Class I T-cell epitope prediction:improvements using a combination of proteasome cleavage, TAP affinity, and MHC binding

Cleavage by the proteasome is responsible for generating the C terminus of T-cell epitopes. Modeling the process of proteasome cleavage as part of a multi-step algorithm for T-cell epitope prediction will reduce the number of non-binders and increase the overall accuracy of the predictive algorithm. Quantitative matrix-based models for prediction of the proteasome cleavage sites in a protein were developed using a training set of 489 naturally processed T-cell epitopes (nonamer peptides) associated with HLA-A and HLA-B molecules. The models were validated using an external test set of 227 T-cell epitopes. The performance of the models was good, identifying 76% of the C-termini correctly. The best model of proteasome cleavage was incorporated as the first step in a three-step algorithm for T-cell epitope prediction, where subsequent steps predicted TAP affinity and MHC binding using previously derived models.

Societal transformation and programmatic change in the CDU

This article places the changing policy profile of the CDU into the context of the gradual transformation of German society since the 1970s and especially since unification in 1990. It argues that in order to understand key areas where the CDU has reformed its programme, we must first understand the broader, meta-level trends in society. In its main section, the article sketches out the long-term changes that have occurred in three principal areas (demographics, labour market outcomes and the economic status and the role of women), and relates these to debates that have taken place in the CDU's programmatic profile. The article therefore concludes that consideration of the societal context complements agency-based explanations for programmatic change. © 2013 Association for the Study of German Politics.

The roots of "Western European societal evolution". A concept of Europe by Jenő Szűcs

Jenő Szűcs wrote his essay entitled Sketch on the three regions of Europe in the early 1980s in Hungary. During these years, a historically well-argued opinion emphasising a substantial difference between Central European and Eastern European societies was warmly received in various circles of the political opposition. In a wider European perspective Szűcs used the old “liberty topos” which claims that the history of Europe is no other than the fulfillment of liberty. In his Sketch, Szűcs does not only concentrate on questions concerning the Middle Ages in Western Europe. Yet it is this stream of thought which brought a new perspective to explaining European history. His picture of the Middle Ages represents well that there is a way to integrate all typical Western motifs of post-war self-definition into a single theory. Mainly, the “liberty motif”, as a sign of “Europeanism” – in the interpretation of Bibó’s concept, Anglo-saxon Marxists and Weber’s social theory –, developed from medieval concepts of state and society and from an analysis of economic and social structures. Szűcs’s historical aspect was a typical intellectual product of the 1980s: this was the time when a few Central European historians started to outline non-Marxist aspects of social theory and categories of modernisation theories, but concealing them with Marxist terminology.

The roots of "Western European societal evolution"

Jenő Szűcs wrote his essay entitled Sketch on the three regions of Europe in the early 1980s in Hungary. During these years, a historically well-argued opinion emphasising a substantial difference between Central European and Eastern European societies was warmly received in various circles of the political opposition. In a wider European perspective Szűcs used the old “liberty topos” which claims that the history of Europe is no other than the fulfillment of liberty. In his Sketch, Szűcs does not only concentrate on questions concerning the Middle Ages in Western Europe. Yet it is this stream of thought which brought a new perspective to explaining European history. His picture of the Middle Ages represents well that there is a way to integrate all typical Western motifs of post-war self-definition into a single theory. Mainly, the “liberty motif”, as a sign of “Europeanism” – in the interpretation of Bibó’s concept, Anglo-saxon Marxists and Weber’s social theory –, developed from medieval concepts of state and society and from an analysis of economic and social structures. Szűcs’s historical aspect was a typical intellectual product of the 1980s: this was the time when a few Central European historians started to outline non-Marxist aspects of social theory and categories of modernisation theories, but concealing them with Marxist terminology.

Comparative Analysis of State and Non-State Higher Educational Institutions in Terms of their Adaptation to New Societal Conditions in Post-Soviet Russia

The present paper investigates post-Soviet non-state and state higher educational institutions in terms of students’ perceptions of school curriculum, quality of teaching, available educational resources and overall organization in their higher educational institutions.

Systematic review of the health and societal effects of medication organisation devices

Acknowledgements The authors would like to thank, Estelle Payerne (article screening, data extraction and bias assessment); Trish Boyton (article retrieval and screening) and Laura Cawley (search terms and title screening) for their invaluable help in conducting this systematic review. Funding The research was funded by the UK National Institute for Health Research Health Technology Assessment Programme.

Topoisomerase 1 (Top1)-associated Genome Instability in Yeast: Effects of Persistent Cleavage Complexes or Increased Top1 Levels

Topoisomerase 1 (Top1), a Type IB topoisomerase, functions to relieve transcription- and replication-associated torsional stress in DNA. Top1 cleaves one strand of DNA, covalently associates with the 3’ end of the nick to form a Top1-cleavage complex (Top1cc), passes the intact strand through the nick and finally re-ligates the broken strand. The chemotherapeutic drug, Camptothecin, intercalates at a Top1cc and prevents the crucial re-ligation reaction that is mediated by Top1, resulting in the conversion of a nick to a toxic double-strand break during DNA replication or the accumulation of Top1cc. This mechanism of action preferentially targets rapidly dividing tumor cells, but can also affect non-tumor cells when patients undergo treatment. Additionally, Top1 is found to be elevated in numerous tumor tissues making it an attractive target for anticancer therapies. We investigated the effects of Top1 on genome stability, effects of persistent Top1-cleavage complexes and elevated Top1 levels, in Saccharomyces cerevisiae. We found that increased levels of the Top1cc resulted in a five- to ten-fold increase in reciprocal crossovers, three- to fifteen fold increase in mutagenesis and greatly increased instability within the rDNA and CUP1 tandem arrays. Increased Top1 levels resulted in a fifteen- to twenty-two fold increase in mutagenesis and increased instability in rDNA locus. These results have important implications for understanding the effects of CPT and elevated Top1 levels as a chemotherapeutic agent.

Assessing the Societal Impact of Research: The Relational Engagement Approach

Marketing and policy researchers seeking to increase the societal impact of their scholarship should engage directly with relevant stakeholders. For maximum societal effect, this engagement needs to occur both within the research process and throughout the complex process of knowledge transfer. A relational engagement approach to research impact is proposed as complementary and building upon traditional approaches. Traditional approaches to impact employ bibliometric measures and focus on the creation and use of journal articles by scholarly audiences, an important but incomplete part of the academic process. The authors suggest expanding the strategies and measures of impact to include process assessments for specific stakeholders across the entire course of impact: from the creation, awareness, and use of knowledge to societal impact. This relational engagement approach involves the co-creation of research with audiences beyond academia. The authors hope to begin a dialogue on the strategies researchers can make to increase the potential societal benefits of their research.

The epidemiology, healthcare and societal burden and costs of asthma in the UK and its member nations: analyses of standalone and linked national databases

Background: There are a lack of reliable data on the epidemiology and associated burden and costs of asthma. We sought to provide the first UK-wide estimates of the epidemiology, healthcare utilisation and costs of asthma. 

Methods: We obtained and analysed asthma-relevant data from 27 datasets: these comprised national health surveys for 2010-11, and routine administrative, health and social care datasets for 2011-12; 2011-12 costs were estimated in pounds sterling using economic modelling. 

Results: The prevalence of asthma depended on the definition and data source used. The UK lifetime prevalence of patient-reported symptoms suggestive of asthma was 29.5 % (95 % CI, 27.7-31.3; n = 18.5 million (m) people) and 15.6 % (14.3-16.9, n = 9.8 m) for patient-reported clinician-diagnosed asthma. The annual prevalence of patient-reported clinician-diagnosed-and-treated asthma was 9.6 % (8.9-10.3, n = 6.0 m) and of clinician-reported, diagnosed-and-treated asthma 5.7 % (5.7-5.7; n = 3.6 m). Asthma resulted in at least 6.3 m primary care consultations, 93,000 hospital in-patient episodes, 1800 intensive-care unit episodes and 36,800 disability living allowance claims. The costs of asthma were estimated at least £1.1 billion: 74 % of these costs were for provision of primary care services (60 % prescribing, 14 % consultations), 13 % for disability claims, and 12 % for hospital care. There were 1160 asthma deaths. 

Conclusions: Asthma is very common and is responsible for considerable morbidity, healthcare utilisation and financial costs to the UK public sector. Greater policy focus on primary care provision is needed to reduce the risk of asthma exacerbations, hospitalisations and deaths, and reduce costs.

Marketing Societal: uma contribuição para o crescimento sustentável das organizações

Hoje é indiscutível a necessidade de as organizações incorporarem o desenvolvimento sustentável ou, pelo menos, minimizarem os impactos causados no desenvolvimento de seu processo produtivo. É vital, para as organizações, a realização de ações que evidenciem a sua parcela de contribuição para com o meio social. Diante disso, as estratégias de marketing nas organizações vêm procurando desenvolver ações voltadas à satisfação de seus clientes, despertando novos desejos nas necessidades já existentes e atendendo-os com o maior nível de qualidade possível em todos os processos. Entretanto, isto não tem sido o suficiente, pois os consumidores têm exigido mais: querem organizações comprometidas com o bem-estar social da sociedade. Com a acirrada concorrência no mercado, as organizações buscam diferenciais essenciais que garantam a sua vantagem competitiva sobre as demais organizações. Tendo em vista tal cenário, a administração conta com uma ferramenta que traz benefícios a todos os envolvidos no processo, que é o Marketing Societal, em que a organização investe no social, provisionando um retorno de resultados para a organização.

Role and modulation of maternal transcripts during the first cleavage divisions in bovine embryos

Ce travail porte sur l’identification, la fonction et la régulation des molécules maternelles d’ARNm qui dirigent la compétence développementale juste après la fécondation chez les bovins. Tout d’abord, en utilisant le modèle du temps écoulé jusqu’au premier clivage zygotique et à travers l’évaluation du transcriptome des embryons à 2-cellules, il fut possible de déterminer la signature moléculaire des niveaux extrêmes de compétence au développement et sélectionner des molécules candidates pour des études postérieures. Les résultats ont montré que les embryons de capacité développementale variable diffèrent dans certaines fonctions comme la réparation de l’ADN, le traitement de l’ARN, la synthèse de protéines et l’expression génique définies par des ARNm synthétisés par l’ovocyte. Pour obtenir une confirmation fonctionnelle, une paire de transcrits maternels (l’un détecté dans notre sondage précédent et l’autre étant une molécule reliée) ont été inhibés par « knock-down » dans des ovocytes. Les effets du knock-down de ces facteurs de transcription sont apparus avant la formation des blastocystes dû à une diminution de la capacité au clivage et celle à progresser après le stage de 8-cellules. L’analyse moléculaire des embryons knock-down survivants suggère qu’un de ces facteurs de transcription est un contrôleur crucial de l’activation du génome embryonnaire, qui représente une fenêtre développementale dans l’embryogenèse précoce. Dans la dernièr étude, nous avons testé si les facteurs de transcription d’intérêt sont modulés au niveau traductionnel. Des ARNm rapporteurs couplés à la GFP (Protéine fluorescente) contenant soit la version courte ou la version longue de la séquence 3’-UTR des deux molécules furent injectées dans des zygotes pour évaluer leur dynamique traductionnelle. Les résultats ont montré que les éléments cis-régulateurs localisés dans les 3’-UTRs contrôlent leur synchronisation traductionnelle et suggèrent une association entre la compétence développementale et la capacité de synthèse de ces protéines. Ceci conduit à l’idée que ces facteurs de transcription cruciaux sont aussi contrôlés au niveau traductionnel chez les embryons précoces. Les connaissances acquises ont joué un rôle essentiel pour définir le contrôle potentiel des molécules maternelles sur les embryons au début de leur développement. Cette étude nous montre aussi une utilisation potentielle de cette information ainsi que les nouveaux défis présents dans le secteur des technologies reproductives.

The ‘peaks and troughs’ of societal violence: Revisiting the actions of Turkish and Kurdish shopkeepers during the 2011 London riots

This article examines an instance of contained violence during the 2011 riots in London, when Turkish and Kurdish ‘shopkeepers’ in Dalston, East London prevented rioters from entering the area. Introducing a ‘peaks’ and ‘troughs’ approach to the sociological study of violence, the article argues that we need to look at the troughs of non-violence in order to understand the peaks of violence and vice-versa. Based on a small-scale empirical study, this article also shows that contrary to the dominant representation of social actors playing fixed roles during social unrest, we found shifting positions and blurred boundaries in the drama of the 2011 riots. The paper demonstrates that the instance of contained violence in Dalston was informed by three types of reverberations. Firstly, we identified anticipatory reverberations, as the shopkeepers were aware of concurrent events elsewhere in London and, as a result, anticipated rioting in Dalston. Secondly, we saw experiential reverberations, as they used their own experience of unrest in Turkey to inform their behaviour. Finally, the representation of the action of the shopkeepers in traditional and social media may have contributed to the containment of violence elsewhere in England, suggesting representational reverberations.

Disentangling Discrimination: The Impact of Political and Societal Discrimination on Democratic (Dis)Engagement

Thesis (Ph.D.)--University of Washington, 2016-08