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Dissertations / Theses on the topic 'Viral disease'
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1
Gangadharan, Bevin. "Proteomics in viral disease." Thesis, University of Oxford, 2006. http://ora.ox.ac.uk/objects/uuid:c66c53ed-a824-4f99-8f2b-d2bc65a984c7.
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The separation, identification, and characterisation of the proteins present in a tissue or biological sample is called ‘proteomics’. This technique can be used for example to identify biomarkers and investigate signalling pathways. Increasingly, proteomics is being applied to the analysis of virus related samples; here two such examples are described. Presently there is no reliable non-invasive way of assessing liver fibrosis. Here a novel 2D-PAGE based proteomics study was used to identify potential fibrosis biomarkers. Serum from patients with varying degrees of hepatic scarring induced by infection with the hepatitis C virus (HCV) was analysed. Several proteins associated with liver scarring and/or viral infection were identified. The most prominent changes were observed when comparing serum samples from cirrhotic patients with healthy controls: Expression of inter-α-trypsin inhibitor heavy chain H4 fragments, α1 antichymotrypsin, apolipoprotein L1 (Apo L1), prealbumin and albumin was decreased in cirrhotic serum, whereas CD5 antigen like protein (CD5L) and β2 glycoprotein I (β2GPI) increased. In general, α2 macroglobulin (a2M) and immunoglobulin components increased with hepatic fibrosis whereas haptoglobin and complement components (C3, C4 and factor H-related protein 1) decreased. Novel proteins associated with HCV-induced fibrosis include the inter-alpha-trypsin inhibitor heavy chain H4 fragments, complement factor H-related protein 1, CD5L, Apo L1, β2GPI and the increase in thiolester cleaved products of a2M. The relationship between these changes is discussed. One of the accessory genes of the HIV viral genome encodes for the Nef protein. Nef is present in lipid rafts and increases viral replication within infected host cells by binding to a guanine nucleotide exchange factor, Vav. This leads to activation of a GTPase, Cdc42, however, the signalling pathway is poorly understood. 2D-PAGE based proteomics was used to identify differentially expressed raft-associated proteins by comparing T cells in the presence and absence of Nef. A ubiquitin conjugating enzyme UbcH7, which acts in conjugation with c-Cbl, was absent from the rafts of Nef-transfected cells. Vav ubiquitination was also absent from these rafts. In collaboration with Dr. Alison Simmons and Prof. Andrew McMichael the absence of UbcH7 in rafts was found to be caused by β-Pix forming a ternary complex with c-Cbl and activated Cdc42. Vav ubiquitination was restored and viral replication was diminished when β-Pix was knocked down providing a new candidate target for inhibiting HIV replication. This thesis demonstrates the use of proteomics in providing novel information for virus related samples. This influential technology benefits in both biomarker discovery to aid clinicians with early diagnosis of diseased individuals and in the elucidation of novel signalling pathways in infected cells to provide new candidate targets.
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Fleeton, Marina N. "Genetic vaccination against acute viral disease /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3811-3/.
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Leo, Nancy Stefany. "Viral Antibodies and Immunoregulation in Autoimmune Disease." Thesis, The University of Arizona, 2012. http://hdl.handle.net/10150/271610.
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The link between autoimmune diseases and viral infections has long been under scrutiny, with potential mechanisms including viral persistence and viral transactivation of cellular cytokine promoters coupling the two phenomenon. In this study, the relationship between autoimmune disease and the persistence of non-structural NS1 human parvovirusB19 (B19V) protein in serum from patients with SLE and RA was investigated. The hypothesis was that due to a failure in the viral host’s ability to silence persistent viral protein transcripts, non-structural NS1 protein remains elevated in individuals with autoimmune disease (post-infection) and contributes to exacerbation of the disease. To test this hypothesis, anti-PARVO non-structural NS1 antibodies were detected in the serum of 15 SLE subjects. B-cell hybridomas from a patient with SLE secreting elevated levels of anti-PARVO non-structural NS1 IgG were generated, which secreted stable human IgG mAbs specific to non-structural NS1. Six mAb hybridoma sub-clones were isolated with low binding titers to the full length (FLNS1). The sub-clones, however, demonstrated increased binding activity to the nuclease domain of NS1. Optimization of the mAb screening system will be performed for future research, which will facilitate the purification and characterization of the human anti-PARVO non-structural NS1 mAbs.
4
Quinlivan, Mark Lee. "Viral genetic variation in varicella zoster virus disease." Thesis, Queen Mary, University of London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418302.
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Stoppelkamp, Sandra. "New viral and transgenic models of Alzheimer's disease." Thesis, University of Aberdeen, 2010. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=136906.
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Mutated human genes associated with human neurodegenerative conditions were used to develop both in vitro and in vivo models to study cellular pathology and disease progression. The in vitro models employed adenoviral vectors for the gene delivery into primary rat hippocampal neurones. Introduction of both APP and Tau transgenes reduced neuronal viability, with the latter leading to accelerated toxicity and faster onset of cell death. Time-lapsing imaging analyses revealed apoptosis-like features for APP-positive neurones, while Tau-positive neuronal death appeared more necrotic. Interestingly, a direct correlation between cell death and protein content in the APP-transduced neurones was not confirmed. A comparison between viral gene delivery and electroporation with the same transgenic constructs confirmed the cellular toxicity of APP and Tau but also showed that with a lower amount of transgene expressing cells per culture dish Tau-induced toxicity was no longer as aggressive as with the viral model. Therefore, electroporation may allow single-cell investigations of functional parameters whereas the large amount of transgene-positive neurones in viral transductions allows faster quantification of cell death. These methods complement each other and thus offer in vitro models suitable for mechanistic studies and drug screening. Accordingly, initial testing of inhibitors of Tau aggregation and amyloid formation were found to ameliorate the transgene-induced damage as proof of principle for our novel in vitro models. Further testing revealed caffeine to be a very promising drug candidate in AD treatment, since it improved viability in both APP and Tau transduced neurones. The transgenic PLB1 mouse knock-in model harbours the same mutated APP and Tau genes as the viral models. A triple transgenic line (PLB1Triple) has been generated with additional mutated presenilin 1 for increased APP processing and accelerated pathology. The mRNA expression of both APP and Tau transgenes was stable over the investigated time (6 and 12 months) with about 2 to 3-fold higher APP over Tau mRNA levels. This expression was specific to the forebrain and negligible in the cerebellum and thus targets a brain region that is vulnerable in AD. The model showed progressive accumulation of AD-linked histopathological features as well as memory- and activity-related symptoms. This low transgene expression in conjunction with a progressive phenotype is advantageous over other aggressive animals models for studying early disease-related pathology.
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Agarwal, Kaushik. "Immunogenetic studies in autoimmune and viral liver disease." Thesis, University of Newcastle upon Tyne, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275585.
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Silverstein, Noah J. "Disease Tolerance, Epigenetic Inheritance, and Surviving Pathogenic Viral Infections." eScholarship@UMMS, 2021. https://escholarship.umassmed.edu/gsbs_diss/1149.
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Health is often defined in terms of absence of disease or pathological processes, but this is a definition of exclusion and incomplete. For example, SARS-CoV-2 viral load does not reliably predict disease severity, and so individuals must vary in their ability to control inflammation and maintain normal tissue homeostasis. This host defense strategy is called disease tolerance, and better understanding of disease tolerance mechanisms could change the way that we treat disease and work to maintain health.
The first project presented in this dissertation found that after accounting for effects of age and sex, innate lymphoid cells (ILCs), but not T cells, were lower in adults and children sick with COVID-19 or MIS-C, independent of lymphopenia. Furthermore, abundance of ILCs, but not of T cells, correlated inversely with disease severity. These blood ILCs were shown to produce amphiregulin, a protein implicated in disease tolerance and tissue homeostasis, and the percentage of amphiregulin-producing ILCs was lower in males. These results suggest that, by promoting disease tolerance, homeostatic ILCs decrease morbidity and mortality associated with SARS-CoV-2 infection, and that lower ILC abundance accounts for increased COVID-19 severity with age and in males.
The second project describes a novel mouse model of epigenetic inheritance wherein paternal influenza A virus (IAV) infection results in less severe influenza disease in IAV infected offspring. This offspring phenotype was not attributable to differences in viral load, indicating a possible difference in disease tolerance. Paternal caloric deprivation decreased, and influenza B virus infection increased, offspring influenza disease severity, and in vitro fertilization demonstrated sperm are sufficient to transfer IAV-associated epigenetic inheritance phenotypes.
These findings represent a foundation for further work that, by continuing to elucidate the mechanisms of disease tolerance and epigenetic inheritance, could provide novel therapeutic interventions to help promote and maintain health.
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Dovigi, Allan Webster-Cyriaque Jennifer. "HIV salivary gland disease a role for viral infection /." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2005. http://dc.lib.unc.edu/u?/etd,297.
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Thesis (M.S.)--University of North Carolina at Chapel Hill, 2006.Title from electronic title page (viewed Oct. 10, 2007). "... in partial fulfillment of the requirements for the degree of Master of Science in the Department of Oral and Maxillofacial Pathology School of Dentistry." Discipline: Oral and Maxillofacial Pathology; Department/School: Dentistry.
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Nitsovych, I. R. "Treatment of polyhydramnios caused by acute respiratory viral disease." Thesis, БДМУ, 2021. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/18719.
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Moody, Adrian John. "Mapping genetic resistance to infectious bursal disease." Thesis, University of Reading, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326754.
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Zaid, Ali, and n/a. "IMMUNE EVASION AND DISEASE MECHANISMS IN ROSS RIVER VIRUS INFECTION." University of Canberra. Biomedical Sciences, 2008. http://erl.canberra.edu.au./public/adt-AUC20091216.122508.
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Ross River virus (RRV) is an Alphavirus distributed throughout Australia. It is transmitted by
mosquitoes and is known to cause moderate to severe disease symptoms in humans. Along with
other alphaviruses such as Sindbis virus and Chikungunya virus, RRV is known to cause arthritic
symptoms, characterised by muscle and joint inflammation. Several investigations have established
the role of macrophage cells and pro-inflammatory host factors in the development of RRV-induced
disease.
In this study, we attempted to determine differences between RRV passaged in mammalian and
mosquito cells. There is strong evidence that arthropod-borne viruses are able to display enhanced
infectivity when passaged into arthropod cell line. We showed that mosquito cell-derived RRV
(mos-RRV) was able to replicate to higher titres than mammalian cell-derived RRV. We also
showed that mos-RRV failed to induce Type I IFN-associated antiviral responses.
The second aim of this study was to investigate the role of TNF-ᬠa pro-inflammatory cytokine
implicated in arthritic diseases, in the development of RRV disease. We treated RRV-infected
C57BL/6J mice with a commercially available TNF-ᠩnhibitor drug and monitored disease signs.
We found that the TNF-ᠩnhibitor does not ameliorate RRV disease (RRVD) symptoms, and that it
does not prevent muscle and joint inflammation. We analysed histological sections of muscle and
joint tissue of Enbrel-treated and untreated, RRV-infected cells. We also determined and compared
host cytokine expression profiles.
Finally, we sought to determine the requirement for natural killer (NK) cells in RRV disease. NK
cells have been detected in the synovium of RRV-infected patients since early studies, but their role
in disease pathogenesis remains unclear. Using a NK-dysfunctional mouse (C57BL/6J-Lystbg), we
showed that mice lacking a functional NK system are more susceptible to RRV disease than wildtype,
C57BL/6J mice. We monitored disease symptoms following RRV infection and assessed
muscle and joint inflammation in Lystbg and C57BL/6J mice.
This thesis examines mechanisms of viral infection and immune evasion employed by RRV, as well
as into the role of host cells and cytokines in RRVD pathogenesis disease mechanisms. We showed
that a functional NK cell system is required for the regulation of RRV-induced muscle and joint
inflammation. Our characterisation of the use of a commercial TNF-ᠩnhibitor in RRV-induced
disease in mice may provide information on the role of TNF-ᠩn viral arthritis, and may help
towards developing safe and effective treatment.
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Larsson, Anna-Karin. "Early life cytokines, viral infections and IgE-mediated allergic disease." Doctoral thesis, Stockholm : Wenner-Gren Institute for Experimental Biology, Stockholm university, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-1224.
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Ribeiro, Ruy Miguel. "Models of viral diversity and disease development in HIV infection." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302403.
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McManus, T. E. "Viral infection and associated inflammation in chronic obstructive pulmonary disease." Thesis, Queen's University Belfast, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426766.
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Türe, Olcay. "Studies on the viral proteins of infectious bursal disease viruses /." The Ohio State University, 1991. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487757723997915.
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Wark, Kim Louise. "Expression and processing of infectious bursal disease virus proteins." Thesis, University of Hertfordshire, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323651.
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Ashraf, Shamaila. "Studies on infectious bursal disease virus." Connect to resource, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1124124381.
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Thesis (Ph. D.)--Ohio State University, 2005.Title from first page of PDF file. Document formatted into pages; contains xvi, 216 p.; also includes graphics (some col.). Includes bibliographical references (p. 180-216). Available online via OhioLINK's ETD Center
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Zhang, Xu-Sheng. "Mathematical models of plant disease epidemics that involve virus interactions." Thesis, University of Greenwich, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.327341.
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Millar, N. S. "Molecular cloning and sequence analysis of Newcastle disease virus." Thesis, University of Newcastle Upon Tyne, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.380750.
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Frisan, Teresa. "Mechanisms of immune escape in EBV associated malignancies : Hodgkin's disease and Burkitt's lymphoma /." Stockholm : Karolinska institutet, 1999. http://diss.kib.ki.se/1999/91-628-3660-9/.
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Yip, Chi-wai. "Characterization of cellular receptors of infectious bursal disease virus in chickens." Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B36759533.
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Wikramaratna, Paul Silva. "The evolution of viral diversity." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:1d718b15-af79-4567-84ef-f97f61f75369.
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This thesis focuses on the population dynamics of three antigenically diverse RNA viruses: dengue, influenza and HIV-1. It comprises a set of studies highlighting the roles of structural constraints on critical antigenic determinants, interactions between immune responses to different antigenic types, host lifespan, and the degree of mixing between different host populations in determining the epidemiology and within-host dynamics of these pathogen systems. Dengue exists in humans as a collection of four antigenically related serotypes. Although infection by one serotype appears to convey life-long protection to homologous infection, it is believed to be a risk factor for severe disease manifestations upon secondary, heterologous infection due to the phenomenon of Antibody-Dependent Enhancement (ADE). It is not clear if third or fourth infections are possible, and if so, how they contribute to dengue epidemiology. In this thesis, I investigate the effect of third and fourth infections on the transmission dynamics of dengue. By contrast with dengue, human influenza viruses are known to be in rapid antigenic flux, manifesting in the sequential replacement of antigenic types. This pattern of evolution does not appear to be the same in shorter-lived hosts such as swine and birds. In this thesis, I have used a simple multi-locus model to explore the relationship between host lifespan and viral evolution, as well as to elucidate the effects of transmission between hosts of different lifespan in effort to capture the cross-species element of influenza transmission. My final chapter concerns the within-host evolution of HIV-1. I propose a new model for the pathogenesis of HIV-1 where the transition to AIDS is primarily linked to the gradual loss of the ability to make new antibody responses as the CD4+ population declines. Together these studies emphasise that it is the changing profile of immune responses – either at the population level or within the host – that is the principal determinant of the dynamics of the pathogen, rather than the mode and tempo of antigenic innovation.
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Dalmau, Moreno Judith. "Viral and host factors involved in rapid HIV-1 disease progression." Doctoral thesis, Universitat Autònoma de Barcelona, 2014. http://hdl.handle.net/10803/133268.
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Els éssers humans mostren una notable variació en el desenvolupament clínic rere la infecció per VIH-1. Si bé algunes persones amb VIH-1 són capaces de suprimir la replicació viral del VIH a nivells molt baixos (<2000 còpies/ml) i/o mantenir els recomptes de CD4 alts durant molts anys en absència de teràpia antiretroviral (Controladors), altres progressen ràpidament a sida o compleixen els criteris actuals per a iniciar tractament antiretroviral en els 3 primers anys rere la infecció primària (Progressors ràpids, RP). D'altra banda, una minoria d'individus amb alts nivells de virèmia roman asimptomàtica i manté els recomptes de cèl·lules T CD4+ elevats (Virèmics no progressors, VNP), similars als observats en el model no progressiu d’infecció per SIV en l’hoste natural.
L'estudi de fenotips extrems pot donar informació rellevant en termes de les interaccions que s'estableixen entre el virus i l'hoste durant la infecció primària pel VIH, així com de l'evolució clínica posterior a la infecció. De fet, l'estudi dels controladors (incloent els controladors d’elit, que mantenen l’ARN viral a nivells indetectables) està proporcionant dades rellevants de la immunopatogènesi de la infecció. L'extrem oposat són els RPs, els quals representen un percentatge relativament petit de la població infectada per VIH-1. No obstant això, les implicacions de les seves característiques immunogenètiques i immunopatogèniques són notables .
Aquesta tesi té el seu origen en l’estudi exhaustiu de 2 casos de progressió extremadament severa i ràpida, que posteriorment es va estendre a la creació i l'estudi d'una cohort gran i ben definida de RPs sense precedents. L'objectiu específic va ser investigar una àmplia gamma de factors virals i de l'hoste implicats en la progressió ràpida de la infecció per VIH-1, en comparació amb altres fenotips, incloent individus amb un perfil estàndard de progressió (progressors estàndard, SP) i VNPs.
Els resultats d'aquest estudi demostren la convergència de factors virals i de l'hoste que contribueixen a la gravetat clínica de la progressió ràpida. Les persones infectades amb virus altament replicatius, dual-tròpics i HLA-adaptats van mostrar ser més propenses a desenvolupar símptomes definitoris de SIDA durant la infecció primària per VIH-1, donat que en molts casos tampoc no són capaces de produir respostes immunitàries humorals i cel·lulars específiques contra VIH-1. La concordança de supertipus d’HLA, la presència d'al·lels d’HLA comuns i d’al·lels de risc, i la baixa freqüència d’al·lels protectius, també van mostrar associació amb l’acceleració de la malaltia. A més, l'anàlisi del transcriptoma va revelar que els RPs tenen un perfil transcriptòmic específic a les cèl·lules T CD4+ i CD8+, similar a l'observat en la infecció patogènica per SIV en rhesus macacs, i caracteritzat per una major expressió de gens estimulats per l'interferó. Els VNPs, en canvi, es caracteritzen per un perfil de regulació de gens similar a la infecció no patogènica per SIV dels sooty mangabeys.
El present estudi proporciona informació rellevant sobre les característiques virals i de l’hoste implicades en la progressió ràpida de la infecció per VIH-1, la qual té implicacions destacables en el nostre coneixement de la patogènesi del VIH-1 i en la importància de la monitorització primerenca de l'evolució de la malaltia.Remarkable variation in clinical outcome can be observed following HIV-1 infection. While some HIV-1–infected individuals are able to suppress viral replication to very low levels (<2000 copies/mL) and/or maintain high CD4+ T-cell counts over many years without antiretroviral therapy (HIV controllers), others quickly progress to AIDS or meet the current criteria for antiretroviral treatment within the first 3 years after primary infection (rapid progressors, RP). Furthermore, a minority of highly viremic individuals remain asymptomatic with high CD4+ T-cell counts (viremic non-progressors, VNP), similar to those observed in the non-progressive disease model of SIV infection in natural hosts. The study of extreme phenotypes can provide important information on the interactions established between the viral variant and the host during primary HIV infection and the subsequent clinical evolution of the infection. Indeed, the study of HIV controllers (including elite controllers, who maintain plasma viral RNA under detectable levels [<50 copies/mL]) is providing relevant data on HIV immunopathogenesis. The other extreme comprises RPs, who account for a relatively small percentage of the HIV-1-infected population. Nevertheless, the implications of their immunogenetic and immunopathogenic characteristics are remarkable. This thesis originates from the comprehensive study of 2 cases of extremely severe rapid progression that was later extended to the recruitment and study of an unprecedentedly large and well-defined cohort of RPs. The specific objective was to investigate a wide range of viral and host factors involved in rapid progression of HIV-1 infection, in contrast to other phenotypes, namely, individuals with an average progression profile (standard progressors, SP) and VNPs. The results of this study demonstrate convergence of the viral and host factors contributing to the clinical severity of rapid progression. Individuals infected with highly replicative, dual-tropic, HLA-adapted viruses were shown to be more prone to develop AIDS-defining symptoms during primary HIV-1 infection, since in many cases they are also unable to mount humoral and cellular HIV-1-specific immune responses. Concordant HLA supertypes between the source and the recipient, the presence of common and risk HLA class I alleles, and the low frequency of protective HLA alleles were also shown to further accelerate disease progression. In addition, transcriptome analysis Revealed that RPs have a specific CD4+ and CD8+ T-cell transcriptome profile similar to that observed in pathogenic SIV-infected rhesus macaques and characterized by higher expression of interferon-stimulated genes. VNPs, on the other hand, were characterized by a gene regulation profile similar to that of non-pathogenic SIV-infected sooty mangabeys. The present study provides important insights into the host and viral traits driving progression of HIV-1 infection, which have relevant implications for our knowledge of HIV pathogenesis and the importance of early monitoring of disease course.
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Axdorph, Ulla. "Clinical and immunopathological studies in Hodgkin's disease with special reference to prognosis /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4442-3/.
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Ramaley, Patricia A. "Host genetics of HIV-1 infection and disease progression in Uganda." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365714.
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Carlsson, Beatrice. "Human Caliciviruses: a study of viral evolution, host genetics and disease susceptibility." Doctoral thesis, Linköpings universitet, Molekylär virologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-76036.
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The viruses described in this thesis are the norovirus and sapoviruses, which belong to the family of human caliciviruses and are known to cause gastroenteritis in humans. Gastroenteritis has emerged as a global health problem and is based on the large number of infected considered as one of the most common diseases today. According to estimates of the World Health Organization (WHO), gastroenteritis causes over five times more pediatric deaths compared to pediatric deaths caused by HIV/AIDS worldwide. Norovirus, the cause of the famous “winter vomiting disease”, is alone responsible for more than 200 000 deaths each year in children less than 5 years of age. The mechanism for emergence and evolution of new human calicivirus strains, as well as protective immunity in the human population is poorly understood. The main focus for this thesis was to elucidate the possible correlation between human calicivirus evolution, host genetics and disease susceptibility. One of the main findings presented in this thesis is the documentation of in vivo capsid gene evolution and quasispecies dynamics during chronic NoV GI.3 infection (Paper 1). In paper II, we reported that the G428A nonsense mutation in the FUT2 gene provides strong but not absolute protection against symptomatic GII.4 NoV infection. In my last two papers (Paper III and IV), we were the first to investigate host genetic susceptibility factors during authentic SaV infection. To summarize, the results presented in this thesis show that the success of human calicivirus infection probably is determined by a delicate interplay between virus evolution and susceptibility of the host, both genetically and immunologically.
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Choudhury, Sourav Roy. "Developing an Adeno-Associated Viral Vector (AAV) Toolbox for CNS Gene Therapy: A Dissertation." eScholarship@UMMS, 2001. http://escholarship.umassmed.edu/gsbs_diss/809.
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Neurological disorders – disorders of the brain, spine and associated nerves – are a leading contributor to global disease burden with a sizable economic cost. Adeno-associated viral (AAV) vectors have emerged as an effective platform for CNS gene therapy and have shown early promise in clinical trials. These trials involve direct infusion into brain parenchyma, an approach that may be suboptimal for treatment of neurodegenerative disorders, which often involve more than a single structure in the CNS. However, overall neuronal transduction efficiency of vectors derived from naturally occurring AAV capsids after systemic administration is relatively low. We have developed novel capsids AAV-AS and AAV-B1 that lead to widespread gene delivery throughout the brain and spinal cord, particularly to neuronal populations. Both transduce the adult mouse brain >10-fold more efficiently than the clinical gold standard AAV9 upon intravascular infusion, with gene transfer to multiple neuronal sub-populations. These vectors are also capable of neuronal transduction in a normal cat. We have demonstrated the efficacy of AAV-AS in the context of Huntington's disease by knocking down huntingtin mRNA 33-50% after a single intravenous injection, which is better than what can be achieved by AAV9 at the particular dose. AAVB1 additionally transduces muscle, beta cells, pulmonary alveoli and retinal vasculature at high efficiency, and has reduced sensitivity to neutralizing antibodies in human sera. Generation of this vector toolbox represents a major step towards gaining genetic access to the entire CNS, and provides a platform to develop new gene therapies for neurodegenerative disorders.
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Choudhury, Sourav Roy. "Developing an Adeno-Associated Viral Vector (AAV) Toolbox for CNS Gene Therapy: A Dissertation." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/809.
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Neurological disorders – disorders of the brain, spine and associated nerves – are a leading contributor to global disease burden with a sizable economic cost. Adeno-associated viral (AAV) vectors have emerged as an effective platform for CNS gene therapy and have shown early promise in clinical trials. These trials involve direct infusion into brain parenchyma, an approach that may be suboptimal for treatment of neurodegenerative disorders, which often involve more than a single structure in the CNS. However, overall neuronal transduction efficiency of vectors derived from naturally occurring AAV capsids after systemic administration is relatively low. We have developed novel capsids AAV-AS and AAV-B1 that lead to widespread gene delivery throughout the brain and spinal cord, particularly to neuronal populations. Both transduce the adult mouse brain >10-fold more efficiently than the clinical gold standard AAV9 upon intravascular infusion, with gene transfer to multiple neuronal sub-populations. These vectors are also capable of neuronal transduction in a normal cat. We have demonstrated the efficacy of AAV-AS in the context of Huntington's disease by knocking down huntingtin mRNA 33-50% after a single intravenous injection, which is better than what can be achieved by AAV9 at the particular dose. AAVB1 additionally transduces muscle, beta cells, pulmonary alveoli and retinal vasculature at high efficiency, and has reduced sensitivity to neutralizing antibodies in human sera. Generation of this vector toolbox represents a major step towards gaining genetic access to the entire CNS, and provides a platform to develop new gene therapies for neurodegenerative disorders.
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Peacey, Matthew, and n/a. "Creation and investigation of a versatile Rabbit haemorrhagic disease virus-like particle vaccine." University of Otago. Department of Microbiology & Immunology, 2008. http://adt.otago.ac.nz./public/adt-NZDU20080215.155033.
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There is a need to develop a range different VLP for use as nanoscale templates and vaccines. The aim of this research was to develop RHDV VLP as a versatile vaccine delivery system easily modified for use against a wide range of different diseases.
Production of Rabbit haemorrhagic disease virus (RHDV) capsid protein in a baculovirus system led to the self-assembly of Virus-like Particles (VLP) that could be purified to greater than 99% purity using simple methods. The capsid gene, vp60, can be manipulated genetically to incorporate immunogenic peptide sequences or a functional DNA-binding site. Fusion of these small epitopes to VP60 was well tolerated, forming VLP and greatly enhanced the presentation of peptide to, and activation of CD4+ T helper cell hybridoma. To avoid constraints imposed on chimeric VLP and dramatically increase the versatility of RHDV VLP, rapid conjugation of antigen was carried out, employing the hetero-bifunctional chemical linker, sulpho-SMCC. Incorporation of sulfhydral groups by design or treatment with SATA allowed for great versatility, in turn enabling many diverse peptides and proteins to be conjugated to VLP.
RHDV VLP and consequently the conjugated GFP antigen were efficiently taken up by DC with more than 85% of DC positive for GFP by flow cytometry. This was also visualised by confocal microscopy and electron microscopy of both gold- labelled VLP and conjugated antigen. RHDV VLP conjugate was shown to induce the significant up regulation of the activation markers CD40, CD80, CD86 and MHC class II on the surface of dendritic cells (DC). As well, DC pulsed with RHDV VLP/OVA effectively presented OVA to both CD4+ and CD8+ T cells transgenic for respective peptide-specific T cell receptors, eliciting a greater proliferative response in both T cell subsets than antigen delivered alone.
The surface accessibility of peptides on VLP was demonstrated, while administration of VLP/Ovalbumin (OVA) conjugate in mice was shown to evoke very high titre antibody responses specific for conjugated antigen. VLP/OVA conjugates were also shown to induce IFN-γ production and OVA-specific cytotoxic killing in vivo, of up to 80% of fluorescently labelled, adoptively transferred target cells. No distinguishable cytotoxicity was detected in unimmunised control mice. This assay was also used to demonstrate the necessity for antigen to be conjugated to VLP, as antigen mixed with VLP induced only sub-optimal killing.
To investigate the anti-tumour effects, mice vaccinated with VLP conjugated to OVA protein, CD4+ or CD8+ T cell OVA epitopes were inoculated with B16- OVA tumour cells and monitored for tumour growth. Untreated control mice had to be sacrificed by day 19, while mice immunised with either VLP/OVA or VLP conjugated with both CD4+ and CD8+ OVA epitopes, showed a significant delay in tumour growth (P = 0.0002), with one mouse remaining free of palpable tumour until day 92.
These results show that RHDV VLP can be easily produced and purified and demonstrate the versatility of this RHDV capsid. Rapid conjugation techniques allowed the modification of VLP with both peptide and protein rendered these antigens highly immunogenic, stimulating both humoral and cell-mediated immunity targeted against conjugated antigens of choice. The versatility and immune stimulating properties of RHDV VLP provides a molecular tool with almost limitless applications within the fields of nanotechnology and immunology.
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Kapulu, Melissa Chola. "Pre-clinical development of viral vectored transmission-blocking malaria vaccines." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:a5610025-28e1-433f-9487-aaa1f6d641a0.
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Malaria transmission-blocking vaccine candidate antigens have been developed to induce antibodies using different delivery systems, mainly protein-in-adjuvant formulations, independently in various laboratories giving varied transmission-blocking activity (TBA). However, only one candidate antigen has been tested in clinical trials. In order to advance the most efficacious target(s) for possible clinical development, a rank order of the leading antigens based on TBA in a head-to-head comparison using a single delivery platform was made. Candidate antigens, AnAPN1, PfsHAP2, Pfs230-C, Pfs25, and Pfs48/45 (with or without N-glycosylation site substitution), were generated as recombinant viral-vectored vaccines using simian adenovirus and modified vaccinia Ankara and administered to mice in a heterologous prime-boost regimen. Vaccine-induced antibody responses were induced to all except PfsHAP2 were maintained up to ten and a half months post-boost. TBA was assessed at the peak response against Plasmodium falciparum NF54 laboratory strain and African field isolates by ex vivo membrane feeding assays in Anopheles stephensi and A. gambiae respectively. Antibodies to three antigens [Pfs230-C, Pfs25 and Pfs48/45+NGln] had TBA against P. falciparum NF54, and those against Pfs230-C and Pfs25 consistently showed efficacy regardless of the parasite exposure in both mosquito species. Further analysis of antibody responses to these two candidate antigens showed concentration-dependent efficacy against P. falciparum field isolates. In a rabbit study, responses to Pfs230-C, Pfs25 and Pfs48/45+NGln also showed IgG concentration-dependent efficacy. To assess TBA against AnAPN1, antibody responses to three fragments were tested. TBA was observed only against N-terminal 135 amino acid fragment. Pfs230-C and Pfs25 were generated as fusion vaccines using either a self-cleaving or glycine-proline linker sequence. Comparable antibody responses were induced between the two fusion strategies that had synergistic effects at inhibiting P. falciparum NF54 development in A. stephensi.
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Rudd, Matthew Francis, and mikewood@deakin edu au. "Virulence determinants of infectious bursal disease virus." Deakin University. School of Biological and Chemical Sciences, 2003. http://tux.lib.deakin.edu.au./adt-VDU/public/adt-VDU20050825.103742.
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The very virulent (vv) pathotype of infectious bursal disease virus (IBDV) has spread rapidly throughout Europe, Asia, and the Middle East. Although Australia is currently unaffected, there remains the potential for incursion of an exotic isolate. The aim of this study was to identify putative virulence determinants of IBDV to facilitate the development of improved diagnostic assays for detection and characterisation of vvIBDV isolates.
Sequencing of Indonesian vvIBDV Tasik94 revealed a unique substitution
[ A¨S222] in the hypervariable region (HVR) of viral protein (VP) VP2, which did not appear to impinge on virulence or antigenicity. Phylogenetic analyses indicated that Tasik94 was closely related to Asian and European vvIBDV strains. Extensive alignment of deduced protein sequences across the HVR of VP2 identified residuesI242 I256 and I294 as putative markers of the vv phcnotype.
Comparison of the pathology induced by mildly-virulent Australian IBDV 002/73 and Indonesian vvIBDV Tasik94, revealed that histological lesions in the spleen, thymus and bone marrow were restricted to Tasik94-infected birds, suggesting the enhanced pathogenicity of vvIBDV might be attributed to replication in non-bursal lymphoid organs.
The biological significance of the VP2 HVR in virulence was assessed using recombinant viruses generated by reverse genetics. Both genomic segments of Australian IBDV 002/73, and recombinant segment A constructs in which the HVR of 002/73 was replaced with the corresponding region of either tissue culture-adapted virus or vvIBDV (Tasik94), were cloned behind T7 RNA polymerase promoter sequences. In vitro transcription/translation of each construct resulted in expression of viral proteins. Co-transfection of synthetic RNA transcripts initiated replication of both tissue culture-adapted parental and recombinant viruses, however attempts to rescue non-adapted viruses in specific-pathogen-free (SPF) chickens were unsuccessful.
Nucleotide sequence variation in the HVR of VP2 was exploited for the development of a new diagnostic assay to rapidly detect exotic IBDV isolates, including vvIBDV, using reverse transcription polymerase chain reaction (RT-PCR) amplification and Bmrl restriction enzyme digestion. The assay was capable of differentiating between endemic and exotic IBDV in 96% of 105 isolates sequenced to date.
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Thomas, Claire Philippa. "The expression of bluetongue virus non-structural protein NS2 and its structure-function relationship." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.292328.
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Wythe, Sarah Elizabeth. "The role of dendritic cells in a polarised model of viral pulmonary disease." Thesis, Imperial College London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502909.
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Prendergast, Andrew John. "Immunological and viral influences on HIV-1 disease progression in children and adults." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526101.
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Yip, Chi-wai, and 葉志偉. "Characterization of cellular receptors of infectious bursal disease virus in chickens." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B36759533.
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MCCOMBIE, SUSAN CAROLE. "CULTURAL FACTORS RELATED TO THE EPIDEMIOLOGY OF VIRAL HEPATITIS IN A SOUTHWESTERN UNITED STATES COUNTY (INFECTIOUS DISEASE, SOCIOECONOMIC, PUBLIC HEALTH, BEHAVIOR, COMMUNICABLE)." Diss., The University of Arizona, 1986. http://hdl.handle.net/10150/188152.
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Viral hepatitis has been a universal human affliction for thousands of years. Only recently has it become understood, and there are still many unanswered questions. This dissertation examines the epidemiology of viral hepatitis in a county in the southwestern United States. An historical review traces the history of concepts of jaundice and details recent advances in the understanding of the transmission of the clinical entities grouped under the heading of viral hepatitis. Age specific incidence rates for all forms of hepatitis in the study population are compared to national rates. Data indicate that the study population experiences higher rates of enteric disease and lower rates of sexually transmitted disease than the nation as a whole. The hypothesis that diseases with similar routes of transmission will be associated with each other and show similar socioeconomic patterns was tested using three year average census tract incidence rates for 1982-84. In almost all samples, hepatitis A and shigellosis are more similar to each other than either is to hepatitis B. A similarity between hepatitis B and syphilis is also evident, but in fewer samples, reflecting their more disparate routes of transmission. Different relationships between incidence rates and socioeconomic variables are evident when the analysis is done using data from the fifty states for 1982. Participant observation as a disease investigator generated information on beliefs about hepatitis among lay and medical personnel. Often these beliefs diverge significantly from accepted facts about hepatitis. These findings have implications for the design of public health programs to control communicable diseases with similar modes of transmission.
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Wong, Hiu-ling Beatrice. "Development of antibody and antigen detection assays and vaccines for SARS associated coronavirus." Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/hkuto/record/B39634024.
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Wong, Hiu-ling Beatrice, and 黃曉靈. "Development of antibody and antigen detection assays and vaccines for SARS associated coronavirus." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39634024.
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Ståhl, Karl. "Bovine viral diarrhoea virus and other reproductive pathogens : epidemiological studies in Peruvian cattle /." Uppsala : Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, 2006. http://epsilon.slu.se/200653.pdf.
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Tanov, Emil Pavlov. "The identification of biologically important secondary structures in disease-causing RNA viruses." University of the Western Cape, 2012. http://hdl.handle.net/11394/4562.
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Magister Scientiae - MScViral genomes consist of either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). The viral RNA molecules are responsible for two functions, firstly, their sequences contain the genetic code, which encodes the viral proteins, and secondly, they may form structural elements important in the regulation of the viral life-cycle. Using a host of computational and bioinformatics techniques we investigated how predicted secondary structure may influence the evolutionary dynamics of a group of single-stranded RNA viruses from the Picornaviridae family. We detected significant and marginally significant correlations between regions predicted to be structured and synonymous substitution constraints in these regions, suggesting that selection may be acting on those sites to maintain the integrity of certain structures. Additionally, coevolution analysis showed that nucleotides predicted to be base paired, tended to co-evolve with one another in a complimentary fashion in four out of the eleven species examined. Our analyses were then focused on individual structural elements within the genome-wide predicted structures. We ranked the predicted secondary structural elements according to their degree of evolutionary conservation, their associated synonymous substitution rates and the degree to which nucleotides predicted to be base paired coevolved with one another. Top ranking structures coincided with well characterized secondary structures that have been previously described in the literature. We also assessed the impact that genomic secondary structures had on the recombinational dynamics of picornavirus genomes, observing a strong tendency for recombination breakpoints to occur in non-coding regions. However, convincing evidence for the association between the distribution of predicted RNA structural elements and breakpoint clustering was not detected.
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Biswas, Sumi. "Prime boost vaccination with viral vectors targeting apical membrane antigen 1." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:a17ab4e4-9b81-4ab3-b02f-41d9da36c6ab.
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Apical membrane antigen 1 (AMA1) is a leading candidate vaccine antigen against blood stage malaria and several clinical trials using mostly protein-in-adjuvant vaccines have shown limited success. This thesis describes the development of recombinant adenoviral (AdHu5) and poxviral (MVA) vectors encoding AMA1 from Plasmodium chabaudi murine parasites. In this murine malaria model, AdHu5 and MVA encoding AMA1 when used in a heterologous prime boost regime showed excellent immunogenicity, both humoral and cellular. The vaccination regime was protective against blood stage challenge and both antibodies and CD4+ T cells found to be important for vaccine induced blood stage protection. In parallel to this novel P. falciparum vaccines encoding AMA1 were also developed and administered in a similar prime boost regime to mice and rabbits. The vaccination regime induced cellular immune response and high titre antibodies against AMA1 and these antibodies showed growth inhibitory activity against the homologous parasite strain. In an effort to overcome the issue of antigenic polymorphism and to circumvent pre-existing immunity to human adenovirus, biallelic simian and human adenoviral vectors and MVA encoding AMA1 vaccines were also developed and administered to mice and macaques. These vectors also induced high titre antibodies and the serum from macaques was found to have growth inhibitory activity. These vaccine candidates are now being taken forward to Phase I/II clinical trials in Oxford. This work also described the attempt to improve MVA as a antibody inducing vector to allow better antibody mediated immunity to blood stage malaria.
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Hsu, Pao-Chu. "Prenatal Stress, Depression, and Herpes Viral Titers." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4818.
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Recent studies suggest that some cases of prenatal depression may be associated with reactivation of latent infections of the herpesvirus family. The possible relationships among stress, prenatal depression, and herpes viral reactivation in pregnancy are understudied and the molecular pathways such as the neuroimmune biogenic amine pathway are unidentified. Chronic stress shifts the T helper-1 cell (Th1) cytokine profile to a Th2 profile, which favors virus induced pathogenesis and survival. Pregnancy is also associated with a similar Th2 dominance. In non-pregnant individuals, exposure to psychological or physical stress may be associated with latent herpes viral reactivation and could result in behavioral deficits and depression. Normally, type-1 cytokines such as Interferon-gamma (IFN -gamma) and inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) induce indoleamine-2, 3-dioxygenase (IDO) activation which inhibits herpes virus replication and reactivation, decreases tryptophan production, and alters phenylalanine /tyrosine metabolism. Thus it is possible that prenatal depression may occur from tryptophan stealing through the IDO pathway which results in decreased serotonin as well as increased risk for latent herpes viral reactivation.
The purpose of this study is to analyze the relationships among stress, herpes viral titers, depression, and metabolites of IDO activation, which involves tryptophan and guanosine-triphosphate-cyclohydrolase-1(GTP-CH1) pathways. This study builds on Influence of Lactation on Postpartum Stress and Immunity (Grant number: R01-NR05000) which investigated perinatal immune, endocrine, and inflammatory changes in pregnancy and the postpartum. A secondary data analysis was conducted on baseline data from women collected at 16 to 25 gestational weeks. This data set included some herpes viral titers, and additional ones were measured in stored plasma samples. The aim of this study is to examine relationships among stress, herpes viral reactivation, depression, and the IDO activation pathway. The results of this study provide information about the possible role of further relationships of prenatal stress, latent herpes viral reactivation, and depression mechanisms. The results will be important in health promotion and disease prevention during pregnancy.
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Lasecka, Lidia. "Studies on the replication of Nairobi sheep disease virus in cultured cells." Thesis, Royal Veterinary College (University of London), 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.618322.
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Navér, Lars. "Perinatal HIV-1 infection : aspects on clinical presentation, viral dynamics and epidemiology /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-983-8/.
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Bollyky, Paul Laszlo. "Viral genetic diversity and clinical disease in Hepatitis B virus infection : a phylogenetic approach." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301179.
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McMillan, Kirsty Jane. "Development and characterisation of viral vectors to study the molecular mechanisms of Parkinson's disease." Thesis, University of Bristol, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.654440.
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MicroRNAs are a newly described class of short endogenous non-coding RNAs, which bind to the 3' untranslated region of a target mRNA molecule and result in either their degradation or inhibition of their translation. Recently microRNAs have been shown to play a role in neurogenesis in the adult brain and with neuronal deterioration in neurodegenerative disorders. In particular, microRNA-7 has been shown to bind to both alpha synuclein and the epidermal growth factor receptor (EGFR). Alpha synuclein is known to play a key role in the pathogenesis of Parkinson's disease (PD), which is a common neurodegenerative disorder, whilst the EGFR has been shown to be decreased in PD patients in the subventricular zone (SVZ). The SVZ is one of two areas of the adult brain thought to be involved in neurogenesis. Therefore the aim of this thesis has been to investigate the role of miRNA-7 in the regulation of alpha synuclein and the EGFR further. Two lentiviruses were produced, one to cause an overexpression of miRNA-7 and another to cause a loss of miRNA-7 by acting as a target/sponge sequence for miRNA-7 (miRNA-7T). These lentiviruses were firstly transduced into HEK293T cells where miRNA-7 was found to bind to the 3 'UTR of the SNCA gene and inhibit translation causing a decrease in alpha synuclein expression. The miRNA-7T lentivirus was found to effectively bind to endogenous miRNA-7 causing an increase in alpha synuclein expression in HEK293T cells. To investigate this further, the miRNA-7T lentivirus was injected into the SNpc of mice. Data showed that 2 injections of the virus were sufficient to cause an overexpression of the virus in the SNpc. This resulted in an upregulation of alpha synuclein 24 weeks after surgery and a significant loss of dopaminergic neurons. However, the animals did not show any motor impairment and the effects on striatal DA was only reduced to 30% at 8 weeks post surgery. There was therefore, a disparity between the loss of dopaminergic neurons and the levels of striatal DA. To investigate the effect of manipulating miRNA-7 levels on dopaminergic neurons the viruses were also transduced into iPSCs. Unfortunately, the viruses had no effect on alpha synuclein expression in these cells, which may have been due to limitations of the experiment.
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Miller, Pamela S. "The relationship between exhaustion, viral pathogenesis, and immuno-inflammatory activation in coronary artery disease." Diss., Restricted to subscribing institutions, 2009. http://proquest.umi.com/pqdweb?did=1872114411&sid=11&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Singanayagam, Aran. "Effect of inhaled corticosteroids on viral and bacterial infection in chronic obstructive pulmonary disease." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/24469.
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Rhinovirus (RV) infections trigger exacerbations of chronic obstructive pulmonary disease (COPD) exacerbations and may precipitate secondary bacterial infections. Inhaled corticosteroids (ICS) are used commonly in COPD but are relatively ineffective in the context of virus-induced exacerbations and may also increase the risk of pneumonia. We hypothesised that, in a mouse model, ICS would suppress anti-viral and anti-bacterial immune responses leading to alteration of the airway microbiota and secondary bacterial infection following RV-induced exacerbation of COPD. Despite extensive optimisation, we were unable to define a representative mouse model of the deficient anti-viral and anti-bacterial responses that are indicative of human COPD. For this reason, and because of difficulties in measuring the airway microbiota in mice, we employed models of primary RV1B and Streptococcus pneumoniae infection as surrogates for viral exacerbation and bacterial colonisation in COPD. Fluticasone propionate (FP) administration prior to RV1B infection suppressed innate and adaptive immune responses leading to impaired virus control, in a dose dependent manner. This effect was causally related to suppression of type I interferon (IFN) as administration of recombinant IFN-β reconstituted IFN-stimulated gene expression and restored virus control. FP suppressed RV-induced airway inflammation but led to enhanced airway mucin production, effects that were unaltered by recombinant IFN-γ. FP administration also suppressed innate responses to S. pneumoniae including expression of anti-bacterial cytokines and cathelicidin-related anti-microbial peptide. High dose FP increased lung tissue bacterial loads with the opposite effect observed with lower dose FP despite similar anti-inflammatory effects. Our findings demonstrate beneficial anti-inflammatory effects of ICS during virus-induced COPD exacerbations but reveal some previously unrecognised detrimental effects including increased virus replication and enhanced mucin production. Additionally, we show that high dose ICS administration may increase bacterial loads and thus increase pneumonia risk but lower doses may conversely reduce bacterial loads and therefore could be safer in COPD.
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Yeung, Yin-shan. "Molecular characterization of apoptosis induced by severe acute respiratory syndrome coronavirus spike protein." Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B38302366.
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Bartley, Lucy Margaret Antonia. "The transmission dynamics of dengue infections." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343215.
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