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1
Kopf, Brigitte Sandra. "Neurochemical mechanisms mediating LPS-induced anorexia /." [S.l.] : [s.n.], 2009. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=18407.
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Wray, Jonathan. "Hypothalamic mechanisms mediating glucocorticoid-induced metabolic effects." Thesis, University of Manchester, 2018. https://www.research.manchester.ac.uk/portal/en/theses/hypothalamic-mechanisms-mediating-glucocorticoidinduced-metabolic-effects(6d4314ad-d89d-4d42-b727-d5bbced74073).html.
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Glucocorticoids (GCs) are widely prescribed for inflammatory and autoimmune conditions. However, patients often develop adverse metabolic effects, including hyperphagia, obesity and hyperglycemia. These effects have been recapitulated in a murine model of GC excess, and we hypothesize that they are mediated, in part, through central mechanisms. Therefore, this thesis aimed to identify genes and pathways in the hypothalamic arcuate nucleus (ARC) that are altered with GC treatment, and evaluate their contribution to GC-induced metabolic abnormalities. To better characterize the metabolic phenotype prior to RNA-seq, corticosterone (Cort; 75μg/ml) was administered in the drinking water to male C57Bl/6J mice for 2 days or 4 weeks. Cort treatment produced an early and sustained increase in food intake, with a delayed increase in body weight and adipose tissue mass. Insulin was elevated at 2 days, which progressed to fasting hyperinsulinemia and insulin resistance by 4 weeks. Indirect calorimetry revealed a persistent increase in respiratory exchange ratio, but no change in energy expenditure with 2 weeks GC treatment. However, UCP1 in brown adipose tissue (BAT) was decreased at 4 weeks, suggesting a delayed decrease in energy expenditure. To identify genes and pathways altered in the ARC, RNA-seq was performed on isolated arcuate nuclei from 2 day and 4 week Cort treated mice. RNA-seq revealed a multitude of genes altered at both timepoints, however the wealth of secondary effects at 4 weeks made interpretation of this dataset difficult. Subsequent work focused on genes altered at 2 days that are predicted to contribute to GC-induced hyperphagia and obesity. RNA-seq identified 131 upregulated and 100 downregulated genes after 2 days of Cort treatment. Among the genes altered were known GC-regulated genes, including Cdkn1a, Fkbp5, Mt1, Mt2, as well as some involved in the control of energy balance, such as Agrp, Ghsr, and Nmb. Results were confirmed by qRT-PCR, with a strong correlation between techniques. Thus, RNA-seq has identified candidate genes for investigation. One gene of interest was type-II iodothyronine deiodinase (Dio2), which increases the local availability of triiodothyronine (T3), and in turn increases food intake. With 2 day Cort treatment Dio2 increased (2-fold) in the ARC, which was confirmed by in situ hybridization. To determine the contribution of Dio2 in the development of GC-induced hyperphagia and obesity, AAV-directed CRISPR-Cas9 injections were used to knock down Dio2 in the MBH. Lack of a specific anti-DIO2 antibody meant that it was not possible to quantify DIO2 knockdown. However, the efficiency of CRISPR guide RNAs was pre-validated in vitro and correct targeting of the MBH was determined by immunofluorescence, and by quantification of Cas9 mRNA in MBH micro-punches. Dio2 knockdown mice were then challenged with Cort for 4 weeks, and showed a mild attenuation in BAT weight gain, as well as a 50% reduction in the GC-induced increase in Agrp. However, Dio2 knockdown conferred no protection from GC-induced hyperphagia, obesity, or hyperglycemia. This study has provided further insight into the development of GC side effects, and has identified several hypothalamic genes that may contribute to these effects. Future studies will further investigate the hypothalamic mechanisms driving GC-induced metabolic side effects, thus informing the development of targeted therapies to prevent the GC-induced metabolic sequelae.
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Lu, Jiao. "Central Mechanisms Mediating Ang II-Salt Hypertension." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/34811.
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Abstract
Statement of problem
Plasma angiotensin II (Ang II) increases blood pressure (BP) through the activation of brain angiotensinergic pathways and the aldosterone-mineralocorticoid receptors (MR)- epithelial Na+ channel (ENaC)-endogenous ouabain (EO) pathway. The response of BP to circulating Ang II is enhanced by high salt intake, but the central mechanisms mediating this elevated response are not known.
Methods of investigation
Study 1) Male Wistar rats were divided into 4 groups and treated with regular salt diet (0.4% NaCl), high salt diet (2% NaCl), sc Ang II infusion (150 ng/kg/min), or sc Ang II infusion together with 2% salt diet for 14 days; plasma aldosterone and corticosterone levels, CYP11B2 mRNA in adrenal cortex and the mRNA levels of Ang II type 1 receptors (AT1R), CYP11B1 (11-β hydroxylase), CYP11B2 (aldosterone synthase), MR, 11βHSD2, ENaC α, ENaC β and ENaC γ in the subfornical organ (SFO), paraventricular nucleus (PVN), supraoptic nucleus (SON) and rostral ventrolateral medulla (RVLM) were measured.
Study 2) MR blockers (eplerenone, spironolactone), ENaC blocker (benzamil), AT1R blocker (losartan) or vehicles were centrally infused in rats treated with Ang II plus high salt, and BP and heart rate (HR) were recorded by telemetry; plasma aldosterone and corticosterone levels and CYP11B2 mRNA expression in adrenal cortex were measured.
Major findings
Ang II alone caused a small increase in BP. Ang II together with 2% salt diet markedly increased the BP and plasma aldosterone level. Sc Ang II decreased 11βHSD2 and MR mRNA expression in the PVN, increased AT1R and ENaC γ expression in the PVN, and increased AT1R mRNA expression in the RVLM. Other genes tested in the four brain nuclei were not affected by sc Ang II or high salt diet. BP and plasma aldosterone increases in response to Ang II and salt, as well as CYP11B2 mRNA expression in adrenal cortex, were largely prevented by central infusion of eplerenone, spironolactone, benzamil or losartan.
Main conclusion
BP and plasma aldosterone responses to Ang II-salt are under the control of central mechanisms, and MR-AT1R activation in the brain plays a critical role in Ang II-salt induced hypertension.
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Fox, Daniel Kenneth. "Identification of bovel mechanisms mediating skeletal muscle atrophy." Diss., University of Iowa, 2016. https://ir.uiowa.edu/etd/3086.
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Skeletal muscle atrophy is a common, debilitating consequence of muscle disuse, malnutrition, critical illness, musculoskeletal conditions, neurological disease, cancer, and organ failure. Despite its prevalence, little is known about the molecular pathogenesis of this devastating condition due in large part to an incomplete understanding of the molecular mechanisms that drive the atrophy process. In previous studies, we identified the transcription factor ATF4 as a critical mediator of skeletal muscle atrophy. We found that ATF4 is necessary and sufficient for skeletal muscle atrophy during limb immobilization. However, ATF4 mKO mice were only partially protected from skeletal muscle atrophy during limb immobilization, indicating the existence of another pro-atrophy factor that acts independently of the ATF4 pathway. Using mouse models, we identify p53 as this ATF4-independent factor. We show that skeletal muscle atrophy increases p53 expression in skeletal muscle fibers. In addition, overexpression of p53 causes skeletal muscle atrophy. Further, p53 mKO mice are partially resistant to muscle atrophy during limb immobilization. Taken together, these data indicate that like ATF4, p53 is sufficient and required for skeletal muscle atrophy during limb immobilization. Importantly, overexpression of p53 induces muscle atrophy in the absence of ATF4, whereas ATF4-mediated muscle atrophy does not require p53. Furthermore, overexpression of p53 and ATF4 induces greater muscle atrophy than p53 or ATF4 alone. Moreover, skeletal muscle lacking both p53 and ATF4 is more resistant to skeletal muscle atrophy than muscle lacking either p53 or ATF4 alone. Taken together, these data indicate that p53 and ATF4 mediate distinct and additive mechanisms to skeletal muscle atrophy. However, the precise mechanism by which p53 and ATF4 cause skeletal muscle atrophy remained unclear. Using genome-wide expression arrays, we identify p21 as a skeletal muscle mRNA that is highly induced by p53 and ATF4 during limb immobilization. Further, overexpression of p21 causes skeletal muscle atrophy. In addition, p21 is required for muscle atrophy due to limb immobilization, p53, and ATF4. Collectively, these results identify p53 and ATF4 as critical and complementary mediators of skeletal muscle atrophy during limb immobilization, and discover p21 as an essential downstream mediator of the p53 and ATF4 pathways.
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Nestel, Frederick P. (Frederick Peter). "Macrophage effector mechanisms mediating acute graft-versus-host disease." Thesis, McGill University, 1993. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=41302.
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The study presented in this thesis is an investigation of M$ phi$ effector mechanisms that mediate the pathogenesis of acute graft-versus-host disease (GVHD). Since the time that the GVH reaction was first described the mechanisms underlying the development of the disease have not been characterized. We have examined the state of M$ phi$ activation in nonirradiated B6AF1 mice injected with either 60 $ times$ 10$ sp6$ (acute GVHD) or 30 $ times$ 10$ sp6$ (nonlethal GVHD) parental B6 lymphoid cells. TNF-$ alpha$ and nitric oxide (NO) generation by M$ phi$ occurs following priming by IFN-$ gamma$ and triggering by LPS. During the early phase of acute GVHD, administration of normally sublethal amounts of LPS triggered release of significant amounts of TNF-$ alpha$ into the serum resulting in death of the animals within 36 hours. The amount of serum TNF-$ alpha$ produced following LPS injection increased during the course of GVHD and was significantly greater in acute GVH reactive mice. Normal animals treated with the same dose of LPS neither died nor produced detectable amounts of serum TNF-$ alpha$. In vitro studies demonstrated that M$ phi$ undergo priming for both TNF-$ alpha$ and NO production during the developing GVH reaction and that priming was greater during acute GVHD than nonlethal GVHD. As a result of M$ phi$ priming during acute GVHD, M$ phi$ mediated the selective release of iron from $ sp{59}$Fe,$ sp{51}$Cr dual-labelled target cells and expressed cytostatic activity when triggered by LPS. NO generation and cytostasis mediated by M$ phi$ from acute GVH-reactive animals were inhibited by NMMA. Endogenous bacterial-derived LPS was detected in the livers and spleens of acute GVH reactive animals and appeared subsequently the serum coincident with the onset of mortality. Immunohistochemical staining for TNF-$ alpha$ during acute GVHD demonstrated TNF-$ alpha$ in the splenic red pulp and liver, however, the hepatic portal infiltrates that characterize acuteOur results demonstrate the entry of bacterial-derived LPS during the acute GVH reaction and that as a result of M$ phi$ priming, LPS in the transplant recipient acts as a trigger for TNF-$ alpha$ and NO production by M$ phi$. The presence of enteric Gram-negative bacteria is a risk factor for development of acute GVHD due to the triggering effect of LPS on M$ phi$ that are primed following bone marrow transplantation. The development of acute GVHD therefore involves the excessive priming of M$ phi$ followed by contact with LPS leading to the activation of NO and TNF-$ alpha$-mediated mechanisms of tissue injury, weight loss, septic shock and death of the transplant recipient.
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Basic, Vladimir. "Molecular mechanisms mediating development of pulmonary cachexia in COPD." Doctoral thesis, Örebro universitet, Institutionen för hälsovetenskap och medicin, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-36104.
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Cigarette smoking (CS) represents the main causative agent underlying development and progress of COPD. Recently, involvement of CS in the pathogenesis of COPDassociated muscle abnormalities is becoming increasingly evident. Nevertheless, involved triggers and underlying mechanisms remain largely unknown. This study was conceived in order to examine effects of cigarette smoke exposure on skeletal muscle morphology, vascular supply and function. For this purpose, we have specifically designed murine COPD/emphysema model and gastrocnemius muscle was examined, while in vitro experiments were conducted using murine C2C12 skeletal muscle myocytes. In addition to the mild emphysematous changes present in the lungs of CS-exposed mice, our results demonstrated evident signs of muscle atrophy reflected by decreased fiber cross-sectional area, profound fiber size variation and reduced body mass. Furthermore, we have observed impairment in terminal myogenesis and lower number of myonuclei in skeletal muscles of CS-exposed animals despite evident activation of muscle repair process. Additionally, our results demonstrate capillary rarefaction in skeletal muscles of CS-exposed animals which was associated with deregulation of hypoxia-angiogenesis signaling, reduced levels of angiogenic factors such as HIF1-α and VEGF and enhanced expression of VHL and its partner proteins PHD2 and Ube2D1. The results of our in-vitro experiments demonstrated that VHL and its ubiquitination machinery can be synergistically regulated by TNF and hypoxia consequentially impairing angiogenic potential of skeletal muscle myocytes. Finally, we have shown that CS elicits chronic ER stress in murine skeletal muscles which is associated with activation of ERAD and apoptotic pathways as mirrored by elevated expression of Usp19, caspase 12 and caspase 3 in skeletal muscles of CSexposed animals. Moreover, molecular and morphological alterations in CS-exposed mice resulted in impairment of muscle function as reflected by their impaired exercise capacity. Taken together, from our results it is evident that cigarette smoke exposure elicits set of morphological, vascular and functional changes highly resembling those observed in COPD. Additionally, CS induces wide range of molecular alterations and signaling pathway deregulations suggesting profound effects of cigarette smoke exposure on skeletal muscle cell homeostasis.
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Booth, Paul James. "Physiological mechanisms mediating nutrition-reproduction interactions in the gilt." Thesis, University of Nottingham, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.254056.
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Christiansen, Anne M. "Neural mechanisms mediating persistent stress relief by comfort food." University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1275921773.
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Crosswhite-Gamble, Jennifer Marie. "Mediating mechanisms understanding the link between parenting and adolescent deviance /." Auburn, Ala., 2005. http://repo.lib.auburn.edu/2005%20Fall/Dissertation/CROSSWHITE_JENNIFER_46.pdf.
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Sharma, Abhishek. "The psychological and physiological mechanisms mediating human oesophageal pain hypersensitivity." Thesis, University of Manchester, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489007.
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Holloway, Jennifer L. "Mechanisms Mediating Social Enhancement of Alcohol Intake in the Rat." W&M ScholarWorks, 1999. https://scholarworks.wm.edu/etd/1539626234.
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Martin, Ruairidh Iain Russell. "Investigation of the mechanisms mediating genetic associations with atrial fibrillation." Thesis, University of Newcastle upon Tyne, 2015. http://hdl.handle.net/10443/2937.
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Genome wide association studies (GWAS) have identified multiple loci which are associated with increased risk of atrial fibrillation (AF). The mechanisms underlying these associations are not understood. None of the variants identified result in alteration of coding sequences; they are therefore likely to act by altering gene expression. Identification of intermediate gene expression phenotypes which are associated with the risk variants could provide important insights into disease pathogenesis which could in turn lead to development of therapeutic targets. One of the genetic variants identified by GWAS is situated within an intron of the gene HCN4, which encodes the major component of the If pacemaker current. This raised the question whether lower activity of HCN4 could be a risk factor for AF. By performing meta-analysis of randomised controlled trials of ivabradine, an If inhibitor, I demonstrated an increase in relative risk of incident AF of 15% in patients treated with ivabradine vs. controls, supporting the role of HCN4 in AF susceptibility. Analysis of total expression and allelic expression ratios of candidate genes in the GWAS hit regions in whole blood identified associations between AF risk variants and increased expression of KCNN3 and SYNE2 and decreased expression of CAV1. Analysis of total expression and allelic expression ratio in right atrial appendage tissue identified further associations between AF risk variants and increased expression of PITX2a/b and decreased expression of MYOZ1, CAV1, C9orf3 and FANCC in right atrial tissue. Furthermore, although the experiments were not designed to detect difference between AF cases and controls, I have shown that AF is associated with reduced expression of SYNE2, HCN4 and CAV1.
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Glennie, Sarah Jane. "The molecular mechanisms mediating the immunosuppressive effects of mesenchymal stem cells." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417349.
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Ghose, Aurnab. "Molecular mechanisms mediating the induction of apoptosis by chemopreventive selenium compounds." Thesis, University of Glasgow, 2001. http://theses.gla.ac.uk/1154/.
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Using the cervical carcinoma cell line, HeLa, molecular mediators of selenium-induced apoptosis were investigated. These studies were later extended to biopsies of normal human oral mucosa cells (NOMCs) and human oral carcinoma cells (SCCs), using a primary culture system. Two selenium compounds were tested: selenodiglutathione (SDG), the primary metabolite of selenite, the most commonly used cancer-protective selenium compound in animal models, and the synthetic compound, 1,4-phenylenebis (methylene)selenocyanate (pXSC), one of the most potent chemopreventive selenium compounds. Both compounds induced apoptosis in the cells tested and this was associated with a strong induction of Fas ligand (Fasl). Blocking Fas activation resulted in inhibition of apoptosis. Activities of stress kinases INK (c-jun N-terminal kinase) and p38 were also induced on selenium treatment and intervention studies using specific chemical inhibitors and/or dominant negative mutants suggested that INK, but not p38, was functionally important for the induction of apoptosis and Fasl. The relative levels of induction of INK activity and Fasl also correlated with the extent of apoptosis observed. On treatment with SDG, but not pXSC, SCCs were found to preferentially activate the JNK/Fasl pathway compared to NOMCs and this correlated with enhanced sensitivity of SCCs to SDG-induced apoptosis. Both SDG and pXSC also appeared to modulate activities of other signalling proteins like extracellular regulated kinases (ERKs) 1,2 & 5 and Akt. However, functional interference with these pathways using specific chemical inhibitors or constitutively activated mutants revealed either none or a small effect on apoptosis-induction. One exception was the activation of Akt by SDG in SCCs: inhibiting its activity sensitised the cells to apoptosis significantly. Finally, preliminary xenograft studies have confirmed the induction of apoptosis in vivo, using chemopreventive dietary levels of selenium.
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Alahakone, Ratnesvary. "Corporate volunteering : an analysis of the drivers, mediating mechanisms and outcomes." Thesis, Kingston University, 2015. http://eprints.kingston.ac.uk/35523/.
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Over the last decade, researchers have been increasingly interested in exploring the nature and potential benefits of an organisation's corporate social responsibility (CSR) activities. CSR refers to "actions that appear to further some social good, beyond the interests of the firm and that which is required by law" (McWilliams and Siegel, 2001, p.117). The majority of research to date has focused on an organisational perspective and demonstrated that engaging in CSR activities results in positive organisational outcomes such as a reduced firm risk (McWilliams and Siegel 2001), increased attractiveness for investors (Aguilera, Rupp, Williams and Ganapathi 2007) and prospective employees (Bhattacharya et al. 2008) and reduced employee turnover (Galbreath 2009). More recently, researchers have turned their attention towards exploring how and organisation's employees respond to CSR activities. Corporate volunteering (CV) is emerging as an important tool through which organisations demonstrate their CSR. A focus on CV answers the call for an employee-centered understanding of CSR. This thesis explores the drivers and consequences of CV for employees and the employing organisation. This study integrates research on functional motivation and organisational support with CV to demonstrate that emploees' integral and external motives offer a perspective towards the CV initiatives in their organisations. This research also contributes to CV literature by examining the consequences of CV for the employee as well as the organisation. As CV involves volunteers who are also regular employees, the researcher expects that participating in CV will have an impact on how employees behave during their regular employment and also for the employing organisation, who in this case are the facilitators of the CV programme. Drawing on social exchange theory and intrinsic motivation theory, the study focuses on organisational outcomes of organisational commitment and work engagement and employee outcomes of job satisfaction and employee health and well-being as a result of CV participation. This study also examined the process through which CV activities influence the above mentioned outcomes. Inconsistencies in findings on research in CV have elicited calls for mediation mechanisms to be identified that will clarify relationships between CV and its outcomes. By focusing on social identity theory, this study suggests that pride and organisational identification (OI) mediates the relationship between employees' attitudes to CV and the consequences. Electronic questionnaires were distributed to employees in organisations that had corporate volunteering initiatives from Malaysia and Singapore. The final sample size after deleting for missing data incomplete questionnaires was 160 respondents. On average, participants were 38 years old with a SD on 9.1 years. 58.2 percent were female and 41.8 percent were male. Partial Least Squares (PLS) was used to analyse the data. The findings suggest that employees participate in CV for a variety of motives, the most significant of which is a desire to experience new learning experiences and to have the opportunity to use these knowledge, skills and abilities that they might not use in their regular jobs. Participating to express altruism, improving relationships with others, protecting the ego from negative features and enhancing positive strivings of the ego proved to be less important. Another important finding is that employees are driven by the support shown by their employers in terms of paid leave and time off. In terms of consequences, the findings suggest that all the dependent variables have a positive relationship with employees' attitudes towards corporate volunteering when mediated by both pride and organisational identification. By conceptualising and examining the relationships in this model, this study makes the following contributions. First, this research integrates several underpinning theories to develop a new theoretical framework that explains the drivers, consequences and mediators of CV. Second, by adopting Clary et al.'s (1998) functional theory and organisational support, this study contributes towards a perspective to explain individuals' attitudes towards their organisations' CV initiatives. It also contributes towards healthy debate on similarities and differences between general volunteering and CV. Third, this study integrates social exchange theory and intrinsic-extrinsic motivation to contribute to the literature on the outcomes of CV by incorporating organisational commitment, work engagement, job satisfaction and health and well-being in one model. Fourth, this study integrates social identity theory and intrinsic-extrinsic motivation theory to examine how pride and organisational identification mediate the processes through which CV activities influence employee outcomes of job satisfaction and health and well-being as well as employer outcomes of organisational commitment and work engagement.
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Rainville, Stéphane Jean Michel. "The spatial mechanisms mediating the perception of mirror symmetry in human vision /." Thesis, McGill University, 1999. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=36688.
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The present thesis reports psychophysical and modeling studies on the spatial properties of visual mechanisms mediating the perception of mirror symmetry in human vision. In a first set of experiments, patterns were filtered for power spectra that decayed with spatial frequency according to variable slopes. Results revealed that symmetry detection is optimal if contrast energy is roughly equated across log-frequency bands (i.e. 1/f2) and that, under such conditions, spatial scales contribute equally and independently to symmetry perception. In a second study, random-noise patterns were filtered for various orientation bands. Results showed that symmetry perception is possible at all orientations, is mediated by oriented mechanisms, and is computed independently in different orientation channels. Data also revealed that the dimensions of the spatial integration region (IR) for symmetry vary with orientation in a way that approximately matches the spatial distribution of information in the stimulus. Finally, symmetry detection was measured for bandpass textures of variable spatial density and variable contrast polarity. For such patterns, it was found that symmetry is computed at a spatial scale proportional to stimulus density and that mechanisms insensitive to contrast polarity (i.e. second-order) are involved in the scale-selection process.Overall, results from empirical and modeling work revealed an intimate link between symmetry perception and the properties of spatial filters. In particular, I argue that the size of the IR tends to vary such that a fixed amount of information is integrated irrespective of the spatial properties of the stimulus. Implications for the functional architecture of symmetry perception are discussed, and a paradigm for future research in symmetry perception is proposed in which spatial filtering is extended to higher orders of spatial complexity.
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Rainville, Stéphane Jean Michel. "The spatial mechanisms mediating the perception of mirror symmetry in human vision." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/NQ64650.pdf.
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Hyatt, Kevin D. "The Mediating and Moderating Effects of Coping Mechanisms Following High School Victimization." Digital Commons @ East Tennessee State University, 2014. https://dc.etsu.edu/etd/2408.
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Victimization from bullying has become a more serious issue as available avenues for bullying have increased and as the media has been alerted to the devastating effects of the phenomenon. Victimization has been linked to increased externalizing and internalizing disorders including depression, anxiety, stress, and at its worst suicide. Research has been focused on the negative outcomes following victimization, with some authors only recently examining the buffering or exacerbating effects of coping mechanisms. Participants (n=642) from a moderately sized southeastern university completed a survey to examine problem-focused and emotion-focused coping as potential moderators and maladaptive coping as a potential mediator between retrospective reports of victimization and depression, anxiety, and stress, and reasons for living. The hypothesis concerning maladaptive coping as a mediator was supported. Implications and limitations are also discussed. Results suggest that maladaptive coping may be a key mechanism explaining the impact of bullying on outcomes years after victimization.
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Lenz, Kathryn M. "Mechanisms mediating the effects of maternal care on the masculinization of spinal motoneurons." [Bloomington, Ind.] : Indiana University, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3380150.
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Thesis (Ph.D.)--Indiana University, Dept. of Psychological and Brain Sciences and the Program in Neuroscience, 2009.Title from PDF t.p. (viewed on Jul 20, 2010). Source: Dissertation Abstracts International, Volume: 70-12, Section: B, page: 7839. Advisers: Dale R. Sengelaub; Gregory E. Demas.
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Zak, Louisa Jane. "Physiological mechanisms mediating nutrition-reproduction interactions in the lactating and weaned primiparous sow." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq21660.pdf.
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Mao, Jiude. "Mechanisms mediating nutritional effects on embryonic survival in cyclic gilts and weaned sows." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0012/NQ59629.pdf.
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Azzarelli, R. "Molecular mechanisms mediating Rnd protein pro-migratory activity in the developing cerebral cortex." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1393953/.
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During the development of the cerebral cortex, newborn neurons migrate radially from the ventricular/subventricular zones of the dorsal telencephalon to reach the above cortical plate, where they acquire laminar-specific characteristics and establish appropriate neuronal connections. Recent works from our laboratory have shown that two proneural factors operating in the embryonic cortex, Neurog2 and Ascl1, control radial migration of cortical neurons through the transcriptional regulation of two small GTP binding proteins, Rnd2 and Rnd3. These studies have shed light onto the genetic programs that regulate neuronal migration in the wider context of cortical development. However, the molecular mechanisms that mediate the pro-migratory activity of Rnd proteins are not yet completely understood. Several studies in non-neuronal cell types have suggested a potential role for the related GTPase RhoA, a major modulator of cell cytoskeleton. Here, we used a series of in vivo genetic interaction and rescue experiments to demonstrate that Rnds stimulate neuronal migration by inhibiting RhoA signalling, a mechanism that, in the case of Rnd3, involves the regulation of a RhoA inhibitor, p190RhoGAP. In addition, we undertook a candidate approach to identify other potential Rnd partners in the control of radial migration. Interestingly, a class of transmembrane receptors that belong to the plexin family of axon guidance molecules was previously shown to functionally interact with Rnd proteins. Here, we found that a member of the PlexinB subfamily, PlexinB2, interacts with Rnd3 and regulates the morphology and the migration of cortical neurons. Moreover, our in vivo genetic interaction studies and our molecular Fluorescence resonance energy transfer (FRET) data indicate that PlexinB2 and Rnd3 are responsible for fine-tuning the levels of RhoA activation in migrating neurons. Through a better characterization of the molecular mechanisms that control neuronal migration, this work will contribute to the understanding of the aetiopathology of several human brain disorders that are associated with neuronal migration defects.
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Heritage, Sarah Ruth. "Mechanisms mediating the effects of vasoactive agents on human placental vessels in vitro." Thesis, St George's, University of London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307675.
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McCarthy, Michelle Marie. "Neocortical mechanisms mediating electroencephalographic oscillations a biomathematical analysis of anesthesia-induced paradoxical excitation /." Diss., Restricted to subscribing institutions, 2007. http://proquest.umi.com/pqdweb?did=1428839101&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Shoop, Jessica A. "SENIOR INFORMATION TECHNOLOGY (IT) LEADER CREDIBILITY: KNOWLEDGE SCALE, MEDIATING KNOWLEDGE MECHANISMS, AND EFFECTIVENESS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1491489274525242.
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Parsons, Marie Patricia. "Molecular mechanisms mediating the action of tri-triiodothyronine in human osteoblast like cells." Thesis, Queen Mary, University of London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486356.
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The mechanisms underlying the action~fT3 on osteoblastic cytokine production have been investigated. Western Blotting studies demonstrated the expression of . functional thyroid hormone receptor (TR) isoforms in primary cultures of osteoblasts (hOb) in human bone marrow stromal cells (hBMS) and in the transformed human osteosarcoma cell lines MG63 and SaOs-2. TRal, TRpl and TRp2 proteins were expressed in all cells although expression was greatest in MG63>hBMS>SaOs-2>hOb. Differences between isoforms were also apparent with TRal> TRp1>TRp2 in all cell types. Transfection studies using an IL6 promoter construct demonstrated constitutive transcription in MG63 cells unaffected by T3 treatment- a finding confirmed in hBMS. Similar studies using an IL8 promoter construct showed that T3 did significantly increase IL8 promoter activity. Studies with actinomycin D suggested that T3 was able to stabilise IL6 mRNA and the presence of two IL6 mRNA transcripts (492bp, 570bp) was shown in MG63 and hBMS cells with production of the more stable 492bp transcript being increased by T3. Potential mechanisms of cytokine stabilisation were investigated and T3 was shown to activate the'p44/42 mitogen-activated protein kinase (MAPK) in MG63 cells by a protein kinase C (PKC)-dependent mechanism. These studies have shown for the first time that differential TR expression occurs in human bone. T3-mediated transcriptional effects on IL6 were minimal but were significant for IL8. A novel mechanism for T3 stabilisation ofIL6 mRNA was demonstrated involving differential usage ofpolyadenylation signals within the IL6 gene. Studies on MAPK signaling, whilst demonstrating clear cut effects of T3 on this pathway, require further investigations to link MAPK activation with IL6 mRNA stabilisation in osteoblasts.
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Parker, Victoria Joanne. "Hypothalamic mechanisms mediating inhibition of prolactin secretion following stress in early pregnant mice." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/6485.
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In early pregnancy prolonged exposure to stress is known to have profound adverse effects on reproduction and is associated with suppressed progesterone secretion and consequent disturbance of the pregnancy-protective cytokine milieu, thus threatening early pregnancy maintenance. Maternal neuroendocrine responses to stress in early pregnancy are poorly understood. Therefore, we designed experiments to (1) study the hypothalamo-pituitary-adrenal (HPA) axis responses to stress in early pregnant mice, to discover whether and how responses change and (2) to determine the effect of stress in early gestation on pregnancy hormones, with a particular focus on the secretion and regulation of prolactin. To establish the effects of stress in early pregnancy (day 5.5) two different ethologically relevant stressors were used: lipopolysaccharide (LPS) or 24h fast stress, to mimic situations that may potentially arise during pregnancy in women: infection or hunger. HPA axis secretory responses to immune stress in early-mid pregnancy were robust and comparable to that in virgins. Vasopressin rather than the usual CRH neurone responses play a key role in maintaining this. However, the mode of action of glucocorticoids in mediating pregnancy complications is not yet established. Prolactin, and its hypothalamic control mechanisms, is a key candidate to mediate brain-to-body responses to stress. Prolactin has important roles in progesterone secretion, pregnancy establishment and immune regulation. We hypothesised that stress would negatively affect prolactin and its neuroendocrine control systems. Prolactin is mainly under the inhibitory control of dopamine, released predominantly from the tuberoinfundibular dopamine (TIDA) neurones. Prolactin also negatively feeds back on itself via prolactin receptors on the TIDA neurones and janus kinase (JAK)2/signal transducer and activator of transcription (STAT)5 signalling. Both immune and fasting stressors strongly inhibited basal prolactin secretion in early pregnancy, accompanied by a mild increase in activation of TIDA as shown by elevated Fos expression, compared to virgins. In addition, pregnancy attenuated LPS-induced recruitment of parvocellular paraventricular nucleus neurones and increased activation of brainstem noradrenergic nuclei which could potentially contribute to altered control of the dopamine-prolactin system. Following either immune or fast stress in early pregnancy ovine prolactin was able to drive enhanced expression of phosphorylated (p)STAT5. However, stress alone did not alter pSTAT5 implying it is not exclusively responsible for the stress-reduced prolactin observed in early pregnancy and another stress-induced stimulus must be activating TIDA neurones in these mice. LPS did not alter dopamine activity the median eminence (DOPAC: dopamine ratio) suggesting dopamine does not underlie stress-reduced prolactin secretion and other mechanisms must be considered. Direct effects of LPS, or its associated cytokines, on pituitary lactotrophs to inhibit prolactin secretion is a possible candidate. To investigate the effect of proinflammatory cytokines on the prolactin system in early pregnancy, d5.5 mice were administered TNF-alpha (a) or interleukin (IL)-6. Both cytokines increased TIDA activation, however, only TNF-a decreased plasma prolactin and progesterone, suggesting additional TNF-alpha action at the pituitary. As prolactin is anxiolytic we further proposed that stress would have a more profound effect on elevated plus maze performance in pregnant mice. However, early pregnant mice were generally more anxious vs. virgins regardless of LPS treatment. Taken together data show that stress in early pregnancy reduces prolactin and progesterone secretion, contributing to pregnancy complications/failure, but the neuroendocrine stress-related mechanism behind this suppression is yet to be determined.
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Holdstock, Jolyon Guy. "Intracellular mechanisms mediating transcriptional regulation and secretion of the pituitary glycoprotein hormone alpha-subunit." Thesis, Queen Mary, University of London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283413.
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Croning, Micahel Daivd Richardson. "An investigation of the mechanisms mediating disturbances in brain ionic homeostasis during oxygen deprivation." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389194.
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Rehan, Maryam Binti Mohamed. "Multiple mechanisms mediating the starvation induced activation of recombination at HIS4 in Saccharomyces cerevisiae." Thesis, University of Leicester, 2012. http://hdl.handle.net/2381/10820.
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Meiotic recombination occurs at relatively high levels at specific regions in the genome called hotspots. The transcription factor-dependent hotspots (α-hotspots) have been widely studied in yeast, and are beginning to be elucidated in mammals. The HIS4 hotspot activity in Saccharomyces cerevisiae requires binding of Bas1p, Bas2p, Rap1p and Gcn4p. Bas1p acts in conjunction with Bas2p to regulate basal level of transcription of their target genes, and can be stimulated under conditions of adenine starvation and accumulation of metabolites AICAR and SAICAR from the purine biosynthesis pathway. Gcn4p activates transcription of yeast genes in response to starvation for amino acids and purines. This study focused on the influence of nutritional starvation on HIS4 hotspot activity, and different mechanisms mediating this effect. Our data suggests that deletion of genes known to accumulate AICAR/SAICAR can stimulate recombination at HIS4 in a Bas1p-dependent manner. Furthermore, intracellular and extracellular starvation for adenine and amino acids also activates recombination at HIS4. In addition, moderate levels of starvation only affect recombination when chromatin is already hyperacetylated, by the inactivation of the Set2p methyltransferase. Bas1p plays an essential role in mediating the effect of starvation and the set2 mutation on recombination. We showed that Gcn4p is not required for HIS4 hotspot activity, but plays a modest role in the effect of starvation in an adenine auxotrophic strain. Additionally, the starvation effect is also mediated by an as yet unknown factor independent from Bas1p/Bas2p and Gcn4p. This work provides additional information regarding the regulation of a transcription factor-dependent hotspot activity, and factors influencing its activation. Furthermore, data in this study indicate that BAS1, and not BAS2 exhibit haploinsufficiency with respect to its function in activating meiotic recombination. This implies that Bas1p is rate-limiting for HIS4 hotspot activity.
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Cindrova-Davies, Tereza. "A study of the signalling mechanisms mediating the proliferative and apoptotic effects of oxysterols." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619645.
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Visser, Schalk W. J. "The mediating effect of organisational justice mechanisms on the relationship between leadership and trust." Diss., University of Pretoria, 2020. http://hdl.handle.net/2263/80423.
Full textAbstract:
The focus of this research was to build on existing literature of leadership, organisational
justice mechanisms and trust. This was done through specific focus on how different
kinds of leadership styles, transformational leadership and transactional leadership,
effects different types of trust, being affect-based trust and cognition-based trust, as
mediated by organisational justice mechanisms, being distributive justice, procedural
justice and interactional justice.
To investigate these complex relationships, and given the number of latent constructs
proposed, the statistical technique used in this research was partial leased squares
structural equation modelling (PLS-SEM). This enabled the researcher to evaluate the
strength and significance of relationships in this complex model.
Findings showed that distributive justice and procedural justice had no significant
mediating effect between leadership style, being transformational leadership and
transactional leadership, and the components of trust, being affect-based trust and
cognition-based trust. However, it was found that interactional justice had a significant
positive mediating effect between transactional leadership and the components of trust,
being affect-based trust and cognition-based trust, but not for transformational
leadership.
Given the context of the study, these findings further support the notion that it is the
responsibility of leaders in an organisation to communicate effectively, clearly and
transparently to their followers at all times and, in doing so, increase the level of
perceived fairness which will then result in trust being built within the organisation. This
in turn will allow employees to put themselves in positions of vulnerability, with the
expectation that positive outcomes will be achieved.Mini Dissertation (MPhil)--University of Pretoria, 2020.
Gordon Institute of Business Science (GIBS)
MPhil
Unrestricted
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Åström, P. (Pirjo). "Regulatory mechanisms mediating matrix metalloproteinase-8 effects in oral tissue repair and tongue cancer." Doctoral thesis, Oulun yliopisto, 2014. http://urn.fi/urn:isbn:9789526206103.
Full textAbstract:
Abstract Tissue repair and cancer progression involve similar mechanisms, including degradation of extracellular matrix in which matrix metalloproteinases (MMPs) play essential roles. The action of MMPs is important in normal physiological processes but MMPs also contribute to various pathological conditions. MMP-8 belongs to a family of collagenases with a diverse set of substrates. MMP-8 action is involved in skin wound healing and in various human cancers. The function of MMP-8 in cancer appears to be highly complex and varies depending on the cancer type and location. Little is known about the involvement of MMP-8 in oral physiology and pathology. The aim of this study was to clarify the role of MMP-8 in oral tissue repair and oral tongue squamous cell carcinoma (OTSCC). Studies with MMP-8 deficient mice revealed that the function of MMP-8 in tissue repair is highly dependent on the spatial aspects. In alveolar bone, MMP-8 increased inflammation and affected collagen metabolism. In tongue wounds, MMP-8 impaired early healing and reduced transforming growth factor (TGF) -β1 levels. This study also revealed the protective role of MMP-8 in OTSCC patients, in agreement with previous studies indicating positive features of MMP-8 in cancer. Low MMP-8 level and high vascular endothelial growth factor (VEGF) -C levels in tumors correlated with worse prognosis in these patients. In mouse tongue fibroblast cell cultures, MMP-8 reduced TGF-β1 signaling molecule phosphorylated Smad2 levels and impaired the collagen contraction ability. TGF-β1, apoptosis factor Fas-ligand (Fas-L) and estrogen receptors (ERs) were identified as novel MMP-8 substrates. In OTSCC cell cultures, MMP-8 impaired cell migration and invasion. Diminished TGF-β1 levels were involved in the defective migration of MMP-8 overexpressing cells. Moreover, MMP-8 affected the expression of MMP-9, MMP-1, cathepsin-K, VEGF-C and TGF-β1. In mouse models of OTSCC, MMP-8 protected against tumor development but was not able to prevent metastasis formation. The main findings of this study were that 1) MMP-8 action in tissue repair depends on the site of the injury and 2) in OTSCC, MMP-8 has tumor suppressive effects, but in mouse, MMP-8 does not inhibit metastasis formation. In addition, 3) four novel MMP-8 substrates (TGF-β1, Fas-L, ER-α and -β) were identified that may explain the spatial and diverse roles of MMP-8Tiivistelmä Kudosvaurioiden paranemiseen ja syövän etenemiseen liittyy useita samankaltaisia mekanismeja. Molemmissa toimivat soluvälitilan muokkaamiseen osallistuvat proteaasit, joista matriksin metalloproteinaaseilla (MMP) on tärkeä merkitys; ne osallistuvat lukuisiin elimistön keskeisiin fysiopatologisiin prosesseihin. Kollagenaasi MMP-8 muokkaa monentyyppisiä molekyylejä. Se on mukana ihohaavan paranemisessa ja useissa syövissä. MMP-8:n toiminta syöpätiloissa on hyvin moninainen riippuen syöpätyypistä ja sijainnista. Väitöstutkimuksessa selvitettiin MMP-8:n merkitystä suun kova- ja pehmytkudosvaurioprosesseissa sekä kielisyövässä, joissa se on ollut tuntematon. MMP-8 poistogeenisillä hiirillä tehdyissä pehmyt- ja kovakudoshaavoissa MMP-8:n vaikutusmekanismit riippuivat kohdekudoksesta. Alveoliluun paranemisen yhteydessä MMP-8 lisäsi tulehdusta ja osallistui kollageenin muokkaamiseen. Akuutin kielihaavan paranemisessa MMP-8 hidasti haavan umpeutumista ja vähensi transformoivan kasvutekijä-β1:n (TGF-β1) määrää. Kuten useissa muissakin syövissä, myös kielisyövässä todettiin MMP-8:lla olevan suojaava vaikutus. Potilaan ennuste huononi, jos kasvainsolukon matala MMP-8-taso yhdistyi korkeaan verisuonten kasvutekijä-C:n (VEGF-C) määrään. Hiiren kielen normaaleissa fibroblastiviljelmissä MMP-8 vähensi TGF-β1:n solunsisäistä signalointia välittävän fosforyloidun Smad2:n määrää sekä solujen kykyä supistaa kollageenikiekkoja. Koeputkessa MMP-8 pilkkoi TGF-β1:tä, estrogeenireseptoreja (ER) ja apoptoositekijä Fas-ligandia (Fas-L). Ihmisen kielikarsinoomasoluviljelmissä korkea MMP-8:n määrä vähensi solujen migraatiota ja invaasiota sekä muutti MMP-1:n, MMP-9:n, katepsiini-K:n, TGF-β1:n ja VEGF-C:n ilmentymistä. Migraation heikentyminen MMP-8:aa tuottavissa soluissa johtui osin vähentyneestä TGF-β1:n määrästä. Hiiren kokeellisissa kielisyövissä MMP-8 hidasti syövän muodostumista mutta ei estänyt etäpesäkkeiden muodostusta. Tässä väitöskirjatutkimuksessa on kolme päälöydöstä: 1) MMP-8:n vaikutus kudoksen paranemisprosessiin riippuu vauriokohdasta, 2) MMP-8 on kielisyövän kehittymisessä puolustuksellinen molekyyli, mutta sen lisääntynyt tuotto ei hiirikokeissa estänyt etäpesäkkeiden muodostusta, 3) MMP-8:lle löydettiin neljä uutta kohdemolekyyliä (TGF-β1, Fas-L, ER-α ja -β), joiden muokkaus saattaa osin selittää MMP-8:n monipuoliset kudos- ja prosessispesifit vaikutukset
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Cunnington, Michael Sheridan. "Investigation of the mechanisms mediating genetic susceptibility to cardiovascular disease on chromosomes 9p21 and 2q24." Thesis, University of Newcastle Upon Tyne, 2011. http://hdl.handle.net/10443/1083.
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Recent genome-wide studies have identified novel loci associated with cardiovascular diseases, but the mechanisms mediating these associations are unknown. Investigation of intermediate phenotypes can identify the pathways involved and potential targets for therapeutic intervention. This study investigated the relationship with intermediate phenotypes at risk loci on chromosome 9p21 and 2q24. Chromosome 9p21 polymorphisms are associated with coronary artery disease and congenital intracranial aneurysms. In the present study risk variants were not associated with traditional risk factors, inflammatory mediators, carotid artery intimamedia thickness, echocardiographic measures of cardiac structure and function, or congenital heart defects. There was no evidence of copy number variation using MLPA. To identify genes involved in mediating disease susceptibility this study examined the association of chromosome 9p21 variants with peripheral blood expression in healthy subjects of three neighbouring genes: two cyclin-dependent kinase inhibitors, CDKN2A and CDKN2B, and a non-coding RNA of unknown function, ANRIL. Novel methodology combining allelic expression data from multiple transcribed markers was more powerful than total expression analysis for mapping cis-acting effects. Multiple loci were independently associated with expression of each gene, suggesting that several sites may modulate disease susceptibility. Disease-associated variants were all associated with allelic expression of ANRIL, while association with the other two genes was only detectable for some risk variants. Variants had an inverse effect on ANRIL and CDKN2B expression, supporting a role of antisense transcription in CDKN2B regulation. This study suggests that modulation of ANRIL expression mediates susceptibility to several important human diseases. Chromosome 2q24 polymorphisms were associated with hypertension in a study involving an Amish population; in vitro experiments suggested that influences on STK39 expression might mediate these effects. In the present study allelic expression analysis confirmed that reported SNPs were associated with STK39 expression in vivo, but were not associated with blood pressure in a large British cohort.
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Li, Rung-chi. "A study of the transduction mechanisms regulated by oxidative stress and prostanoids in mediating apoptosis." Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.614853.
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Short, Douglas Mackay. "Chemical mechanisms underlying some biological reactions mediating the cytotoxicity and therapeutic potential of nitric oxide." Thesis, University of St Andrews, 1999. http://hdl.handle.net/10023/14102.
Full textAbstract:
Some in vitro reactions of peroxynitrite are examined using 15N CIDNP NMR spectroscopy to elucidate more information about the radical nature of nitration, nitrosation and isomerisation mechanisms. Preliminary work on the nitration of tyrosine with H15NO3 confirms that 3-nitrotyrosine forms predominantly by the same radical mechanism established for other activated aromatic compounds such as 4-methylphenol. Reaction of alkaline [15N] peroxynitrite with biotarget-type molecules such as tyrosine, a tyrosine-containing tripeptide and thiol-containing amino acids allows nuclear polarisation effects to be discerned which are consistent with free and solvent-caged NO2 and HOo or CO3. The phase of the nitrate signal observed during peroxynitrite isomerisation at pH 7.4 is opposite to that observed during reaction with a biotarget-type molecule, suggesting dimerisation of NO2 to N2O4 and its subsequent hydrolysis in addition to in cage geminate pair collapse. Mechanisms in accord with the observations are suggested and their implications and extent to which they concur with established theories are discussed. Kinetic simulations are used to estimate the relative importance of nitryl chloride and peroxynitrite as in vivo reactive nitrogen species. Three furazan 2-oxide (furoxan) derivatives with potent NO- donating activity were synthesised according to literature methods and their decomposition in aqueous solution to yield NO was examined using EFR spectroscopy by spin trapping with Fe2+-N-methyl-D-glucamine dithiocarbamate (Fe2+-MGD). Ammonia, arising from thiol-mediated reductive decomposition pathways, was also detected in quantities up to approximately 8% of the nitrogen- containing decomposition products. A commercially-available enzymatic assay based on reductive amination of 2-oxoglutai-ate using L-glutamate dehydrogenase and NADPH was used. The proportion of furoxan giving rise to these products is estimated and possible mechanisms for their generation are suggested.
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Mongeon, Luc Roland. "The right atrial pacemaker complex: The underlying mechanisms mediating the multicentric origin of atrial depolarization." Case Western Reserve University School of Graduate Studies / OhioLINK, 1993. http://rave.ohiolink.edu/etdc/view?acc_num=case1060777680.
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Hall, Benjamin B., Jon R. Webb, and Jameson K. Hirsch. "Spirituality and Suicidal Behavior: The Mediating Role of Self-forgiveness and Psychache." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/etsu-works/5550.
Full textAbstract:
Growing evidence for the salubrious association of spirituality with physical and mental health related outcomes has led to the consideration of spirituality as a protective factor against suicidal behavior. Although support for this basic association is robust, particularly in the context of religious belief and attendance, spirituality has yet to be explored as it relates to psychache—intense, unrelenting psychological pain. Additionally, self-forgiveness has emerged as an important protective factor against suicidal behavior, but has not been explored in the context of psychache. Following a model developed by Webb, Hirsch, and Toussaint (2015), we examine the protective role of spirituality on suicidal behavior, based on three dimensions of spirituality: ritualistic, theistic, and existential. Cross-sectional data were collected from the self-report surveys of 262 individuals drawn from the larger U.S. community. Results suggest that existential spirituality may be the dimension of spirituality most robustly associated with suicidal behavior. Further, self-forgiveness and psychache were found to be mediators of the relationship between existential spirituality and suicidal behavior. Synthesis of the findings from this study, and the implications thereof, are discussed.
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Rabon, Jessica Kelliher, Jon R. Webb, Edward C. Chang, and Jameson K. Hirsch. "Forgiveness and Suicidal Behavior in Primary Care: Mediating Role of Future Orientation." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/etsu-works/2788.
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Forgiveness, a cognitive-emotional and behavioral reduction of negative responses to offenses, is directly related to less suicide risk, but may be indirectly related via its relation with future orientation, the ability to envision a positive future. In 100 rural primary care patients, we examined the association between self-forgiveness, other-forgiveness, and forgiveness by God and suicidal behavior, with future orientation as a mediator. Forgiveness was related to greater future orientation and, in turn, to, less suicidal behavior. Addressing the past may promote adaptive views of the future and reduce suicide risk, results suggesting potential temporal and forgiveness-based points for suicide prevention.
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Radulovic, Ana. "Forgiveness in leader-member exchange (LMX) relationships : a multi-study examination of mediating and moderating mechanisms." Thesis, Aston University, 2017. http://publications.aston.ac.uk/30856/.
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Drawing upon theories from both the leadership and forgiveness domains, the overarching aim of this thesis was to answer a fundamental question. Namely, how and when does forgiveness unfold in Leader-Member Exchange (LMX) relationships and what are its outcomes? Even though it has been suggested that generic relationship knowledge from close relationship science can inform the understanding of LMX relationship maintenance, surprisingly little theoretical or empirical studies have addressed this area. By integrating both a framework of relationship maintenance mechanisms and a model of forgiveness in close relationships with LMX theory, study one developed and tested a model of forgiveness in LMX relationships. In a cross-sectional study involving 254 employees from eight organisations it was found that high LMX quality lead to higher job satisfaction and subjective well-being via greater follower’s forgiveness and subsequent follower’s relational efforts. Furthermore, it was found that higher levels of follower’s relationship self-efficacy and Leader-Member Exchange Social Comparison (LMXSC) enhanced follower’s forgiveness. The results of study one demonstrated that forgiveness of interpersonal transgressions in LMX relationships can lead to positive outcomes, and thus has important implications for LMX relationship maintenance and repair. Building on study one, study two adopted an experimental scenario design in order to examine the causal associations between LMX and forgiveness. Additionally, the study investigated the moderating role of forgiveness climate and the type of offence on follower’s forgiveness. The causal links between LMX and forgiveness were found for a competence-based offence but not for an integrity-based offence. Furthermore, it was found that forgiveness climate enhanced follower’s forgiveness in low quality (but not high quality) LMX relationships. This impact of forgiveness climate was found only following a low severity competence-based offence, and not following a high severity of competence-based or integrity-based offence. Overall, the findings of the thesis demonstrate that LMX relationships are vulnerable to interpersonal offences and that forgiveness could be used as a relationship maintenance strategy that yields positive outcomes.
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McKinney, Jessica, Lauren Beuttel, Jon R. Webb, Peter C. Britton, and Jameson K. Hirsch. "Forgiveness and Suicidal Behavior in Veterans: Mediating Role of Posttraumatic Growth." Digital Commons @ East Tennessee State University, 2016. https://dc.etsu.edu/etsu-works/622.
Full textAbstract:
Suicide rates are higher in veterans compared to the general population, making up a disproportionate 22% of suicides reported annually in the U.S. One factor related to suicidal behavior among veterans is increased exposure to traumatic events. However, not all traumatized veterans engage in suicidal behavior, perhaps due to the presence of protective factors. One such factor, forgiveness (of self, others, and by God), conceptualized as a positive change in cognition, emotion, and behavior, toward a transgressor or transgression, may buffer against suicide risk by facilitating a “letting go” of experienced offenses, and by allowing individuals to respond to trauma in a meaningful way via posttraumatic growth (PTG). This premise has not been tested, however. We hypothesized that forgiveness and PTG would be positively related with each other, and negatively related to suicidal behaviors. We also hypothesized that PTG would mediate the association between forgiveness and suicidal behaviors, such that higher levels of forgiveness would be associated with greater PTG and, in turn, to less suicidal behavior. Participants (N=545; 70.1% male (n=382); 86.4% Caucasian (n=469), Mean Age=49.86, SD=16.78) were community-dwelling veterans who self-identified as having experienced a trauma, and completed the PTG Inventory, the forgiveness subscale from the Fetzer Multidimensional Measure of Religiousness and Spirituality, and Suicide Behaviors Questionnaire-Revised. Bivariate correlations and simple mediation analyses were conducted covarying age, sex, and ethnicity. Supporting bivariate hypotheses (p-values
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Avdic, Alen. "Criterion-Related Validity of Narrow-Trait Personality for Predicting Job Performance, and the Test of Mediating Mechanisms." OpenSIUC, 2012. https://opensiuc.lib.siu.edu/dissertations/448.
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Personality, as a frequently used predictor of job performance, has often been criticized for its low criterion-related validity when compared to cognitive tests and some other predictors. The present study investigated incremental validity of narrow-trait personality to distinguish predictive from non-predictive facets of Conscientiousness and Extraversion dimensions. In addition, some intermediate mechanisms that may link the two personality dimensions with the criterion, such as different types of person-environment (P-E) fit and job involvement variables, were tested as well. The institution's job performance scale, NEO-PI-3 personality scale, person-organization (P-O) fit, needs-supplies (N-S) fit, demands-abilities (D-A) fit, job involvement questionnaire (JIQ), and demographic measures were administered in an online survey to 295 professional and civil service employees of a midsize Midwestern university. The sample was predominantly female and Caucasian with a mean age of 45.8 years and a median length of current employment of 5.1 years. Both personality dimensions were positively related to overall job performance. Conscientiousness was a stronger predictor of task performance, whereas Extraversion was related more consistently to contextual performance. In stepwise multiple regression analyses containing facets of personality dimensions as predictors of overall job performance, Competence emerged as the only facet of Conscientiousness, and Warmth and Assertiveness as the only facets of Extraversion that accounted for a meaningful amount of variance in the criterion. The use of narrow-trait personality to predict overall job performance enhances criterion-related validity of the construct and renders it a more efficient predictor of job performance than global-trait personality. Among the potential mediators, P-O and D-A fit partially mediated the personality-performance relationship providing evidence for the importance of perceptions of congruence in values and the ability to meet demands of the job. Current results are considered in light of limitations. Implications for theory, research, and practice, as well as future research directions are discussed.
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Taimur, Nadia. "A study of molecular and genetic mechanisms mediating the formation of twin sperm cells in Arabidopsis thaliana." Thesis, University of Leicester, 2014. http://hdl.handle.net/2381/37237.
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In flowering plants, the male gametophyte produces a pair of functional sperm cells that are transported to the embryo sac for double fertilisation. Asymmetric division of the microspore establishes the germline and division of the germ cell results in two sperm cells, however, the molecular mechanisms governing the germ cell specification and division are yet to be uncovered. DUO1 has been identified as a germline-specific MYB binding transcription factor that coordinates germ cell division with gamete specification. One of the major objectives of this thesis is the characterization of an EMS-induced germ cell division mutant termed as duo pollen 5 (duo5) in Arabidopsis. Mutant duo5 germ cells were shown to elongate and enter mitosis but fail to complete the division cycle. Genetic analysis showed that duo5 is an incompletely penetrant gametophytic mutation that has reduced transmission thorough the male. Map based cloning defined duo5 to a genetic interval of ~250 kb region on the lower arm of chromosome IV. The thesis also explores the expression and regulation of two novel DUO1-activated zinc finger genes, DAZ3 and DAZ3L. The reduction in the activity of both promoters in duo1 germ cells suggested that DUO1 is required for their activation in the male germline. Analysis suggests that DUO1 possibly employ both direct and indirect mechanisms to activate DAZ3 and DAZ3L. Furthermore, analysis of protein fusion constructs demonstrated that DAZ3 and DAZ3L expression is predominantly localized in the sperm cell cytoplasm and this expression pattern persists in the developing pollen tubes. The analysis of DAZ3 expression in germ cell division mutants revealed that late activation of DAZ3 promoter is independent of germ cell division. The work demonstrated, will further add to the knowledge of male gametophyte development and will provide new opportunities to understand molecular and genetic mechanisms involved in the production of two plant sperm cells.
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Webb, Jon R., Jameson K. Hirsch, Preston L. Visser, and Kenneth G. Brewer. "Forgiveness and Health: Assessing the Mediating Effect of Health Behavior, Social Support, and Interpersonal Functioning." Digital Commons @ East Tennessee State University, 2013. https://dc.etsu.edu/etsu-works/669.
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Religiousness and spirituality are important to most Americans and while beneficial associations between forgiveness and health are consistently observed, little is known regarding the mechanism of association. Cross-sectional multiple mediation-based analyses of associations between dimensions of forgiveness and physical and mental health were conducted using a sample of 363 undergraduate students from rural Southern Appalachia. Controlling for demographic variables (i.e., gender, age, education, ethnicity, and marital status) and lifetime religiousness, multivariable analyses reflected associations of forgiveness of self and forgiveness of others, but not feeling forgiven by God, with physical health status, somatic symptoms, mental health status, and psychological distress. All such associations operated through health behavior and/or social support; however, only in the context of forgiveness of self did such associations also operate through interpersonal functioning (problems). While forgiveness of self and forgiveness of others each appear to have a robust indirect relationship with health, mediation-based associations involving forgiveness of self were nearly twice as frequent. It may be that forgiveness of self is relatively more important to health-related outcomes.
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Rabon, Jessica K., A. Turner, Jon R. Webb, Edward C. Chang, and Jameson K. Hirsch. "Forgiveness and Suicidal Behavior in Primary Care: Mediating Role of Future Orientation." Digital Commons @ East Tennessee State University, 2015. https://dc.etsu.edu/etsu-works/615.
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Hirsch, Jameson K., K. L. Walker, S. Nsamenang, and P. Loess. "Affect and Suicidal Behaviors: The Mediating Role of Alcohol and Drug Use." Digital Commons @ East Tennessee State University, 2012. https://dc.etsu.edu/etsu-works/606.
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Skrnjug, Ivana [Verfasser], and PD Dr Simone [Akademischer Betreuer] Bergmann. "Identification of molecular mechanisms mediating the adjuvanticity of cyclic di-nucleotides / Ivana Skrnjug ; Betreuer: PD Dr. Simone Bergmann." Braunschweig : Technische Universität Braunschweig, 2015. http://d-nb.info/1175818607/34.
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McFerran, Brian William. "An investigation into the mechanisms mediating calcium ion-stimulated ACTH secretion from AtT-20 anterior pituitary tumour cells." Thesis, University of St Andrews, 1996. http://hdl.handle.net/10023/14880.
Full textAbstract:
The mouse AtT-20/D16-16 anterior pituitary tumour cell line was employed as a model system for the study of the mechanisms mediating calcium ion-stimulated adrenocorticotropin (ACTH) secretion. The present study indicates that calcium ion-stimulated ACTH secretion from AtT-20 cells is mediated by a GTP-binding protein which is present in a variety of other cell types and has been dubbed Ge (for reviews see Gomperts, 1990; Lindau & Gomperts, 1991). In AtT-20 cells the nature of Ge remains elusive with the selective heterotrimeric GTP-binding protein activator AIF(3-5) proving not to be a useful pharmacological tool under the conditions employed in the present study. Ge present in this cell line does however display characteristics consistent with it being a heterotrimeric GTP-binding protein. The results of this study would also suggest that in AtT-20 cells Ge is insensitive to both pertussis toxin and cholera toxin. Both cyclic AMP-dependent protein kinase (PKA) (Guild, 1991) and protein kinase C (PKC) (Guild & Reisine, 1987; Reisine, 1989) have been implicated in the regulation of calcium ion-stimulated ACTH secretion from AtT-20 cells. Results from the present study suggest that calcium ion/Ge-stimulated ACTH secretion from AtT-20 cells is not mediated by PKA, PKC or any other kinase but is in fact mediated by a phosphatase. PKC appears to provide a direct stimulus to secretion, which is independent of calcium ion/Ge-stimulated secretion, in contrast to PKA which is unable to stimulate secretion by itself but seems to play a modulatory role with regard to both calcium ion/Ge- and PKC-stimulated secretion.
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Zhong, Liang. "microRNAs mediating E-selectin-dependent metastatic abilities of colon cancer cells and the signaling mechanisms behind their regulation." Doctoral thesis, Université Laval, 2018. http://hdl.handle.net/20.500.11794/31426.
Full textAbstract:
L’extravasation des cellules cancéreuses circulantes est importante pour la dissémination métastatique qui est initiée par l’adhérence de cellules cancéreuses aux cellules endothéliales vasculaires. Elle nécessite l’interaction entre les récepteurs d’adhérence comme E-sélectine sur les cellules endothéliales et leurs ligands sur les cellules cancéreuse. Notamment, E-sélectine influence le potentiel métastatique des cancers du sein, de la vessie, de l’estomac, du pancréas et du côlon, des leucémies et lymphomes. Ici on montre que l’expression de E-sélectine est ciblée par deux groupes distinctifs de microRNAs (miRNAs); i.e. miR-31, qui cible directement le mRNA de E-sélectine, et miR-146a et -181a/b, qui répriment l’expression de E-sélectine, indirectement en ciblant la voie de NF-κB en amont. La voie des MAP kinases joue un rôle pivot dans la transcription de deux de ces miRNAs en réponse à l’IL-1β, étant donné que p38 et JNK contrôlent la transcription de miR-31, et que p38, ERK et JNK médient la transcription de miR- 146a. Les facteurs de transcription en aval des MAP kinases, GATA2, c-Fos et c-Jun, modulent la transcription de ces deux miRNAs. L’inhibition de p38 augmente l’activité de NF-κB au moins partiellement par miR-146a. L’inhibition de p38 augmente aussi l’expression de Esélectine au niveau post-transcriptionnel en diminuant miR-31. En réponse à l’IL-1β, p38 MAP kinase réprime donc l’expression de E-sélectine aux niveaux transcriptionnel et posttranscriptionnel via miR-146a et miR-31, respectivement. Ces résultats révèlent un nouveau mécanisme par lequel p38 inhibe l’expression de E-sélectine par les miRNAs suivant une stimulation pro-inflammatoire. L’inhibition de E-sélectine médiée par miR-31/-146a diminue le potentiel métastatique de cellules de cancer du côlon en réduisant leur adhérence à l’endothélium, et leur migration transendothéliale. Ces résultats soulignent pour la première fois que les miRNAs médient l’extravasation des cellules du cancer du côlon dépendante de E-sélectine.Extravasation of circulating cancer cells is a key event of metastatic dissemination that is initiated by the adhesion of cancer cells to vascular endothelial cells. It requires the interaction between adhesion receptors such as E-selectin present on endothelial cells and their ligands on cancer cells. Notably, E-selectin influences the metastatic potential of breast, bladder, gastric, pancreatic, and colorectal carcinoma as well as of leukemia and lymphoma. Here, we show that E-selectin expression is targeted by two distinct sets of microRNAs (miRNAs); i.e. miR-31, which targets E-selectin mRNA directly, and miR-146a and -181a/b, which repress E-selectin expression indirectly by targeting the upstream pro-inflammatory NF-κB pathway. MAP kinases play pivotal roles in the transcription of some of these miRNAs in response to IL-1β, in that p38 and JNK control the transcription of miR-31, and that p38, ERK and JNK mediate the transcription of miR-146a. The downstream transcription factors of MAK kinases, namely GATA2, c-Fos and c-Jun modulate the transcription of both miRNAs. Inhibiting p38 MAP kinase increases NF-κB activity, at least partially via miR-146a. Inhibiting p38 also increases the expression of E-selectin at the post-transcriptional level via decreasing miR-31. In response to IL-1β, p38 MAP kinase hence represses the expression of E-selectin at the transcriptional and the post-transcriptional levels, via miR-146a and miR-31, respectively. These results highlight a novel mechanism by which p38 downregulates the expression of E-selectin through microRNAs following inflammatory stimuli. The miR-31/-146a-mediated repression of E-selectin impairs the metastatic potential of colon cancer cells by decreasing their adhesion to, and migration through, the endothelium. These results highlight for the first time that miRNAs mediate E-selectindependent extravasation of colon cancer cells.
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Chow, Jonathan Jenn-Sheng. "COCAINE CHOICE: A NOVEL PROCEDURE FOR INVESTIGATING NEURONAL ACTIVATION MEDIATING COCAINE PREFERENCE." UKnowledge, 2018. https://uknowledge.uky.edu/psychology_etds/151.
Full textAbstract:
Cocaine use disorder is a significant health problem, negatively impacting individuals afflicted. While preclinical self-administration research has provided invaluable insight into the neurobehavioral mechanisms that underlie cocaine abuse, cocaine use outside of the laboratory occurs within an environment where other goods are also available ubiquitously. Although there is an ever-increasing literature investigating drug vs. non-drug choice in rodent models and how alternative goods can compete with the subjective value of cocaine, the neurobiological mechanisms that are associated with cocaine preference remains largely unknown. Additionally, current drug vs. non-drug choice studies use procedures that confound preference with intake, such that preference measures are directly reflective of individual experience with drug and non-drug reinforcers earned through the choices that are made; simply, preference and intake are the same. Moreover, differences in cocaine experience can result in differential neural adaptations, thus making it difficult to determine if the neurobiological mechanisms underlying choice are related to preference or drug intake. Herein a novel choice procedure, which controls for reinforcer intake (controlled reinforcer ratio; CRR), was used to explore how certain reinforcer dimensions (i.e., magnitude and frequency) influence cocaine preference. In addition, neuronal activity, measured via c-fos expression, in the orbitofrontal cortex and nucleus accumbens, areas associated with decision-making and valuation, for cocaine and food were independently targeted and labeled using fluorescent in situ hybridization and fluorescent immunohistochemistry. First, unlike prototypical choice procedures where preference and intake are confounded, the CRR choice procedure was able to dissociate the two. Under the CRR choice procedure, it was revealed that both magnitude and frequency, independent dimensions of reinforcement, greatly influence preference for cocaine. Furthermore, the CRR choice procedure was sensitive to manipulations known to influence cocaine preference while keeping reinforcer intake constant. When neuronal activity was examined after CRR training, the number of cocaine activated cells, relative to food activated cells, did not correlate with individual preferences for cocaine despite overall reinforcer intake being held constant. Instead, results suggest neuronal activity for cocaine was related to overall cocaine intake. Overall, these results give impetus for utilizing the CRR choice procedure to better investigate how drug and non-drug reinforcers are afforded differential subjective value and compete for preference. Moreover, use of a CRR choice procedure may lead to identification of specific neurobehavioral mechanisms and lead toward future development of more effective pharmacological and behavioral treatments to ameliorate substance use disorders.