The Effect of Diphenylethane Side-chain Substituents on Dibenzocyclohexadiene Formation and their Inhibition of α-Synuclein Aggregation in vitro

NSERCPeer ReviewedThe naturally-occurring di-catechol lignan nordihydroguaiaretic acid (NDGA) and an analog without methyl groups on the butyl linker both undergo intramolecular cyclization at pH 7.4 to form dibenzocyclooctadienes. Both NDGA and these dibenzocyclooctadienes have been shown to prevent in vitro aggregation of α-synuclein, an intrinsically disordered protein associated with Parkinson's disease. NDGA possesses two vicinal methyl groups on the butyl linker and the presence of these methyl groups attenuates the rate of intramolecular cyclization versus the unsubstituted analog, in opposition to the anticipated Thorpe-Ingold effect, likely due to steric repulsions during cyclization. Numerous 1,2-bis-ethane di-catechols are known to inhibit α-synuclein aggregation in vitro and we hypothesize that these compounds undergo a similar intramolecular cyclization and the cyclized products may be responsible for the activity. To test this hypothesis we prepared a series of 1,2-bis-ethane di-catechols with 0, 2 and 4 methyl substituents on the linker. We have confirmed that these compounds undergo intramolecular cyclization to form dibenzocyclohexadienes and that steric interactions between the methyl substituents leads to an increase in the rate of intramolecular cyclization, which is in contrast to what was observed for lignan di-catechols. The rate of cyclization to form six-membered rings is 10-30 times more rapid than formation of eight membered rings and the dibenzocyclohexadienes also prevent in vitro aggregation of α-synuclein

A crise financeira mundial e as empresas seguradoras norte-americanas: o caso da American Internation Group (AIG)

Compreender os objetivos das políticas financeiras contra a crise e seu desempenho para se evitar o risco sistêmico que a cerca.Compreender os objetivos das políticas financeiras contra a crise e seu desempenho para se evitar o risco sistêmico que a cerca

Effects of acid-base imbalance on vascular reactivity

Acid-base homeostasis maintains systemic arterial pH within a narrow range. Whereas the normal range of pH for clinical laboratories is 7.35-7.45, in vivo pH is maintained within a much narrower range. In clinical and experimental settings, blood pH can vary in response to respiratory or renal impairment. This altered pH promotes changes in vascular smooth muscle tone with impact on circulation and blood pressure control. Changes in pH can be divided into those occurring in the extracellular space (pHo) and those occurring within the intracellular space (pHi), although, extracellular and intracellular compartments influence each other. Consistent with the multiple events involved in the changes in tone produced by altered pHo, including type of vascular bed, several factors and mechanisms, in addition to hydrogen ion concentration, have been suggested to be involved. The scientific literature has many reports concerning acid-base balance and endothelium function, but these concepts are not clear about acid-base disorders and their relations with the three known mechanisms of endothelium-dependent vascular reactivity: nitric oxide (NO/cGMP-dependent), prostacyclin (PGI2/cAMP-dependent) and hyperpolarization. During the last decades, many studies have been published and have given rise to confronting data on acid-base disorder and endothelial function. Therefore, the main proposal of this review is to provide a critical analysis of the state of art and incentivate researchers to develop more studies about these issues.FAPESPFAEP

A ameaça norte-coreana e as relações interamericanas: o que a história tem para nos dizer?

O texto busca, em perspectiva histórica, relacionar a projeção militar norte-coreana e suas repercussões prováveis para as relações interamericanas.O texto busca, em perspectiva histórica, relacionar a projeção militar norte-coreana e suas repercussões prováveis para as relações interamericanas

O Lugar da Democracia na Atual Configuração Internacional

The role of democracy in the international system has stimulated the recentdebate on world order. Underlying the theme is the discussion on globalization and itsconsequences for the nation state. There is no intention of a literature review, but only a fewcritical notes on certain aspects, principles and concepts suggested for the debate. In handlingthese issues, are given positions which have been characterized by the adoption of theoreticalperspectives and interpretations divergent. The text, however, focuses mainly on analyses ofDavid Held, while other views are raised to the extent that their arguments are contradicted,particularly that proceeding from (neo) realist theory.O papel da democracia no sistema internacional tem acalentado o debate recentesobre ordem mundial. Subjacente ao tema encontra-se a discussão sobre a globalização esuas consequências para o Estado-nação. Não se pretende uma revisão bibliográfica, masapenas alguns apontamentos críticos sobre certos aspectos, princípios e conceitos peloassunto aventados. No tratamento dessas questões, são apresentadas posições as quais setêm caracterizado pela adoção de perspectivas teóricas e de interpretações prático-políticasdivergentes. O texto, no entanto, está centrado principalmente nas análises de David Held,ao passo que outras visões são evocadas à medida que se contraponham às suas argumentações,particularmente aquelas provenientes da teoria (neo) realista

YPFS Lessons Learned Oral History Project: An Interview with Raymond Dalio

Suggested Citation Form: Dalio, Ray, 2019. “Lessons Learned Interview. Interview by Andrew Metrick. Yale Program on Financial Stability Lessons Learned Oral History Project. October 17, 2019. Transcript. https://ypfs.som.yale.edu/library/ypfs-lesson-learned-oral-history-project-interview-ray-dali

Cyclization of Polyphenols from Natural Products: Potential Pharmacological and Toxicological Implications

Previously our group identified that the dicatechol lignan nordihydroguaiaretic acid (NDGA) can undergo spontaneous autoxidation and intramolecular cyclization at pH 7.4 to form a dibenzocyclooctadiene (cNDGA). We also observed that autoxidation of NDGA or cNDGA was required for inhibition of -synuclein aggregation in vitro, a protein associated with Parkinson’s disease. A number of dicatechol ethanes have been shown to inhibit -synuclein aggregation in vitro and we propose that the anti-aggregation effects are the result of autoxidation/ intramolecular cyclization. My first goal was to determine if dicatechol ethanes could spontaneously autoxidize/ cyclize and inhibit -synuclein aggregation in vitro. In order to assess the formation of 6-membered ring dicatechols, I synthesized and characterized three diphenylethane analogs with 0, 2 or 4 methyl groups on the 2-carbon linker. I determined that all of the analogs spontaneously cyclize at pH 7.4 into the corresponding dibenzocyclohexadienes which were also oxidatively labile and formed additional oxidation products. The rate of cyclization to form dibenzocyclohexadienes is 10-30 times faster than for dibenzocyclooctadienes and both the diphenylethanes and dibenzocyclohexadienes inhibit -synuclein aggregation in vitro. A second goal of my project was to study the metabolism of quebecol, a triphenylethane natural product isolated from maple syrup production which is under investigation as a chemopreventive and chemotherapeutic, although there are no reports on the hepatic metabolism of quebecol. In order to assess hepatic metabolism, I synthesized and isolated quebecol and investigated its in vitro metabolism in rat liver microsomes (RLM) and human liver microsomes (HLM). I anticipated that phase II metabolism would predominate, and I observed formation of three glucuronide metabolites in both RLM and HLM. To determine the hepatic contribution to first-pass glucuronidation, I validated an HPLC-UV method following FDA and EMA guidelines (selectivity, linearity, accuracy and precision) to quantify quebecol metabolism in microsomes. In vitro enzyme kinetics were performed for quebecol glucuronidation in HLM including 8 concentrations from 5-30 M. I determined a Michaelis-Menten constant (KM) of 5.1 M, intrinsic clearance (Clint) of 0.04 mL/min/mg and maximum velocity (Vmax) of 0.22 mol/min/mg. In contrast I was unable to detect any P450 metabolites of quebecol in either RLM or HLM. In spite of the presence of three phenols that could form para-quinone methides, glutathione (GSH) trapping experiments provided no evidence for reactive intermediate formation. To confirm the absence of para-quinone methides I attempted to prepare standards using MnO2 as oxidant and trapping with GSH. Rather than observe the expected para-quinone methides, instead I observed ortho-quinone formation resulting from MnO2-mediated dealkylation. Together with extensive phase II glucuronidation, this suggests that the risk of reactive intermediate formation from quebecol is negligible

Morfologia da deposição de trombos murais: trajeto da luz residual em aneurismas de aorta abdominal infra-renal

PURPOSE: To assess the most frequent deposition site of mural thrombi in infrarenal abdominal aorta aneurisms, as well as the route of the residual lumen. METHODS: Assessment of CT scan images from 100 patients presenting asymptomatic abdominal aorta aneurism, and followed at HC-FMRP-USP. RESULTS: In 53% of the cases the mural thrombus was deposited on the anterior wall; from these, in 22%, the residual lumen described a predominantly right sided route; in 22%, a left sided route; on the mid line in 5%; and crossing over the mid line in 1%. In 23%, the deposition of thrombi was concentric. In 11% it occured on the posterior wall; from these, in 5%, the route of the residual anterior lumen was predominantly right sided; in 5%, left sided; and crossed over the mid line in 1%. In 13% complex morfological deposition patterns were found. CONCLUSION: Mural thrombi formation was predominantly found on the anterior wall of the aneurismatic mass, with the route of the residual lumen projecting towards the posterior wall.OBJETIVOS: Avaliar o local mais freqüente de deposição do trombo mural em aneurismas de aorta abdominal infrarenal, bem como o trajeto da luz residual. MÉTODOS: Avaliação de tomografias de 100 pacientes do HC-FMRP-USP apresentando aneurisma de aorta abdominal assintomático. RESULTADOS: O trombo mural se deposita na parede anterior em 53% dos casos, sendo que a luz residual posterior descreveu um trajeto predominantemente à direita em 22% dos casos, à esquerda em 22%, na linha mediana em 5% e cruzando da direita para a esquerda em 4%. 23% dos casos apresentaram deposição concêntrica do trombo e 11% apresentaram deposição na parede posterior, sendo o trajeto da luz residual anterior predominante a direita em 5% dos casos, a esquerda em 5% e cruzando a linha mediana em 1%. Padrões morfológicos complexos de deposição do trombo foram encontrados em 13% dos casos. CONCLUSÃO: A formação do trombo mural predominou na parede anterior da massa aneurismática, com o trajeto da luz residual se projetando para a parede posterior.FAEP

Expressão da apoptose em enxertos de veias safenas humana para restauração do fluxo sanguíneo coronariano por derivação

OBJECTIVE: To investigate the possible role of apoptosis on brief distensions of human saphenous veins at different pressures. METHODS: Fresh isolated grafts of human saphenous vein were assigned as control or distended (D) for fifteen seconds at 100, 200 and 300 mmHg. The degree of apoptotic caspases 3, 8, 9 and anti-apoptotic protein Bcl-2 expression were assessed by immunohistochemistry. RESULTS: Fresh isolated segments of distended human saphenous veins presented similar apoptotic protein expression when compared with control veins. However, the Bcl-2 expression was significantly higher in the 300 mmHg distended segments compared with the control vein. CONCLUSION: These findings show that intact segments of human saphenous veins submitted to distensions at different pressures have similar apoptotic proteins expression when compared with non-distended control veins. Therefore, brief distensions commonly performed during surgical harvesting do not trigger apoptosis, and probably are not involved on the physiopathological mechanisms that lead to graft failureOBJETIVO: Investigar o possível papel da apoptose em distensões breves de veias safenas humanas em diferentes pressões. MÉTODOS: Segmentos frescos isolados de veia safena humana foram distribuídos em 4 grupos: controle ou distendidos (D) por quinze segundos a 100, 200 e 300 mmHg. O grau de apoptose das caspases 3, 8, 9 e expressão da proteína anti-apoptótica Bcl-2 foram avaliados por imuno-histoquímica. RESULTADOS: Segmentos frescos distendidos isolados de veias safenas humanas apresentaram expressão protéica para apoptose similar às veias controle. No entanto, a expressão de Bcl-2 foi significativamente maior nos segmentos distendidos a 300 mmHg, quando comparados à veia controle. CONCLUSÃO: Estes achados demonstram que segmentos intactos de veias safenas humanas submetidos a distensões em diferentes pressões têm expressão de proteínas apoptóticas similares quando comparados com veias controle nãodistendidas. Por conseguinte, breves distensões comumente realizadas durante a coleta cirúrgica não ativam o processo de apoptose e, provavelmente, não estão envolvidas em mecanismos fisiopatológicos que levam à falência do enxertoFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)(FAEPA) Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (USP) - Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínica

PpCRN7 and PpCRN20 of phythophthora parasitica regulate plant cell death leading to enhancement of host susceptibility

Phytophthora species secrete cytoplasmic effectors from a family named Crinkler (CRN), which are characterised by the presence of conserved specific domains in the N- and C-terminal regions. P. parasitica causes disease in a wide range of host plants, however the role of CRN effectors in these interactions remains unclear. Here, we aimed to: (i) identify candidate CRN encoding genes in P. parasitica genomes; (ii) evaluate the transcriptional expression of PpCRN (Phytophthora parasitica Crinkler candidate) during the P. parasitica interaction with Citrus sunki (high susceptible) and Poncirus trifoliata (resistant); and (iii) functionally characterize two PpCRNs in the model plant Nicotiana benthamiana. Results Our in silico analyses identified 80 putative PpCRN effectors in the genome of P. parasitica isolate 'IAC 01/95.1'. Transcriptional analysis revealed differential gene expression of 20 PpCRN candidates during the interaction with the susceptible Citrus sunki and the resistant Poncirus trifoliata. We have also found that P. parasitica is able to recognize different citrus hosts and accordingly modulates PpCRNs expression. Additionally, two PpCRN effectors, namely PpCRN7 and PpCRN20, were further characterized via transient gene expression in N. benthamiana leaves. The elicitin INF-1-induced Hypersensitivity Response (HR) was increased by an additive effect driven by PpCRN7 expression, whereas PpCRN20 expression suppressed HR response in N. benthamiana leaves. Despite contrasting functions related to HR, both effectors increased the susceptibility of plants to P. parasitica. Conclusions PpCRN7 and PpCRN20 have the ability to increase P. parasitica pathogenicity and may play important roles at different stages of infection. These PpCRN-associated mechanisms are now targets of biotechnological studies aiming to break pathogen's virulence and to promote plant resistance19CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ445390/2014–0; 465440/2014–