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1
Yeudall, W. Andrew. "Human papillomavirus types in oral squamous cell carcinogenesis." Thesis, University of Glasgow, 1991. http://theses.gla.ac.uk/40921/.
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The DNAs of human papillomavirus (HPV) types 4, 16 and 18 have been detected in biopsies of normal and malignant human oral mucosa by Southern blot hybridisation and polymerase chain reaction (PCR). By the former technique HPV-4, HPV-16 and HPV-18 DNAs were detected in three separate carcinomas, but only found in adjacent dysplastic and normal tissue by PCR. The PCR technique also allowed detection of HPV-16 and HPV-18 DNA in additional carcinomas and normal samples. The oral HPV-4 DNA has been molecularly cloned and extensive restriction analysis and nucleotide sequencing showed identity with the prototype HPV-4 DNA. The HPV-18 DNA detected by Southern blot hybridisation showed an altered restriction pattern in the El region of the viral genome; however direct nucleotide sequencing of PCR products from the E6 ORF showed no sequence alterations in either normal or malignant samples. HPV-16 DNA detected in one carcinoma by Southern blot hybridisation revealed altered PstI and Hpall restriction patterns as compared with the prototype viral genome. The expected 2.6kb Hpall and 1.55kb PstI bands, which overlap, were absent, and an additional band of reduced molecular weight was visible in the Hpall digest, suggesting that the oral HPV-16 genome had undergone a deletion or rearrangement. In a further two carcinoma samples positive for HPV-16 DNA by PCR, amplification of a late region fragment of the viral genome produced fragments of reduced molecular weight. When these PCR fragments were used as probes, hybridisation was observed to the 1.78kb PstI and 1.81kb Hpall-BamHI bands of HPV-16 DNA, and also (as a smear) to human genomic DNA from both tumour and normal samples. This suggests that the viral DNA in these samples had undergone recombination events with repetitive cellular sequences, perhaps as a prelude to viral integration or as a means of activating cellular genes. A keratinocyte culture (T45) derived from an oral squamous cell carcinoma was found to be non-tumorigenic in vivo. PCR analysis revealed that a proportion of cells in the culture contained HPV-16 early sequences. The establishment of HPV-positive and HPV-negative clones from this culture will provide an excellent system for studying the role of viral and cellular factors in oral squamous cell carcinogenesis.
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Björklund, Frida. "Subcellular mapping of cell types in healthy human pancreatic islets." Thesis, KTH, Proteinvetenskap, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-302215.
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Pancreatic islets are composed of endocrine cells that secrete hormones essential for blood-glucose homeostasis. Prior research has revealed that the gene expression and functionality of human islet cells is heterogenous. However, it is not currently understood how the heterogeneity correlates to normal islet cell function and dysfunction in diabetes pathogenesis. Subsequently, an international collaborative project has been initiated to elucidate what constitutes islet cell heterogeneity from a transcriptional, proteomic, and functional perspective in both health and disease. In this study, a highly multiplex tissue image assay was developed to allow for the study of the localization and distribution of proteins previously identified to correlate with functional activity and heterogeneity in islet cells using the CO-Detection by indEXing (CODEX) platform. In total, 22 proteins were studied simultaneously of which 10 were specifically expressed in islet cells. These included generic pancreatic markers such as C-peptide (C-pep) marking insulin-secreting β-cells, glucagon (GCG) and somatostatin (SST), but also less well-characterized proteins such as Shisa like 2B (FAM159B) and Neural proliferation, differentiation and control 1 (NPDC1). The multiplex tissue imaging allowed for single-cell analysis of protein expression in human islet cells showing that most islet specific proteins were heterogeneously expressed. The observations made in this study serves as a validation to that the human islet microenvironment is highly complex due to islet cell heterogeneity. Additionally, the study demonstrated that multiplex tissue imaging has the potential to reveal novel cell types and interactions.Langerhanska öar består av endokrina celler som utsöndrar hormoner nödvändiga för reglering av blodsockernivåerna. Tidigare forskning har visat att genuttrycket och funktionaliteten är heterogen i de celler som utgör mänskliga Langerhanska öar. Dock är förståelsen för hur heterogeniteten korrelerar till normal cellfunktion och dysfunktion i diabetespatogenes fortfarande ofullständig. Följaktligen har ett internationellt samarbete inletts i syfte att undersöka vad som utgör heterogenitet i Langerhanska öar ur ett transkriptionellt, proteomiskt och funktionellt perspektiv i såväl friska som sjuka individer. I denna studie utvecklades en metod för multiplex mikroskopisk avbildning av vävnad för att möjliggöra undersökningen av hur proteiner som tidigare korrelerats med endokrin cellspecifik aktivitet och heterogenitet i Langerhanska öar var lokaliserade med hjälp av plattformen för Co-Detection by indEXing (CODEX). Totalt undersöktes 22 proteiner samtidigt varav 10 var specifikt uttryckta i celler som utgör Langerhanska öar. Bland dessa proteiner fanns generella markörer för vanligt förekommande celltyper i Langerhanska öar såsom C-peptid (C-pep) som markör för insulinsekreterande β-celler, glukagon (GCG) och somatostatin (SST) såväl som proteiner med färre kända funktioner såsom Shisa like B (FAM159B) och Neural proliferation, differentiation and control 1 (NPDC1). Med hjälp av multiplex mikroskopisk avbildning av vävnad kunde uttrycket av proteiner specifikt uttryckta i celler som utgör Langerhanska öar analyseras för enskilda celler i vävnaden. Denna analys visade att de flesta proteiner specifikt uttryckta i celler som Langerhanska öar består av var heterogent uttrycka. Resultaten från denna studie validerar att mikromiljön i Langerhanska öar är mycket komplex på grund av cellernas heterogenitet. Vidare visade denna studie att multiplex mikroskopisk avbildning av vävnad har potentialen att identifiera nya celltyper och interaktioner.
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Butterworth, B. H. "Immunocytochemical characterization of the cell populations of the human placenta." Thesis, University of Cambridge, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.372864.
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Reid, Fiona Jane. "Plasminogen activators and their inhibitor synthesized by human mesangial cells and other cell types." Thesis, University of Aberdeen, 1994. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU539471.
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The plasminogen activator synthesized by human mesangial cells was identified as tissue-type plasminogen activator (t-PA). Glomerular epithelial cells synthesized t-PA and urokinase (u-PA). Both mesangial cells and glomerular epithelial cells synthesized plasminogen activator inhibitor-1 (PAI-1) into culture supernatant. In this study experimental techniques were developed to allow quantification of matrix-associated PAI-1. PAI-1 associated with the matrix of mesangial cells was less than 1% of the total PAI-1 synthesized by the cells. Similar amounts were detected in the matrix of human umbilical vein endothelial cells and Hep G2 cells. When cultured in the presence of transforming growth factor- (TGF-), PAI-1 synthesized by mesangial cells was significantly increased and this up-regulation was shown to occur at the mRNA level. PAI-1 associated with the matrix of mesangial cells also significantly increased, though matrix-associated PAI-1 still constituted less than 1% of the total PAI-1 synthesized by the cells. TGF- stimulated the synthesis of PAI-1 by whole glomeruli, epithelial cells and epithelial-mesangial cell co-cultures, while decreasing their overall plasminogen activator synthesis. When cultured in the presence of platelet-derived growth factor-BB (PDGF-BB) there was no effect on either PA or PAI-1 synthesized by the glomerular cells examined. TGF- has been implicated in the development of glomerulonephritis via an effect on matrix production. Our results suggest tht TGF- also plays a role in the proteolytic balance within the glomerulus, leading to an environment favouring its deposition.
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Schnyder-Candrian, Silvia. "Gene expression of neutrophil-activating peptides in various human cell types /." [S.l.] : [s.n.], 1994. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Gibson, Douglas Alistair. "Role for oestrogen in dynamic interactions between cell types within the human endometrium." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/9890.
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The human endometrium is a complex multicellular tissue, located within the cavity of the uterus. Its luminal surface is defined by a layer of epithelial cells supported on a multicellular stroma containing fibroblasts, glands (lined by a secretory epithelium), blood vessels (lined with endothelial cells) and several populations of immune cells; the latter includes a unique population of natural killer (uNK) cells. The endometrium undergoes dynamic remodelling across the menstrual cycle in response to fluctuating levels of sex steroids secreted by ovarian cells. The phases of the endometrial cycle include an oestrogendominated proliferative phase, a progesterone-dominated secretory phase and menses (endometrial shedding precipitated by falling levels of progesterone). A key feature of the secretory phase is differentiation (decidualisation) of endometrial stromal fibroblasts (ESC) an event characterised by transformation of cell shape, secretion of growth factors/cytokines, angiogenesis/vascular remodelling and an increase in the numbers of resident immune cells. Decidualisation ensures an appropriate nutritional and hormonal environment exists during the establishment of pregnancy. Studies in mice suggest that de novo biosynthesis of oestrogen within the uterus may play an essential role in regulation of decidualisation but no data exist for human. Endometrial endothelial and uNK cells both contain oestrogen receptors but the impact of oestrogens on their function has not been explored. In the current studies three questions have been addressed: 1. Is oestrogen biosynthesis a feature of human endometrial stromal cell decidualisation? 2. What is the impact of oestrogen on uNK cell function? 3. What role (if any) does oestrogen play in the interplay between decidual, immune and vascular cells within the human endometrial stroma? Results obtained provide the first evidence that de novo biosynthesis of oestrogens occurs during decidualisation of human ESC. This was attributed to changes in expression patterns of mRNAs encoding proteins that play a critical role in regulation of oestrogen biosynthesis (STAR, CYP11A1, CYP19A1 [aromatase], HSD17B2 [17βHSD2] and STS [steroid sulphatase]). Changes in the pattern of metabolism were confirmed using thin layer chromatography and analysis of concentrations of oestrone (E1) and oestradiol (E2) in culture media. Secretion of E1 and E2 was reduced by addition of an aromatase inhibitor. Data derived from studies described within this thesis also show for the first time that incubation of uNK cells with E2 not only enhanced cell migration but also stimulated secretion of factors that had a significant impact on endothelial cell angiogenesis. These findings were supported by novel evidence that E2 had a significant impact on expression of genes associated with cell motility and angiogenesis. In addition, factors, including E1/E2, secreted by decidualised stromal cells, stimulated chemotaxis of uNK cells. Future experiments will focus on determining the identity of the angiogenic factors secreted by uNK cells in response to E2 and the mechanisms responsible for uNK cell movement. In summary, new data presented in this thesis provide evidence that local biosynthesis of oestrogens within the endometrial stroma may play a previously unrecognised role in regulating the function of uNK cells and endometrial endothelial cells in women. These results have implications for treatment of disorders such as infertility, heavy menstrual bleeding and endometriosis.
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WATANABE, KAZUYOSHI, MITSUO MAEHARA, and MASAO KITO. "THREE TYPES OF VOLTAGE-DEPENDENT CALCIUM CURRENTS IN CULTURED HUMAN NEUROBLASTOMA CELLS." Nagoya University School of Medicine, 1995. http://hdl.handle.net/2237/16080.
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Ito, Akiko. "Histamine modulates three types of K^+ current in a human intestinal epithelial cell line." Kyoto University, 1997. http://hdl.handle.net/2433/202235.
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Dimas, Antigone. "The role of regulatory variation in sculpting gene expression across human populations and cell types." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608695.
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Johnson, Travis Steele. "Estimation of Neural Cell types in the Allen Human Brain Atlas using Murine-derived Expression Profiles." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1461243036.
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Peters, Andrew. "Clinical, molecular, and phylogenetic characterisations of human T-cell lymphotropic virus types I and II in Canada." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0020/MQ58073.pdf.
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Ordway, Gregory A., Attila Szebeni, Michelle M. Duffourc, and Katalin Szebeni. "Laser Capture Microdissection and RT- PCR Analyses of Specific Cell Types in Locus Coeruleus From Postmortem Human Brain." Digital Commons @ East Tennessee State University, 2007. https://dc.etsu.edu/etsu-works/8624.
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Morphological studies have shown pathology of neurons and glia in many brain disorders, including psychiatric disorders such as major depression. However, most biochemical characterizations of postmortem human brain tissue have not made a distinction between neurons and glia. Laser capture microdissection (LCM) to isolate specific cell types has the potential to advance our understanding of human brain pathologies. Here, RT-PCR was used to evaluate the utility of LCM in the capture of noradrenergic neurons, astrocytes and oligodendrocytes from the locus coeruleus (LC) of postmortem human brain. The 3 LC cell types were individually identified using modifications of established histological and morphological methods. LCM settings were optimized for each cell type and captured cell bodies were those having no nearby cell body of a different phenotype. LC neurons (200), astrocytes (500), and oligodendrocytes (500) were captured within the LC from 3 postmortem brains. RNA was isolated, reversed transcribed, and markers for neurons (tyrosine hydroxylase [TH], dopamine beta-hydroxylase [DBH]), astrocytes (glial fibrillary acidic protein [GFAP]), and oligodendrocytes (myelin oligodendrocyte glycoprotein [MOG]), along with 3 references (actin, GAPDH, ubiquitin C) were PCR amplified and quantified by standardized end-point PCR. RNA quality as assessed by RIN was not altered by LCM as compared to RNA isolated from homogenized tissue. TH gene expression was found only in neurons in 2 of the 3 brains. DBH gene expression was ~5-fold greater in neurons than in astrocytes and oligodendrocytes. GFAP gene expression in astrocytes was 7- and 5-fold greater than that in neurons and oligodendrocytes, respectively. MOG gene expression was only detected in oligodendrocytes. Different expression ratios of marker genes between neurons and glia suggest that simple cross contamination of mRNA is unlikely. Glial cells may contain DBH mRNA. Alternatively, DBH, but not TH, mRNA may occur in neuronal dendrites or axons in close association with glial cells that become captured with glia during LCM. GFAP may be expressed in low levels in neurons and oligodendrocytes, or alternatively, GFAP mRNA may be located in astrocytic processes in close association with neuronal and oligodendrocyte cell bodies. Use of a single marker to identify a cell type may be insufficient; other cell types for comparison or additional markers may be required. Multiple well-characterized markers can be used to evaluate clarity of cell capture for each sample. With due regard for specific limitations, LCM can be used to evaluate the molecular pathology of specific cell types in postmortem human brain.
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Kelsey, William Patrick V. "Proteomic Analysis of the Nuclear Membranes of Human Periodontal Ligament Fibroblast and Gingival Fibroblast Cell Types: A Comparison Study." Columbus, Ohio : Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1243618431.
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Rose, Stephanie Leigh. "Human immunodeficiency virus type 1 (HIV-1) gag-pro genetic variability is related to therapy response and impacts viral fitness in specific cell types." [Gainesville, Fla.] : University of Florida, 2002. http://purl.fcla.edu/fcla/etd/UFE1001177.
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Boytard, Ludovic. "Analyse moléculaire des types cellulaires impliqués dans l'anévrysme de l'aorte abdominale." Phd thesis, Université du Droit et de la Santé - Lille II, 2012. http://tel.archives-ouvertes.fr/tel-00825204.
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L'anévrysme de l'aorte abdominale (AAA) est une maladie vasculaire consistant en une dilatationde l'aorte abdominale. Son caractère asymptomatique rend importante la recherche debiomarqueurs afin de faciliter la prise en charge des patients.Le but de mes travaux de thèse a été d'étudier spécifiquement les types cellulaires impliqués dansl'AAA.Après obtention d'une banque d'échantillons d'AAA, nous avons localisé ces types cellulaires etrepéré 3 zones d'intérêt : le thrombus intraluminal contenait des neutrophiles, lymphocytes T,mastocytes et macrophages M2. Les macrophages M1 étaient localisés dans l'adventice, avec leslymphocytes B et des mastocytes. La média contenait des cellules musculaires lisses (CML) dont lephénotype variait entre les états sain, anévrysmal et apoptotique.Ces résultats suggérant une implication différente des deux types de macrophages et uneévolution des CML au cours de l'AAA, nous avons isolé ces deux types cellulaires du tissu anévrysmalpar microdissection laser afin d'y étudier l'expression de biomarqueurs potentiels. Nous avons ainsimontré que l'augmentation plasmatique de peroxiredoxine-1 provient des macrophages M1 et quel'augmentation d'ADAMTS5 provient des CML anévrysmales allongées.Nous avons ensuite comparé les protéomes des macrophages M1 et M2 afin d'élucider leur rôledans l'AAA et d'identifier de nouveaux biomarqueurs. Cinq protéines différentielles ont étéidentifiées impliquées dans la phagocytose ou la réponse au stress.L'étude des différents types cellulaires impliqués dans l'AAA pourrait nous permettre unemeilleure compréhension de ses mécanismes et l'identification de biomarqueurs potentiels de cettepathologie.
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Bailer, Robert T. "Human T-lymphotrophic virus types I/II in autoimmune diseases, growth characteristics and cytokine expression in AIDS-related Kaposi's sarcoma derived cell strains and patients, and constitutive cytokine expression in HTLV and STLV.. /." The Ohio State University, 1994. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487856076415404.
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Bain, Peter A., and n/a. "Gene Expression Profiling of Cylindrospermopsin Toxicity." Griffith University. School of Biomolecular and Physical Sciences, 2007. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20080404.145834.
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Cylindrospermopsin (CYN) is a toxic alkaloid produced by several freshwater cyanobacterial species, the most prevalent in Australian waters being Cylindrospermopsis raciborskii. The occurrence of CYN-producing cyanobacteria in drinking water sources worldwide poses a potential human health risk, with one well-documented case of human poisoning attributed to the toxin. While extensive characterisation of CYN-induced toxicity has been conducted in rodents both in vivo and in primary cell cultures, little is known about mechanisms of toxicity in human cell types. This thesis describes studies undertaken to further define the molecular mechanisms of CYN toxicity in human cells. Concentration-response relationships were determined in various cultured human cell types using standard toxicity assays. As expected, CYN caused dose-dependent decreases in the growth of three cell lines, HepG2, Caco-2 and HeLa, and one primary cell type, human dermal fibroblasts, according to tetrazolium reduction assays. CYN treatment did not disrupt cellular membranes according to the lactate dehydrogenase release assay in HepG2 or Caco-2 cells after 24, 48 or 72 h exposure, but did cause membrane disruption in fibroblasts after 72 h exposure to relatively high concentrations of the toxin. Apoptosis occurred more readily in HeLa cells than HepG2 cells or fibroblasts, with 72 h exposure to 1 &mug/mL required before statistically significant rates of apoptosis occurred in the latter cell types. CYN did not appear to directly affect the structure of actin filaments or microtubules under the conditions used in the present study. The major portion of the work presented in this thesis comprises a large-scale interrogation of changes in gene expression induced by the toxin in cultured cells. To assess the effects of CYN on global gene expression, relative messenger RNA (mRNA) levels in human dermal fibroblasts and HepG2 cells after 6 h and 24 h exposure to 1 &mug/mL CYN were determined using oligonucleotide microarrays representing approximately 19 000 genes. Overall, the number of transcripts significantly altered in abundance was greater in fibroblasts than in HepG2 cells. In both cell types, mRNA levels for genes related to amino acid biosynthesis, carbohydrate metabolism, and protein folding and transport were reduced after CYN treatment, while transcripts representing genes for apoptosis, RNA biosynthesis and RNA processing increased in abundance. More detailed data analyses revealed the modulation of a number of stress response pathways—genes regulated by NF-&kappaB were induced, DNA damage response pathways were up-regulated, and a large number of genes involved in endoplasmic reticulum stress were strongly down-regulated. Genes for the synthesis and processing of mRNA, tRNA and rRNA were strongly up-regulated, indicating that CYN treatment may increase the turnover of all forms of cellular RNA. A small group of genes were differentially expressed in HepG2 cells and fibroblasts, revealing cell-specific responses to the toxin. Selected changes in transcript level were validated using real-time quantitative reverse transcriptase PCR (qRT-PCR). The modulation of stress response pathways by CYN, indicated by microarray analysis, was further investigated using other methods. The role of tumour suppressor protein p53 in CYN-mediated gene expression was confirmed by measuring the expression of known p53-regulated genes following CYN treatment of HepG2 cells and human dermal fibroblasts using qRT-PCR. Western blotting of protein extracts from CYNtreated cells showed that p53 protein accumulation occurred in HepG2 cells, providing additional evidence of the activation of the p53 pathway by CYN in this cell line. The immediate-early genes JUN and FOS were found to be induced by CYN in a concentration-dependent manner, and MYC was induced to a lesser extent. The mitogen-activated protein kinase c-Jun NH2-terminal kinase, implicated in the ribotoxic stress response initiated by damage to ribosomal RNA, appeared to become phosphorylated in HeLa cells after CYN exposure, suggesting that ribotoxic stress may occur in response to CYN in at least some cell types. The expression of a reporter gene under the control of a response element specific for NF-&kappaB was induced at the mRNA level but inhibited at the protein level. This shows that while transcription factors such as p53 and NF-&kappaB are apparently activated in response to the toxin, transactivation of target genes may not necessarily manifest a corresponding increase at the protein level. The current work contributes significantly to the current understanding of cylindrospermopsin toxicity in human-derived cell types, and provides further insight into putative modes of action.
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Bain, Peter A. "Gene Expression Profiling of Cylindrospermopsin Toxicity." Thesis, Griffith University, 2007. http://hdl.handle.net/10072/367068.
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Cylindrospermopsin (CYN) is a toxic alkaloid produced by several freshwater cyanobacterial species, the most prevalent in Australian waters being Cylindrospermopsis raciborskii. The occurrence of CYN-producing cyanobacteria in drinking water sources worldwide poses a potential human health risk, with one well-documented case of human poisoning attributed to the toxin. While extensive characterisation of CYN-induced toxicity has been conducted in rodents both in vivo and in primary cell cultures, little is known about mechanisms of toxicity in human cell types. This thesis describes studies undertaken to further define the molecular mechanisms of CYN toxicity in human cells. Concentration-response relationships were determined in various cultured human cell types using standard toxicity assays. As expected, CYN caused dose-dependent decreases in the growth of three cell lines, HepG2, Caco-2 and HeLa, and one primary cell type, human dermal fibroblasts, according to tetrazolium reduction assays. CYN treatment did not disrupt cellular membranes according to the lactate dehydrogenase release assay in HepG2 or Caco-2 cells after 24, 48 or 72 h exposure, but did cause membrane disruption in fibroblasts after 72 h exposure to relatively high concentrations of the toxin. Apoptosis occurred more readily in HeLa cells than HepG2 cells or fibroblasts, with 72 h exposure to 1 µg/mL required before statistically significant rates of apoptosis occurred in the latter cell types. CYN did not appear to directly affect the structure of actin filaments or microtubules under the conditions used in the present study. The major portion of the work presented in this thesis comprises a large-scale interrogation of changes in gene expression induced by the toxin in cultured cells. To assess the effects of CYN on global gene expression, relative messenger RNA (mRNA) levels in human dermal fibroblasts and HepG2 cells after 6 h and 24 h exposure to 1 µg/mL CYN were determined using oligonucleotide microarrays representing approximately 19 000 genes. Overall, the number of transcripts significantly altered in abundance was greater in fibroblasts than in HepG2 cells. In both cell types, mRNA levels for genes related to amino acid biosynthesis, carbohydrate metabolism, and protein folding and transport were reduced after CYN treatment, while transcripts representing genes for apoptosis, RNA biosynthesis and RNA processing increased in abundance. More detailed data analyses revealed the modulation of a number of stress response pathways—genes regulated by NF-?B were induced, DNA damage response pathways were up-regulated, and a large number of genes involved in endoplasmic reticulum stress were strongly down-regulated. Genes for the synthesis and processing of mRNA, tRNA and rRNA were strongly up-regulated, indicating that CYN treatment may increase the turnover of all forms of cellular RNA. A small group of genes were differentially expressed in HepG2 cells and fibroblasts, revealing cell-specific responses to the toxin. Selected changes in transcript level were validated using real-time quantitative reverse transcriptase PCR (qRT-PCR). The modulation of stress response pathways by CYN, indicated by microarray analysis, was further investigated using other methods. The role of tumour suppressor protein p53 in CYN-mediated gene expression was confirmed by measuring the expression of known p53-regulated genes following CYN treatment of HepG2 cells and human dermal fibroblasts using qRT-PCR. Western blotting of protein extracts from CYNtreated cells showed that p53 protein accumulation occurred in HepG2 cells, providing additional evidence of the activation of the p53 pathway by CYN in this cell line. The immediate-early genes JUN and FOS were found to be induced by CYN in a concentration-dependent manner, and MYC was induced to a lesser extent. The mitogen-activated protein kinase c-Jun NH2-terminal kinase, implicated in the ribotoxic stress response initiated by damage to ribosomal RNA, appeared to become phosphorylated in HeLa cells after CYN exposure, suggesting that ribotoxic stress may occur in response to CYN in at least some cell types. The expression of a reporter gene under the control of a response element specific for NF-?B was induced at the mRNA level but inhibited at the protein level. This shows that while transcription factors such as p53 and NF-?B are apparently activated in response to the toxin, transactivation of target genes may not necessarily manifest a corresponding increase at the protein level. The current work contributes significantly to the current understanding of cylindrospermopsin toxicity in human-derived cell types, and provides further insight into putative modes of action.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Physical Sciences
Faculty of Science, Environment, Engineering and Technology
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Furuta, Rie. "Human T-cell leukemia virus type 1 infects multiple lineage hematopoietic cells in vivo." Kyoto University, 2018. http://hdl.handle.net/2433/232110.
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Bayraktutan, Ulvi. "Studies on human urokinase-type plasminogen activator receptor." Thesis, University of Nottingham, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.262679.
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Mulgrew, Christopher James. "T-type calcium channels and human mesangial cell proliferation." Thesis, King's College London (University of London), 2012. https://kclpure.kcl.ac.uk/portal/en/theses/ttype-calcium-channels-and-human-mesangial-cell-proliferation(8d963ed0-7b21-4f73-bc94-ec5a76205bdd).html.
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Aberrant proliferation of human mesangial cells (MC) is a critical step in the pathogenesis of mesangioproliferative renal diseases. The T-type calcium channel (T-CaCN) has been proposed to play an important role in the proliferation of a number of non-excitable cell types, but T-CaCN expression and functional significance in MC is not known. The aim of this thesis was to investigate the hypothesis that T-CaCN may play an important role in the proliferation of MC in primary culture. Expression of mRNA encoding the α1H isoform (Cav3.2 clone) (but not the α1G nor α1I T-CaCN isoforms) was demonstrated in human MC by RT-PCR. Expression of α1H T-CaCN protein was difficult to assess directly due to the lack of a highly sensitive and specific antibody, despite attempts at upregulation of the protein. Electrophysiological studies of MC demonstrated an inward calcium current in a proportion of cells with characteristics consistent with T-CaCN. Culture of MC with the T-CaCN antagonists mibefradil, Ni2+ and TTL-1177 resulted in a significant reduction in the growth velocity of MC. This effect was not seen upon incubation with verapamil, an L-type calcium channel antagonist. DNA synthesis in MC treated with each of the T-CaCN antagonists was significantly reduced by up to 50% as shown by BrdU incorporation. This anti-proliferative effect was not associated with direct drug-induced cytotoxicity or apoptosis. FACS analysis of MC incubated with T-CaCN antagonists illustrated an increased proportion of cells remaining in G1 and not progressing into S-phase. Treatment of cultured MC with TTL-1177 resulted in a significant reduction in the signalling protein p-ERK within 30 minutes, an effect not seen with verapamil, suggesting a possible mechanism needing further investigation. MC transfection with siRNA targeting the α1H isoform resulted in significant knockdown of T-CaCN α1H mRNA and a reduction in the growth velocity of cultured MC of approximately 50% compared to control siRNA transfection, with an associated 37% reduction in DNA synthesis. These results demonstrate evidence for an important role for T-type calcium channels in the proliferation of human mesangial cells, justifying further study in in greater detail. This could potentially lead to a novel therapy in the treatment of proliferative renal diseases.
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Sasada, Amane. "APOBEC3G targets human T-cell leukemia virus type 1." Kyoto University, 2006. http://hdl.handle.net/2433/143870.
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Pise-Masison, Cynthia Ann. "Human Immunodeficiency Virus Type-1 Infection of Human Myeloid Cells." eScholarship@UMMS, 1994. https://escholarship.umassmed.edu/gsbs_diss/87.
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Infection with human immunodeficiency virus type 1 (HIV-1) results in a wide range of immunologic and hematopoietic abnormalities. The overall goal of this dissertation was directed toward obtaining a better understanding of the interactions of HIV-1 and myeloid cells in relation to the pathogenesis of AIDS. The human myelomonocytic cell line, HL-60, was used as a model system to determine if HIV-1 infects myeloid progenitor cells and subsequently, if infection affects their differentiation. HL-60 cells and the human prototypic T cell line, H9 were infected with three different HIV-l isolates (IIIB, PM213, and NL4-3) which are known to infect T cells. All three isolates productively infected both H9 and HL-60 cells; however, HIV-1 antigen expression and cytopathicity was delayed by approximately 15 days in infected HL-60 cells compared H9 cells. To examine the effect of HIV-l infection on myeloid differentiation, chronically infected HL-60 cells and clonal lines derived from them were induced to differentiate into either granulocytes by treatment with dimethyl formamide (DMF) or into monocytes by treatment with phorbol l2-myristate 13 acetate (PMA). By both cellular morphology and function, approximately the same percentage of treated, HIV-infected HL-60 cells differentiated into either granulocytes or monocytes as treated, control HL-60 cells. Taken together, these results indicate that HIV-1 infection does not affect the morphological or functional differentiation of HL-60 cells.
In an effort to understand the differences in the regulation of HIV-l infection in myeloid versus T cells, the life cycle of NL4-3 was examined in HL-60 cells and H9 cells. Initially, NL4-3 replication was restricted in HL-60 cells compared to H9 cells. This restriction was overcome 15 days after infection by the generation of a viral isolate, NL4-3(M). NL4-3(M), harvested during the lytic phase of NL4-3 infection of HL-60 cells, caused cell death approximately 8 days after infection in both H9 and HL-60 cells. Although measurements of viral entry kinetics demonstrated that the timing of entry of NL4-3 and NL4-3(M) in HL-60 cells and NL4-3 in H9 cells was similar, a quantitative polymerase chain reaction (PCR) analysis of newly reverse transcribed NL4-3 DNA in H9 and HL-60 cells revealed that NL4-3 infected H9 cells and NL4-3(M) infected HL-60 cells contain consistently higher amounts of newly reverse transcribed DNA than NL4-3 infected HL-60 cells. The delay in NL4-3 replication in HL-60 cells was further amplified by inefficient spread of the virus throughout the HL-60 culture as measured by RNA production and DNA integration suggesting that another step in the viral life cycle after reverse transcription was also restricted. These results suggest that the efficiency of NL43 replication in HL-60 cells is restricted at several steps in the viral life cycle. Further, these restrictions are overcome by the generation of a viral variant, NL4-3(M), which efficiently replicates in myeloid cells.
The tropism of NL4-3(M) was further characterized by testing its growth in monocyte-derived macrophages (MDM). Unlike NL4-3, NL4-3(M) productively infected MDM cultures. The ability of NL4-3(M) to infect macrophages was conferred by the envelope gene. This was demonstrated by the ability of the recombinant virus, NL4-3envA, which contains the envelope of NL4-3(M) in the context of the NL4-3 genome, to infect and replicate in MDM cultures. The envelope gene of NL4-3(M), however, did not confer ability to rapidly kill HL-60 cells. Together, these findings demonstrate that viral determinants controlling entry into MDM are different trom the determinants controlling the cytopathic phenotype in HL-60 cells.
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Moad, Mohammad. "Influence of cell type of origin to the differentiation potential of induced pluripotent stem cells derived from human urinary tract cells." Thesis, University of Newcastle upon Tyne, 2015. http://hdl.handle.net/10443/2803.
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Background: Direct reprogramming of human somatic cells to pluripotent embryonic stem (ES) cell -like cells, termed induced pluripotent stem (iPS) cells, can be achieved by expression of defined transcription factors. The potential use of iPS cells derived from the urinary tract provides a substantial opportunity in developing new disease models, drug screening and tissue engineering. We aimed to generate, for the first time, human induced pluripotent stem cells derived from the urinary tract (UT-iPS) cells and to assess capacity for directed differentiation into bladder lineages. Methods: Human primary culture cells derived from benign bladder and ureters were transduced with OCT4, SOX2, KLF4 and C-MYC genes to generate human UT-iPS cells. Generated cells were characterised using RT-PCR and immunofluorescence. Differentiation capacity was evaluated by embryoid body formation in vitro and teratoma assay in vivo. Established co-culture based directed differentiation into bladder cells was assessed in comparison with classical skin-derived iPS cells. Results: We demonstrated successful re-programming of adult urinary tract cells from both bladder and ureter into human UT-iPS cells. Most of the clones showed efficient transgene silencing and maintained a normal diploid karyotype. Specifically, we showed expression of ES cell markers and functional pluripotency by the generation of endodermal, ectodermal and mesodermal lineages. Differentiation into bladder lineages was demonstrated by expression of urothelial-specific markers, uroplakins (UPIb, UPII, UPIIIa, and UPIIIb), claudins (CLD1 and CLD5) and cytokeratin (CK7); and stromal smooth muscle markers a-SMA, calponin, and desmin. Human UT-iPS cells were shown to be more efficient than skin-derived iPS cells in undergoing bladder differentiation, underlining the importance of the origin of the parent cell for re-programming. Conclusions: We demonstrated that the induction of human urinary tract cells into iPS cells is possible, offering a new exciting opportunity for tissue engineering and for the study of bladder disease.
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Helt, Anna-Marija. "Multiple biological activities of the human papillomavirus type 16 E7 oncoprotein contribute to the abrogation of human epithelial cell cycle control /." Thesis, Connect to this title online; UW restricted, 2002. http://hdl.handle.net/1773/11514.
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Davis, Adam James. "Transcriptional analysis of human immunodeficiency virus type 1 infection following cell-to-cell transmission /." Title page, contents and abstract only, 1997. http://web4.library.adelaide.edu.au/theses/09PH/09phd2609.pdf.
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Parish, Joanna L. "The induction of apoptosis by the human papillomavirus type 16 E2 protein." Thesis, University of Bristol, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.391157.
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Leeuwen, Ester Marga Maria van. "Induction and maintenance of human virus-specific T cells." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2005. http://dare.uva.nl/document/78986.
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Jong, Annemieke de. "T cell immunity against early antigens of human papillomavirus type 16 /." Leiden : Nautilus, 2005. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=014895978&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Chang, Miao. "Cell type specific regulation of human placenta growth factor gene transcription /." Available to subscribers only, 2008. http://proquest.umi.com/pqdweb?did=1597612421&sid=3&Fmt=2&clientId=1509&RQT=309&VName=PQD.
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Thesis (Ph.D.)--Southern Illinois University Carbondale, 2008."Department of Molecular Biology, Microbiology and Biochemisty." Includes bibliographical references (p. 123-150). Also available online.
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Heminger, Katherine Ann. "LOSS OF HDMX LEADS TO ALTERATIONS IN GENE EXPRESSION AND INHIBITION OF CELL GROWTH IN TUMOR CELLS WITH WILD-TYPE p53." Wright State University / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=wright1175282827.
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Kunnari, A. (Anne). "Genetic, epidemiological and cell culture studies on human resistin." Doctoral thesis, University of Oulu, 2008. http://urn.fi/urn:isbn:9789514289477.
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Abstract Resistin was discovered in the year 2000. In the mouse, it was reported to be produced by adipocytes and to be linked with insulin resistance and obesity. Human resistin has been shown to be produced by leucocytes but the literature contains contradictory results on its association with obesity and type 2 diabetes. Aim of this study was to clarify the role of resistin in the human context especially in type 2 diabetes and atherosclerosis. The first study examined the possible association of human resistin gene variants with type 2 diabetes. The studied three variants were not associated with type 2 diabetes though they were demonstrated in the second study to be associated with the plasma resistin concentration. However, two gene variants were associated with the prevalence of cerebrovascular disease in subjects with type 2 diabetes. In the third work, the association of the plasma resistin level with the risk factors of atherosclerosis and early atherosclerosis measured with carotid artery intima-media thickness (IMT) were studied. Plasma resistin level was not associated with IMT independently from the known risk factors of atherosclerosis. However, resistin was associated with inflammatory markers highly sensitive CRP and the number of leucocytes whereas insulin resistance did not associate with resistin. In the fourth study, resistin expression in different leucocytes and its modulation, as well as the effect of resistin on monocyte adhesion to endothelium were evaluated. The novel discovery was that resistin is expressed in all the main leucocyte lineages, with monocytes and neutrophils exhibiting the highest relative mRNA and protein levels of resistin. Resistin expression was up-regulated by pro-inflammatory factors in the cells of both innate and adaptive immunity. The present results demonstrating that resistin increases adhesion and expression of some adhesion molecules support the hypothesis that resistin may be involved in the development of atherosclerosis. The above results indicate that resistin is widely produced by leucocytes and therefore may participate in inflammatory processes. Since it may be considered as an inflammatory cytokine, resistin may also influence the development of atherosclerosis. In the future, resistin could possibly be used as a marker of inflammationTiivistelmä Vereen erittyvä uusi hormoni, resistiini, löydettiin vuonna 2000. Hiirellä resistiinin on havaittu erittyvän rasvasoluista ja sen on arveltu toimivan linkkinä lihavuuden ja insuliiniresistenssin välillä. Ihmisellä resistiinin tehtävä on toistaiseksi huomattavasti epäselvempi ja toisin kuin hiirellä ihmisen resistiinin korkein ilmentymistaso on valkosoluissa. Tämän väitöstutkimuksen tarkoituksena oli selvittää ihmisen resistiinin toimintaa ja erityisesti sen liittymäkohtia tyypin 2 diabetekseen ja ateroskleroosiin. Ensimmäisessä osatyössä on selvitetty resistiini-geenin nukleotidimuuntelun yhteyttä tyypin 2 diabetekseen ja siihen liittyviin tekijöihin diabetespotilasaineistossa. Resistiinin geenimuuntelu ei tulosten perusteella ole yhteydessä tyypin 2 diabetekseen, vaikka sillä näyttääkin olevan vaikutusta plasman resistiini-pitoisuuteen, mikä havaittiin toisessa osatyössä. Geenimuuntelulla oli havaittavissa yhteyttä aivovaltimosairauteen. Kolmannessa osatyössä plasman resistiinipitoisuuden yhteyttä valtimonkovettumatautiin ja sen riskitekijöihin tutkittiin Pohjois-Pohjanmaalta kerätyssä aineistossa (n = 525). Plasman resistiinipitoisuudella ei havaittu itsenäistä yhteyttä kaulavaltimonseinämänpaksuuteen, joka kuvastaa alkuvaiheen valtimokovettumataudin tasoa. Tulehdukselliset merkit kuten veren valkosolujen määrä ja plasman CRP-pitoisuus liittyivät suurentuneeseen plasman resistiinipitoisuuteen mutta insuliiniresistenssimuuttujat eivät. Neljännessä osatyössä tutkittiin resistiinin ilmentymistä. Resistiinin havaittiin ilmentyvän kaikissa keskeisissä valkosolutyypeissä ja lisäksi tulehdustekijät lisäsivät sen tuottoa. Erityisesti neutrofiileissä ja monosyyteissä resistiinin ilmentymistasot olivat korkeita. Endoteelisoluilla selvitettiin resistiinin vaikutuksia ateroskleroosiin liittyviin muutoksiin. Resistiini lisäsi monosyyttien kiinnittymistä endoteelisoluihin, mikä on tyypillinen ilmiö varhaiselle ateroskleroosille. Tämän työn tulosten perusteella ihmisen resistiinillä ei ole merkittävää yhteyttä insuliiniresistenssiin ja tyypin 2 diabetekseen. Sen sijaan havainto resistiinin ilmentymisestä useammissa valkosolutyypeissä, kuin mitä aikaisemmin on raportoitu, ja yhteys tulehdustekijöihin osoittaa, että ihmisen resistiinin toiminta liittyy tulehdustiloihin. Resistiini aiheuttaa myös endoteelisoluissa samanlaisia ateroskleroosille altistavia muutoksia kuin muutkin tulehdustekijät. Tulevaisuudessa plasman resistiini-pitoisuutta voidaan mahdollisesti käyttää tulehdustilojen arvioinnissa
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Ramos, Rodríguez Mireia. "β-cells cis-regulatory networks and type 1 diabetes." Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/672192.
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Type 1 Diabetes (T1D) is a celltargeted autoimmune disease, leading to a reduction in pancreatic cell mass that renders patients insulindependent for life. In early stages of the disease, cells from the immune system infiltrate pancreatic islets in a process called insulitis. During this stage, a crosstalk is established between cells in the pancreatic islets and the infiltrating immune cells, mediated by the release of cytokines and chemokines. Studying the gene regulatory networks driving cell responses during insulitis, will allow us to pinpoint key gene pathways leading to cell lossoffunction and apoptosis, and also to understand the role cells have in their own demise. In the present thesis, we used two different cytokine cocktails, IFN and IFN + IL1, to model early and late insulitis, respectively. After exposing cells and pancreatic islets to such proinflammatory cytokines, we characterized the changes in their chromatin landscape, gene networks and protein profiles. Using both models, we observed dramatic chromatin remodeling in terms of accessibility and/or H3K27ac histone modification enrichment, coupled with upregulation of the nearby genes and increased abundance of the corresponding protein. Mining gene regulatory networks of cells exposed to IFN revealed two potential therapeutic interventions which were able to reduce interferon signature in cells: 1) Inhibition of bromodomain proteins, which resulted in a downregulation of IFNinduced HLAI and CXCL10 expression; 2) Baricitnib, a JAK1/2 inhibitor, which was able to reduce both IFNinduced HLAI and CXCL10 expression levels and cell apoptosis. In
cells exposed to IFN + IL1, we were able to identify a subset of novel
regulatory elements uncovered upon the exposure, which we named Induced Regulatory Elements (IREs). Such regions were enriched for T1Dassociated risk variants, suggesting that cells might carry a portion of T1D genetic risk. Interestingly, we identified two T1D lead variants overlapping IREs, in which the risk allele modulated the IRE enhancer activity, exposing a potential T1D mechanism acting through cells. To facilitate the access to these genomic data, together with other datasets relevant for the pancreatic islet community, we developed the Islet Regulome Browser (http://www.isletregulome.org/), a free web application that allows exploration and integration of pancreatic islet genomic data.
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Ferguson, Gayle Christy. "The Human Cell as an Environment for Horizontal Gene Transfer." Thesis, University of Canterbury. Biological Sciences, 2002. http://hdl.handle.net/10092/1374.
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Horizontal gene transfer (HGT) is now indisputably the predominant driving force, if not the sole force, behind speciation and the evolution of novelty in bacteria. Of all mechanisms of horizontal gene transfer (HGT), conjugation, the contact-dependent plasmid-mediated transfer of DNA from a bacterial donor to a recipient cell, is probably the most universal. First observed between bacteria, conjugation also mediates gene transfer from bacteria to yeast, plant and even animal cells. The range of environments in which bacteria naturally exchange DNA has not been extensively explored. The interior of the animal cell represents a novel and potentially medically relevant environment for gene transfer. Since most antibiotics are ineffective inside mammalian cells, our cells may be a niche for the evolution of resistance and virulence in invasive pathogens. Invading bacteria accumulate in vacuoles inside human cells, protected from antibiotics. Herein, I demonstrate the ability of intracellular Salmonella typhimurium to meet and exchange plasmid DNA by conjugation within animal cells, revealing the animal intracellular milieu as a permissive environment for gene exchange. This finding evokes a model for the simultaneous dissemination of virulence and antibiotic resistance within a niche protected from both antibiotics and the immune system and extends the variety of environments in which bacteria are known to exchange genes. Unlike conjugation between bacteria, conjugation between bacteria and eukaryotic cells requires the import of transferred DNA into the nucleus before the transferred genes can be expressed and inherited. Plant-cell nuclear transformation by the conjugation system of the Agrobacterium tumefaciens Ti plasmid is believed to be mediated by nuclear localization sequences (NLSs) carried within the proteins that accompany the T-DNA during transfer. Whether NLSs are equally important for transmission of other conjugative plasmids to eukaryotic cells is unknown. Herein, I demonstrate nuclear localization potential within the putative conjugative escort protein TraI of the IncPa plasmid RP4. In contrast, MobA, the putative escort protein from the IncQ plasmid RSF1010, lacked any clear nuclear localization potential. It is therefore likely that specific nuclear localization signals within conjugative proteins are not essential for nuclear transformation per se, although they may assist in efficient plasmid transmission.
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Patel, Amar. "The effects of human heme oxygenase-1 (hHO-1) on wild type and mutant (A30P) alpha-synuclein expression in human neuroblastoma cells /." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=98762.
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Alpha-synuclein is a major protein constituent of neuronal Lewy bodies (LB) in Parkinson's disease (PD). Astroglial over-expression of the heme-degrading enzyme, heme oxygenase-1 (HO-1) in the PD substantia nigra promotes mitochondrial iron sequestration and may sensitize dopaminergic neurons to oxidative injury (51). The effects of transient hHO-1 transfection on levels of endogenous or co-transfected alpha-synuclein (WT or A30P) were measured by Western blot in M17 cells in the presence or absence of the HO and proteasome inhibitors, SnMP and lactacystin, respectively. Deferoxamine and bilirubin were administered to sister cultures to delineate the role(s) of iron and bilirubin (heme breakdown products) on altered alpha-synuclein metabolism. hHO-1 transfection significantly decreased endogenous and transgenic WT alpha-synuclein levels, effects reversed by SnMP, lactacystin or deferoxamine (but not bilirubin), but had no effects on A30P levels. Thus, iron liberated by HO-1 over-expression may induce proteasomal degradation of WT alpha-synuclein, thereby promoting synaptic dysfunction. Conversely, failure of HO-1 to suppress mutant alpha-synuclein and its putative toxic gain of function may predispose to familial PD.
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Kito, Masao, Mitsuo Maehara, and Kazuyoshi Watanabe. "Three Types of Voltage-Dependent Calcium Currents Developing inCultured Human Neuroblastoma Cells." 名古屋大学医学部, 1999. http://hdl.handle.net/2237/6205.
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Halsey, Richard James. "Construction and characterization of chimaeric human immunodefiency virus type 1 subtype C Gag virus-like particles." Master's thesis, University of Cape Town, 2006. http://hdl.handle.net/11427/4269.
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Includes bibliographical references (leaves 114-128).In this study I explored the possibility of making HIV-1 subtype C Pr55gag-based chimaeric virus-like particles (VLPs) as a boost to the HIV-IC multigene DNA vaccine pTHr.grttnC, which encodes a modified Gag-RT-Tat-Nef fusion protein (GRTTN). Furthermore, an attempt was made to produce VLP analogues to the HIV-IA polyepitope DNA vaccine pTHr.HIVA. A range of in-frame fusions with the C-termini of myristylation-competent p6-truncated Gag and native Pr55gag were made to test how the length of polypeptide and its sequence might affect VLP formation and structure.
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Dinh, Louie. "Estimating cell type proportions in human cord blood samples from DNAm arrays." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/63224.
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Epigenome-wide association studies are used to link patterns in the epigenome to human phenotypes and disease. These studies continue to increase in num- ber, driven by improving technologies and decreasing costs. However, results from population-scale association studies are often difficult to interpret. One major chal- lenge to interpretation is separating biologically relevant epigenetic changes from changes to the underlying cell type composition. This thesis focuses on computa- tional methods for correcting cell type composition in epigenome-wide association studies measuring DNAm in blood. Specifically, we focus on a class of methods, called reference-based methods, that rely on measurements of DNAm from puri- fied constituent cell types. Currently, reference-based correction methods perform poorly on human cord blood. This is unusual because adult blood, a closely related tissue, is a case-study in successful computational correction. Several previous attempts at improving cord blood estimation were only partially successful. We demonstrate how reference-based estimation methods that rely on for cord blood can be improved. First, we validated that existing methods perform poorly on cord blood, especially in minor cell types. Then, we demonstrated how this low per- formance stems from missing cell type references, data normalization and violated assumptions in signature construction. Resolving these issues improved estimates in a validation set with experimentally generated ground truth. Finally, we com- pared our reference-based estimates against reference-free techniques, an alterna- tive class of computational correction methods. Going forward, this thesis provides a template for extending reference-based estimation to other heterogeneous tissues.Science, Faculty of
Computer Science, Department of
Graduate
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Li, Min. "Kinetic analysis of Human T-cell leukemia virus type 1 gene expression." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1228156327.
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Nakahara, Tomomi. "Modulation of the cell division cycle by human papillomavirus type 18 E4." Kyoto University, 2003. http://hdl.handle.net/2433/148728.
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Nasu, Akira. "Genetically Matched Human iPS Cells Reveal that Propensity for Cartilage and Bone Differentiation Differs with Clones, not Cell Type of Origin." Kyoto University, 2014. http://hdl.handle.net/2433/189661.
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Peat, D. S. "The effect of herpes simplex virus type 1 on chromosomes of human cells." Thesis, University of Cambridge, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383841.
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Do, Rosario Yanez Romana de Jesus. "Expression optimization of a human papillomavirus type 16 therapeutic vaccine candidate in Nicotiana benthamiana leaves." Master's thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/23410.
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High risk human papillomaviruses (HPVs) are the causative agents of cervical cancer. The three approved prophylactic vaccines do not benefit already infected individuals; therefore, there is still an urgent need for therapeutic vaccines. The HPV oncoproteins E6 and E7 are ideal targets for the development of such vaccines, as they are expressed throughout the viral life cycle and in tumours. They could be used to elicit strong cytotoxic lymphocyte (CTL) responses which would aid in viral clearance, and could also be effective against tumours. Granadillo et al. (2011) developed an Escherichia coli-produced therapeutic vaccine candidate, consisting of the HPV-16 E7 protein and a cell membrane- penetrating and immunomodulatory peptide (LALF), whose fusion to HPV-16 E7 aided in the immunogenicity and antigen presentation of the oncoprotein. However, such vaccines need not only to be effective, but also to have a low cost. Plant expression systems represent an attractive alternative to conventional expression systems based on bacterial, yeast, mammalian and other cell cultures, and are potentially far more cost- effective. The aim of the present project was to produce LALF-E7 in Nicotiana benthamiana leaves via Agrobacterium-mediated transient expression, and to optimize its expression, extraction and purification. This was done by expressing LALF-E7 using different expression vectors, testing different subcellular localizations, and testing the effect of gene silencing suppressors. By using our group's replicating expression vector and targeting LALF-E7 to the chloroplasts, the expression of the candidate vaccine in N. benthamiana leaves was increased 26.8 fold compared to non-replicating vectors or cytoplasmic localization. Furthermore, silencing suppressors did not significantly increase the expression of LALF-E7 when expressed by the replicating vector and targeted to the chloroplasts. I showed, by fluorescence microscopy, that LALE-E7 was indeed being targeted to the plants' chloroplasts and that it possibly forms proteins bodies (PBs) that are closely associated to the chloroplast envelope. I further hypothesized a mechanism by which the PBs-like structures form. Once the expression of LALF-E7 was optimized in plant leaves, a purification strategy was developed by testing different extraction methods and using metal ion affinity chromatography. The extraction protocol developed pre-purified LALF-E7 by removing the majority of soluble proteins from the final extract. However, LALF-E7 was not fully purified by affinity chromatography, suggesting that other purification strategies should be used. Finally, I tested the partially purified plant-produced LALF-E7 candidate, and compared it to the E. coli-produced counterpart, in tumour regression experiments using mice as animal models. Due to low antigen doses and a large number tumourigenic cells used to inoculate the mice animal models, the effect of the plant-produced LALF-E7 as a therapeutic vaccine was inconclusive. However, it was suggested that it could potentially be comparable to the E. coli-produced counterpart. In summary, I report for the first time the entire chain of research involving the expression of LALF-E7 in plants, its extraction, purification and the testing of its immunogenicity in a mouse model. This research also suggests new avenues for the use of the LALF peptide as a PB-inducer which could be useful in increasing the expression of other recombinant proteins.
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Pais, Correia Ana Monica. "Biofilm-like extracellular viral assemblies mediate HTLV-1 (human T cell leukemia virus type-1) cell-to-cell transmission at virological synapses." Paris 7, 2009. http://www.theses.fr/2009PA077233.
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Près de 20 millions d'individus sont infectés par HTLV-1 (human T cell leukemia virus type-1). La plupart des patients n'ont aucun symptôme, seulement 5-10% d'entre eux développeront des maladies associées à l'infection virale. La particularité d'HTLV-1 est de se transmettre par des contacts cellulaires désignés « synapses virologiques », qui partagent certaines caractéristiques avec les synapses immunologiques. Ce projet a permis de mieux comprendre le processus de transmission cellule à cellule et introduit un nouveau concept de transmission virale par des « biofilms viraux ». Contrairement à ce qui avait été suggéré, nous démontrons qu'HTLV-1 s'accumule à la surface des cellules infectées, dans des structures composées de matrice extracellulaire (HSPG agrine, collagène) et de molécules de type « linker » (galectine, tetherine). Ces structures facilitent l'adhésion et la cohésion du virus et sont essentielles pour une transmission virale efficace, car leur détachement diminue fortement l'infection de cellules cibles («80%). Les structures que nous avons décrites concentrent et protègent le virus, permettent son stockage et aident à sa propagation. Ces caractéristiques ressemblent à celles des biofilms bactériens ou des champignons. Ainsi, nous proposons le nom « biofilm viral» pour désigner ce nouveau processus de transmission viraleApproximately 20 million people are infected by HTLV-1 (human T cell leukemia virus type-1). Although the majority of infected individuals remain asymptomatic, around 10% will develop HTLV-1-associated disease. HTLV-1 has been described to efficiently propagate through cell-cell contacts. Designated as virological synapses, these cellular contacts exhibit some of the characteristics of immunological synapses. This project has allowed a better comprehension of how HTLV-1 propagates from cell-to-cell and proposes a completely novel concept of virus transmission through 'viral biofilms'. Contrary to what was previously suggested we have shown that HTLV-1 is accumulated at the surface of infected cells, in extracellular viral assemblies. Viral assemblies are composed of extracellular matrix (HSPG agrin, collagen) and linker molecules (galectin, tetherin) that provide the adhesion and cohesion forces needed to maintain viruses at the cell surface. More importantly, we have shown that HTLV- 1 viral assemblies contribute to the majority of virus cell-cell transmission since their removal significantly inhibits infection (« 80%). Viral assemblies, store, concentrate, disseminate and protect the virus. These characteristics recapitulate most of the features of bacterial or fungal biofilms. Therefore, we propose the use of the term 'viral biofilm' to designate this new mode of cell-to-cell virus spread
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Kohl, Thomas Oliver. "An investigation into the development of plant-derived vaccines against human papillomavirus type 11 and Cottontail rabbit papillomavirus." Doctoral thesis, University of Cape Town, 2004. http://hdl.handle.net/11427/7433.
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Includes bibliographical references (leaves 207-241).The principal object of this thesis was to investigate the feasibility of developing a novel plant-derived vaccine against Human papillomavirus type 11 (HPV -11), the causal agent of genital warts and laryngeal condylomas. A secondary objective was a proof-of-concept study using Cottontail rabbit papillomavirus (CRPV), as this is a viable animal model for human papillomavirus vaccines. Accordingly, I investigated and compared the potential of two different plant expression systems.
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Lambeth, Cassandra Rashida De Silva Aravinda Manu. "Interactions between dengue type 3 viruses and human dendritic cells." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1238.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.Title from electronic title page (viewed Mar. 26, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Microbiology and Immunology in the School of Medicine." Discipline: Microbiology and Immunology; Department/School: Medicine.
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Sayers, Charlotte. "Herpes simplex virus type 1 infection of human keratinocyte cells." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/11112.
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Infection of herpes simplex virus type 1 (HSV-1) begins at the epidermis, a stratified layer composed primarily of keratinocytes. The physiologically relevant cell type for the study of HSV-1 assembly is therefore the human keratinocyte. Nonetheless, relatively little is known about the replication of HSV-1 in this natural host cell. Comparison of virus growth in monolayers of keratinocyte cells and Vero cells, a routinely used cell line for HSV-1 studies, revealed that these keratinocytes support a more productive virus replication than Vero cells. Furthermore, newly assembled virus is produced more rapidly in keratinocytes and this enhancement occurs prior to, or upon the initiation of immediate early gene transcription. This augmented replication in keratinocytes can be at least partially attributed to the method of entry of the virus. We have found by penetration assays and electron microscopy that the virus is able to penetrate keratinocyte cells much more rapidly than Vero cells. We have also shown that the virus entry mechanism is more efficient at lower temperatures in nTERT cells, with virus entering cells at temperatures as low as 7°C. Additionally preliminary work implies that depletion of one of the herpes virus entry receptors, Nectin-1, does not affect entry into nTERT cells, whereas entry is reduced up to 65% in HeLa cells. Taken together, these results imply a role for other entry receptors, possibly as yet unidentified, in the entry of human keratinocyte cells. This work also identifies a role for cellular Rab proteins, GTPases essential for the regulation of vesicle trafficking, in HSV-1 infection of keratinocytes. In particular Rab6, which was also found to play a role in infected HeLa cells (Elliott Group), appears to have a similar function in both these cells and together support a model for HSV-1 morphogenesis involving Rab-regulated vesicle trafficking of viral glycoproteins to the cell surface. Several other Rabs identified by this screen now provide interesting opportunities to elucidate further roles of Rab proteins in HSV-1 infection of keratinocyte cells. This project has broadly characterised the replication of HSV-1 in keratinocyte cells and explored the role of Rab GTPases in virus trafficking within keratinocytes - a cell type that is physiologically relevant to infection.
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Greatorex, Jane. "Studies of the dimer linkage of human T-cell leukaemia virus type 1." Thesis, Open University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298172.
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Yamamoto, Brenda Michiyo. "Molecular Analysis of Human T-cell Leukemia Virus Type 2 Accessory Protein p28." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1241708950.
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Doueiri, Rami. "CHARACTERIZATION OF THE HUMAN T-CELL LEUKEMIA VIRUS TYPE-2 P28 ACCESSORY PROTEIN." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1343453789.
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