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In this study, we analyzed PFO implications in atrial fibrillation (AF) ablation.Six hundred and twenty-five consecutive patients with AF undergoing PV isolation were included. We considered that a large and/or compliant PFO was present if the catheters advanced gently into the LA without puncturing the septum. Atrial tachyarrhythmias after the 3-month blanking period were classified as a recurrence.Out of the 625 patients included, 36 (5.8%) were found to have PFO. No significant differences were observed in the clinical characteristics of patients with PFO compared with patients without PFO. Nevertheless, patients with PFO had lower acute success in PV isolation compared with patients without PFO (98.2% vs. 88.5%; p = 0.006) even after adjusting for age, sex, type of AF, LA area, cardiomyopathy, time from AF diagnosis to the ablation, and ablation technique (odds ratio: 0.1; 95% confidence interval (CI): 0.02-0.9; p = 0.039). In 546 patients followed more than 6 months, the recurrence rate of any atrial tachyarrhythmia after 18.6 ± 11.9 months was significantly higher in patients with PFO compared with patients without PFO (41.9 vs. 70%; p = 0.012). This difference remained significant after adjusting for age, sex, type of AF, LA area, cardiomyopathy, time from AF diagnosis to the ablation, and ablation technique (hazard ratio: 1.9; 95% CI: 1.1-3.3; p = 0.015).The presence of a large and/or compliant PFO is an independent factor for PV isolation failure and arrhythmia recurrence rate after the ablation.

Additional file 7: Figure 7. ATR-FTIR on Aβ42 fibrils and Aβ42CC oligomers.

Additional file 2: Figure 2. SEC-MALS of an oligomeric synthetic Aβ42CC preparation.

Additional file 4: Figure 4. Antibody binding using a direct ELISA against different aggregated states of Aβ42CC.

Additional file 6: Figure 6. Standard curve for ELISA quantification of ALZ-201-reactive Aβ42 oligomers.

Additional file 9: Figure 9. Mab158 binding to protofibrils and fibrils.

Additional file 8: Figure 8. One-site ELISAs against different Aβ species.

Additional file 1: Figure 1. SEC-MALS of an oligomeric recombinant Aβ42CC preparation.

Additional file 5: Figure 5. SEC-MALS of Aβ42CC at different oligomeric states.

Additional file 3: Figure 3. Inhibition ELISA experiment.

Bibliotecarios, arquivistas, museologos, restauradores e outros tem papel decisivo na concretizacao de estudos de arqueologia das midias. Esse campo do saber, bastante difundido na Europa, nao se faz muito presente em investigacoes cientificas brasileiras. Tendo duas obras – Thomas Elsaesser e Marey & Muybridge – recentemente publicadas no Brasil como ponto de partida, elabora-se breve analise da arqueologia das midias, como uma atividade que realiza investigacoes nas camadas que constituem a historia das midias sob uma perspectiva pragmatica, e sobre o Cinema, enquanto inovacao tecnologica e fenomeno sociocultural, como matriz e presenca ubiqua nos modos contemporâneos de comunicacao. Comenta-se breve historico da Cinemateca Brasileira e o papel das instituicoes de guarda e preservacao de filmes em âmbito mundial. Analisa-se a atuacao e o papel dos ‘profissionais da memoria’ nos estudos mais abrangentes no campo da Comunicacao sob a otica da Ciencia da Informacao. Palavras-chave: Arqueologia das midias; Ciencia da Informacao; Cinema; Comunicacao

Apresenta o Trabalho Temático, prática pedagógica concebida no planejamento do Curso de Graduação em Biblioteconomia da FaBCI/FESPSP, de 2011, como um instrumento que possui características do ensino com pesquisa. O relato objetiva destacar as características do paradigma emergente em educação em contraposição ao paradigma newtoniano-cartesiano presente no ensino de Biblioteconomia desde seu reconhecimento como disciplina do conhecimento. Tal distinção entre paradigmas científicos demonstra o acompanhamento das instituições de ensino das mudanças que afetam a Educação e a formação dos profissionais. O percurso metodológico é exploratório e as autoras analisam o relacionamento entre os conceitos explicitados na revisão bibliográfica sobre o ensino com pesquisa articulando-os com a descrição do processo de realização do Trabalho Temático que envolve docentes e discentes. As considerações apontam a relevância do ensino com pesquisa para a construção de uma prática de aprendizagem consciente e a consolidação de uma visão processual da formação do e pelo discente bem como do docente, em que o sujeito cognoscente é gerador de conhecimento enquanto aprende.Palavras-chave: Trabalhos Temáticos. Ensino de Biblioteconomia. Ensino com Pesquisa. Graduação em Biblioteconomia.Link: http://abecin.org.br/portalderevistas/index.php/rebecin/article/view/77

Aggregation of tau protein and formation of paired helical filaments is a hallmark of Alzheimer's disease and other tauopathies. Compared to other proteins associated with neurodegenerative diseases, the reported in vitro aggregation kinetics for tau protein are less consistent presenting a relatively high variability. Here we describe the development of an in vitro aggregation assay that mimics the expected steps associated with tau misfolding and aggregation in vivo. The assay uses the longest tau isoform (huTau441) which contains both N-terminal acidic inserts as well as four microtubule binding domains (MBD). The in vitro aggregation is triggered by addition of heparin and followed continuously by thioflavin T fluorescence in a 96 well microplate format. The tau aggregation assay is highly reproducible between different wells, experimental runs and batches of the protein. The aggregation leads to tau PHF-like morphology which is very efficient in seeding the formation of de novo fibrillar structures. In addition to its application in studying the mechanism of tau misfolding and aggregation, the current assay is a robust tool for screening drugs that could interfere with the pathogenesis of tau.

Aggregation of tau protein and formation of paired helical filaments is a hallmark of Alzheimer's disease and other tauopathies. Compared to other proteins associated with neurodegenerative diseases, the reported in vitro aggregation kinetics for tau protein are less consistent presenting a relatively high variability. Here we describe the development of an in vitro aggregation assay that mimics the expected steps associated with tau misfolding and aggregation in vivo. The assay uses the longest tau isoform (huTau441) which contains both N-terminal acidic inserts as well as four microtubule binding domains (MBD). The in vitro aggregation is triggered by addition of heparin and followed continuously by thioflavin T fluorescence in a 96 well microplate format. The tau aggregation assay is highly reproducible between different wells, experimental runs and batches of the protein. The aggregation leads to tau PHF-like morphology which is very efficient in seeding the formation of de novo fibrillar structures. In addition to its application in studying the mechanism of tau misfolding and aggregation, the current assay is a robust tool for screening drugs that could interfere with the pathogenesis of tau.

Misfolding and aggregation of tau protein are closely associated with the onset and progression of Alzheimer’s Disease (AD). By interrogating IgG+ memory B cells from asymptomatic donors with tau peptides, we have identified two somatically mutated VH5-51/VL4-1 antibodies. One of these, CBTAU-27.1, binds to the aggregation motif in the R3 repeat domain and blocks the aggregation of tau into paired helical filaments (PHFs) by sequestering monomeric tau. The other, CBTAU-28.1, binds to the N-terminal insert region and inhibits the spreading of tau seeds and mediates the uptake of tau aggregates into microglia by binding PHFs. Crystal structures revealed that the combination of VH5-51 and VL4-1 recognizes a common Pro-Xn-Lys motif driven by germline-encoded hotspot interactions while the specificity and thereby functionality of the antibodies are defined by the CDR3 regions. Affinity improvement led to improvement in functionality, identifying their epitopes as new targets for therapy and prevention of AD.

Alzheimer's disease (AD) is a progressive neurodegenerative condition in which aggregated tau and amyloid proteins accumulate in the brain causing neuronal dysfunction which eventually leads to cognitive decline. Hyperphosphorylated tau aggregates in the neuron are believed to cause most of the pathology associated with AD. These aggregates are assumed to be released into the extracellular compartment and taken up by adjacent healthy neurons where they induce further tau aggregation. This "prion-like" spreading can be interrupted by antibodies capable of binding and "neutralizing" extracellular tau aggregates as shown in preclinical mouse models of AD. One of the proposed mechanisms by which therapeutic antibodies reduce pathology is antibody-mediated uptake and clearance of pathological aggregated forms of tau by microglia. Here, we describe a quantitative cell-based assay to assess tau uptake by microglia. This assay uses the mouse microglial cell line BV-2, allows for high specificity, low variability and medium throughput. Data generated with this assay can contribute to a better characterization of anti-tau antibody effector functions.

A coordenação modular é um sistema para ordenação relativa de dimensões, espaços e componentes construtivos. Sua aplicação tem manifestações remotas por princípios que controlam a composição e fixam escalas convenientes para as partes e o todo, todavia foi a produção seriada industrial que determinou o papel que a disciplina teria no século XX. No Brasil, seu desenvolvimento aconteceu entre as décadas de 1950 e 1970, quando foi determinada a formatação fundamental da disciplina. Identifica-se a partir da década de 1980 um intervalo nas discussões específicas que durou até a virada do século, quando foi recuperado o interesse pela área. É consenso entre os autores que ainda não houve no Brasil sucesso na implantação de modelos abrangentes da coordenação modular, mas faltam análises atualizadas. O objetivo da dissertação - examinar o desenvolvimento da disciplina no Brasil após 1986 - está fundamentado em indícios de que as discussões recentes não se aprofundam em temas atuais e de que há um enfraquecimento de uma visão integrada do problema. As principais conclusões indicam que o desenvolvimento da construção civil vem sendo acompanhado do afastamento da arquitetura de etapas da produção, o que afeta o exercício da coordenação modular e que o programa habitacional e as ações políticas de financiamento foram determinantes para a retomada das pesquisas. Entretanto, há ecos dos modelos estabelecidos pelo setor privado, com ênfase à racionalização e à aplicação de componentes industriais. Diante disso, destaca-se que a coordenação modular, como campo da coordenação dimensional, está ligada às necessidades humanas. Modular coordination is a system for relative ordering of dimensions, spaces, and building components. Its application presents remote manifestations through principles that control the design and set suitable scales for the parts and the whole. Nevertheless, the industrial mass production defined the role that the subject would play during the 20th century. In Brazil, its development took place between the 1960s and the 1970s; period that several authors consider decisive in what regards the subject\'s fundamental formatting. From the 1980s on, the specific debates about the matter went through a gap that lasted until the turn of the century when the interest in the field resurfaced. It is consensual among authors that Brazil still has not been successful to implement comprehensive modular coordination standards, but there is a lack of up-to-date analysis as well. The objective of the dissertation - to examine the discipline\'s development in Brazil after 1986 - is based on indications that recent discussions are leaving aside current issues and that there is a weakening of an integrated view of the matter. The main conclusions indicate that a dissociation between architecture and construction has accompanied the building industry\'s development, which affects the application of modular coordination. Moreover, the housing program and the research funding were decisive for the resumption of the field; nonetheless, there are echoes from the models established by the private sector, with emphasis on the rationalization and application of industrial components. In this context, it should be noted that modular coordination, as a field of dimensional coordination, is linked to human needs.

The aggregation of amyloid-beta peptide (Ab) has been linked to the formation of neuritic plaques, which are pathological hallmarks of Alzheimer's disease. We synthesized peptides containing fluorinated amino acids and studied their effect on the Ab aggregation. The peptides were based on the sequence LVFFD, in which valine was substituted by either 4,4,4-trifluorovaline or 4-fluoroproline, or the phenylalanine at position 3 was replaced by 3,4,5-trifluorophenylalanine. Our results demonstrate that fluorination of the hydrophobic residue valine or phenylalanine is effective in preventing the Ab aggregation. This study opens up the possibility of using new sequences based on fluorinated amino acids to inhibit the amyloid- fibril formation.

The study of drug candidates for the treatment of amyloidosis and neurodegenerative diseases frequently involves in vitro measurements of amyloid fibril formation. Macromolecular crowding and off-pathway aggregation (OPA) are, by different reasons, two important phenomena affecting the scalability of amyloid inhibitors and their successful application in vivo. On the one hand, the cellular milieu is crowded with macromolecules that drastically increase the effective (thermodynamic) concentration of the amyloidogenic protein. On the other hand, off-pathway aggregates, rather than amyloid fibrils, are increasingly appointed as causative agents of toxicity. The present contribution reveals that insoluble off-pathway aggregates of hen egg-white lysozyme (HEWL) are a peculiar type of crowding agents that, unlike classical macromolecular crowders, decrease the thermodynamic concentration of protein. Illustrating this effect, OPA is shown to resume after lowering the fraction of insoluble aggregates at a constant soluble HEWL concentration. Protein depletion and thioflavin-T fluorescence progress curves indicate that OPA rebirth is not accompanied by additional amyloid fibril formation. The crystallization-like model extended to account for OPA and time-dependent activity coefficients is able to fit multiple kinetic results using a single set of three parameters describing amyloid nucleation, autocatalytic growth, and off-pathway nucleation. The list of fitted results notably includes the cases of aggregation rebirth and all types of progress curves measured for different HEWL concentrations. The quantitative challenges posed by macromolecular crowding and OPA find here a unified response with broader implications for the development of on- and off-pathway inhibitors

A partir da constatação do método científico e da filosofia de ação propostos por Arthur Conan Doyle para seu detetive Sherlock Holmes, questiona-se a ocorrência desses elementos na ficção televisiva contemporânea. Estabelece-se um paralelo entre a série inglesa Sherlock (2010-2014) e a série americana The good wife (2009-2015), pela análise dos personagens Sherlock Holmes e Kalinda Sharma, a serviço, respectivamente, da acusação e da defesa. O referencial teórico é composto por Jason Mittell quanto a narrativas complexas, André Mendes Machado para o direito processual anglo-americano e por Marcello Truzzi e Carlo Ginsburg para esclarecimento da relação das histórias de Doyle com as formas de pensamento lógico científico.

O modelo Catell-Horn-Carroll divide a inteligência em dez fatores gerais, decompostos em fatores específicos. Estudos da área abordam a possibilidade de estimulação da inteligência, por meio de programas específicos para esse fim. O objetivo do presente estudo foi desenvolver atividades para estimulação de três componentes desse modelo - Inteligência Fluida, Inteligência Cristalizada e Memória de Curto Prazo -, bem como implementar um programa de estimulação e avaliar sua eficácia. O programa foi realizado ao longo de 13 sessões. Participaram do estudo 22 crianças com idade entre 7 e 10 anos, divididas em dois grupos para a realização das atividades. Os instrumentos utilizados no pré e pós-teste foram a Escala Weschsler de Inteligência para Crianças - III, o Teste de Desempenho Escolar e as Matrizes Progressivas Coloridas de Raven. Os resultados apontaram aumento significativo no escore total da Escala Wechsler em todas as análises e no Teste de Desempenho Escolar, no que se refere à estimulação da inteligência cristalizada e memória de curto prazo, o que parece ser indicativo da eficácia do programa. Cattell-Horn-Carroll Model splits intelligence into ten general factors, broken down into specific factors. Studies in the area have discussed whether or not cognitive stimulation is possible through programs designed to do so. The aims of the present study were to develop tasks in order to stimulate three factors of Cattell-Horn-Carroll model - Fluid Intelligence, Crystallized Intelligence and Short-term Memory, to present a program comprised of these tasks, and to assess its efficacy. Program was developed during the course of thirteen sessions. Participants were 22 schoolchildren, age-range from 7 to 10 years, divided into two groups to perform activities. They were evaluated by Wechsler Intelligence Scale for Children III, School Performance Test and Raven's Colored Progressive Matrices during pre and post-test. Results showed significant rise in total score for Wechsler Intelligence Scale for Children III in all analyses; and in School Performance Test for crystallized intelligence and short-term memory, which seems to be indicative of program efficacy.

This work shows promising applications of ultrasound in promoting protein crystallization, which is important for structure determination by X-ray crystallography. It was observed that ultrasound can be used as a nucleation promoter as it decreases the energy barrier for crystal formation. Crystallization experiments on egg-white lysozyme were carried out with and without ultrasonic irradiation using commercial crystallization plates placed in temperature-controlled water baths. The nucleation-promoting effect introduced by ultrasound is illustrated by the reduction of the metastable zone width, as measured by the isothermal microbatch technique. The same effect was confirmed by the increased number of conditions leading to the formation of crystals when vapour diffusion techniques were carried out in the presence of ultrasound. By inducing faster nucleation, ultrasound leads to protein crystals grown at low supersaturation levels, which are known to have better diffraction properties. In fact, X-ray diffraction data sets collected using 13 lysozyme crystals (seven grown with ultrasound and six without) show an average 0.1 Å improvement in the resolution limit when ultrasound was used (p< 0.10). Besides the immediate application of ultrasound in nucleation promotion, the preliminary diffraction results also suggest a promising application in crystal quality enhancement.

It contributes to the formation of a model of integrating management of three distinct collections – Library, Technical Collection and Documentation – in an Engineering Advisory Organization. It presents theoretical reference about knowledge management, better practices of information management and its applicability in the corporative environment. It maps the possibilities of performance of a professional of Information Science area in that context, starting from the demands of the labor market and from the limitations of the academic formation. Supported by attendance observation and by academic papers, it lists management and functional aspects to awell succeeded management of an Information Unit.

Some of the most prevalent neurodegenerative diseases are characterized by the accumulation of amyloid fibrils in organs and tissues. Although the pathogenic role of these fibrils has not been completely established, increasing evidence suggests off-pathway aggregation as a source of toxic/detoxicating deposits that still remains to be targeted. The present work is a step toward the development of off-pathway modulators using the same amyloid-specific dyes as those conventionally employed to screen amyloid inhibitors. We identified a series of kinetic signatures revealing the quantitative importance of off-pathway aggregation relative to amyloid fibrillization; these include non-linear semilog plots of amyloid progress curves, highly variable end point signals, and half-life coordinates weakly influenced by concentration. Molecules that attenuate/intensify the magnitude of these signals are considered promising off-pathway inhibitors/promoters. An illustrative example shows that amyloid deposits of lysozyme are only the tip of an iceberg hiding a crowd of insoluble aggregates. Thoroughly validated using advanced microscopy techniques and complementary measurements of dynamic light scattering, CD, and soluble protein depletion, the new analytical tools are compatible with the high-throughput methods currently employed in drug discovery.

The methodology adopted by Michaelis and Menten in 1913 is still routinely used to characterize the catalytic power and selectivity of enzymes. These kinetic measurements must be performed soon after the purified enzyme is mixed with a large excess of substrate. Other time scales and solution compositions are no less physiologically relevant, but fall outside the range of applicability of the classical formalism. Here we show that the complete picture of an enzyme's mode of function is critically obscured by the limited scope of conventional kinetic analysis, even in the simplest case of a single active site without inhibition. This picture is now unveiled in a mathematically closed form that remains valid over the reaction time for all combinations of enzyme/substrate concentrations and rate constants. Algebraic simplicity is maintained in the new formalism when stationary reaction phases are considered. By achieving this century-old objective, the otherwise hidden role of the reversible binding step is revealed and atypical kinetic profiles are explained. Most singular kinetic behaviors are identified in a critical region of conditions that coincide with typical cell conditions. Because it is not covered by the Michaelis-Menten model, the critical region has been missed until now by low- and high-throughput screenings of new drugs. New possibilities are therefore raised for novel and once-promising inhibitors to therapeutically target enzymes.

Associated with neurodegenerative disorders such as Alzheimer, Parkinson, or prion diseases, the conversion of soluble proteins into amyloid fibrils remains poorly understood. Extensive "in vitro" measurements of protein aggregation kinetics have been reported, but no consensus mechanism has emerged until now. This contribution aims at overcoming this gap by proposing a theoretically consistent crystallization-like model (CLM) that is able to describe the classic types of amyloid fibrillization kinetics identified in our literature survey. Amyloid conversion represented as a function of time is shown to follow different curve shapes, ranging from sigmoidal to hyperbolic, according to the relative importance of the nucleation and growth steps. Using the CLM, apparently unrelated data are deconvoluted into generic mechanistic information integrating the combined influence of seeding, nucleation, growth, and fibril breakage events. It is notable that this complex assembly of interdependent events is ultimately reduced to a mathematically simple model, whose two parameters can be determined by little more than visual inspection. The good fitting results obtained for all cases confirm the CLM as a good approximation to the generalized underlying principle governing amyloid fibrillization. A perspective is presented on possible applications of the CLM during the development of new targets for amyloid disease therapeutics.

Small temperature oscillations (TOs) are shown to increase the success rates of protein crystallization experiments by enhancing protein nucleation and by inducing the formation of larger crystals. This effect was initially found when we accidentally used a defective crystallization incubator and it is now confirmed for the crystallization of egg-white lysozyme at 14 and 20 degrees C, and also glucose isomerase at 20 degrees C, both under experimental conditions close to the nucleation zone of the proteins' phase diagram. Measurements of the nucleation times at constant lysozyme and precipitant concentrations show that the nucleation promoting effect is due to favourable crystallization pathways induced by TOs. The imposed TOs were +/- 1.0 degrees C during complete cycles of 20 min. X-Ray diffraction studies show worst and more disperse resolution limits when the lysozyme crystals are grown at constant temperature (2.05 +/- 0.51 angstrom without TOs, and 1.79 +/- 0.15 angstrom with TOs).