Brugada Type 1 Pattern and Risk Stratification for Sudden Death: Does the Key Hide in the ECG Analysis?

Primary prevention of ventricular fibrillation is at the heart of the management of Brugada syndrome. Several recent studies have shown that the analysis of simple electrocardiographic criteria could help to stratify the risk of sudden death. In the present work, 12 markers were studied: spontaneous and permanent type 1 pattern, first-degree atrioventricular block, sinus node dysfunction, wide QRS in V2, aVR sign, fragmented QRS, S-waves in DI, early repolarization pattern, atrial fibrillation, type 1 in peripheral leads pattern, and long Tpeak-Tend interval. These electrical markers reflect abnormalities in conduction, depolarization, and repolarization that may indicate the severity of the disease. In this chapter, we carry out a review of these markers, their method of determination on the surface ECG, and the main studies highlighting their prognostic impact. We also review the main underlying pathophysiological hypotheses of Brugada syndrome

La dame aux camélias

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CARACTERÍSTICAS TECNOLÓGICAS DAS MADEIRAS DE Eucalyptus grandis W.Hill ex Maiden E Eucalyptus cloeziana F. Muell VISANDO AO SEU APROVEITAMENTO NA INDÚSTRIA MOVELEIRA

Este trabalho se desenvolveu na Universidade de Brasília e no Laboratório de Produtos Florestais (IBAMA), Brasília, DF. Foram estudadas duas espécies de eucalipto (Eucalyptus grandis W.Hill ex Maiden e Eucalyptus cloeziana) para confecção de peças mobiliárias. A madeira de E. grandis apresenta propriedades físicas (densidade e retratibilidade) e mecânicas (flexão estática e dureza) extremamente positivas para a indústria moveleira, sendo complementado por seu bom desempenho perante equipamentos e máquinas, além de receber bem produtos de acabamento. A cor da madeira e o seu desenho levaram os consumidores a mostrar ótima aceitação do móvel fabricado com a espécie. A madeira de Eucalyptus cloeziana, apesar de mostrar propriedades físicas e mecânicas com valores mais elevados que as do Eucalyptus grandis W.Hill ex Maiden, apresenta características desejadas para indústria moveleira. A sua coloração cinza oliva é uma opção para o consumidor. Alguns cuidados especiais com essa espécie deverão ser tomados durante operações com máquinas e equipamentos. Os valores da propriedade dureza apresentados por essa madeira a indicam para fabricação de piso

Aberrant Splicing Is the Pathogenicity Mechanism of the p.Glu314Lys Variant in CYP11A1 Gene

Context: The cholesterol side chain cleavage enzyme (CYP11A1) catalyzes the conversion of cholesterol to pregnenolone, the first rate-limiting step of steroidogenesis. CYP11A1 mutations are associated with primary adrenal insufficiency (PAI) as well as disorders of sex development (DSD) in 46,XY patients.Objective: To define the pathogenicity mechanism for the p.Glu314Lys variant, previously reported, and found in four additional patients with CYP11A1 deficiency.Subjects and Methods: DNA of four patients presenting with delayed PAI and/or 46,XY DSD were studied by Sanger or Massively Parallel sequencing. Three CYP11A1 mutations were characterized in vitro and in silico, and one by mRNA analysis on testicular tissue.Results: All patients were compound heterozygous for the previously described p.Glu314Lys variant. In silico studies predicted this mutation as benign with no effect on splicing but mRNA analysis found that it led to incomplete exon 5 skipping. This mechanism was confirmed by minigene experiment. The protein carrying this mutation without exon skipping should conserve almost normal activity, according to in vitro studies. Two other mutations found in trans, the p.Arg120Gln and p.Arg465Trp, had similar activity compared to negative control, consistent with the in silico studies.Conclusions: We provide biological proof that the p. Glu314Lys variant is pathogenic due to its impact on splicing and seems responsible for the moderate phenotype of the four patients reported herein. The present study highlights the importance of considering the potential effect of a missense variant on splicing when it is not predicted to be disease causing

In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma

International audiencePurpose: Germline mutations in genes encoding mitochon-drial succinate dehydrogenase (SDH) are found in patients with paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, and renal cancers. SDH inactivation leads to a massive accumulation of succinate, acting as an oncometabolite and which levels, assessed on surgically resected tissue are a highly specific biomarker of SDHx-mutated tumors. The aim of this study was to address the feasibility of detecting succinate in vivo by magnetic resonance spectroscopy. Experimental Design: A pulsed proton magnetic resonance spectroscopy (1 H-MRS) sequence was developed, optimized, and applied to image nude mice grafted with Sdhb À/À or wild-type chromaffin cells. The method was then applied to patients with paraganglioma carrying (n ¼ 5) or not (n ¼ 4) an SDHx gene mutation. Following surgery, succinate was measured using gas chromatography/mass spectrometry, and SDH protein expression was assessed by immunohistochemistry in resected tumors. Results: A succinate peak was observed at 2.44 ppm by 1 H-MRS in all Sdhb À/À-derived tumors in mice and in all paragangliomas of patients carrying an SDHx gene mutation, but neither in wild-type mouse tumors nor in patients exempt of SDHx mutation. In one patient, 1 H-MRS results led to the identification of an unsus-pected SDHA gene mutation. In another case, it helped define the pathogenicity of a variant of unknown significance in the SDHB gene. Conclusions: Detection of succinate by 1 H-MRS is a highly specific and sensitive hallmark of SDHx mutations. This non-invasive approach is a simple and robust method allowing in vivo detection of the major biomarker of SDHx-mutated tumors. Clin Cancer Res; 22(5); 1120–9. Ó2015 AACR

Technological characteristics of the wood of Eucalyptus grandis W.Hill ex Maiden and Eucalyptus cloeziana F. Muell, as a supply for the furniture industry

Este trabalho se desenvolveu na Universidade de Brasília e no Laboratório de Produtos Florestais (IBAMA), Brasília, DF. Foram estudadas duas espécies de eucalipto (Eucalyptus grandis W.Hill ex Maiden e Eucalyptus cloeziana) para confecção de peças mobiliárias. A madeira de E. grandis apresenta propriedades físicas (densidade e retratibilidade) e mecânicas (flexão estática e dureza) extremamente positivas para a indústria moveleira, sendo complementado por seu bom desempenho perante equipamentos e máquinas, além de receber bem produtos de acabamento. A cor da madeira e o seu desenho levaram os consumidores a mostrar ótima aceitação do móvel fabricado com a espécie. A madeira de Eucalyptus cloeziana, apesar de mostrar propriedades físicas e mecânicas com valores mais elevados que as do Eucalyptus grandis W.Hill ex Maiden, apresenta características desejadas para indústria moveleira. A sua coloração cinza oliva é uma opção para o consumidor. Alguns cuidados especiais com essa espécie deverão ser tomados durante operações com máquinas e equipamentos. Os valores da propriedade dureza apresentados por essa madeira a indicam para fabricação de piso.This work was carried out at Universidade de Brasília at the Wood Products of Forestry Laboratory (IBAMA, Brasília, DF, Brazil). Two species of eucalypt wood (Eucalyptus grandis W.Hill ex Maiden and Eucalyptus cloeziana) were studied to supply the furniture making industry. The wood of Eucalyptus grandis W.Hill ex Maiden shows physical properties (density and retractibility) and mechanical properties (static bending and hardness) very suitable for the industry of wood furniture. Such characteristics are complemented by its excellent behaviour in machining and also good finishing with varnishes. The colour and patterns the wood bring to the consumers a good feeling as well as for the furnitures built with such a species. The wood of Eucalyptus cloeziana, in spite of its mechanical and physical properties higher than those of Eucalyptus grandis W.Hill ex Maiden, presents good characteristics for the manufacture of furniture. Its grey-olive colouring is consistent with a good choice and taste for the consumers. However, some precaution must be observed during the machining of the wood. This wood’s hardness makes it suitable for parquetry

The eNMR platform for structural biology

The e-NMR project is a European cooperation initiative that aims at providing the bio-NMR user community with a software platform integrating and streamlining the computational approaches necessary for the analysis of bio-NMR data. The e-NMR platform is based on a Grid computational infrastructure. A main focus of the current implementation of the e-NMR platform is on streamlining structure determination protocols. Indeed, to facilitate the use of NMR spectroscopy in the life sciences, the eNMR consortium has set out to provide protocolized services through easy-to-use web interfaces, while still retaining sufficient flexibility to handle specific requests by expert users. Various programs relevant for structural biology applications are already available through the e-NMR portal, including HADDOCK, XPLOR-NIH, CYANA and csRosetta. The implementation of these services, and in particular the distribution of calculations to the GRID infrastructure, has required the development of specific tools. However, the GRID infrastructure is maintained completely transparent to the users. With more than 150 registered users, eNMR is currently the second largest European Virtual Organization in the life sciences

Protein–protein HADDocking using exclusively pseudocontact shifts

In order to enhance the structure determination process of macromolecular assemblies by NMR, we have implemented long-range pseudocontact shift (PCS) restraints into the data-driven protein docking package HADDOCK. We demonstrate the efficiency of the method on a synthetic, yet realistic case based on the lanthanide-labeled N-terminal ε domain of the E. coli DNA polymerase III (ε186) in complex with the HOT domain. Docking from the bound form of the two partners is swiftly executed (interface RMSDs < 1 Å) even with addition of very large amount of noise, while the conformational changes of the free form still present some challenges (interface RMSDs in a 3.1–3.9 Å range for the ten lowest energy complexes). Finally, using exclusively PCS as experimental information, we determine the structure of ε186 in complex with the HOT-homologue θ subunit of the E. coli DNA polymerase III

TECHNOLOGICAL CHARACTERISTICS OF THE WOOD OF Eucalyptus grandis W.Hill ex Maiden AND Eucalyptus cloeziana F. Muell, AS A SUPPLY FOR THE FURNITURE INDUSTRY

Este trabalho se desenvolveu na Universidade de Bras\uedlia e no Laborat\uf3rio de Produtos Florestais (IBAMA), Bras\uedlia, DF. Foram estudadas duas esp\ue9cies de eucalipto ( Eucalyptus grandis W.Hill ex Maiden e Eucalyptus cloeziana ) para confec\ue7\ue3o de pe\ue7as mobili\ue1rias. A madeira de E. grandis apresenta propriedades f\uedsicas (densidade e retratibilidade) e mec\ue2nicas (flex\ue3o est\ue1tica e dureza) extremamente positivas para a ind\ufastria moveleira, sendo complementado por seu bom desempenho perante equipamentos e m\ue1quinas, al\ue9m de receber bem produtos de acabamento. A cor da madeira e o seu desenho levaram os consumidores a mostrar \uf3tima aceita\ue7\ue3o do m\uf3vel fabricado com a esp\ue9cie. A madeira de Eucalyptus cloeziana, apesar de mostrar propriedades f\uedsicas e mec\ue2nicas com valores mais elevados que as do Eucalyptus grandis W.Hill ex Maiden, apresenta caracter\uedsticas desejadas para ind\ufastria moveleira. A sua colora\ue7\ue3o cinza oliva \ue9 uma op\ue7\ue3o para o consumidor. Alguns cuidados especiais com essa esp\ue9cie dever\ue3o ser tomados durante opera\ue7\uf5es com m\ue1quinas e equipamentos. Os valores da propriedade dureza apresentados por essa madeira a indicam para fabrica\ue7\ue3o de piso.This work was carried out at Universidade de Bras\uedlia at the Wood Products of Forestry Laboratory (IBAMA, Bras\uedlia, DF, Brazil). Two species of eucalypt wood ( Eucalyptus grandis W.Hill ex Maidenand Eucalyptus cloeziana ) were studied to supply the furniture making industry. The wood of Eucalyptus grandis W.Hill ex Maiden shows physical properties (density and retractibility) and mechanical properties (static bending and hardness) very suitable for the industry of wood furniture. Such characteristics are complemented by its excellent behaviour in machining and also good finishing with varnishes. The colour and patterns the wood bring to the consumers a good feeling as well as for the furnitures built with such a species. The wood of Eucalyptus cloeziana, in spite of its mechanical and physical properties higher than those of Eucalyptus grandis W.Hill ex Maiden, presents good characteristics for the manufacture of furniture. Its grey-olive colouring is consistent with a good choice and taste for the consumers. However, some precaution must be observed during the machining of the wood. This wood\u2019s hardness makes it suitable for parquetry

Pushing the limits of what is achievable in protein–DNA docking: benchmarking HADDOCK’s performance

The intrinsic flexibility of DNA and the difficulty of identifying its interaction surface have long been challenges that prevented the development of efficient protein–DNA docking methods. We have demonstrated the ability our flexible data-driven docking method HADDOCK to deal with these before, by using custom-built DNA structural models. Here we put our method to the test on a set of 47 complexes from the protein–DNA docking benchmark. We show that HADDOCK is able to predict many of the specific DNA conformational changes required to assemble the interface(s). Our DNA analysis and modelling procedure captures the bend and twist motions occurring upon complex formation and uses these to generate custom-built DNA structural models, more closely resembling the bound form, for use in a second docking round. We achieve throughout the benchmark an overall success rate of 94% of one-star solutions or higher (interface root mean square deviation ≤4 Å and fraction of native contacts >10%) according to CAPRI criteria. Our improved protocol successfully predicts even the challenging protein–DNA complexes in the benchmark. Finally, our method is the first to readily dock multiple molecules (N > 2) simultaneously, pushing the limits of what is currently achievable in the field of protein–DNA docking