Inflammasomes: Caspase-1-Activating Platforms with Critical Roles in Host Defense

Activation of the inflammatory cysteine protease caspase-1 in inflammasome complexes plays a critical role in the host response to microbial infections. Inflammasome activation induces inflammation through secretion of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and through extracellular release of the alarmin high mobility group box 1. Moreover, caspase-1 activation by inflammasomes counters bacterial replication and induces pyroptosis, a specialized cell death program that removes infected immune cells as part of the host defense system. It is thus not surprising that bacterial and viral pathogens evolved virulence factors targeting inflammasome activation and activity. Here, we provide an overview of the distinct inflammasome complexes that are activated in a pathogen-specific manner and discuss the diverse strategies employed by viruses and bacteria to modulate inflammasome function

Letter to Sonora Dodd from the Evande Company, Publishers, April 4, 1911

Letter to Sonora Dodd from the Evande Company, Publishers, Utica, New York.https://digitalcommons.whitworth.edu/fathers-day-correspondence/1008/thumbnail.jp

MEDIDAS TRIBUTÁRIAS PARA O ENFRENTAMENTO DA PANDEMIA DO CORONAVÍRUS: ALTERNATIVAS PARA O BRASIL

: Este artigo analisa de que forma medidas tributárias podem ser utilizadas como instrumento de combate às consequências econômicas da pandemia do Coronavírus. Para isso são listadas diversas medidas tributárias de curto prazo já tomadas no mundo, comparando-as com as adotadas no Brasil, com o objetivo de avaliar se as nossas foram suficientes. São também considerados os ajustes recomendados no processo de saída do confinamento e as alternativas de políticas tributárias que órgãos internacionais e a academia, estrangeira e pátria, sugerem para o pagamento das dívidas assumidas e a reconstrução das economias nacionais e global. Conclui-se com uma análise crítica da possibilidade de adoção de algumas dessas alternativas em nosso país. A metodologia empregada é a pesquisa bibliográfica, baseada em revisão da bibliografia internacional e nacional sobre medidas tributárias adotadas e propostas para o enfrentamento da pandemia do Coronavírus publicadas entre fevereiro e maio de 2020. O método de pesquisa adotado é o hipotéticodedutivo

O Papel do Poder Judiciário em Matéria Tributária no Contexto da Calamidade Pública

Objetivos: O artigo analisa as principais decisões tomadas em matéria tributária no contexto da pandemia causada pela Covid-19 em 2020. A pesquisa concentra-se nos casos em que os efeitos da pandemia foram tomados como causa de pedir, separando-os em quatro temas: (1) suspensão do pagamento de tributos; (2) pedidos de substituição do depósito judicial por seguro garantia; (3) suspensão das restrições impostas pela Lei de Responsabilidade Fiscal para a concessão de benefícios fiscais e (4) refinanciamento da dívida pública.Metodologia: A pesquisa adotou uma abordagem dedutiva e técnica de pesquisa bibliográfica e documental, com a análise da literatura jurídica e de julgados de diferentes instâncias de tribunais brasileiros relacionados à temática do artigo.Resultados: O texto conclui que as competências do Judiciário, especialmente do Supremo Tribunal Federal, foram exercidas de modo parcimonioso em matéria tributária, com predomínio da função acautelatória à espera de pronunciamentos legislativos para os temas em questão.Contribuições: O artigo traz análise original da postura do Supremo Tribunal Federal no período da pandemia, ressaltando sua atitude de autocontenção frente às competências legislativas no enfrentamento geral da crise econômica em matéria tributária, e de forte efetividade, com o uso de instrumentos virtuais, na conclusão de julgamentos de feitos relacionados a tributos que há muito aguardavam apreciação do Plenário.Palavras-chave: Contencioso judicial tributário; pandemia; Covid-19; Política Tributária. ABSTRACTObjective: This article analyzes the main decisions related to tax matters in the context of the pandemic caused by Covid-19 in 2020. The survey focuses on cases in which the effects of the pandemic were taken as the main reason of the action, considering four issues: (1) taxes payment suspension; (2) requests for replacement of the judicial deposit for surety bonds; (3) suspension of restrictions imposed by the Fiscal Responsibility Law to the granting of tax benefits and (4) public debt refinancing.Methodology: The research adopted a deductive approach and bibliographic and documental research techniques, with the analysis of legal literature and of judgments of different instances of the Judiciary Branch on the subject.Results: The text concludes that the Judiciary Branch, especially the Federal Supreme Court, used its powers with caution in tax matters, as a rule limiting its decisions to protective measures while waiting for legislative ruling.Contributions: The article makes an original analysis of the Federal Supreme Court's stance during the pandemic, highlighting its attitude of self-restraint towards the legislative competences related to the economic crisis confrontation in tax matters, and of strong effectiveness, with the use of virtual instruments, in the conclusion of tax judgments that have long awaited the appreciation of the Court Full Bench.Keywords: Tax litigation; pandemic; Covid-19; Tax Policy

International Cooperation in Tax Matter: the Exchange of Tax Information in the Context of a Global Tax Authority

Este artigo analisa a participação do Brasil no processo de consolidação da cooperação jurídica em matéria tributária, no que se convencionou chamar de “Autoridade Tributária Global”, bem como o modo como a evolução desse debate repercutiu na orientação jurisprudencial adotada pelo STF quanto à possibilidade de o Fisco acessar informações bancárias dos contribuintes sem necessidade de prévia autorização judicial. Avalia, ainda, os cuidados a serem tomados nesse percurso, em especial com os direitos dos contribuintes, a proteção de dados e os custos de implementação. A metodologia empregada é a pesquisa bibliográfica, baseada na revisão de literatura internacional e nacional e de precedentes judiciais sobre o tema. O método de pesquisa adotado é o hipotético-dedutivo.info:eu-repo/semantics/publishedVersio

Cystathionine β-Synthase Mutations: Effect of Mutation Topology on Folding and Activity

Misfolding of mutant enzymes may play an important role in the pathogenesis of cystathionine β-synthase (CBS) deficiency. We examined properties of a series of 27 mutant variants, which together represent 70% of known alleles observed in patients with homocystinuria due to CBS deficiency. The median amount of SDS-soluble mutant CBS polypeptides in the pellet after centrifugation of bacterial extracts was increased by 50% compared to the wild type. Moreover, mutants formed on average only 12% of tetramers and their median activity reached only 3% of the wild-type enzyme. In contrast to the wild-type CBS about half of mutants were not activated by S-adenosylmethionine. Expression at 18°C substantially increased the activity of five mutants in parallel with increasing the amounts of tetramers. We further analyzed the role of solvent accessibility of mutants as a determinant of their folding and activity. Buried mutations formed on average less tetramers and exhibited 23 times lower activity than the solvent exposed mutations. In summary, our results show that topology of mutations predicts in part the behavior of mutant CBS, and that misfolding may be an important and frequent pathogenic mechanism in CBS deficiency. Hum Mutat 31:1–11, 2010. © 2010 Wiley-Liss, Inc

Cystathionine beta-synthase mutants exhibit changes in protein unfolding: conformational analysis of misfolded variants in crude cell extracts

Protein misfolding has been proposed to be a common pathogenic mechanism in many inborn errors of metabolism including cystathionine β-synthase (CBS) deficiency. In this work, we describe the structural properties of nine CBS mutants that represent a common molecular pathology in the CBS gene. Using thermolysin in two proteolytic techniques, we examined conformation of these mutants directly in crude cell extracts after expression in E. coli. Proteolysis with thermolysin under native conditions appeared to be a useful technique even for very unstable mutant proteins, whereas pulse proteolysis in a urea gradient had limited values for the study of the majority of CBS mutants due to their instability. Mutants in the active core had either slightly increased unfolding (p.A114V, p.E302K and p.G307S) or extensive unfolding with decreased stability (p.H65R, p.T191M, p.I278T and p.R369C). The extent of the unfolding inversely correlated with the previously determined degree of tetrameric assembly and with the catalytic activity. In contrast, mutants bearing aminoacid substitutions in the C-terminal regulatory domain (p.R439Q and p.D444N) had increased global stability with decreased flexibility. This study shows that proteolytic techniques can reveal conformational abnormalities even for CBS mutants that have activity and/or a degree of assembly similar to the wild-type enzyme. We present here a methodological strategy that may be used in cell lysates to evaluate properties of proteins that tend to misfold and aggregate and that may be important for conformational studies of disease-causing mutations in the field of inborn errors of metabolism

Human Polycomb 2 Protein Is a SUMO E3 Ligase and Alleviates Substrate-Induced Inhibition of Cystathionine β-Synthase Sumoylation

Human cystathionine β-synthase (CBS) catalyzes the first irreversible step in the transsulfuration pathway and commits homocysteine to the synthesis of cysteine. Mutations in CBS are the most common cause of severe hereditary hyperhomocysteinemia. A yeast two-hybrid approach to screen for proteins that interact with CBS had previously identified several components of the sumoylation pathway and resulted in the demonstration that CBS is a substrate for sumoylation. In this study, we demonstrate that sumoylation of CBS is enhanced in the presence of human polycomb group protein 2 (hPc2), an interacting partner that was identified in the initial yeast two-hybrid screen. When the substrates for CBS, homocysteine and serine for cystathionine generation and homocysteine and cysteine for H2S generation, are added to the sumoylation mixture, they inhibit the sumoylation reaction, but only in the absence of hPc2. Similarly, the product of the CBS reaction, cystathionine, inhibits sumoylation in the absence of hPc2. Sumoylation in turn decreases CBS activity by ∼28% in the absence of hPc2 and by 70% in its presence. Based on these results, we conclude that hPc2 serves as a SUMO E3 ligase for CBS, increasing the efficiency of sumoylation. We also demonstrate that γ-cystathionase, the second enzyme in the transsulfuration pathway is a substrate for sumoylation under in vitro conditions. We speculate that the role of this modification may be for nuclear localization of the cysteine-generating pathway under conditions where nuclear glutathione demand is high

Alterations in stress granule dynamics driven by TDP-43 and FUS: A link to pathological inclusions in ALS?

Stress granules (SGs) are RNA-containing cytoplasmic foci formed in response to stress exposure. Since their discovery in 1999, over 120 proteins have been described to be localized to these structures (in 154 publications). Most of these components are RNA binding proteins (RBPs) or are involved in RNA metabolism and translation. SGs have been linked to several pathologies including inflammatory diseases, cancer, viral infection and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In ALS and FTD, the majority of cases have no known etiology and exposure to external stress is frequently proposed as a contributor to either disease initiation or the rate of disease progression. Of note, both ALS and FTD are characterized by pathological inclusions, where some well-known SG markers localize with the ALS related proteins TDP-43 and FUS. We propose that TDP-43 and FUS serve as an interface between genetic susceptibility and environmental stress exposure in disease pathogenesis. Here, we will discuss the role of TDP-43 and FUS in SG dynamics and how disease-linked mutations affect this process

Quadro comparativo da Constituição Federal com a Proposta de Emenda Constitucional nº 110, de 2019, do Senado Federal

Consultoria Legislativa - Área III - Direito Tributário e Tributação.Apresenta quadro comparativo entre a Constituição Federal e a Proposta de Emenda Constitucional nº 110, de 2019, do Senado Federal, que trata da reforma tributária