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This thesis comprises of four experiments from which related but independent analyses were undertaken. The interventions employed were designed to investigate the effect of cardiovascular adaptation, both in the short and long term on the cardiovascular responses to orthostatic stress. The first study, described in Chapter 3, tested the hypothesis that the cardiovascular system (CVS) could adapt to repeated orthostatic challenges in a single session. 14 subjects were exposed to ten +75° head-up tilts (HUT) over 70 mins. Each tilt involved a 5 min supine period (SUPINE) followed by 2 min HUT (TILT). Various indices of cardiovascular function were determined non-invasively. Cardiovascular responses to HUT10 for the final 30s of SUPINE and the first 30s of TILT were compared with those of HUT1. Integrated cardiac baroreflex sensitivity (BRS) was assessed using the Valsalva Manoeuvre (VM). Results showed MAP and DBP increased in both SUPINE (MAP p=0.009, DBP p=0.002) and TILT (MAP p=0.003, DBP p=0.009) for HUT10 compared with HUT1. TPR increased during TILT only (p=0.001) during HUT10 compared with HUT1. CO and SV were decreased during SUPINE at HUT10 relative to HUT1, however, there were no differences in TILT at HUT10 for either CO or SV. There was no change in the response of BRS, HR or SBP from HUT1 to HUT10. This study indicated that 10 repetitive HUTs can elicit changes in the cardiovascular responses to orthostasis, reflected by an increased TPR. The second study, described in Chapter 4, investigated the effect of the repeated HUT protocol outlined above on the cardiovascular responses to the squat-stand test (SST). 16 subjects were randomly allocated into either a tilting group that underwent ten +75° HUTs in 70 min (TILTING) or a control group that underwent 70 min of rest (CONTROL). Before and after the 70 min of either HUT or rest, subjects performed a SST (SST1 and SST2 respectively). The same cardiovascular parameters as those used in Chapter 3 were determined during both SSTs. The final 30s of SQUAT and the first 30s of STAND (divided into three 10-sec blocks termed STAND10, STAND20 and STAND30) were compared between SST1 and SST2, results were as follows. TILTING: during the SQUAT phase of SST2, SBP, MAP, DBP and TPR were significantly elevated (p less than 0.05) and HR was significantly decreased (p=0.032) compared with SST1; at STAND10, DBP and MAP were significantly increased (p less than 0.05); at STAND20, SBP was increased (p=0.03); and, at STAND30, DBP, SBP and MAP (p less than 0.05) were increased. There were no differences observed between SST1 and SST2 in the CONTROL group. Results indicated that ten consecutive +75° HUTs can improve the CVS responses to the SST. This is predominantly due to an increase in DBP, indicative of a change in vascular resistance. The third study, outlined in Chapter 5, investigated the effect of lower limb unilateral and bilateral resistance exercise on the blood pressure (BP) and HR responses in young males. 12 normotensive, sedentary young males were divided into 2 groups; one group exercised unilaterally and the other bilaterally. Thirty seconds of resting data were collected before subjects performed 4 SETs of 10-12 reps on a seated leg press. SET 1 was performed at 50% of 10-12RM, SET 2 was performed at 75% and SET 3 and SET 4 were performed at 10- 12RM. Bilateral resistance exercise elicited greater increases in SBP than unilateral exercise at SETs 2, 3 and 4 (p less than 0.05). DBP was only greater with bilateral exercise relative to unilateral exercise at SET 2 (p=0.036). There were no differences between the groups for the HR response. This study demonstrated that the BP response to bilateral lower limb resistance exercise was significantly greater than that of unilateral exercise in young sedentary males. This information could be beneficial to many populations for whom lower BP responses to exercise would be an advantage. Following on from this, to investigate long term improvements in cardiovascular responses to orthostasis the study outlined in Chapter 6, investigated the effect of acute (10 weeks) and chronic (more than 4 years) resistance training (RT) on the cardiovascular responses to both HUT and SST. 22 young males were allocated into three groups. The UNILATERAL (N=7) and the BILATERAL (N=7) groups performed baseline testing followed by 10 weeks of lower limb RT (performed unilaterally or bilaterally), followed by repeats of the tests performed at baseline. The CONTROL group (N=8) followed the same protocol except they were asked to perform no resistance training during the 10 weeks between testing sessions. An additional 7 subjects were allocated to a CHRONIC group consisting of individuals who had been training for more than 4 years. These subjects only performed the baseline testing. Baseline testing consisted of a number of cardiovascular tests, ultrasound for vein diameter, BRS via VM, and tests for calf ejection fraction and venous elasticity. Results demonstrated that neither unilateral nor bilateral RT caused an alteration in the cardiovascular response to the HUT or SST. There were no changes in any cardiovascular variable in response to acute RT relative to the control group. The CHRONIC group had a decreased cardiovascular response to both orthostatic challenges, with a decrease in SV in response to HUT being greater in the chronic group relative to the other groups (p less than 0.05) and the TPR response to SST being significantly less than the control group (p less than 0.05). The CHRONIC group also had a smaller elastic modulus for the right leg in comparison to the other groups (p less than 0.05). Results indicate that heavy resistance exercise may cause a decreased cardiovascular response to orthostatic stress and that these decreases may be controlled by a decreased venous elasticity. Collectively, these results demonstrate that the CVS is highly adaptable to repeated orthostatic stress and the dominant underlying feature of this protective adaptation is increased vascular resistance. Following the repeated HUT the CVS is in a more protected state and has become better able to defend itself against the adverse consequences of rapidly applied hydrostatic force. However lower limb RT performed bilaterally (with large increases in BP) or unilaterally (with lower increases in BP) does not improve CVS response to orthostatic stress, in fact chronic RT (more than 4 yrs) appears to impair the CVS response to orthostasis, potentially due to decreased venous elasticity.

Thesis (M.A.)--University of Chicago, Department of Economics. / Also available on the Internet.

Zugl.: München, Univ., Habil.-Schr., 2005

The first committed step in DNA biosynthesis occurs by direct reduction of ribonucleotides. This reduction is catalyzed by ribonucleotide reductase (RNR), an enzyme which uses a unique radical mechanism to facilitate the transformation. All four DNA precursors are synthesized by a single enzyme. Therefore, an intricate pattern of regulation has evolved to insure that RNR generates the proper quantity of each deoxyribonucleotide. It is this regulation, and conditions that influence this regulation, that are the central focal points of this dissertation. The studies described in this thesis have been aided by the development of a novel RNR assay. Unlike the traditional assay, this new procedure permits the simultaneous monitoring of all four RNR activities. This four-substrate assay was used to investigate whether the four enzyme activities of RNR were differentially sensitive to inhibition by the radical scavenger, hydroxyurea. The assay results, along with the results of a technique that measured enzyme inhibition as a function of radical decay, suggest that all activities of RNR are equally inhibited by hydroxyurea. Instead of differential inhibition, it appears that the activity level of RNR determines the relative sensitivity to hydroxyurea. The effects of nucleotide effectors and substrates on the relative turnover rates of the vaccinia virus and T4 phage RNR were also investigated by use of the four-substrate assay. When physiological concentrations of the allosteric effectors and substrates were added to the reaction mixtures, both enzyme forms produced dNDPs in ratios that approximate the nucleotide composition of their respective genomes. Non-physiological nucleotide concentrations generated significantly different product profiles, indicating that RNR has evolved to function within a defined nucleotide environment. Interestingly, the substrate component of the nucleotide environment proved to be as important as the allosteric effectors in modulating the reaction rates. Although the allosteric effects of nucleoside triphosphates have been known for some time, little attention has been given to the potential role that substrates play in the regulation of RNR. The results from my research suggest that the regulation of RNR in vivo results from a complex interplay between the enzyme and its substrates, products, and allosteric effectors. / Graduation date: 1998

Resilience implies the ability to quickly recover from a negative life event and adapt to changing situations. The goal of the current study was to explore the mechanisms underlying resilience, including the roles of cognitive emotion regulation (reappraisal) and cognitive flexibility. Although all aforementioned mechanisms were investigated, there was a particular focus on the relationship between resilience and "affective flexibility," a term used to describe cognitive flexibility in processing affective stimuli. In the current study, participants completed several self-report personality and behavioral scales, including measures of trait-resilience and cognitive reappraisal, a cognitive flexibility task, a working memory task and two novel affective flexibility tasks. Results showed that one of the two affective flexibility tasks was a valid measure of the affective flexibility construct; affective flexibility significantly predicted level of resilience above and beyond cognitive flexibility and working memory. Cognitive flexibility was also a unique predictor of resilience when controlling for affective flexibility and working memory. Cognitive reappraisal was positively correlated with resilience but it did not appear to mediate the relationship between affective flexibility and resilience. This study was the first to demonstrate that resilience is related to specific cognitive abilities rather than general executive functioning. It is also the first to introduce and operationalize the construct of affective flexibility and show that it is a distinct process from cognitive flexibility. Research limitations and future directions are discussed.

Two experiments compared the effects of two cognitive responses (i.e., rumination and cognitive reappraisal) individuals may adopt when confronted with a threat to self-regard. In Study 1, participants received negative feedback about their social skills and then rated the credibility of the source of the criticism. In Study 2, participants received negative feedback and then were given the opportunity to enhance the self on an unrelated task. Compared to reappraising the negative feedback, ruminating about the feedback led to poorer evaluations of the source of negative feedback and increased self-enhancement, respectively. These findings suggest that, compared to rumination, cognitive reappraisal helps to minimize defensive responses to ego threat.

Type IV collagens are components of basement membranes throughout the body and are involved in maintenance of the structural integrity of tissues as well as cellular differentiation, growth, and adhesion. Members of this collagen family are uniquely arranged in pairs in a head-to-head orientation and share a proximal promoter region. The COL4A5-COL4A6 gene pair is involved in numerous human diseases and cancer metastasis. For these reasons, defining the mechanisms that regulate collagen gene expression is of specific interest. To study type IV collagens, an in vitro model system was characterized. Comparative genomics was utilized to identify conserved, non-coding DNA in COL4A5 and COL4A6. These sequences were transfected into cell lines differing in type IV collagen expression and tested for the ability to regulate transcription of a reporter gene. Each cell line was also treated with the epigenetic modifying agents, 5-Aza and TSA. The effects on type IV collagen expression were determined. The COL4A5-COL4A6 promoter region was extensively characterized using ChIP analysis; antibodies against RNAPII, acetylated histone H3, and H3K9me2 were used. Additionally, bisulfite sequencing was carried out on each cell line to determine the methylation status of CpG dinucleotides in the promoter. Cell lines differing in expression of COL4A5 and COL4A6 were identified: 1) SCC-25 keratinocytes and HEK-293 cells transcribed both COL4A5 and COL4A6, 2) HT-1080 cells selectively activated COL4A5, and 3) SK-N-SH neuroblastoma cells did not express either gene. In SK-N-SH cells, histone modifications were shown to facilitate formation of condensed chromatin to prevent transcription initiation; repression was independent of DNA methylation. Activation of COL4A5 and COL4A6 in SCC-25 and HEK-293 cells involved acetylation of histones, although differences between the two cell types were seen. In addition, conserved, non-coding sequences were shown to affect transcription of a reporter gene; these sequences may be interacting with the transcription machinery to modulate collagen expression. Finally, repression of COL4A6 in HT-1080 cells appeared to be mediated through DNA methylation of the promoter; selective activation of COL4A5 may involve conserved, non-coding DNA. In summary, epigenetic modifications as well as conserved sequences are intimately involved in regulation of type IV collagen gene expression.