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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.

The taxonomy of Terminalia (Combretaceae) and related genera

Al-Mayah, Abdul-Ridha Akber Alwan January 1983 (has links)
No description available.

Cytoskeletal regulation of endothelial polarisation and apical specification

Richards, Mark D. January 2015 (has links)
During developmental growth, tissue repair and disease the vasculature is remodelled and expanded through the process of angiogenesis to enhance oxygen and nutrient supply. Sprouting angiogenesis is the principal mechanism by which this occurs and takes place following the activation of endothelial cells (ECs) and surrounding pericytes by pro-angiogenic signals. Subsequent degradation of the basement membrane and invasion of ECs into the surrounding extracellular matrix leads to the formation of an angiogenic sprout that forms contacts with neighbouring vessels and undergoes lumen formation and stabilisation to produce a functional vessel through which blood can flow. This process requires dramatic changes in EC polarity and shape that is orchestrated by a highly dynamic cytoskeleton. Previous work from our lab identified the formin FMNL3 as an important regulator of sprouting angiogenesis. The mechanistic understanding of FMNL3s function in this process is however poorly understood. Through the use of in vitro assays of endothelial migration and polarity FMNL3 was found to be important for the reorientation of cell polarity during endothelial migration. Following the formation of an angiogenic sprout ECs need to become less invasive and reorient their polarity along their apical-basolateral axis to allow lumen formation. The function of FMNL3 in endothelial polarisation during migration led to the investigation of a role for FMNL3 in apical-basolateral polarisation. FMNL3 was found to be required for the localisation of the protein Podocalyxin-like 1 (PODXL) to the apical surface of ECs through the assembly and remodelling of endothelial apical actin filaments. This function of FMNL3 was found to occur downstream of RhoJ. PODXL associates with apical actin filaments and is transported along it through Myosin Vb and Rab25. PODXL is important for specification of the apical surface prior to lumen formation and this study identifies FMNL3 as an important protein in the localisation of PODXL to the apical membrane through regulation of the endothelial cytoskeleton.

Study of a mouse model for the oromandibulo-facial limb hypogenesis (OMFL) syndrome following chorionic villus sampling

Chang, Han-Hsin Judy January 1998 (has links)
A mouse model has been established to investigate the teratogenic effects of amniotic sac puncture (ASP) performed during a similar period during gestation when chorionic villus sampling (cvs) would normally be carried out clinically. Many genes are expressed temporally and spatially in the interdigital zone during limb morphogenesis, and may play a key role of triggering the pre-set program within these areas. Of the latter, msx-1 is believed to maintain the proliferative and undifferentiated status of cells in the interdigital zones as well as being associated with the control of programmed cell death that occurs in these areas. Detection of the expression of msx-1 in the interdigital zones at intervals after ASP confirmed that this gene is upregulated in this area in the experimental autopods by 4h after ASP, and that this is accompanied by evidence of epithelial hypertrophy. This study demonstrated that msx-1 maintains the cells in the interdigital zones in a proliferative and undifferentiated state, as has been hypothesized by others, perhaps partly due to interference with epithelial-mesenchymal interaction. When Halothane, instead of Avertin was used as the anaesthetic during ASP, we have speculated that this could not only dramatically <I>reduce </I>the recovery time, but also improve the embryonic/fetal circulation to the autopod after ASP. Although similar overall rates of abnormalities were observed, the incidence of <I>syndactyly </I>was highly significantly reduced. This supported our hypothesis that venous stasis along with vascular disruption in the distal extremities may abolish the normal pre-set programs in the interdigital zones and influence the type of limb defects observed. In summary, if inadvertent rupture of the amnion occurs during the cvs procedure, fetal/embryonic venous stasis could occur as a secondary consequence of the compression of the embryo/fetus by uterine muscles and extraembryonic membranes. The induction of a similar range of limb defects in our mouse model to those observed clinically following cvs were investigated in this study. In addition, vascular disruption in the limbs following ASP was observed histologically, and it is suspected that this may be closely associated with the induction of syndactyly which was observed in more than 37% of the cases in this model.

The role of p53 in the embryonic stem cell response to DNA damage

Corbet, Sula Wendeline January 1999 (has links)
The hypothesis that p53 deficiency enhances survival of DNA-damage bearing cells was investigated in embryonic stem (ES) cells with inactivation of one or both endogenous <I>p53</I> genes. ES cells were treated with a variety of DNA-damaging agents including UV light, γ-radiation and the topoisomerase I and II inhibitors, camptothecin and etoposide. Both topoisomerase inhibitors rapidly induced high levels of apoptosis in wild-type ES cells resulting in loss of most of the cell population within 48 hours. Consistent with results previously obtained from other cell types, the apoptotic response to etoposide was found to be p53-dependent at low doses but at the highest dose used p53-independent pathways became evident. Following UV-C irradiation, p53-protein was rapidly induced in wild-type cells and p53-dependent apoptosis followed within 8 hours, leading to death of the majority of cells within 36 hours. Treatment with ionising radiation led to enhanced expression of p53 but resulted in little induction of apoptosis irrespective of p52 status. Evasion of apoptosis in the short term does not necessarily imply a continued capacity for growth and therefore long term survival, measured by clonogenic potential, was also examined. Following both UV and γ-irradiation, clonogenic survival of <I>p53</I>-null cells was significantly higher than survival of wild-type cells, particularly after high levels of DNA-damage where survival was enhanced more than ten-fold. The data confirm that p53 restricts the numbers of cells bearing mutations that survive DNA damage induced by either agent, albeit by mechanisms that differ.

Molecular mechanisms of +TIPs in axonal extension

Beaven, Robin January 2013 (has links)
During development of the nervous system axons must extend to their specific target cells,such as other neurons or muscles, in order to connect into the functional networks that formthe basis of brain function. Due to the high precision required, this process is susceptible toperturbations which cause a host of neurodevelopmental disorders including forms of mentalretardation. Furthermore, many of the same mechanisms which drive axon growth arereiterated during axon regeneration following injury, stroke or degeneration. Axon extension is performed by growth cones (GCs) at the tip of the extending axons,guided to their targets through extracellular signals. Intracellularly, the cytoskeletal machinerydrives the morphogenetic processes implementing GC behaviour. Whereas F-actinpredominantly regulates the directionality of axon growth, microtubules (MTs) essentiallyimplement axon extension, and sustain the structural integrity of axons and the transportbetween soma and GCs. Therefore, an important aim of axon growth research is to understandhow MT networks are regulated. This is the overarching objective of my project. MT-binding proteins (MTBPs) interact with MTs, with one another and with F-actin,thus forming complex regulatory networks. This complexity can be tackled with efficientgenetic approaches possible in the fruit fly Drosophila, using its well established axon growthreadouts in vivo complementary to the high resolution readouts for cytoskeleton in culturedprimary neurons. I focussed my work on a specific class of MTBPs, so called +TIP, whichbind to the polymerising plus ends of MTs to regulate their dynamics, a process thatessentially contributes to MT network formation and organisation. To be able to carry out my project, I first optimised the use of the culture system. Iestablished approaches to assess MT network organisation, and MT dynamics. My initialstudies showed that fundamental properties of MT networks are highly conserved betweenvertebrates and Drosophila. I used these new approaches to contribute to ongoing work onfunctions of the actin-MT linker Shot during axon growth. I demonstrated novel roles of Shotin regulating MT polymerisation dynamics and guidance which simultaneously validated thenewly established imaging strategies. I then carried out a systematic analysis of thelocalisation patterns of different +TIPs (CLASP, CLIP, APC1, APC2, p150glued and Lis1)which I found to be highly conserved with patterns of their vertebrate homologues describedin the literature. I then used loss of function analyses identified promising axonal growthphenotypes to be used in my further study. I selected CLIP-190 as a promising candidate because of its prominent localisation inGCs and its strong mutant axon overgrowth phenotype. Well into my studies, further testsunfortunately revealed the axon growth phenotype to be due to loss of the neighbouring gene,Lrch, an actin-binding protein for which my experiments revealed a putative role in MTregulation downstream of F-actin networks. Meticulous loss of CLIP-190 analyses, includingdouble- and triple mutant combinations with all of the above +TIP members, failed to revealany neuronal phenotypes in primary neurons. Neither did CLIP-190 loss show axon growth orNMJ phenotypes in vivo. Accordingly, in neurons CLIP-190 is tethered in large patches in theGCs, via its central coiled-coil domain, and a link to myosin VI, but shows little affinity forMT plus ends, via its EB1-binding domain. Parallel studies with the close mammalianhomologue CLIP-170 showed the same localisation patterns in neurons, suggesting that CLIP-170 doesn’t play a significant role in the nervous system. Overall, my studies in Drosophilaneurons have firmly established this system for the systematic analysis of MT regulation,likely to produce mechanistic understanding that can be applied also to mammals.

Investigating the cell population of the adult human nucleus pulposus

Ludwinski, Francesca January 2014 (has links)
Low back and neck pain are prevalent conditions in developed societies, and are linked to degeneration of the intervertebral disc (IVD), where aberrant cell biology, particularly in cells of the nucleus pulposus (NP) is thought to drive these degenerative changes. Recent microarray investigations have shed some light as to the phenotype of NP cells; an area of IVD research previously undefined, but the unique gene markers identified have yet to be investigated in a cohort of specimens representative of a range of ages and stages of degeneration, as well as localised to cells of the disc. Additionally, evidence regarding the expression of novel marker genes at the protein level is to date, largely unaddressed, but is imperative in order to fully characterise the adult human NP cell phenotype, as it is not understood whether all NP cells will express these proteins, or just a subset of cells. Similarly, few studies have assessed variations in the novel gene and protein expression profile of adult NP cells with ageing and degeneration, and it is therefore essential to determine this and identify whether the phenotype of NP cells alters as a consequence of such variables. Furthermore, the cervical NP cell phenotype is at present poorly characterised and it is therefore assumed that it is comparable to that of lumbar NP cells, with regards to chondrogenic and catabolic gene expression. Elucidation of whether NP cells derived from the two spinal regions are comparable with regards to phenotype may allow for the interchangeable use of cervical and lumbar IVD specimens for in vitro purposes. This study aimed to investigate the adult human NP cell phenotype, through comparison of gene expression levels determined by quantitative real-time PCR in specimens obtained from a range of adult human disc levels of varying ages and degenerative grades, and to assess the expression of novel NP and notochordal (NC) cell marker proteins by immunohistochemistry, in order to ascertain whether expression is ubiquitous, or whether discrete NP cell sub-populations exist in vivo, particularly with regards to NC cell marker expression using flow cytometry techniques. It has been postulated that the phenotype of NP cells is influenced by microenvironmental factors akin to those observed in vivo, and therefore an ex vivo model system for studying the effects of microenvironmental factors on the gene expression and histological profiles of cells within the NP was developed. Analysis of the cervical NP cell gene expression profile, and comparison to lumbar specimens confirmed that specimens from the two spinal regions were phenotypically similar and could therefore be used interchangeably. Following this, investigation of novel NP and NC cell marker expression in a cohort of degenerate human IVD samples identified differential expression of a range of markers, indicative of cell sub-populations existing within the tissue. It was subsequently demonstrated that discrete NC cell-like and NP cell-like cellular sub-populations exist, but crucially, provided support against the loss of NC cells from the NP with ageing, and intimate either that they differentiate into chondrocyte-like NP cells or that the subsets of NP cells are discrete with regards to ontogeny. The mechanisms underlying this required elucidation, and a novel ex vivo model system has been developed here, allowing for the assessment of NC cell phenotypic response to microenvironmental factors. Preliminary testing has indicated that hypoxic culture of porcine IVD explants results in alterations in the NP ECM and cellularity as compared to normoxic cultures, suggesting that microenvironment may influence alterations to NC cell phenotype. Taken together, these findings suggest that adult human NP tissues are comprised of heterogeneous cell populations, with differential expression of both NP and NC cell markers. Future work to investigate whether the functions of these phenotypically distinct cells differs may elucidate an optimal cell type for recapitulation in novel cell-based regenerative therapies for repair of the degenerate IVD.

The physico-chemical characterisation of bioactive glass air-abrasion on human enamel

Milly, Hussam January 2014 (has links)
Objectives: This research aimed to characterise the physico-chemical interaction of bioactive glass 45S5 (BAG) air-abrasion with human enamel including the controlled and selective removal of substrates and the remineralisation of enamel white spot lesions (WSLs). Materials and methods: The effect of six operating parameters on air-abrasion dynamic cutting efficiency/patterns was assessed using an enamel analogue material (MacorTM) and white light profilometry. Standardised resin composite restorations created within MacorTM blocks, were removed in simulated clinical conditions and scanned using triangulation laser profilometry to investigate the effect of operating parameters on the selective resin composite removal using BAG air-abrasion. The remineralisation of artificial enamel WSLs treated using BAG mixtures were evaluated using Raman micro-spectroscopy, microhardness and scanning electron microscopy (SEM) coupled with energy dispersive X-ray spectrometry (EDX). The physical and optical changes in WSLs pre-conditioned using air-abrasion with BAG-polyacrylic acid (PAA-BAG) powder were detected using non-contact profilometry and optical coherence tomography (OCT). All comparisons were considered statistically significant if p < 0.05. Results: Significant differences in air-abrasion cutting efficiency / pattern were observed according to the tested parameters. BAG air-abrasion removed resin composite more selectively than conventional alumina air-abrasion and the effect of altering the unit’s operating parameters was significant. Enamel WSLs treated with BAG mixtures exhibited a significantly higher Knoop microhardness compared to the negative control. Raman micro-spectroscopy detected significantly higher phosphate content and the SEM images revealed mineral depositions on the surface of treated lesions. Pre-conditioning WSL surfaces with PAA-BAG air-abrasion increased WSL surface area. This pre-treatment increased Knoop microhardness and the mineral content of remineralised WSLs. Conclusions: The ultraconservative clinical applications of BAG air-abrasion can be improved by altering the operating parameters. BAG and PAA-BAG can remineralise enamel WSLs. Pre-conditioning the lesion surface with PAA-BAG air-abrasion modifies the lesion surface physically and consequently enhances remineralisation using BAG 45S5 therapy.

Insulin signalling in endothelial cells

Philippeos, Christina January 2014 (has links)
Insulin is known to act as an anti-inflammatory agent and protect vascular endothelial cells during ischaemic damage in vivo. Although it is known that insulin signals in part through phosphatidylinositol 3-kinases (PI3Ks) and Akt, its effects on endothelial junctions and actin cytoskeleton are unknown. This study aimed to characterise endothelial responses to insulin, identify endothelial insulin-­‐induced changes in protein phosphorylation and determine the roles of these changes in regulating endothelial functions. Insulin stimulation induced dose-dependent Akt activation in both primary human umbilical vein endothelial cells (HUVECs) and an endothelial cell line, human bone-marrow endothelial cells (HBMECs). Insulin decreased basal HUVEC permeability, increased angiogenic loop formation in vitro and increased cell migration in a wound-healing model, compared to untreated cells. Insulin-stimulated changes in protein phosphorylation were identified using a 14-3-3 affinity purification proteomic screen, as 14-3-3 proteins interact specifically with phosphorylated Ser/Thr residues within 14-3-3-binding motifs. A total of 390 14-3-3-binding proteins were identified from insulin-stimulated HBMECs, from which 12 proteins were selected based on predicted roles in endothelial cytoskeleton regulation. Validation of these hits, performed by Far-Western overlay analysis, identified 4 IGF-I-regulated 14-3-3-binding proteins: Parg1 (ARHGAP29), RICH-1 (ARHGAP17), LMO7 and Epsin2. Parg1 depletion in HUVECs induced stress fibre formation, increased endothelial permeability, severely decreased angiogenic loop formation and decreased cell migration, compared to siRNA control-treated cells. This suggests that Parg1 regulates contractility and hence could affect endothelial cell-cell junctional stability. Depletion of RICH-1 and LMO7 in HUVECs resulted in mislocalisation of the tight junction protein ZO-1. However, this did not affect endothelial permeability, suggesting that these proteins are important for maintaining tight junction integrity. LMO7 and Epsin2 depletion each resulted in an increase in angiogenic loop formation, but did not detectably affect cell migration. Insulin stimulation of Epsin2 might increase lamellipodium formation, although further studies are required to establish the mechanisms involved. In conclusion, this thesis describes a 14-3-3-based proteomic screen that identified novel regulators of endothelial function. These proteins could contribute to the anti-inflammatory roles of insulin.

Skeletal malformations in the fuzzy mutant mouse

Yannakoudakis, Basil January 2015 (has links)
The skeleton is an important structural framework for vertebrates that consists of bone and cartilage. Generally, the vertebrate skeletal system can be categorized into the appendicular, trunk and craniofacial skeletons. Each of these have different cellular origins and form through two distinct mechanisms: endochondral ossification, in which a cartilaginous template is first formed and then replaced by bone; or intramembranous ossification, in which cellular precursors are directly differentiated into bone. Some skeletal structures, such as the mandible, are unique and form via combinations of both processes. Skeletal dysplasias can affect both types ossification. Patients with ciliopathies manifest with multiple defects that affect most skeletal systems. In addition, two other classes of disease, the craniosynostosis syndromes and the chondrodysplasias, have several skeletal phenotypes also seen in ciliopathies, such as short limbs and craniosynostosis. In this project I focus on a ciliopathic mouse model, Fuzzy, in which both endochondral and intramembranous bones are affected. Cilia are cellular organelles that have multiple functions from fluid flow to signal transduction. They are associated with signalling perturbations in different pathways such as Hedgehog and Wnt. Specifically, I investigate molecular mechanisms, which cause micrognathia, mandibular hyperossification and short long bones. Furthermore, this project aims to compare and contrast some overlapping phenotypes between ciliopathies, chondrodysplasias and craniosynostosis syndromes, such as vertebral and sternal defects. Results obtained indicate that many craniofacial defects in the Fuzzy mutant, including micrognathia, mandibular hyperossification and craniosynostosis, can be rescued with genetic reduction of Fgf8. Defects affecting other skeletal elements are not rescued. These data suggest that loss of Fuzzy converges on Fgf8 regulation during craniofacial development, but effects on other skeletal systems are probably due to other signalling perturbations, notably Hedgehog signalling.

Recent human history : inferences from the Y-chromosome and mitochondrial DNA

Abernethy, J. K. January 2005 (has links)
Disciplines such as palaeoanthropology, archaeology, anthropology, and history have been instrumental in formulating hypotheses relating to human history. Genetics has developed into a powerful tool for human population analysis hence it can complement information derived from other disciplines. To date, however, such studies of genetic history have predominantly focussed on prehistoric events. The aim of this thesis was to address several questions formulated from written sources and oral tradition relating to the recent history of populations in the British Isles and Africa. Y-chromosome markers and sequence information from the mitochondrial genome were employed. The male gene pool of the British Isles was investigated using a thorough sampling strategy, with respect to the impact of historical invaders, revealing geographic structuring within the Isles as a result of differential contact with these invaders. With these data for Britain available, the fidelity of (British) surname inheritance was investigated using the Y-chromosome, revealing evidence for the random and non-random adoption of surnames. The scope in Britain was narrowed to the small, but assumed diverse, metropolitan district of Greater London, to assess levels of Y-chromosome and mitochondrial DNA diversity in relation to the rest of Britain and Europe. Finally, the maternal history of the Lemba from Africa was investigated oral tradition and Y-chromosome evidence suggests a Semitic component. The evidence presented here precludes a Jewish maternal heritage, but a Middle Eastern component is possible. This thesis has shown that genetic information can be informative for elucidating the recent history of these populations, therefore confirming the value of including recent events within the scope of genetic history.

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