Proteins perform many important functions in the cell and are essential to the health of the cell and the organism. As such, there is much effort to understand the function of proteins. Due to the advances in sequencing technology, there are many sequences of proteins whose function is yet unknown. Therefore, computational systems are being developed and used to help predict protein function. Most computational systems represent proteins using features that are derived from protein sequence or protein structure to predict function. In contrast, there are very few systems that use the biomedical literature as a source of features. Earlier work demonstrated the utility of biomedical literature as a source of text features for predicting protein subcellular location. In this thesis we build on that earlier work, and examine the effectiveness of using text features to predict protein function. Using the molecular function and biological process terms from the Gene Ontology (GO) as our function classes, we trained two classifiers (k-Nearest Neighbour and Support Vector Machines) to predict protein function. The proteins were represented using text features that were extracted from biomedical abstracts based on statistical properties. For evaluation, the performance of our two classifiers was compared to that of two baseline classifiers: one that assigns function based solely on the prior distribution of protein function, and one that assigns function based on sequence similarity. The systems were trained and tested using 5-fold cross-validation over a dataset of more than 36,000 proteins. Overall, we show that text features extracted from biomedical literature can be used to predict protein function for any organism. Our results also show that our text-based classifier typically has comparable performance to the sequence-similarity baseline classifier. Based on our results and what previous work had shown, we believe that text features can be integrated with other types of features to provide more accurate predictions for protein function. / Thesis (Master, Computing) -- Queen's University, 2013-04-24 21:07:13.983

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The metabolic function of the glyoxalase system was investigated in (a) the differentiation and proliferation of human tumour cells in vitro, (b) the cell-free assembly of microtubules and (c) in the red blood cells during hyperglycaemia associated with Diabetes Mellitus. Chemically-induced differentiation of human promyelocytic HL60 leukaemia cells to neutrophils, and K562 erythroleukaemia cells, was accompanied by a decrease and an increase in the activity of glyoxalase I, respectively. Growth-arrest of Burkitt's lymphoma Raji cells and GM892 lymphoblastoid cells was accompanied by an increase and a decrease in the activity of glyoxalase I respectively. However, differentiation and growth arrest generally proceeded with an increase in the activity of glyoxalase II. Glyoxalase I activity did not consistently correlate with cell differentiation or proliferation status; hence, it is unlikely that glyoxalase I activity is either an indicator or a regulator of cell differentiation or proliferation. Conversely, glyoxalase II activity consistently increased during cell differentiation and growth-arrest and may be both an indicator and regulator of cell differentiation or proliferation. This may be related to the control of cellular microtubule assembly. S-D-Lactoylglutathione potentiated the cell-free, GTP-promoted assembly of microtubules. The effect was dose-related and was inhibited by glyoxalase II. During assembly, S-D-lactoylglutathione was consumed. This suggests that the glyoxalase system, through the influence of S-D-lactoylglutathione, may regulate the assembly of microtubules in cellular systems The whole blood concentrations of methylglyoxal and S-D-lactoylglutathione were increased in Diabetes Mellitus. There was no significant difference between red blood cell glyoxalase activities in diabetics, compared to healthy controls. However, insulin-dependent diabetic patients with retinopathy had a significantly higher glyoxalase I activity and a lower glyoxalase II activity, than patients without retinopathy. Diabetic retinopathy correlated with high glyoxalase I activity and low glyoxalase II activity and suggests the glyoxalase system may be involved in the development of diabetic complications.

Le rein est particulièrement exposé à de nombreux composés chimiques dont des médicaments, potentiellement néphrotoxiques. Parmi-eux, le Tacrolimus, un anti-calcineurine largement utilisé en transplantation rénale, est associé à l’apparition plus ou moins rapide de lésions histologique de toxicité conduisant à la fibrose rénale et, à terme, à la perte de fonction du greffon. Des systèmes enzymatiques et protéiques impliqués dans la prise en charge cellulaire des xénobiotiques, ainsi que des protéines aux propriétés anti-fibrosantes, telles que la cavéoline-1, lui permettent de se défendre contre ce type d’agression locale prolongée. La mesure de l’expression de 380 gènes impliqués dans la prise en charge des xénobiotiques dans des échantillons de tissu rénal humain sain nous a permis de confirmer que le rein possède un arsenal de défense important et complet. Ces différents systèmes de défense étant hautement polymorphes, le principal objectif de notre travail était de déterminer l’impact de certains polymorphismes génétiques sur la susceptibilité individuelle à la néphrotoxicité du Tacrolimus.Dans un premier temps, l’impact sur les paramètres pharmacocinétiques du Tacrolimus et le devenir du greffon de deux polymorphismes génétiques affectant les CYP3A5 et ABCB1, deux protéines participant au transport et au métabolisme du Tacrolimus, a été évalué dans une cohorte de 209 patients transplantés rénaux. Le génotypage a été réalisé à la fois sur l’ADN des receveurs et des donneurs. Les patients ont été suivis jusqu'à 2 ans après transplantation rénale. Cette étude a confirmé que les receveurs sous Tacrolimus (Prograf) porteurs d’au moins un allèle CYP3A5*1 fonctionnel nécessitent, quelque soit le moment de la greffe, des posologies de Tacrolimus plus élevées. Malgré ces doses, leur taux résiduel de Tacrolimus (C0) reste plus faible. Cependant, l’analyse de la distribution des rapports résiduelles/posologies de Tacrolimus montre qu’il existe une forte zone de chevauchement entre les deux populations *1/- vs *3/*3. Ainsi, certains patients ayant un CYP3A5 génétiquement déficitaire se comportent phénotypiquement comme des patients fonctionnels. D’autres polymorphismes génétiques sont probablement à l’origine de ce phénomène. En ce qui concerne le devenir du greffon, malgré son impact sur la pharmacocinétique du Tacrolimus, le polymorphisme génétique du CYP3A5 du donneur ou du receveur n’est statistiquement pas associé à la survenue de rejet, de retard de fonctionnement de greffon, ou n’a d’impact direct sur la fonction rénale (MDRD) et la survie du greffon. La mutation 3435C>T affectant le gène ABCB1 du donneur ou du receveur n’influence ni les paramètres pharmacocinétiques, ni le devenir clinique du greffon. Par ailleurs, le Tacrolimus est désormais disponible sous une forme à libération prolongée (Advagraf), permettant une prise unique journalière. Des pharmacocinétiques sur 24h ont été réalisées chez 32 patients (17 fonctionnels et 15 non fonctionnels pour le CYP3A5) avant conversion et quinze jours après conversion Prograf-Advagraf. Les résultats ont montré que, après conversion, l’exposition au Tacrolimus diminue de manière significative pour les patients CYP3A5 fonctionnelsEnfin, l’influence d’un polymorphisme génétique, rs4730751, affectant le gène CAV1 (codant la cavéoline-1, une protéine inhibitrice de la fibrose tissulaire) sur la survie du greffon rénal a récemment été rapporté. Nous avons confirmé dans une cohorte de 475 transplantés rénaux que les patients porteurs de ce polymorphisme génétique à l’état homozygote (ADN du greffon rénale) ont une altération de la fonction rénale significativement plus rapide. / Tacrolimus is highly effective in preventing acute rejection after renal transplantation, but displays a narrow therapeutic index and high inter-individual pharmacokinetic variations. As Tacrolimus is a substrate of CYP3A and ABCB1, the effect of potentially relevant genetic polymorphisms, CYP3A5 6986A>G and ABCB1 3435C>T, in both donors and recipients on Tacrolimus pharmacokinetics and clinical outcome was investigated in 209 kidney transplant patients. Methodology/Principal Findings:The mean duration follow-up was 21.8±9 months. Tacrolimus dose, trough blood levels (C0) and C0/dose ratio were statistically correlated with only the recipient CYP3A5 genotype. Concerning the allograft clinical outcome, CYP3A5 and ABCB1 genotypes exhibit no influence on the incidence of Biopsy Proven Acute Rejection and Delayed Graft Function. Renal function was not affected by CYP3A5 and ABCB1 genotypes. Histological evaluation of biopsies revealed also no significant association between Tacrolimus toxicity features and donor or recipient CYP3A5 and ABCB1 polymorphisms. Tacrolimus and steroids sparing was similar in groups of patients according to their genotypes. Conclusions/Significance: Recipient CYP3A5 6986A>G polymorphism explains part of the inter-individual variability in the pharmacokinetics of Tacrolimus. At two years, clinical outcome does not appear to be related to either donor’s or recipient’s CYP3A5 6986A>G and ABCB1 3435C>T polymorphisms. Interestingly, tapering of immunosuppressive therapy may be achieved even for patients experiencing extensive Tacrolimus metabolism, independently of CYP3A5 genotype.

Doctor of Philosophy / Department of Economics / Steven P. Cassou / This dissertation consists of three chapters. The first chapter surveys recent studies on the stability of the money demand function in selected developing countries. This chapter presents specific details about modeling and estimating the money demand function. Also, reasons behind the mixed results in the literature on the stability of the money demand function are explored as well as providing a guideline for future research on the stability of the money demand function in developing countries. The second chapter empirically investigates the stability of the money demand function in South Korea and Malaysia. The conventional money demand specification and cointegration framework with a single unknown structural break are conducted. The results of the residual-based tests for cointegration reveal that the M1, M2, and M3 demand are stable in the long run in Malaysia. However, there is no evidence of the stability for all three measures of the money demand in South Korea. The results of the residual-based tests suggest that structural breaks in the cointegration vectors are important and need to be accounted for in the specification of the M1, M2, and LF demand in South Korea, where LF includes M2 in addition to the reserves of nonbanking financial institutions and long-term deposits. The third chapter complements the previous chapter. It aims to evaluate the stability of the money demand function in South Korea and Malaysia using a cash in advance model and cointegration framework with one unknown structural break. This theoretical model adds short-term foreign interest rates and real exchange rates in addition to short-term domestic interest rates and real income. Also, the Granger causality and currency substitution analysis are conducted in this chapter. The results of the residuals-based tests indicate that the M2 and LF demand in South Korea, and M1, M2, and M3 demand in Malaysia are stable in the long run. The structural breaks may not be fairly absorbed when a cash in advance model is used for M1 in South Korea. Thus, the residual-based tests suggest that the structural break is still important and needs to be included in the specification of the M1 demand in South Korea.

Purpose: To compare the pulmonary function of older runners with non-runners and also the population norms. Method: 40 males ages 45 to 65 were compared for respiratory muscle strength, spirometry and maximum voluntary ventilation. Univariate and multivariate analysis (p < 0.05) were used to determine differences Results: No significant differences in age, height, or respiratory muscle strength were found. A significant difference was found for weight and BMI with the non-runners having greater values. The dependent variables of FVC, FEV1, FEF25-75%, PEF, and MVV resulted in a significant difference with the runners having greater values. A significant difference was also found for pulmonary function between runners and the general population. Conclusion: Continued and habitual aerobic exercise in the form of running in 45 to 65 year old men resulted in pulmonary function values that were significantly greater than those of the non-runners and also greater than population norms.

Motor deficits are debilitating in that they affect everyday function in human beings (Zillmer & Spiers, 2001). Cerebral Palsy (CP) is one particular disorder that is primary characterised by motor deficits, more specifically gross motor function deficits. As a result, people with CP are restricted in their everyday function and lack independence and self-sufficiency. With other factors such as stigmatisation and prejudice, social participation becomes limited which leads to isolation and loneliness, which may further lead to psychological disorders such as depression, anxiety, low self esteem and poor quality of life. These assumptions are based on the application of the mental health model, and one could assume the poorer the level of functioning the more likely a person’s psychological well-being will suffer. Thus, the study attempted to investigate these assumptions by exploring the relationship between levels of gross motor function and psychological well-being. A sample of 43 participants based in a care centre in Johannesburg completed a demographic questionnaire, the Major Depression Inventory (MDI), The Becks Anxiety Inventory (BAI), The Rosenburg Self Esteem Scale (RSE) and the Comprehensive Quality of Life Scale (COMQOL – A5). In addition, through observation, the level of gross motor function was determined by utilising the Gross Motor Function Classification System (GMFCS). The data that was gathered and was statistically manipulated to explore three main questions. Before the relationship between gross motor function and psychological well-being could be explored it was necessary to examine the suitability of the use of psychological measure on an adult with CP sample. Results indicated that the MDI (r = 0.78), BAI (r = 0.76). RSE (0.77), and COMQOL (r = 0.99) had high internal constancy reliability. The relationship between demographical variables, namely, age, gender, years of residency, experience of motor deterioration and presence of epilepsy, were tested against the level of gross motor function. No significant results were found apart from motor PDF created with pdfFactory trial version www.softwarelabs.com 4 deterioration. More participants with a higher level of gross motor function experienced motor deterioration (77%) than those with a lower level of gross motor function (44%). Lastly, the relationship between psychological variables and gross motor function was investigated as well as difference between the levels. Correlations revealed very weak positive relationships, with the exception of depression having a very weak negative relationship. All relationship were non significant. Although slight differences were seen between levels, they were non significant. 7% of participants were diagnosed with depressive disorders, and 47% with anxiety disorders. Problems with certain questions pertaining to the BAI raised concerns over the suitability of its use in CP adult samples. The study concluded that psychological measures, excluding the BAI, were suitable for use on a sample of adults with CP. It also highlighted that the level of motor functioning is not related to or determines psychological well-being in adults with CP. PDF created with pdfFactory trial version www.softwarelabs.com

Faculty of science School of Pathology 9602685e limenako.matsoso@nhls.co.za / The aerobic respiratory chain of mycobacteria consists of at least two branches, a cytochrome c branch terminating in an aa3-type cytochrome c oxidase, and a quinol branch terminating in cytochrome bd oxidase. The structure and function of the former branch, leading from the menaquinone-menaquinol pool to the cytochrome bc1 complex and terminating in the aa3-type cytochrome c oxidase, was characterized in Mycobacterium smegmatis. Allelic exchange mutants of M. smegmatis in the bc1 complex (ΔqcrCAB::hyg) and in subunit II of the aa3-type cytochome c oxidase (ΔctaC::hyg) were constructed and analyzed for growth, and gene expression using lacZ reporter assays and genome expression profiling by DNA microarray. Both mutants were found to be profoundly growth impaired. Disruption of this pathway resulted in an adaptation of the respiratory network that is characterized by a marked up-regulation of cydAB, which encodes the bioenergetically less-efficient and microaerobically induced cytochrome bd-type menaquinol oxidase that is required for the growth of M. smegmatis under O2-limiting conditions. Other adaptations to re-routing of the electron flux through the branch terminating in the bd-type oxidase were revealed by comparative expression profiling of the bc1-deficient mutant and its parental wild type strain using a partialgenome microarray of M. smegmatis that is enriched in essential genes. The majority of the genes up-regulated in the mutant are involved in intermediary metabolism and respiration. Also induced were several genes including, uspL and a homologue of Rv1592c, which were previously shown to be up-regulated by hypoxia in M. smegmatis (uspL) and M. tuberculosis (uspL and Rv1592). The cytochrome bc1-aa3 branch is required for growth of M. smegmatis under aerobic conditions and its disruption results in growth attenuation and up-regulation of cytochrome bd oxidase.

This dissertation follows the history of functional ideas and their pedagogy, illuminates with many examples the implementation of my updated system of Functional Analysis, and discusses the pedagogical implications that this updated system implies. The main goal is to update a system of labeling to be as pedagogically friendly as possible, in order to assist students and teachers of harmony to more easily and enjoyably learn, teach, and engage with common-practice tonal harmonic practice. Example syllabi, assignments, classroom demonstrations, and long projects are also included, and each aspect of the labeling is carefully discussed as it is presented. By surveying the history of functional thinking in music theory, we find that desire to analyze for function is not a new idea, and has been a goal of many theorists and harmony teachers for centuries. However, the current methods for instructing in function still leave students confused or baffled, as they struggle to match functional concepts to labels that do not exemplify their analysis goals and methods that insist on starting from tiny detail instead of coming from a more complete musical perspective. The elaboration of each detail of my Functional Analysis system shows how each part of Functional Analysis has been designed to help make harmonic analysis quicker, easier, more intuitive, and more personalized. The greater pedagogical implications on a larger scale involving courses and curricula are also covered, informed by my experience both as a teacher of today’s standard system and from teaching Functional Analysis in the classroom.