Dissertations / Theses: 'Functional integrity of the kidney'

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Stokesberry, Susan Anne. "Functional effects of temperature on pancreatic beta-cell insulin secretion and integrity." Thesis, University of Ulster, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.422895.

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John, Stephen G. "The cardiovascular and functional consequences of chronic kidney disease in older people." Thesis, University of Nottingham, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.594588.

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Chronic kidney disease is common, affecting up to 25% of the elderly population. CKD is associated with both increased morbidity and mortality. The mainstay of treatment is blood pressure control. Whilst hypertension guidelines exist, there is significant concern amongst many practicing clinicians about their applicability to the older person. This concern is primarily due to falls risk. Falls are a significant problem in this age-group with a serious impact on those who fall, their families and the wider health economy. Whilst falls risk is multi-factoral, medication load (especially antihypertensives) is both significant and modifiable. The aim of this thesis is therefore to explore the risk-benefit relationship between blood pressure control, antihypertensive therapy and falls in older people with CKD. This was performed via an interlinked collection of clinical trials, culminating in an interventional drug trial. Traditionally such trials have focused on the effect of a drug (or combination of therapeutic agents), whereas we examined the effect of the therapeutic strategy of blood pressure control itself, as well as the effects of therapy beyond blood pressure itself. Our key results are: • Impairment of autonomic nervous system function can predict mortality in CKD, independent of other significant predictors. • Autonomic function is highly modifiable even in patients established on dialysis, and that these can be affected by factors such as PD fluid composition. • Body composition is highly variable over time in CKD. This is seen both in those on dialysis, and in pre-dialysis patients. • Antihypertensive therapy is associated with an acute reduction in circulating endotoxaemia. Whilst the long-term effect of this alteration is unknown, endotoxaemia is known to be associated with poor outcomes in many disease populations similar to CKD. • Antihypertensive therapy causes significant acute improvement in many markers of cardiovascular health in a cohort of older people with CKD (and non-CKD controls). Other effects of goal-directed AHT are also described, including changes to bone mineral biochemistry. • Antihypertensive therapy causes sustained improvement in many markers of cardiovascular health over a 12 month period in older people. Non-cardiovascular changes are also seen, some sustained from the original acute AHT use, whilst others regress towards baseline values. Falls remain relatively rare, and appear non-cardiovascular in origin. Cardiovascular disease in CKD is complex, and BP control remains a key component of its management. The data presented herein suggest that older people with CKD may benefit from aggressive risk reduction with AHT, just as young people do, and it is not appropriate to significantly modify this approach as a response to increased age alone.

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Antoniv, A. A. "Kidneys functional status in patients with chronic kidney disease and nonalcoholic steatohepatitis." Thesis, БДМУ, 2020. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/18082.

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Dudka, Ya A. "Influence of the pineal hormone on the functional state of the kidney." Thesis, БДМУ, 2022. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/19364.

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Self, Michelle Maxey. "Characterization of the functional roles of Six2 during kidney and stomach development." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2008. http://hdl.handle.net/1765/13554.

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Koufaki, Pelagia. "The effects of erythropoietin therapy and exercise rehabilitation on physiological and functional capacity of patients with end stage renal disease." Thesis, Manchester Metropolitan University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364706.

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Korsheed, Shvan. "The cardiovascular and functional consequences of arteriovenous fistula formation in chronic kidney disease." Thesis, University of Nottingham, 2011. http://eprints.nottingham.ac.uk/12032/.

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Background. Native arteriovenous fistula (AVF) is the vascular access of choice and its use c.f. catheters is associated with sustained reduction in mortality. This may be due to factors beyond dialysis catheter associated sepsis. This study aims to investigate the impact of AVF formation on the spectrum of cardiovascular factors that might be important in the pathophysiology of cardiovascular diseases in CKD patients. Methods. We recruited 43 pre-dialysis patients who underwent AVF formation. Patients were studied two weeks prior to AVF operation, two weeks and three months postoperatively. Haemodynamic variables were measured using pulse wave analysis, carotid femoral pulse wave velocity (CF-PWV) by applanation tonometry and AVF blood flow by Doppler ultrasound. Bioimpedence analysis was performed and patients underwent serial transthoracic echocardiography. Laser Doppler Perfusion Imaging and iontophoresis were used to assess endothelial dependant (ED) and non-endothelial dependant (NED) vasodilatation. Results. AVF formation was successful in 30/43 patients. Two weeks postoperatively, total peripheral resistance decreased (-17 18%, p=0.001), stroke volume tended to rise (12 30ml, p=0.053) and both heart rate (4 8bpm, p=0.01) and cardiac output (1.1 1.5l/min, p=0.001) increased. Systolic and diastolic blood pressures reduced (-9 18mmHg; -9 10mmHg; ≤ p=0.006). CF-PWV reduced (-1.1 1.5m/sec, p=0.004). Left ventricular ejection fraction (LVEF) increased (6 8%, p<0.001). Patients with successful AVF formation had a significantly reduced ED vasodilatation in the fistula arm -36±46%, p<0.001. Only NED vasodilatation was significantly reduced in the non-fistula arm 23±40%, p=0.01. Patients who had unsuccessful AVF operation exhibited no recordable changes. All the observed haemodynamic changes were largely maintained after 3 months. No change in hydration status/body composition was observed. AVF formation resulted in a sustained reduction in arterial stiffness and BP as well as an increase in LVEF. Furthermore, there were significant changes in the local and systemic microcirculation. Overall, post AVF adaptations might be characterised as potentially beneficial in these patients and supports the widespread use of native vascular access, including older or cardiovascular compromised individuals.

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Waqar, Tehreem. "Functional, structural and molecular alterations in the heart and kidney during diabetes mellitus." Thesis, University of Central Lancashire, 2016. http://clok.uclan.ac.uk/16733/.

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Background: Diabetes mellitus (DM) is a major metabolic disorder leading to severe long term complications including cardiomyopathy, nephropathy, retinopathy and neuropathy that are common in type 1 DM (T1DM) and type 2 DM (T2DM). Epidemiological studies have demonstrated a role of hyperglycaemia (HG) in eliciting adverse cardiac and renal outcomes including heart failure (HF), diastolic and renal dysfunction. This study investigated the effect of HG on left ventricle (LV) and kidney structural remodelling, function and underlying molecular events associated with the two organs over a period of 2 and 4 months compared to age-matched control. Methods: Molecular mechanisms underlying HG-induced remodelling changes including extracellular matrix (ECM) and myocyte apoptosis deposition, underlying cytokine induction, recapitulation of foetal genes, and transcriptional alterations that may influence the ECM and intracellular calcium [Ca2+]i handling in the LV and kidney of T1DM as well as T2DM were examined in this study. LV and kidney isolations following 2 and 4 months of the development of T1DM were used to assess the remodelling changes and underlying transforming growth factor β1 (TGFβ1) activity, gene expression profile of the ECM and calcium mediators using histological, immunohistochemical and quantitative gene expression analyses compared to age-matched Wistar control rats. Results: The results show that T1DM over 4 months can elicit severe structural and molecular changes in the LV and the kidney compared to 2 months of DM. The severity of these changes was significantly less in respective healthy age-matched control animals. The isolated ventricular cardiomyocytes from T1DM rats displayed altered cellular calcium (Ca2+) homeostasis and [Ca2+]i translating to alterations in mRNA abundance of key Ca2+ handling proteins, cardiac sarcoplasmic reticulum Ca2+ATPase 2a (SERCA2a), ryanodine receptor (RyR2), Na2+/Ca2+ exchanger, phospholamban (Plb), L-type Ca2+ channel proteins (Cav1.2 and Cav1.3), calmodulin2 (Calm2) and Ca2+/calmodulin-dependant protein kinase II delta (CaMK2d) were significantly (p < 0.05) altered in DM compared to age-matched control animals. The results showed LV and kidney remodelling in the T1DM rats with increased ECM deposition that translated into increased gene expressions of key components (collagen 1α, collagen 3α, fibronectin and elastin) and modulators i.e. MMP2 and MMP9 and their tissue inhibitor (TIMP4), connective tissue growth factor (CTGF), integrin 5α and connexin 43 (Cx43) of the ECM. Molecular derangements underlying this phenotype included increased TGFβ1 transcription and activity, recapitulation of foetal gene phenotype atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) with marked hypertrophy, underscored by caspase-3 mediated cell apoptosis. Electron microscopic analysis revealed ultrastructural alterations in LV highlighted by increased mitochondrial number and altered mitochondrial population, whereas the kidney presented with increase glomerular basement membrane thickness in T1DM compared to controls. These data clearly show that adult vs young adult, in combination with STZ-induced T1DM, can elicit severe changes to both the heart and the kidney, respectively in structural, functional and biochemical alterations. The final part of the study revealed exercise training after 2-3 months may have beneficial effects in T2DM animals compared to sedentary control rats. Ventricular myocyte and shortening were generally well preserved despite alterations in mRNA gene expression encoding a variety of cardiac muscle proteins in the exercised trained adult GK diabetic rat. LV remodelling in GK rat presented with marked hypertrophy of cardiomyocytes and increased ECM deposition that altogether translated into increased ECM components and regulators which were reversed by exercise training. Conclusions: The present results have demonstrated that T1DM, if left untreated, can lead to severe changes to both the heart and the kidney. These changes seem to occur at structural and molecular levels leading to dysfunction of the heart and kidney and the severity of the damage is enhanced over time. Data suggests that diabetic cardiomyopathy (DCM) may have possible origins in pro-fibrotic and pro-hypertrophic mechanisms. Moreover, this study demonstrates that physical exercise training continues to be one of the most valuable forms of non-pharmacological therapy in DM. Data concerning molecular signalling cascades and ECM phenotype is particularly significant as targeting features of structural remodelling may delay onset and severity of myocardial and renal complications.

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Antoniv, A. A. "The kidneys functional state in chronic kidney disease in patients with nonalcoholic steatohepatitis." Thesis, БДМУ, 2021. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/18584.

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Cruz-Almeida, Yenisel. "Functional Integrity of Somatosensory Pathways in the Neuropathic Pain Conditions After Spinal Cord Injury." Scholarly Repository, 2011. http://scholarlyrepository.miami.edu/oa_dissertations/694.

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Neuropathic pain (NP) after spinal cord injury (SCI) can significantly and negatively affect a person’s quality of life and is often refractory to currently available treatments. In order to advance the field and find effective therapeutic avenues; signs, symptoms, and biomarkers in humans should be identified and related to specific pain-generating mechanisms. The present work utilizes quantitative sensory testing (QST) and magnetic resonance spectroscopy (MRS) to evaluate the relationship between the functional integrity of the dorsal column-medial lemniscus pathway (DCML), the spinothalamic tract (STT), and metabolic markers of neuronal loss and glial activation in the thalamus of persons with/without NP after SCI. This work was based on the hypothesis that the presence/severity of NP after SCI is dependent both on function of ascending somatosensory pathways and changes in neuronal and glial markers in the thalamus. The results indicate that NP is associated with a decreased afferent DCML input to the thalamus resulting in a loss of inhibitory neurons and that residual function from STT afferents may contribute to thalamic glial activation and NP. Based on this work, in combination with previous studies in animals and humans, it can be proposed that NP after SCI partly results from the combination of residual STT function and loss of neuronal inhibition leading to neuronal hyperexcitability in the spinal cord and the thalamus. Thus, the presence of NP in chronic SCI is dependent on several underlying mechanisms which may be measured in human subjects with methods such as QST and MRS. Clinical implications and recommendations for further research are enclosed.

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Ziegler, David A. (David Allan). "Cognition in healthy aging and Parkinson's disease : structural and functional integrity of neural circuits." Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/68169.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, September 2011. This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. "September, 2011." Cataloged from student submitted PDF version of thesis. Includes bibliographical references. This dissertation documents how healthy aging and Parkinson's disease (PD) affect brain anatomy and physiology and how these neural changes relate to measures of cognition and perception. While healthy aging and PD are both accompanied by a wide-range of cognitive impairments, the neural underpinnings of cognitive decline in each is likely mediated by deterioration of different systems. The four chapters of this dissertation address specific aspects of how healthy aging and PD affect the neural circuits that support sensory processes and high-level cognition. The experiments in Chapters 2 and 3 examine the effects of healthy aging on the integrity of neural circuits that modulate cognitive control processes. In Chapter 2, we test the hypothesis that the patterns of age-related change differ between white matter and gray matter regions, and that changes in the integrity of anterior regions correlate most strongly with performance on cognitive control tasks. In Chapter 3, we build upon the structural findings by examining the hypothesis that age-related changes in white matter integrity are associated with disrupted oscillatory dynamics observed during a visual search task. Chapter 4 investigates healthy age-related changes in somatosensory mu rhythms and evoked responses and uses a computational model of primary somatosensory cortex to predict the underlying cellular and neurophysiolgical bases of these alterations. In contrast to the widespread cortical changes seen in healthy OA, the cardinal motor symptoms of PD are largely explained by degeneration of the dopaminergic substantia nigra, pars compacta (SNc). Cognitive sequelae of PD, however, likely result from disruptions in multiple neurotransmitter systems, including nondopaminergic nuclei, but research on these aspects of the disease has been hindered by a lack of sensitive MRI biomarkers for the affected structures. Chapter 5 presents new multispectral MRI tools that visualize the SNc and the cholinergic basal forebrain (BF). We applied these methods to test the hypothesis that degenerative processes in PD affect the SNc before the BF. This experiment lays important groundwork for future studies that will examine the relative contribution of the SNc and BF to cognitive impairments in PD. by David A. Ziegler. Ph.D.

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Law, Becker M. P. "The functional characterisation of human innate lymphocytes in renal fibrosis and chronic kidney disease." Thesis, Queensland University of Technology, 2019. https://eprints.qut.edu.au/132513/1/Becker%20Meng-Po_Law_Thesis.pdf.

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This thesis by publication is a step forward in understanding the function of discrete immune cell populations in kidneys with chronic inflammation and fibrosis. We have successfully identified various human immune cells of the innate immune system as critical drivers of chronic kidney disease. The findings of this thesis sheds light on novel functions of innate immune cells and opens opportunities for the development of novel kidney therapies.

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Pu, Zhengwen. "CRYOGENIC MACHINING AND BURNISHING OF AZ31B MAGNESIUM ALLOY FOR ENHANCED SURFACE INTEGRITY AND FUNCTIONAL PERFORMANCE." UKnowledge, 2012. http://uknowledge.uky.edu/me_etds/5.

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Surface integrity of manufactured components has a critical impact on their functional performance. Magnesium alloys are lightweight materials used in the transportation industry and are also emerging as a potential material for biodegradable medical implants. However, the unsatisfactory corrosion performance of Mg alloys limits their application to a great extent. Surface integrity factors, such as grain size, crystallographic orientation and residual stress, have been proved to remarkably influence the functional performance of magnesium alloys, including corrosion resistance, wear resistance and fatigue life. In this dissertation, the influence of machining conditions, including dry and cryogenic cooling (liquid nitrogen was sprayed to the machined surface during machining), cutting edge radius, cutting speed and feed rate, on the surface integrity of AZ31B Mg alloy was investigated. Cryogenic machining led to the formation of a "featureless layer" on the machined surface where significant grain refinement from 12 μm to 31 nm occurred due to dynamic recrystallization (DRX), as well as increased intensity of basal plane on the surface and more compressive residual stresses. Dry and cryogenic burnishing experiments of the same material were conducted using a fixed roller setup. The thickness of the processed-influenced layer, where remarkable microstructural changes occurred, was dramatically increased from the maximum value of 20 μm during machining to 3.4 mm during burnishing. The burnishing process also produced a stronger basal texture on the surface than the machining process. Preliminary corrosion tests were conducted to evaluate the corrosion performance of selected machined and burnished AZ31B Mg samples in 5% NaCl solution and simulated body fluid (SBF). Cryogenic cooling and large edge radius tools were found to significantly improve the corrosion performance of machined samples in both solutions. The largest improvement in the material's corrosion performance was achieved by burnishing. A finite element study was conducted for machining of AZ31B Mg alloy and calibrated using the experimental data. A user subroutine was developed and incorporated to predict the grain size changes induced by machining. Good agreements between the predicted and measured grain size as well as thickness of featureless layers were achieved. Numerical studies were extended to include the influence of rake angle, feed rate and cutting speed on the featureless layer formation.

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Cegama, Bernardo Ortega Ladron de. "Functional expression and membrane trafficking of Kâ†iâ†r1.1b in Madin-Darby Canine Kidney cells." Thesis, University of Sheffield, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312366.

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Velyka, A. Ya. "PECULIARITIES OF RAT KIDNEY FUNCTIONAL STATE UNDER CONDITIONS OF EXPERIMENTAL NEPHROPATHY AGAINST SALT LOADING BACKGROUND." Thesis, Міжнародної науково-практичної конференції студентів та молодих вчених, м. Суми, 21–22 квітня 2016 року, 2016. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/11660.

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Human and animal kidneys are the efferent organs which provide support of the organism with water electrolytic balance, acid-base and osmotic homeostasis. It has been studied from literary sources that the development of early stage of poliuria acute renal failure 72 hours after administration of mercury chloride is characterized by activation of lipid peroxide oxidation with increasing content of diene conjugates and malonic aldehyde in the cortical substance of the kidneys. This stage of the pathological process is accompanied by increased glomerular filtration rate and urine output compared with the period of oliguria, but as compared with the control of these parameters it was noted decrease in glomerular filtration and urine output. Water and salt loading were carried out 2 hours before euthanasia, intragastrically through a metal tube. 2 hours after loading the animals were decapitated under the light ether anesthesia. Mercury chloride intoxication of animals was conducted subcutaneously by aqueous solution of mercury chloride (II) at a dose of 5 mg per kg body weight.

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Velyka, A. Ya. "Peculiarities of rat kidney functional state under conditions of experimental nephropathy against salt loading background." Thesis, Sumy State University, 2016. http://essuir.sumdu.edu.ua/handle/123456789/45180.

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Human and animal kidneys are the efferent organs which provide support of the organism with water electrolytic balance, acid-base and osmotic homeostasis. It has been studied from literary sources that the development of early stage of poliuria acute renal failure 72 hours after administration of mercury chloride is characterized by activation of lipid peroxide oxidation with increasing content of diene conjugates and malonic aldehyde in the cortical substance of the kidneys. This stage of the pathological process is accompanied by increased glomerular filtration rate and urine output compared with the period of oliguria, but as compared with the control of these parameters it was noted decrease in glomerular filtration and urine output. Water and salt loading were carried out 2 hours before euthanasia, intragastrically through a metal tube. 2 hours after loading the animals were decapitated under the light ether anesthesia. Mercury chloride intoxication of animals was conducted subcutaneously by aqueous solution of mercury chloride (II) at a dose of 5 mg per kg body weight.

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Chen, Ming-Jiu. "Functional study to determine the role of TREX2 and TREX1 in maintaining genome integrity : a dissertation /." San Antonio : UTHSC, 2006. http://proquest.umi.com/pqdweb?did=1251820381&sid=3&Fmt=2&clientId=70986&RQT=309&VName=PQD.

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Bhattarai, Amita. "A Novel Role of Hrr25 in Cell Wall Integrity Maintenance and Functional Analysis of Hrr25 Domains." ScholarWorks@UNO, 2019. https://scholarworks.uno.edu/td/2663.

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Hrr25 is a highly conserved serine/threonine protein kinase with diverse functions and it localizes to a number of intracellular sites. Hrr25 possesses an N-terminal kinase domain, a middle region, and a C-terminal proline/glutamine rich domain. In this thesis, we systematically characterized the roles of these three domains of Hrr25 on cell growth, cell morphology, and its cellular localizations. Additionally, we identified a novel target of Hrr25, Pin4. We show that Hrr25-dependent phosphorylation of Pin4 is required for cell wall integrity maintenance. We found that that Hrr25 and Pin4 physically interact in vivo and that the C-terminal domain of Hrr25 is required for this interaction and for maintaining cell wall integrity. Together, we identified a new target and a novel function for Hrr25 and provided insights into the structure-function relationship of Hrr25 domains.

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Martin, Emma J. "Increasing treatment integrity of functional behavior assessment based support plans in general education settings through performance feedback /." view abstract or download file of text, 2001. http://wwwlib.umi.com/cr/uoregon/fullcit?p3024522.

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Thesis (Ph. D.)--University of Oregon, 2001. Typescript. Includes vita and abstract. Includes bibliographical references (leaves 150-159). Also available for download via the World Wide Web; free to University of Oregon users.

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Andrushchak, M. O. "Functional kidney damage as a consequence of the effects of antiretoviral therapy in patients with severe immunodeficiency." Thesis, БДМУ, 2021. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/18880.

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Chen, Yuejin. "Characterization of the Vasoactivity of Tachykinins in Isolated Rat Kidney: Functional Studies and in Vitro Receptor Autoradiography." Digital Commons @ East Tennessee State University, 1994. https://dc.etsu.edu/etd/2892.

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Although tachykinins have potent vascular actions, their effect on renal resistance blood vessels is currently unknown. The vasoactive properties of tachykinins and related analogs were assessed in isolated perfused rat kidney. At a basal perfusion pressure (PP) of 75 $\pm$ 6 mm Hg (n = 5), bolus injections of substance P (SP) had no significant vasoactive effect. Following a sustained increase in baseline PP (134 $\pm$ 10 mm Hg) produced by phenylephrine (1 $\mu$M), SP evoked a dose-dependent increase in PP. The largest dose of SP increased PP by 60 $\pm$ 5 mm Hg. The vasoconstrictor response to SP was not blocked by phentolamine when angiotensin II was used to increase basal tone. Thus, the response to SP is not mediated by norepinephrine. Pressor responses to SP were not potentiated by peptidase inhibitors, captopril and thiorphan. SP(1-7) had no effect on PP, suggesting that the pressor response to SP is C-terminal dependent and tachykinin receptor mediated. The selective NK-1 receptor agonist, (Sar$\sp9$,Met(O$\sb2)\sp{11}\rbrack$SP, had no effect on PP. In contrast, both the selective NK-2 and NK-3 receptor agonists, GR-64349 and (MePhe$\sp7$) NKB, produced dose-dependent pressor responses (116 $\pm$ 8 and 134 $\pm$ 15 mm Hg increases in PP at 33 nmol, respectively) and were more potent than SP. Infusion of capsaicin (500 nM) produced an initial increase in PP following by a more prolonged decrease in PP. Clamping the renal vein produced a marked increase in PP. The localization of NK-3 receptors in rat kidney evaluated by film autoradiography using $\sp{125}$I- (MePhe$\sp7\rbrack$NKB revealed a high density of specific binding sites on the proximal ureter and renal pelvis, moderate density in the renal vein and its large branches, and a low density in the inner strip of outer medulla, but no specific binding on the renal artery system and cortex. High resolution autoradiograms demonstrated $\sp{125}$I- (MePhe$\sp7\rbrack$NKB binding sites on the tunica media of the renal vein and tunica muscularises of renal pelvis and ureter. Specific binding of $\sp{125}$I-BHSP was found in association with the renal artery and renal pelvis. No specific SP binding sites were associated with renal vein. These data indicate that the pressor effect of tachykinins in the isolated rat kidney can be mediated by NK-2 and/or NK-3 receptors. The latter may be on the vascular smooth muscle of the renal vein.

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Pedroza-Garcia, José Antonio. "Functional characterization of the DNA Polymerase epsilon and its involvement in the maintenance of genome integrity in Arabidopsis." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS248.

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Contrairement aux animaux, les plantes ont un développement largement post-embryonnaire et forment continuellement de nouveaux organes et tissus grâce à l’activité de leurs méristèmes. Ces massifs de cellules indifférenciées conservent la capacité à se diviser tout au long de la vie de la plante, et c’est également à partir du méristème caulinaire que se forment les gamètes. Chaque cycle de division peut être la source de mutations, suite par exemple à des erreurs de réplication. De plus, les méristèmes sont relativement exposés aux stress environnementaux qui peuvent également endommager l’ADN des cellules. Les mécanismes impliqués dans la détection des lésions de l’ADN ou des défauts de réplication et l’arrêt de la prolifération cellulaire en réponse à ces dommages jouent donc un rôle fondamental dans le maintien de la stabilité du génome, aussi bien au cours du développement végétatif que lors de la reproduction sexuée. Chez tous les eucaryotes, l’ADN Polymérase ε est un acteur central de ces mécanismes parce qu’elle assure non seulement la réplication fidèle de l’ADN au cours de la phase S du cycle cellulaire, mais est également directement impliquée dans la réparation de l’ADN, et dans la perception du stress réplicatif. L’étude détaillée de sa fonction est cependant rendue difficile chez beaucoup d’organismes par le fait que son inactivation est létale. Dans ce travail, nous avons utilisé des approches de génétique pour étudier le rôle de l’ADN Pol ε d’Arabidopsis au cours de la progression du cycle cellulaire et dans la réponse au stress réplicatif et aux lésions de l’ADN. Nous avons ainsi pu montrer que la sous-unité catalytique du complexe Pol ε ainsi que sa principale sous-unité accessoire DPB2 sont essentielles à la détection des défauts de réplication, et fonctionnent en amont de la kinase ATR pour induire l’arrêt du cycle cellulaire et activer les voies de réparation au cours du développement végétatif. En outre, nous avons découvert un nouveau point de contrôle activé lors de la phase de réplication pré-méiotique qui permet l’activation d’une mort cellulaire programmée en réponse à des défauts survenus pendant cette phase, grâce au facteur de transcription SOG1.Tous les stress biotiques ou abiotiques auxquels la plante est soumise pouvant conduire à la formation de lésions au niveau de l’ADN, nos résultats ouvrent des perspectives de recherche pour comprendre la réponse des plantes aux stress environnementaux. En outre, la disponibilité de mutants viables pour différents facteurs impliqués dans la réplication ou la réponse aux lésions de l’ADN nous a permis d’explorer chez un eucaryote pluricellulaire des mécanismes qui sont pour l’instant essentiellement décrits chez la levure, et ainsi d’acquérir des connaissances qui pourront être transférées aux systèmes animaux et notamment à l’Homme Plant development is a largely post-embryonic process that depends on the activity of meristems. These pools of undifferentiated cells retain the ability to proliferate throughout the lifespan of the plant, and are at the origin of gamete formation relatively late in its life cycle. Mutations can arise at each round of cell division, for example due to replication errors. In addition, meristems are relatively exposed to all kinds of environmental stresses that can also induce DNA damage. Detection of DNA lesions or replication defects and subsequent cell cycle arrest are thus instrumental to the maintenance of genome integrity, both during vegetative and reproductive growth. In all eukaryotes, DNA Pol ε is a key player of these mechanisms because it is not only responsible for the faithful reproduction of the genetic information during S-phase, but also directly involved in DNA repair and replicative stress perception. Detailed analysis of its function has however been complicated by the lethality of its inactivation in most organisms. In this work, we have used genetic approaches to investigate its role during cell cycle progression and replicative stress response. We have shown that both its catalytic sub-unit and its main accessory sub-unit DPB2 are involved in replicative stress sensing and that they function upstream of the ATR kinase to induce cell cycle arrest and DNA repair during vegetative growth. In addition, we have found that a specific checkpoint exists during pre-meiotic DNA replication that activates a cell death program via the SOG1 transcription factor upon replicative stress. Because all types of biotic and abiotic stresses can generate DNA damage, our work opens new research prospects to understand how plants cope with adverse conditions. Furthermore, the viability of Arabidopsis mutants deficient for various factors involved in DNA replication or DNA Damage Response allowed us to analyse into details in a multicellular eukaryote crucial cellular mechanisms that had until now been mainly investigated in yeast. This work thus allowed us to generate data that can be transferred to animal systems and notably to Human

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Sibomana, Isaie. "‘Functional Metabolomics’ Enhances Assessment of Tissue Dysfunction as Demonstrated in a Rat Model of Sub-Acute D-serine Exposure." Wright State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=wright1323713109.

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Ting, Stephen M. S. "Cardiovascular reserve in adult patients with advanced chronic kidney disease : a novel functional assessment by cardiopulmonary exercise testing." Thesis, University of Warwick, 2013. http://wrap.warwick.ac.uk/58567/.

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Cardiovascular disease in particular heart failure is the leading cause of mortality in the growing epidemic of chronic kidney disease (CKD). In addition to a myriad of risk factors or co-morbidities associated with CKD, there are adverse cardiovascular morphological and functional alterations that complicate these CKD patients who most often have poor exercise tolerance and compromised quality of life. Emphasis on addressing the traditional Framingham risk factors has failed to fully explain the increased risk of premature death in these patients complicated by the fact that some of these risk factors are inversely associated with poor outcome, a phenomena known as ‘reverse epidemiology’. Risk stratifying CKD patients using single surrogate markers such as dyslipidemia and left ventricular hypertrophy undermines the underlying complex processes that are involved in the pathophysiology of cardiovascular disease in CKD. Some of these mechanisms involved accelerated arterial stiffness, excess pressure overload with hypertension, volume overload, endothelial dysfunction, reduced myocardial capillary density, cardiac fibrosis, ventricular stiffness and unspecified uraemic-related factors. Kidney transplantation currently confers a survival advantage over dialysis or any existing drug therapy, most likely due to reduction in cardiovascular death and this could serve as a model by which we could derive insights to the complex cardiac and renal interactions. Although improvement in the resting left ventricular echocardiographic measures following transplantation has been documented, the effect of these alterations on functional cardiovascular reserve and thereby survival have not be demonstrated. Reduced cardiovascular reserve measurable by maximal cardiopulmonary exercise testing (CPET) has been shown to be powerful prognostic indicator in patients with various cardiac diseases but particularly in chronic heart failure patients who have reduced cardiovascular reserve. The primary aim of this thesis is to describe the evaluation of functional cardiovascular reserve by CPET in patients with advanced CKD who are initially waitlisted for kidney transplantation in comparison to subjects with treated essential hypertension who are otherwise healthy. This novel assessment is complemented by the use of vascular applanation tonometry and transthoracic echocardiography. The capability of CPET derived measures obtained prior to kidney transplantation in predicting peri- and post-operative morbidity and identifying those at risk of premature all-cause mortality pre- and post-kidney transplantation are demonstrated for the first time through prospective observational studies described in this thesis. Additional analyses have shown that impaired LV compliance and arterial stiffness in CKD adversely influenced functional cardiovascular reserve. Furthermore, the loss of adaptive LV functional properties in CKD subjects that was uniquely apparent compared to the hypertensive but otherwise healthy cohort has provided a pathophysiological background for understanding the association between kidney failure and reduced cardiovascular reserve. Future work originating from this research endeavour will be to describe prospective time-course correlation between cardiovascular morphology and functional cardiovascular reserve following kidney transplantation. This will allow us to carefully define the degree of changes in these variables and identify factors that hinder cardiovascular recovery. This will generate important insights for new effective cardiovascular strategies and interventions for the CKD population. One of the proposed aims is to produce an integrated measure of important prognostic variables that will be used in future intervention trials. With these insights, cardiovascular risk stratification of patients being worked up for kidney transplantation can potentially be improved.

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31

Kato, Michiko. "High Pressure Effects on Biomembrance : Structual and Functional Studies of Membrane-Bond Na^{+}, K^{+}-ATPase from Pig Kidney." Kyoto University, 1999. http://hdl.handle.net/2433/181372.

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Kyoto University (京都大学) 0048 新制・課程博士 博士(農学) 甲第7966号 農博第1075号 新制||農||786(附属図書館) 学位論文||H11||N3300(農学部図書室) UT51-99-M271 京都大学大学院農学研究科農芸化学専攻 (主査)教授林力丸, 教授清水昌, 教授松野隆一 学位規則第4条第1項該当

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32

Kourtis, Georgios. "Path-functional dependencies and the two-variable guarded fragment with counting." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/pathfunctional-dependencies-and-the-twovariable-guarded-fragment-with-counting(eac338a1-4fd4-49b6-91ee-8ea2ffaee9d2).html.

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We examine how logical reasoning in the two-variable guarded fragment with counting quantifiers can be integrated with databases in the presence of certain integrity constraints, called path-functional dependencies. In more detail, we establish that the problems of satisfiability and finite satisfiability for the two-variable guarded fragment with counting quantifiers, a database, and binary path-functional dependencies are EXPTIME-complete; we also establish that the data complexity of these problems is NP-complete. We establish that query answering for the above fragment (with a database and binary path-functional dependencies) is 2-EXPTIME-complete with respect to arbitrary models, and provide a 2-EXPTIME upper bound for finite models. Finally, we establish that the data complexity of query answering is coNP-complete, both with respect to arbitrary and finite models.

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33

Li, Yuanhao. "Structural and functional study of bovine herpesvirus 1 glycoprotein B in the interaction with Madin Darby bovine kidney cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1996. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq24030.pdf.

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34

Patterson, Melanie Sian. "Meeting the Learning Needs of Individual Children in the Mainstream Classroom." Thesis, University of Canterbury. School of Educational Studies and Human Development, 2008. http://hdl.handle.net/10092/2275.

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A teacher in a mainstream classroom identified six children with behaviour difficulties or learning difficulties who were not receiving any assistance outside of the classroom. The teacher was to independently complete a functional assessment of each child to reach a hypothesis about the cause of the difficulty, and then choose and implement an appropriate intervention. Treatment integrity was monitored throughout the interventions to ensure correct implementation. It became apparent that the teacher was unable to complete adequate functional assessments or maintain appropriate interventions because of the time constraints associated with being in a classroom and her lack of specialist knowledge.

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35

Pannozzo, Mercede Alcina. "Effect of hypertension on the structural and functional integrity of the young and aged brain in an inducible transgenic model." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/9776.

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Hypertension has been associated with causing deleterious effects to the cerebrovasculature, which are thought to underlie the formation of white matter lesions (WML) and predispose individuals to age related cognitive decline. In humans hypertension frequently occurs concomitantly with other vascular risk factors making it difficult to ascertain the primary mechanisms of hypertension in isolation. Animal models of hypertension have been used in an aid to establish the mechanisms of hypertension in isolation. To date the knowledge gleaned from animal models has undoubtedly provided an insight as to the role of hypertension and cerebrovasculature remodelling but, these models have limitations such as lack of genetically matched controls and the inability to control the severity of hypertension, restricting the understanding of the underlying mechanisms. All studies within this thesis used the Cyp1a1 Ren2 inducible hypertensive rat model, induced by dietary addition of Indole-3-carbinol (I3C), allowing the severity and duration of hypertension to be tightly controlled and compared to genetically matched controls. This thesis set out to address the hypothesis that sustained hypertension will lead to alterations to the structural integrity of the cerebrovasculature and white matter, which will be exacerbated with age and that hypertension will be associated with alterations to gene expression and cognitive function. Initially this thesis sought to investigate the effect of hypertension on the structural integrity of the vasculature in the Cyp1a1 Ren2 rat model. Firstly, blood pressure in the Cyp1a1 Ren2 rat model was characterised and it was found that the dietary addition of I3C, caused a sustained level of increased blood pressure in all three cohorts. Cerebrovascular alterations were found to consist of increased eNOS expression in the young brain, which progressed with increased duration of hypertension to vascular morphological alterations of decreased vessel width and a redistribution of tight junction protein claudin-5. With age, hypertensive vascular alterations consisted of increased eNOS expression and vascular density. Additionally, there was evidence that hypertension caused a vascular inflammatory response in the young and aged brain. Secondly, this thesis investigated the effect of hypertension on gene expression. Overall it was found that hypertension altered genes related to collagen growth factors, ion channels, eNOS related Map-Kinase pathway and inflammatory genes. Thirdly, this thesis sought to investigate the impact of hypertension on the overall structural integrity of the brain and white matter examining neurons, myelin, oligodendrocytes, axons and microglia, in several regions of the young and aged brain. In general, this study found that hypertension did not cause overt structural or myelin alterations in the majority of regions analysed, with only evidence of myelin alterations occurring within the subcortex of hypertensive animals from each of the young cohorts analysed. However, an adverse subcortical inflammatory response was found in hypertensive animals of the young 6-month cohort and also in hypertensive animals from the aged 4-month cohort, where the inflammatory response was not exclusive to the subcortex of hypertensive animals but also occurred in multiple white matter tracts. Lastly this thesis chose to examine the effect of hypertension on cognitive function, specifically spatial reference and working memory using the Morris water maze and found no evidence of alterations in the cognitive functions examined. Conclusions The results presented within this thesis demonstrated that hypertension in isolation leads to modest alterations to the integrity of the cerebrovasculature and white matter, with no evidence of alterations to specific cognitive functions examined, demonstrating the importance of studying hypertension in isolation. Additionally, this study highlights the initial hypertensive induced alterations to the cerebrovasculature, such as endothelial signalling, vascular structure and inflammation, providing a window for therapeutic intervention at a time point when there are minimal alterations to the overall structural integrity of the brain. Future studies in this model should concentrate on examining different severities of hypertension and also hypertension concomitantly with other vascular risk factors to try and recapitulate pathological alterations found in humans.

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Caravaca, Carlos Francisco. "Modified functional surfaces for increased biointegration : Surface chemistry, mechanical integrity and long-term stability of zirconia and alumina based ceramics." Thesis, Lyon, 2016. http://www.theses.fr/2016LYSEI080/document.

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Les céramiques bioinertes (zircone, alumine), sont utilisées dans des dispositifs médicaux pour l’orthopédie et l’odontologie. Leurs surfaces peuvent avoir plusieurs fonctions : fixation du dispositif dans le milieu vivant (ex : implants dentaires), rôle tribologique (prothèses articulaires)… Dans tous les cas, ces surfaces sont traitées pour maximiser leur performance, mais ces modifications peuvent entrainer des conséquences négatives. Ainsi, le 2e chapitre montre qu’introduire de la rugosité par sablage joue sur l’intégrité mécanique et sur la stabilité à long terme de l’alumine, de la zircone et d’un composite alumine-zircone. Par ailleurs, dans les prothèses articulaires, la lubrification joue un rôle fondamental pour minimiser l’usure et donc augmenter la durée de vie moyenne des implants, permettant en outre de favoriser l’adsorption de protéines réduisant le contact direct entre les deux surfaces glissantes. La chimie des surfaces (y compris la présence de contamination) peut modifier ces aspects. Dans le 3e chapitre de ma thèse j’ai étudié l’effet de la contamination et des différentes techniques de nettoyage permettant de la réduire sur la mouillabilité des matériaux typiquement utilisés dans les prothèses de hanche, et sur l’adsorption de protéines à leurs surfaces. Finalement, les cellules utilisent les protéines en surface comme points de fixation et identification. Les implants avec une surface capable de recruter plus de protéines aidant à l’adhésion des cellules auront plus des chances d’être intégrés que des implants recrutant des protéines qui empêchent l’adhésion. Dans le 4e chapitre, j’ai exploré un nouveau concept de modification de surface de la zircone consistant en un greffage d’organosilanes directement sur sa surface, de manière à prouver le potentiel de cette technique à améliorer l’ostéointegration sans diminuer la performance mécanique Bioinert ceramics (zirconia, alumina) are used in medical devices in orthopedics and dentistry. Their surfaces may provide different functions: fixation of the device in the living tissue (e.g. dental implants), tribological role(joint substitutions),… In all cases the surfaces are treated to maximize their performance, but this modifications may entail negative consequences. The use of roughness to promote osseointegration of implants is a common practice, especially on dental implants. Roughening is often conducted by mechanical treatments, the most common being sandblasting. Therefore, chapter 2 focus on the implications of roughening by sandblasting on the mechanical behaviour of zirconia, alumina and a zirconia-alumina composite, and the differences between them. The work brought in chapter 3 was carried out entirely during a six-month secondment at CeramTec GmbH. In a bearing couple, lubrication mechanisms are complex and wettability and proteins play a yet-to understand role. The study compared the wettability of different materials, their ability to welcome protein adsorption and the effect of different cleaning procedures on wettability measurements and protein adsorption. Finally, the influence of the surface on cell activity is not driven exclusively by roughness: chemical modifications of the surface may enhance the perception of cells for the surface, and by careful tuning of the surface properties one may achieve a better integration without the downsides of roughness. In chapter 4, we explored a novel modification of zirconia, based on known techniques in chemistry, which introduces molecules with special functional groups capable of rendering the surface friendlier for cell adhesion, and opening the window for new exciting developments in the field of bioinert ceramics

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Dimitroglou, Arkadios. "Effects of dietary mannan oligosaccharide (MOS) supplementation in relation to intestinal integrity, microbiota, health and production of cultured fish species." Thesis, University of Plymouth, 2010. http://hdl.handle.net/10026.1/296.

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A series of investigations were conducted in order to evaluate the effect of MOS supplementation in finfish aquaculture. Fish with great potential in aquaculture industry were tested with regards to effect of dietary MOS supplementation on intestinal histology and microbiology as well as overall animal health and production. Two levels of MOS supplementation were applied 0.2% and 0.4%. Experimental fish were Atlantic salmon (Salmon salar), rainbow trout (Oncorhynchys mykiss), sole (Solea senegalensis) and gilthead sea bream (Sparus aurata). The results from the sea bream studies revealed that MOS supplementation may have a beneficial effect on growth performance of fish greater than 100 g. Additionally, there is a systemic improvement of the intestinal histology for all species investigated, especially when using 0.4% of MOS supplementation level. Both light and electron microscopy revealed increased intestinal surface and improved intestinal integrity of MOS fed fish. MOS alters the intestinal microbiota, in the case of gilthead sea bream modulation was evident even when fish were fed 0.2% dietary MOS for as little as 2 weeks. Blood immune parameters were also affected by the MOS inclusion and total leukocytes counts were increased and leukocytes relative abundance was also changed. MOS induced intestinal microbial modulation was more evident in fish are reared in outdoor conditions. Feed utilization and digestibility were improved with the addition of 0.4% MOS supplementation in the Atlantic salmon. The sole experiment revealed that MOS could reduce fish mortalities induced by pasteurelliosis. These investigations, suggest a potential role for application of MOS in aquaculture. Future research should be conducted in order to evaluate other parameters that MOS may influence and ascertain optimum dosage for each fish species and developmental stage.

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38

Stabinska, Julia [Verfasser], Hans-Jörg [Gutachter] Wittsack, and Axel [Gutachter] Görlitz. "Development of quantitative chemical exchange saturation transfer MRI for functional kidney imaging / Julia Stabinska ; Gutachter: Hans-Jörg Wittsack, Axel Görlitz." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2020. http://d-nb.info/1219727512/34.

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39

Ketela, Troy W. "Functional characterization of the Saccharomyces cerevisiae SKN7 and MID2 genes, and their roles in osmotic stress and cell wall integrity signaling." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0033/NQ64586.pdf.

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40

Ketela, Troy W. "Functional characterization of the Saccharomyces cerevisiae SKN7 and MID2 genes, and their roles in osmotic stress and cell wall integrity signaling." Thesis, McGill University, 1999. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=36620.

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The yeast SKN7 gene encodes a transcription factor that is involved in a variety of processes in cell physiology including cell wall synthesis, cell cycle progression, and oxidative stress resistance. Using a transcriptional reporter-based system, it has been demonstrated that Skn7p is regulated by the two-component osmosensor Sln1p in a manner that requires the phosphorelay molecule Ypd1p, but not the response regulator Ssk1p. Consistent with its regulation by an osmosensor, Skn7p is involved in negative regulation of the osmoresponsive HOG MAP kinase cascade. Cells lacking SKN7 and the protein serine/threonine phosphatase encoded by PTC1 are severely disabled for growth, and hyperaccumulate intracellular glycerol. The growth defect of skn7Delta ptc1Delta mutants can be bypassed by overexpression of specific phosphatase genes, or by deletion of the HOG MAP kinase pathway-encoding genes PBS2 or HOG1. MID2 was isolated in a screen designed to identify upstream regulators of Skn7p. Mid2p is an extensively O-mannosylated protein that is localized to the plasma membrane. Mutants with defective beta-1,6-glucan synthesis grow more quickly when MID2 is absent. Conversely, MID2 is essential for viability in cells lacking FKS1, the gene encoding the primary catalytic subunit of beta-1,3-glucan synthase. mid2Delta mutants are resistant to calcofluor white, a drug that interferes with cell wall chitin synthesis, while cells overexpressing MID2 are supersensitive to the drug. mid2Delta mutants have a significant reduction in stress-induced chitin synthesis, while cells overexpressing MID2 hyperaccumulate cell wall chitin. Consistent with a proposed role in sensing and responding to cell wall stress, high copy expression of specific components of the cell wall integrity MAP kinase cascade suppress various mid2Delta phenotypes, and Mid2p is essential for full activation of the Mpk1p MAP kinase during various cell wall stress and morphogenic conditions. Observations from genetic and biochemical experiments suggest that Mid2p is a regulator of the small G-protein encoded by RHO1. Deletion of MID2 is lethal to mutants lacking the Rho1p GEF Rom2p, but suppresses the low temperature growth defect of mutants lacking the Rho1p GAP Sac7p. Conversely, high copy expression of MID2 is a strong suppressor of mutants lacking TOR2, an upstream activator of Rom2p, but is toxic to sac7Delta mutants. High copy expression of MID2 causes increased GEF activity towards Rho1p. Mid2p appears to act in parallel to Rom1p and Rom2p in promoting GDP-GTP exchange for Rho1p in a mechanism that is not yet understood.

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41

Kruber, Philip [Verfasser], Manfred [Gutachter] Gessler, Ricardo [Gutachter] Benavente, and Svenja [Gutachter] Meierjohann. "Functional analysis of DROSHA and SIX1 mutations in kidney development and Wilms tumor / Philip Kruber ; Gutachter: Manfred Gessler, Ricardo Benavente, Svenja Meierjohann." Würzburg : Universität Würzburg, 2019. http://d-nb.info/1185397205/34.

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42

Rambichler, Stephan [Verfasser], and Barbara [Akademischer Betreuer] Schraml-Schotta. "Localization and functional characterization of renal dendritic cell subsets during steady state and after acute kidney injury / Stephan Rambichler ; Betreuer: Barbara Schraml-Schotta." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2020. http://d-nb.info/1222909251/34.

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43

Peterson, Emily. "Proteoliposome Proton Flux Assays Establish Net Conductance, pH-Sensitivity, and Functional Integrity of a Novel Truncate of the M2 Ion "Channel" of Influenza A." BYU ScholarsArchive, 2010. https://scholarsarchive.byu.edu/etd/2420.

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A novel truncate of Influenza A M2 protein (residues 22-62), incorporated into a uniquely tailored proteoliposome proton uptake assay, demonstrated proton flux more characteristic of an ion transporter than a traditional ion "channel." The liposome paradigm was essential for testing the conductance activity of this M2 truncate at a range of extraphysiological pHs appropriate for channel vs. transport function determination. In addition to transporter-typical proton flux, M2(22-62) showed the key characteristics of functional integrity: selective proton uptake into liposomes and block of uptake by amantadine. Two sets of proteoliposome proton flux assays were carried out, Set 1 at pH values of 6.5, 6.0. 5.5, 5.0, and 4.5; Set 2 at pH values of 6.25, 6.0, 5.75, 5.5, 5.25, 5.0, and 4.75. Observed flux rates followed a proton transport saturation curve similar to that observed in mouse erythroleukemia cells1. Proton transport was maximal at pH 5.5 in Set 1 (139 H+/second/tetramer) and at pH 5.75 in Set 2 (43 H+/second/tetramer). Amantadine block was strongest at pH 5.5 in Set 1 and 6.25 in Set 2, and apparent desensitization of the protein severely reduced proton flux and amantadine sensitivity below pH 5.5 in both sets of experiments. Decreased external pH increased proton uptake with an apparent pKa of 6 (Set 1) or 6.5 (Set 2). These data indicate acid activation of M2(22-62) between pH 5.5-6, optimal amantadine block between pH 5.5-6.25, and a loss of peptide functionality between pH 5.9-4.7.

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BONANNO, SILVIA. "FM19G11 preserves blood-brain barrier structural and functional integrity by reducing astrocyte toxicity in a human-derived in vitro model of amyotrophic lateral sclerosis." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2019. http://hdl.handle.net/10281/241255.

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La Sclerosi Laterale Amiotrofica (SLA) è una patologia neurodegenerativa progressiva in cui le disfunzioni della barriera emato-encefalica (BEE) contribuiscono alla patogenesi e limitano significativamente lo sviluppo di nuove terapie. Gli astrociti di pazienti affetti da forme familiari e sporadiche di SLA rilasciano fattori solubili implicati nel danno della BEE e nell’aumento della P-glicoproteina (P-gp), la principale pompa dell’efflusso di farmaci espressa dalle cellule endoteliali nel cervello, responsabile dei fenomeni di progressiva farmacoresistenza nella SLA. Recentemente è stato dimostrato che FM19G11, un nuovo composto chimico, limita l’attivazione astrocitaria in un modello di lesione del midollo spinale, riducendo la risposta cellulare allo stress. Lo scopo di questa tesi era esaminare gli effetti del trattamento con FM19G11 sugli astrociti reattivi di pazienti SLA a livello della BEE. Abbiamo quindi realizzato un modello in vitro di BEE derivato da cellule staminali umane pluripotenti indotte (hiPSC) e composto da cellule endoteliali controllo (EC) in co-coltura con astrociti ottenuti da iPSC di un soggetto controllo, un paziente SLA familiare con mutazione SOD1-A4V e un soggetto con SLA sporadica. Gli astrociti venivano trattati con FM19G11 per 48h. Parallelamente, le cellule endoteliali erano coltivate su una membrana porosa all’interno di inserti affinchè formassero il monostrato della barriera. Dopo 48h il terreno di coltura degli astrociti veniva sostituito con nuovo terreno e gli inserti con le cellule endoteliali (rappresentanti il “lato del circolo ematico” della BEE) venivano trasferite al di sopra delle colture di astrociti ( il “lato encefalico” della BBB). Le co-colture, che garantivano la contiguità tra i surnatanti evitando il contatto diretto tra le diverse popolazioni cellulari, venivano protratte per 5 giorni. La formazione e l’integrità del monostrato di cellule endoteliali veniva valutato tramite: immunocitochimica per Zonula Occludens-1 (ZO-1), una delle principali proteine costituenti le giunzioni serrate presenti tra le cellule endoteliali nel cervello; misurazione della resistenza elettrica trans-endoteliale (TEER); analisi della permeabilità di fluoresceina sodica (NaF), una molecola solubile in acqua che attraversa la barriera solo tramite diffusione paracellulare, indicatore quindi dell’integrità delle giunzioni tra le cellule endoteliali. Al fine di valutare la presenza del fenomeni di farmacoresistenza, abbiamo misurato l’attività di trasporto di P-gp tramite l’efflusso di Rodamina (Rh123), un substrato specifico di P-gp. Inoltre, l’espressione di P-gp da parte delle cellule endoteliali è stata analizzata tramite immunocitochimica e immunofissazione. Per valutare le vie molecolari sottese alla modulazione delle cellule endoteliali abbiamo calcolato il rapporto tra espressione nucleare e citoplasmatica del fattore NF-kB tramite analisi di immunocitochimica. Inoltre, abbiamo analizzato, tramite specifiche metodiche fluorometriche, l’effetto di FM19G11 sui possibili mediatori dell’attivazione di NF-kB rilasciati dagli astrociti reattivi da pazienti SLA, le specie reattive dell’ossigeno (ROS) e il glutammato. Rispetto alle co-colture composte da astrociti non trattati, le cellule endoteliali coltivate con gli astrociti SOD1-A4V a sporadici trattati con FM19G11 hanno mostrato: ì) una maggiore resistenza, congrua con una minore permeabilità, del monostrato; ii) una ridotta espressione e funzione di efflusso di P-gp; iii) una ridotta attivazione di NF-kB, in linea con la minore produzione di ROS e glutammato da parte degli astrociti SOD1-A4V e sporadici trattati con FM19G11. FM19G11 mantiene l’integrità della BEE e riduce la sovra espressione di P-gp ,diminuendo la reattività astrocitaria, pertanto potrebbe essere considerato per futuri approcci terapeutici combinatoriali per la terapia della SLA. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease in which blood brain barrier (BBB) dysfunction contributes to the pathogenesis and significantly limits the development of successful therapies. Astrocytes from familial and sporadic ALS patients release soluble factors implicated in BBB injury and upregulation of P-glycoprotein (P-gp), the main multidrug efflux transporter in brain endothelial cells, responsible for progressive pharmacoresistance in ALS. Recently, FM19G11, a new chemical compound, was shown to counteract astrogliosis in a spinal cord injury model, decreasing cell stress response in the microenvironment. Specific objectives of this thesis were: i) to evaluate the potential effect of FM19G11 treatment on astrocyte-driven BBB dysruption and pharmacoresistance; ii) to identify ALS astrocyte molecular features targeted by FM19G11 compound. To this purpose, we set up a human induced pluripotent stem cells (hiPSCs)-derived BBB in vitro system composed of control iPS-endothelial cells (ECs), co-cultured with hiPSCs-derived astrocytes from control, familial SOD1-A4V and Sporadic ALS patients. Control and ALS-astrocytes were conditioned with FM19G11 500nM for 48h. In parallel, ECs were seeded on transwell porous membrane inserts, allowing to form the endothelial monolayer. After 48h, astrocyte culture medium was replaced with fresh medium, and ECs-inserts (representing the “blood side” of the BBB) were placed atop of the pre-treated astrocyte layer (representing the “brain side”). Co-cultures in the transwell culture system, which guaranteed supernatant interaction, avoiding cell contact, were maintained for 5 days. Formation and integrity of human iPSC endothelial monolayer were examined by: immunostaining for Zonula Occludens-1 (ZO-1), a major protein constituent of brain endothelial tight junctions (TJs); trans-endothelial electric resistance (TEER) assessment; sodium fluorescein (NaF) permeability assay, a water-soluble molecule that cross the BBB only through paracellular diffusion, thus being an indicator of endothelial cell-to-cell cohesion. In order to investigate pharmacoresistance occurrence, we determined P-gp transport activity by calculating Rhodamine 123 (Rh123), a P-gp specific substrate, efflux ratio. P-gP expression was assessed on endothelial monolayers by immunocytochemistry and western-blot analysis. To examine the molecular signaling underlying endothelial cells modulation, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) nuclear to cytoplasmic ratio was investigated by immunocytochemical expression analysis. Further, we examined FM19G11 effect on potential NF-kB upstream mediators released by reactive ALS astrocytes. Hence, astrocyte-derived reactive oxygen species (ROS) and glutamate levels in astrocyte conditioned medium were also measured by highly sensitive fluorometric approaches. Compared to co-cultures composed by untreated ALS-astrocytes, endothelial monolayers co-cultured with FM19G11-conditioned SOD1-A4V and sporadic astrocytes showed: i) an improvement in endothelial monolayer resistance, compatible with a decreased passive permeability across the BBB in vitro model; ii) a consistently lower P-gp expression and efflux activity; ììì) a reduced NF-kB activation, in line with the detected decreased ROS and glutamate production by FM19G11-treated SOD1-A4V and sporadic astrocytes. FM19G11 preserves BBB integrity, and restrains P-gP overexpression, by reducing cell stress factors released from familial SOD1-A4V and sporadic ALS astrocyte in a human-derived in vitro cell model. The outcome of our investigation suggests that FM19G11 is able to limit BBB dysfunction and could impact brain accessibility of therapeutics thus, it might be considered for future combinatorial therapeutic strategies for ALS.

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45

Lee, Anna Sunjin [Verfasser]. "Characterization of the embryonic kidney development in Danio rerio and functional analysis of Arl13b, Scorpion during embryonic development in Danio rerio / Anna Sunjin Lee." Kiel : Universitätsbibliothek Kiel, 2009. http://d-nb.info/1019868848/34.

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Ricci, Pierbruno. "The Renal Cysts and Diabetes syndrome : from transcriptional profiling and functional analysis of a novel mouse model to biomarkers evaluation in human patients." Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS111/document.

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Les mutations hétérozygotes du gène codant pour le facteur de transcription HNF1B sont à l'origine d'un syndrome multisystémique complexe connu sous le nom de « Renal Cysts and Diabetes » (RCAD). Un modèle de souris généré dans notre laboratoire s'est avéré reproduire plusieurs caractéristiques de la maladie humaine. Nous avons réalisé un séquençage ARNm-microARN à différents stades de développement (E14,5 ; E15,5 ; E17,5) de ce modèle. Nous avons montré que les gènes les plus dérégulés étaient impliqués dans les processus métaboliques de transport, de lipides et d’acides organiques et étaient exprimés dans les tubules proximaux et, dans une moindre mesure, dans l’anse de Henlé et les canaux collecteurs. Nous avons sélectionné quatre microARN (miR-802, 194-2, 192 et -30a), régulés à la baisse et potentiellement contrôlés par HNF1B. Des expériences de transactivation de gène rapporteur dans des cellules HEK-293 ont montré que HNF1B était capable de transactiver la transcription de ces microARN via des sites de liaison présents dans les séquences régulatrices de ces gènes. En utilisant des microARN MIMICS nous avons par la suite montré que mir-802, mir-194-2 et mir-192 étaient capables d'inhiber l’expression d’un gène rapporteur contenant la région 3'UTR de HNF1B. L'analyse d'échantillons d'urine de 22 patients RCAD et de 22 contrôles sains a permis d'identifier 146 peptides excrétés de manière différentielle et associés au syndrome. En utilisant ces résultats dans un modèle mathématique, classificateur prédit efficacement le syndrome RCAD avec une sensibilité de 91.7% et une spécificité de 91.1% sur une large population de patients Heterozygous mutations in the gene encoding the transcription factor HNF1B are the cause of a complex multisystem syndrome known as Renal Cysts And Diabetes (RCAD). A mouse model generated in our laboratory was shown to reproduce several features of the human disease. We performed high-throughput mRNA-microRNA sequencing at different developmental stages (E14.5, E15.5, E17.5). We showed that the most down-regulated genes were involved in transport, lipid and organic acid metabolic processes and expressed in proximal tubules and to a lesser extent in the loop of Henle and collecting ducts. We then selected four microRNAs (mir-802, 194-2, 192 and -30a), which were down-regulated and potentially controlled by HNF1B. Luciferase assays in HEK-293 cells showed that HNF1B was able to specifically transactivate in a dose response mode these microRNAs through binding HNF1B-binding sites in their regulatory promoter/enhancer upstream sequences. We subsequently showed by luciferase assays using miRNA MIMICS that mir-802, mir-194-2 and mir-192 were able to inhibit luciferase vectors containing the 3’UTR of Hnf1b. Analysis of urine samples from 22 RCAD patients and 22 healthy controls led to the identification of 146 peptides differentially excreted and associated with RCAD including a similarity regarding collagen and uromodulin fragments with the RCAD mouse model. Combining the peptides into a mathematical model we used independent cohorts of patients to validate the prediction of the RCAD syndrome. Our classifier efficiently predicted RCAD syndrome with 91.7% sensitivity and 91.1% specificity on a wide population

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47

McGregor, Lesley M. "An investigation into the functional and psychosocial impact of living organ donation." Thesis, University of Stirling, 2010. http://hdl.handle.net/1893/2338.

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General Abstract Objective: In April 2006, the Scottish Liver Transplant Unit (SLTU) became the first NHS transplant unit in the UK to offer the option of Living Donor Liver Transplantation (LDLT). This represented a unique opportunity to evaluate the functional and psychosocial impact of LDLT upon healthy donors and their recipients. Subsequent aims were to investigate the challenge of introducing LDLT in Scotland and to establish the perceived deterrents and attractions of the procedure. An additional aim was to evaluate the impact of Living Donor Kidney Transplantation (LDKT) upon donors and recipients. Design: A series of cross sectional and longitudinal studies were designed for the purpose of this thesis (3 quantitative, 2 qualitative, and 1 mixed methods). Method: Self report questionnaires were used in each of the quantitative studies, with the addition of neuropsychological computerized tests in two studies. Semi-structured interviews were employed in the qualitative studies. Main Findings: •Prior to its introduction general support for the option of LDLT was found, although it was highlighted that the risk involved was not well understood by the general public. •Since becoming available LDLT has not been a readily acceptable treatment option from the perspective of patients due to the perceived risk for the donor, but it may be considered as a “last option”. Family members were motivated to save their loved one’s life but the personal implications of donating resulted in reconsideration of LDLT. • Staff at the SLTU perceived a lack of family commitment in relation to LDLT, which is explained as a cultural factor contributing to the slow uptake of LDLT. In Scotland, a donation from a younger to an older generation is not easily accepted. This, in addition to patients’ optimism that a deceased donation will arrive, and the poor health of potential donors, is thought to have affected the uptake of LDLT. As has the unit’s conservative approach to the promotion of LDLT. This approach is the result of a perceived reduction in the need for LDLT and a preference to avoid the risk to a healthy donor and conduct transplants with deceased donations. • In over 3 years, only one couple completed LDLT. The recipient showed functional and psychosocial improvement from pre to post procedure, whilst the donor showed slight deterioration in aspects of quality of life 6 weeks post donation, which did not always completely return to a baseline level by 6 months. The donor made sacrifices to provide her husband with a fresh start to life and unmet expectations were found to effect quality of life. •Willingness to become a liver donor is not thought to be influenced by the frame of the information provided. •Like the LDLT donor, LDKT donors experience some functional and psychosocial deterioration at 6 weeks post donation, but donors largely recover by 6 months post donation. However, the anticipated benefit to recipients was not evident and may not be quantifiable until after 6 months post operation. Conclusion: This thesis has added to current knowledge on living organ donation and specifically represents the first psychological evaluation of a UK LDLT programme. The slow uptake of LDLT was unexpected and has resulted in informative, novel research.

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Domsch, Katrin [Verfasser], and Manfred [Akademischer Betreuer] Frasch. "Functional analysis of abba and mib2, two genes required for maintaining the integrity of muscle and sarcomeric structures in Drosophila melanogaster / Katrin Domsch. Betreuer: Manfred Frasch." Erlangen : Universitätsbibliothek der Universität Erlangen-Nürnberg, 2013. http://d-nb.info/1029869405/34.

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Samantaray, Sweta. "Analysing the role of the GEF Rom2 in cell wall integrity and significance of functional septa for echinocandin tolerance in the opportunistic pathogenic mold Aspergillus fumigatus." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-176604.

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Aspergillus fumigatus is a major opportunistic, filamentous fungal pathogen causing invasive aspergillosis (IA), a fatal systemic infection in immunocompromised patients with significant mortality rate. The fungal cell is protected by a rigid but highly dynamic cellular structure, the cell wall that forms the first level of defence against environmental stress. The cell wall being an essential and unique structure of the fungus has always been an ideal drug target. The major antifungal drugs used currently either target the fungal cell membrane or cell wall. However, due to the poor efficacy of current antifungal therapy, the CWI (cell wall integrity) pathway has emerged as the focus of research in recent years to discover potential molecular drug targets for designing antifungal therapy with novel mode of action. This signaling cascade is dedicated to monitoring and maintaining functional integrity of the cell wall, remodelling its structure in response to cell surface stress. This MAPK (mitogen activated protein kinase) cascade is highly coordinated to transduce the stress signals to the nucleus and consequently trigger necessary gene expression to counteract the stress. In this study, we explored the pivotal role of guanine nucleotide exchange factor (GEF), Rom2 in cell wall stress response and antifungal drug susceptibility. The findings of this work reveal that the Rom2 GEF is essential for viability of the pathogen. Additionally, characterization of a conditional rom2 mutant functionally links it to the previously identified CWI sensors, namely, Wsc1, Wsc3 and MidA in A. fumigatus. The conditional mutant shows severe growth defects under repressive conditions such as hyper-susceptibility to heat, Calcofluor white and Congo red, similar to the ∆midA mutant. Additionally, similar to the ∆wsc1, the rom2 mutant cultured under repressive conditions is increasingly susceptible to the actively used antifungal and inhibitor of cell wall β-1,3-glucan synthesis, echinocandin such as caspofungin. Furthermore, the Rom2 shows a sub-cellular localization similar to the Rho1 GTPase to hyphal tips and also physically interacts with the GTPase. Thus, these relevant findings establish the integral role of Rom2 as an intermediate relay molecule acting between the cell surface sensors and Rho1 GTPase as well as the downstream MAPK module. This study also reports a novel mechanism imparting echinocandin tolerance to the pathogen. This work explores two possibilities that may explain the fungistatic nature of echinocandins against Aspergillus: one either owing to incomplete inhibiton of β-1,3-glucan synthesis or that the cell wall β-1,3-glucan is not essential for A. fumigatus viability. In order to evaluate the role of the β-1,3-glucan synthase subunit, Fks1 in viability, growth and antifungal response of the mold, a conditional fks1 mutant was generated. Downregulation of fks1 expression results in characteristic growth behaviour which phenocopies the effect of wild type treated with echinocandins. The mutant cultured under repressive growth conditions also displays significant decrease in cell surface β-1,3-glucan and enhanced galactomannan shedding, marked with a compensatory increase in chitin content. Importantly, the growth of the conditional fks1 mutant is not completely abolished in presence of echinocandin and an fks1 deletion mutant is surprisingly viable. These results strongly reflect that β-1,3-glucan is not essential in A. fumigatus, and thereby justifies the limited activity of β-1,3-glucan synthesis inhibitor echinocandin on the mold. The novel findings of the work also suggest that presence of septa is an essential means of survival for A. fumigatus upon echinocandin treatment. Compounds inhibiting septum formation exhibit significant synergism with the echinocandin caspofungin. Thus, the present study identifies and proposes that septum inhibition is a promising strategy for enhancing echinocandin fungicidal potency and improving existing antifungal therapy.

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MARIGGIO', GREGORIO. "A novel functional coating and a reliable design approach to fully exploit the strength of annealed glass." Doctoral thesis, Politecnico di Torino, 2022. http://hdl.handle.net/11583/2971516.

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Dissertations / Theses on the topic 'Functional integrity of the kidney'

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