Dentre os vários marcadores genéticos existentes, alguns SNPs (Single Nucleotide Polymorphisms) podem estar associados à determinação de uma série de características fenotípicas (cor de pele, olhos e cabelos, estatura, forma do rosto, espessura do fio de cabelo) tendo sua predição um grande valor nas investigações forenses. Dentre os principais genes conhecidos por controlarem a pigmentação humana, através da produção da melanina, o SLC24A5 (solute carrier family 24, member 5) e o MC1R (melanocortin 1-receptor) apresentam um papel fundamental na melanogênese. O advento do sequenciamento de nova geração permitiu o processamento de várias regiões genômicas e indivíduos simultaneamente, aumentando a disponibilidade e precisão de dados de genomas completos, como alcançado em estudos como o 1000 Genomes Project. Nossas análises preliminares demonstraram que os dados de Fase 3 do 1000 Genomes são muito mais confiáveis do que as versões anteriores. Com esses dados, obtidos para 26 populações globais, foram realizadas análises populacionais (diversidade haplotípica, desequilíbrio de ligação, redes de haplótipo e de variância molecular) para os genes MC1R e SLC24A5 a fim de se compreender melhor seus padrões de diversidade, correlacionando-os à prováveis eventos de seleção natural que tenham moldado sua história evolutiva, como por exemplo a intensidade da radiação UV nas diferentes regiões geográficas. Alguns padrões foram encontradas entre os grupos africano, europeu e asiático, de acordo com a história evolutiva já descrita para estes grupos. Apesar disso, foi observado um padrão claro de varredura seletiva para o SLC24A5 nos resultados obtidos, como o alto desequilíbrio de ligação e baixa diversidade haplotípica. As análises da diversidade do SLC24A5 associadas com as zonas de incidência UV, no entanto, não apresentaram uma correlação clara entre a intensidade da radiação UV e a diversidade haplotípica / Among the various existing genetic markers, some SNPs may be associated with the determination of a series of phenotypic characteristics (skin, eyes and hair color, height, face shape, hair thickness) and its prediction could have a great value in forensic investigations. Among the major genes known to control human pigmentation through melanin production, SLC24A5 (solute carrier family 24, member 5) and MC1R (melanocortin-1 receptor) have a major role in melanogenesis. The advent of next-generation sequencing has enabled processing of several individuals and genomic regions simultaneously while increasing the availability and accuracy of whole genomes data, such as 1000 Genomes Project has achieved. Our preliminary analysis showed that Phase 3 data from the 1000 Genomes are far more reliable than previous versions. Using this data, obtained for 26 global populations, several analyzes were performed (haplotype diversity, linkage disequilibrium, haplotype networks and molecular variance) for MC1R and SLC24A5 in order to better understand their diversity patterns, correlating them to natural selection events which may have shaped their evolutionary history, such as UV radiation intensity in different geographical regions. Some patterns were found between African, European and Asian groups, according to the evolutionary history already described for these groups. Nevertheless, a strong pattern of selective sweep was observed for SLC24A5 in our data, such as high linkage disequilibrium and low haplotype diversity. Analysis of SLC24A5 diversity associated to UV, however, did not show a clear correlation between the UV radiation intensity and haplotype diversity

Book Summary: Its not enough for teachers to read through the Next Generation Science Standards (NGSS) and correlate their content to the established curriculum. Teachers must prepare to make the vision of the NGSS come alive in their classrooms. Editor Jack Rhoton maintains that the preparation will be most effective if it begins in undergraduate coursework and is sustained by ongoing professional development designed to bring about real change. The goal of Preparing Teachers for Three-Dimensional Instruction is to contribute to that preparation and that change. It showcases the many shifts that higher education science faculty, teacher education faculty, and others are already making to bring the standards to life.Preparing Teachers was written specifically for preservice science teachers, but science education faculty and practicing K 12 teachers can also benefit from it. The authors of the 18 chapters are outstanding classroom practitioners and science educators at all levels. Section I provides examples of teaching models that fulfill the intent of the NGSS. Section II describes approaches to professional development that can improve practice. Sections III and IV consider what can be done in both teacher preparation courses and undergraduate science courses for preservice science teachers. Section V explores ways to enlist the business community and other partners in support of the changes the standards can bring about. Rhoton calls the book a motivating resource for the science education community. Use it to achieve the ultimate goal of the NGSS: to move science education away from the formulaic classroom methods many students are now experiencing and instead support them in becoming true practitioners of science.

We will share examples of hands-on investigations combining the 5Es and the CER Framework with supporting literacy activities to help upper elementary students demonstrate learning.

The purpose of this study was to characterize ways in which teaching practice in classroom undergoing first semester implementation of an argument-based inquiry approach changes in whole-class discussion. Being that argument is explicitly called for in the Next Generation Science Standards and is currently a rare practice in teaching, many teachers will have to transform their teaching practice for inclusion of this feature. Most studies on Argument-Based Inquiry (ABI) agree that development of argument does not come easily and is only acquired through practice. Few studies have examined the ways in which teaching practice changes in relation to the big idea or disciplinary core idea (NGSS), the development of dialogue, and/or the development of argument during first semester implementation of an argument-based inquiry approach. To explore these areas, this study posed three primary research questions: (1) How does a teacher in his first semester of Science Writing Heuristic professional development make use of the "big idea"?, (1a) Is the indicated big idea consistent with NGSS core concepts?, (2) How did the dialogue in whole-class discussion change during the first semester of argument-based inquiry professional development?, (3) How did the argument in whole-class discussion change during the first semester of argument-based inquiry professional development? This semester-long study that took place in a middle school in a rural Midwestern city was grounded in interactive constructivism, and utilized a qualitative design to identify the ways in which the teacher utilized big ideas and how dialogue and argumentative dialogue developed over time. The purposefully selected teacher in this study provided a unique situation where he was in his first semester of professional development using the Science Writing Heuristic Approach to argument-based inquiry with 19 students who had two prior years' experience in ABI. Multiple sources of data were collected, including classroom video with transcripts, teacher interview, researcher field notes, student journals, teacher lesson plans from previous years, and a student questionnaire. Data analysis used a basic qualitative approach. The results showed (1) only the first time period had a true big idea, while the other two units contained topics, (2) each semester contained a similar use for the given big idea, though its role in the class was reduced after the opening activity, (3) the types of teacher questions shifted toward students explaining their comprehension of ideas and more students were involved in discussing each idea and for more turns of talk than in earlier time periods, (4) understanding science term definitions became more prominent later in the semester, with more stating science terms occurring earlier in the semester, (5) no significant changes were seen to the use of argument or claims and evidence throughout the study. The findings have informed theory and practice about science argumentation, the practice of whole-class dialogue, and the understanding of practice along four aspects: (1) apparent lack of understanding about big ideas and how to utilize them as the central organizing feature of a unit, (2) independent development of dialogue and argument, (3) apparent lack of understanding about the structure of argument and use of basic terminology with argument and big ideas, (4) challenges of ABI implementation. This study provides insight into the importance of prolonged and persistent professional development with ABI in teaching practice.

La capacité à assurer la mobilité sans couture avec une E2E QoS sera capitale pour la réussite du NGN (Next Generation Network). Pour ce faire, les verrous à lever que nous avons relevés dans cette thèse se positionnent à l'interconnexion de trois domaines, à savoir : les mobilités, l'hétérogénéité et les préférences utilisateur. Notre première proposition d'ordres organisationnel et fonctionnel, pour laquelle nous préconisons la convergence des trois plans (user, contrôle et gestion) et les fonctionnalités associées. Ainsi nous obtenons une QoS dynamique pour satisfaire l'approche orientée "User-Centric ". Afin de mettre en œuvre la E2E QoS incluant la personnalisation dans la session "User-Centric", nous avons proposé une "Signalisation dynamique d'E2E QoS", qui est d'ordre protocolaire, sur le niveau de service afin de parvenir à la fourniture des services demandés par l'user et de se conformer au SLA. Pour couvrir tout impact de mobilité, nous avons ensuite proposé un " cross layer E2E Session Binding" au sein de notre architecture à quatre niveaux de visibilité (Equipement, Réseau, Service et User). Par le binding nous assurons la cohérence des informations entre les quatre niveaux de visibilité. Au-delà du binding, notre contribution sur la dimension informationnelle a porté sur les profils impliqués dans chaque étape du cycle de vie du service incluant les critères de QoS, les quels fournissent une image générique des composants du système de l'utilisateur et de toutes les ressources ambiantes. Finalement, nous montrons la faisabilité de nos contributions à travers des expérimentations sur notre plate-forme.

La tesi è strutturata in 3 capitoli e analizza gli investimenti e la regolamentazione nel broadband market". Il primo capitolo analizza la letteratura teorica ed empirica sul rapporto tra gli investimenti e la regolamentazione nel settore delle telecomunicazioni. Il secondo capitolo fornisce un'analisi teorica sullo "stepping-stone theory". La terza parte fornisce un'analisi sull'impatto dei diversi regimi normativi per la costruzione della Next Generation Networks. / This dissertation is composed of three papers and discusses the issue of investment and regulation in broadband market. The first paper reviews the specialized but growing branch of the literature. It surveys the relevant theoretical and empirical literature on the relationship between regulation, at both retail and wholesale level, and investment in telecoms infrastructures. Theoretical analyses state that with respect to retail (incentive) regulation, the firm‘s incentive to invest is related to the level of price cap. As for access regulation, mandatory unbundling can possibly discourage firms‘ incentive to invest, but this is not the case for all circumstances because some studies have displayed an opposite (positive) effect on investment. The influence of regulators‘ limited ability to make credible commitment ex ante is not negligible either. Evidence in empirical findings exhibits a certain disunity. The majority concludes that local loop unbundling based on forward-looking cost methodology discourages both ILECs and CLECs from investing in networks, so that the stepping-stone theory is possibly not supported by the data; other findings support the non-negative effect of access regulation on investment. The second paper provides theoretical analysis on the stepping-stone theory. We dynamically model the competition between a vertically-integrated incumbent firm and a facilities-free new entrant in broadband market, where both firms are entitled with investment options: not only can the incumbent decide how much to spend in upgrading its existing network, but also the entrant can choose whether and when to invest on the construction of its own network. The analysis is conducted under three different kinds of competition: pure services-based, pure facilities-based and mixed competition. We find that the entrant's ability to provide value-added services affects the incumbent's investment choice. Our simulation results support the stepping-stone theory that access regulation provides an impetus for the entrant to invest in their own facilities after entering the market based on leased lines. It is also socially desirable because both the overall welfare and the consumer surplus are maximized in a regulated market under mixed competition. The third paper studies impacts of different regulatory regimes on the construction of Next Generation Networks (NGNs). We model the competition between a vertically-integrated incumbent firm and a facilities-free entrant firm in broadband market, where the incumbent has an investment option to upgrade its current network to the NGN. In order to analyze how policy settings affect the incumbent firm‘s investment choice, three kinds of regulatory regimes are discussed: no regulation, partial regulation (only the traditional network is regulated and the NGN is unregulated) and full regulation (both the traditional network and the NGN are regulated). We find that not only the entrant‘s ability to provide value-added services, but also the substitution factor that indexes the decrease in consumers‘ willingness to pay for the traditional service once the investment occurs, affect the incumbent‘s investment choice. Moreover, the comparison of results under different regimes shows that the incumbent invests the most under partial regulation, which sheds some light on impelling the deployment of Next Generation Networks.

Myoclonus-Dystonia (MD) is an inherited, rare, autosomal dominant movement disorder characterized by quick, involuntary muscle jerking or twitching (myoclonus) and involuntary muscle contractions that cause twisting and pulling movements, resulting in abnormal postures (dystonia). The first MD locus was mapped to 7q21-q31 and called DYT11; this locus corresponds to the SGCE gene. Our group previously identified a second MD locus (DYT15) which maps to a 3.18 Mb region on 18p11. Two patients were chosen to undergo next-generation sequencing, which identified 2,292 shared novel variants within the critical region. Analysis of these variants revealed a 3 bp duplication in a transcript referred to as CD108131, which is believed to be a long non-coding RNA. Characterization of this transcript determined that it is 863 bp in size, it is ubiquitously expressed, with high expression in the cerebellum, and it accounts for ~3% of MD cases.

Recent advances in next generation sequencing have provided unprecedented opportunities for high-throughput genomic research, inexpensively producing millions of genomic sequences in a single run. Analysis of massive volumes of data results in a more accurate picture of the genome complexity and requires adequate bioinformatics support. We explore computational challenges of applying next generation sequencing to particular applications, focusing on the problem of reconstructing viral quasispecies spectrum from pyrosequencing shotgun reads and problem of inferring informative single nucleotide polymorphisms (SNPs), statistically covering genetic variation of a genome region in genome-wide association studies. The genomic diversity of viral quasispecies is a subject of a great interest, particularly for chronic infections, since it can lead to resistance to existing therapies. High-throughput sequencing is a promising approach to characterizing viral diversity, but unfortunately standard assembly software cannot be used to simultaneously assemble and estimate the abundance of multiple closely related (but non-identical) quasispecies sequences. Here, we introduce a new Viral Spectrum Assembler (ViSpA) for inferring quasispecies spectrum and compare it with the state-of-the-art ShoRAH tool on both synthetic and real 454 pyrosequencing shotgun reads from HCV and HIV quasispecies. While ShoRAH has an advanced error correction algorithm, ViSpA is better at quasispecies assembling, producing more accurate reconstruction of a viral population. We also foresee ViSpA application to the analysis of high-throughput sequencing data from bacterial metagenomic samples and ecological samples of eukaryote populations. Due to the large data volume in genome-wide association studies, it is desirable to find a small subset of SNPs (tags) that covers the genetic variation of the entire set. We explore the trade-off between the number of tags used per non-tagged SNP and possible overfitting and propose an efficient 2LR-Tagging heuristic.

Biosynthetic natural products are invaluable resources that have been gleaned from the environment for generations, and they play an essential role in drug development. Natural product biosynthesis also possesses the latent ability to affect biological systems adversely. This work implements recent advances in genomic, proteomic and microbiological technologies to understand further biosynthetic molecules that may influence progression of human disease. Azinomycin A and B are antitumor metabolites isolated from the terrestrial bacterium Streptomyces sahachiroi. The azinomycins possess an unusual aziridine [1,2-a] pyrrolidine ring that reacts in concert with an epoxide moiety to produce DNA interstrand cross-links. Genomic sequencing of S. sahachiroi revealed a putative azinomycin resistance protein (AziR). Overexpression of AziR in heterologous hosts demonstrated the protein increases cell viability and decreases DNA damage response in the presence of azinomycin. Fluorescence titration indicated AziR functions as an azinomycin binding protein. An understanding of azinomycin resistance is important for future engineering and drug delivery strategies. Additionally, the S. sahachiroi draft genome obtained via 454 pyrosequencing and Illumina sequencing revealed several silent secondary metabolic pathways that may provide new natural products with biomedical application. β-lactoglobulin (BLG), the most abundant whey protein in bovine milk, has been observed to promote the self-condensation of retinal and similar α,β-unsaturated aldehydes. BLG is a possible non-genetic instigator of cycloretinal and A2E accumulation in the macula, a condition associated with age-related macular degeneration. BLG-mediated terpenal condensation has been optimized for in vitro study with the retinal mimic citral. In rabbits fed retinal and BLG or skim milk, cycloretinal formation was detected in the blood by 1H-NMR, and SDS-PAGE analysis indicated BLG was present in blood serum, suggesting the protein survives ingestion and retains catalytic activity. Mass spectrometry and site-directed mutagenesis provided mechanistic insight toward this unusual moonlighting behavior. The experiments described in this dissertation serve to further natural product biosynthesis discovery and elucidation as they relate to consequences for human health. Efforts to solve azinomycin biosynthesis via enzymatic reconstitution, characterize compounds produced by orphan gene clusters within S. sahachiroi, and obtain a clear mechanism for BLG-promoted cycloterpenal formation are immediate goals within the respective projects.

The Department of Energy and the Idaho National Laboratory are developing a Next Generation Nuclear Plant (NGNP) to serve as a demonstration of state-of-the-art nuclear technology. The purpose of the demonstration is two fold: 1) efficient low cost energy generation and 2) hydrogen production. Although a next generation plant could be developed as a single-purpose facility, early designs are expected to be dual-purpose. While hydrogen production and advanced energy cycles are still in their early stages of development, research towards coupling a high temperature reactor, electrical generation and hydrogen production is under way. Many aspects of the NGNP must be researched and developed to make recommendations on the final design of the plant. Parameters such as working conditions, cycle components, working fluids, and power conversion unit configurations must be understood. Three configurations of the power conversion unit were modeled using the process code HYSYS; a three-shaft design with 3 turbines and 4 compressors, a combined cycle with a Brayton top cycle and a Rankine bottoming cycle, and a reheated cycle with 3 stages of reheat were investigated. A high temperature steam electrolysis hydrogen production plant was coupled to the reactor and power conversion unit by means of an intermediate heat transport loop. Helium, CO2, and an 80% nitrogen, 20% helium mixture (by weight) were studied to determine the best working fluid in terms cycle efficiency and development cost. In each of these configurations the relative heat exchanger size and turbomachinery work were estimated for the different working fluids. Parametric studies away from the baseline values of the three-shaft and combined cycles were performed to determine the effect of varying conditions in the cycle. Recommendations on the optimal working fluid for each configuration were made. The helium working fluid produced the highest overall plant efficiency for the three-shaft and reheat cycle; however, the nitrogen-helium mixture produced similar efficiency with smaller component sizes. The CO2 working fluid is recommend in the combined cycle configuration.