Le remodelage osseux est un phénomène finement régulé selon la balance de formation et de résorption osseuse. La régulation de la résorption osseuse se fait principalement par l'apoptose des ostéoclastes. Nous avons démontré auparavant que plusieurs facteurs comme TRAIL, FASL et TGF-[bêta]1 induisent l'apoptose des ostéoclastes humains. Par contre, nous ne connaissons pas l'effet de l'OPG sur l'apoptose ostéoclastique en plus de ne pas connaître les mécanismes impliqués dans la mort cellulaire induite par le TGF-[bêta]1 chez les ostéoclastes. Afin de vérifier ces effets, nous avons utilisé une culture primaire d'ostéoclastes humains produite à partir de monocytes de sang de cordon ombilical. Ces ostéoclastes sont différenciés à l'aide du M-CSF et du RANKL. L'OPG est un membre de la famille des récepteurs du TNF. L'OPG est un récepteur soluble pour RANKL et pour TRAIL. Nous avons démontré que l'OPG permettait de diminuer l'apoptose des ostéoclastes cultivés dans un milieu sans M-CSF et sans RANKL. Cette baisse surprenante de la mort a été expliquée par une augmentation d'expression de TRAIL par les ostéoclastes lorsque ceux-ci sont cultivés en absence de ses facteurs de survie (M-CSF et RANKL). L'OPG agit sur l'apoptose en séquestrant le TRAIL produit par les ostéclastes [ostéoclastes] empêchant ainsi l'induction de l'apoptose par le TRAIL des ostéoclastes environnants. Ceci en fait un mécanisme de régulation autocrine de la survie des ostéoclastes lors du remodelage osseux. De plus, nous avons aussi démontré un mécanisme expliquant l'apoptose des ostéoclastes par le TGF-[bêta]1. Nous avons premièrement démontré la présence des récepteurs de type I et II à la surface des ostéoclastes proposant une action directe du TGF-[béta]1. Par la suite, nous avons démontré que le TGF[bêta]1 induisait une activation de la caspase 9 objectivant ainsi une apoptose par la voie mitochondriale. Cette activation de l'apoptose par la voie intrinsèque serait le résultat de l'activation de la voie de p38 des MAPK et de la voie des Smad suivie par une augmentation de l'expression des homologues de Bcl-2 pro-apoptotiques Box et Bim. En sachant que le TGF-[béta]1 peut être libéré et activé de la matrice osseuse lors de la résorption, l'induction de l'apoptose des ostéoclastes par ce facteur de croissance en fait un autre mécanisme de régulation du remodelage osseux.

Primary human hepatocytes are a scarce resource with variable function, which diminishes with time in culture. As a consequence their use in tissue modelling and therapy is restricted. Human embryonic stem cells (hESCs) could provide a stable source of human tissue due to their properties of self-renewal and their ability to give rise to all three germ layers. hESCs have the potential to provide an unlimited supply of hepatic endoderm (HE) which could offer efficient tools for drug discovery, disease modelling and therapeutic applications. In order to create a suitable environment to enhance HE formation, hESC culture needed to be standardised. As such, a media trail was carried out to define serum free media capable of maintaining hESC in a pluripotent undifferentiated state. We also ensured hESC cultured in the various media could be directly differentiated to HE in a reproducible and efficient manner. The project then focused on the effect of post-translational modifications (PTMs), specifically SUMOylation, in hepatocyte differentiation and its subsequent manipulation to enhance HE viability. SUMOylation is a PTM known to modify a large number of proteins that play a role in various cellular processes including: cell cycle regulation, gene transcription, differentiation and cellular localisation. We hypothesised that SUMO modification may not only regulate hESC self renewal, but also maybe required for efficient hESC differentiation. We therefore interrogated the role of SUMOylation in hESC differentiation to hepatic endoderm (HE). hESC were differentiated and the cellular lysates were analysed by Western blotting for key proteins which modulate the conjugation and de conjugation of SUMO. We demonstrate that peak levels of SUMOylation were detectable in hESC populations and during cellular differentiation to definitive endoderm (DE), day 5. Following commitment to DE we observed a decrease in the level of SUMO modified proteins during cellular specialisation to a hepatic fate, corresponding with an increase in SENP 1, a SUMO deconjugation enzyme. We also detected reduced levels of hepatocyte nuclear factor 4 α (HNF4α), a critical regulator of hepatic status and metabolic function, as SUMOylation decreased. As a result, we investigated if HNF4α was SUMOylated and if this process was involved in modulating HNF4α’s critical role in HE. HNF4α is an important transcription factor involved in liver organogenesis during development and is a key regulator for efficient adult liver metabolic functions. We observed a decreasing pattern of HNF4α expression at day 17 of our differentiation protocol in conjunction with a decrease in SUMO modified proteins. In order to further investigate and validate a role of SUMOylation on HNF4α stability Immunoprecipitation (IP) was employed. HNF4α protein was pulled down and probed for SUMO 2. Results show an increase in the levels of SUMO2 modification as the levels of HNF4α decrease. Through deletion and mutation analysis we demonstrated that SUMO modification of HNF4α was restricted to the C-terminus on lysine 365. Protein degradation via the proteasome was responsible for the decrease in HNF4α, demonstrated by the use of a proteasome 26S inhibitor MG132. Additionally, a group at the University of Dundee has shown that polySUMOylation of promyelocytic leukaemia protein (PML) leads to its subsequent ubiquitination via RNF4, an ubiquitin E3 ligase, driving its degradation. Using an in vitro ubiquitination assay, we show that polySUMOylated HNF4α is preferentially ubiquitinated in the presence of RNF4. Overall polySUMOylation of HNF4α may reduce its stability by driving its degradation, hence regulating protein activity. In conclusion, polySUMOylation of HNF4α is associated with its stability. HNF4α is subsequently important for HE differentiation both driving the formation of the hepatocytes and in maintaining a mature phenotype, in agreement with a number of different laboratories. Creating the ideal environment for sustaining mature functional hepatocytes, primary and those derived from hESCs and iPSCs, is essential for further use in applications such as drug screening, disease modelling and extracorporeal devices.

We present a calculation of vector and axial-vector form factors for each of the octet hyperon semi-leptonic transition matrix elements by using the techniques of lattice QCD where simulations were performed with Nf = 2 + 1 flavours of dynamical O(a)-improved Wilson fermions. We also study the electromagnetic form factors, axial charges and other properties of octet baryons. Errors due to extrapolation to zero transferred momentum are reduced by applying a twist to the boundary conditions on the lattice. Our form factor results compare favourably with experiment and other lattice QCD determinations. By considering an expansion about the SU(3)-flavour symmetric limit we seek to investigate and quantify the symmetry breaking effects in these matrix elements due to the mass splitting between the strange and light quarks. We find good agreement with the Ademollo-Gatto theorem for the vector form factor, a measurable amount of breaking in the axial-vector form factor and significant effects in the weak magnetism form factor. Knowledge of the parameterisation of SU(3)-flavour symmetry breaking allows for a series of constrained fits to be made to the form factor results which are used to arrive at a 'baryonic' estimation of the Cabibbo-Kobayashi-Maskawa matrix element |Vus|.

Epithelial-mesenchymal transition (EMT) is an evolutionarily conserved process during which cells lose epithelial characteristics and gain a migratory phenotype. Although downregulation of epithelial cadherins by Snail and other transcriptional repressors is generally considered a prerequisite for EMT, recent studies have challenged this view. Here we investigate the relationship between E-cadherin and P-cadherin expression and localization, Snail function and EMT during gastrulation in chicken embryos. Expression analyses show that while E-cadherin transcripts are detected in the epiblast but not in the primitive streak or mesoderm, P-cadherin mRNA and protein are present in the epiblast, primitive and mesoderm. Antibodies that specifically recognize E-cadherin are not presently available. During EMT, P-cadherin relocalizes from the lateral surfaces of epithelial epiblast cells to a circumferential distribution in emerging mesodermal cells. Cells electroporated with an E-cadherin expression construct undergo EMT and migrate into the mesoderm. An examination of Snail function showed that reduction of Slug (SNAI2) protein levels using a morpholino fails to inhibit EMT, and expression of human or chicken Snail in epiblast cells fails to induce EMT. In contrast, cells expressing the Rho inhibitor peptide C3 rapidly exit the epiblast without activating Slug or the mesoderm marker N-cadherin. Together, these experiments show that epiblast cells undergo EMT while retaining P-cadherin, and raise questions about the mechanisms of EMT regulation during avian gastrulation.

Human adenoviruses (HAdVs) are common viruses often associated withgastrointestinal, ocular and respiratory infections. They can infect a widevariety of cells, both dividing and non-dividing. HAdVs attach to and infecttarget cells through interactions with cellular receptors. It has also beenshown that HAdVs can use soluble host components in body fluids forindirect binding to target cells, a feature that enables the usage of new typesof receptors resulting in a more efficient HAdV infection. We thereforeevaluated the influence of soluble components from four different bodyfluids on HAdV infection of epithelial cells, representing the respiratory andocular tropism of most HAdVs. We found that plasma, saliva, and tear fluidpromote binding and infection of HAdV-5 (species C) and that plasmapromotes infection of HAdV-31 (species A). Further binding and infectionexperiments identified coagulation factor IX (FIX) and X (FX) as thecomponents of plasma responsible for increase of HAdV-5 infection whileFIX alone mediates increase of HAdV-31 infection. We found that as little as1% of the physiological concentration of these factors is required to facilitatemaximum binding. The effect of coagulation factors on HAdV infection was thereafterextended to include all species A HAdVs: HAdV-12, -18 and -31. Species AHAdVs normally cause infections involving the airways and/or the intestine.These infections are often mild but species A HAdVs in general, and HAdV-31 in particular, have been shown to cause severe and life-threateninginfections in immunocompromised patients. We show here that FIXefficiently increase HAdV-18 and -31 (but not HAdV-12) binding andinfection of human epithelial cells, representing the respiratory andgastrointestinal tropism. FIX was shown to interact with the hexon proteinof HAdV-31 and surface plasmon resonance analysis revealed that theHAdV-31:FIX interaction is slightly stronger than that of the HAdV-5:FIX/FX interactions, but more interestingly, the half-lives of theseinteractions are profoundly different. By performing binding and infectionexperiments using cells expressing specific glycosaminoglycans (GAGs) and ivGAG-cleaving enzymes we found that the HAdV-31:FIX and HAdV-5:FIX/FX complexes bind to heparan sulfate-containing GAGs on targetcells, but we could also see a difference in GAG dependence and specificitybetween these complexes.We conclude that the use of coagulation factors might be of moreimportance than previously recognized and that this may affect not only theliver tropism seen when administering adenovirus vectors into thecirculation but also regulate primary infections by wild-type viruses of theirnatural target cells. We also believe that our findings may contribute tobetter design of HAdV-based vectors for gene and cancer therapy and thatthe interaction between the HAdV-31 hexon and FIX may serve as a targetfor antiviral treatment. HAdV vectors are mainly based on HAdV-5 and several problems haverecently become evident when using these vectors. Major challenges withHAdV-5 based vectors include pre-existing neutralizing antibodies, pooraccess to the receptor CAR (coxsackie and adenovirus receptor), and offtarget effects to the liver due to interactions with coagulation factors. Theneed for new HAdV vectors devoid of these problems is evident.HAdV-52 is one of only three HAdVs that are equipped with two differentfiber proteins, one long and one short. We show here, by means of bindingand infection experiments, that HAdV-52 can use CAR as a cellular receptor,but that most of the binding is dependent on sialic acid-containingglycoproteins. Flow cytometry, ELISA and surface plasmon resonanceanalyses revealed that the terminal knob domain of the long fiber (52LFK)binds to CAR, and the knob domain of the short fiber (52SFK) binds tosialylated glycoproteins. X-ray crystallographic analysis of 52SFK in complexwith sialic acid revealed a new sialic acid binding site compared to otherknown adenovirus:glycan interactions. Moreover, glycan array analysisidentified α2,8-linked oligosialic acid, mimicking the naturally occurringpolysialic acid (PSia), as a potential sialic acid-containing glycan receptor for52SFK. ELISA and surface plasmon resonance confirmed the ability of52SFK to interact with PSia. Flow cytometry analysis also showed a fivefold vincrease in binding of 52SFK to PSia-expressing cells compared to controlcells. X-ray crystallographic analysis of 52SFK in complex with oligo-PSiarevealed engagement at the non-reducing end of oligo-PSia to the canonicalsialic acid-binding site, but also suggested the presence of a 'steering rim'consisting of positively charged amino acids contributing to the contact bylong-range electrostatic interactions. PSia is nearly absent on cells in healthy adults but can be expressed inhigh amounts on several types of cancers including: glioma, neuroblastomaand lung cancer. We show here that the short fiber of HAdV-52 bindsspecifically to PSia. Taking into account that HAdV-52 has a supposedly lowseroprevalence and is incapable of interacting with coagulation factors webelieve that HAdV-52 based vectors can be useful for treatment of cancertypes with elevated PSia expression.

No description available.

The a of TNFa in title is the Greek alpha. / Thesis (MSc)--University of Stellenbosch, 2002. / ENGLISH ABSTRACT: Background: Cardiac hypertrophy is an adaptive process occurring in response to mechanical overload or tissue injury. The stimuli for cardiac hypertrophy are diverse and vary from increased afterload on the heart to cardiac remodeling in response to cytokines. Amongst others, obesity is characterized by excessive body weight resulting in metabolic disorders. This excess body weight necessitates an increased blood and oxygen delivery to the peripheral tissues, which is achieved by an elevated cardiac output. Total blood volume is also increased in the obese due to the increased tissue volume and vascularity. With time, the obesity induced increase in cardiac preload results in left ventricular hypertrophy and dilatation. Obesity is also associated with complications such as hypertension, insulin resistance and impaired glucose metabolism. In addition, adipose tissue has been implicated to contribute to elevated circulating TNFa levels in obesity and may contribute to the pathophysiology of the heart in obese individuals. The heart is a major cytokine-producing organ that generates amongst others tumor necrosis factor a (TNFa). TNFa is a proinflammatory cytokine, which acts to increase its own production, has cytotoxic and cytostatic effects on certain tumor cells and influences growth and differentiation in virtually all cell types including cardiomyocytes. Elevated levels of TNFa are detected peripherally in almost all forms of cardiac injury and in hypertrophic cardiomyopathy. These elevations are proposed to be deleterious to the heart, although an adaptive role for low levels of TNFa has been proposed. Aim: The aim of the study was to determine whether there is a correlation between obesity and serum, myocardial, and adipose tissue TNFa levels and cardiac hypertrophy. We also wished to determine whether the hearts from the obese animals functioned normally under normoxic conditions and whether they responded differently to ischaemia/reperfusion when compared with their concurrent controls. Materials and Methods: Male Sprague-Dawley rats (n=100) were fed a high caloric diet (HCD) containing 33% rat chow, 33% condensed milk, 7% sucrose and 27% water, or standard laboratory rat chow for 6-12 weeks. Food consumption, body weight gain, heart weight and tibia length were measured. Serum glucose, insulin and lipid levels were also determined. Hearts were excised and perfused on the isolated Working Heart perfusion apparatus and cardiac function was monitored and documented. Hearts were then subjected to 15 minutes of total global ischaemia at 370C, and reperfused for 30 minutes. Cardiac function was again documented. A separate series of hearts were freeze-clamped at different time points during the experimental protocol and stored in liquid nitrogen for the determination of myocardial TNFa and cGMP levels. Serum TNFa levels were determined after 12 weeks on the high caloric or normal/control diet. After 12 weeks on the diet myocardial TNFa levels of the HCD fed animals and their concurrent controls were determined before and during ischaemia. Adipose tissue and myocardial tissue TNFa levels were also determined after 6, 9 and 12 weeks on the respective diets. Myocardial cGMP levels were measured in the HCD fed rats and the control rats after 6, 9, and 12 weeks. These data were used as an indirect index to determine whether the myocardial NOcGMP pathway was activated in the normoxic hearts on the respective diets. Results: The body weight of the HCO fed animals was significantly higher compared with their respective controls after 12 weeks on the diet (459.9 ± 173.8 g and 271.5 ± 102.6 g respectively (p<0.05». The HCO fed animals also had heart weight to body weight ratios that were significantly greater compared with the controls (4.2 ± 0.1 mglg and 3.7 ± 0.1 mglg respectively (p<0.05». The plasma glucose levels of the HCO fed animals were higher than their respective controls (9.2 ± 0.3 mmoiII and 7.8 ± 0.3 mmoiII respectively (p<0.05)), but their insulin levels were similar (12.87 ± 1.02 IlIUlml and 12.42 ± 5.06 IlIU/ml). Plasma lipid profiles (plasma cholesterol, high density lipoprotein (HOL) cholesterol and plasma triacylglyceride (TAG)) were abnormal in the HCO fed animals compared with the control rats. Plasma TAG levels in the HCO fed animals were significantly higher compared with the control rats (0.664 ± 0.062 mmoiII and 0.503 ± 0.043 (p<0.05», while plasma cholesterol levels (1.794 ± 0.058 mmoIII and 2.082 ± 0.062 mmoiII (p<0.05» and HOL cholesterol levels were significantly lower (1.207 ± 0.031 mmoiII and 1.451 ± 0.050 mmoiII (p<0.05». Cardiac mechanical function was similar for both groups before ischaemia, but the percentage aortic output recovery was lower for the hearts from the HCO fed animals when compared with their controls (47.86 ± 7.87% and 66.67 ± 3.76 % respectively (p<0.05». Serum TNFa levels of the HCO fed animals were higher compared with the control animals (51.04 ± 5.14 AU and 31.46 ± 3.72 AU respectively (p<0.05», but myocardial TNFa levels remained lower in these animals (312.0 ± 44.7 pglgram ww and 571.4 ± 132.9 pg/gram ww respectively (p<0.05)). During ischaemia these myocardial TNFa levels increased above those of the controls (442.9 ± 12.4 pg/gram ww and 410.0 ± 12.5 pg/gram ww respectively (p<0.05)). The adipose tissue TNFa levels were significantly increased after 12 weeks on the high caloric diet compared with the control animals (4.4 ± 0.4 pg/gram ww and 2.5 ± 0.3 pg/gram ww respectively (p<0.05)). There was no significant difference in the myocardial cGMP levels of the HCD rats compared with the conrol rats after 6, 9 and 12 weeks. Conclusion: 1) The high caloric diet induced obesity, which lead to cardiac hypertrophy in this study. 2) There was a strong correlation between elevated adipose tissue and serum TNFa levels, and cardiac hypertrophy. 3) Elevated serum TNFa levels did not lead to activation of the myocardial NO-cGMP pathway in the normoxic hearts in this model. 4) The hypertrophied hearts from the HCD fed animals had poorer post-ischaemie myocardial functions than their concurrent controls. / AFRIKAANSE OPSOMMING: Agtergrond: Miokardiale hipertrofie is In aanpassing wat gebeur as In gevolg van meganiese oorbelading of weefsel beskadiging. Verskillende stimuli kan tot miokardiale hipertrofie aanleiding gee soos byvoorbeeld In verhoging in nalading, of miokardiale hermodellering in respons op sitokiene. Verhoging van voorbelading in vetsug mag ook tot hipertrofie aanleiding gee. Vetsug word gekenmerk deur In oormatige liggaamsmassa wat tot metaboliese versteurings lei. Die oormatige liggaamsmassa vereis In verhoging in bloed- en suurstofverskaffing aan die perifere weefsel wat deur In verhoging in die kardiale uitset vermag kan word. Die bloed volume van In vetsugtige individu word ook verhoog as gevolg van In verhoging in weefselvolume en vaskulariteit en met verloop van tyd induseer die verhoogde kardiale voorbelading linker ventrikulêre hipertrofie en dilatasie. Vetsug word ook met verskeie ander siekte toestande soos hipertensie, insulien weerstandigheid en versteurde glukose metabolisme, geassosieer. Vetweefsel dra ook by tot verhoging van tumor nekrose faktor alfa (TNFa) vlakke in die bloed, wat op sy beurt tot miokardiale hipertrofie mag bydra. TNFa is In proinflammatoriese sitokien wat sy eie produksie kan stimuleer. Dit het ook sitotoksiese en sitostatiese effekte op sekere tumor selle en kan groei en differensiasie in bykans alle seltipes, insluitende kardiomiosiete, stimuleer. Die hart kan ook TNFa produseer en verhoogde TNFa vlakke word feitlik in alle vorms van miokardiale besering en hipertrofiese kardiomiopatie waargeneem. Daar word voorgestel dat verhoogde TNFa vlakke vir die hart nadelig is, ten spyte van die vermoeding dat die sitokien In potensiële aanpassings rol by laer vlakke het. Doelstelling: Die doel van hierdie studie was om vas te stelof daar 'n verband tussen vetsug en serum, miokardiale en vetweefsel TNFa vlakke en miokardiale hipertrofie, bestaan. Ons het ook gepoog om te bepaal of harte van vetsugtige diere normaal funksioneer en of die response van sulke harte op isgemie-herperfusie van die van ooreenstemmende kontroles verskil. Materiaal en tegnieke: Manlike Sprague-Dawley rotte (n=100) is vir 6-12 weke op 'n hoë kalorie dieët (HKD) geplaas. Die HKD het uit 33% rotkos, 33% gekondenseerde melk, 7% sukrose en 27% water bestaan. Kontrole diere het standaard laboratorium rotkos ontvang. Voedselinname, liggaamsmassa toename, serum insulien, glukose en lipied vlakke is ook bepaal. Harte is geïsoleer en geperfuseer volgens die Werk Hart perfusie metode en hart funksie is gemonitor en gedokumenteer. Harte is vervolgens aan 15 minute globale isgemie by 3rC blootgestel en daarna weer vir 30 minute geherperfuseer waartydens hartfunksie weer gedokumenteer is. 'n Aparte groep harte is op spesifieke tydsintervalle gedurende die eksperimentele protokol gevriesklamp en in vloeibare stikstof gestoor vir die bepaling van miokardiale TNFa en sGMP vlakke. Serum TNFa vlakke is bepaal na 12 weke op die dieët. Na die diere 12 weke op die HKD was, is hierdie diere en hulooreenstemmende kontroles se miokardiale TNFa vlakke voor en na isgemie bepaal. Vetweefsel en miokardiale TNFa vlakke is ook onderskeidelik na 6, 9 en 12 weke bepaal. Miokardiale sGMP vlakke is in die HKD diere en in die kontrole diere na 6, 9 en 12 weke bepaal. sGMP vlakke is gebruik as 'n indirekte indeks van aktivering van die miokardiale NO-sGMP boodskapper pad. Resultate: Na 12 weke op die dieët was die liggaamsmassa van die HKD diere beduidend hoër in vergeleke met hulooreenstemmende kontroles (459.9 ± 173.8 g en 271.5 ± 102.6 g (p<0.05)). Die HKD diere se hart massa tot liggaam massa verhouding was ook beduidend hoër in vergelyking met die van kontroles (4.2 ± 0.1 mglg en 3.7 ± 0.1 mglg (p<0.05)). Alhoewel insulien vlakke dieselfde was (12.42 ± 5.06 j.lIU/ml en 12.87 ± 1.02 j.lIU/ml), was serum glukose vlakke van die HKD diere hoër as die van die ooreenstemmende kontroles (9.2 ± 0.3 mmoiii en 7.8 ± 0.3 mmoiii (p<0.05)). Plasma lipied profiele (HOL cholesterol, plasma cholesterol en trigliseriede) was abnormaal in die HKD diere. Plasma TAG vlakke in die HKD diere was beduidend hoër as die van die kontroles (0.664 ± 0.062 mmoiii en 0.503 ± 0.043 (p<0.05)), terwyl plasma cholesterol vlakke (1.794 ± 0.058 mmoiii en 2.082 ± 0.062 mmoiii (p<0.05)) en HOL cholesterol vlakke beduidend laer was (1.207 ± 0.031 mmoiii en 1.451 ± 0.050 mmoiii (p<0.05)). Miokardiale meganiese funksie was dieselfde vir beide groepe voor isgemie, maar die persentasie aorta omset herstel tydens herperfusie was laer in die HKD diere in vergelyking met die van kontrole diere (47.86 ±. 7.87% en 66.67 ± 3.76% (p<0.05)). Serum TNFa vlakke van die HKD diere was beduidend hoër as die van kontrole diere (51.04 ± 5.14 AU en 31.46 ± 3.72 AU (p<0.05)), maar miokardiale TNFa vlakke was laer (312.0 ± 44.7 pglgram nat gewig en 571.4 ± 132.9 pglgram nat gewig (p<0.05)). Die vetweefsel TNFa vlakke was ook beduidend verhoog na 12 weke op "n hoë kalorie dieët wanneer dit vergelyk word met die van kontrole diere (4.4 ± 0.4 pglgram nat gewig en 2.5 ± 0.3 pglgram nat gewig respektiewelik (p<0.05)). Daar was geenbeduidende verskille in die miocardiale vlakke van sGMP in die HKD diere in vergelyking met die kontroles na 6, 9 en 12 weke. Gevolgtrekkings: 1) "n Hoë kalorie dieët het in dié studie vetsug geïnduseer en tot miokardiale hipertrofie gelei. 2) Daar was "n positiewe korrelasie tussen verhoogde vetweefsel en serum TNFa vlakke, en miokardiale hipertrofie. 3) Verhoogde serum TNFa vlakke het nie tot die aktivering van die miokardiale NO-sGMP pad in hierdie model gelei nie. 4) Die hipertrofiese harte het tydens herperfusie ná isgemie swakker as hulooreenstemmende kontroles gefunksioneer.

published_or_final_version / Zoology / Doctoral / Doctor of Philosophy

published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Medical Sciences / Master / Master of Medical Sciences