Persons with spinal cord injury (SCI) suffer life-long consequences including paralysis, loss of involuntary bodily functions, and chronic pain. A subset of SCI patients develop neuropathic pain (NP), a chronic condition resulting from damage to the spinal cord. Hyperexcitability of spinal cord sensory neurons near damaged tissue is believed to underlie SCI-related NP. Although many therapies have been employed clinically to combat SCI-NP, few give satisfactory long-term relief. Transplantation of cells that release GABA, a molecule that inhibits neuronal activity, is being explored as an alternative to current SCI-NP therapies. My experiments made progress toward preclinical modeling of GABA cell therapy for SCI-NP. First, I sought to determine whether quisqualic acid (QUIS)-induced SCI altered responses to tonic pain stimuli or altered GABAergic neural circuitry in rats. Second, I sought to determine whether a combination of genetic and trophic manipulations could promote a GABAergic phenotype in rat embryonic neural precursor cells (NPCs) in an in vitro culture system. The results revealed that QUIS-SCI rats exhibit unusually prolonged nocifensive responses to hind paw formalin injections. There was no significant difference between QUIS-SCI and sham surgery rats in c-Fos immunolabeling of spinal cord sensory neurons after formalin-induced neuronal activity. However, immunohistochemistry revealed substantial decreases in staining for markers of GABA presynaptic vesicles in injured spinal cord tissue. NPCs were enriched for a neuronal phenotype by combining withdrawal of the growth factor FGF-2 from culture media and overexpression of the transcription factor MASH1 in transfected cells. Although glial marker expression was suppressed in NPCs by these manipulations, expression of neuronal markers none the less declined through time. MASH1-overexpressing NPCs exhibited greater clonal expansion and decreased stress-induced PDI expression after FGF-2 withdrawal as compared to naïve. In light of existing data, these results suggest that the QUIS-SCI model may be useful for testing the efficacy of GABAergic NPC transplantation to reduce neuropathic pain. MASH1 overexpression and FGF-2 withdrawal could serve as a first step toward enriching GABA in NPCs for transplantation. Although the mechanism for MASH1 cytoprotection remains unclear, MASH1 may enhance survival of NPCs grafted into the spinal cord. These experiments contributed to the preclinical basis for application of therapeutic GABAergic stem cell transplantation for NP in human SCI patients.

The purpose of this study was to compare the health profiles of women seeking residential treatment for substance abuse with women in the community. These 2 data sets consisted of a total of 621 participants. An additional aim of the present study was to examine whether these health profiles differ between the monosubstance abusing and polysubstance abusing women within the treatment group. There were a total of 257 participants in this group. All analyses controlled for the effects of age, insurance, marital status, employment and race/ethnicity. Binary logistic regressions were used to compare between and within the specified groups on the following variables: asthma, dyslipidemia, diabetes, Hepatitis B vaccination, HIV testing, hypertension, Pap smear testing, mental health problems, overweight/obesity and smoking. A follow-up analyses examined whether differences in the variables could be explained by the effects of specific control variables. Results suggested that differences in four outcomes might be explained by a single or smaller number of specific control variables. The overall results revealed that age was one of the strongest predictors of differences between the treatment and community group. When we controlled for age, marital status, low socioeconomic status (insurance, employment) and ethnicity we found that only two variables were significantly different. Women in residential showed significantly more smoking and mental health symptoms than were found in the community sample. There were no significant differences in the health profiles of polysubstance substance abusing than were found in monosubstance abusing women. The findings of the present study indicate that women seeking treatment are individuals with similar health disorders and health maintaining behaviors as the general population of women. However, women seeking treatment have significant increases in mental health disorders and smoking. Older age was related to increases in the odds of having dyslipidemia, diabetes, hypertension, and decreases in the odds of being immunized for Hepatitis B, tested for HIV, and having a Pap test in the last year. Due to anticipated-age related disorders, screening for dyslipidemia, diabetes, and hypertension should be provided for older women seeking admission to treatment. Substance abuse treatment centers for women should provide for mental health services and offer smoking cessation.

Heart valve structures open and close during the cardiac cycle to provide unidirectional blood flow through the heart, critical for efficient cardiovascular function. Valve dysfunction results in either incomplete opening or incomplete closure of the valve. Both types of valve dysfunction decrease efficiency of blood flow, increasing the load on the myocardium and leading to secondary heart disease such as pathological hypertrophy and heart failure. There are currently no effective treatments to prevent or slow the progression of valve disease, and there are no pharmacological treatments for advanced valve disease. Although most valve disease is associated with aging, increasing evidence suggests that valve disease often has origins in development. Congenital valvuloseptal defects affect many newborns, ranging from life-threatening malformations requiring immediate repair to more subtle, often undiagnosed defects that increase susceptibility to valve disease later in life. Therefore, an improved understanding of the mechanisms of heart valve formation and maintenance of adult valves may serve as an important step in improving valve disease treatment options. In this work, the mechanisms of normal valve development and the role of Sox9 in developing and mature valves are further studied. The temporal and spatial expression of extracellular matrix genes and proteins are examined throughout normal murine valve development. Sox9 function in the processes of valve development and valve maintenance is examined using mouse models of conditional Sox9 loss-of-function. Heart valve phenotypes in mice with reduced Sox9 function are examined throughout development and in adult mice with resultant calcific valve disease. The possible causative mechanisms of calcific valve disease in mice with reduced Sox9 function are further investigated by identification of novel possible targets of Sox9 transcriptional regulation. Together these studies improve our understanding of heart valve development, characterize a model of heart valve calcification with genetic etiology, and identify and characterize novel targets of Sox9.

The purpose of this research was to explore the factorial validity of the National Survey of Student Engagement (NSSE), a survey widely used by institutions of higher education. Specifically, using data collected from first-year students and seniors at The University of Tennessee, Knoxville (UT), this research addressed three research questions. First, to what extent does the five-factor model of NSSE (i.e., the benchmark model) exhibit factorial validity? Second, to what extent is Pike’s (2006b) scalelet model of the NSSE factorially valid? Finally, is there a model that depicts the NSSE data better than the models consisting of benchmarks or scalelets? The participants of this study were first-year (n = 981) and senior (n = 944) students at UT who completed the online version of the NSSE in the spring of 2009. Using confirmatory factor analysis, results suggested poor model fit for both the benchmark model and Pike’s (2006b) scalelet model. Exploratory factor analysis with oblique rotation (Promax) resulted in a six-factor solution consisting of 27 items that accounted for approximately 39 percent of variance. The six-factor model failed, however, to exhibit sufficient model fit when confirmatory factor analysis was applied to a different data set (i.e., NSSE data collected in the spring of 2010). Overall, results suggest that much more validation research is needed for the National Survey of Student Engagement to ensure that its use among institutions of higher education is appropriate.

Thesis (Ph. D.)--University of Chicago, Dept. of Pathology, December 2001. / Includes bibliographical references. Also available on the Internet.

Thesis (Ph.D.)--University of Delaware, 2006. / Principal faculty advisors: Dionisios G. Vlachos and Jeremy S. Edwards, Dept. of Chemical Engineering. Includes bibliographical references.

A gauged SU(4) flavor symmetric hadronic Lagrangian with empirical hadron masses is constructed to study charmonium absorption and charmed hadron production in hadronic reactions. For the coupling constants, empirical values are used if available. Otherwise, they are determined from known coupling constants using the SU(4) relations. To take into account the finite sizes of hadrons, form factors are introduced at strong interaction vertices with empirical cutoff parameters. For J/ψabsorption by nucleons, we have included both two-and three-body final states and find that with a cutoff parameter of 1 GeV at interaction vertices involving charm hadrons, the cross section is at most 5 mb and is consistent with that extracted from J/ψproduction from both photo-and proton-nucleus reactions. We have also evaluated the cross sections for charmed hadron production from pion and rho meson interactions with nucleons. With the same cutoff parameter of 1 GeV at interaction vertices, we find that these cross sections have values of a few tenths of mb and are dominated bythe s-channel nucleon pole diagram. For charmed hadron production from proton-proton reactions, their cross sections including bothtwo-andthree-body final states are about 1 batcenter-of-mass energyof 11.5 GeV, which is comparable to the measured inclusive cross section in these reactions.Including photon as a U(1) gauge particle, we have extended the model to study charmed hadron production in photon-proton reactions with both two-and three-body final states included. For form factors, an overall one is introduced in each processin order to maintain the gauge invariance of the total amplitude. Fitting the cutoff parameter in the form factor to the measured total cross section for charmed hadron production in photon-proton reactions at a center-of-mass energy of 6 GeV, the ratio of the cross sections for two-body and three-body final states is consistent with available experimental data.This result is further compared with predictions from the leading-order perturbative QCD calculation. Knowledge of the cross sections for charmonium absorption byhadrons and for charmed hadron production in hadronic reactions is essential for understanding charm production in heavy ion collisions at the Relativistic Heavy Ion Collider (RHIC), where a quark-gluon plasma is expected to be formed during the initial hot dense stage.

The core competency of the most effective organizations will be their capacity to learn in an increasingly complex and unpredictable business environment and HRD should expand its role to become a partner in the transformation of the entire organization. Organizational learning style, therefore, is an important research topic for the field of HRD (human resource development). This study had four primary purposes, which were germane to the corporations in the Republic of Korea: 1) to identify what organizational learning styles exist; 2) to identify the factors that differentiate the organizations with different organizational learning styles; 3) to identify the roles of HRD to facilitate organizational learning within the organizations in each organizational learning style; and 4) to identify the differences in the roles of HRD to facilitate organizational learning among the organizations with different organizational learning styles. The population for this study was the key informants at the corporations in the three industry areas: wholesale and retail trade; manufacturing; and hotels and restaurants. The survey instrument was delivered to 353 key informants, i.e. HR persons, at 240 corporations and 237 key informants at 166 corporations returned the survey instrument for a return rate of 67.1%. The findings of this study revealed the followings: 1) there are four types of organizational learning styles and the characteristics of each type of organizational learning style is determined by the combination of the organizations?? learning orientations, i.e. Knowledge Source, Learning Content, Dissemination Mode, and Learning Scope; 2) types of organizational culture, industry classification, and the size of an organization are the factors that differentiate the organizations with different organizational learning styles; 3) all roles of HRD are necessary for facilitating organizational learning; and 4) there are not differences in the roles of HRD to facilitate organizational learning among the organizations with different organizational learning styles.

The thesis contains four essays covering topics in the field of macroeconomic forecasting. The first two chapters consider factor models in the context of real-time forecasting with many indicators. Using a large number of predictors offers an opportunity to exploit a rich information set and is also considered to be a more robust approach in the presence of instabilities. On the other hand, it poses a challenge of how to extract the relevant information in a parsimonious way. Recent research shows that factor models provide an answer to this problem. The fundamental assumption underlying those models is that most of the co-movement of the variables in a given dataset can be summarized by only few latent variables, the factors. This assumption seems to be warranted in the case of macroeconomic and financial data. Important theoretical foundations for large factor models were laid by Forni, Hallin, Lippi and Reichlin (2000) and Stock and Watson (2002). Since then, different versions of factor models have been applied for forecasting, structural analysis or construction of economic activity indicators. Recently, Giannone, Reichlin and Small (2008) have used a factor model to produce projections of the U.S GDP in the presence of a real-time data flow. They propose a framework that can cope with large datasets characterised by staggered and nonsynchronous data releases (sometimes referred to as “ragged edge”). This is relevant as, in practice, important indicators like GDP are released with a substantial delay and, in the meantime, more timely variables can be used to assess the current state of the economy. The first chapter of the thesis entitled “A look into the factor model black box: publication lags and the role of hard and soft data in forecasting GDP” is based on joint work with Gerhard Rünstler and applies the framework of Giannone, Reichlin and Small (2008) to the case of euro area. In particular, we are interested in the role of “soft” and “hard” data in the GDP forecast and how it is related to their timeliness. The soft data include surveys and financial indicators and reflect market expectations. They are usually promptly available. In contrast, the hard indicators on real activity measure directly certain components of GDP (e.g. industrial production) and are published with a significant delay. We propose several measures in order to assess the role of individual or groups of series in the forecast while taking into account their respective publication lags. We find that surveys and financial data contain important information beyond the monthly real activity measures for the GDP forecasts, once their timeliness is properly accounted for. The second chapter entitled “Maximum likelihood estimation of large factor model on datasets with arbitrary pattern of missing data” is based on joint work with Michele Modugno. It proposes a methodology for the estimation of factor models on large cross-sections with a general pattern of missing data. In contrast to Giannone, Reichlin and Small (2008), we can handle datasets that are not only characterised by a “ragged edge”, but can include e.g. mixed frequency or short history indicators. The latter is particularly relevant for the euro area or other young economies, for which many series have been compiled only since recently. We adopt the maximum likelihood approach which, apart from the flexibility with regard to the pattern of missing data, is also more efficient and allows imposing restrictions on the parameters. Applied for small factor models by e.g. Geweke (1977), Sargent and Sims (1977) or Watson and Engle (1983), it has been shown by Doz, Giannone and Reichlin (2006) to be consistent, robust and computationally feasible also in the case of large cross-sections. To circumvent the computational complexity of a direct likelihood maximisation in the case of large cross-section, Doz, Giannone and Reichlin (2006) propose to use the iterative Expectation-Maximisation (EM) algorithm (used for the small model by Watson and Engle, 1983). Our contribution is to modify the EM steps to the case of missing data and to show how to augment the model, in order to account for the serial correlation of the idiosyncratic component. In addition, we derive the link between the unexpected part of a data release and the forecast revision and illustrate how this can be used to understand the sources of the latter in the case of simultaneous releases. We use this methodology for short-term forecasting and backdating of the euro area GDP on the basis of a large panel of monthly and quarterly data. In particular, we are able to examine the effect of quarterly variables and short history monthly series like the Purchasing Managers' surveys on the forecast. The third chapter is entitled “Large Bayesian VARs” and is based on joint work with Domenico Giannone and Lucrezia Reichlin. It proposes an alternative approach to factor models for dealing with the curse of dimensionality, namely Bayesian shrinkage. We study Vector Autoregressions (VARs) which have the advantage over factor models in that they allow structural analysis in a natural way. We consider systems including more than 100 variables. This is the first application in the literature to estimate a VAR of this size. Apart from the forecast considerations, as argued above, the size of the information set can be also relevant for the structural analysis, see e.g. Bernanke, Boivin and Eliasz (2005), Giannone and Reichlin (2006) or Christiano, Eichenbaum and Evans (1999) for a discussion. In addition, many problems may require the study of the dynamics of many variables: many countries, sectors or regions. While we use standard priors as proposed by Litterman (1986), an important novelty of the work is that we set the overall tightness of the prior in relation to the model size. In this we follow the recommendation by De Mol, Giannone and Reichlin (2008) who study the case of Bayesian regressions. They show that with increasing size of the model one should shrink more to avoid overfitting, but when data are collinear one is still able to extract the relevant sample information. We apply this principle in the case of VARs. We compare the large model with smaller systems in terms of forecasting performance and structural analysis of the effect of monetary policy shock. The results show that a standard Bayesian VAR model is an appropriate tool for large panels of data once the degree of shrinkage is set in relation to the model size. The fourth chapter entitled “Forecasting euro area inflation with wavelets: extracting information from real activity and money at different scales” proposes a framework for exploiting relationships between variables at different frequency bands in the context of forecasting. This work is motivated by the on-going debate whether money provides a reliable signal for the future price developments. The empirical evidence on the leading role of money for inflation in an out-of-sample forecast framework is not very strong, see e.g. Lenza (2006) or Fisher, Lenza, Pill and Reichlin (2008). At the same time, e.g. Gerlach (2003) or Assenmacher-Wesche and Gerlach (2007, 2008) argue that money and output could affect prices at different frequencies, however their analysis is performed in-sample. In this Chapter, it is investigated empirically which frequency bands and for which variables are the most relevant for the out-of-sample forecast of inflation when the information from prices, money and real activity is considered. To extract different frequency components from a series a wavelet transform is applied. It provides a simple and intuitive framework for band-pass filtering and allows a decomposition of series into different frequency bands. Its application in the multivariate out-of-sample forecast is novel in the literature. The results indicate that, indeed, different scales of money, prices and GDP can be relevant for the inflation forecast.

La malignité des astrocytomes est établie sur base de critères morphologiques définis au sein de la classification de l’Organisation Mondiale de la Santé (OMS). Ce système de gradation, qui s’échelonne de I à IV, constitue actuellement l’outil pronostique le plus fiable. Par facilité, les cliniciens regroupent les astrocytomes de grade I (astrocytomes pilocytiques) et les astrocytomes diffus de grade II sous le terme d’« Astrocytomes de bas-grade » par opposition aux astrocytomes de haut-grade, constitués des astrocytomes anaplasiques (grade III) et des glioblastomes (GBM ; grade IV). Cette terminologie conduit à des prises en charge cliniques inadéquates car elle englobe des tumeurs très différentes en terme d’agressivité : les astrocytomes de grade I, majoritairement non infiltrants, non évolutifs et indolents et les astrocytomes diffus de grade II, toujours infiltrants et évolutifs, progressant systématiquement en astrocytomes de haut-grade et entraînant le plus souvent le décès prématuré du patient. Bien que ces tumeurs soient définies par la classification de l’OMS comme des entités clinicopathologiques distinctes, peu de données sont disponibles dans la littérature pour expliquer leurs particularités biologiques et la pratique quotidienne montre que les différencier peut être difficile. Le but des études entreprises au cours de ce travail de thèse est d’apporter une contribution à la compréhension des mécanismes de tumorigenèse qui différencient l’astrocytome de grade I des astrocytomes diffus (grade II-IV), de manière à identifier des voies biologiques qui permettraient, au moins en partie, d’expliquer ces différences de comportement. Au cours de la première partie de ce travail, nous avons caractérisé les profils d’expression génomique des astrocytomes de grade I et de grade II, en comparant les données d’expression de gènes (évaluées par des technologies de micropuces d’ADN) de travaux publiés entre 2000 et 2005. L’expression des gènes identifiés a été validée par des analyses de RT-PCR quantitative sur une série indépendante d’astrocytomes de grade I, II et IV. Les fonctions biologiques des protéines codées par chacun de ces gènes ont fait l’objet de recherches bibliographiques détaillées afin de proposer un modèle permettant d’approcher les différences de comportement de ces tumeurs. Cette analyse nous a permis d’identifier TIMP4 (tissue inhibitor of metalloproteinases 4) et IGFBP2 (insulin-like growth factor binding protein 2) comme gènes candidats pour améliorer la caractérisation biologique et clinique des astrocytomes de grade I par rapport aux astrocytomes diffus. TIMP4 et IGFBP2 codent respectivement pour un inhibiteur endogène des métalloprotéinases matricielles (MMPs) et une protéine de liaison capable d’inhiber l’action des « insulin-like growth factors » (IGFs, dont IGFI et IGFII), des facteurs impliqués dans la croissance et la migration des astrocytes normaux et tumoraux. Sur base de la surexpression de TIMP4 et d’IGFBP2 dans les astrocytomes de grade I, en comparaison aux astrocytomes diffus de grade II, nous avons posé l’hypothèse suivante : « L’absence d’agressivité des astrocytomes de grade I, en comparaison aux astrocytomes diffus (grade II-IV) pourrait en partie être liée à l’inhibition par TIMP-4 de la protéolyse des complexes IGFBP2-IGFII au sein de ces tumeurs ». Cette protéolyse, qui diminue l’affinité d’IGFBP2 pour IGFII, pourrait contribuer à libérer IGFII dans la matrice extracellulaire (MEC), favoriser la liaison d’IGFII à son récepteur IGF-IR et stimuler la croissance et la migration des cellules astrocytaires tumorales. Pour tester cette hypothèse, nous avons réalisé différentes analyses biochimiques afin i) de caractériser les actions protéolytiques de MMP-2, MMP-9 et MT1-MMP sur le complexe IGFBP2-IGFII, ii) d’identifier la libération d’IGFII lors du clivage de ce complexe, et iii) d’étudier l’action inhibitrice de TIMP-4. A l’aide d’un modèle cellulaire in vitro (lignée astrocytaire tumorale LN229), nous avons ensuite observé l’influence de la protéolyse du complexe IGFBP2-IGFII sur la croissance et la motilité cellulaire. Cette étude a montré : (1) la protéolyse du complexe IGFBP2-IGFII par MMP-9, (2) l’inhibition partielle de cette protéolyse par TIMP-4, (3) la libération d’IGFII résultant de cette protéolyse et (4) les effets stimulants de la libération d’IGFII sur la croissance et la motilité des cellules LN229. Cette étude souligne le rôle important de la protéolyse des complexes IGFBP2-IGFII dans l’agressivité des astrocytomes diffus. Elle confirme les effets stimulants propres d’IGFII, d’IGFBP2 et de MMP-9 sur la motilité et/ou la croissance des cellules astrocytaires tumorales. Enfin, elle identifie un rôle inhibiteur potentiel de TIMP-4 sur la protéolyse du complexe IGFBP2-IGFII, qui pourrait contribuer à expliquer le caractère plus indolent des astrocytomes de grade I en comparaison aux astrocytomes diffus. Au cours de la troisième partie de ce travail, nous avons caractérisé l’expression de TIMP-4 et de son récepteur potentiel, la tétraspanine CD63, sur une série de 471 gliomes, dont 354 astrocytomes de grade I à IV par la méthode d’immunohistochimie quantitative appliquée aux « tissue-microarrays ». Pour chaque patient, les variables cliniques suivantes ont été collectées : âge, localisation tumorale et multifocalité, comportement infiltrant de la tumeur, étendue de la résection chirurgicale, grade histologique, type de traitement adjuvant, et suivi, évalué en termes de récidive tumorale et de durée de survie spécifiquement liée à la tumeur. Cette troisième étude confirme la surexpression de TIMP-4 dans les astrocytomes de grade I, en comparaison aux astrocytomes diffus de grade II, et montre que CD63 suit un profil d’expression similaire. Par conséquent, nous proposons l’utilisation de la co-expression TIMP-4/CD63 comme un nouveau marqueur diagnostique de l’astrocytome pilocytique de grade I dans la prise en charge anatomo-pathologique des « Astrocytomes de bas-grade ». Cette étude souligne également l’intérêt d’utiliser TIMP-4 et CD63 pour différencier le phénotype astrocytaire du phénotype oligodendroglial des gliomes diffus. Enfin, ce travail identifie CD63 et le profil de co-expression TIMP-4/CD63 comme nouveaux marqueurs pronostiques indépendants associés à une évolution défavorable des astrocytomes diffus et des oligoastrocytomes. Ce travail nous a donc permis, à partir de données de micropuces d’ADN, d’identifier TIMP4 et IGFBP2 comme gènes d’intérêt dans l’étude des astrocytomes. A partir de ces deux gènes, nous avons posé une hypothèse visant à expliquer le caractère non infiltrant des astrocytomes de grade I. Les tests in vitro menés dans le cadre de cette hypothèse confirment l’intérêt des protéines TIMP-4, IGFBP2 et IGFII dans la tumorigenèse des astrocytomes. Enfin, la caractérisation clinique de l’expression de TIMP-4 et de CD63, son récepteur potentiel, valide l’intérêt clinique que ces protéines représentent pour la prise en charge des patients porteurs d’un gliome. Il reste toutefois la nécessité d’approfondir nos connaissances sur les voies de signalisation utilisées par TIMP-4 et/ou CD63. Ces recherches permettraient de proposer de nouvelles stratégies thérapeutiques visant à améliorer le traitement de ces tumeurs et ainsi pallier au pronostic sombre des patients porteurs de gliomes diffus.