SURVEY AND SUMMARY: Recent advances in the elucidation of the mechanisms of action of ribozymes

The cleavage of RNA can be accelerated by a number of factors. These factors include an acidic group (Lewis acid) or a basic group that aids in the deprotonation of the attacking nucleophile, in effect enhancing the nucleophilicity of the nucleophile; an acidic group that can neutralize and stabilize the leaving group; and any environment that can stabilize the pentavalent species that is either a transition state or a short-lived intermediate. The catalytic properties of ribozymes are due to factors that are derived from the complicated and specific structure of the ribozyme–substrate complex. It was postulated initially that nature had adopted a rather narrowly defined mechanism for the cleavage of RNA. However, recent findings have clearly demonstrated the diversity of the mechanisms of ribozyme-catalyzed reactions. Such mechanisms include the metal-independent cleavage that occurs in reactions catalyzed by hairpin ribozymes and the general double-metal-ion mechanism of catalysis in reactions catalyzed by the Tetrahymena group I ribozyme. Furthermore, the architecture of the complex between the substrate and the hepatitis delta virus ribozyme allows perturbation of the pKa of ring nitrogens of cytosine and adenine. The resultant perturbed ring nitrogens appear to be directly involved in acid/base catalysis. Moreover, while high concentrations of monovalent metal ions or polyamines can facilitate cleavage by hammerhead ribozymes, divalent metal ions are the most effective acid/base catalysts under physiological conditions.

The brain-specific activator p35 allows Cdk5 to escape inhibition by p27Kip1 in neurons.

Cell cycle withdrawal in postmitotic cells involves cyclin-dependent kinase (Cdk) inhibitors that repress cell cycle Cdk activity. During mouse neurogenesis, cortical postmitotic neurons are shown here to accumulate high levels of the p27 Cdk inhibitor compared with their progenitor neuroblasts. Elevated p27 levels in staged embryo brain extracts correlate with p27 binding to Cdk2, and Cdk inactivation. Yet, Cdk5, which is associated with the noncyclin activator p35 in neurons, remains active in the presence of high p27 levels. Both in vitro and in vivo, p27 and related inhibitors can recognize a cyclin D-Cdk5 complex but not a p35-Cdk5 complex. The results indicate that the choice of activator determines the susceptibility of Cdk5 to p27 and related Cdk inhibitors, and thus its ability to act in postmitotic cells.

Conformation, energy, and folding ability of selected amino acid sequences.

Evolutionary selection of sequences is studied with a knowledge-based Hamiltonian to find the design principle for folding to a model protein structure. With sequences selected by naive energy minimization, the model structure tends to be unstable and the folding ability is low. Sequences with high folding ability have only the low-lying energy minimum but also an energy landscape which is similar to that found for the native sequence over a wide region of the conformation space. Though there is a large fluctuation in foldable sequences, the hydrophobicity pattern and the glycine locations are preserved among them. Implications of the design principle for the molecular mechanism of folding are discussed.

Nutraceutical approach to the modulation of cholesterol metabolism: in vitro and in vivo studies

Negli ultimi anni, si sono diffusi nuove strategie per il trattamento delle malattie cardiovascolari, che possano supportare una terapia medica, o in alcuni casi, sostituirla. Infatti, l’abbandono delle terapie è il più importante problema di salute pubblica del mondo occidentale, soprattutto per le malattie croniche. Ciò è dovuto alla complessità delle terapie farmacologiche e ai numerosi e in alcuni casi gravi effetti collaterali dei farmaci somministrati. Di conseguenza, una riduzione di questi effetti migliorerebbe le condizioni di vita del paziente e quindi diminuirebbe il rischio di abbandono della terapia. Per ottenere ciò, è possibile affiancare al trattamento farmacologico una terapia nutraceutica, consistente nella somministrazione di complessi molecolari o microorganismi, provenienti da piante, latte o cibi funzionali. Lo scopo generale di questo studio è indagare le attività ipolipidemizzanti di un composto nutraceutico e di un ceppo batterio specifico nel modello animale che presenta elevati alti livelli plasmatici di colesterolo. Inoltre, sono stati analizzati gli effetti del trattamento nutraceutico sui meccanismi fisiologici che contrastano la creazione della placca aterosclerotica come l’efflusso di colesterolo dalle “foam cells” presenti nell’ateroma, o la riduzione dell’assorbimento intestinale di colesterolo. La presente tesi è divisa in due parti. Nella prima parte, abbiamo analizzato la capacità dei Bifidobacteria di ridurre i livelli di colesterolo nel medium di crescita. Dall’analisi, si è osservato che vari ceppi del genere Bifidobacteria presentano un’ampia capacità di assimilazione del colesterolo all’interno della cellula batterica, in particolare il Bifidobacterium bifidum PRL2010. Le analisi di trascrittomica del Bb PRL2010 incubato in presenza di colesterolo, hanno rivelato un significativo aumento dei livelli di trascrizione di geni codificanti trasportatori e riduttasi, responsabili del meccanismo di accumulo all’interno della cellula batterica e della conversione del colesterolo in coprostanolo. L’attività ipolipidemizzante del Bb PRL2010 è stata poi valutata nel modello murino, mostrando la modificazione del microbiota dei topi trattati dopo somministrazione del batterio in questione. Nella seconda parte del progetto di ricerca, abbiamo indagato sugli effetti di un composto coperto da brevetto, chiamato “Ola”, sull’efflusso di colesterolo di criceti trattati con questo composto nutraceutico. L’efflusso di colesterolo è il primo step del meccanismo fisiologico noto come Trasporto Inverso del Colesterolo, che consente l’eliminazione del colesterolo dalle placche aterosclerotiche, attraverso l’interazione fra le HDL, presenti nella circolazione sanguigna, e specifici trasportatori delle foam cells, come ABCA1/G1 e SR-BI. In seguito, le lipoproteine rilasciano il colesterolo alle cellule epatiche, dove è metabolizzato ed escreto attraverso le feci. Per valutare l’effetto dell’Ola sul profilo lipidico dei criceti, sono state condotte analisi in vitro. I risultati mostrano un aumento dell’efflusso di colesterolo in cellule che esprimono il trasportatore ABCA1, comparato con il gruppo controllo. Questi due studi mostrano come l’approccio nutraceutico può essere un importante modo per contrastare l’aterosclerosi. Come mostrato in letteratura, gli effetti dei composti nutraceutici sull’aterosclerosi e su altre malattie croniche, hanno portato a un ampio uso come supporto alle terapie farmacologiche, ed in alcuni casi hanno rimpiazzato la terapia farmacologica stessa.

Rigorous Design of Complex Distillation Columns Using Process Simulators and the Particle Swarm Optimization Algorithm

We present a derivative-free optimization algorithm coupled with a chemical process simulator for the optimal design of individual and complex distillation processes using a rigorous tray-by-tray model. The proposed approach serves as an alternative tool to the various models based on nonlinear programming (NLP) or mixed-integer nonlinear programming (MINLP) . This is accomplished by combining the advantages of using a commercial process simulator (Aspen Hysys), including especially suited numerical methods developed for the convergence of distillation columns, with the benefits of the particle swarm optimization (PSO) metaheuristic algorithm, which does not require gradient information and has the ability to escape from local optima. Our method inherits the superstructure developed in Yeomans, H.; Grossmann, I. E.Optimal design of complex distillation columns using rigorous tray-by-tray disjunctive programming models. Ind. Eng. Chem. Res.2000, 39 (11), 4326–4335, in which the nonexisting trays are considered as simple bypasses of liquid and vapor flows. The implemented tool provides the optimal configuration of distillation column systems, which includes continuous and discrete variables, through the minimization of the total annual cost (TAC). The robustness and flexibility of the method is proven through the successful design and synthesis of three distillation systems of increasing complexity.

ConfChem Conference on A Virtual Colloquium to Sustain and Celebrate IYC 2011 Initiatives in Global Chemical Education—The Global Experiment of the IYC2011: Creating Online Communities for Education and Science

The Global Experiment, Water: A Chemical Solution, was one of the flagship activities of the International Year of Chemistry (IYC). During the virtual colloquium of the spring 2012 online ConfChem conference, the main results of this year-long experiment were presented and discussed online for a week. Some of the main conclusions of the virtual conversations relate to the benefits of creating online communities of people sharing similar interests, the use of online educational platforms to gather massive amounts of data, and specific questions about the development of this IYC initiative. The activities of the global water experiment (GWE) were designed by a team of experts and the protocols are available online on the GWE Web site. The results were shown in one interactive world map that allowed students to learn about data visualization, validation, and interpretation. The feedback obtained from the participants of the GWE and later by the contributors of the virtual colloquium was very positive. Many participants asked specific and technical questions about the development of this experiment, while others excitedly endorsed the convenience of these large open-access activities to promote chemistry worldwide. The estimate is that over 2 million people took part in the GWE during the IYC. This communication summarizes one of the invited papers to the ConfChem online conference: A Virtual Colloquium to Sustain and Celebrate IYC 2011 Initiatives in Global Chemical Education, held from May 18 to June 29, 2012 and hosted by the ACS DivCHED Committee on Computers in Chemical Education and the IUPAC Committee on Chemistry Education.

Teachers’ beliefs about diversity: an analysis from a personal and professional perspective

The purpose of this study was to examine the beliefs that teachers have about diversity and their level of sensitivity towards some topics related to it. Moreover, beliefs were compared according to teachers’ personal and professional views and teaching experience. The Personal and Professional Beliefs about Diversity Scales (Pohan and Aguilar, 1999) were administered to a sample of 233 teachers. Results showed highly positive beliefs towards diversity in all its dimensions (cultural, linguistic and social diversity, ability, gender, sexual orientation and religion), especially regarding its personal implications compared to the professional ones. Likewise, it was observed a significant relationship between years of teaching experience and professional beliefs about diversity, so teachers with no school experience showed a higher tolerance than those with teaching experience, mainly in aspects related to cultural, linguistic and social differences, ability and gender. The implications that these results have for educational practice and the need for the development of multicultural education courses that favour an effective teaching are discussed.

Enseñando a programar: un camino directo para desarrollar el pensamiento computacional

Está ampliamente aceptado que es fundamental desarrollar la habilidad de resolver problemas. El pensamiento computacional se basa en resolver problemas haciendo uso de conceptos fundamentales de la informática. Nada mejor para desarrollar la habilidad de resolver problemas usando conceptos informáticos que una asignatura de introducción a la programación. Este trabajo presenta nuestras reflexiones acerca de cómo iniciar a un estudiante en el campo de la programación de computadores. El trabajo no detalla los contenidos a impartir, sino que se centra en aspectos metodológicos, con la inclusión de experiencias y ejemplos concretos, a la vez que generales, extensibles a cualquier enseñanza de programación. En general, aunque se van desarrollado lenguajes cada vez más cercanos al lenguaje humano, la programación de ordenadores utilizando lenguajes formales no es una materia intuitiva y de fácil comprensión por parte de los estudiantes. A la persona que ya sabe programar le parece una tarea sencilla, pero al neófito no. Es más, dominar el arte de la programación es complejo. Por esta razón es indispensable utilizar todas las técnicas y herramientas posibles que faciliten dicha labor.

Expertise in Ultra-Endurance Triathletes Early Sport Involvement, Training Structure, and the Theory of Deliberate Practice

The theory of deliberate practice (Ericsson, Krampe, & Tesch-Römer, 1993) is predicated on the concept that the engagement in specific forms of practice is necessary for the attainment of expertise. The purpose of this paper was to examine the quantity and type of training performed by expert UE triathletes. Twenty-eight UE triathletes were stratified into expert, middle of the pack, and back of the pack groups based on previous finishing times. All participants provided detailed information regarding their involvement in sports in general and the three triathlon sports in particular. Results illustrated that experts performed more training than non-experts but that the relationship between training and performance was not monotonic as suggested by Ericsson et al. Further, experts' training was designed so periods of high training stress were followed by periods of low stress. However, early specialization was not a requirement for expertise. This work indicates that the theory of deliberate practice does not fully explain expertise development in UE triathlon.

Considering Efficacy of an Outdoor Environmental Education Program: Facilitating Elementary Students’ Environmental Knowledge, Attitudes, and Behaviours

Various sources have sought to consider the educational interventions that foster changes in perception of and attitudes toward nature, with the ultimate intent of understanding how education can be used to encourage environmentally responsible behaviours. With these in mind, the current study identified an outdoor environmental education program incorporating these empirically supported interventions, and assessed its ability to influence environmental knowledge, attitudes, and behaviours. Specifically, this study considered the following research questions: 1) To what degree can participation in this outdoor education program foster environmental knowledge and encourage pro-environmental attitudes and self-reported pro-environmental behaviours? 2) How is this effect different among students of different genders, and those who have different prior experiences in nature? Two motivational frameworks guided inquiry in the current study: the Value-Belief-Norm Model of Environmentalism (VBN) and the Theory of Planned Behaviour (TPB). The study employed a quantitative survey methodology, combining contemporary data measuring knowledge, attitudes, and behaviours with archived data collected by program staff, reflecting frequency of environmentally responsible behaviour. Further, a single qualitative item was included for which students provided “the first three words that [came] to mind when [they] think of the word nature.” Terms provided before and after the program were compared for differences in theme to detect subtle or underlying changes. Quantitative results indicated no significant change in student knowledge or attitudes through the outdoor environmental education program. However, a significant change in self-reported behaviour was identified from both the contemporary and archived data. This agreement in positive findings across the two data sets, collected using different measures and different participants, lends evidence of the program’s ability to encourage self-reported pro-environmental behaviour. Further, qualitative results showed some change in students’ perceptions of nature through the program, providing direction for future research. These findings suggest that this particular outdoor education program was successful in encouraging students’ self-reported environmentally responsible behaviour. This change was achieved without significant change in knowledge or environmental attitudes, suggesting that external factors not measured in this study might have played a role in affecting behaviour.

Une ethnographie de la gestion de la population rom en Albanie

Cette thèse propose une ethnographie de la gestion de la population rom en Albanie, saisie sur deux périodes historiques : communisme et postcommunisme. L’analyse porte sur la façon dont divers instruments de gestion des populations en tant que techniques de pouvoir, sont mises en œuvre ; comment une population donnée devient-elle un sujet politique ? Quels sont les effets d’une telle gestion sur les populations en général et sur les populations roms en particulier ? Cette approche, une approche foucaldienne, replace ainsi au centre de l’analyse empirique les politiques, les pratiques et les discours concernant les Roms en Albanie et essaye de saisir les effets qu’ils produisent sur cette population. Cette thèse part de ces éléments pour interroger plus largement les transformations sociétales dans l’Albanie postcommuniste. Ce travail s’inscrit dans le champ de l’anthropologie politique et conjugue à la fois une anthropologie de l’État et une anthropologie de la violence. Il s’articule autour de trois parties. La première porte sur la contextualisation de cette thèse, du point de vue conceptuel, méthodologique et théorique. La deuxième partie propose une analyse des relations que l’État a entretenues avec les Roms pendant la période communiste, phase durant laquelle la population rom a été exposée à diverses mesures administratives visant sa normalisation, à travers une sédentarisation forcée et d’autres mesures coercitives. La troisième partie, précédée par un intermède sur la période de la transition, interroge la relation entre l’État, la violence, la mobilité et la gestion de la population rom en Albanie depuis la chute du communisme. L’analyse se fait à partir d’un cas spécifique, celui des familles roms déplacées et en déplacement aux alentours de Tirana ; une mobilité forcée notamment par peu d’opportunités de sortir de la précarité pour plusieurs familles roms, mais aussi une mobilité induite par les politiques, les pratiques et les discours étatiques, notamment par leur non-action. Au fur et à mesure que l’analyse des pratiques et des discours – complétée par une ethnographie des documents d’archives et dans les quartiers et les campements roms – s’approfondit pendant les deux périodes historiques, elle dévoile de nombreuses – mais différentes – contradictions et controverses au sein du dispositif, lesquelles produisent à leur tour discrimination, exclusion, violence, indifférence et abandon.

Commonalities and Differences in Labour Market Developments and Constraints in Different EU Regions. Factor Markets Working Paper No. 22, February 2012

This paper provides a detailed overview of the differences across EU member states’ labour markets, through the extensive use of descriptive statistics. The objective is two-fold: firstly, it identifies the commonalities and differences in rural labour markets across EU regions and their developments, with special regard to agriculture, and secondly it emphasises the constraints that may hinder the efficient functioning of labour markets. Therefore, the paper starts with a description of the main indicators in the general labour market theory, such as the structure of the population in terms of age and gender distribution, unemployment and activity rates, employment levels, quality of human capital, migration patterns, and so forth. Secondly, we focus on the differences among rural and urban areas to then look closely at the agricultural sector. The institutional framework in which labour market institutions operate is also included. Lastly, as an attempt to summarise the analysis and to classify the EU member states according to certain rural and specific agricultural indicators, cluster analysis is also employed. Policy implications include investment in human capital and vocational training, support to young farmers, promoting economic diversification and upgrading infrastructure, with special regard to the new member states and to the Southern parts of Europe.

Skill formation in Britain and Germany: Recent developments in the context of traditional differences. CES Germany & Europe Working Papers, No.06.1, 2006

This paper proposes a comparison of skill formation in Germany and Britain over the last decades. Taking historical trends into account, the two cases can be regarded as representing different types of skill production regimes. Institu-tional features include a relatively low degree of standardization of training and a larger amount of on-the-job training in Britain. In Germany, post-compulsory training has been conducted predominantly within the dual system of vocational training, underlining the vocational specificity of a large part of the labor market. As a consequence, international differences in individual skill investments, transitions from school to work and other life-course patterns can be observed. At least in Britain, however, the situation seems to have changed considerably during the 1990s. The paper argues that the divergence in more recent developments can still be understood as an expression of historical path-dependency given the traditional connections between the post-compulsory training system and the broader societal context in which it is embedded. These concern, in particular, links with the system of general and academic education as the basis for – and also a possible competitor with – vocational training; links with the labor market as they are indicated by specific skill requirements and returns to qualifications; and, links with the order of social stratification in the form of the selective acquisition and the social consequences of these qualifications. The links manifest themselves as typical individual-level consequences and decisions. Founded on the basis of these distinctions, the aim of this paper is to investigate the preceding conditions for recent developments in the qualification systems of Britain and Germany, which have adapted to specific challenges during the last decades.

The proteasome inhibitor MLN-273 blocks exoerythrocytic and erythrocytic development of Plasmodium parasites.

Protein degradation is regulated during the cell cycle of all eukaryotic cells and is mediated by the ubiquitin-proteasome pathway. Potent and specific peptide-derived inhibitors of the 20S proteasome have been developed recently as anti-cancer agents, based on their ability to induce apoptosis in rapidly dividing cells. Here, we tested a novel small molecule dipeptidyl boronic acid proteasome inhibitor, named MLN-273 on blood and liver stages of Plasmodium species, both of which undergo active replication, probably requiring extensive proteasome activity. The inhibitor blocked Plasmodium falciparum erythrocytic development at an early ring stage as well as P. berghei exoerythrocytic progression to schizonts. Importantly, neither uninfected erythrocytes nor hepatocytes were affected by the drug. MLN-273 caused an overall reduction in protein degradation in P. falciparum, as demonstrated by immunoblots using anti-ubiquitin antibodies to label ubiquitin-tagged protein conjugates. This led us to conclude that the target of the drug was the parasite proteasome. The fact that proteasome inhibitors are presently used as anti-cancer drugs in humans forms a solid basis for further development and makes them potentially attractive drugs also for malaria chemotherapy.

Une ethnographie de la gestion de la population rom en Albanie

Cette thèse propose une ethnographie de la gestion de la population rom en Albanie, saisie sur deux périodes historiques : communisme et postcommunisme. L’analyse porte sur la façon dont divers instruments de gestion des populations en tant que techniques de pouvoir, sont mises en œuvre ; comment une population donnée devient-elle un sujet politique ? Quels sont les effets d’une telle gestion sur les populations en général et sur les populations roms en particulier ? Cette approche, une approche foucaldienne, replace ainsi au centre de l’analyse empirique les politiques, les pratiques et les discours concernant les Roms en Albanie et essaye de saisir les effets qu’ils produisent sur cette population. Cette thèse part de ces éléments pour interroger plus largement les transformations sociétales dans l’Albanie postcommuniste. Ce travail s’inscrit dans le champ de l’anthropologie politique et conjugue à la fois une anthropologie de l’État et une anthropologie de la violence. Il s’articule autour de trois parties. La première porte sur la contextualisation de cette thèse, du point de vue conceptuel, méthodologique et théorique. La deuxième partie propose une analyse des relations que l’État a entretenues avec les Roms pendant la période communiste, phase durant laquelle la population rom a été exposée à diverses mesures administratives visant sa normalisation, à travers une sédentarisation forcée et d’autres mesures coercitives. La troisième partie, précédée par un intermède sur la période de la transition, interroge la relation entre l’État, la violence, la mobilité et la gestion de la population rom en Albanie depuis la chute du communisme. L’analyse se fait à partir d’un cas spécifique, celui des familles roms déplacées et en déplacement aux alentours de Tirana ; une mobilité forcée notamment par peu d’opportunités de sortir de la précarité pour plusieurs familles roms, mais aussi une mobilité induite par les politiques, les pratiques et les discours étatiques, notamment par leur non-action. Au fur et à mesure que l’analyse des pratiques et des discours – complétée par une ethnographie des documents d’archives et dans les quartiers et les campements roms – s’approfondit pendant les deux périodes historiques, elle dévoile de nombreuses – mais différentes – contradictions et controverses au sein du dispositif, lesquelles produisent à leur tour discrimination, exclusion, violence, indifférence et abandon.