B lymphocytes produce a wide array of antibodies to recognize a countless number of antigens. This highly diverse repertoire is produced during B cell development in the bone marrow from the immunoglobulin heavy chain (Igh) and light chain (Igk and Igl) loci. The mouse Igh is a large (~3Mb) multigene locus that contains 195 variable (V), 10 diversity (D) and 4 joining (J) genes that undergo developmentally regulated V(D)J recombination to produce the variable region of the antibody. Gene expression depends on spatial organisation of chromatin. To ensure that all V genes have a chance to recombine, they are brought into physical proximity to the D-J region by locus contraction and DNA looping. Not all V genes recombine with equal frequencies and we aim to investigate how dynamic changes in 3D structure of the Igh locus facilitate V(D)J recombination. Chromosome conformation capture techniques have revolutionised studies of genome conformation. I have applied a novel form of enriched Hi-C to study both intra-locus (cis) and genome-wide (trans) interactions of the immunoglobulin loci in pro-B and pre-B cells. This method provides a higher resolution than Hi-C and is less biased than 4C and 5C. I have mapped all cis interactions within the Igh locus to produce a comprehensive view of the structure of the locus prior to recombination. This approach has shown that the 3’ superanchor (3’CBEs) and the Intergenic Control Region 1 (IGCR1) containing CTCF sites are the two most interacting regions in the locus making long-range contacts with all V genes. A second major conformational feature is that the distal V genes form a large tightly looped domain forming the centre of mass of the locus to which the 3’CBEs and IGCR1 loop. Thanks to a collaboration on polymer modelling, 5000 single conformations were simulated based on the ensemble Hi-C data. This showed that every structure is different, supporting a model of dynamic and flexible organisation of the locus rather than hierarchical subdomains therein. Moreover, there is only a slight trend for V genes interacting more often with the D-J region to have higher recombination scores, supporting an ‘equal opportunity for all’ model in which participation of V genes in V(D)J recombination is not constrained by linear genomic distance from the DJ region. Nevertheless, CTCF binding level does contribute to V gene recombination frequency. I have also discovered that Igh and Igk loci participate in a highly specialised network of genome-wide (trans) interactions involving genes encoding B cell-specific factors essential for activation and maintenance of B cell identity, including Pax5, Foxo1, Ebf1, and Runx1. I have validated these by 3D DNA FISH and found that at the pro-B cell stage the Igh is involved in many trans interactions, whereas Igk does not make any contacts. In contrast, Igk gains numerous trans interactions at the pre-B cell stage, many of which overlap with the interactions Igh participates in at both developmental stages. Together, these findings reveal a complex developmentally regulated orchestration of genome conformation changes that underpins B cell development.

Locus of desired control and participation in a retirement preparation program was investigated in relation to retirement attitudes and adjustment. Fifty-nine subjects, consisting of older workers and retirees from a large southwestern corporation, comprised the sample. An experimental group, consisting of 12 subjects, completed questionnaires prior to and following their participation in the retirement preparation program. A control group, consisting of 15 subjects, completed the same questionnaires at approximately the same times as did the experimental group, but did not receive retirement preparation. A third group, consisting of 20 retirees who had a previous retirement preparation experience and 12 retirees who had not had such a retirement preparation experience, completed similar questionnaires.

The frequently studied lobula giant movement detector (LGMD) system of the locust responds most strongly to approaching objects. This thesis describes simulations which were designed with the ultimate aim of constructing a comprehensive model of the neural circuitry showing the effects of individual neurons on the overall responses of the system. The Rind and Bramwell neural network model of the LGMD was studied using new stimuli which revealed that the responses of the model are dependent on the shape of the stimulus. A modification of the model removes this dependence and allows the model to respond to more complex stimuli. Two models of a locust photoreceptor were developed with the aim of producing a detailed model of a light-adapting photoreceptor which could be used to study the responses of the LGMD to natural scenes. The first model, an electrical model of the cell membrane which describes the principal ionic conductances, was found to be overly complex for use in large scale simulations. However, the model was used to calculate from the photoreceptor's impulse response the average conductance change produced by individual photons. The second photoreceptor model, which is suitable for large scale simulations, uses two leaky integrators to mimic the effects of light adaptation on the photoreceptor's response. An electrical model of the lamina region of the optic lobe allowed the proposal that inhibition in the lamina is produced by electrical presynaptic inhibition to be studied, along with the possible effects of this inhibition on the visual input to the LGMD. The responses of the model correspond well with those measured from the LMCs of locusts and other insects, and their implications for the LGMD system are discussed.

Approved for public release; distribution is unlimited / The purpose of this thesis is to find suitable ways to design feedback compensators for high order systems by using Root-Locus methods. As a starting point we will examine a motor amplidyne system and a position control system that were previously designed using Bode methods. Then we generalize the method and extend it to other systems. The final subject of this thesis is to design feedback compensators as filters by using state feedback coefficients to define zeros of the filter, then we extend this idea to build cascade filters. / http://archive.org/details/designingfeedbac00kork / Lieutenant, Junior Grade, Turkish Navy

Magister Artium (Psychology) - MA(Psych) / This study aimed to synthesise the debates on factors associated with promoting resilience among women survivors of sexual abuse. Using systematic review methodology, six electronic databases (EBSCO, PsychINFO, SAGE, Science Direct, Springerlink and JSTOR) were used. Several keywords related to resilience and sexual abuse were utilised to search for articles published between January 2000 and December 2013 for inclusion. These primary studies were collocated, systematically assessed, synthesised and interpreted. Using two reviewers, data extraction was conducted in three stages, namely: the title reading, the abstract reading and the full text reading of articles. For the quality assessment, four instruments were employed, two of which were self-constructed tools. Thirty articles acquired an acceptable threshold score during the analysis and were used to compose this systematic review. Findings of this review highlighted that resilience is multidimensional; that is, it is made up of intrinsic and extrinsic resources/factors and is also a complex gradual dynamic process with specific indicators. These indicators include demonstration of competence and excellent functioning in important areas of life such as work, relationships, self-management, psychological well-being, and good health. Ten interacting factors were identified as promoting resilience including, 1) availability of social support from family and friends; 2) ego resources; 3) temperament/personality factors; 4) biographic characteristics; 5) ability to regulate emotions; 6) cultural factors; 7) positive life opportunities; 8) religion and spirituality; 9) abuse related factors; and 10) coping skills/strategies. These factors interact together, leading the survivor to be resilient. Major findings of the study as well as the implications for practice and further research are discussed.

The purpose of this study was to examine control beliefs and their role in the different ways victims cope with burglary. Two studies were conducted. In the first study, participants were college students who had been burglarized within the previous year. The volunteers were men and women between the ages of 19 and 37 (N=61). The participants completed Levenson's (1981) locus of control scale. The following week, in order to assist recall, the participants viewed a 2-minute video that depicted a residential burglary in progress. Immediately following the video, they completed a coping measure, situational appraisals of control measure, and importance of outcome measure. The second study was a conceptual replication of the first study and therefore followed the same procedures. However, in order to assess locus of control prior to victimization, participants were male and female college students (N=102) who had never been burglarized (experimentally induced victims). Zero-order correlations, discriminant analysis, and hierarchical multiple regression were used to examine the main, mediating, and moderating effects of locus of control, importance of outcome, situational appraisals of control, and gender on coping functions. Because previous research has found gender differences in reaction to criminal victimization, i t was hypothesized that the influence that gender has on coping results from an individual's locus of control orientation. It was also expected that the direction or strength of the locus of control and coping relation would be influenced by an individual's gender and by how much importance he or she attached to the victimization experience. In both the victim group and experimentally induced victim group, emotion-focused coping was significantly predicted by gender, locus of control, importance of outcome, and situational appraisals of control. However, problem-focused coping was significantly predicted by gender, locus of control, importance of outcome, and situational appraisals of control for the victim group only. Locus of control did not influence the gender and coping relation. The results indicated that in both groups men who held strong powerful others locus of control beliefs used less emotion-focused coping. In contrast, in the burglary victim group, women who held strong powerful others locus of control beliefs used more emotion-focused coping. However, there was no relationship between powerful others locus of control beliefs and emotion-focused coping for women in the experimentally induced victim group. For experimentally induced victims, both men and women with high chance locus of control beliefs used more emotion-focused coping. In both groups, importance of outcome did not moderate the locus of control and coping relation. Implications of these results and suggestions for future research are discussed. / Education, Faculty of / Educational and Counselling Psychology, and Special Education (ECPS), Department of / Graduate

The first genetic CAD risk locus to be identified by genome-wide association studies, single nucleotide polymorphisms (SNPs) at 9p21.3 predispose to increased risk of CAD. By bioinformatics scan analysis of the 9p21.3 locus; we interrogated the 59 linked SNPs over the 53,202bp to identify putative transcription factor-binding consensus sequences. We hypothesize that some genetic polymorphisms at the 9p21.3 locus are functional and will disrupt specific regulatory sequences within enhancers. Here, I investigated how polymorphisms affect TEAD-dependent regulation at the 9p21.3 locus, and also how polymorphisms affect GATA factor-dependent regulation at the 9p21.3 locus, using cultured HEK293 and primary human aortic smooth muscle cells (HAoSMCs) to transfect the pGL3-promoter plasmid constructs containing the reference or risk variant sequences (rs10611656, rs4977757, rs10757269, rs9632885). We showed by luciferase reporter assay that the risk allele of the SNPs disrupt activation by various TEAD transcription factors. We also performed electrophoretic mobility shift assay (EMSA) to test for allele-specific transcription factor binding that affect the family of TEAD transcription factors and the GATA factors. EMSA showed binding of TEAD3 and TEAD4, and differential binding for both GATA genotypes, and luciferase reporter assay confirmed that TEAD3 and TEAD4 activate the non-risk but not the risk allele, and for GATA factors no significant activation was shown. Our investigations lead us to conclude that rs10811656 and rs4977757 are functional and disrupt specific TEAD regulatory sequences within enhancers

This study examines the extent to which locus of control and social support are linked to self-efficacy with regard to disease management in HIV-positive adults. Perceived ability to effectively manage illness was measured with the Self-Efficacy for Managing Chronic Disease Scale. Scores from the Multidimensional Scale of Perceived Social Support and the Multidimensional Locus of Control Scale were used as predictors. The gender-balanced sample (N = 69) of HIV+ adults was primarily African-American (65.3%) and European American (30.5%), with a mean age of 47 years (SD = 8.37). Correlational analyses suggested significant positive relationships between self-efficacy, social support, and locus of control due to powerful others. A regression analysis found that the model accounted for 23% of the variance in self-efficacy (adj. R-squared =.23, F (5, 63) = 4.81, p < .01), with social support (&#946; = .37, t = 3.28, p < .01) and locus of control (&#946; = .25, t = 2.26, p < .05) both significant predictors. Results suggest that social support and locus of control contribute to the belief that HIV can be managed. Interestingly, an external locus of control contributed to this belief, perhaps due to the perception of a physician, religious icon, or partner as a "powerful other." Results suggest that a strong supportive relationship with a trusted other along with enhanced social support typically associated with group-based interventions may improve health outcomes by increasing self-efficacy in disease management in HIV-positive adults.

The hippocampus (HPC) is a brain area in the medial temporal lobe involved in spatial navigation, as well as the formation of episodic memories. A subset of the principal cells of the HPC, known as place cells, are active in specific locations of an environment, called the place fields. Dorsal hippocampal area CA1 contains place fields that are known to change their firing during spatial tasks where animals learn the location of a reward, known as goal-oriented learning (GOL) – CA1 place fields shift toward rewarded locations. Previous studies suggest that this preferentially occurs at novel rewarded locations in a familiar environment, but the mechanism is unknown. The locus coeruleus (LC) is a neuromodulatory nucleus in the brainstem that projects throughout the brain and releases norepinephrine and a small amount of dopamine. Stimulating locus coeruleus-hippocampal area CA1 projections (LC-CA1) was recently shown to improve performance on spatial memory tasks. Since performance on the GOL task is correlated with the degree of overrepresentation of rewarded locations, we hypothesized that the LC-CA1 projection was involved in reward-related place field reorganization. Using in vivo two photon calcium imaging, we recorded the activity of the LC-CA1 projection during a head fixed GOL task with two phases – during the first phase, a water reward was presented in one location (RZ1), and in the second phase, it was moved to a novel location (RZ2). In the first phase of the task, the LC-CA1 axons were correlated with running, but in the second phase they showed an increase in activity preceding RZ2. To determine whether the LC-CA1 is involved in place field reorganization that normally occurs in RZ2, we optogenetically activated the projection just before RZ1, and saw a pronounced place field reorganization right before the reward. Conversely, inhibition of LC-CA1 at RZ2 attenuated place field reorganization at this site. Finally, LC-CA1 stimulation away from the reward did not lead to place field reorganization, indicating that the LC influences place field shifts in conjunction with other signals that are differentially active around rewards. A full account of the effects of neuromodulation should also include astrocytes, since they respond to neuromodulators with large calcium signals that may be able to affect the function of neurons. We also recorded HPC astrocyte calcium activity during different behavioral tasks. Astrocytes showed occasional large calcium signals, with some differences in synchronicity and activity levels between hippocampal layers and behavioral paradigms. Future studies should determine whether the LC-CA1 projection affects place fields directly by affecting neural activity, indirectly via astrocytes, or both.

Obesity, diabetes, hypertension, and heart disease are highly heritable conditions that in aggregate are the major causes of morbidity and mortality in the developed world and are growing problems in developing countries. To map the causal genes, we conducted a population screen for these conditions on the Pacific Island of Kosrae. Family history and genetic data were used to construct a pedigree for the island. Analysis of the pedigree showed highly significant heritability for the metabolic traits under study. DNA samples from 2,188 participants were genotyped with 405 microsatellite markers with an average intermarker distance of 11 cM. A protocol using LOKI, a Markov chain Monte Carlo sampling method, was developed to analyze the Kosraen pedigree for height, a model quantitative trait. Robust quantitative trait loci for height were found on 10q21 and 1p31. This protocol was used to map a set of metabolic traits, including plasma leptin to chromosome region 5q35; systolic blood pressure to 20p12; total cholesterol to 19p13, 12q24, and 16qter; hip circumference to 10q25 and 4q23; body mass index to 18p11 and 20q13; apolipoprotein B to 2p24-25; weight to 18q21; and fasting blood sugar to 1q31-1q43. Several of these same chromosomal regions have been identified in previous studies validating the use of LOKI. These studies add information about the genetics of the metabolic syndrome and establish an analytical approach for linkage analysis of complex pedigrees. These results also lay the foundation for whole genome scans with dense sets of SNPs aimed to identifying causal genes.