Unraveling principles of lead discovery: from unfrustrated energy landscapes to novel molecular anchors.

The search for novel leads is a critical step in the drug discovery process. Computational approaches to identify new lead molecules have focused on discovering complete ligands by evaluating the binding affinity of a large number of candidates, a task of considerable complexity. A new computational method is introduced in this work based on the premise that the primary molecular recognition event in the protein binding site may be accomplished by small core fragments that serve as molecular anchors, providing a structurally stable platform that can be subsequently tailored into complete ligands. To fulfill its role, we show that an effective molecular anchor must meet both the thermodynamic requirement of relative energetic stability of a single binding mode and its consistent kinetic accessibility, which may be measured by the structural consensus of multiple docking simulations. From a large number of candidates, this technique is able to identify known core fragments responsible for primary recognition by the FK506 binding protein (FKBP-12), along with a diverse repertoire of novel molecular cores. By contrast, absolute energetic criteria for selecting molecular anchors are found to be promiscuous. A relationship between a minimum frustration principle of binding energy landscapes and receptor-specific molecular anchors in their role as "recognition nuclei" is established, thereby unraveling a mechanism of lead discovery and providing a practical route to receptor-biased computational combinatorial chemistry.

Peptide vaccination can lead to enhanced tumor growth through specific T-cell tolerance induction.

Vaccination with synthetic peptides representing cytotoxic T lymphocyte (CTL) epitopes can lead to a protective CTL-mediated immunity against tumors or viruses. We now report that vaccination with a CTL epitope derived from the human adenovirus type 5 E1A-region (Ad5E1A234-243), which can serve as a target for tumor-eradicating CTL, enhances rather than inhibits the growth of Ad5E1A-expressing tumors. This adverse effect of peptide vaccination was rapidly evoked, required low doses of peptide (10 micrograms), and was achieved by a mode of peptide delivery that induces protective T-cell-mediated immunity in other models. Ad5E1A-specific CTL activity could no longer be isolated from mice after injection of Ad5E1A-peptide, indicating that tolerization of Ad5E1A-specific CTL activity causes the enhanced tumor outgrowth. In contrast to peptide vaccination, immunization with adenovirus, expressing Ad5E1A, induced Ad5E1A-specific immunity and prevented the outgrowth of Ad5E1A-expressing tumors. These results show that immunization with synthetic peptides can lead to the elimination of anti-tumor CTL responses. These findings are important for the design of safe peptide-based vaccines against tumors, allogeneic organ transplants, and T-cell-mediated autoimmune diseases.

Mutations in the MSH3 gene preferentially lead to deletions within tracts of simple repetitive DNA in Saccharomyces cerevisiae.

Eukaryotic genomes contain tracts of DNA in which a single base or a small number of bases are repeated (microsatellites). Mutations in the yeast DNA mismatch repair genes MSH2, PMS1, and MLH1 increase the frequency of mutations for normal DNA sequences and destabilize microsatellites. Mutations of human homologs of MSH2, PMS1, and MLH1 also cause microsatellite instability and result in certain types of cancer. We find that a mutation in the yeast gene MSH3 that does not substantially affect the rate of spontaneous mutations at several loci increases microsatellite instability about 40-fold, preferentially causing deletions. We suggest that MSH3 has different substrate specificities than the other mismatch repair proteins and that the human MSH3 homolog (MRP1) may be mutated in some tumors with microsatellite instability.

Integrando o conhecimento de usuários: um estudo sobre a capacidade de absorção de conhecimento de lead users

Os custos elevados de aquisição de conhecimento, a intensificação da concorrência e a necessidade de aproximação do consumidor vêm estimulando empresas a buscar formas alternativas de aumentar seu potencial de inovação pela integração de usuários. No entanto, a literatura e o senso comum convergem ao afirmar que nem todo usuário está habilitado a trazer conhecimentos que sustentem a vantagem competitiva das inovações. Nesse contexto, emerge a figura do lead user que, por definição, é capaz de sentir necessidades de produtos e serviços ainda não expressos por usuários regulares. Esses conhecimentos, quando adequadamente absorvidos, trazem benefícios expressivos às empresas que os incorporam ao DNP. Sabendo que as formas de incorporação de usuários apresentam variações, este estudo se destina a entender como empresas de diferentes setores absorvem conhecimentos de lead users por diferentes práticas de integração. Para tanto, foi escolhido o método de estudo de casos múltiplos incorporados, observados em três multinacionais de grande porte: Natura, Whirlpool e Microsoft (Bing). Ao todo foram avalidados cinco modos de integração distintos, escolhidos a partir de duas formações: individual (conhecimentos isolados de usuários distintos) e coletivo (conhecimentos articulados em discussões em grupo), analisados pelos métodos de indução analítica com síntese cruzada de dados. Os resultados mostraram que as categorias teóricas utilizadas para observação inicial do fenômenol: parâmetro de identificação e técnica de seleção (aquisição); mecanismo de interação (assimilação); mecanismos de socialização (transformação) e sistema de formalização (exploração) apoiaram parcialmente o entendimento das atividades do processo e, por esta razão, precisaram se complementadas pelas categorias emergentes: criação de contexto, motivação (aquisição); estímulos, parâmetro de observação, interpretação (assimilação); definição de papéis, coordenação de processos, combinação de conhecimento (transformação) e gestão do conhecimento (exploração), coletadas na fase empírica Essa complementação aumentou a robustez do modelo inicial e mostrou como a absorção de conhecimentos pode ser avaliada pelas dimensões absortivas. No entanto, as análises intra e intercasos que se seguiram, mostraram que esse entendimento era insuficiente para explicar a capacidade de absorção por diferentes práticas, uma vez que o fenômeno é influenciado por fatores contextuais associados tanto à prática de integração quanto ao modo como cada empresa se organiza para inovar (tipo de acesso ao colaborador). As reflexões teóricas realizadas a partir desses resultados permitiram contribuir com a teoria existente de duas formas: I) pelo entendimento estendido das atividades de absorção necessárias para incorporação de conhecimentos de lead users e III) pela proposição de um modelo conceitual amplo que abarcou diferentes práticas de integração considerando também os antecedentes de inovação, as atividades absortivas e os fatores adjuntos, inerentes a cada prática. Esta pesquisa objetiva contribuir para o conhecimento teórico sobre inovação e motivar reflexões que possam ser úteis para gerentes e executivos interessados em aprimorar suas práticas e processos de captação de conhecimentos de lead users.

Building Resilience in Young Black Males: Determining the Factors that Lead to Success for Black Men in America

It is no secret that Black men have struggled over the years to obtain the same level of high earning financial success as their White counterparts. Black men face an incredible challenge with regard to educational obtainment, career success, and physical health. Black men are often revered as the most dangerous, least educated, and more unhealthy than any other race or gender. This must change. This researcher investigated the lives of eight successful Black men with the hope of determining how they were able to attain their success. The findings of this research suggest that there are several factors that are key contributors in becoming a successful Black man in America. With a greater understanding of how Black men have managed to gain success, despite the obstacles they have faced, it is hopeful that this research will help other Black men reach the level of success that is often desired and seldom realized.

Protecting Children: The United States Did Not Get the Lead Out

The lack of education and awareness of the potential of lead based paint hazards in residents across the United States is still a problem today. Simple educational tools and regulation changes can protect children who are at risk from being harmed by this hazard. Currently, there is inadequate outreach to educate the general public about lead based paint. A questionnaire was provided to families that have children under the age of seven and that live in residences built prior to 1978. The research and questionnaires confirm that more education, as well as regulation changes, is needed to keep children safe from lead paint hazards.

Developmental Activities That Lead to Dropout and Investment in Sport

Background: Studies suggest that expert performance in sport is the result of long-term engagement in a highly specialized form of training termed deliberate practice. The relationship between accumulated deliberate practice and performance predicts that those who begin deliberate practice at a young age accumulate more practice hours over time and would, therefore, have a significant performance advantage. However, qualitative studies have shown that a large amount of sport-specific practice at a young age may lead to negative consequences, such as dropout, and is not necessarily the only path to expert performance in sport. Studies have yet to investigate the activity context, such as the amount of early sport participation, deliberate play and deliberate practice within which dropout occurs. Purpose: To determine whether the nature and amount of childhood-organized sport, deliberate play and deliberate practice participation influence athletes' subsequent decisions to drop out or invest in organized sport. It was hypothesized that young athletes who drop out will have sampled fewer sports, spent less time in deliberate play activities and spent more time in deliberate practice activities during childhood sport involvement. Participants: The parents of eight current, high-level, male, minor ice hockey players formed an active group. The parents of four high-level, male, minor ice hockey players who had recently withdrawn from competitive hockey formed a dropout group. Data collection: Parents completed a structured retrospective survey designed to assess their sons' involvement in organized sport, deliberate play and deliberate practice activities from ages 6 to 13. Data analysis: A complete data-set was available for ages 6 through 13, resulting in a longitudinal data-set spanning eight years. This eight-year range was divided into three levels of development corresponding to the players' progress through the youth ice hockey system. Level one encompassed ages 6–9, level two included ages 10–11 and level three covered ages 12–13. Descriptive statistics were used to report the ages at which the active and dropout players first engaged in select hockey activities. ANOVA with repeated measures across the three levels of development was used to compare the number of sports the active and dropout players were involved in outside of hockey, the number of hours spent in these sports, and involvement in various hockey-related activities. Findings: Results indicated that both the active and dropout players enjoyed a diverse and playful introduction to sport. Furthermore, the active and dropout players invested similar amounts of time in organized hockey games, organized hockey practices, specialized hockey training activities (e.g. hockey camps) and hockey play. However, analysis revealed that the dropout players began off-ice training at a younger age and invested significantly more hours/year in off-ice training at ages 12–13, indicating that engaging in off-ice training activities at a younger age may have negative implications for long-term ice hockey participation. Conclusion: These results are consistent with previous research that has found that early diversification does not hinder sport-specific skill development and it may, in fact, be preferable to early specialization. The active and dropout players differed in one important aspect of deliberate practice: off-ice training activities. The dropout players began off-ice training at a younger age, and participated in more off-ice training at ages 12 and 13 than their active counterparts. This indicates a form of early specialization and supports the postulate that early involvement in practice activities that are not enjoyable may ultimately undermine the intrinsic motivation to continue in sport. Youth sport programs should not focus on developing athletic fitness through intense and routine training, but rather on sport-specific practice, games and play activities that foster fun and enjoyment.

Computational Methods for Identifying Hypertrophic Cardiomyopathy using 12-lead ECG

Hypertrophic cardiomyopathy (HCM) is a cardiovascular disease where the heart muscle is partially thickened and blood flow is - potentially fatally - obstructed. It is one of the leading causes of sudden cardiac death in young people. Electrocardiography (ECG) and Echocardiography (Echo) are the standard tests for identifying HCM and other cardiac abnormalities. The American Heart Association has recommended using a pre-participation questionnaire for young athletes instead of ECG or Echo tests due to considerations of cost and time involved in interpreting the results of these tests by an expert cardiologist. Initially we set out to develop a classifier for automated prediction of young athletes’ heart conditions based on the answers to the questionnaire. Classification results and further in-depth analysis using computational and statistical methods indicated significant shortcomings of the questionnaire in predicting cardiac abnormalities. Automated methods for analyzing ECG signals can help reduce cost and save time in the pre-participation screening process by detecting HCM and other cardiac abnormalities. Therefore, the main goal of this dissertation work is to identify HCM through computational analysis of 12-lead ECG. ECG signals recorded on one or two leads have been analyzed in the past for classifying individual heartbeats into different types of arrhythmia as annotated primarily in the MIT-BIH database. In contrast, we classify complete sequences of 12-lead ECGs to assign patients into two groups: HCM vs. non-HCM. The challenges and issues we address include missing ECG waves in one or more leads and the dimensionality of a large feature-set. We address these by proposing imputation and feature-selection methods. We develop heartbeat-classifiers by employing Random Forests and Support Vector Machines, and propose a method to classify full 12-lead ECGs based on the proportion of heartbeats classified as HCM. The results from our experiments show that the classifiers developed using our methods perform well in identifying HCM. Thus the two contributions of this thesis are the utilization of computational and statistical methods for discovering shortcomings in a current screening procedure and the development of methods to identify HCM through computational analysis of 12-lead ECG signals.

ISSP Position Stand: To Sample or to Specialize? Seven Postulates About Youth Sport Activities that Lead to Continued Participation and Elite Performance

A comprehensive approach to sport expertise should consider the entire situation that is comprised of the person, the task, the environment, and the complex interplay of these components (Hackfort, 1986). Accordingly, the Developmental Model of Sport Participation (Côté, Baker, & Abernethy, 2007; Côté & Fraser-Thomas, 2007) provides a comprehensive framework for sport expertise that outlines different pathways of involvement in sport. In pathways one and two, early sampling serves as the foundation for both elite and recreational sport participation. Early sampling is based on two main elements of childhood sport participation: 1) involvement in various sports and 2) participation in deliberate play. In contrast, pathway three shows the course to elite performance through early specialization in one sport. Early specialization implies a focused involvement on one sport and a large number of deliberate practice activities with the goal of improving sport skills and performance during childhood. This paper proposes seven postulates regarding the role that sampling and deliberate play, as opposed to specialization and deliberate practice, can have during childhood in promoting continued participation and elite performance in sport.

All Roads Lead to Rome: Background, Context and Legacy of the Treaty on the European Community. Jean Monnet/Robert Schuman Paper Series Special Issue 3, August 2012

From the Introduction. The rejection by the French National Assembly of the ill-fated European Defense Community (EDC) Treaty in August 30, 1954, together with the automatic shelving of the equally faulty European Political Community (EPC) proposal, put an end, at least for the time being, to any form of political and military union of the existing Western Europe on a supranational level. The times were difficult in Europe and the international atmosphere was cloudy. The end of the Korean War coincided with the insistence of the Soviets to stick to a policy of détente, leading to the suppression of the Hungarian rebellion. France was facing opposition to her colonial presence in Indochina, as well as in North Africa. But the crisis of Suez prompted the French government to distance itself from the British and the United States. The defeat of the EDC and EPC was not going to be the end of the story and the dream inaugurated by Monnet and Schuman in 1950. It was not long before plans in favor of a European re-launch were taking shape. 1