Indiana University-Purdue University Indianapolis (IUPUI) / Accurate estimation of alcohol price elasticity is important for policy analysis – e.g.., determining optimal taxes and projecting revenues generated from proposed tax changes. Several approaches to specifying and estimating the price elasticity of demand for alcohol can be found in the literature. There are two keys to policy-relevant specification and estimation of alcohol price elasticity. First, the underlying demand model should take account of alcohol consumption decisions at the extensive margin – i.e., individuals' decisions to drink or not – because the price of alcohol may impact the drinking initiation decision and one's decision to drink is likely to be structurally different from how much they drink if they decide to do so (the intensive margin). Secondly, the modeling of alcohol demand elasticity should yield both theoretical and empirical results that are causally interpretable. The elasticity estimates obtained from the existing two-part model takes into account the extensive margin, but are not causally interpretable. The elasticity estimates obtained using aggregate-level models, however, are causally interpretable, but do not explicitly take into account the extensive margin. There currently exists no specification and estimation method for alcohol price elasticity that both accommodates the extensive margin and is causally interpretable. I explore additional sources of bias in the extant approaches to elasticity specification and estimation: 1) the use of logged (vs. nominal) alcohol prices; and 2) implementation of unnecessarily restrictive assumptions underlying the conventional two-part model. I propose a new approach to elasticity specification and estimation that covers the two key requirements for policy relevance and remedies all such biases. I find evidence of substantial divergence between the new and extant methods using both simulated and the real data. Such differences are profound when placed in the context of alcohol tax revenue generation.

Indiana University-Purdue University Indianapolis (IUPUI) / Phosphatase of Regenerating Liver 3 (PRL3) is suspected to be a causative factor toward cellular metastasis when overexpressed. To date, the molecular basis for PRL3 function remains an enigma, justifying the use of 'shot-gun'-style phosphoproteomic strategies to define the PRL3-mediated signaling network. On the basis of aberrant Src tyrosine kinase activation following ectopic PRL3 expression, phosphoproteomic data reveal a signal transduction network downstream of a mitogenic and chemotactic PDGF (α and β), Eph (A2, B3, B4), and Integrin (β1 and β5) receptor array known to be utilized by migratory mesenchymal cells during development and acute wound healing in the adult animal. Tyrosine phosphorylation is present on a multitude of signaling effectors responsible for Rho-family GTPase, PI3K-Akt, Jak-STAT3, and Ras-ERK1/2 pathway activation, linking observations made by the field as a whole under Src as a primary signal transducer. Our phosphoproteomic data paint the most comprehensive picture to date of how PRL3 drives pro-metastatic molecular events through Src activation. The Src-homology 2 (SH2) domain-containing tyrosine phosphatase 2 (SHP2), encoded by the Ptpn11 gene, is a bona-fide proto-oncogene responsible for the activation of the Ras/ERK1/2 pathway following mitogen stimulation. The molecular basis for SHP2 function is pTyr-ligand-mediated alleviation of intramolecular autoinhibition by the N-terminal SH2 domain (N-SH2 domain) upon the PTP catalytic domain. Pathogenic mutations that reside within the interface region between the N-SH2 and PTP domains are postulated to weaken the autoinhibitory interaction leading to SHP2 catalytic activation in the open conformation. Conversely, a subset of mutations resides within the catalytic active site and cause catalytic impairment. These catalytically impaired SHP2 mutants potentiate the pathogenesis of LEOPARD-syndrome (LS), a neuro-cardio-facial-cutaneous (NCFC) syndrome with very similar clinical presentation to related Noonan syndrome (NS), which is known to be caused by gain-of-function (GOF) SHP2 mutants. Here we apply hydrogen-deuterium exchange mass spectrometry (H/DX-MS) to provide direct evidence that LS-associated SHP2 mutations which cause catalytic impairment also weaken the autoinhibitory interaction that the N-SH2 domain makes with the PTP domain. Our H/DX-MS study shows that LS-SHP2 mutants possess a biophysical property that is absolutely required for GOF-effects to be realized, in-vivo.

Att läsa har en avgörande roll i barn och ungdomars utveckling, men läsmotivationen bland elever i Sverige har sjunkit de senaste åren. Sociala robotar har potential att väcka intresse för läsning, men forskningen är fortfarande i ett tidigt skede. Studien syftar till att utforska och stödja utformningen av designförslag för läsaktiviteter med den sociala roboten Bokbotten. Målet är att undersöka hur läsaktiviteter med Bokbotten kan stimulera mellanstadieelevers intresse och motivation för läsning. För att uppnå studiens syfte användes Design Research Methodology (DRM). DRM är en iterativ metod med tre faser som kombinerar forskning, design och utvärdering för att generera insikter och lösningar. I förståelsefasen analyserades videomaterial från tidigare prototyptestning för att identifiera effektiva och problematiska aspekter av interaktionen mellan elever och Bokbotten. I designfasen utvecklades designförslag baserat på dessa insikter och kvalitativ innehållsanalys av expertintervjuer. Slutligen utvärderades designförslagen av en expertgrupp för att identifiera svagheter, utmaningar och intressanta aspekter. Resultaten visar att Bokbotten har potential att skapa en trygg och engagerande lärmiljö som främjar läslust genom att stödja elevernas autonomi, kompetens och samhörighet. Baserat på de insikter som gavs av studien föreslås följande designriktlinjer: förstärkt autonomi, samarbete med lärare, konceptuellt lärande, samhörighet och inkludering och bidra till känsla av kompetens. / Reading plays a crucial role in the development of children and adolescents, yet reading motivation among students in Sweden has declined in recent years. Social robots have the potential to spark interest in reading, but the research is still in its early stages. This study aims to explore and develop design proposals for reading activities using the BookBot. The overall goal is to examine how reading activities with the BookBot can stimulate middle school students’ interest and motivation for reading. To achieve the study’s objective, the Design Research Methodology (DRM) was employed. DRM is an iterative method comprising three phases - Descriptive Study I, Prescriptive Study, and Descriptive Study II - that integrate research, design, and evaluation to generate insights and solutions. In Descriptive Study I, recorded material from previous prototype testing was analyzed to identify effective and problematic aspects of the interaction between students and the BookBot. In Prescriptive Study, design proposals were developed based on the insights from Descriptive Study I and qualitative content analysis of expert interviews. Finally, the design proposals were evaluated by an expert group to identify weaknesses, challenges, and interesting aspects. The results indicate that the Bookbot has the potential to create a safe and engaging learning environment that fosters motivation for reading. This effect is achieved by supporting three key student needs identified in Self-Determination Theory: autonomy, competence, and relatedness. Based on the insights provided by the study, the following design guidelines are proposed: enhanced autonomy, collaboration with teachers, conceptual learning, relatedness and inclusion, and fostering a sense of competence.

This thesis is a case study, conducted within a paradigm of action research, of the English 100 course at the University of the North West (now the Mafikeng campus of North West University), as taught by the author in the years 2000 - 2001. Its aim is to investigate the effect of the integration of language and literature on the first year of the undergraduate programme. The case study is placed in context through a consideration of educational change in South Africa. This includes changes taking place in the study of English as a second language at tertiary level, as well as the broader innovations to South African education brought about by government legislation. Two aspects of the latter are singled out for special attention: outcomes-based education and quality assurance. The case study is also contextualized at an international level through a survey of the theory and practice of an integrated approach to the teaching of language and literature to ESOL students. A survey of the literature, mainly in the last twenty years, reveals a growing interest in this approach. An attempt is then made to encapsulate this research in the form of fourteen statements about the supposed benefits of integrating language and literature. Through a detailed analysis of the performance of the first-year students, the case study subsequently attempts to test the validity of these claims. The study is presented as a process involving syllabus design, materials development, implementation of the course and an evaluation of its efficacy by the teacher-researcher. In line with the methodology of action research, a variety of methods is used to gather data. These include introspection and reflection (through the use of a teacher's journal and lesson reports), the analysis of written work produced by students, classroom observation by a `critical friend', triangulation (through the use of questionnaires, students' journals and self-reflective tasks) and documentation from the Department of English and university administration. The analysis of these data is both quantitative and qualitative. In keeping with the philosophy of action research and current educational practice, an attempt was made to incorporate and act upon the insights of students and colleagues. Reports on work-in-progress were also published in a number of fora: references are given in the thesis. The assumptions of action research are also apparent in the way in which the study is situated within cycles of action, reflection and improvement of pedagogical practice. The conclusion of the thesis is partly stated in terms of quality assurance: an attempt is made to assess the suitability of the integrated approach with regard to its fitness of and for purpose. It is concluded that a number of contextual factors, such as the conditions under which the English 100 course was taught and the under-preparedness of many of the students, militated against its success. The case-study is also assessed in terms of its contribution to international research in the field, and the personal development of the researcher. As is commonly found both in action research and in case study research, the findings of the study are context specific: consequently, no claim is made that they are generalizable to all other contexts. / English Studies / D.Litt. et Phil.

Os óculos se destacam por sua função social no atendimento das necessidades humanas, se considerados os indivíduos que dependem deste produto em sua condição de órtese. Este trabalho considera que para o público infantil, o projeto do produto de armações, demanda estudos e pesquisas, para propor resoluções técnicas, formais e estéticas adequadas, mas, sobretudo para captar os aspectos perceptivos, subjetivos e emocionais, que despertem a afeição desse segmento social com este objeto. A pesquisa teve como principal objetivo a definição e proposta de diretrizes para auxiliar no projeto do produto óculos para o público infantil. Para isto, foram utilizadas abordagens metodológicas do design, que consideram os indivíduos envolvidos como elementos centrais no processo do projeto, a exemplo do Design Centrado no Humano (DCH), adotado como estratégia fundamental no enfoque desta dissertação.A pesquisa presenta um levantamento histórico sobre o produto óculos e sobre as normas já existentes para o seu projeto; além de uma revisão sobre as abordagens metodológicas de design centradas nos indivíduos; e as coletas de dados considerando as crianças usuárias de óculos de 6 a 11 anos e as seguintes partes envolvidas, ou seja, os stakeholders - os responsáveis ou cuidadores; os oftalmopediatras e os atendentes das óticas. Para cada grupo foi definido um método a ser aplicado, com intuito de coletar informações sobre as diferentes visões do produto, considerando principalmente os aspectos emocionais e comportamentais envolvidos nas relações das crianças com as armações. Foram utilizados os procedimentos de storytelling e \'prototipar para empatia\', aplicados com as crianças; entrevistas individuais realizadas com oftalmopediatras e atendentes de óticas; e questionários com os cuidadores. A análise e a discussão dos resultados obtidos em cada um dos métodos foram confrontadas através de relações de triangulação, contribuindo para elencar as diretrizes para o projeto das armações, com conteúdose aspectos objetivos e subjetivos, referendando o uso das metodologias adotadas, e desta perspectiva de aproximação com as emoções de desejos das crianças em relação aos seus óculos, como fundamentais para a atuação em design de produto. / The glasses stands out for their social function in the attendance of human needs, if we consider whom depends on this product in orthoses condition. This research considered for the children audience, the demand for glasses design studies and research to propose technical, formal and appropriate aesthetic resolutions, but, especially to capture the perceptual, subjective and emotional aspects that arouse affection of this social segment with this object. The research aimed to define and propose guidelines to design glasses for children. The methodological approaches adopted considered the user and the individuals involved in the process as central elements in the design process, such as the study of Human Centered Design (HCD). The research presents historical study on the glasses and the existing standards for its project; the design methodologies geared to individuals, and the data collection considering children whom wear glasses of 6 to 11 years and the following third parties involved called stakeholders - the adults caregivers; the pediatric ophthalmology and the optical attendants. For each stakeholder was defined a method to be applied, aiming to collect information about the different views of the product, especially considering the emotional and behavioral relationships involved in children\'s issues with the frames. For the children were applied two methods, the storytelling and prototype for empathy; the individual interviews method was applied with pediatric ophthalmology and optical attendants and questionnaire method was applied with caregivers. The analysis and discussion of the results obtained in each method was compared using triangulation relationship, contributing to define the guidelines for design children glasses, based on the adopted methodology the guidelines has objective and subjective aspects in its contents, approaching of the children\'s emotions and wishes regarding their glasses, a very important issue for design this product.

O trabalho propõe uma metodologia para a condução de pesquisas de desenvolvimento de métodos, processos e sistemas construtivos voltadas para a criação de inovações tecnológicas que possam efetivamente contribuir para a evolução da atividade de construção de edifícios. São analisados os principais conceitos que identificam-se com o desenvolvimento tecnológico dos meios de produção de edifícios e estabelecidas definições para os mesmos. São também analisados os condicionantes que delimitam o contexto deste desenvolvimento no país. A metodologia proposta, entendida como um conjunto de preceitos destinados a orientar a condução de uma investigação e que se fundamenta na busca da máxima racionalização construtiva, é apresentada em dois níveis, o da doutrina e o da estratégia. A metodologia foi aplicada no desenvolvimento de um inovador processo construtivo de alvenaria estrutural de blocos cerâmicos. Este processo é apresentado e descreve-se como se deu o seu desenvolvimento, dos estudos iniciais à construção de edifícios protótipos. Conclue-se pela importância que a adoção de uma metodologia específica representa para a busca de soluções válidas para o conjunto da sociedade e como pode contribuir para a mudança da caótica situação atual por que passa a construção civil. / This thesis proposes a methodology to carry on the development research on building methods, processes and systems aiming at technological innovations which may effectivelly contribute for buildings construction activities evolution. The main concepts related to the technological development of the ways for the production process are analysed and their definitions established. It is also analysed the facts that restrain such development in Brazil. The proposed methodology is defined as a set of principles which objective is to point out the guidance for a scientific investigation and supported by the maximum building rationalization. This methodology is presented in two distinctive levels: the doctrine and the strategy. The methodology is applied specifically in the development of an innovative structural masonry process with ceramic blocks. The process is described, as well as the development performed stages: from the first studies to the prototype buildings construction. It is concluded that by adopting a specific methodology important solutions for the society as a whole are obtained and it gives essential support to change the disordered situation currently faced by the civil construction.

With antimicrobial resistance to current drugs steadily rising, the development of new antibiotics with novel mechanisms of action has become an imperative. The majority of life-threatening infections worldwide are caused by "ESKAPE" pathogens which are encountered in more than 40% of hospital-acquired infections, and are resistant to the majority of commonly used antibiotics. Naturally occurring cyclic depsipeptides, microbial secondary metabolites that contain one or more ester bonds in addition to amide bonds, have emerged as an important source of pharmacologically active compounds or lead structures for the development of novel antibiotics. Some of those peptides are either already marketed (daptomycin) or in advanced stages of clinical development (ramoplanin). Structurally simple, yet potent, fusaricidin/LI-F and lysobactin families of naturally occurring antibiotics represent particularly attractive candidates for the development of new antibacterial agents capable of overco ming infections caused by multidrug-resistant bacteria. These natural products exhibit potent antimicrobial activity against a variety of clinically relevant fungi and Gram-positive bacteria. Therefore, access to these classes of natural products and their synthetic analogs, combined with elucidation of their mode of action represent important initial steps toward full exploitation of their antmicrobial potential. This dissertation describes a general approach toward the solid-phase synthesis of fusaricidin/LI-F and lysobactin analogs and an extensive structure-activity relationship (SAR) study. We have devised a simple and robust preparation strategy based on standard Fmoc solid-phase peptide synthesis protocols. / The SAR study revealed key structural requirements for fusaricidin/LI-F and related cyclic lipopeptides antibacterial activity, including the presence of the guanidino moietly at the end of the lipidic tail, hydrophobic amino acid residues, and peptide conformation Moreover, substitution of the ester bond with an amide bond significantly improved stability under physiologically relevant conditions and reduced toxicity. In addition, we have shown that these antibacterial peptides exert their mode of action via a novel mechanism, which invloves bacterial membrane interactions, followed by peptide internalization. Altogether, the research described in this dissertation demonstrates that new antibiotics derived from fusaricidin/LI-F natural products, have the potential to meet the challenge of antibiotic resistance in Gram-positive bacteria. / by Nina Bionda. / Thesis (Ph.D.)--Florida Atlantic University, 2013. / Includes bibliography. / Mode of access: World Wide Web. / System requirements: Adobe Reader.

Diabetic retinopathy is an ischemic retinal neovascular disease causing vision loss among adults. The studies presented involve the design and testing of a gene therapy vector to inhibit retinal revascularization, similar to that found in diabetic retinopathy. Gene therapy has proven to be an effective method to introduce therapeutic proteins to treat retinal diseases. Targeting a specific cell type and expression of therapeutic proteins according to the tissue microenvironment should have an advantage over traditional gene therapy by avoiding unwanted transgene expression. Hypoxia plays a significant role in the pathophysiology of many retinal ischemic diseases. Retinal Mèuller cells provide structural and functional support to retinal neurons, as well as playing a significant role in retinal neovascularization. Targeting Mèuller cells may be an effective strategy to prevent retinal neovascularization under pathological conditions. ... The hypoxia regulated, glial specific vector successfully reduced the abnormal neovascularization in the periphery by 93% and reduced the central vasobliterated area by 90%. A substantial amount of exogenous endostatin was produced in the retinas of P17 OIR mice. A significant increase in human endostatin protein and reduced vascular endothelial growth factor (VEGF) were identified by Western blot and ELISA, respectively. These findings suggest hypoxia-regulated, glial cell-specific scAAV mediated gene expression may be useful to prevent blindness found in devastating retinal diseases involving neovascularization. / by Manas Ranjan Biswal. / Thesis (Ph.D.)--Florida Atlantic University, 2012. / Includes bibliography. / Mode of access: World Wide Web. / System requirements: Adobe Reader.

O presente estudo nasceu da Pesquisa Multicêntrica de Indicadores Clínicos de Risco para o Desenvolvimento Infantil que validou para uso pediátrico o instrumento denominado Indicadores Clínicos de Risco para o Desenvolvimento Infantil (IRDI), construído a partir da teoria psicanalítica. Além dos resultados diretamente relacionados à validação dos indicadores, a Pesquisa IRDI forneceu evidências empíricas para algumas importantes formulações teóricas psicanalíticas e se inscreveu também em um campo de discussão metodológica ao propor a articulação do método experimental com o método clínico. O presente estudo teve dois grandes objetivos: ampliar as bases teóricas do IRDI e propor uma discussão metodológica. Teve ainda dois objetivos específicos: a) explorar os resultados específicos da subamostra de 130 crianças em torno do eixo da função paterna; b) Contribuir para o campo de estudos psicanalíticos sobre os bebês. Para realizar a ampliação teórica, o estudo examinou os fundamentos teóricos de cada um dos 31 indicadores propostos pela pesquisa IRDI. A discussão metodológica foi realizada neste estudo tendo como direção de pesquisa a seguinte pergunta: o uso da metodologia experimental compromete as bases psicanalíticas da Pesquisa IRDI? O presente estudo buscou também explorar os resultados de uma amostra específica de 130 crianças. Em relação à subamostra, os achados clínicos apontaram o aparecimento significativo de duas sintomatologias nas crianças aos três anos, agressividade e ausência de enredo no brincar, efeitos de uma operação frágil da função paterna. Em relação à discussão metodológica, conclui-se que a conceituação e os fundamentos da pesquisa são psicanalíticos e que as metodologias utilizadas possibilitaram uma convergência interdisciplinar (Hans) e interações da psicanálise (Mijolla-Mellor) com outras disciplinas. Propõe-se considerar que a utilização de diferentes métodos não se contrapõe à semiologia psicanalítica porque a psicanálise não é uma só modalidade de investigação e sua referência metodológica não é única. Essa diversidade e heterogeneidade constitutiva colocam a psicanálise em posição de interagir com as demais disciplinas, como propõe Mijolla. / The present study originated in the Mulri-Center Reaserch on Clinical Risk Indicators for Child Development, which validated the pediatric use of a tool named Clincal Risk Indicators for Child Development (CRICD) Indicadores Clínicos de Risco para o Desenvolvimento Infantil (IRDI), based on the psychoanalytical theory. Besides the results directly related to the validation of risk indicators, CRICD Research provided empirical evidence of some important psychoanalytic theoretical formulations and incited methodological discussions by proposing a combination of the experimental and clinical methods. The present study aims at two relevant goals: to widen CRICDs theoretical basis and to propose a methodological discussion. And had also two specific objectives: a) explore in greater detail results obtained from a specific sample group of 130 children which are related to the theoretical axis called Paternal Function; b) unveiling the psychopathology of early infancy. To accomplish the expansion theory, the study examined the theoretical fundamentals of each one of the 31 indicators proposed by the CRICD Research.The methodological discussion contained in this study was guided by the following question, which in turn oriented our research: does the use of experimental methodology undermine the psychoanalytical basis of CRICD Research? Regarding the specific sample of 130 childrens. The present study also explores in greater detail results obtained from a specific sample group of 130 children. Clinical findings show the emergence of two significant symptomalogies in three-year old children: aggressiveness and the lack of a plot when playing, which are understood as the effects of a fragile performance of the paternal function. By means of a methodological discussion, we conclude that the conceptualization and fundamentals of this study are indeed psychoanalytical and the methodology employed allowed for an interdisciplinary convergence (Hans) and interactions of psychoanalysis (Mijolla-Mellor) with other disciplines. It intends to show that the use of different methods is not conflictive with psychoanalytical semiology. Psychoanalysis is neither a unique research modality, nor is its methodological reference unique. Such constitutive diversity and heterogeneity allow for psychoanalysis to interact with other disciplines and to progress by means of diverse and heterogenic sources, as Mijolla proposes.

Made available in DSpace on 2017-07-21T20:32:00Z (GMT). No. of bitstreams: 1 WILIAN CARLOS CIPRIANI BAROM.pdf: 3010462 bytes, checksum: a59c674db80d4c73ec52cabcae9d767c (MD5) Previous issue date: 2012-09-20 / With this work we seek to contribute to the area of Didactics of history. To do this, we use an analysis of academic research – theses and dissertations – around the teaching of history, to identify how the concept of historical consciousness has been used. For the case of this research, the theoretical bias with which conceptualize historical consciousness refers to the peculiar array Germanic, from the trilogy entitled theory of history of the philosopher JörnRüsen. In this sense, built a first chapter in which our understanding of the concepts presented, as well as rüsenianos is a possible interrelation between these concepts around axis teaching. The second chapter was a look about the empirical data to identify how these concepts are being used in research on the teaching of history. Do not set ourselves the task of judging these appropriations regulatory concepts and underlying theory, but yes, naming trends and possibilities that were found, forms of interpretation of theory and specific contributions in the process of establishment of the area of Didactics of history, for then we trace a bird's-eye view and handling of this area. These studies examined were taken as documents, ' traces ', intentions of groups/individuals, which in turn relate in society, which inserts in the category of documentary research. Thirty-four academic works were analyzed, being ten theses and twenty-four dissertations. / Com este trabalho buscamos contribuir à área da Didática da História. Para tanto, recorremos a uma análise das pesquisas acadêmicas – teses e dissertações – em torno do Ensino da História, a fim de se identificar como o conceito de Consciência Histórica vem sendo empregado. Para o caso desta pesquisa, o viés teórico com o qual conceituamos consciência histórica refere-se à peculiar matriz germânica, a partir da trilogia intitulada Teoria da História do filósofo JörnRüsen. Neste sentido, construímos um primeiro capítulo no qual nossa compreensão dos conceitos rüsenianos é apresentada, assim como uma possível inter-relação entre estes conceitos em torno do eixo Ensino. Ao segundo capítulo coube um olhar sobre os dados empíricos a se identificar como estes conceitos estão sendo utilizados nas pesquisas que versam sobre o ensino da História. Não nos propusemos à tarefa normativa de julgarmos as apropriações destes conceitos e teoria subjacente, mas sim, de apontarmos as tendências e possibilidades que foram encontradas, formas de interpretação da teoria e contribuições específicas no processo de instituição da área da Didática da História, para seguidamente traçarmos uma visão panorâmica e de movimentação da área da ciência da Didática da História. Estas pesquisas analisadas foram tomadas como documentos, ‘vestígios’, intenções de grupos/indivíduos, que por vez se relacionam em sociedade, o que nos insere na categoria de pesquisa documental. Foram trinta e quatro trabalhos acadêmicos analisados, sendo dez teses e vinte e quatro dissertações.