Nowadays we have tremendous amount of genetic data needing to be interpreted. Somatic mutations, copy number variations and methylation are example of the genetics data we are dealing with. Discovering driver mutations from these combined data types is challenging. Mutations are unpredictable and have broad heterogeneity, which makes our goal hard to accomplish. Many methods have been proposed to solve the mystery of genetics of cancer. In this project we manipulate those above mentioned genetics data types and choose to use and modified an existing method utilizing Markov Chain Monte Carlo (MCMC). The method introduced two properties, coverage and exclusivity. We obtained the data from The Cancer Genome Atlas (TCGA). We used MCMC method with three cancer types: Glioblastoma Multiform (GBM) with 214 patients, Breast Invasive Carcinoma (BRCA) with 474 patients and Colon Adenocarcinoma (COAD) with 233 patients.

The enteric nervous system controls the gut through the release of specific neurotransmitter and neuromodulators at specific sites such as mucosal secretory cell or smooth muscle cell. In the present study, we have examined the response to one of these neurohumoral agents, Neurotensin, in the rat distal colon. Neurotensin is a paracrine and endocrine modulator of the digestive tract. Even though these effects have been seen in colonic preparations, there are very few functional studies of the effects of Neurotensin in the rat colon, especially the distal colon. In the current study we propose the following hypothesis that Neurotensin will lead to contractile effect on basal tone and phasic contraction in the distal rat colon and will mediate this process primarily through the NT1 receptor. This hypothesis is based on evidence from the mixed action of Neurotensin in other regions of the gut and the more widespread distribution of the NT1 receptor. We have identified two specific aims to investigate this hypothesis. Aim 1 is to investigate the role of Neurotensin in tonic contraction and phasic contraction of the distal rat colon. In this aim, we will expose distal rat colon strips to varying doses of Neurotensin and record changes in basal tone and phasic activity. For our second aim, we will investigate the receptors mediating these responses to Neurotensin. In this aim, we will introduce NT1, NT2, and nonspecific inhibitors to distal rat colon and observe modulation in Neurotensin effects. We will also determine the existence of the receptors via Western Blot. The rat distal colon did respond in a dose-response fashion to varying doses of Neurotensin, but elicited different effects dependent on the strip preparation. When the mucosa was intact, circular muscle responded with an inhibitory effect to phasic activity, but there was little to no change in tonic activity. When the mucosa was removed, the circular muscle responded to Neurotensin by eliciting an increase in tonic activity, but had no effect on phasic activity. The use of SR48692, a specific NT1 receptor inhibitor, showed that the effects that were observed due to Neurotensin were not mediated through the NT1 receptor. With the use of SR142948, a non-selective NT1/NT2 inhibitor, the effects of Neurotensin was completely abolished. This led us to believe that the observed effects were mediated through a Neurotensin receptor and that receptor is likely the NT2 receptor. This was confirmed by the use of the specific NT2 receptor antagonist, levocabastine. The existence of the receptor in rat colon had to be confirmed in order to ensure that the effects observed were mediated through the NT2 receptor and not from an outside mediator. Western Blot analysis confirmed the existence of the NT2 receptor within the mucosa, within the muscle, and within the intact preparation of the distal rat colon. Although these results conflict with our hypothesis, it provides for an interesting template and avenue of exploration.

The human dopamine transporter (hDAT) provides the primary mechanism for dopamine clearance in synapses and thus facilitates the regulation of dopaminergic functions in cognition and reward. It is the molecular target of many centrally-active agents including amphetamines and cocaine. Therefore, an understanding of hDAT function and its modulation by these therapeutic drugs and drugs of abuse can provide insight into the mechanisms of abuse and addiction. In the presented studies, hDAT is tagged with a hexahistidine construct and heterologously expressed in Xenopus laevis oocytes. The plasma membranes are isolated, solubilized, and applied to a Nickel affinity column to obtain purified hDAT with preserved functionality. Purified hDAT reconstituted in planar lipid bilayers exhibited channel behaviors at physiological membrane potentials. We observed that the current mediated by single hDAT molecules is (1) induced by dopamine, (2) dependent on the sodium electrochemical gradient, and (3) blocked by cocaine. Our data support hDAT channel activity that is associated with dopamine uptake and presents a novel electrophysiological approach to studying monoamine transporter function and modulation by drugs.

It is commonly assumed that the voltage dependence for activation of voltage-gated channels is an intrinsic characteristic of the protein that remains unchanged during electrical activity. However, sporadic reports have suggested otherwise by showing that voltage dependence changes in a use-dependent manner resulting in a voltage dependence shift towards negative potentials (Bezanilla et al., 1982; Bruening-Wright and Larsson, 2007; Kuzmenkin et al., 2004; Labro et al., 2012; Larsson and Elinder, 2000; Olcese et al., 1997; Piper et al., 2003; Shirokov et al., 1992). Although the mechanism underlying the shift in voltage dependence remains unclear, this process seems to have two components. The first stage has been proposed to be related to the stabilization of the open conformation of the pore domain (Labro et al., 2012). The second stage seems to involve the stabilization of the activated state of the voltage sensing domain (VSD) (Labro et al., 2012; Lacroix et al., 2011) through a process known as VSD relaxation (Villalba-Galea, 2012; Villalba-Galea et al., 2008). This latter process has been proposed to be an intrinsic property of the VSD in which the domain is stabilized in an active-like state referred to as the relaxed state. Yet, the underlying mechanism remains unknown. This project expands upon the hypothesis that the movement of the fourth transmembrane (S4) segment of the VSD can induce conformational changes using the loop connecting the third and fourth transmembrane segments (S3-S4 loop) to couple VSD activation to VSD relaxation. Using the Drosophila potassium-selective, voltage-gated channel Shaker as a model, I show here that mutations in the S3-S4 loop of the VSD modulate the time constant of deactivation of the conductance and cause an apparent partial immobilization of the sensing charges of the VSD. These results hint, for the first time, at a mechanism for VSD relaxation. Particularly, these results indicate that the S3-S4 loop is intimately involved in the mechanism of coupling VSD activation to VSD relaxation.

v anglickém jazyce: The fundamental theme of this diploma paper is the phenomenology of the body which is related to the investigation of the act of the appearing itself in the works of the French philosopher Michel Henry. The phenomenological approach of this thinker is going to be defined primarily by the confrontation with intentional phenomenology of Edmund Husserl, which in the matter of the appearance keeps itself within the bounds of the relation to the world. This classical version of the phenomenology will be compared with Henrys phenomenology of the life. The life which is understood in such a manner is invisible or unapparent because it is radically immanent and never appears in the exteriority of the world. Anyhow, the redefinition of the classical conception of the appearance should make possible access to the most important and the most interesting thing for us that is to say to subjective or transcendental body, which appears and experiences itself directly in its affective self- experience of the invisible interiority. Therefore, the subjective body is going to be described upon these grounds together with Henry as immanent being that is at the same time appearance. Thus we are going to present philosophy of Michel Henry, which is called radical phenomenology of interiority that is...

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This study was designed to investigate and analyze the relationship between pastoral theology, objectives, methods, and practical application of discipleship in local SBC churches in Indiana. Pastors participating were senior or solo pastors serving in both full-time and bi-vocational pastorates. The survey instrument was organized in two sections, the first being the demographic data. The second section consisted of 60 statements using a Likert response scale organized for research purposes into four categories (theology, objective, process or model and application). The data revealed the need for pastors to demonstrate alignment with belief and practice in their life and discipleship ministry as seen in the areas of accountability and leadership development. The data revealed significant discontinuity between theological belief and practical application. There appears to be a disconnect between pastoral perception of discipleship and the reality in the local church as demonstrated in the increasing level of ambiguity found in the survey as it progressed from theology, to objective, to process, to application of discipleship. The data revealed that pastors demonstrated solid theological principles and understood the objectives of discipleship. There was a lack of clarity on the model or process to communicate discipleship, and even less clarity in the practical application of discipleship. Pastors need skills to transition from theory to practical application. To remedy the confusion and correct the discontinuity between theology and practice of discipleship, the researcher suggests the use of this research by state conventions and local associations to help pastors bridge the gap between theology, objectives, process and practical application of discipleship. There are conferences where a pastor could have the opportunity to take the survey instrument and view his own results. This study could be used in a seminar format as classroom material, and it could be published for pastoral enrichment. The pastor must verbally, and in written form, consistently communicate that his number one passion is to make disciples and to help people develop toward maturity in Christ. The bar of expectation and accountability placed upon members and leadership may need to be raised. The data revealed the need for pastors to grasp and work out their leadership role in the discipling process. Pastors appear confused about how they are to equip their members. If the confusion continues, local churches may have little impact upon their communities because pastors and members will likely have a skewed understanding of their purpose and role in the Kingdom of God and the society in which God has placed them. / This item is only available to students and faculty of the Southern Baptist Theological Seminary. If you are not associated with SBTS, this dissertation may be purchased from <a href="http://disexpress.umi.com/dxweb">http://disexpress.umi.com/dxweb</a> or downloaded through ProQuest's Dissertation and Theses database if your institution subscribes to that service.

A research report submitted to the Faculty of Health Sciences, University of Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the Degree of Master of Dentistry (Community Dentistry) Johannesburg, 2015 / This study aims to assess Oral Health-Related Quality of Life among children with special needs, from the caregiver’s perspective. The objectives of the study were: (i) To describe the demographic profile of the caregivers in terms of age, gender and socio-economic status,(ii) To assess the dental caries status of children with special needs,(iii) To establish the caregivers’ perceived Oral Health-Related Quality of Life of the children with special needs using the short-form Parent-Caregiver Perception Questionnaire, (iv) To assess the impact of the dental caries status on the families of children with special needs using the Family Impact Scale questionnaire. Results: The study consisted of 150 caregiver child pairs, the mean age of the caregivers was 39.52 years (SD 9.26) and mean age of children was 8.72 years (SD 6.07). There was a high prevalence of untreated caries regardless of the type of disability. The highest caries prevalence in both the primary and permanent dentition was found in the Epilepsy and the Autism groups (75%-83%) while the lowest was found among Down syndrome and Cerebral palsy groups (30%-47%).All the caregivers expressed impact on the Oral Health-Related Quality of Life.The mean Parent-Caregiver Perception Questionnaire score was 12.88 (SD 12.14) while the mean Family Impact score was 6.05 (SD 6.77). The highest Parent-Caregiver Perception score of 20.5 (SD 11.07) was found in the complex disability group followed by the Down syndrome group 15.87 (SD 13.87). The highest scores were found in the oral symptoms, functional limitation and emotional wellbeing domains which contributed more to the parent perception score. Conclusion: Caregivers of children with special needs in the current study experienced a negative impact on Oral Health-Related Quality of Life. Caries experience of the children with special needs was slightly lower than in the general population irrespective of disabilities and had no impact on the FIS and overall global rating-well-being.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Medicine in the discipline of Dermatology Johannesburg, 2017 / Introduction: Vitiligo is a skin pigmentation disorder and has an estimated global prevalence of around one to two percent. Vitiligo can significantly affect patients’ Quality of life (QoL). It is cosmetically and psychologically devastating, and can affect anyone irrespective of race, skin type or ethnicity. There is a paucity of research evaluating the QoL amongst vitiligo patients in Africa and Sub-Saharan Africa in particular. The objectives of this study were to demonstrate how vitiligo has altered the QoL of vitiligo patients treated at the skin outpatients’ clinics in Johannesburg, South Africa. Methods: Our research was a prospective cross-sectional study of all individuals who were diagnosed with vitiligo at the three dermatology outpatients’ clinics in three academic public hospitals, and the phototherapy daycare centre in Johannesburg. All patients fulfilling the inclusion criteria were requested to take part in the study. Data was obtained from enrolled individuals using a data collection sheet and the Dermatology Life Quality index questionnaire. This information was analysed using statistical software (STATA version 12). Results: A total of ninety-five (n=95) respondents were included as per inclusion criteria in our study. Our cohort comprised of sixty-two females (n=62, 65.26%), thirty-three males (n=33, 34. 74%). DLQI scores were in the ranges of 0 to 28 and the mean was 10.06±6.52, which indicates a moderate Quality of life (QoL) impairment in our cohort. Conclusion: Our study has shown that vitiligo moderately affects the QOL life of adult South African vitiligo patients. Therefore, treatment measures should be directed towards medical and psychological aspects of our patients for better treatment outcomes and improved QoL. This would be an argument for establishment of psychodermatology clinics at our referral hospitals. / MT2017

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Medicine in the branch of Ophthalmology Date: 22 June 2017 / Purpose: The purpose of this study was to explore the quality of life of patients who underwent an eye amputation after open globe injury. The study addressed both general and vision related quality of life, focussing on anxiety and depression. The demographics of the study participants/respondents were compared to similar studies. Design and Method: The study design was a quantitative, prospective cross- sectional study using as a data tool, a self-administered questionnaire with demographic information, an extract of the WHO PBD VF20 questionnaire and the EQ5D. The participants were sampled using the convenience sampling method from the oculo-prosthesis clinic at the St John Eye Hospital, Chris Hani Baragwanath Academic Hospital, Johannesburg, Gauteng, during March 2016 to June 2016. The information was collated and the data analysed using SAS to determine means, distributions and comparisons among the groups. Results: The demographics were comparable to other studies, except that more females were recruited in this current study. Vision specific quality of life: 51% of the respondents experienced no problems, 26.4% experienced problems, sometimes, and 9.3% experienced problems, very often. General health quality of life: 52,3% experienced an ideal life state. Only three respondents experienced a quality of life that was less than 50% of the ideal health state, all of whom indicated that they suffered severe pain. 83,8% of the study participants/respondents experienced a quality of life that was more than 75% of the ideal health state. Conclusion: Primary evisceration in severe ocular trauma is justified at the St John Eye Hospital due to the high burden of disease on the public health system (>70% of households), provided that certain criteria are met with regards to the visual potential of the eye. The higher female incidence could be due to alcohol misuse and gender violence; however, this will require further research. Despite the majority of the respondents having a health score of more than 75%, those with a higher pain score recorded a lower quality of life score. The participants who sustained open eye injuries leading to amputation were more prone to high levels of anxiety and depression. Continued health surveillance at the oculo-prosthesis clinic is advised with appropriate referrals to a social worker and or a psychologist/ psychiatrist and further on- referrals. / MT2017