Metabolites of PPI-2458, a selective, irreversible inhibitor of methionine aminopeptidase-2: structure determination and In vivo activity

The natural product fumagillin exhibits potent antiproliferative and antiangiogenic properties. The semisynthetic analog PPI-2458, (3R,4S,5S,6R)-5-methoxy-4-(2R,3R)-2-methyl-3-(3-methylbut-2-enyl) oxiran-2-yl]-1-oxaspiro2.5]octan-6-yl] N-(2R)-1-amino-3-methyl-1-oxobutan-2-yl]carbamate, demonstrates rapid inactivation of its molecular target, methionine aminopeptidase-2 (MetAP2), and good efficacy in several rodent models of cancer and inflammation with oral dosing despite low apparent oral bioavailability. To probe the basis of its in vivo efficacy, the metabolism of PPI-2458 was studied in detail. Reaction phenotyping identified CYP3A4/5 as the major source of metabolism in humans. Six metabolites were isolated from liver microsomes and characterized by mass spectrometry and nuclear resonance spectroscopy, and their structures were confirmed by chemical synthesis. The synthetic metabolites showed correlated inhibition of MetAP2 enzymatic activity and vascular endothelial cell growth. In an ex vivo experiment, MetAP2 inhibition in white blood cells, thymus, and lymph nodes in rats after single dosing with PPI-2458 and the isolated metabolites was found to correlate with the in vitro activity of the individual species. In a phase 1 clinical study, PPI-2458 was administered to patients with non-Hodgkin lymphoma. At 15 mg administered orally every other day, MetAP2 in whole blood was 80% inactivated for up to 48 hours, although the exposure of the parent compound was only similar to 10% that of the summed cytochrome P450 metabolites. Taken together, the data confirm the participation of active metabolites in the in vivo efficacy of PPI-2458. The structures define a metabolic pathway for PPI-2458 that is distinct from that of TNP-470 ((3R, 4S, 5S, 6R)-5-methoxy-4-(2R, 3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro2.5]octan-6 -yl] N-(2-chloroacetyl)carbamate). The high level of MetAP2 inhibition achieved in vivo supports the value of fumagillin-derived therapeutics for angiogenic diseases.

Study of Multilevel Sinusoidal PWM methods for Cascaded H-Bridge Multilevel Inverters

This paper is a study of Multilevel Sinusoidal Pulse Width Modulation (MSPWM) methods; Phase Disposition (PD), Alternate Phase Opposition Disposition (APOD), Phase Opposition Disposition (POD) on a single phase Cascaded H-Bridge Multilevel inverter. Various factors such as amplitude modulation index (Ma), frequency modulation index (M-f), phase angle between carrier and reference modulating wave (phi) have been considered for simulation. Variation in these factors and their effect on inverter performance is evaluated. Factors such as DC bus utilization, output r.m.s voltage, total harmonic distortion (%THD), dominant harmonic order, switching losses are evaluated based on simulation results.

Do carboximide-carboxylic acid combinations form co-crystals? The role of hydroxyl substitution on the formation of co-crystals and eutectics

Carboxylic acids, amides and imides are key organic systems which provide understanding of molecular recognition and binding phenomena important in biological and pharmaceutical settings. In this context, studies of their mutual interactions and compatibility through co-crystallization may pave the way for greater understanding and new applications of their combinations. Extensive co-crystallization studies are available for carboxylic acid/amide combinations, but only a few examples of carboxylic acid/imide co-crystals are currently observed in the literature. The non-formation of co-crystals for carboxylic acid/imide combinations has previously been rationalized, based on steric and computed stability factors. In the light of the growing awareness of eutectic mixtures as an alternative outcome in co-crystallization experiments, the nature of various benzoic acid/cyclic imide combinations is established in this paper. Since an additional functional group can provide sites for new intermolecular interactions and, potentially, promote supramolecular growth into a co-crystal, benzoic acids decorated with one or more hydroxyl groups have been systematically screened for co-crystallization with one unsaturated and two saturated cyclic imides. The facile formation of an abundant number of hydroxybenzoic acid/cyclic carboximide co-crystals is reported, including polymorphic and variable stoichiometry co-crystals. In the cases where co-crystals did not form, the combinations are shown invariably to result in eutectics. The presence or absence and geometric disposition of hydroxyl functionality on benzoic acid is thus found to drive the formation of co- crystals or eutectics for the studied carboxylic acid/imide combinations.

Peptide delta-Turn: Literature Survey and Recent Progress

Among the various types of a-peptide folding motifs, delta-turn, which requires a central cis-amide disposition, has been one of the least extensively investigated. In particular, this main-chain reversal topology has been studied in-depth neither in linear/cyclic peptides nor in proteins. This Minireview article assembles and critically analyzes relevant data from a literature survey on the d-turn conformation in those compounds. Unpublished results from recent conformational energy calculations and a preliminary solution-state analysis on a small model peptide, currently ongoing in our laboratories, are also briefly outlined.

Molecular Mechanism Underlying ATP-Induced Conformational Changes in the Nucleoprotein Filament of Mycobacterium smegmatis RecA

RecA plays a central role in bacterial DNA repair, homologous recombination, and restoration of stalled replication forks by virtue of its active extended nucleoprotein filament. Binding of ATP and its subsequent recognition by the carboxamide group of a highly conserved glutamine (GIn196 in MsRecA) have been implicated in the formation of active RecA nucleoprotein filaments. Although the mechanism of ATP-dependent structural transitions in RecA has been proposed on the basis of low-resolution electron microscopic reconstructions, the precise sequence of events that constitute these transitions is poorly understood. On the basis of biochemical and crystallographic analyses of MsRecA variants carrying mutations in highly conserved Gln196 and Arg198 residues, we propose that the disposition of the interprotomer interface is the structural basis of allosteric activation of RecA. Furthermore, this study accounts, for the contributions of several conserved amino acids to ATP hydrolysis and to the transition from collapsed to extended filament forms in Mycobacterium smegmatis RecA (MsRecA). In addition to their role in the inactive compressed state, the study reveals a role for GIn196 and Arg198 along with Phe219 in ATP hydrolysis in the active extended nucleoprotein filament. Finally, our data suggest that the primary, but not secondary, nucleotide binding site in MsRecA isomerizes into the ATP binding site present in the extended nucleoprotein filament.

La cuestión del estatus de la bioética contemporánea

Resumen: Este artículo es una breve exposición sobre la consolidación de la bioética como práctica social que, a través de la atención acentuada en el actuar de la gente común y sus principios generales de resolución, describe conductas humanas capaces de resolver situaciones específicas con dilemas éticos. Además, muestra la disposición de la bioética para encarar amenazas de la biomedicina o consecuencias negativas del mercantilismo y pragmatismo en la manipulación de la vida, la medicina o la fármaco-industria; así también, su capacidad para facilitar el diálogo sobre la admisibilidad moral de nuevas bio-tecnologías, para desarrollar la cosmovisión profesional en la toma de posicionamiento moral, o como una institución social en formación.

Analyses of the mechanical properties and microstructure of bamboo epoxy composites

Bamboo reinforced epoxy possesses reasonably good properties to waarrant its use as a structural material, and is fabricated by utilizing bamboo, an abundant material resource, in the technology of fibre composites. Literature on bamboo-plastics composites is rare. This work is an experimental study of unidirectional bamboo-epoxy laminates of varying laminae number, in which tensile, compressive, flexural and interlaminar shear properties are evaluated. Further, the disposition of bamboo fibre, the parenchymatous tissue, and the resin matrix under different loading conditions are examined. Our results show that the specific strength and specific modulus of bamboo-epoxy laminates are adequate, the former being 3 to 4 times that of mild steel. Its mechanical properties are generally comparable to those of ordinary glass-fibre composites. The fracture behaviour of bamboo-epoxy under different loading conditions were observed using both acoustic emission techniques and scanning electron microscopy. The fracture mode varied with load, the fracture mechanism being similar to glass and carbon reinforced composites. Microstructural analyses revealed that natural bamboo is eligibly a fibre composite in itself; its inclusion in a plastic matrix will help solve the problems of cracking due to desiccation and bioerosion caused by insect pests. Furthermore, the thickness and shape of the composite can be tailored during fabrication to meet specific requirements, thereby enabling a wide spectrum of applications.

The influence of buoyancy on the oscillatory thermocapillary convection with small bond number

This work is an experimental study of unidirectional bamboo-epoxy laminates of varying laminae number, in which tensile, compressive, flexural and interlaminar shear properties are evaluated. Further, the disposition of bamboo fibre, the parenchymatous tissue, and the resin matrix under different loading conditions are examined. Our results show that the specific strength and specific modulus of bamboo-epoxy laminates are adequate, the former being 3 to 4 times that of mild steel. Its mechanical properties are generally comparable to those of ordinary glass-fibre composites. The fracture behaviour of bamboo-epoxy under different loading conditions were observed using both acoustic emission techniques and scanning electron microscopy. The fracture mode varied with load, the fracture mechanism being similar to glass and carbon reinforced composites. Microstructural analyses revealed that natural bamboo is eligibly a fibre composite in itself; its inclusion in a plastic matrix will help solve the problems of cracking due to desiccation and bioerosion caused by insect pests. Furthermore, the thickness and shape of the composite can be tailored during fabrication to meet specific requirements, thereby enabling a wide spectrum of applications.

Analysis of SUMOylated proteins using SUMO-traps

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Petrarca y las primeras ediciones de Terencio

[ES] De entre las ediciones de Terencio publicadas en las primeras décadas de la imprenta, las de Vindelino de Espira son las que muestran una mayor voluntad filológica y, sin duda, las que ofrecen un texto más correcto. Estas ediciones dependen del texto terenciano reconstruido por Petrarca: concretamente, IGI 9408 desciende de una fase textual anterior a la que queda fijada en 1358 y responde además a algunos de los criterios propugnados por Petrarca en la Vita Terrentii; IGI 9409, por su parte, depende —parcialmente— del texto de 1358 y muestra indicios de haber sufrido la influencia de otro ejemplar de Petrarca. En fin, la presencia de la Vita Terrentii en la transmisión impresa de Terencio es una muestra más de la vigencia de la filología terencia de Petrarca durante aquellos años.

Euskal autore zaharren irakaskuntza Lehen Hezkuntzan: proiektu berritzaile baten proposamena

Euskara: Lan honek euskal autore zaharrak Lehen Hezkuntzako ikasleei hurbiltzea du helburu. Ezinbestekoa da neska-mutilek ikasgeletan klasikoen ondarea ezagutzeko aukera izatea, euskal autore zaharren irakaskuntza-ikaskuntza prozesua suspertzeko. Izan ere, idazle klasikoak oinarrizko hezkuntzan duten tokia ez da handia izan, hauek lantzeak zailtasunak dakartzalako. Beraz, zailtasun horiek aztertuta eta lekuko idazle ezberdinen lan hautatuen egokitze-lana aintzat hartuz, proiektu berritzaile baten proposamena eskaini nahi da, euskarazko literatura zaharra irakurtzeko eta lantzeko zaletasuna sustatzeko bidea erakusteko asmoz. Horrela izanik, ikasleek euren neurrira eta interesetara moldatutako egitasmoa eskura izango dute, egungo hezkuntza-sisteman beharrezkoak diren oinarrizko gaitasunak barneratuz, beti ere gaiarekiko motibazioa eta jakin-mina aintzat hartuta.

Emissões de compostos orgânicos voláteis de um aterro controlado e o potencial formador de ozônio

O presente estudo teve como objetivo quantificar as emissões de Compostos Orgânicos Voláteis do Aterro Controlado Morro do Céu localizado na cidade de Niterói, Rio de Janeiro, Brasil. Para tanto, vinte amostras foram coletadas, usando uma bomba de ar operada a bateria durante dois dias de dezembro de 2009. Uma câmara de fluxo cilíndrica de PVC de 30L foi inserida 5 cm no solo do aterro, e as amostras foram coletadas através de uma válvula na parte superior da câmera. Os resultados indicaram um valor de 1.980 Kg Km-2 h-1. O modelo Gaussiano de dispersão atmosférica ISCST3 foi utilizado para calcular a difusão e transporte dos poluentes a fim de estimar as concentrações de COV no bairro, usando dados topográficos, meteorológicos e de emissões. Valores de 525 μg m-3 de COV foram encontrados a 500 metros do aterro. As emissões do aterro foram usadas em conjunto com dados meteorológicos, utilizando o modelo de trajetória OZIPR e o mecanismo químico SAPRC para demonstrar o impacto na formação do ozônio troposférico na região. É conhecido que o ozônio é formado pela reação entre COV, NOx e luz solar. A contribuição de valores elevados de COV provenientes das emissões do aterro conduzirá a uma nova situação com valores mais elevados de ozônio na região. Os resultados da modelagem indicaram um aumento maior que 1000% nos níveis de ozônio na região do aterro, se comparado com a modelagem do ozônio para a região metropolitana do Rio de Janeiro. Os resultados mostram ser necessário que maior atenção seja dada à política de gerenciamento de RSU no Brasil, incluindo a escolha adequada para o local de instalação, o monitoramento da área durante e após o período de operação e técnicas mais adequadas de disposição dos resíduos sólidos urbanos

A eloquência do mundo: a heteronímia como potência retórica impessoal

A partir da suspeita de que o pensamento e sua expressão não se limitam a uma única forma, o presente trabalho investiga de que modo podemos pensar, a partir de Fernando Pessoa, uma relação possível entre filosofia e literatura. Quais os pressupostos que permitem considerar o fenômeno heteronímico pessoano como um expediente trágico que diz respeito ao próprio pensamento, ou ainda, como entrever, no projeto pessoano, o lugar de embate trágico, por excelência entre aquilo que somos, enquanto sujeitos, e os processos que franqueiam à escrita a constituição de uma subjetividade outra? Desdobrada em heterônimos, a obra de Pessoa comportaria em si a justaposição de formas diversas de ver e compreender o mundo, mas o processo pelo qual este desdobramento se dá poderia ser tomado como anterior às formas constituídas das personalidades particulares, apresentando-se como uma disposição anti-dialética do pensamento. Privilegiando como ponto de partida os escritos do heterônimo louco e filósofo de Fernando Pessoa, António Mora, nosso intuito é analisar de que modo sua crítica à tradição metafísica ocidental, em ressonância com a filosofia francesa contemporânea de inspiração nietzschiana, pode se constituir como um intercessor capaz de dar a ver uma potência impessoal atuando entre a filosofia e a literatura, representada pelo verso de Alberto Caeiro: a natureza é partes sem um todo"

Avaliação númérica de ensaios push-out com conectores de cisalhamento tipo pino e perfobond.

Recentemente a utilização de estruturas mistas, aço concreto, vem ganhando espaço nas construções. Isso deve-se principalmente a economia de tempo em sua execução. Além disto, nesta solução a utilização do aço e do concreto otimiza as características estruturais de seus elementos: a resistência a tração do aço e a compressão do concreto. A transferência dos esforços entre os dois materiais possui grande influência no desempenho de uma estrutura mista, sendo comum a utilização de conectores de cisalhamento na região da interface entre estes dois materiais. O Eurocode 4 define um ensaio experimental denominado push-out de modo a determinar a resistência e ductilidade de conectores de cisalhamento. Seu desempenho é influenciado pelas resistências do concreto a compressão, as dimensões e taxa de armadura da laje de concreto, dimensões do perfil de aço, a disposição e a geometria dos conectores e pelas características dos aços utilizados no conector, no perfil e nas barras de reforço. Nota-se com isso uma grande quantidade de variáveis que influenciam o ensaio. Assim, o presente trabalho apresenta o desenvolvimento de um modelo em elementos finitos com base no programa ANSYS para simulação de ensaios push-out. Os resultados numéricos apresentados neste trabalho foram calibrados com resultados obtidos em ensaios experimentais existentes na literatura de ensaios push-out para conectores do tipo pino com cabeça (stud) e conectores tipo perfobond. Estes últimos apresentam elevada resistência sendo influenciados por inúmeros fatores como: número e diâmetro dos furos no conector e a inclusão ou não de barras de reforço extras nestes furos.

Keep an "eye" on the text: The Use of Self-mention in the Academic Writing of Experts

One of the most controversial inquiries in academic writing is whether it is admissible to use first person pronouns in a scientific paper or not. Many professors discourage their students from using them, rather favoring a more passive tone, and thus causing novices to avoid inserting themselves into their texts in an expert-like manner. Abundant research, however, has recently attested that negotiation of identity is plausible in academic prose, and there is no need for a paper to be void of an authorial identity. Because in the course of the English Studies Degree we have received opposing prompts in the use of I, the aim of this dissertation is to throw some light upon this vexed issue. To this end, I compiled a corpus of 16 Research Articles (RAs) that comprises two sub-corpora, one featuring Linguistics RAs and the other one Literature RAs, and each, in turn, consists of articles written by American and British authors. I then searched for real occurrences of I, me, my, mine, we, us, our and ours, and studied their frequency, rhetorical functions and distribution along each paper. The results obtained certainly show that academic writing is no longer the faceless prose that it used to be, for I is highly used in both disciplines and varieties of English. Concerning functions, the most typically used roles were the use of I to take credit for the writer’s research process, and also those involving plural forms. With respect to the spatial disposition, all sections welcomed first person pronouns, but the Method and the Results/Discussion sections seem to stimulate their appearance. On the basis of these findings, I suggest that an L2 writing pedagogy that is mindful not only of the language proficiency, but also of the students’ own identity may have a beneficial effect on the composition of their texts.