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1
Ekberg, Johan, and Fredrik Isaksson. "Viral Marknadsföring." Thesis, Linköping University, Department of Management and Economics, 2000. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-705.
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<p>Bakgrund: I massmedia har det på senare tid börjat uppmärksammas ett nytt fenomen inom internetbaserad marknadsföring som kallas för viral marknadsföring. Det har dock inte gjorts några studier om vad begreppet egentligen innebär. </p><p>Syfte: Att ge en innebörd åt begreppet viral marknadsföring och att undersöka de faktorer som kan påverka möjligheten att kunna utnyttja viral marknadsföring. </p><p>Avgränsningar: I denna studie har vi avgränsat oss genom att säga att teorierna kring viral marknadsföring endast går att applicera på Internet. I studien behandlas endast konsumentrelaterade produkter. Genomförande: Undersökningen har genomförts via studier av artiklar och litteratur och med en empirisk del som består av enkätundersökning, intervju samt data från ett fallföretag. </p><p>Resultat: Viral marknadsföring handlar om att låta utomstående personer marknadsföra det egna företaget via Internet. Spridning av viral marknadsföring kan ske aktivt eller passivt. I uppsatsen identifieras olika typer av viral marknadsföring beroende på vilken typ av produkt eller tjänst som marknadsförs. Avslutningsvis redovisas en modell som beskriver de faktorer som bör beaktas vid utformandet av en viral marknadsföringsstrategi, detta med avseende på produkten, kunden och marknaden.</p>
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Azevedo, Lúcia Alexandra Fernandes. "Bronquiolite viral aguda." Master's thesis, Universidade da Beira Interior, 2009. http://hdl.handle.net/10400.6/889.
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Contextualização: A bronquiolite é a infecção das vias respiratórias inferiores mais comum em crianças com idade inferior a dois anos, sendo uma importante causa de internamento nos meses de Inverno. Resulta da infecção e inflamação da mucosa respiratória das vias aéreas distais por uma grande variedade de vírus sazonais, sendo o Vírus Sincicial Respiratório o agente etiológico mais frequentemente implicado. O diagnóstico é baseado na história clínica típica e no exame físico. O tratamento é essencialmente de suporte, contudo persiste o recurso a terapêuticas cuja prática não é suficientemente sustentada por evidência científica. Apesar de ser uma doença frequente existe pouco consenso acerca da melhor abordagem diagnóstica e terapêutica. Objectivos: O objectivo principal deste estudo foi analisar a orientação diagnóstica e terapêutica das crianças com bronquiolite. Como objectivo secundário foi determinada a frequência dos diversos agentes etiológicos virais isolados e analisada a gravidade da doença em função destes. Metodologia: Foi conduzido um estudo prospectivo descritivo em crianças com bronquiolite, com idade inferior a 24 meses, que recorreram ao Serviço de Urgência Pediátrica do Centro Hospitalar da Cova da Beira, entre 1 de Novembro de 2008 e 31 de Março de 2009. Procedeu-se ao registo de informações relativas aos dados demográficos, manifestações clínicas, exames complementares de diagnóstico solicitados e intervenções terapêuticas efectuadas.
Resultados: Foram incluídas no estudo 78 crianças, 60% eram do sexo masculino e a média de idade foi de 8,5 meses. Cinquenta e três por cento das crianças necessitaram de internamento tendo sido a duração média deste de 7 dias. A prova terapêutica com salbutamol foi realizada a 59% das crianças, tendo sido continuado em 32,4% das tratadas no domicílio e em 56,1% das internadas. A antibioterapia sistémica foi prescrita em 19,2% das crianças. Durante o internamento 95% das crianças necessitaram de oxigénio suplementar, a aspiração de secreções foi realizada em 56%, e em 61% houve necessidade de hidratação endovenosa. A cinesioterapia respiratória foi realizada em 22% das crianças internadas. A radiografia do tórax foi realizada em 38,5%, o hemograma e PCR em 28,2% e a hemocultura em 17,9% das crianças. A pesquisa de vírus respiratórios foi positiva em 78,7%, tendo sido detectada infecção concomitante com dois vírus em 23% das crianças. O VSR foi identificado em 69,3% e o BoVh em 22,7%. Em 88% das crianças com amostras positivas para o BoVh foi detectada simultaneamente infecção com o VSR. As crianças com infecção concomitante com VSR e BoVh necessitaram mais frequentemente de internamento comparativamente às crianças com infecção simples por VSR (80% vs 60%). Conclusões: Tendo em consideração a evidência actual em relação à abordagem diagnóstica e terapêutica da bronquiolite detectaram-se dois aspectos passíveis de optimização que são a redução da administração de salbutamol e do recurso a exames complementares de diagnóstico. Os resultados do estudo confirmam o VSR como o principal agente etiológico da bronquiolite, e destacam o BoVh como um vírus também frequentemente associado a esta doença, demonstrando ainda uma elevada taxa co-detecção deste com o VSR. Neste estudo não foi possível associar a co-infecção com VRS e BoVh a uma maior gravidade da doença, comparativamente à infecção simples por VSR.<br>Backgroud: The bronchiolitis is the most common lower tract respiratory infection in
children under two years and is a major cause of hospitalization during the winter
months. It´s the result of infection and inflammation of the distal airways respiratory
mucosa the by a variety of seasonal virus, and Respiratory Syncytial Virus is the
etiologic agent most frequently implicated. The diagnosis is based on typical clinical
history and physical examination. Treatment is essentially supportive however,
therapeutics not sufficiently supported by scientific evidence remain being used.
Despite being a common disease there is little consensus about the best diagnostic and
therapeutic approach.
Objectives: The main objective of this study was to analyze therapeutic and diagnostic
approaches of children with bronchiolitis. The secondary objective was to determine
the frequency of various viral pathogens isolated and analyze the severity of the
disease according to these.
Methodology: We conducted a prospective descriptive study in children with
bronchiolitis, with the age below 24 months, which have been taken at Pediatric
Emergency Service of Hospital of Cova da Beira, between 1 November 2008 and 31
March 2009. It has been registrated information related to demographics, clinical
manifestations, additional diagnostic tests and therapeutic interventions.
Results: We included 78 children in the study, 60% were male and mean age was 8.5
months. Fifty-three percent of children required hospitalization and the average
duration of that was 7 days. Proof therapy with salbutamol was performed at 59% of
children, and was continued in 32.4% of those treated at home and in 56.1% of those
hospitalized. Systemic antibiotics were prescribed in 19.2% of children. Along hospitalization 95% of children required supplemental oxygen. Nasopharyngeal suction
was performed in 56%, and 61% of the children needed intravenous hydration. Chest
physiotherapy was performed in 22% of hospitalized children. Chest X-ray was
performed in 38.5%, blood count and PCR in 28.2% and blood culture in 17.9% of
children.
In viral diagnostic testing at least one virus was detected in 78.7% and
concomitant infection with two viruses was detected in 23% of children. The RSV was
identified in 69.3% and BoVh in 22.7% of children. In 88% of children with positive
samples for BoVh it has been detected simultaneously RSV infection. Children with
concomitant infection with RSV and BoVh required more often hospitalization
compared with children infected with RSV alone (80% vs 60%).
Conclusions: Given the current evidence regarding the diagnostic approach and
treatment of bronchiolitis there were found two issues that are likely to be optimized:
the reduction of salbutamol prescription and the use of complementary tests of
diagnosis.
These results confirm RSV as the primary etiologic agent of bronchiolitis, and
highlight the BoVh as a virus often associated with this disease, also showing a high
rate of co-detection with RSV. Given the limitations of the study it wasn’t possible to
associate the co-infection with RSV and BoVh with a greater severity of illness,
compared to infection by RSV alone.
3
Kymalainen, Hanna. "Development of viral & non-viral episomal vectors for gene therapy applications." Thesis, University of London, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.589000.
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Gene therapy consists of methods which attempt to repair or replace defective genes responsible for disease, or to add genes to a therapeutic effect. To achieve this, two episomally maintained recombinant viral vectors have shown promising results: integration-deficient lentiviral vectors (IDLVs), and adeno-associated virus (AA V) vectors. The non-integrating nature of these vectors improves their safety profile but also limits transgene retention as nuclear episomes generally get lost during cell division. In the present study, the establishment of stable replicating episomes via transduction with AA V and IDL V gene therapy vectors was examined in CHO cells. Different DNA elements and cell culture conditions were evaluated, and in particular the effects of (i) DNA elements called S/MARs (scaffold/matrix attachment regions) which are involved in chromatin organisation, transcription and replication, and (ii) induction of transient cell cycle arrest in transfected and transduced cell populations. In the case of both AA V and IDL V vectors, the incorporation of S/MAR elements into vector transcription units had only marginal effects on the establishment of stable transgene- positive cell populations, either with or without induction oftransient cell cycle arrest. However, a striking general result was observed in cell populations transduced with IDL Vs and subjected to a transient cell cycle arrest soon after transduction. Under these conditions, following release from cell cycle arrest and in the absence of any selection pressure, substantial populations (10-25%) of proliferating and stably transduced cells emerged and were maintained over at least 100 population doublings. This establishment of stable transduction was seen only with IDLVs, was crucially . dependent on the induction of a period of transient cell cycle arrest, occurred independently of the presence of S/MAR elements, and resulted in transgene-positive cell populations which could be isolated and propagated as stable clonal cell lines. In these polyclonal and clonal IDL V -transduced cell lines, the existence of non-integrated vector genomes in the form of multi-copy nuclear episomes was confirmed by evidence from linear amplification -mediated PCR, deep sequencing, Southern blotting and FISH (fluorescent in situ hybridisation). 2 The cumulative evidence suggests that transduction of eHO cells with IDL Vs followed by a short period of induced cell cycle arrest leads to the establishment of stable IDL V- based nuclear episomes which are transcriptionally active and undergo replication and segregation during cell division without the need for antibiotic-based or other positive selection pressure. Preliminary investigations were also done to test the capacity of combined IDL V transduction and transient cell cycle arrest to establish stable episome Hel.a cells and murine haematopoietic stem cells. However, further experiments are required either to optimise the protocol in these cells or to find other clinically relevant cell types in which the protocol can be implemented. The transfer of this technology to a variety of clinically relevant human stem or progenitor cell populations could improve the safety profile of a range of gene therapy strategies currently under investigation. 3
4
Paton, David James. "Bovine viral diarrhoea virus : studies of viral epitopes and of porcine infections." Thesis, University of Surrey, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317374.
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Ruoss, Sven. "Erfolgsfaktoren des Viral Marketing." St. Gallen, 2008. http://www.biblio.unisg.ch/org/biblio/edoc.nsf/wwwDisplayIdentifier/02600278002/$FILE/02600278002.pdf.
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Stirnemann, Sandra. "Verhaltenswirksamkeit des Viral Marketing." St. Gallen, 2008. http://www.biblio.unisg.ch/org/biblio/edoc.nsf/wwwDisplayIdentifier/02601128002/$FILE/02601128002.pdf.
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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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Phillips, Angela Marie Ph D. Massachusetts Institute of Technology. "Chaperoning viral protein evolution." Thesis, Massachusetts Institute of Technology, 2018. http://hdl.handle.net/1721.1/118276.
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Thesis: Ph. D. in Biological Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2018.<br>Cataloged from PDF version of thesis. Vita.<br>Includes bibliographical references.<br>Preventing viral pandemics and developing effective antiviral therapeutics demands understanding the molecular mechanisms that both potentiate and constrain viral evolution. The rapid evolution of viruses is mediated in part by their high mutation rates, enabling resistance to antiviral drugs, seasonal vaccines, and innate and adaptive immune responses. Fortunately for us, the same mutations responsible for resistance are often biophysically deleterious to viral proteins. Thus, viral evolution is inherently constrained by the proper folding of viral proteins into functional, stable conformations. In cells, protein folding and homeostasis are assisted by complex networks of chaperones and quality control machinery. Though the evolutionary implications of most chaperones and quality control factors remain unexplored, the HSP90 chaperone can buffer and potentiate the phenotypic effects of mutations in endogenous client proteins in bacteria, fungi, plants, and other eukaryotic organisms. Viruses acquire mutations at a rate several orders of magnitude above that of the aforementioned organisms, yet they do not encode any machinery to assist destabilized protein variants to their folded, functional conformations. However, viral proteins are known to interact with host chaperones and quality control machinery. My graduate work has focused on determining whether and how host proteostasis machinery modulates viral protein evolution. First, I employed a serial passaging approach to evolve influenza in host cells with remodeled proteostasis capacities, revealing that cytosolic host proteostasis capacity is indeed a critical determinant of influenza evolutionary trajectories. This work motivated systematic quantification of influenza protein mutational tolerance upon perturbation of host proteostasis, for which I applied deep mutational scanning to comprehensively profile the mutational tolerance of influenza nucleoprotein and hemagglutinin in modulated cytosolic and endoplasmic reticulum (ER) folding environments, respectively. The nucleoprotein work provides the first experimental evidence that host chaperones can enhance the accessibility of biophysically deleterious, adaptive viral protein variants. The hemagglutinin work establishes evolutionary implications for the ER proteostasis machinery, and demonstrates that ER proteostasis mechanisms enhance mutational tolerance across the entire HA protein. Overall, it is clear that host chaperones and quality control machinery crucially impact viral protein fitness, and likely also impact the fitness of endogenous variants.<br>by Angela Marie Phillips.<br>Ph. D. in Biological Chemistry
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Larsson, Tom. "Kan jag bli viral?" Thesis, Malmö högskola, Fakulteten för teknik och samhälle (TS), 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:mau:diva-20056.
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Integrationen av sociala medier i dagens samhälle har bidragit till framväxten av en mersammankopplad och global värld. En värld som erbjuder fler tekniska möjligheter än tidigare, men som även bidrar med nya utmaningar. En av dessa utmaningar är hur man ska agera för att bli positivt utmärkt på den alltmer konkurrensutsatta arbetsmarknaden. Denna studie syftar till att angripa denna utmaning genom att undersöka hur den sociala applikationen Instagram kan användas som en kanal för personlig marknadsföring. Studiens slutsatser, vilka är baserade på en kombination av resultat från litteraturstudier samt kvalitativt inriktade intervjuer och innehållsanalyser, tyder på att Instagram kan användas som ett personligt marknadsföringsverktyg. Resultatet av studien indikerar att man bör börja med att klargöra sina unika och attraktiva egenskaper, mål och färdigheter för att skapa sig ett personligt varumärke.Detta varumärke kan sedan kommuniceras på Instagram genom skapandet och applicerande av en intresseveckande markandsföringsstrategi. För att höja chanserna att strategin ska lyckas bör den vara autentisk, tydlig, konsekvent och tilltalande för potentiella arbetsgivare. Resultaten tyder även på att det är viktigt att t.ex. använda hashtags och kommentarer för att skapa positiva interaktioner och uppmärksamhet kring ens varumärke/Instagramkonto. Slutligen bör man även utvärdera resultatet av ens ansträngningar för att se om ens mål blivit uppfyllda.<br>The integration of social media in today's society has largely contributed to the development of a more accessible and global world. Even if this evolution raises countless possibilities it also creates challenges, one of those is how to become positively distinguished in the increasingly competitive employment market. This study addresses this challenge by investigating how the new and popular social application Instagram can be used as a tool for personal branding. The findings, which are based on a combination of literature reviews, qualitatively oriented interviews and content analysis, concludes that Instagram can be used a personal branding tool. The recommended way to do this is by first clarify one's unique brandable attributes, values and goals by constructing a personal brand. This brand can then be communicated through Instagram by the use of a captivating strategy, which are evaluated and reviewed after some time. This in order to gradually develop the value offered so that the brand remains contemporary and competitive. To increase the chances of succeeding with the strategy, it should be authentic, clear, consistent and appealing for prospective employers. Findings also show that it is important to use e.g. hashtags and comments to create positive interactions and buzz around one's brand/Instagram account.
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Nishikawa, Hiroki. "Development of Novel Anti-viral Agents against Class I Viral Membrane Fusion Process." 京都大学 (Kyoto University), 2011. http://hdl.handle.net/2433/142504.
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Klinger, Michaela. "Virales Marketing : die Macht der sozialen Netzwerke /." Saarbrücken : VDM, Müller, 2006. http://deposit.d-nb.de/cgi-bin/dokserv?id=2874943&prov=M&dok_var=1&dok_ext=htm.
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ALBUQUERQUE, Breno Moacir Farias de. "Aplicação da PCR em Tempo Real Para Detecção, Tipificaçãoe Carga Viral de Papilomavírus Bovino." Universidade Federal de Pernambuco, 2012. https://repositorio.ufpe.br/handle/123456789/18509.
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Previous issue date: 2012<br>O Papilomavírus bovino(BPV) é o agente etiológico da papilomatosebovina. Esta apresenta lesões que normalmente são benignas e tendem a regredir, porém podem progredir a uma neoplasia. Muitas metodologias utilizadas para detecção de BPV se mostram inespecíficas e apresentam reações cruzadas com outros organismos relacionados. No entanto, a reação quantitativa em tempo real emcadeia da polimerase (qPCR) é uma ferramenta de destaque na detecção, tipificação e quantificação de nucleotídeos e vem sendo utilizada na clínica para avaliar carga viral. O objetivo do trabalho foi desenvolver um novo protocolo de detecção, tipificação e quantificação de BPV através daqPCR. Foram desenhados cinco pares de primers, que possuem como alvo uma região conservada do genoma viral (gene L1) de diferentes BPVs. A seletividade dos primers foi testada in vitroe DNA extraído de células MDBK não infectadas foram utilizados como controle negativo. A técnica de qPCR permitiu detectar, tipificar e quantificar material viral dos BPVs 1, 2, 4, 5 e 6. O limiar relativo da detecção foi de 4fg de DNA,emtorno de 30-40 cópias de DNA/μL. Dos cinco pares de primers produzidos, quatro apresentaram mesmo perfil térmico durante a qPCR (qPCRBPV2, 4, 5 e 6), permitindo em um único procedimento detectar e tipificar os quatro tipos virais. A distinção das amostrasfoi realizada através da análise de meltingque permitiu tipificá-las. Através da metodologia desenvolvida foi observado que em lesões cutâneas de bovinos infectados com BPV a carga viral não se mostrou inferior a 1000 cópias/μL, enquanto que a técnica permite quantificar até um limiar de 40 copias de DNA/μl. Este trabalho possui relevância para validação de qPCR como diagnóstico da papilomatose bovina e particular importância quando aplicado em estudos da infecção pelo BPV e no monitoramento por veterinários da eficácia das futuras vacinas.<br>Bovine papillomavirus (BPVs) is the etiologic agent of bovine papilomatose which is characterized by hyper proliferative lesions. Papillomas in cattle are typically benignandoften regress, but occasionally lesions can persist and progress to malignant neoplasia.The majority of current techniques for identification of BPV is unspecific andpossessescross-reactivity with closely related organisms.The Real-time quantitative polymerase chain reaction assay (qPCR) has become an exceptional tool for detection and quantification of oligonucleotides and has been utilized increasingly on viral load evaluation.Aiming to develop a new protocol for fast detection, typification and quantification of BPV in qPCR, we designed five pairs of Oligonucleotides for BPV1, 2, 4, 5 and 6 focusing on L1 gene. The qPCR primers sets were testedin vitroandMadin-Darby Bovine Kidney Cells (MDBK)DNA was also used as negative control.The Real-time qPCR assay provided an accurate detection and quantification for the BPVs 1, 2, 4, 5 and 6. The relative detection limit for the assays was 4fg or 30 to 40genome equivalents. Four primers pairs (qPCRBPV2, 4, 5 and 6) had the same annealing temperature and their products showed differences on meltingpoints analyses. Through the meltingpoint analysis, samples can be identified and discriminated as a screening and then samples can be run for viral load. In our study we tested the viral load in bovine cutaneous skin warts and observed infections with 1000 copies/μl at least. However, this assay could reach levels of 40copies/μL. In conclusion, this methodology has an important impact on the validation of qPCR as a BPV diagnosis. Its relevance is proved when applied to BPV infection studies and the monitoring of the efficacy of future BPV vaccinesby veterinarians.
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Gholamzadeh, Caroline, and Karolina Jakobsson. "Viral Marketing : A Quantitative Study about how Viral Marketing affects the Consumers Buying Act." Thesis, Högskolan i Halmstad, Sektionen för ekonomi och teknik (SET), 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:hh:diva-16192.
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Ilar, Sandra. "The Hunger Games Viral Marketing Campaign : A Study of Viral Marketing and Fan Labor." Thesis, Stockholms universitet, Institutionen för mediestudier, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-105864.
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This essay examines Lionsgate’s viral marketing campaign for The Hunger Games (Gary Ross, 2012) and the marketing teams’ use of new marketing techniques and the online fan base. The essay also asks the question to what extent the fans’ participation in Lionsgate’s marketing campaign can be called fan labor. The study is based on a film industrial perspective and academic literature that deals with film marketing, the film industry, fandom and digital labor. The material used for the analysis of The Hunger Games marketing campaign is collected from newspaper articles and news interviews with Lionsgate’s marketing personnel. The study shows that although Lionsgate used many new marketing strategies associated with viral marketing, it is problematic to depict these strategies as a wholesale movement from older marketing techniques. It points to the importance of a nuanced understanding of how producers and consumers operate in the digital age with a holistic view on film marketing practices. The study also shows that Lionsgate’s use of the online fan base correspond with many characteristics of fan labor on the internet. It is, however, problematic to establish that this necessarily means that the fans’ contributions to the marketing campaign were exploited or that it demands compensations. The essay argues that the popularity of viral marketing among film studios and their use of fans and fan created content for promotional purposes calls for further investigations.
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Stone, Jeffrey K. "Understanding viral quasispecies, viral escape, and implications for the design of novel antiviral strategies." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2007. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3261270.
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Moustafa, Rehab. "Characterization of functional determinants in the C-terminal part of hepatitis C virus E1 glycoprotein ectodomain." Thesis, Lille 2, 2019. http://www.theses.fr/2019LIL2S002/document.
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Aujourd’hui, le Virus de l'Hépatite C (VHC) infecte plus 70 millions de personnes dans le monde. L’Organisation mondiale de la santé prévoit l’élimination du virus VHC d’ici 2030, grâce aux récentes découvertes dans le milieu du développement médical. Ces derniers ont conduit à la production des antiviraux pangenotypiques à action directe (ADD). Le VHC est un virus enveloppé de l’ARN, avec une polarité positive. Il est constitué de nucléocapside entouré d’une membrane lipidique. La nucléocapside contient l’acide ribonucléique (ARN) et la protéine core. La membrane lipidique quant à elle contient à la surface les glycoprotéines E1 et E2. Ainsi ces protéines, sont les premières à rencontrer les hépatocytes, c’est donc grâce à elles que le virus parvient à entrer dans les cellules. Parmi les deux protéines, l’E2 a été la mieux caractérisée pour ses fonctions de liaisons aux récepteurs spécifiques. De plus les anticorps neutralisants ciblent majoritairement cette protéine. En se basant sur le fait que ce virus est membre de la famille des Flaviviridae, il a été suggéré par analogie, que le VHC contient des protéines de fusion de classe II et que la protéine E2 est la protéine de fusion. Cependant, les structures cristallines récentes d’E2 ont révélé qu'il lui manquait les caractéristiques structurelles des protéines de fusion de classe II. Ainsi, tous les regards se sont tournés sur la glycoprotéine E1, suggérant qu’elle est responsable de l’étape de fusion, seule ou à l’aide d’E2. En effet, la partie N-terminale de l'ectodomaine E1 a été récemment cristallisée. La caractérisation des résidus conservés dans cette région a démontré son importance pour l'infectivité du virus, pour l'interaction entre E1 et E2, ainsi que pour son implication dans l'interaction avec les récepteurs du VHC. En soutenant le rôle potentiel d'E1 dans le processus de fusion, différents segments de l'extrémité C-terminale de l'ectodomaine seraient impliqués dans les interactions avec les membranes modèles. Nous avons étudié en particulier deux régions d’intérêt. La première située dans la zone du peptide de fusion putatif (PFP) entre les acides aminés 270 et 291. Cette région se compose des séquences hydrophobes, soutenant son implication dans l'étape de fusion. La deuxième région englobant les acides aminés 314-342, d’une activité membranotrope située à proximité de la zone transmembranaire d’E1, a été démontrée par la cristallographie aux rayons X et les études de RMN comme comprenant deux hélices α (α2 et α3).Nous avons introduit 22 mutations dans la partie C-terminale de l'ectodomaine E1 dans le contexte d'un clone infectieux JFH1. Nous avons remplacé les résidus les plus conservés par de l'alanine, puis analysé l'effet des mutations sur le cycle de vie du virus. Vingt des vingt-deux mutants ont été atténué ou ont perdu leur pouvoir infectieux, ce qui indique leur importance dans le cycle viral. Nous avons observé différents phénotypes; certaines mutations ont modulé la dépendance du virus vis-à-vis des récepteurs CLDN1 et SRBI pour l’entrée cellulaire. Plusieurs mutations dans la région PFP, ont affecté la sécrétion et l'assemblage du virus, ainsi que l'hétérodimérisation E1E2. D’autres mutations, telles que les mutations de l'hélice α2 ont entraîné une atténuation grave ou une perte complète d'infectivité, sans affecter le repliement d’E1 et E2, ni la morphogenèse virale. Une caractérisation plus poussée de certains mutants au sein de la région hélice α2 a suggéré l'implication de cette région dans une étape tardive de l'entrée du VHC. Enfin, nos résultats montrent le rôle important joué par la glycoprotéine E1 dans l'hétérodimérisation de E1E2, la morphogenèse du virus, ainsi que son interaction avec les récepteurs du VHC et son implication potentielle dans l'étape de fusion<br>Hepatitis C virus is currently estimated to infect around 71 million people around the world. However, recent advances in drug development led to the generation of pangenotypic direct acting antivirals (DAA), which may make it possible to eliminate HCV by 2030 as planned by the World health organization (WHO). HCV is a small RNA enveloped virus of positive sense. The RNA is encapsidated and surrounded by a lipid bilayer in which the E1 and E2 envelope glycoproteins are anchored on the surface. Thus, E1 and E2 are the first viral proteins to encounter the hepatocytes and mediate the entry step. HCV entry into hepatocytes is a sophisticated process that includes several steps ranging from interaction of glycoproteins with cellular host attachment factors and HCV specific-receptors, which is followed by internalization via clathrin-mediated endocytosis. Finally, viral and endosomal membranes merge at acidic pH leading to the release of viral RNA into the cytoplasm. Among the two glycoproteins, E2 has been the better characterized, as it is responsible for binding to cellular receptors and targeted by neutralizing antibodies. As a member of the Flaviviridae family, it has been suggested by analogy that HCV encodes class II fusion proteins and that E2 is the fusion protein. Nevertheless, the recent crystal structures of E2 revealed that it lacks structural features of class II fusion proteins. Thus, E1 glycoprotein became under the spotlight with the assumption that it is responsible for the fusion step whether alone or with the help of E2. Indeed, the N-terminal part of E1 ectodomain was recently crystallized, and the characterization of conserved residues within this region demonstrated its importance for virus infectivity, E1E2 interaction as well as its involvement in the interplay with HCV receptors. Supporting the potential role of E1 in the fusion process, different segments in the C-terminal of the ectodomain have been reported to be involved in interactions with model membranes. In particular, we investigated two regions of interest. The first one located in the putative fusion peptide (PFP) region between amino acid 270 and 291, containing hydrophobic sequences, supporting its involvement in the fusion step. The second region spanning amino acids 314-342, a membranotropic region located proximal to the transmembrane region of E1 and has been shown by X-ray crystallography and NMR-studies to comprise two α-helices (α2 and α3). We introduced 22 mutations in the C-terminal part of E1 ectodomain in the context of a JFH1 infectious clone. We replaced the most conserved residues with alanine and analyzed the effect of the mutations on the viral life cycle. Twenty out of the 22 mutants were either attenuated or lost their infectivity, indicating their importance for the viral life cycle. We observed different phenotypes; some mutations modulated the dependence of the virus on CLDN1 and SRBI receptors for cellular entry. Most mutations in the PFP region affected virus secretion and assembly as well as E1E2 heterodimerization. Nevertheless, the majority of mutations in the α2-helix (aa 315-324) led to severe attenuation or complete loss of infectivity without affecting E1E2 folding or viral morphogenesis. Further characterization of some mutants within this region suggested the involvement of the α2-helix in a late step of HCV entry. Finally, our results show the important role of E1 played in E1E2 heterodimerization, virus morphogenesis, interaction with HCV receptors and its potential involvement in the fusion step
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Bryce, Michael. "Viral marketing potential and pitfalls." Saarbrücken VDM, Müller, 2004. http://deposit.ddb.de/cgi-bin/dokserv?id=2761738&prov=M&dok_var=1&dok_ext=htm.
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Hägele, Holger. "Molekulare Mechanismen viral getriggerter Glomerulonephritis." Diss., lmu, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-155778.
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Dou, Dengfeng. "Mammalian and viral protease inhibitors." Diss., Wichita State University, 2010. http://hdl.handle.net/10057/3281.
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Chronic Obstructive Pulmonary Disease (COPD) is currently the fourth leading cause of death in the US. COPD is a multi-factorial disorder characterized by an oxidant/antioxidant imbalance, inflammation, a protease/antiprotease imbalance and apoptosis. This dissertation describes a general strategy for the design, synthesis and biochemical evaluation of dual function inhibitors which could potentially interrupt the above disorder, thereby enhancing the treatment of COPD. An example of this type inhibitor based on the 1,2,5-thiadiazolidin-3-one scaffold has been proven effective against both human neutrophil elastase (HNE) and caspase-1, two key enzymes responsible for elastin degradation and inflammation, respectively. In addition, an X-ray crystal structure and a high resolution mass spectrum of inhibitor bonded HNE have proven the proposed mechanism of HNE inactivation. Furhtermore, simple reversible competitive inhibitors of COPD-related enzymes (HNE and proteinase 3) have also been designed, synthesized and evaluated biochemically.
West Nile virus and Dengue virus are recognized as a major health threat that affects millions of people worldwide. However, there is currently no treatment or vaccine available for the virus infection. This dissertation describes the design, synthesis and biochemical evaluation of reversible competitive inhibitors of both West Nile virus and Dengue virus NS2B-NS3 protease. Combinatorial chemistry and click chemistry methods have been used in the design of the protease inhibitor and the identified hit was optimized using computational programs (AutoDock4 and SYBYL). Several more hits were identified during the optimization and further development could potentially lead to very potent inhibitors of NS2B-NS3 protease with good pharmacokinetics and oral bioavailability.<br>Thesis (Ph.D.)--Wichita State University, College of Liberal Arts and Sciences, Dept. of Chemistry
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Beier, Kevin. "Viral Tracing of Neuronal Circuitry." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10241.
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To understand how the nervous system processes information, a map of the connections among neurons is essential. Viral transsynaptic transmission has gained popularity as a method for labeling neural circuits. In particular, the development of retrograde monosynaptic tracing vectors has enabled visualization of the pre-synaptic inputs onto defined sets of postsynaptic neurons. This system utilized the rabies virus (RABV), in which the glycoprotein gene in the virus was deleted, and re-supplied in trans. In order to build alternative, more flexible tracers, we made recombinant VSV genomes, first developing the use of vesicular stomatitis virus (VSV) for tracing neuronal connections. Viruses encoding several different fluorescent proteins were made, giving brilliantly labeled neurons, bright enough for live imaging and characterization of the detailed morphologies of cells. Expression was very rapid, facilitating identification of neurons both in vivo and in ex vivo applications. In addition, the use of an avian glycoprotein (ASLV-A) allowed specific targeting to cells expressing an avian glycoprotein receptor (TVA). This allowed monosynaptic tracing from defined starter cells. In order to alter the direction and cell type specificity of transmission, we then fitted VSV with a glycoprotein from one of multiple other viruses. Glycoproteins such as the rabies virus glycoprotein (RABV-G) endowed VSV with the ability to spread in a retrograde transsynaptic pattern, while the glycoproteins from viruses such as the lymphocytic choriomeningitis virus (LCMV) gave an anterograde pattern of transsynaptic spread. This anterograde or retrograde spread was observed in all species tested, and even for other non-VSV viruses, such as lentiviruses. We also developed transsynaptic tracing viruses which direct viral spread between defined cell types, instead of from a defined cell type to any upstream of downstream cell. In all, we developed an extensive transsynaptic tracing repertoire for tracing neuronal connections.
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Adams, Edward Stephen. "Soil bacterial and viral dynamics." Thesis, University of Nottingham, 2006. http://eprints.nottingham.ac.uk/10201/.
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Viruses have been shown to be responsible for considerable bacterial mortality and nutrient cycling in aquatic systems. As yet no detailed studies have been published on the role of viruses in natural soil bacterial communities despite common knowledge that viruses exist in the soil. This thesis sought to address some key questions on the ecology of soil bacterial viruses and their hosts. Disturbance through soil desiccation, nutrient inputs, rhizosphere effects and protozoan predation pressure were investigated. The first study of lysogeny in natural soil systems was also undertaken. The work presented here utilised tools and techniques commonplace in aquatic systems research and applied them to soil. A novel protocol was developed based on physical extraction of bacteria and viruses from soil and direct counting with epifluorescence microscopy. Physical extraction was achieved using shaking, ultrasound sonication and low speed centrifugation. The fluorochrome SYBR Gold was used to stain nucleic acid of extracted bacteria and viruses, and image analysis software used to determine bacterial cell volumes. Bacterial and viral abundances were in the region of 107-109 per gram of soil over a range of soil types. Significant fluctuations in viral and bacterial abundances were recorded at timescales of less than 24 h. Glucose and nitrogen addition led to substantial increases in bacterial and viral abundance. Loss of soil moisture resulted in peaks of viral abundance in sandy soils but not in a clay soil. A six-week microcosm study demonstrated that phage were not a significant regulator of bacterial abundance. Low levels of lysogeny were recorded over a range of soils when measured explicitly with Mitomycin C. The implication from that study was that viruses in soil behave differently to those in aquatic systems. Bacterial and viral abundances were highly coupled in most instances, irrespective of the potential activity of bacteria. Further fundamental studies are recommended.
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Procter, Charlotte Anne. "The post-viral fatigue syndrome." Thesis, Durham University, 1990. http://etheses.dur.ac.uk/6221/.
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Post-viral fatigue syndrome (myalgic encephalomyelitis) is a physically debilitating disorder associated with chronic disabling fatigue. This thesis presents two studies which look at the impact of illness from a personal-psychological and from a family perspective. The first investigates the psychological features of the syndrome. The prevalence of psychiatric disorder in 20 patients with the PVFS was determined. Sixty percent satisfied criteria for a current psychiatric disorder. Diagnoses were of neurotic depression and other neuroses. Only 25 % of a comparatively disabled group of 20 arthritis sufferers received similar diagnoses. Diagnoses did not substantially differ in type from a group of 20 subjects with major depressive disorders, although selected differences in symptom profile and the role of previous life-time psychiatric episodes, suggest that the PVFS cannot be regarded as a variant form of depressive disorder. A logistic regression analysis achieved a satisfactory separation of the two disorders on the basis of psychiatric symptoms. The second study investigates 9 school-aged children with mothers suffering from the syndrome, and 9 children with healthy parents. The children in the PVFS group had been exposed to their mother's illness from between 18 months and 14 years. They were found to have significantly more problems in the school environment in comparison to controls, rated as more shy and anxious, less assertive and with more relationship problems with peers. General family orientation was less active with fewer out-of-home family pursuits. Family interactions were somewhat more negative. Child adjustment is discussed in terms of the linkages between family, school and peer-group in the lives of these children. Investigations into the adaptive potential of such linkages and the permeability of the boundaries between the spheres raise important questions for ameliorative work in the counselling of PVFS sufferers and their families.
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Wang, Ami M. "Lifecycle of viral YouTube videos." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/97377.
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Thesis: S.B., Massachusetts Institute of Technology, Department of Architecture, 2014.<br>Cataloged from PDF version of thesis.<br>Includes bibliographical references (page 28).<br>YouTube was founded in 2005 as a video-sharing website. Today, it's a powerhouse social media platform where users can upload, view, comment, and share content. For many, it's the first site visited when looking for songs, music videos, TV shows, or just general entertainment. Along with the sharing potential provided by social media like Twitter, Facebook, Tumblr, and more, YouTube videos have the potential to spread like wildfire. A term that has been coined to describe such videos is "viral videos." This comes from the scientific definition of viral, which involves the contagious nature of the spread of a virus. Virality on the Internet is not a new concept. Back when email was the hottest new technology, chain e-mails spreading hoaxes and scams were widely shared by emailing back and forth. As the Internet aged, however, new forms of virality have evolved. This thesis looks at a series of 20 viral videos as case studies and analyzes their growth over time via the Lifecycle Theory. By analyzing viral videos in this manner, it aids in a deeper understanding of the human consciousness's affinity for content, the sociology of online sharing, and the context of today's media culture. This thesis proposes that the phenomenon of virality supports the claim of Internet as heterotopia.<br>by Ami M. Wang.<br>S.B.
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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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Oliveira, Vivian Leite. "Impact of viral mmunomodulatory proteins." Doctoral thesis, Universidade Nova de Lisboa. Instituto de Tecnologia Química e Biológica, 2013. http://hdl.handle.net/10362/11946.
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Dissertation presented to obtain the Ph.D degree in Biology<br>Cerca de 50% do genoma dos vírus de DNA evoluiu direcionado para a manipulação de importantes funções celulares do hospedeiro.
Estas estratégias são muito diversas e conferem ao vírus vantagens
importantes sobre o sistema imunitário do hospedeiro. Esses genes são, por isso, potenciais fontes de informação para a geração de novos fármacos
dirigidos à manipulação da resposta imunológica na saúde e na doença. Esta tese centra-se na análise da função de dois genes virais distintos,
ambos com funções imunomoduladoras. O gene do Vírus da Peste
Suína Africana codificado pela “open reading frame” I329L (ORF I329L), e o gene do vírus herpes-gama-68 de murino codificado pela “open reading frame” M2 (ORF M2). Ambos os vírus são conhecidos por codificar várias proteínas capazes de manipular componentes vitais da resposta antiviral. Neste trabalho nós demonstramos que tanto a ORF I329L quanto ORF M2 são capazes de manipular a imunidade inata ou adquirida.(...)
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Ahlberg, Jakob. "Successful Methods of Viral Marketing." Thesis, Internationella Handelshögskolan, Högskolan i Jönköping, IHH, Marketing and Logistics, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:hj:diva-39843.
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Mahadevan, Geetha B. "Viral suppression of host defenses." Link to electronic thesis, 2004. http://www.wpi.edu/Pubs/ETD/Available/etd-0507104-110551.
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Carratalà, Ripollès Anna. "Contaminació viral del medi ambient: persistència i traçabilitat / Environmental viral pollution: persistence and source tracking." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/111289.
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Les poblacions humanes i animals excreten una gran diversitat de virus patògens en les seves femtes i orina, de manera que l’aigua residual que generen representa un dels principals vehicles de la disseminació de patògens a les aigües superficials, subterrànies o costaneres i conseqüentment, als aliments. La contaminació del medi ambient suposa un risc greu de salut pública. S’ha estimat que en el conjunt del planeta, aproximadament 3.000 milions de persones no disposen d’aigua potable i que el 95% de l’aigua residual domèstica és abocada al medi ambient sense tractar.
Aquesta tesi doctoral es basa en dues àrees d’estudi de la virologia ambiental. Per una banda s’ha avaluat l’estabilitat de virus contaminants en condicions naturals (Capítol I) i davant processos de desinfecció (Capítol II). En aquests estudis, els indicadors virals/patògens HAdV i JCPyV han estat analitzats. D’altra banda, s’ha proposat una nova eina per a la identificació de l’origen de la contaminació fecal al medi ambient (Capítol III).
Al Capítol I, que inclou els estudis 1, 2 i 3, s’ha caracteritzat els factors ambientals i els mecanismes que intervenen en la inactivació natural dels HAdV a diferents ambients aquàtics i aliments, considerant la temperatura i la llum solar com els agents potencialment més rellevants, així com l’estandardització entre diferents laboratoris d’un mètode de qPCR per a la quantificació dels HAdV en mostres d’aliments (fruits rojos). Al Capítol II (estudis 4, 5 i 6) s’ha estudiat l’efectivitat de tractaments químics (clor) i físics (llum ultraviolada) en la inactivació de virus contaminants. Finalment, al Capítol III (estudi 7), s’ha considerat que era interessant completar les eines moleculars existents per a identificar les fonts de contaminació fecal en aigua i aliments, i s’ha desenvolupat una nova tècnica molecular per a traçar la contaminació fecal d’aviram al medi ambient, mitjançant la detecció i quantificació dels parvovirus de pollastre i gall d’indi.
És evident que la contaminació viral en el medi representa un risc d’infecció important en països en vies de desenvolupament però també en zones industrialitzades on els tractaments d’aigua no aconsegueixen eliminar la totalitat dels virus presents. Durant el desenvolupament d’aquesta tesi doctoral s’ha demostrat que, en molts casos, els mètodes de desinfecció més habituals en la inactivació de virus contaminants no són completament eficients i sovint es detecten virus infecciosos després de tractaments a les dosis o concentracions habitualment utilitzades. Aquesta observació demostra la importància de seguir treballant per a caracteritzar els diversos factors i mecanismes particulars que condicionen la inactivació natural dels virus patògens al medi ambient, i de desenvolupar i optimitzar nous mètodes de desinfecció per assolir la inactivació d’un rang de microorganismes més ampli, més enllà dels indicadors bacterians tradicionals.
Els avanços en la virologia ambiental han d’anar forçosament acompanyats d’avenços en els tècniques i mètodes utilitzats, que han de permetre detectar, quantificar i caracteritzar els virus presents al medi de manera rutinària. En aquest sentit, els mètodes moleculars representen eines valuoses que faciliten l’estudi de diversos aspectes de la disseminació de virus al medi ambient, com per exemple identificar l’origen de la contaminació fecal per a implementar mesures de remediació a les fonts de contaminació més rellevants en cada localitat. Els virus patògens contaminants representen un problema de salut pública que cal resoldre imperativament millorant els processos de control microbiològica de recursos tant imprescindibles com són l’aigua i els aliments, introduint paràmetres virals que complementin als indicadors fecals bacterians estàndards.
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Schobel, Seth Adam Micah. "The viral genomics revolution| Big data approaches to basic viral research, surveillance, and vaccine development." Thesis, University of Maryland, College Park, 2016. http://pqdtopen.proquest.com/#viewpdf?dispub=10011480.
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<p> Since the decoding of the first RNA virus in 1976, the field of viral genomics has exploded, first through the use of Sanger sequencing technologies and later with the use next-generation sequencing approaches. With the development of these sequencing technologies, viral genomics has entered an era of big data. New challenges for analyzing these data are now apparent. Here, we describe novel methods to extend the current capabilities of viral comparative genomics. Through the use of antigenic distancing techniques, we have examined the relationship between the antigenic phenotype and the genetic content of influenza virus to establish a more systematic approach to viral surveillance and vaccine selection. Distancing of Antigenicity by Sequence-based Hierarchical Clustering (DASH) was developed and used to perform a retrospective analysis of 22 influenza seasons. Our methods produced vaccine candidates identical to or with a high concordance of antigenic similarity with those selected by the WHO. In a second effort, we have developed VirComp and OrionPlot: two independent yet related tools. These tools first generate gene-based genome constellations, or genotypes, of viral genomes, and second create visualizations of the resultant genome constellations. VirComp utilizes sequence-clustering techniques to infer genome constellations and prepares genome constellation data matrices for visualization with OrionPlot. OrionPlot is a java application for tailoring genome constellation figures for publication. OrionPlot allows for color selection of gene cluster assignments, customized box sizes to enable the visualization of gene comparisons based on sequence length, and label coloring. We have provided five analyses designed as vignettes to illustrate the utility of our tools for performing viral comparative genomic analyses. Study three focused on the analysis of respiratory syncytial virus (RSV) genomes circulating during the 2012- 2013 RSV season. We discovered a correlation between a recent tandem duplication within the G gene of RSV-A and a decrease in severity of infection. Our data suggests that this duplication is associated with a higher infection rate in female infants than is generally observed. Through these studies, we have extended the state of the art of genotype analysis, phenotype/genotype studies and established correlations between clinical metadata and RSV sequence data.</p>
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Pelliccia, M. "STRATEGIES FOR ENHANCING VIRAL GENE TRANSFER AND THE THERMOSTABILITY OF VIRAL VECTORS IN VACCINE APPLICATIONS." Doctoral thesis, Università degli Studi di Milano, 2015. http://hdl.handle.net/2434/265518.
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At the most basic level viruses are biological nano-containers constituted by genetic material enclosed in a protein shell, capsid. A peculiar feature of viruses, both bacterial and some eukaryotic viruses, lies in the high packaging density of the genome in order to fit itself in the small capsid and hence the high internal osmotic pressure. Virus is a relatively stable particle equipped with fascinating mechanical properties of the capsid that are crucial for the virus lifecycle. Viruses have only one purpose: infect a host cell for reproducing themselves in order to generate new viral progeny (Roos et al. 2007). Therefore, the first and foremost consideration arising from the concept of virus reflects its pathogenesis and virulence that can ultimately result in many important infectious diseases such as common cold, influenza, hepatitis, rabies, measles, cancer and AIDS. As a consequence, pathogenic viruses represent a heavy hurdle for the global health and there is a strong need for developing robust strategies such as vaccines or antiviral drugs against virus infections (Baram- Pinto et al. 2010). On the other hand, viruses in the course of evolution have become efficient specialized gene delivery agents. Therefore they represent powerful tools in biomedicine for gene therapy and vaccine purposes (Schaffer et al. 2008). For successful gene therapy and immunization programs, the efficiency and stability of viral vectors are fundamental aspects (Jorio et al. 2006).
To address this challenge, in the present research project we have investigated the interaction between viruses and nanomaterials. In the last years materials on the nanoscale for their unique properties have provided a broad range of potential biomedical uses (Verma et al. 2008) and for that reason we decided to explore their application with viruses. More specifically, we have examined three types of sulfonate- functionalized gold nanoparticles (AuNPs), namely, MUS:OT, MUS and MUS:brOT NPs, which are less than 5 nm in size, negatively charged and poorly cytotoxic (Verma et al. 2008). The NPs are coated with self-assembled monolayer (SAM) of thiolated organic molecules and one of the ligand is a sulfonated molecule, MUS (Verma et al. 2008). The MUS ligand itself was tested in our experiments as well. As virus models we focused on human recombinant adenovirus type 5 (Ad), one of the most promising viral vector as vaccine and gene therapy carrier and two picornaviruses of the genus enterovirus, namely, EV1 and CVB3, important human pathogens associated with several infectious diseases (e.g. myocarditis, aseptic meningitis, encephalitis, paralysis)(Kossila et al. 2002)(Marjomäki et al. 2014a). In spite of their medical impact, there are no therapeutic treatments available against picornavirus infections and the only vaccine products are against three types of poliovirus and hepatitis A virus (Merilahti et al. 2012).
Two sets of experiments were carried out: (1) Short-term incubation of Ad with nanomaterials for 1 h at 37°C prior
transducing HeLa cells or before in vivo administration in zebrafish and mice. The results demonstrated that Ad shortly pre-treated with nanomaterials showed a significant increase in the gene expression in vitro and in vivo The NPs’enhanced adenovirus transduction aims to reduce Ad vector doses in vivo thereby minimizing the adverse reactions of the immune response due to high vector dosage; (2) Long-term thermostabilization studies of Ad, EV1 and CVB3 in vitro in the presence and in the absence of our nanomaterials and other substances such as sugars (sucrose, glucose, glycerol) and Polyethylene glycol (PEG) molecules at 37°C or room temperature for extensive periods of time. Our results showed the capability of the nanomaterials and sucrose to increase substantially the heat stability of the viruses. In order to elucidate the thermal inactivation mechanism of viral particles and the stabilizing effect provided by some compounds on viruses we set out to formulate an analytical theory. This line of research fits in the context of developing more thermo-stable viral vector preparations for vaccine purposes that do not require the maintenance of the challenging cold chain system in order to preserve the effectiveness of viral vaccines during the storage, shipment and administration to the patients and hence to ensure the success of global immunization programs (Alcock et al. 2010).
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Nilsson, Ida, and Magnus Svensson. "The viral makes you aware : how is brand association affected by viral marketing through individual networks." Thesis, Kristianstad University College, School of Health and Society, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:hkr:diva-5930.
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<p>Nowadays the internet has become more and more important in today’s technology addicted society. Consumers of today use the internet as a tool to communicate, do shopping and search for information. Hence, the internet has become a convenient way for organizations to reach out to consumers in an easy and cheap way, specially through the tool viral marketing. In this paper we research the phenomenon brand awareness and brand association affected by viral marketing. This is done through two research questions: <em>How does a commercial affect consumers to create a network Viral marketing campaign?</em> And <em>Why do consumers purchase a brand when they are reacting negatively on a commercial?. </em></p><p> </p><p>To answer the research questions we chose a well discussed Swedish commercial from Apoliva as an example, especially since the commercial has received many negative reactions. Based on the commercial, we made a survey on the internet community site Facebook to measure how and why users reacted to the commercial and spread the reactions further; if and how their opinions changed toward the commercial and if and why consumers buy from the brand.</p><p> </p><p>The conclusions we draw from the research questions are that consumers tend to buy a brand although they do not like the commercial related to the brand, since the commercial itself is not of importance and in most cases the consumers do not relate the commercial with the brand. Furthermore, consumers tend to discuss a commercial if it is not a mainstream commercial. Although consumers discuss with their network on the internet, most of the discussion tend to be mouth-to-mouth and the spreading of opinion on the internet is mostly to vent their feelings.</p>
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Douglas, Kimberly L. "Non-viral gene therapy : design and characterisation of novel non-viral vectors for improved cellular transfection." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=102495.
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The promise of gene therapy, once hailed as the medical treatment of the future, has yet to be achieved. Problems related to the safety and efficacy of gene therapies have checked the enthusiasm once surrounding this field. The future of gene therapy relies on the development of safe and effective non-viral vectors for gene delivery.<br>This doctoral thesis describes the development and evaluation of a novel nanoparticle system that demonstrates characteristics suitable for gene delivery purposes. The work presented in this thesis is divided into three main phases: (1) Development of a novel delivery system. The development of a novel carrier was undertaken with the goal of producing a system that is biocompatible, biodegradable and non-toxic. The alginate-chitosan polyelectrolyte system, chosen for development due to its desirable characteristics at the macro- and micro-scales, was successfully used to prepare nanoparticles of appropriate size for delivery purposes. (2) Evaluation of the delivery system as a gene carrier. Alginate-chitosan nanoparticles were shown to complex DNA and effectively protect it from degradation. The inclusion of alginate in the system was confirmed to reduce the strength of binding between chitosan and DNA, thereby facilitating its release intracellularly. Cell viability studies confirm the non-toxicity of the system, while in vitro studies confirm the ability of alginate-chitosan nanoparticles to mediate efficient transfection. (3) Investigation of the transfection process. The cell line-dependent transfection ability of these nanoparticles, as observed with many non-viral vectors, led to the investigation of the processes involved in successful transfection. The intracellular trafficking of the non-viral vectors to the endosomal-lysosomal pathway, determined to be critical for efficient transfection, was found to be directly dependent on the internalisation mechanisms of the complexes.<br>The development and evaluation of the alginate-chitosan nanoparticle system confirms their suitability for gene delivery applications. The additional information provided by the thorough investigation of the cellular internalisation and intracellular trafficking pathways of the alginate-chitosan nanoparticles can be exploited to further develop the system to allow tailoring to improve transfection.
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Jung, Cindy. "Quantitative analysis of lentivirus incorporation of heterologous viral and non-viral proteins for lung gene therapy." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/26648.
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Thesis (Ph.D)--Biomedical Engineering, Georgia Institute of Technology, 2008.<br>Committee Chair: Joseph M. Le Doux; Committee Member: Andrés J. Garcia; Committee Member: Cheng Zhu; Committee Member: Nael McCarty; Committee Member: Richard Compans. Part of the SMARTech Electronic Thesis and Dissertation Collection.
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CORTESE, MARIA FRANCESCA. "HIV and HBV infection as models of viral DNA integration and mechanisms of viral-associated carcinogenesis." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2015. http://hdl.handle.net/2108/203036.
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My PhD was focused on two viruses, both responsible of persistent infection: HIV and HBV. The
two viruses show high worldwide prevalence and both are associated with high morbidity and
mortality.
HIV establishes a persistent infection through different mechanisms, first of all with the integration
of its DNA into the host genome, thus forming the provirus. However, a consistent part of the viral
DNA within the infected cells is unintegrated (circular or not). The project following presented
aims to analyse the kinetic of viral replication (measured as p24 production) and HIV DNA integration in primary lymphocytes (CD4+ ad PBMC) and Monocyte-derived Macrophages (MdM)
in presence and absence of Integrase inhibitors (INIs). HIV DNA quantification (as proviral,
unintegrated and 2-LTR) was assessed at different time points. The presented data reconfirmed, as
previously reported in literature, the different kinetic of HIV replication in lymphocytes (CD4+ T
cells and PBMCs, much faster) compared to macrophages (more slow), and suggested the presence
of a different kinetic of HIV DNA integration between the two cellular systems, too. Both INIs
efficiently inhibit the viral replication and the integration of HIV DNA. However, a little but
consistent amount of HIV DNA was observed at 30 days post treatment in macrophages, which are
the main reservoirs of the infection. By analysing the composition of this little HIV DNA amount,
we observed a very little difference between the two drug which could be probably explained by the
well-described different kinetic of dissociation of the DTG-enzyme complex. In conclusion these
data could give new information about the different kinetic of HIV replication between
lymphocytes and macrophages, suggesting also the implication of a different kinetic of HIV DNA
integration. Both the integrase inhibitors efficiently inhibit HIV replication and integration.
Nonetheless, in presence of INI, although an almost total inhibition of HIV replication was
observed, a little but consistent amount of viral DNA was maintained in macrophages. This
evidence could have important implication in the study of HIV persistence and viral rebound after treatment interruption. The data above mentioned were presented at the 12th edition of the
European congress on HIV e hepatitis, in Barcelona in 2014 (26-28 March), and a manuscript is in
preparation.
HBV is another important virus able to establish a persistent infection that usually causes cirrhosis
and hepatocarcinoma (HCC). HBV could indirectly (through compensative cellular replication) or
directly (through event of random integration or due to the viral proteins) promote carcinogenesis.
Among the viral proteins the trans-activating HBV protein (HBx) covers a key role in this sense.
The project here presented aims to highlight specific mutations in HBX gene associated with HCC
in a group of chronically-HBV infected patients. By analysing the sequences of 75 HBV chronically
infected patients, we observed the mutation F30V prevalently in the HCC group. This is located
within the N-terminal region of HBx which seems to be involved in the negative regulation of the
HBx trans-activation function. By analysing the results obtained in vitro, we observed that the
mutation would reduce the viral replication, probably due to its localization in a domain within the
N-terminal region known to be involve in the dimerization of the protein. HBx protein, both wt and
mutated, did not alter the cycle progression of exposed cells. On the contrary, the mutation could to
be associated with less cellular susceptibility to apoptotic death related to what observed in
presence of the HBx wt. This observed cell survival could probably promote the maintenance of
aberrant cellular clones thus favouring the appearance of tumour. Of consequence, considering the
obtained results, it is possible to propose that F30V mutation could interfere with HBV replication
and can have a role in HBV-driven carcinogenesis by reducing the rate of apoptosis. However,
further studies are required in order to understand the potential role of F30V as HCC prognostic
factor in HBV chronically infected patients.
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ARMIJOS, RIVERA JORGE ISAAC. "Targeting cellular kinases and viral factors for molecular therapy of cancer, neurodegenerative diseases and viral infections." Doctoral thesis, Università degli studi di Pavia, 2018. http://hdl.handle.net/11571/1214796.
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Nobre, Rita Luisa Valentim de Avelar. "Viral interferon antagonists and antiviral drugs /." St Andrews, 2009. http://hdl.handle.net/10023/818.
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Gayarre, German, and Carlos Larrea. "Diffusion of innovative ideas : Viral marketing." Thesis, Halmstad University, School of Business and Engineering (SET), 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:hh:diva-1593.
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Flür, Katharina. "Molekulare Mechanismen der viral-getriggerten Glomerulonephritis." Diss., lmu, 2010. http://nbn-resolving.de/urn:nbn:de:bvb:19-115463.
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Ibeh, Neke. "Inferring Viral Dynamics from Sequence Data." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/35317.
Full textAbstract:
One of the primary objectives of infectious disease research is uncovering the direct
link that exists between viral population dynamics and molecular evolution. For
RNA viruses in particular, evolution occurs at such a rapid pace that epidemiological
processes become ingrained into gene sequences. Conceptually, this link is easy to
make: as RNA viruses spread throughout a population, they evolve with each new
host infection. However, developing a quantitative understanding of this connection
is difficult. Thus, the emerging discipline of phylodynamics is centered on reconciling
epidemiology and phylogenetics using genetic analysis. Here, we present two research studies that draw on phylodynamic principles in order to characterize the progression and evolution of the Ebola virus and the human immunodefficiency virus (HIV). In the first study, the interplay between selection and epistasis in the Ebola virus genome is elucidated through the ancestral reconstruction of a critical region in the Ebola virus glycoprotein. Hence, we provide a novel mechanistic account of the structural changes that led up to the 2014 Ebola virus outbreak. The second study applies an approximate Bayesian computation (ABC) approach to the inference of epidemiological parameters. First, we demonstrate the accuracy of this approach with simulated data. Then, we infer the dynamics of the Swiss HIV-1 epidemic, illustrating the applicability of this statistical method to the public health sector. Altogether, this
thesis unravels some of the complex dynamics that shape epidemic progression, and
provides potential avenues for facilitating viral surveillance efforts.
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Ljungberg, Karl. "Variable viral genes as genetic immunogens /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-399-6/.
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Estmer, Nilsson Camilla. "Viral Control of SR Protein Activity." Doctoral thesis, Uppsala : Acta Universatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-5124-1/.
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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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Bonhoeffer, Sebastian. "Models of viral evolution and pathogenesis." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294217.
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Gupta, Ajay. "Viral studies in renal transplant recipients." Thesis, University of Newcastle Upon Tyne, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.519564.
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Eriksson, Mikael. "Viral Facebook integration i mobilspelet Gravel." Thesis, Linköpings universitet, Institutionen för datavetenskap, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-107533.
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Steinmetz, Nicole Franziska. "Viral capsids as programmable nanobuilding blocks." Thesis, University of East Anglia, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.439897.
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Manley, Robyn Anna. "Emerging viral diseases of pollinating insects." Thesis, University of Exeter, 2017. http://hdl.handle.net/10871/29677.
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The risks posed by rapidly evolving RNA viruses to human and animal health are well recognized. Epidemics in managed and wildlife populations can lead to considerable economic and biodiversity losses. Yet, we lack understanding of the ecological and evolutionary factors that promote disease emergence. Host-switching viruses may be a particular threat to species important for human welfare, such as pollinating bees. Both honeybees and wild bumblebees have faced sharp declines in the last decades, with high winter mortality seen in honeybees. Infectious and emerging diseases are considered one of the key drivers of declines, acting in synergy with habitat loss and pesticide use. Here I focus on multihost viruses that pose a risk to wild bumblebees. I first identify the risk factors driving viral spillover and emergence from managed honeybees to wild bumblebees, by synthesising current data and literature. Biological factors (i.e. the nature of RNA viruses and ecology of social bees) play a clear role in increasing the risk of disease emergence, but anthropogenic factors (trade and transportation of commercial honeybees and bumblebees) creates the greatest risk of viral spillover to wild bees. Basic knowledge of the pathogenic effect of many common pollinator viruses on hosts other than A. mellifera is currently lacking, yet vital for understanding the wider impacts of infection at a population level. Here, I provide evidence that a common bumblebee virus, Slow bee paralysis virus (SBPV), reduces the longevity of Bombus terrestris under conditions of nutrition stress. The invasion of Varroa destructor as an ectoparasitic viral vector in European honeybees has dramatically altered viral dynamics in honeybees. I test how this specialist honeybee vector affects multi-host pathogens that can infect and be transmitted by both honeybees and wild bumblebees. I sampled across three host species (A. mellifera, B. terrestris and B. pascuorum) from Varroa-free and Varroa-present locations. Using a combination of molecular and phylogenetic techniques I find that this specialist honeybee vector increases the prevalence of four multi-host viruses (deformed wing virus (type A and B), SBPV and black queen cell virus) in sympatric wild bumblebees. Furthermore, wild bumblebees are currently experiencing a DWV epidemic driven by the presence of virus-vectoring Varroa in A. mellifera. Overall this thesis demonstrates that wild bumblebees are at high risk of viral disease emergence. My research adds to the ever-expanding body of evidence indicating that stronger disease controls on commercial bee operations are crucial to protect our wild bumblebees.
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Matthews, Philip Trystan. "Viral interference with T lymphocyte recognition." Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621627.
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Fischer, Gilberto Bueno. "Fatores prognosticos para bronquiolite viral aguda." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 1994. http://hdl.handle.net/10183/139229.
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Bronquiolite Viral Aguda (BVA) é uma doença de alta prevalência no Rio Grande do Sul e causa um importante número de hospitalizações em crianças menores de um ano de idade. Os pacientes com maior gravidade, nos três primeiros dias de internação, podem evoluir para insuficiência ventilatória e necessitarem oxigênio ou até ventilação mecânica, como forma de tratamento. Com o objetvo de identificar precocemente os episódios mais graves, investigaram-se fatores prognósticos através de sinais clínicos e laboratoriais, durante a hospitalização de crianças com BVA. Estudou-se uma coorte de 213 crianças menores de um ano com BVA admitidas no Hospital da Criança Santo Antônio de Porto Alegre. Esses pacientes foram seguidos desde a hospitalização, nos três dias subseqüentes, na alta hospitalar e até 30 e 60 dias após. Caracterizou-se a necessidade de oxigênio no terceiro dia ou de ventilação mecânica nos três primeiros dias de hospitalização, como critérios de gravidade. As hospitalizações ocorreram, predominantemente, nos meses de julho a setembro, e a maior parte das crianças (60%) apresentava idade inferior a quatro meses. Dentre as características sócio-econômicas estudadas, observou-se que 50% das famílias tinham renda mensal menor que três salários mínimos e 18% viviam em residências aglomeradas. Das 213 crianças acompanhadas até a alta hospitalar, 61(29%) necessitaram de oxigênio no terceiro dia, e 12(6%), ventilação mecânica nas primeiras 72 horas. Verificou-se que 17% dos pacientes apresentavam história de prematuridade, 24% estavam sendo amamentados quando hospitalizaram e 12% nunca haviam mamado no peito. Cerca de 35% das famílias referiram história de asma brônquica. As principais características clínicas na hospitalização foram: freqüência respiratória maior que 60(67%), presença de sibilos(76%) e estertores crepitantes(57%) à ausculta pulmonar e tiragem subcostal (56%). Entre os sinais investigados, assodaramse significativamente com nlaior gravidade: frequência respiratória maior que 70, enchimento capilar lento, cianose de extremidades e tiragem supraesternal. A saturação transcutânea de oxigênio da hemoglobina inferior a 91% e atelectasia ao exame radiológico de tórax, mostraram-se associadas significativamente com maior gravidade. Entre os fatores prognósticos, identificou-se o risco relativo associado a maior gravidade: idade inferior a 4 mes{~s (RRl~7), peso de nascimento inferior a 2500g (RR 2,3) e desnutrição grave(RR 2,0). Constituíram-se escalas de gravidade através de análise discriminante incluindo-se os seguintes itens: idade inferior a 3 meses, prostração, batimento de asas do nariz, freqüência respiratória maior ou igual a 70, tiragem (subcostal, intercostal e supraesternal), saturação de oxigênio menor ou igual a 90%, uso de oxigênio, internação em UTI e uso de ventilação mecânica. Através do somatório de cada um dos itens, resultaram os escores de gravidade. Os escores foram dicotomizados em menores ou iguaisl a 3 e maiores que 3 (mais graves). No seguimento após a alta hospitalar, observou-se que a Inaioria dos pacientes que compareceram apresentou episódios de sibilância e que foi elevado o número de reinternações (26% aos 60 dias).<br>Acute viral bronchiolitis(AVB) has a high prevalence in Rio Grande do Sul. It accounts for a high number of hospital admissions in infants. The patients with a more severe disease, in the first three days of hospitalization may develop respiratory failure and might need oxygen or mechanical ventilation . The aim of this study was to investigate prognostic factors (clinicaI signs and laboratory tests) in hospitalized infants with AVB. The research conducted was a cohort study of 213 infants with AVB who were admitted to the Hospital da Criança Santo Antônio, Porto Alegre. These patients were followed up from the admission, in the three first days, to their discharge and at 30 and 60 days after admission. Severity criteria were defined such as need of oxygen in the third day of admission or mechanical ventilation in the first three days. The admissions occurred predominantly from July to September and the majority (60%) were infants under four months of age. It was observed that 50% of the families had monthly wages below three minimum saIaries and 18% lived in crowded homes. Sixty one (29%) of the children needed oxygen in the third day of admission and 12 (6%) were put on mechanical ventilation. It was observed that 17% of the patients had a past history of prematurity, 24% were being breast fed at admission and 12% had never been breast fedo Around 35% of the families had a past history of bronchial asthma. The main clinicaI characteristics were: respiratory rate above 60 (67%), wheezes (76%), crepitations (57%) and subcostal retraction (56%). The following findings were significantly associated to severity : respiratory rate above 70 mpm, peripheric cyanosis, low capillary filling, supraesternal retraction, transcutaneous oxygen saturation below 91%, atelectasis at the chest X-ray. Among the prognostic features, some were identified as presenting high relative risk associated to severity: Age under 4 months (RR 1,7), birth weight below 2500 g (RR 2,3) and malnutrition (RR 2,0). Severity scales have been developed using discriminant analysis with the following items: age under 3 months, prostration, flaring of the alae nasi, respiratory rate above 70 mpm, retractions (subcostal, intercostal and supraesternal), transcutaneous oxygen saturation, need of oxygen, admission in intensive care unit and use of mechanical ventilation. Severity scores resulted from the addition of the value attributed to each of the items (O or 1). They were dichotomized in above (more severe) and below or equal to 3. At the follow up, after the discharge it was observed that the majority of the children who had been seen at thirty and sixty days had wheezing episodes and there was a high rate of re admissions (26% at 60 days).
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Nikin-Beers, Ryan Patrick. "Immunoepidemiological Modeling of Dengue Viral Infection." Diss., Virginia Tech, 2018. http://hdl.handle.net/10919/82924.
Full textAbstract:
Dengue viral infection is a mosquito-borne disease with four distinct strains, where the interactions between these strains have implications on the severity of the disease outcomes. The two competing hypotheses for the increased severity during secondary infections are antibody dependent enhancement and original antigenic sin. Antibody dependent enhancement suggests that long-lived antibodies from primary infection remain during secondary infection but do not neutralize the virus. Original antigenic sin proposes that T cells specific to primary infection dominate cellular immune responses during secondary infections, but are inefficient at clearing cells infected with non-specific strains.
To analyze these hypotheses, we developed within-host mathematical models. In previous work, we predicted a decreased non-neutralizing antibody effect during secondary infection. Since this effect accounts for decreased viral clearance and the virus is in quasi-equilibrium with infected cells, we could be accounting for reduced cell killing and the original antigenic sin hypothesis.
To further understand these interactions, we develop a model of T cell responses to primary and secondary dengue virus infections that considers the effect of T cell cross-reactivity in disease enhancement. We fit the models to published patient data and show that the overall infected cell killing is similar in dengue heterologous infections, resulting in dengue fever and dengue hemorrhagic fever. The contribution to overall killing, however, is dominated by non-specific T cell responses during the majority of secondary dengue hemorrhagic fever cases. By contrast, more than half of secondary dengue fever cases have predominant strain-specific T cell responses. These results support the hypothesis that cross-reactive T cell responses occur mainly during severe disease cases of heterologous dengue virus infections.
Finally, using the results from our within-host models, we develop a multiscale model of dengue viral infection which couples the within-host virus dynamics to the population level dynamics through a system of partial differential equations. We analytically determine the relationship between the model parameters and the characteristics of the solutions, and find thresholds under which infections persist in the population. Furthermore, we develop and implement a full numerical scheme for our model.<br>Ph. D.