Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells

Advanced hormone-refractory prostate cancer is associated with poor prognosis and limited treatment options. Members of the pyrrolo-1,5-benzoxazepine (PBOX) family of compounds exhibit anti-cancer properties in cancer cell lines (including multi-drug resistant cells), ex vivo patient samples and in vivo mouse tumour models with minimal toxicity to normal cells. Recently, they have also been found to possess anti-angiogenic properties in vitro. However, both the apoptotic pathways and the overall extent of the apoptotic response induced by PBOX compounds tend to be cell-type specific. Since the effect of the PBOX compounds on prostate cancer has not yet been elucidated, the purpose of this study was to investigate if PBOX compounds induce anti-proliferative effects on hormone-refractory prostate cancer cells. We examined the effect of two representative PBOX compounds, PBOX-6 and PBOX-15, on the androgen-independent human prostate adenocarcinoma cell line, PC3. PBOX-6 and -15 displayed anti-proliferative effects on PC3 cells, mediated initially through a sustained G2/M arrest. G2/M arrest, illustrated as DNA tetraploidy, was accompanied by microtubule depolymerisation and phosphorylation of anti-apoptotic proteins Bcl-2 and Bcl-xL and the mitotic spindle checkpoint protein BubR1. Phosphorylation of BubR1 is indicative of an active mitotic checkpoint and results in maintenance of cell cycle arrest. G2/M arrest was followed by apoptosis illustrated by DNA hypoploidy and PARP cleavage and was accompanied by degradation of BubR1, Bcl-2 and Bcl-xL. Furthermore, sequential treatment with the CDK1-inhibitor, flavopiridol, synergistically enhanced PBOX-induced apoptosis. In summary, this in vitro study indicates that PBOX compounds may be useful alone or in combination with other agents in the treatment of hormone-refractory prostate cancer.

The United Kingdom, the United Nations Human Rights Council and the first cycle of the Universal Periodic Review

The introduction of the Universal Periodic Review (UPR) mechanism as an innovative component of the new Human Rights Council in 2006 has suffered little academic scrutiny. This is partly because it holds as its objective an improvement in human rights situations on the ground, a goal that is difficult to test amongst so many possible causal factors attributable to law reform and policy change, and partly due to the fact that the mechanism has only completed one full cycle of review. This article seeks to remedy this absence of analysis by examining the experience of the United Kingdom during its first review. In doing so, the article first considers the conception of the UPR, before progressing to examine the procedure and recommendations made to the UK by its peers. Finally, the article considers the five year review of the UPR which occurred as a subset of the Human Rights Council Review in 2011 and the resulting changes to the process modalities.

Techno-Economic and Life Cycle Assessment on Lignocellulosic Biomass Thermochemical Conversion Technologies: A Review

Bioenergy derived from biomass provides a promising energy alternative and can reduce the greenhouse gas (GHG) emissions generated from fossil fuels. Biomass-based thermochemical conversion technologies have been acknowledged as apt options to convert bioresources into bioenergy; this bioenergy includes electricity, heat, and fuels/chemicals in solid, liquid, and gaseous phases. In this review, the techno-economic and life cycle assessment of these technologies (combustion, gasification, pyrolysis, liquefaction, carbonization, and co-firing) are summarized. Specific indicators (production costs in a techno-economic analysis, functional units and environmental impacts in a life cycle analysis) for different technologies were compared. Finally, gaps in research and future trends in biomass thermochemical conversion were identified. This review could be used to guide future research related to economic and environmental benefits of bioenergy.

HES6 drives a critical AR transcriptional programme to induce castration-resistant prostate cancer through activation of an E2F1-mediated cell cycle network

Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance, other factors such as c-Myc and the E2F family also play a role in later stage disease. HES6 is a transcription co-factor associated with stem cell characteristics in neural tissue. Here we show that HES6 is up-regulated in aggressive human prostate cancer and drives castration-resistant tumour growth in the absence of ligand binding by enhancing the transcriptional activity of the AR, which is preferentially directed to a regulatory network enriched for transcription factors such as E2F1. In the clinical setting, we have uncovered a HES6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted by inhibition of PLK1 with restoration of sensitivity to castration. We have therefore shown for the first time the critical role of HES6 in the development of CRPC and identified its potential in patient-specific therapeutic strategies.

The synapsin cycle:a view from the synaptic endocytic zone

Although the synapsin phosphoproteins were discovered more than 30 years ago and are known to play important roles in neurotransmitter release and synaptogenesis, a complete picture of their functions within the nerve terminal is lacking. It has been shown that these proteins play an important role in the clustering of synaptic vesicles (SVs) at active zones and function as modulators of synaptic strength by acting at both pre- and postdocking levels. Recent studies have demonstrated that synapsins migrate to the endocytic zone of central synapses during neurotransmitter release, which suggests that there are additional functions for these proteins in SV recycling.

A magnetic cycle of τ Bootis? The coronal and chromospheric view

τ Bootis is a late F-type main sequence star orbited by a Hot Jupiter. During the last years spectropolarimetric observations led to the hypothesis that this star may host a global magnetic field that switches its polarity once per year, indicating a very short activity cycle of only one year duration. In our ongoing observational campaign, we have collected several X-ray observations with XMM-Newton and optical spectra with TRES/FLWO in Arizona to characterize τ Boo's corona and chromosphere over the course of the supposed one-year cycle. Contrary to the spectropolarimetric reconstructions, our observations do not show indications for a short activity cycle.

Engenharia Geológica na Universidade de Évora. A experiência dos estágios integrados em empresas no 1º Ciclo – Modelo 3G; Prosseguimento de estudos e integração de alunos no exterior no âmbito do 2º Ciclo.

Resumo Resultado de um investimento em meios humanos e materiais no domínio da Geo-Engenharia, ao longo de quase três décadas, a Universidade de Évora detém hoje um reconhecimento junto dos empregadores que têm acolhido os alunos desta instituição nas suas empresas. Este trabalho destina-se a partilhar a experiência que a Universidade de Évora (UE) acumulou no Ensino e Formação em Geo-Engenharia, em contexto empresarial. O Curso de Licenciatura em Engenharia Geológica da Universidade de Évora (LEG), assim como mais dois cursos da UE são pioneiros em Portugal, na medida em que preveem nos seus planos curriculares a possibilidade de os alunos puderem realizar estágios em contexto de trabalho no âmbito de Unidades Curriculares do 6º Semestre dos respetivos Cursos. No caso do LEG, apôs um período intensivo de quatro a cinco semanas de formação na Universidade, seguem-se três semanas de estágio numa empresa a eleger entre as trinta e duas que até agora aceitaram estabelecer protocolos para este fim. Este processo repete-se duas vezes por semestre. Em alternativa, os alunos que não desejem frequentar estes estágios terão uma formação clássica na Universidade. Neste artigo, apresentam-se os resultados até agora alcançados com este ensino diferenciado. A adaptação ao modelo de Bologna dos ensinos de 1º e 2º Ciclo resultou num défice de formação curricular indispensável para o pleno exercício da profissão de Engenheiro Geólogo. As competências específicas adquiridas ao fim de cada ciclo foram indicadas pela Ordem dos Engenheiros que contudo ressalva a necessidade de uma formação em Engenharia no 1º Ciclo para reconhecer as competências a atribuir a cada graduado nos mestrados de Engenharia. A experiência de formação no 2º ciclo em Engenharia Geológica, onde sensivelmente metade dos alunos é externa a Universidade de Évora, é alvo de análise neste trabalho. Palavras-Chave: Ensino; Engenharia Geológica; Bolonha; Competências; Empregabilidade Abstract Result of an investment in human and material resources in the field of Geo-Engineering, over nearly three decades, the University of Évora has now a recognition among employers that have accepted students of this institution in their companies. This work intended's to share University of Évora (UE) business context accumulated experiences in Education and Training in Geo-Engineering. The Degree in Geological Engineering from the University of Évora (LEG), as well as two courses in the UE are pioneers in Portugal, to the extent their curricula to possible students internships that can be perform in the workplace under Curricular Units of the 3th Year of the courses. In the case of the LEG, after an intensive period of four to five weeks of training at the University the students who desire it, can have a three weeks internship in a company to elect between the thirty-two that so far agreed to establish protocols with the UE, for this purpose. This process is repeated twice per semester. Alternatively, students who do not wish to attend these stages will have a classical education at the University. In this article, we present the results achieved so far with differentiated teaching. The adaptation to the Bologna model of 1st and 2nd cycles resulted in a lack of training curriculum essential to the full exercise of the Engineer Geologist profession. The specific skills acquired at the end of each cycle were indicated by the Engineers Chamber, however pointed needed training in the 1st Cycle Engineering to recognize the skills to give each graduate in Masters of Engineering. The experience of training in the 2nd cycle in Geological Engineering, where roughly half of the students came outside of the University of Évora, is also analyzed in this work. Keywords: Education, Engineering Geology, Bologna; Skills; Employability

A new combined joules supercritical rankine cycle exergetic analysis and optimization

The application of a supercritical Rankine cycle in combined cycles does not happen in today’s thermoelectric power stations. Nevertheless, the most recent development in gas turbines, that allows a high efficiency and high exhaust gases temperatures, and the improvement of high pressure and temperature alloys, makes this cycle possible. This study’s intent is to prove the viability of this combined cycle, since it can break the 60% efficiency barrier, which is the plafond in actual power stations. To attain this target, several configurations for this cycle have been simulated, optimized and analyzed [1]. The simulations were done with the computational program IPSEpro [2] and the optimizations were effectuated with software developed for the effect, using the DFP method [3]. In parallel with the optimization that claims the cycle’s efficiency maximization, an exergetic analysis was also made [4] to all the cycle components. In opposite to what happens in subcritical combined cycles, it was demonstrated that in supercritical combined cycles the higher efficiency takes place with a single steam pressure in the heat recovery steam generator (HRSG).

The life cycle of Engraulis encrasicolus sensu lato in the Guadiana estuary: Ecology, Ecohydrology and Biology

Tese dout., Ecologia das populações, Universidade do Algarve, 2007

Le rapport aux traces écrites en situation d'évaluation de lecture de textes narratifs brefs le cas d'élèves au deuxième cycle du secondaire

La présente recherche porte sur les traces écrites laissées par des élèves de quatrième secondaire sur leur texte en situation de préparation à une évaluation sommative. Compte tenu des milieux d'où ils proviennent et de leurs connaissances antérieures, force est de constater que les compétences en lecture de ces élèves sont très variables et ont des conséquences importantes non seulement dans leur cours de français, mais aussi dans toutes les autres matières: plus les élèves avancent dans leur cheminement scolaire, plus les enseignants leur demandent de lire des textes longs et complexes. Pourtant, force est de constater que les résultats en lecture des élèves de quatrième et cinquième secondaire restent faibles. De nombreuses études ont démontré que la lecture de textes narratifs mobilise tous les aspects de la lecture et augmente les compétences générales à lire. Pour les enseignants de français, une façon courante d'évaluer la lecture au deuxième cycle du secondaire est donc de distribuer un texte narratif bref (conte, nouvelle, extrait de roman) à l'avance aux élèves et de leur suggérer d'y laisser des traces écrites de leur réflexion ou des stratégies utilisées, dans le but de favoriser leur compréhension et leur interprétation du texte. Ces traces peuvent prendre la forme, par exemple, de soulignements, de surlignements, d'annotations dans les marges, de schémas. Toutefois, peu de recherches scientifiques se sont attardées aux opinions, aux conceptions et aux pratiques des élèves lorsqu'il s'agit de se préparer à une évaluation de la sorte. Notre recherche, exploratoire et descriptive, vise deux objectifs spécifiques: premièrement, décrire l'investissement, les opinions et attitudes, les conceptions et le mode d'investissement d'élèves de quatrième secondaire et, deuxièmement, décrire les relations entre ces quatre dimensions afin de dresser un portrait global du rapport des élèves aux traces écrites lors de leur préparation à une évaluation de lecture. Pour ce faire, nous avons privilégié une collecte de données en trois phases: après avoir passé, à un échantillon de 41 élèves volontaires, des questionnaires présentant des items à coter sur une échelle de Likert, nous avons observé les textes sur lesquels des traces de leur travail de préparation étaient visibles. Pour finir, nous avons rencontré quatre de ces élèves en entrevue semi-dirigées, choisis en fonction de leurs réponses aux questionnaires et du type de traces qu'ils avaient laissées. Pour augmenter la validité des résultats, les données recueillies à chacune des phases [ont] été croisées afin d'obtenir un maximum d'informations sur le rapport des élèves aux traces écrites. Les résultats obtenus montrent que, malgré le fait que les élèves ont des perceptions généralement assez positives du recours aux traces écrites, les traces qu'ils laissent généralement sur leurs textes sont peu pertinentes dans la mesure où elles ne contribuent pas, pour la plupart, à établir des liens essentiels à la compréhension globale du texte narratif, comme les liens de causalité. Les entrevues nous apprennent que certains élèves ont effectivement l'impression que certaines traces écrites sont plus pertinentes que d'autres, mais qu'ils ignorent souvent lesquelles et comment y recourir pendant leur lecture. Le rapport aux traces écrites est complexe, dépend de la situation et varie d'un individu à l'autre en fonction de plusieurs facteurs contextuels: les expériences et connaissances antérieures de l'élève, la résistance du texte imposé et les contacts avec les pairs. Tous ces facteurs influencent l'élève dans ce qu'il pense, ce qu'il ressent et ce qu'il fait lors de la préparation à une évaluation de lecture.

Mythotextuality and the evolution of ideologies the reuse of the Epic of Gilgamesh in North American texts

When the scribes of ancient Mesopotamia rewrote the Epic of Gilgamesh over a period of over two thousand years, the modifications made reflected the social transformations occurring during the same era. The dethroning of the goddess Inanna-Ishtar and the devaluation of other female characters in the evolving Epic of Gilgamesh coincided with the declining status of women in society. Since the 1960s, translations into modern languages have been readily available. The Mesopotamian myth has been reused in a wide variety of mythic and mythological texts by Quebecois, Canadian and American authors. Our analysis of the first group of mythic texts, written in the 1960s and 1970s, shows a reversal of the tendency of the Mesopotamian texts. Written at a time when the feminist movement was transforming North American society, these retellings feature a goddess with her high status restored and her ancient attributes re-established. Another group of writers, publishing in the 1980s and 1990s, makes a radical shift away from these feminist tendencies while still basically rewriting the Epic. In this group of mythic texts, the goddess and other female characters find their roles reduced while the male gods and characters have expanded and glorified roles. The third group of texts analysed does not rewrite the Epic. The Epic is reused here intertextually to give depth to mythological works set in the twentieth century or later. The dialogue created between the contemporary text and the Epic emphasises the role that the individual has in society. A large-scale comparative mythotextual study of texts that share a common hypotext can, especially when socio-historical factors are considered, provide a window onto the relationship between text and society. A comparative study of how the Epic of Gilgamesh is rewritten and referred to intertextually through time can help us relativize the understanding of our own time and culture.