeled exams analyzed by the Telehealth Network of Minas Gerais and collected under the scope of the CODE (Clinical Outcomes in Digital Electrocardiology) study. The DNN outperform cardiology resident medical doctors in recognizing 6 types of abnormalities in 12-lead ECG recordings, with F1 scores above 80% and specificity over 99%. These results indicate ECG analysis based on DNNs, previously studied in a single-lead setup, generalizes well to 12-lead exams, taking the technology closer to the standard clinical practice

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results

Jet size dependence of single jet suppression in lead-lead collisions at sqrt(s(NN)) = 2.76 TeV with the ATLAS detector at the LHC

Measurements of inclusive jet suppression in heavy ion collisions at the LHC provide direct sensitivity to the physics of jet quenching. In a sample of lead-lead collisions at sqrt(s) = 2.76 TeV corresponding to an integrated luminosity of approximately 7 inverse microbarns, ATLAS has measured jets with a calorimeter over the pseudorapidity interval |eta| < 2.1 and over the transverse momentum range 38 < pT < 210 GeV. Jets were reconstructed using the anti-kt algorithm with values for the distance parameter that determines the nominal jet radius of R = 0.2, 0.3, 0.4 and 0.5. The centrality dependence of the jet yield is characterized by the jet "central-to-peripheral ratio," Rcp. Jet production is found to be suppressed by approximately a factor of two in the 10% most central collisions relative to peripheral collisions. Rcp varies smoothly with centrality as characterized by the number of participating nucleons. The observed suppression is only weakly dependent on jet radius and transverse momentum. These results provide the first direct measurement of inclusive jet suppression in heavy ion collisions and complement previous measurements of dijet transverse energy imbalance at the LHC.Comment: 15 pages plus author list (30 pages total), 8 figures, 2 tables, submitted to Physics Letters B. All figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/HION-2011-02

Measurement of the polarisation of W bosons produced with large transverse momentum in pp collisions at sqrt(s) = 7 TeV with the ATLAS experiment

This paper describes an analysis of the angular distribution of W->enu and W->munu decays, using data from pp collisions at sqrt(s) = 7 TeV recorded with the ATLAS detector at the LHC in 2010, corresponding to an integrated luminosity of about 35 pb^-1. Using the decay lepton transverse momentum and the missing transverse energy, the W decay angular distribution projected onto the transverse plane is obtained and analysed in terms of helicity fractions f0, fL and fR over two ranges of W transverse momentum (ptw): 35 < ptw < 50 GeV and ptw > 50 GeV. Good agreement is found with theoretical predictions. For ptw > 50 GeV, the values of f0 and fL-fR, averaged over charge and lepton flavour, are measured to be : f0 = 0.127 +/- 0.030 +/- 0.108 and fL-fR = 0.252 +/- 0.017 +/- 0.030, where the first uncertainties are statistical, and the second include all systematic effects.Comment: 19 pages plus author list (34 pages total), 9 figures, 11 tables, revised author list, matches European Journal of Physics C versio

Observation of a new chi_b state in radiative transitions to Upsilon(1S) and Upsilon(2S) at ATLAS

The chi_b(nP) quarkonium states are produced in proton-proton collisions at the Large Hadron Collider (LHC) at sqrt(s) = 7 TeV and recorded by the ATLAS detector. Using a data sample corresponding to an integrated luminosity of 4.4 fb^-1, these states are reconstructed through their radiative decays to Upsilon(1S,2S) with Upsilon->mu+mu-. In addition to the mass peaks corresponding to the decay modes chi_b(1P,2P)->Upsilon(1S)gamma, a new structure centered at a mass of 10.530+/-0.005 (stat.)+/-0.009 (syst.) GeV is also observed, in both the Upsilon(1S)gamma and Upsilon(2S)gamma decay modes. This is interpreted as the chi_b(3P) system.Comment: 5 pages plus author list (18 pages total), 2 figures, 1 table, corrected author list, matches final version in Physical Review Letter