Fast, multi-band photon detectors based on quantum well devices for beam-monitoring in new generation light sources

In order to monitor the photon-beam position for both diagnostics and calibration purposes, we have investigated the possibility to use InGaAs/InAlAs Quantum Well (QW) devices as position-sensitive photon detectors for Free-Electron Laser (FEL) or Synchrotron Radiation (SR). Owing to their direct, low-energy band gap and high electron mobility, such QW devices may be used also at Room Temperature (RT) as fast multi-band sensors for photons ranging from visible light to hard X-rays. Moreover, internal charge-amplification mechanism can be applied for very low signal levels, while the high carrier mobility allows the design of very fast photon detectors with sub-nanosecond response times. Segmented QW sensors have been preliminary tested with 100-fs-wide 400 nm laser pulses and X-ray SR. The reported results indicate that these devices respond with 100 ps rise-times to such ultra-fast laser pulses. Besides, linear scan on the back-pixelated device has shown that these detectors are sensitive to the position of each ultrashort beam bunch

Structure-based Development of Secondary Amines as Aspartic Protease Inhibitors

As novel promising scaffold for HIV protease inhibition pyrrolidine-derived inhibitors have recently been reported. In this thesis the stepwise improvement of this compound class to potent inhibitors of wildtype as well as selected mutant proteases utilizing rational drug discovery methods is reported. Based on the crystal structure of a (rac)-3,4-dimethyleneamino-pyrrolidine in complex with HIV-1 protease symmetric pyrrolidine-diesters possessing the same stereochemistry were synthesized following a chiral-pool approach. The most potent compounds of the series achieve one-digit micromolar inhibition towards wild type as well as two mutant proteases (Ile50Val and Ile84Val). The cocrystal structure of one derivative in complex with the Ile84Val HIV protease revealed that two inhibitor molecules are bound in the large active site cavity comprising an area encompassed by the catalytic dyad and the flaps in the open conformation. This is the first HIV protease cocrystal structure in which the open-flap conformation of the enzyme is stabilized by an inhibitor that concomitantly addresses the catalytic dyad. As an alternative approach towards HIV protease inhibitors, the development of symmetric 3,4-bis N-alkyl sulfonamide-pyrrolidines is described. The initial lead structure possessing benzene sulfonamide groups and benzyl substituents exhibited a Ki of 2.2 µM. The X-ray structure in complex with the HIV protease enabled the rational design of a second series of inhibitors and revealed three promising symmetric substitution patterns for further lead optimization: (A) Elongation of the P1/P1’-benzyl moieties with hydrophobic substituents in para-position, (B) ortho-substitution at the P2/P2’-phenyl ring systems, and (C) para-substitution at the P2/P2’-phenyl moieties. All three strategies were pursued and resulted in inhibitors with improved affinities up to 260 nM. To elucidate the underlying factors accounting for the SAR, the crystal structures of four representatives, at least one of each modification type, in complex with HIV protease were determined. These structures provided deeper insights into the protein–ligand interactions and the underlying principles of the SAR thus enabling to choose the most promising combination of substituents in the next design cycle. The combination of these substituents rendered a final inhibitor showing a significantly improved affinity of Ki = 74 nM and the cocrystal structure in complex with the HIV protease confirmed the successful application of the pursued optimization strategy. Subsequently the influence of the active site mutations Ile50Val and Ile84Val on these inhibitors is investigated by structural and kinetic analysis. Whereas the Ile50Val mutation leads to a significant decrease in affinity for all compounds in this series, they retain or even show increased affinity towards the crucial Ile84Val mutation. By detailed analysis of the crystal structures of two representatives in complex with wild-type and mutant proteases the structural basis of this phenomenon was elucidated. Inhibitors bearing smaller N-alkyl substituents revealed a selectivity profile not being explicable with the initial SAR. By cocrystallization of the most potent derivative of a small series with HIV-1 protease, astonishingly two different crystal forms, P2(1)2(1)2(1) and P6(1)22, were obtained. Structural analysis revealed two completely different binding modes, the interaction of the pyrrolidine nitrogen atom to the catalytic aspartates being the only similarity. Encouraged by the successful utilization of cyclic secondary amines as anchoring group in the development of HIV protease inhibitors, this strategy was expanded into a general approach for lead structure identification for aspartic proteases. An initial library comprising eleven inhibitors based on easily accessible achiral linear oligoamines was developed and screened against six selected aspartic proteases (HIV-1 protease, plasmepsin II, plasmepsin IV, renin, BACE-1, and pepsin). Several hits could be identified, among them selective as well as rather promiscuous inhibitors. The design concept was consecutively confirmed by determination of the crystal structure of two derivatives in complex with HIV-1 protease. The binding modes exhibit high similarity to the binding orientation of substrates as well as to that of peptidomimetic inhibitors. Using this information, a generalization of this binding situation to other aspartic proteases appears reasonable, thus providing a first insight into the observed structure-activity relationships

On symmetric X-ray beam splitting with high efficiency by use of reflection gratings with rectangular profile in the extreme off-plane configuration.

In order to be reflected or diffracted off a surface structure soft X-rays and hard X-rays need to impinge at grazing angles of incidence onto the surface. In case of a reflection grating of highly symmetric structure with rectangular groove profile these grooves can be oriented parallel to the beam trajectory. In such a symmetric situation the distribution of the diffracted intensity with respect to the plane of incidence is then expected to be symmetric. This is indeed observed with symmetrically oriented diffraction peaks. It can be predicted that for appropriate structure parameters the intensity can be contained mostly in two symmetrically oriented diffraction peaks. This will also be the case for hard X-rays. The diffraction efficiency will be particularly high, when the angle of grazing incidence is chosen in the total reflection regime below the critical angle of the grating coating. These predictions were experimentally verified in this work for hard X-rays with photon energies between 4 keV and 12.4 keV. In the experiment of the order of 30% of the incident intensity was diffracted into the two first orders. This is to be compared to reflectivities of the order of 50% measured at the same coating in an unruled area of the substrate. Consequently the relative structural diffraction efficiency for each first order was about 30%, while ideally it could have been 40%. The presented grating structure will thus be a rather efficient amplitude beam splitter for hard X-rays, e.g. in the coherent beam from a free electron laser. In addition such object could then be used as the first component in Michelson interferometers for the beam characterisation or for introducing a time delay between two coherent beams

Hematological and biochemical profiles of canine CD45−T lymphomas are different from other immunophenotypes

Fondo María Viñas - ANI

Quem venceu a Guerra do Iraque? Um estudo sobre a Doutrina Bush, a invasão do Iraque e suas consequências para a República Islâmica do Irã

TCC (graduação) - Universidade Federal de Santa Catarina. Centro Sócio-Econômico. Relações Internacionais.A guerra do Iraque, iniciada em 2003 com a invasão estadunidense ao país, é um dos conflitos mais destrutivos do século XXI. Suas consequências, que se deram em todos os âmbitos - nacionais e internacionais -, se estendem até os dias de hoje, e a nação iraquiana ainda as vive diariamente. Porém, outros países foram também afetados diretamente pelo conflito. No caso do Irã, a invasão do Iraque representou um momento de mudança e de aproximação com seu antigo rival, além de introduzir uma nova organização de forças e uma nova geopolítica na região do Oriente Médio. O presente trabalho tem como hipótese principal a de que o Irã foi beneficiado em termos econômicos e estratégicos pela invasão dos Estados Unidos ao Iraque. A partir de um método de abordagem hipotético-dedutivo e o uso de dados primários e empíricos, a pesquisa apresenta um arcabouço teórico formado pela teoria realista, uma revisão da política externa estadunidense, uma análise da política externa da Doutrina Bush sob um viés realista ofensivo e uma revisão historiográfica da formação dos Estados do Irã e do Iraque com o objetivo de contextualizar o leitor e auxiliar a testar a hipótese - o que será feito a partir da análise de dados empíricos.The Iraq war, which began in 2003 with the US invasion of the country, is one of the most destructive conflicts of the 21st century. Its consequences, which took place in all spheres - national and international -, extend to the present day, and the Iraqi nation still lives them daily. However, other countries were also directly affected by the conflict. In the case of Iran, the invasion of Iraq represented a moment of change and rapprochement with its former rival, as well as introducing a new organization of forces and a new geopolitics in the Middle East region. The present work has as its main hypothesis that Iran was benefited in economic and strategic terms by the US invasion of Iraq. From a hypothetical-deductive approach method and the use of primary and empirical data, the research presents a theoretical framework formed by realist theory, a review of US foreign policy, an analysis of the Bush Doctrine's foreign policy under an offensive realist bias and a historiographical review of the formation of the states of Iran and Iraq in order to contextualize the reader and help test the hypothesis - which will be done from the analysis of empirical data

Efeito do canabidiol sobre a reconsolidação da memória de medo ao contexto: envolvimento dos receptores CB1 do córtex pré-límbico

Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia, Florianópolis, 2014.A busca por drogas que prejudicam a reconsolidação de memórias traumáticas pode ter um impacto clínico bastante importante. O canabidiol (CBD) é o principal componente da Cannabis sativa desprovido de efeitos psicotomiméticos e seguro para o uso em animais de laboratório e em humanos. Considerando que o CBD atenua a expressão da ansiedade e facilita o processo de extinção de memórias aversivas, o objetivo do presente trabalho foi investigar em ratos se ele também interfere com a reconsolidação de uma memória de medo condicionada ao contexto, bem como avaliar a participação do córtex pré-frontal medial (CPFm) no processo de reconsolidação e nos efeitos sistêmicos do CBD. Para tanto, imediatamente após a evocação da memória de ratos previamente condicionados, o CBD foi administrado (3 ? 30 mg/kg). Foi observado, uma redução na porcentagem de congelamento até 22 dias após o tratamento com a dose de 10 mg/kg. Não ocorreu reinstalação da memória, e o mesmo efeito foi observado quando testado em uma memória mais velha (7 dias), foi bloqueado pelo antagonista dos receptores canabinoides do tipo 1 (AM251 1 mg/kg; CB1), mas não pelo antagonista dos receptores de serotonina do tipo 5-HT1A (WAY 0,1 mg/kg), e não foi evidente quando a evocação da memória foi omitida. Tais resultados indicam que o CBD prejudica a reconsolidação de uma memória aversiva, um efeito dependente da ativação indireta do sistema endocanabinoide. Uma hora após a evocação da memória, foi observado um aumento na expressão da proteína Zif268 no CPFm, principalmente nas subdivisões do córtex cingulado (CC) e pré-límbico (PL), mas não no infralímbico (IL). Esse aumento não foi observado quando a memória não foi evocada e foi atenuado com a administração de CBD. Esse conjunto de resultados sugere que o CC participa da reconsolidação, indicando também um papel para o PL nesse fenômeno. Para confirmar o papel do córtex PL na reconsolidação, essa estrutura foi inativada imediatamente após a evocação da memória de 1, 7 e 21 dias. Em todos os casos, foi observada, uma redução na porcentagem de congelamento quando os animais foram retestados no dia seguinte. Novamente, esse efeito foi duradouro e não sofreu reinstalação, confirmando que a atividade do córtex PL é importante para essa etapa de re-estabilização da memória. Quando o CBD foi administrado sistemicamente, o bloqueio dos receptores CB1 com AM251 (50 pmol/0.2 µL) no córtex PL preveniu o efeito amnéstico. A inibição da FAAH pelo URB597 (200 pmol/0,2 µL)administrado diretamente no córtex PL imediatamente após a evocação da memória, também prejudica a reconsolidação. Em conjunto, esses resultados confirmam a participação do córtex PL na reconsolidação de uma memória de medo e demonstram que os receptores CB1 dessa área são recrutados pelo CBD quando ele prejudica a reconsolidação.Abstract : The search for reconsolidation blockers may uncover clinically relevant drugs to disrupt memories of significant stressful life experiences. In this sense, cannabidiol (CBD), the major non-psychotomimetic component of Cannabis and a compound safe to be used in rodents and in humans, might be relevant. Based on the fact that CBD facilitates fear extinction and is anxiolityc, and on the evidence that many CBD effects are mediated by the medial prefrontal cortex activity (mPFC), the aim of the present study was to evaluate whether the systemic injection of CBD in rats, could mitigate an established contextual fear memory, by blocking its reconsolidation, evaluating the role of mPFC in this step of memory processing and in the CBD effects. CBD (3 ? 30 mg/kg) was administered immediately after fear memory retrieval in rats previously conditioned. It was observed a reduction in the percentage of freezing time until 22 days after the treatment, with the most effective dose (10 mg/kg). This effect was not accompanied by fear memory reinstatement, it was seen when tested in an older memory (7 days old), it could be blocked by the cannabinoid receptor CB1 antagonist AM251 (1 mg/kg), but not by the serotonin receptor 5-HT1A antagonist WAY100635 (0.1 mg/kg), suggesting that CBD disrupts fear memory reconsolidation by the endocannabinoid system. One hour after retrieval, it was observed an increase in Zif268 expression in the mPFC, mainly in its cingulate (CC) and prelimbic (PL) parts, but not in infralimbic (IL). When memory retrieval was omitted, the Zif268 expression was not seen and the CBD systemic administration prevented the expression in CC and PL. These results confirm the CC role in reconsolidation and suggest a role for PL cortex. To confirm the role of PL cortex in fear memory reconsolidation, this structure was temporarily inactivated with muscimol (4.0 nmol/0.2 µL) immediately after retrieval of different memory ages (1, 7 and 21 days old). In all cases, a reduction in the percentage of freezing time was observed one day later. This effect was long lasting and did not present reinstatement, confirming that PL cortex activity subserves fear memory reconsolidation. When the CBD was administered systemically, the blockade of CB1 receptors with AM251 (50 pmol/0.2 µL) in PL cortex prevented the CBD effect in fear memory reconsolidation. The inhibition of FAAH by URB597 injected bilaterally into the PL cortex (200 pmol/0.2 µL) immediately after fear memory retrieval also impaired its reconsolidation. Altogether, the results confirm that theactivity of PL cortex subserves fear memory reconsolidation, acting as a neural substrate to the CBD effects

Estupro Genocida: como a tática de guerra marcou a sociedade ruandesa

O presente artigo objetiva analisar a utilização do estupro como arma de guerra nos conflitos, tendo como foco o genocídio em Ruanda. Para tal, traçar-se-á um panorama da violação sexual de mulheres durante enfrentamentos bélicos, as construções sociais que explicam a eficácia da tática, assim como a evolução do Direito Internacional perante o assunto. Após, realizar-se-á um estudo de caso sobre o genocídio ruandês, a utilização do estupro durante o conflito e as consequências de tal estratégia, as quais as autoras concluem ainda serem percebidas na sociedade ruandesa