Tesis: "Determinants and dynamics of infectious diseases"

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Eames, K. "Dynamics of infectious diseases on mixing networks." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598725.

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This thesis describes the development of models designed to capture the dynamics of infections taking place within mixing networks. These models, formulated as systems of differential equations using pair-wise moment closure techniques, are investigated for a wide variety of situations and shown to be highly flexible and often very different from traditional approaches. When compared to full stochastic simulations on computer-generated networks they are remarkably accurate, giving excellent agreement both to the initial growth and the equilibrium behaviour of epidemics. The models are used to investigate a range of interventions, including targeted control measures and contact tracing. Contact tracing, which attempts to identify contacts of infected individuals, is an intrinsically network-based intervention that the pair-wise models developed here are well suited to capturing. It is shown to be a naturally targeted and powerful control that can reduce prevalence by automatically concentrating efforts on high-risk subpopulations. Network methods are particularly applicable to sexually transmitted diseases (STDs), for which networks are relatively easy to define and frequently measured. To better capture the behaviour of STDs in the general population, a monogamous network model is developed, including partnership turnover within a serially monogamous society. The influence of turnover rates is apparent, and the reduced impact of high mixing groups within such populations has ramifications for the design of control policies. The presence of partnership dynamics within monogamous networks introduces a second time-scale that allows the existence of multiple pathogen strains whereas, in a polygamous environment, only one would be able to persist. The coexistence of otherwise mutually exclusive strains has implications for disease evolution, and demonstrates the importance of population mixing patterns and behaviour.

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2

Okonna, Ime Udo. "Time-delayed models of infectious diseases dynamics." Thesis, University of Sussex, 2018. http://sro.sussex.ac.uk/id/eprint/73551/.

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This research work is on time-delayed models of infectious diseases dynamics. The dynamics of infectious diseases are studied in the presence of time delays representing temporary immunity or latency. We have designed and analysed time-delayed models with various parameters to simulate disease dynamics, in a view to gaining insight into the behaviour of a population in the presence of infectious diseases, and the reaction of the population to changes in the management procedure of such infections.

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3

Gupta, Sunetra. "Heterogeneity and the transmission dynamics of infectious diseases." Thesis, Imperial College London, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309107.

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4

Russell, Colin Andrew. "Dynamics of acute infectious diseases in heterogeneous environments." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.614196.

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5

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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6

Song, Wei Ash, and 宋威. "Demographic determinants of risk perception of newly emerging respiratory infectious diseases." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46941617.

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7

Gaythorpe, Katherine. "The impact of natural disasters on the dynamics of infectious diseases." Thesis, University of Bath, 2016. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.681058.

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Over the course of this thesis we will build and develop a model for the dynamics of an environmentally transmitted disease such as cholera. We will also develop methods to analyse and understand that model. The dynamics of a disease in a heterogeneous developing world city have not yet been fully explored, particularly when those dynamics are affected by a natural disaster. Yet, natural disasters such as floods alter infrastructure and population characteristics in a manner that affects disease transmission. Therefore, we shall address this omission from the literature. We will also develop a novel model analysis framework for 'systems epidemiology' where we combine systems biology techniques with epidemiological modelling.

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8

Wilson, David. "The mathematical modelling of the cellular dynamics of human infectious diseases." Thesis, Queensland University of Technology, 2003. https://eprints.qut.edu.au/37155/8/David%20Wilson%20Thesis.pdf.

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9

Gabel, Michael [Verfasser], and Ursula [Akademischer Betreuer] Kummer. "Quantifying CD8+ T cell dynamics in infectious diseases / Michael Gabel ; Betreuer: Ursula Kummer." Heidelberg : Universitätsbibliothek Heidelberg, 2018. http://d-nb.info/1177251787/34.

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10

O'Connor, Daniel. "Genetics determinants of vaccine responses." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:6e529d46-4a1a-423e-87e1-eaee8977791d.

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Vaccines have had a profound influence on human health with no other health intervention rivalling their impact on the morbidity and mortality associated with infectious disease. However, the magnitude and persistence of vaccine immunity varies considerably between individuals, a phenomenon that is not well understood. Recent studies have used contemporary technologies to correlate variations in the genome and transcriptome to complex phenotypic traits, and these approaches have started to provide fresh insight into the intrinsic factors determining the generation and persistence of vaccine-induced immunity. This thesis aimed to describe the relationship between genomic and transcriptomic variations, and the immunogenicity of childhood immunisations. Candidate gene and genome-wide genotyping was conducted to evaluate the influence of genetic variants on vaccine-induced immunity following childhood immunisation. Furthermore, contemporary methodologies were used to assess non-coding and coding gene transcript profiles following vaccination, to further dissect the molecular systems involved in vaccine responses. Key findings from this thesis include the description of the first genome-wide association studies into the persistence of immunity to three routine childhood immunisations: capsular group C meningococcal (MenC) conjugate vaccine, Haemophilus influenzae type b (Hib) conjugate vaccine and tetanus toxoid (TT) vaccine. Genome-wide genotyping was completed on over 2000 participants, with an additional 1000 participants genotyped at selected genetic markers. Genome-wide significant associations (p<5×10−8) were described between single- nucleotide polymorphisms (SNPs) in two genes, CNTN6 and ENKUR, and the persistence of serological immunity to MenC following immunisation of children 6-15 years of age. In addition, genome-wide significant associations were described between SNPs within an intergenic region of chromosome 10 and the persistence of TT-specific IgG concentrations following childhood immunisations. Furthermore, a number of variants in loci with putative involvement in the immune system such as FOXP1, the human leukocyte antigen locus and the lambda light chain immunoglobulin locus, were shown to have suggestive associations (p<1×10−5) with the persistence of vaccine-induced serological immunity. The fundamental challenge will be to describe functional mechanisms associated with these findings, and to translate these into innovative and pragmatic strategies to develop new and more effective vaccines.

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11

Alkaitis, Matthew S. "Biochemical determinants of nitric oxide synthesis in severe malaria." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:dde50b9c-fea1-432a-8c5f-35e97e641061.

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Inhibition of nitric oxide (NO) signalling may contribute to the pathogenesis of severe malaria. This thesis examines the impact of Plasmodium infection on three key determinants of nitric oxide synthase (NOS) biochemistry: substrate availability, substrate/inhibitor homeostasis and cofactor availability. Arginine, the NOS substrate, is depleted in human patients with severe Plasmodium falciparum malaria and mice infected with P. berghei ANKA. Using heavy isotope tracer infusions to quantify arginine metabolism in infected mice, we found no evidence of increased catabolism by the enzyme arginase, widely assumed to be responsible for arginine depletion. Genetic knock-out of parasite arginase had no effect on arginine depletion in mice. Instead, our findings link arginine depletion to decreased rates of arginine and citrulline appearance in the plasma of infected mice. Asymmetric dimethylarginine (ADMA) competes with arginine for binding to the NOS catalytic site. We observed elevation of the ADMA/arginine ratio in Gambian children with severe malaria, favouring NOS inhibition. In mice infected with P. berghei ANKA, we found evidence of degradation of dimethylarginine dimethylaminohydrolase 1 (DDAH1), the enzyme primarily responsible for ADMA metabolism. We also observed reduced DDAH activity and accumulation of intracellular ADMA in hepatic tissue of infected mice, suggesting that DDAH dysfunction could contribute to disruption of ADMA/arginine homeostasis. Tetrahydrobiopterin (BH4) is an essential NOS cofactor. In P. berghei ANKA-infected mice, BH4 concentrations were decreased in plasma, erythrocytes and brain tissue, which could inhibit NO synthesis and promote NOS-dependent superoxide production. To reverse deficiencies of NOS substrate and cofactor availability, we infused P. berghei ANKA-infected mice with citrulline, an arginine precursor, and sepiapterin, a BH4 precursor. Restoration of systemic arginine and BH4 availability in infected mice improved whole blood nitrite concentrations, a biomarker of NO synthesis, but did not prevent onset of disease symptoms. These studies have identified biochemical disturbances that may contribute to severe malaria pathogenesis by inhibiting NO synthesis.

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12

Godfrey, Elinor. "Social and environmental determinants of changing distribution and incidence of tick-borne encephalitis in Western Europe." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:fd0a7241-b85f-4d49-abe4-a5ec4057c96e.

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In Western Europe the incidence of tick-borne encephalitis (TBE) has increased over the last 30 years, coupled with changes in distribution. Modifications in the TBE enzootic cycle, through a combination of changes in temperature, vertebrate abundance and habitat suitability may have increased the risk of TBE in recent years. In Switzerland, analysis using satellite-derived climate data demonstrated that the environment of areas with TBE since the 1980s and areas that recently became endemic for TBE have become more similar between 2001 and 2009. This was coupled with an increase in April, May and June temperature, which could have affected the tick population and/or human exposure to ticks. Deer and boar abundance also changed in some cantons. In Germany, spatio-temporal modelling demonstrated the importance of temperature, vertebrate abundance and unemployment in the incidence and distribution of TBE between 2001 and 2009. Changes in TBE reporting, April, May and June temperature, vertebrate abundance and pesticide use may have contributed to increases in TBE in 1992 and 2001. Human exposure patterns, however, appear to be as important as the enzootic cycle in shaping the incidence of TBE, not only in determining the overall trend but also in interacting with the weekly, seasonal and yearly patterns of tick hazard to give the observed incidence. In Switzerland, in weeks with warm, sunny weather, human exposure to ticks is promoted and short-term increases in tick bites are seen. Human outdoor activity also shifts the seasonal pattern of tick bites, when compared with tick questing. There was no apparent increase in time spent in outdoor activities between the 1990s and 2000s in Italy, Germany and Austria, but survey data demonstrated that walking and hiking were already popular activities across Europe by the 1990s. The popularity of mushroom and berry foraging as a source of income in Latvia, Lithuania and Poland, coupled with the expense of vaccination, provide an inverse link between economic wellbeing and TBE risk. Correspondingly, in 2009, the economic recession was associated with an increase with TBE in these three countries.

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13

Earnhart, Christopher G. "Dynamics of the host-parasite interaction: in vitro correlates of Crassostrea-induced modulation of Perkinsus marinus function." W&M ScholarWorks, 2004. https://scholarworks.wm.edu/etd/1539616637.

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Perkinsus marinus is an alveolate protozoan parasite of the eastern oyster (Crassostrea virginica) which is responsible for much of the decline in United States oyster populations. Perkinsus marinus can be cultured in vitro, but is rapidly attenuated in the process. Supplementation of a protein-free medium with oyster products altered proliferation, changed protease expression in the parasite extracellular products (ECP), induced morphological forms typically seen in vivo, and partially reversed parasite attenuation. Supplements derived from dissected oyster tissues were used to determine if these changes could be differentially elicited. These supplements, with the exception of adductor muscle, reduced proliferation. Whole oyster and digestive gland/gonad supplements favored palintomic, rather than binary, fission. The total ECP protease activity was generally decreased in supplemented cultures, though gill/mantle supplements may have induced proteases. A low molecular weight subset of proteases was upregulated most effectively by heart- and adductor muscle-derived supplements. Serine proteases and other ECP proteins may be virulence factors. Attempts to create antibodies to study P. marinus cells and ECP have been largely unsuccessful due to poor immune responses and crossreactivity. Ultrafiltration-concentrated P. marinus ECP were poorly immunogenic and toxic to experimental animals. Immunogenicity was not substantially affected by heat denaturation or proteolytic inhibition. Co-administration of ECP with oyster plasma caused a suppression in the anti-plasma antibody response with restriction of epitope recognition. Analysis of medium constituents revealed that a surfactant, Pluronic F-68 (PF68), was immunosuppressive. Although isolated protein antigens from the ECP remained immunosuppressive, separation of the antigens from PF68 enabled antibody production. Five monoclonal antibodies were created against ECP from unsupplemented medium and were used to study ECP function, regulation, and mechanism of storage and release. ECP are secreted by release from the cell wall and from two morphologically distinct intracellular compartments. A sandwich ELISA allowed quantification of an ECP protein with significantly reduced expression in supplemented cultures. Another antibody, which specifically bound to trophozoite and tomont walls, was used to investigate morphological and antigenic changes during thioglycollate-induced formation of prezoosporangia, and confirm supplement-induced formation of prezoosporangia. This antibody labeled P. marinus cells in fixed oyster tissue in a species-specific manner.

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14

Cavanagh, Rachel. "Interactions between population dynamics, body condition and infectious diseases (cowpox virus and Mycobacterium microti) of wild rodents." Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250372.

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15

Jones, Darbi Rae. "The Effect of Vaccination and Host Genetics on Transmission Dynamics of Infectious Hematopoietic Necrosis Virus and Flavobacterium Psychrophilum in Rainbow Trout (Oncorhynchus Mykiss)." W&M ScholarWorks, 2019. https://scholarworks.wm.edu/etd/1582642565.

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Globally, infectious diseases are responsible for major conservation and economic losses in wild and farmed fish populations. Prevention tools, including vaccination and breeding for genetic disease resistance, are used in many systems to prevent mortality by such diseases. Studies are often done to evaluate the efficacy of a preventative method at reducing disease, but the impact on transmission is rarely studied. Protection under diverse field conditions, such as variable pathogen exposure dosages, is also not fully understood. Furthermore, there is little information on how preventative methods alter host-pathogen relationships. For example, it is largely unknown how vaccination impacts non-target pathogens that co-infect the host. These knowledge gaps make it difficult to infer the epidemiological impacts of disease prevention tools. In an attempt to fill these gaps, we investigated two leading pathogens in rainbow trout (Oncorhynchus mykiss) aquaculture: infectious hematopoietic necrosis virus (IHNV) and Flavobacterium psychrophilum. We evaluated the impacts of vaccination and genetic disease resistance on mortality and transmission across a range of challenge dosages of IHNV and F. psychrophilum to accurately reflect field variability. There was evidence of a dosage effect; as dosage increased, shedding increased and vaccine efficacy decreased. We also evaluated how vaccination and genetic disease resistance impact transmission dynamics during simultaneous and sequential co-infection of IHNV and F. psychrophilum. Our results indicate co-infected fish shed more of both pathogens than they do in single infections, and the order that the pathogen infected the host may impact transmission in both pathogens. Furthermore, vaccine efficacy may be diminished by co-infection. These studies are aimed at developing a more robust framework for inferring the efficacy of disease prevention strategies. Our results will also help to inform and improve disease management in one of the top aquaculture species in the United States.

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16

Cuny, Gérard. "Les crises épidémiques de l'empire romain, 27 av. J.-C. - 476 ap. J.-C." Electronic Thesis or Diss., Montpellier 3, 2023. http://www.theses.fr/2023MON30036.

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De nombreuses sources attestent d’épidémies, et divers récits font référence à des « pestes », noms génériques pour désigner de graves maladies infectieuses épidémiques qui ont marqué l’Empire Romain. Les récits qui nous sont parvenus ne donnent pas ou très rarement des indications sur l’épidémiologie, les symptômes, les signes ou l’évolution des maladies responsables, mais à défaut de pouvoir poser un diagnostic précis il parait plausible, compte-tenu de nos connaissances actuelles, d’avancer des hypothèses sur leur nature. Pour chaque épidémie, l’identification des agents pathogènes potentiellement responsables, et leurs interactions avec les populations du passé, est réalisée. Ensuite, une recherche/compréhension est menée, afin d’expliquer l’apparition de la maladie infectieuse, la dynamique de son comportement temporel et spatial, la taille critique des populations hôtes, l’importance et les effets de modifications environnementales ou bioclimatiques qui ont contribué à sa diffusion. Pour mieux expliciter ces événements épidémiques, un état des lieux des connaissances médicales de l’époque était indispensable : quelles conceptions avaient les médecins des maladies, de leurs causes et de leurs variétés, des notions de transmissibilité des maladies infectieuses. Sont abordés ensuite les différents facteurs démographiques (densité de peuplement, état sanitaire, migrations), socio-économiques (pauvreté, carences nutritionnelles, pressions humaines sur l'environnement), climatiques et écologiques qui, individuellement ou en conjonction, pouvaient favoriser le développement d’une épidémie. Enfin, la perception du risque épidémique, dans ses dimensions cognitives (connaissance et compréhension du risque) et émotionnelle (ressenti du risque et comportement), ainsi que la manière dont l’Etat et les populations s’attachaient à se prémunir ou à subir les flambées épidémiques sont considérées. L’Empire romain a été confronté à des épidémies majeures, premières pandémies meurtrières décrites dans l’histoire qui vont contribuer à son affaiblissement et indirectement à l’essor du christianisme Many sources attest to epidemics, and various stories refer to "plagues", generic names to designate serious epidemic infectious diseases that marked the Roman Empire. The stories that have come down to us do not or very rarely give any information on the epidemiology, symptoms, signs or evolution of the diseases responsible, but in the absence of being able to make a precise diagnosis, it seems plausible, taking into account our current knowledge, to put forward hypotheses on their nature. For each epidemic, the identification of potentially responsible pathogens, and their interactions with past populations, is carried out. Then, a research/understanding is carried out, in order to explain the appearance of the infectious disease, the dynamics of its temporal and spatial behavior, the critical size of the host populations, the importance and the effects of environmental or bioclimatic modifications which have contributed to its dissemination. To better explain these epidemic events, an inventory of medical knowledge of the time was essential: what were the conceptions that doctors had of diseases, their causes and their varieties, notions of the transmissibility of infectious diseases. The various demographic (population density, health status, migrations), socio-economic (poverty, nutritional deficiencies, human pressures on the environment), climatic and ecological factors which individually or in conjunction could favor the development of a epidemic. Finally, the perception of the epidemic risk, in its cognitive (knowledge and understanding of the risk) and emotional (feeling of the risk and behavior) dimensions, as well as the way in which the State and the populations endeavored to protect themselves or to suffer the epidemic outbreaks are considered. The Roman Empire was confronted with major epidemics, the first deadly pandemics described in history which will contribute to its weakening and indirectly to the rise of Christianity

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17

Ramamoorthy, Divya. "Design of Novel Inhibitors for Infectious Diseases using Structure-based Drug Design: Virtual Screening, Homology Modeling and Molecular Dynamics." Scholar Commons, 2012. http://scholarcommons.usf.edu/etd/4393.

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The main aim of the study in this thesis was to use structure-based protocols to design new drugs for enzymes, DXS and DXR in the non mevalonate pathway. Another aim of this study was to identify the dimer interface in E.coli FabH as an allosteric binding site for designing new class of anti-infective drugs. We have attempted to identify potential inhibitors for DXS by docking the NCI Diversity set compounds, compound libraries available from GSK-MMV and St. Jude's Children's research center. FabH dimer interface has been identified as a potential target using SiteMap, Alanine mutagenesis and docking studies. The first chapter gives an overview of the computational methods. The next two chapters briefly introduce the biological targets in the author's study. Chapter two explains the importance of non-mevalonate pathway in microbes. Different enzymes in the non-mevalonate pathway are discussed and the importance of terpenoids in biological processes and also the use of terpenoids as drugs have been extensively discussed in this chapter. The crystal structures available for DXS and DXR are also discussed. Chapter three brings out the importance of FabH as an anti-infective target. Crystal structure of FabH E.coli is discussed and the importance of FabH as a dimer has been discussed in this chapter. Chapter 3 describes the methods, homology models generated, and analysis from docking studies. The homology models for PvDXS and PvDXR have been used in this study to identify potential inhibitors. Domain swapping and the structural organization of PvDXS before and after domain swaping are discussed. Identification of domain swaping in PvDXS using entropy changes has been extensively discussed. Chapter 4 focuses on FabH (Fatty Acid Biosynthesis, enzyme H also referred to as β-ketoacyl-ACP-synthase III) dimer interface as an allosteric target. SiteMap analysis and MD simulations on the FabH monomer and dimer structures revealed the dimer interface as a binding region. Further analyses were done by mutagenesis studies on the Phe87 residue, a key residue at the dimer interface region and validating the results using docking studies. NCI Diversity Set compounds were docked at the dimer interface of FabH, which revealed that compounds NSC91529 and NSC19803 docked best at the dimer interface region with the phenyl ring of both the compounds

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18

Athri, Prashanth. "Application of Computer-Aided Drug Discovery Methodologies Towards the Rational Design of Drugs Against Infectious Diseases." Digital Archive @ GSU, 2008. http://digitalarchive.gsu.edu/chemistry_diss/20.

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Computer-aided drug discovery involves the application of computer science and programming to solve chemical and biological problems. Specifically, the QSAR (Quantitative Structure Activity Relationships) methodology is used in drug development to provide a rational basis of drug synthesis, rather than a trial and error approach. Molecular dynamics (MD) studies focus on investigating the details of drug-target interactions to elucidate various biophysical characteristics of interest. Infectious diseases like Trypanosoma brucei rhodesiense (TBR) and P. falciparum (malaria) are responsible for millions of deaths annually around the globe. This necessitates an immediate need to design and develop new drugs that efficiently battle these diseases. As a part of the initiatives to improve drug efficacy QSAR studies accomplished the formulation of chemical hypothesis to assist development of drugs against TBR. Results show that CoMSIA 3D QSAR models, with a Pearson’s correlation coefficient of 0.95, predict a compound with meta nitrogens on the phenyl groups, in the combinatorial space based on a biphenyl-furan diamidine design template, to have higher activity against TBR relative to the existing compound set within the same space. Molecular dynamics study, conducted on a linear benzimidazole-biphenyl diamidine that has non-classical structural similarity to earlier known paradigms of minor groove binders, gave insights into the unique water mediated interactions between the DNA minor groove and this ligand. Earlier experiments suggested the interfacial water molecules near the terminal ends of the ligand to be responsible for the exceptianlly high binding constant of the ligand. Results from MD studies show two other modes of binding. The first conformation has a single water molecule with a residency time of 6ns (average) that is closer to the central part of the ligand, which stabilizes the structure in addition to the terminal water. The second conformation that was detected had the ligand completely away from the floor of the minor groove, and hydrogen bonded to the sugar oxygens.

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19

Neal, Aaron T. "Identifying genetic determinants of impaired PfEMP1 export in Plasmodium falciparum-infected erythrocytes." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:0cc3f09c-9178-448b-92f8-8f9564398585.

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The virulence of Plasmodium falciparum is largely attributed to the ability of asexual blood-stage parasites to cytoadhere to the microvascular endothelium of the human host. This pathogenic behavior is mediated by the primary parasite virulence factor P. falciparum erythrocyte membrane protein 1 (PfEMP1), an understanding of which is crucial to develop interventions to ameliorate the morbidity and mortality of P. falciparum malaria. The work presented in this thesis describes the application of a phenotype-to-genotype experimental approach to identify novel parasite proteins involved in the trafficking and display of PfEMP1. Guided by the overall hypothesis that the in vitro culture-adapted parasite line 3D7 harbors 1 or more genetic determinants of impaired PfEMP1 trafficking, surface PfEMP1 levels were first measured in 3D7, the presumably trafficking-competent parasite line HB3, and 16 unique progeny from an HB3 x 3D7 genetic cross (chapter 2). These phenotypes were then combined with genome-wide SNP data in QTL analysis to identify genetic polymorphisms potentially responsible for the impaired trafficking in 3D7 (chapter 3). A near-significant QTL containing a single protein-coding gene, the putative kinesin Pf3D7_1245600, was identified, characterized, and investigated in CRISPR-Cas9-driven allele-exchange parasite transfection experiments to establish a causal link between the gene and PfEMP1 trafficking (chapter 4). The parasite transfections were unsuccessful, but the potential role of Pf3D7_1245600 in PfEMP1 trafficking was indirectly assessed through the disruption of microtubules with colchicine (chapter 4), which significantly impacted the surface PfEMP1 levels of HB3 but not 3D7. The findings of this thesis suggest that kinesins and microtubules may play previously unconsidered roles in the regulation, production, or trafficking of PfEMP1.

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20

Rosenbloom, Daniel Scholes. "Dynamics of infection, mutation, and eradication, in HIV and other evolving populations." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:10791.

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This work uses mathematical models of evolutionary dynamics to address clinical questions about HIV treatment, public health questions about vaccination, and theoretical questions about evolution of high mutation rates.

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21

Moreno, Torres Karla Irazema. "The Wildlife-Livestock Interface of Infectious Disease Dynamics: A One Health Approach." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1460896947.

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22

O'Bryan, Joel M. "Telomere Length Dynamics in Human T Cells: A Dissertation." eScholarship@UMMS, 2011. https://escholarship.umassmed.edu/gsbs_diss/568.

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Telomere length has been shown to be a critical determinant of T cell replicative capacity and in vivo persistence in humans. We evaluated telomere lengths in virus-specific T cells to understand how they may both shape and be changed by the maintenance of memory T cells during a subsequent virus re-infection or reactivation. We used longitudinal peripheral blood samples from healthy donors and samples from a long-term HCV clinical interferon therapy trial to test our hypotheses. To assess T cell telomere lengths, I developed novel modifications to the flow cytometry fluorescence in situ hybridization (flowFISH) assay. These flowFISH modifications were necessary to enable quantification of telomere length in activated, proliferating T cells. Adoption of a fixation-permeabilization protocol with RNA nuclease treatment prior to telomere probe hybridization were required to produce telomere length estimates that were consistent with a conventional telomere restriction fragment length Southern blot assay. We hypothesized that exposure to a non-recurring, acute virus infection would produce memory T cells with longer telomeres than those specific for recurring or reactivating virus infections. We used two acute viruses, vaccinia virus (VACV) and influenza A virus (IAV) and two latent-reactivating herpesviruses, cytomegalovirus (CMV) and varicella zoster virus (VZV) for these studies. Combining a proliferation assay with flowFISH, I found telomeres in VACV-specific CD4 + T cells were longer than those specific for the recurring exposure IAV; data which support my hypothesis. Counter to my hypothesis, CMV-specific CD4 + T cells had longer telomeres than IAV-specific CD4 + T cells. We assessed virus-specific CD4 + T cell telomere length in five donors over a period of 8-10 years which allowed us to develop a linear model of average virus-specific telomere length changes. These studies also found evidence of long telomere, virus-specific CD45RA + T cell populations whose depletion may precede an increased susceptibility to latent virus reactivation. I tested the hypothesis that type I interferon therapy would accelerate T cell telomere loss using PBMC samples from a cohort of chronic hepatitis C virus patients who either did or did not receive an extended course of treatment with interferon-alpha. Accelerated telomere losses occurred in naïve T cells in the interferon therapy group and were concentrated in the first half of 48 months of interferon therapy. Steady accumulation of CD57 + memory T cells in the control group, but not the therapy group, suggested that interferon also accelerated memory turnover. Based on our data, I present proposed models of memory T cell maintenance and impacts of T cell telomere length loss as we age.

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23

Rosà, Roberto. "The importance of aggregation in the dynamics of host-parasite interaction in wildlife : a mathematical approach." Thesis, University of Stirling, 2003. http://hdl.handle.net/1893/50.

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This study examines, from a modelling point of view, the dynamics of infectious diseases in wildlife caused by macroparasites and by tick-borne infections. The overall aim was to investigate the important role played by parasite aggregation in the dynamics of both systems. For macroparasites we first developed some deterministic models that incorporate explicit mechanisms for generating aggregation in parasite distribution, specifically multiple infections and host heterogeneity. We explored the role of aggregation in host regulation and in determining a threshold value for parasite establishment. A large aggregation makes it more difficult for parasites both to regulate hosts, and to get established in a population at carrying capacity. Furthermore, the stabilization yielded by aggregation strongly depends on the mechanism that produces the aggregation. We then introduced some uncertainties into the host-macroparasite system, presenting an individual-based stochastic model that incorporated the same assumptions as the deterministic model. Stochastic simulations, using parameter values based on some real case studies, preserved many features of the deterministic model, like the average value of the variables and the approximate length of the cycles. An important difference is that, even when deterministic models yield damped oscillations, stochastic simulations yield apparently sustained oscillations. The amplitude of such oscillations may be so large as to threaten the parasites’ persistence. With respect to tick-borne diseases we presented a general model framework that incorporated both viraemic and non-viraemic routes of infections. We compute the threshold for disease persistence and study its dependence on the parameters and on host densities. The effects of tick aggregation and correlation between different tick stages on the host have both an important effect on infection persistence, if non-viraemic transmission occurred. In the case of Lyme Disease and Tick-borne Encephalitis (TBE) in Trentino (northern Italy) we showed some numerical results, using parameter estimates based on a detailed field study, and explored the effects of uncertainty on the endemic equilibrium of both diseases assuming only viraemic transmission for Lyme Disease while for TBE we permitted only non-viraemic transmission through co-feeding ticks. In conclusion we have examined the patterns and changes of aggregation in a number of contrasting systems and believe that these studies highlight both the importance of considering heterogeneities in modelling host-parasite interactions and, more specifically, modelling the biological mechanisms that produce aggregation in parasite distributions.

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24

Sundqvist, Martin. "Antibiotic Resistance and Population Dynamics of Escherichia coli in Relation to a Large Scale Antibiotic Consumption Intervention." Doctoral thesis, Uppsala universitet, Infektionssjukdomar, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-112190.

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Antibiotic resistance challenges the practice and development of modern medicine. The aim of this thesis was to test the hypothesis that antibiotic resistance is reversible once the selection pressure of an antibiotic is removed. A decisive reduction (85%) in trimethoprim and trimethoprim-sulfamethoxazole over 24 months in Kronoberg County, Sweden, is described. The resistance baseline prior to the intervention and the effects of the intervention on resistance levels, trimethoprim resistance genes (dfr-genes) and population structure in Escherichia coli were studied. The effects of different algorithms for excluding patient duplicate isolates were small but systematic. An identical algorithm was used throughout. The drastic decrease in the use of trimethoprim containing drugs did not result in a corresponding decrease in trimethoprim resistance. This was true both for total trimethoprim resistance and for trimethoprim mono-resistance. The distributions of E. coli phenotypes, dfr-genes and E. coli sequence types were stable. The marginal effect on resistance rates was explained by a low fitness cost of trimethoprim resistance observed in vitro and the high levels of associated resistance in trimethoprim resistant isolates. Trimethoprim resistance was, although widespread in the E. coli population, more common in certain E. coli sequence types. The distributions of dfr-genes were different in E. coli and K. pneumoniae and between different E. coli sequence types. These results indicate mechanisms related to the genetic back-bone of E coli to be important for the acquisition and persistence of antibiotic resistance. The findings of this thesis indicates that, at least for some classes of antibiotics, we may have overestimated the usefulness of a strategy for reversing antimicrobial resistance based on the fitness cost of resistance. We have equally underestimated the conserving effects of associated resistance. The stability of the dfr-genes and E. coli sequence types underlines the importance of associated resistance and successful lineages in the spread and maintenance of antibiotic resistance in E. coli.

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Lourenço, José. "Unifying the epidemiological, ecological and evolutionary dynamics of Dengue." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:cb4db8dd-5467-4c6e-8d3e-3e0fe738bc0a.

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In under 6 decades dengue has emerged from South East Asia to become the most widespread arbovirus affecting human populations. Recent dramatic increases in epidemic dengue fever have mainly been attributed to factors such as vector expansion and ongoing ecological, climate and socio-demographic changes. The failure to control the virus in endemic regions and prevent global spread of its mosquito vectors and genetic variants, underlines the urgency to reassess previous research methods, hypotheses and empirical observations. This thesis comprises a set of studies that integrate currently neglected and emerging epidemiological, ecological and evolutionary factors into unified mathematical frameworks, in order to better understand the contemporary population biology of the dengue virus. The observed epidemiological dynamics of dengue are believed to be driven by selective forces emerging from within-host cross-immune reactions during sequential, heterologous infections. However, this hypothesis is mainly supported by modelling approaches that presume all hosts to contribute equally and significantly to the selective effects of cross-immunity both in time and space. In the research presented in this thesis it is shown that the previously proposed effects of cross-immunological reactions are weakened in agent-based modelling approaches, which relax the common deterministic and homogeneous mixing assumptions in host-host and host-pathogen interactions. Crucially, it is shown that within these more detailed models, previously reported universal signatures of dengue's epidemiology and population genetics can be reproduced by demographic and natural stochastic processes alone. While this contrasts with the proposed role of cross-immunity, it presents demographic stochasticity as a parsimonious mechanism that integrates, for the first time, multi-scale features of dengue's population biology. The implications of this research are applicable to many other pathogens, involving challenging new ways of determining the underlying causes of the complex phylodynamics of antigenically diverse pathogens.

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26

Ramirez, Ramirez Lilia Leticia. "On the dynamics of infectious diseases in non-homogeneous populations." Thesis, 2008. http://hdl.handle.net/10012/4054.

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The principal motivations for studying epidemics and their dynamics are understanding the biological characteristics of the epidemic agents and reducing the economical and social costs originating from epidemic outbreaks. The most commonly used epidemic models have important assumptions such as the law of mass action, and the latent and infectious periods being exponentially distributed with xed parameters. Under this kind of suppositions the models are analyzed with well known algorithms as the Euler and Euler-Maruyama, and methodology and results from the theory of Markovian processes. However, these assumptions are selected largely for their analytic convenience and in many cases are far from describing the agent's transmissibility attributes in the population and its biological characteristics in a host. The epidemic models studied here relax two important epidemic assumptions. The first to be relaxed is the one that susceptible individuals are equally likely to acquire the disease. A structure for the kind of individual contacts that can result in the infection transmission is incorporated in the population. This contact structure can be non-homogeneous and it is modeled as a random graph whose edges describe the contacts between individuals. The second assumption that is generalized, is the distribution of the latent and infectious period in the host individuals. This research work allows the latent and infectious period to have a distribution other than the exponential and hence the epidemic process is more general than a Markovian process. As in most stochastic models, the infectious contact is modeled as a random variable with Poisson distribution. However, to introduce the individual variations, the transmission rate is assumed to be a non negative random variable. This work extends the epidemic models suggested by Newman (2002) in two directions. The first, studies the hierarchical networks that have a more complex network structure, involving the interaction of populations. The second direction examines the evolution in times for outbreaks in networks. In this work, results for discrete and continuous time are obtained. The results for the continuous time model considers the infectious process to be a bivariate Markovian process. However, the results for the final outbreaks size and the developed simulation program include the general case were the latent and infectious period can have a distribution other than exponential. This research work also analyze the effect of four control measures in the contact structure, and using the simulation program and Monte Carlo-likelihood methodology, it estimates the parameters for measles and influenza. The results here obtained can be directly applied to study the dynamics of other kind of “agents” such as information and ideas. For example, the dynamics can involve the spread of computer viruses, rumors, eating habits and personal positions regarding a fact or idea.

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27

"Structural and Biophysical Studies of Pathological Determinants in Cancer and Infectious Diseases." Doctoral diss., 2020. http://hdl.handle.net/2286/R.I.62824.

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abstract: This work advances structural and biophysical studies of three proteins important in disease. First protein of interest is the Francisella tularensis outer membrane protein A (FopA), which is a virulence determinant of tularemia. This work describes recombinant expression in Escherichia coli and successful purification of membrane translocated FopA. The purified protein was dimeric as shown by native polyacrylamide gel electrophoresis and small angle X-ray scattering (SAXS) analysis, with an abundance of β-strands based on circular dichroism spectroscopy. SAXS data supports the presence of a pore. Furthermore, protein crystals of membrane translocated FopA were obtained with preliminary X-ray diffraction data. The identified crystallization condition provides the means towards FopA structure determination; a valuable tool for structure-based design of anti-tularemia therapeutics. Next, the nonstructural protein μNS of avian reoviruses was investigated using in vivo crystallization and serial femtosecond X-ray crystallography. Avian reoviruses infect poultry flocks causing significant economic losses. μNS is crucial in viral factory formation facilitating viral replication within host cells. Thus, structure-based targeting of μNS has the potential to disrupt intracellular viral propagation. Towards this goal, crystals of EGFP-tagged μNS (EGFP-μNS (448-605)) were produced in insect cells. The crystals diffracted to 4.5 Å at X-ray free electron lasers using viscous jets as crystal delivery methods and initial electron density maps were obtained. The resolution reported here is the highest described to date for μNS, which lays the foundation towards its structure determination. Finally, structural, and functional studies of human Threonine aspartase 1 (Taspase1) were performed. Taspase1 is overexpressed in many liquid and solid malignancies. In the present study, using strategic circular permutations and X-ray crystallography, structure of catalytically active Taspase1 was resolved. The structure reveals the conformation of a 50 residues long fragment preceding the active side residue (Thr234), which has not been structurally characterized previously. This fragment adopted a straight helical conformation in contrast to previous predictions. Functional studies revealed that the long helix is essential for proteolytic activity in addition to the active site nucleophilic residue (Thr234) mediated proteolysis. Together, these findings enable a new approach for designing anti-cancer drugs by targeting the long helical fragment. Dissertation/Thesis Doctoral Dissertation Biochemistry 2020

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Kgasago, Tshepo Matenatena Blessings. "Modelling the transmission dynamics of infectious diseases with vaccination and temporary immunity." Thesis, 2008. http://hdl.handle.net/10386/347.

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Thesis (M.Sc.) (Applied Mathematics) --University of Limpopo, 2008. In this dissertation, two non-linear mathematical models are proposed and analyzed to investigate the spread of infectious diseases in a variable size population through horizontal transmission in the presence of preventive or therapeutic vaccines which are capable of inducing temporary immunity and wane in time. In modeling the transmission dynamics, the population is divided into three subclasses namely; Susceptibles, Infectives and Vaccinated groups. It is assumed that both Vaccinated and Susceptible individuals are recruited into the community and can only become infected via contacts with the infectives group but the rate at which the vaccinated group may contract the diseases is extremely very low depending on the efficacy of the vaccine. All infectives are assumed to move at a constant rate to both Vaccinated and Susceptible groups. These models are analyzed by using the stability theory of differential equations and numerical simulation. The models exhibit two equilibria namely; the disease-free and the endemic equilibria. It is shown that if the vaccination reproduction number R0 < 1, the disease-free equilibrium is always globally asymptotically stable and in such a case the endemic equilibrium does not exist and the disease can be totally eliminated in the community. However, if R0 > 1, a unique endemic equilibrium exists that is locally asymptotically stable and consequently the equilibrium values of infective, vaccinated and susceptible population can be maintained at desired levels. Numerical simulations implemented on MAPLE using both Adomian decomposition technique and Runge-Kutta integration schemes, support our analytical conclusions and illustrate possible behaviour scenarios of the models. International Pentecostal Holiness Church, Limpopo Provincial Treasury, National Student Financial Aid Scheme and National Research Foundation

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29

"On the Dynamics of Infectious Diseases in Modern Landscapes: Urban Settings and Drug Resistance." Doctoral diss., 2014. http://hdl.handle.net/2286/R.I.24917.

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abstract: Extraordinary medical advances have led to significant reductions in the burden of infectious diseases in humans. However, infectious diseases still account for more than 13 million annual deaths. This large burden is partly due to some pathogens having found suitable conditions to emerge and spread in denser and more connected host populations, and others having evolved to escape the pressures imposed by the rampant use of antimicrobials. It is then critical to improve our understanding of how diseases spread in these modern landscapes, characterized by new host population structures and socio-economic environments, as well as containment measures such as the deployment of drugs. Thus, the motivation of this dissertation is two-fold. First, we study, using both data-driven and modeling approaches, the the spread of infectious diseases in urban areas. As a case study, we use confirmed-cases data on sexually transmitted diseases (STDs) in the United States to assess the conduciveness of population size of urban areas and their socio-economic characteristics as predictors of STD incidence. We find that the scaling of STD incidence in cities is superlinear, and that the percent of African-Americans residing in cities largely determines these statistical patterns. Since disparities in access to health care are often exacerbated in urban areas, within this project we also develop two modeling frameworks to study the effect of health care disparities on epidemic outcomes. Discrepant results between the two approaches indicate that knowledge of the shape of the recovery period distribution, not just its mean and variance, is key for assessing the epidemiological impact of inequalities. The second project proposes to study, from a modeling perspective, the spread of drug resistance in human populations featuring vital dynamics, stochasticity and contact structure. We derive effective treatment regimes that minimize both the overall disease burden and the spread of resistance. Additionally, targeted treatment in structured host populations may lead to higher levels of drug resistance, and if drug-resistant strains are compensated, they can spread widely even when the wild-type strain is below its epidemic threshold. Dissertation/Thesis Ph.D. Applied Mathematics for the Life and Social Sciences 2014

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30

"Understanding the Impact of Social Factors on the Transmission Dynamics of Infectious Diseases Across Highly Heterogeneous Risk Environments." Doctoral diss., 2018. http://hdl.handle.net/2286/R.I.49368.

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abstract: This dissertation explores the impact of environmental dependent risk on disease dynamics within a Lagrangian modeling perspective; where the identity (defined by place of residency) of individuals is preserved throughout the epidemic process. In Chapter Three, the impact of individuals who refuse to be vaccinated is explored. MMR vaccination and birth rate data from the State of California are used to determine the impact of the anti-vaccine movement on the dynamics of growth of the anti-vaccine sub-population. Dissertation results suggest that under realistic California social dynamics scenarios, it is not possible to revert the influence of anti-vaccine contagion. In Chapter Four, the dynamics of Zika virus are explored in two highly distinct idealized environments defined by a parameter that models highly distinctive levels of risk, the result of vector and host density and vector control measures. The underlying assumption is that these two communities are intimately connected due to economics with the impact of various patterns of mobility being incorporated via the use of residency times. In short, a highly heterogeneous community is defined by its risk of acquiring a Zika infection within one of two "spaces," one lacking access to health services or effective vector control policies (lack of resources or ignored due to high levels of crime, or poverty, or both). Low risk regions are defined as those with access to solid health facilities and where vector control measures are implemented routinely. It was found that the better connected these communities are, the existence of communities where mobility between risk regions is not hampered, lower the overall, two patch Zika prevalence. Chapter Five focuses on the dynamics of tuberculosis (TB), a communicable disease, also on an idealized high-low risk set up. The impact of mobility within these two highly distinct TB-risk environments on the dynamics and control of this disease is systematically explored. It is found that collaboration and mobility, under some circumstances, can reduce the overall TB burden. Dissertation/Thesis Doctoral Dissertation Applied Mathematics for the Life and Social Sciences 2018

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Alakesh. "Delineating the dynamics of neutrophil response in multiple inflammatory stimuli and its consequences." Thesis, 2023. https://etd.iisc.ac.in/handle/2005/6141.

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In this thesis, we investigate the regulation of neutrophils, an important component of the immune system, and its implications on inflammation and pathological conditions. We use biomaterial implants to induce chronic sterile inflammation in mice and examine the effects on neutrophil production rates, maturation times, and lifespan in various tissue compartments. We demonstrate that in case where inflammation leads to emergency granulopoiesis (EG), we observe increased neutrophils progenitors, reduced maturation time in the bone marrow, reduced lifespan in circulation, and prolonged residence time at the inflammatory site. These changes aim to maintain high neutrophil numbers at the site of inflammation while keeping the circulating neutrophil count constant. However, this also results in an increase in immature neutrophils in circulation. Next, we explore the response of neutrophils to a second inflammation in mice undergoing EG. In a PVA sponge model of second inflammation, we observe increased presence of immature neutrophils and CD38+ M1-type macrophages at the second inflammatory site, indicating heightened inflammatory reactions. Next, a lung inflammation model is employed to mimic a clinically relevant scenario, again showing increased infiltration of immature neutrophils, and CD38-expressing M1-type macrophages in the lungs of mice with EG, which correlates with increased lung damage over time. Although the exact mechanism remains to be determined, the initial data suggests that inflammatory responses are intensified at the second inflammation site in mice with EG. Lastly, our study demonstrates that while the phenotype and numbers of neutrophils are altered in mice with EG, they still possess the ability to eliminate bacteria in the presence of bacterial infections at the second inflammation site. In conclusion, the research highlights the alterations in neutrophil phenotype, numbers, and function following high-grade inflammatory insults, which subsequently impact the innate immune response to a second inflammation, resulting in similar bacterial control but increased immunopathology.

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32

Ogut, Hamdi. "Biological and mathematical modeling of dynamics of furunculosis in chinook salmon (Oncorhynchus tshawytscha) and infectious hematopoietic necrosis (IHN) in rainbow trout (Oncorhynchus mykiss)." Thesis, 2001. http://hdl.handle.net/1957/32662.

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A series of experiments with Aeromonas salmonicida and infectious hematopoietic necrosis virus (IHNV) were carried out to determine dynamics of the spread of infection in chinook salmon (1.2-1.98g) and rainbow trout (1.2-3.1g). It was found in experiments with A. salmonicida that fish infected by bath immersion became infectious at 4 days postexposure (dpe), one day prior to dying from furunculosis. In cohabitation experiments with a single infected fish donor, an average of 75% disease specific mortality was obtained. There was suggestive evidence that there is a positive relationship between holding volumes and furunculosis prevalence in cohabitation experiments with single donor fish. Median day to infection was inversely correlated with density. The threshold density at density of 1.97 fish/L was approximately 30 times less than the density of 0.08 fish/L, 13.33 and 320 fish respectively. Reproductive ratio (R₀) and transmission coefficient (β) in the furunculosis epizootic were 3.23 and 0.021 (individuals*day)⁻¹ respectively. The mortality rate (α) of infected animals was 28.7% per day. The models constructed successfully mirrored the results of laboratory experiments. Data produced by simulation of the models were significantly associated with the data obtained from laboratory experiments for susceptible (S) class and also for infected class. In similar experiments carried out with IHNV, it was found that donor fish became infectious 3 dpe. The virus levels in donor fish and prevalence levels were also highly associated. Smaller volumes of that led to higher prevalence levels than observed in bigger volumes with 60 or 30 fish in each. A single donor fish was able to transfer virus to recipient fish. However, unlike the A. salmonicida experiment, transmission was insufficient to initiate a full-scale infectious hematopoietic (IHN) epizootic. Estimated parameters for dynamics of infection were approximately half of the values for A. salmonicida (R₀=2.57,β=0.008 (individuals*day)⁻¹ and α=0.15). The models constructed for IHNV spread were used to simulate the results of density experiment. However, it was not possible to test the association between susceptible and infected classes due to inadequate number of infected fish. Graduation date: 2001

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