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1
Steele, John. "Molecular recognition in plant immunity." Thesis, University of East Anglia, 2016. https://ueaeprints.uea.ac.uk/58564/.
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Plant pathogens constitute a major threat to global food security. The use of naturally resistant crop varieties can limit crop losses, however new races of pathogen can arise that are able to overcome these defences. Plant breeding for race-specific resistance typically relies on disease-resistance genes, which generally encode proteins with nucleotide-binding and leucine-rich repeat domains (NB-LRRs). NB-LRRs are a large of proteins found in both plants and animals, with plant NB-LRRs further classified by the presence of N-terminal coiled-coil or toll-interleukin receptor domains. Although qualitative models exist to describe R-protein regulation and activation, these are predominantly based on genetic and molecular studies. Biochemical investigations into R-protein function have been hampered by difficulties obtaining sufficient yields of material. When suitable material has been identified, biochemical studies have been used to complement well-established in planta assays to validate numerous hypotheses. This work describes the screening processes undertaken to obtain R-protein domains suitable for downstream experiments. Using E. coli for high-throughput screening of constructs from a single R-protein, traditional construct design to investigate multiple R-protein domains and expanding our expression hosts to eukaryotic systems we successfully purified four coiled-coil domains and a single NBARC domain for use in downstream experiments. Characterisation of this NBARC domain by circular dichroism and small-angle X-ray scattering indicates that the protein is well-folded and stable in solution, allowing in vitro investigations. In testing models for R-protein regulation we were able to confirm previous findings, such as low levels of ATPase activity, however we were unable to find evidence for a commonly cited method of signal repression. A preliminary crystal structure of the NBARC domain shows significant similarity to Apaf-1, and highlights the importance of conserved motifs in NBARC architecture. The tools presented here should prove a valuable resource to complement existing models to better understand the structure, biochemistry, and ultimately regulation of plant R-proteins.
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Argyriou, Catherine. "Enhanced immunity in Mclk1 +/- mice." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=117161.
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MCLK1 (a.k.a. COQ7) is an evolutionarily conserved mitochondrial hydroxylase necessary ubiquinone biosynthesis. Mclk1+/- mice display a 50% reduction in this protein, as well as an array of phenotypes including increased longevity, decreased ubiquinone in the inner mitochondrial membrane, decreased mitochondrial respiration, and increased mitochondrial oxidative stress. We report here by various measures that Mclk1+/- mutants also exhibit an enhanced immune response in vivo. That is, Mclk1+/- mice mount a more extreme inflammatory response to bacterial lipopolysaccharide stimulation and bacterial infection, evidenced by increased measures of plasma cytokine levels. These mice also demonstrate resilience to tumour development, evidenced by a prolonged, dose-dependent delay in tumour onset following tumour cell xenograft. Furthermore, we report that Mclk1+/- mice react differently than wild-type mice following rapamycin injection. That is, circulating cytokine levels are attenuated in mutants but increased in wild-type mice following rapamycin administration. Despite their more extreme immune response, we demonstrate that Mclk1+/- mutants sustain less tissue damage as a result of infection or old age. Finally, using mouse models of high mitochondrial or cytoplasmic oxidative stress, we report that the Mclk1+/- phenotype is not simply due to increased reactive oxygen species in the mitochondria. These findings suggest characteristics that may contribute to the increased lifespan of these mice, though the causes of these characteristics require further investigation.MCLK1 (COQ7) est une enzyme hydroxylase conservée au cours de l'évolution et nécessaire pour la biosynthèse de l'ubiquinone. Les souris Mclk1+/- présentent une réduction de 50% du niveau de cette protéine, ainsi qu'une gamme de phénotypes, tels qu'un accroissement de la longévité, une réduction de la quantité d'ubiquinone dans la membrane interne mitochondriale, une réduction de la respiration mitochondriale, et une augmentation du stress oxydatif mitochondrial. Différentes mesures ont démontrées que les souris Mclk1+/- arborent également une meilleure réponse immunitaire suite à la stimulation par des lipopolysaccharides bactériens (LPS) ainsi que par l'infection bactérienne, comme en témoigne une augmentation du niveau de plusieurs cytokines plasmatiques en réponse à ces stimulations. Les mutants Mclk1+/- sont aussi plus résistants au développement de tumeurs, comme en témoigne le délai dans l'apparition de tumeurs après une xénogreffe de cellules tumorales. En outre, nous avons découvert que les souris Mclk1+/- réagissent différemment par rapport aux souris de type sauvage à un traitement avec la rapamycine. Nous avons observé que suite à l'administration prolongée de rapamycine suivi par une injection de LPS, le niveau de cytokines circulantes diminue chez les souris mutantes alors que chez les souris de type sauvage ce niveau augmente. Malgré leur réponse immunitaire plus intense, nous avons démontré que les souris Mclk1+/- subissent moins de dommages tissulaires à la suite d'une infection ou du processus de vieillissement. Enfin, en utilisant des modèles murins de stress oxydatif mitochondrial ou cytoplasmique augmenté, nous avons aussi établi que le phénotype Mclk1+/- ne résulte pas simplement de l'augmentation des radicaux libres dans les mitochondries.
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Wlasiuk, Battagliotti Gabriela. "THE MOLECULAR EVOLUTION OF INNATE IMMUNITY GENES." Diss., The University of Arizona, 2009. http://hdl.handle.net/10150/195184.
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It is not clear whether genes of the innate immune system of vertebrates are subject to the same selective pressures as genes of the adaptive immune system, despite the fact that innate immunity genes lie directly at the interface between host and pathogens. The lack of consensus about the incidence, type, and strength of selection acting on vertebrate innate immunity genes motivated this study. The goal of this work was to elucidate the general principles of innate immune receptor evolution within and between species. A phylogenetic analysis of the Toll-like receptor 5 (TLR5) in primates showed an excess of nonsynonymous substitutions at certain codons, a pattern that is consistent with recurrent positive selection. The putative sites under selection often displayed radical substitutions, independent parallel changes, and were located in functionally important regions of the protein. In contrast with this interspecific pattern, population genetic analysis of this gene in humans and chimpanzees did not provide conclusive evidence of recent selection. The frequency and distribution of a TLR5 null mutation in human populations further suggested that TLR5 function might be partially redundant in the human immune system (Appendix A). Comparable analyses of the remaining nine human TLRs produced similar results and further pointed to a biologically meaningful difference in the pattern of molecular evolution between TLRs specialized in the recognition of viral nucleic acids and the other TLRs (Appendix B). The general picture that emerges from these studies challenges the conventional idea that pattern recognition receptors are subject to an extreme degree of functional constraint dictated by the recognition of molecules that are essential for microbial fitness. Instead, TLRs display patterns of substitution between species that reflect an old history of positive selection in primates. A common theme, however, is that only a restricted proportion of sites is under positive selection, indicating an equally important role for purifying selection as a conservative force in the evolution of this gene family. A comparative analysis of evolutionary rates at fifteen loci involved in innate, intrinsic and adaptive immunity, and mating systems revealed that more promiscuous species are on average under stronger selection at defense genes (Appendix C). Although the effect is weak, this suggests that sexual promiscuity plays some role in the evolution of immune loci by affecting the risk of contracting infectious diseases.
4
Leung, Kit-Yi. "Molecular recognition between colicins and their immunity proteins." Thesis, University of East Anglia, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338294.
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Tusco, Radu. "Molecular mechanisms of selective autophagy in innate immunity." Thesis, University of Warwick, 2017. http://wrap.warwick.ac.uk/95261/.
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Autophagy is an evolutionarily conserved process of cellular material degradation, involved in development, starvation-induced nutrient-level control, degradation of aggregated proteins and pathogen removal. The specificity of this process is governed by selective autophagy receptors, messenger proteins which identify cargo and deliver it to Atg8a – a component of the core autophagic machinery. Receptors bind to Atg8-family proteins via the LIR motif, a short amino-acid sequence that is conserved across the animal kingdom. We performed a bioinformatics screen in order to identify new putative Atg8a interacting proteins. We searched the Drosophila proteome for proteins containing LIRmotifs and ubiquitin-binding domains. We identified the protein Kenny (homologue of human IKKg), which contains a LIR motif and a conserved UBAN domain. Kenny is a modulator of the Drosophila Immune deficiency (IMD) pathway, an innate immunity response targeted at gram-negative bacteria. Using biochemical approaches and in vivo studies in Drosophila we observed that Kenny interacted directly with Atg8a via its LIR motif and was selectively degraded by autophagy. We found that Kenny accumulated in autophagy depleted flies, which was accompanied by a constitutive activation of the IMD pathway and expression of antimicrobial peptides. This caused a hyperproliferation of stem cells in the midgut, reduced defecation rates and shortened the overall fly lifespan. Given sequence similarities between Kenny and another described receptor, Optineurin, we also investigated Kenny’s potential role in mitophagy and/or xenophagy. Kenny accumulated and localised with mitochondria in thorax muscles of flies, treated with FCCP. Kenny was found to localise in the vicinity of phagocytosed Staphylococcus aureus in larval haemocytes, cultured ex vivo. We propose that Optineurin could be a new functional mammalian orthologue of Kenny, in addition to the established mammalian homologue, NEMO.
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Watson, Aleksandra. "Molecular structure and function of C-type lectin-like molecules in innate immunity." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.504625.
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Fytrou, Anastasia. "Drosophila immunity : QTL mapping, genetic variation and molecular evolution." Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/4742.
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Drosophila is involved in a wide range of interactions with parasites and pathogens (parasitoid wasps, bacteria, fungi, viruses). Drosophila hosts vary greatly at the species, population and individual level, in their response against such organisms, and much of this variation has a genetic basis. In this thesis I explored three aspects of this variation. First, using recombination mapping based on SNPs and a variation of bulk segregant analysis, I identified a QTL region on the right arm of the third chromosome of D. melanogaster associated with resistance to at least some of the parasitoid species / strains used in the experiments. The location of the QTL was further explored with deficiency complementation mapping and was narrowed down to the 96D1-97B1 region. The success of the deficiency mapping suggests that the resistant allele is not completely dominant. Second, I investigated patterns of molecular evolution in a set of immunity-related genes, using sequences from a D. melanogaster and a D. simulans population and a set of genes without known involvement in immunity for comparison. I found evidence that several of these genes have evolved under different selection pressure in each species, possibly indicating interactions with different parasites. The immunity genes tested appear to be evolving faster compared to non-immunity genes, supporting the idea that the immune system is evolving under strong selective pressure from parasites. Finally, in a D. melanogaster – sigma virus system, I measured genetic variation in the transmission of different virus genotypes, in different environments. There was poor correlation between temperatures, suggesting that environmental heterogeneity could constraint evolution of resistance (to virus transmission). The correlation between viral genotypes was also low, although relatively stronger for more closely phylogenetically related viral strains. Such interactions between host genotypes, virus genotypes and environmental conditions can maintain genetic variation in virus transmission.
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Kneeshaw, Sophie. "Molecular mechanisms of redoxin-mediated signalling in plant immunity." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/18754.
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Posttranslational modification (PTM) of proteins is essential to creating a diverse proteome with the complex functions necessary to regulate key cellular processes. Redox-based PTMs exhibit many desirable characteristics to finely modulate transcriptional regulators; they occur rapidly and can alter protein conformation, localisation and activity. The plant immune system offers an excellent model in which to study redox-based modifications due to the rapid accumulation of oxidising agents that occurs during immune invasion. This so-called “oxidative burst” causes spontaneous oxidation of cysteine residues that are present in many regulatory proteins. These modifications fine-tune the activities of proteins that harbour them, enabling them to act in a concerted effort to reprogram the transcriptome, prioritising the expression of immune-related genes over housekeeping genes. Disulphide bonds (S-S) and S-nitrosothiols (SNO, i.e. the addition of an NO group to a cysteine moiety) have been shown to play particularly important roles in plant immunity. However, what still remains unclear is how these redox-based PTMs are rendered reversible, enabling them to act as molecular signalling switches. The work presented in this thesis explores a class of enzymes that are responsible for controlling the cellular levels of protein oxidation: the Thioredoxins. In addition to their well-established role in reducing disulphide bonds, I demonstrate in Chapter 3 that Thioredoxins are able to reverse protein S-nitrosylation during plant immune signalling. Immune-inducible Thioredoxin-h5 (TRXh5) was shown to be unable to restore immunity in gsnor1 mutants that display excessive accumulation of the NO donor S-nitrosoglutathione, but rescued impaired immunity and defence gene expression in nox1-mutants that exhibit elevated levels of free NO. This data indicates that TRXh5 discriminates between protein-SNO substrates to provide previously unrecognized specificity and reversibility to protein-SNO signalling in plant immunity. Furthermore, data is presented to show that TRXh5 reversed the effects of S.nitrosylation on many immune-related transcriptional regulators in vitro, forming the initial stages of an investigation into which proteins and pathways might be controlled by reversible S-nitrosylation in plant immunity (Chapters 3 & 4). Although the majority of transcriptional regulators are likely modified at their site of action, the nucleus, very little is currently known about nuclear redox signalling in plants. Therefore, in Chapter 5 a subclass of theThioredoxin superfamily was studied, the Nucleoredoxins, which have previously been shown to display disulphide reduction activity and localise in part to the nucleus. Here it is revealed that the activity and nuclear accumulation of Nucleoredoxin 1 (NRX1) is induced by the plant leaf pathogen Pseudomonas syringae, suggesting a key role for this protein in immune signalling. Target-capture experiments and subsequent mass spectrometry analysis identified the first in vitro targets of NRX1 and revealed many proteins with roles in oxidative stress, including the hydrogen peroxide scavenger Catalase 2 (CAT2). Moreover, overexpression of NRX1 was shown to be able to rescue the enhanced cell death phenotype of cat2 knockout mutants in response to the oxidative stressor, methyl viologen. Accordingly, nrx1 knockout mutants also exhibited an enhanced cell death phenotype in response to methyl viologen treatment. Together, these data indicate that NRX1 plays a key role in the control of oxidative stress-mediated cell death, potentially through direct regulation of Catalase proteins. Taken together, the work in this thesis implicates members of the Thioredoxin family as key regulators of transcriptional reprogramming during plant immunity and uncovers a novel role for Thioredoxin superfamily member, NRX1, in the control of oxidative stress.
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Ma, Yan. "Molecular mechanisms of NLR pair-mediated immunity in Arabidopsis." Thesis, University of East Anglia, 2016. https://ueaeprints.uea.ac.uk/63111/.
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Central to plant survival is the ability to activate immunity upon pathogen perception. Plants deploy immune receptors to recognise specific pathogenderived molecules (effectors) and to trigger defence. These receptors usually recognise a specific effector, but some work in pairs and can detect multiple effectors. The Arabidopsis RRS1-R/RPS4 receptor pair forms an immune complex, conferring recognition of two distinct bacterial effectors, AvrRps4 and PopP2. A paralogous pair linked to RRS1/RPS4, designated as RRS1B/RPS4B, only recognises AvrRps4. My work has revealed that both pairs detect AvrRps4 via an integrated WRKY domain of RRS1 or RRS1B, which mimics the effector’s host targets: the WRKY transcription factors (TF). It has also been shown that the WRKY TF-targeting PopP2 is also perceived by the RRS1-R WRKY domain. Together, we suggest that RRS1 (or RRS1B) with the WRKY domain fusion has evolved to protect defence-regulating WRKY proteins from being attacked by effectors. These integrated domains of immune receptors are becoming popular targets for synthetic resistance engineering. However, one of the biggest challenges is to avoid auto-activity while enabling new recognition capacity when manipulating the integrated domains. To better understand how these receptors operate to convert effector perception into defence activation, I investigated the dynamic molecular interactions in the pre-activation complex, and those that change upon effector perception. I found that RRS1-R/RPS4 complex is negatively regulated by the WRKY domain during pre-activation, and effector-triggered activation is likely mediated by de-repression of the WRKY domain. After effector-triggered RRS1 de-repression, the activation signal is transduced to RPS4. Domain swaps between RRS1-R/RPS4 and RRS1B/RPS4B have revealed the key interaction required for this transduction is between RRS1 domain 4 and the RPS4 C-terminal domain. Furthermore, I discovered possible distinct domain-domain interactions that enable AvrRps4- and PopP2- triggered activation. The mechanistic insights into complex auto-inhibition and activation described in this thesis will prove valuable for many other cooperative immune receptor systems.
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Jun, Janice. "THE OFFENSE-DEFENSE BALANCE IN IMMUNITY." Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1467997330.
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Buranakitjaroen, P. "Molecular studies on merozoites of Plasmodium falciparum." Thesis, University of Oxford, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375230.
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Fang, Xu. "Genetic and molecular analysis of resistance protein mediated plant immunity." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/50783.
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Upon recognition of pathogen effectors, plant resistance proteins trigger strong defence responses that restrict the growth and spread of pathogens. Most of these immune receptors are nucleotide-binding (NB) and leucine-rich repeat (LRR) domain-containing proteins (NLRs). SNC1 (Suppressor of npr1, constitutive 1) is an Arabidopsis Toll/interleukin-1 Receptor (TIR)-type NLR that was originally identified through a gain-of-function autoimmune mutant, snc1, from a forward genetic screen. My Ph.D. thesis is comprised of three projects, all taking advantage of the unique autoimmune phenotypes of snc1 to enable efficient genetic screening.
Firstly, MOS12 was identified from the snc1 suppressor screen, which encodes a protein homologous to cyclin L of mouse and human. MOS12 is required for both SNC1- and RPS4- mediated defense response through its involvement in alternative splicing of SNC1 and RPS4. MOS12 associates with the MAC in planta and MAC components also contribute to proper splicing of SNC1 and RPS4. This study provides the emerging regulatory details of alternative splicing of certain NLR genes.
Secondly, the transcription factor bHLH84 was isolated from a reverse genetic screen by its ability to confer enhanced immunity when overexpressed. bHLH84 and its homologs function redundantly in SNC1- and RPS4-mediated defense response. While bHLH84 does not seem to regulate the expression of NLR-encoding genes directly, it associates with SNC1 and RPS4 to fulfil their function in plant immunity. Being a transcription activator, bHLH84 associates with nuclear NLR proteins, probably in parallel with NLR-associated transcription repressors, enabling potentially fast and robust transcriptional reprogramming upon pathogen recognition.
Lastly, the identification and functional study of MUSE6 revealed the crucial impact of N-terminal acetylation on the turnover of SNC1. Biochemical analysis uncovered that SNC1 undergoes alternative translation initiation, which provides respective substrates for NatA and NatB. SNC1 peptides translated from the first Met are targeted by NatA, and the acetylation serves as a degron, while SNC1 peptides initiated from the second Met are targeted by NatB, which stabilizes the protein. Different acetylation events on SNC1 are speculated to provide more flexibility to maintain its homeostasis.
Overall, my Ph.D thesis research contributes to the better understanding of NLR protein regulation and activation.Science, Faculty of
Botany, Department of
Graduate
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Martinelli, Axel. "Strain-specific immunity in malaria : a molecular and genetic approach." Thesis, University of Edinburgh, 2003. http://hdl.handle.net/1842/12590.
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Alzaid, Abdullah. "Molecular regulation of growth & immunity tradeoffs in Salmonid fishes." Thesis, University of Aberdeen, 2017. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=232280.
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Growth and immunity are essential physiological functions that are each energetically costly. Thus, energetic allocation into these systems must be appropriately balanced throughout life. Such 'tradeoffs' require molecular-level cross talk between growth and immunity. Limited data suggests that the growth hormone (GH) – insulin-like growth factor (IGF) axis, a key pathway regulating vertebrate growth, also has a role in immune function. Here I exploit salmonid fishes to characterise the regulation of GH-IGF axis genes under multiple experimental contexts where growth and immunity were being traded-off. Specifically, I examined the transcriptional response of the GH-IGF axis to in vivo immune-stimulation at different stages of ontogeny, considering several tissue contexts (i.e. whole fish, immune tissues, and skeletal muscle) and animals with distinct growth rates driven by GH-overexpression. To better contextualise the data, I established the regulation of key gene markers for muscle growth and immune status. Further, I considered gene duplicates retained from whole-genome duplication events in salmonid evolutionary history, exploiting new genomic resources for gene characterisation (e.g. novel IGF-IR paralogues). Four major conclusions arose from my studies. First, up-regulation of IGFBP-1A1 and IGFBP-6A2 (known IGF inhibitors), following disease challenge, suggests that IGF signalling is repressed during infection, promoting energetic reallocation towards immunity. Second, the combined regulation of multiple IGF system genes in immune tissues suggests that while IGF signalling is repressed during infection, IGFBP-6A2 may directly stimulate immune tissues, likely via IGF-independent mechanisms. Third, coregulation of IGFBP-1A1 and IGFBP-6A2 with immune markers indicates direct regulation of the IGF system by conserved cytokine pathways. Finally, an altered skeletal muscle response to immune-stimulation suggests that modulation of GH-IGF axis regulation by GH-overexpression results in compromised fish health. Overall, these findings have broad implications for aquaculture, where fast growth and immunocompetence are traded-off, while improving our basic understanding of fish growth and immunity.
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Linde, Annika. "Comparative studies on cardiac innate immunity." Diss., Manhattan, Kan. : Kansas State University, 2008. http://hdl.handle.net/2097/946.
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Zettervall, Carl-Johan. "Signaling pathways in the activation and proliferation of Drosophila melanogaster blood cells." Doctoral thesis, Umeå : Umeå centrum för molekylär patogenes (UCMP), 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-513.
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Tabassum, Shāhīnah. "Molecular and seroepidemiological studies of rotavirus from children in Bangladesh." Thesis, University of Liverpool, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307710.
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Kao, Cheng-Yuan. "Molecular characterization of human airway epithelium innate immunity by IL-17 regulation /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2005. http://uclibs.org/PID/11984.
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Morel, Bertrand. "NMR and computational studies of molecular recognition in colicin-immunity protein interactions." Thesis, University of East Anglia, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398497.
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Markov, Peter V. "Molecular epidemiology, evolution and adaptation of hepatitis C virus to population immunity." Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.711633.
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Bittante, Alessandra. "Molecular basis of NAIP/NLRC4 inflammasome activation by flagellin." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/275741.
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The overall aim of this project was to determine the molecular mechanisms by which the flagellin gene from Salmonella enterica serovar Typhimurium (S. Typhimurium) activates the NAIP/NLRC4 inflammasome and its contribution to the host protective immune response against salmonellosis. Inflammasomes are multi-protein complexes formed in response to the activation of pattern recognition receptors (PRRs). The NOD-like receptor (NLR)-family of inflammasome complexes are formed from the cytosolic NLR receptors, ASC adaptor and caspase-1 in response to pathogen- associated molecules or danger-associated signals. The NAIP/NLRC4 inflammasome is activated by the S. enterica flagellar filament protein (FliC), the SPI-1 type III secretion system needle (PrgI) and inner rod proteins (PrgJ). Recognition of these bacterial ligands by the NAIP receptors allows oligomerisation with NLRC4 and subsequent recruitment of caspase-1. Caspase-1 mediates pyroptosis, while recruitment of ASC is also required for cleavage of pro-IL-1β and pro-IL-18 to their active forms by caspase-1. Differential recognition of the flagellar filament proteins (flagellin) by the NAIP/NLRC4 inflammasome forms an important part of my thesis. Here, I have looked at the molecular mechanisms and immunological consequences of the differential recognition of flagellin by the NAIP/NLRC4 inflammasome using S. Typhimurium SL1344 and the non-pathogenic E. coli strain K12-MG1655. An important part of my work was to try and determine which regions of fliC are required for NAIP/NLRC4 inflammasome activation and whether they can be mutated while preserving motility. To do this a panel of ten strains expressing chimeric fliC genes were created and characterised in macrophage infection experiments and bacterial motility assays. My results confirm the C-terminus of FliC is critical for both inflammasome activation and motility in agreement with published reports. To further investigate this differential recognition by the NAIP/NLRC4 inflammasome I modified S. Typhimurium strain of moderate virulence (M525P) to express flagellin from E. coli K12-MG1655. This strain (M525PΔfliC::fliCK12-MG1655CmR) retained motility and both in vitro and in vivo characterisation was carried out in macrophages and using a murine model of sublethal salmonellosis respectively. Activation of the NAIP/NLRC4 inflammasome was impaired in murine macrophages infected with M525PΔfliC::fliCK12-MG1655CmR when compared to those infected with M525P. Mice infected with M525PΔfliC::fliCK12-MG1655CmR had increased liver and spleen bacterial burdens compared to those infected with M525P, indicating that optimal NAIP/NLRC4 inflammasome activation is key for efficient control of microbial spread in vivo. The role of NAIP receptors in inflammasome formation was further investigated with the use of CRISPR/Cas9 to generate mutant murine macrophage cell lines. To investigate the consequence of gene deletions cell lines were designed to lack NAIP 1, 2, 5 and 6, while others were designed to express tagged NAIP proteins to elucidate the cellular localisation of the NAIP proteins during inflammasome formation by microscopy. Characterisation of these cell lines is ongoing, with extensive optimisation of the CRISPR/Cas9 technique undertaken during this study.
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Malick, Adrien Paul. "Tumor-induced immunosuppression: Contribution of a high molecular weight inhibitor and Prostaglandin E2." Diss., Virginia Polytechnic Institute and State University, 1987. http://hdl.handle.net/10919/53639.
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A heat-stable soluble inhibitor of T cell proliferation was demonstrated in splenic and peritoneal macrophage (Mφ) culture supernatants. Concentrated supernatants were prostaglandin E₂ (PGE₂)-free and yet inhibited proliferation in the mixed lymphocyte reaction (MLR) and mitogen assays. The high mw inhibitory factor was apparently >67 kd, as shown by S-200 Sephacryl chromatography and gel electrophoresis. DEAE-Cellulose chromatography suggested that the pl of the inhibitory factor was < 7.7. lsoelectric focusing revealed that the Mφ-mediated inhibitory activity differed in charge, with a pl of 6.5-7.6 for normal hosts and 4.0-6.0 for tumor bearing hosts (TBH). Normal and TBH Mφ supernatants showed different hydroxylapatite fractionation, with the latter being resistant to proteolytic enzymes but sensitive to neuraminidase. Lectins such as wheat germ agglutinin, concanavalin A, Ricin communi: and Bandeirea simplicifolia were not useful in affinity purification of the high mw inhibitory monokine. Sugar-BSA conjugates suggested that inhibitory activity was vested in a terminal ßl,4 linked galactose. The inhibitory activity was apparently hydrophobic and heat·stable, but heat-stability was lost if supernatants were boiled at an acidic pH. The high mw monokine inhibited the proliferation of P388D₁ and A4A cells, but enhanced the proliferation of BW 5147.3 cells. Time course addition to the MLR revealed that PGE; may be required for inhibitory activity to be manifested early (0 and 24 hr) but not if the high molecular weight (mw) inhibitor was added late (>48 hr). Indomethacin blocked activity of the inhibitory factor early in the MLR using normal host T cells and augmented the proliferation of TBH T cells in the MLR. Both normal and TBH Mo supernatants suppressed the generation of interleukin 2 but with a dose- and time·dependent difference. Cell cycle analysis of mitogen- stimulated cells revealed that TBH MPh. D.
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Tessmer, Marlowe S. "Biological functions and molecular associations of the killer cell lectin-like receptor G1." View abstract/electronic edition; access limited to Brown University users, 2008. 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:3318364.
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Baldrich, Patricia. "Role of microRNAs in plant innate immunity." Doctoral thesis, Universitat Autònoma de Barcelona, 2015. http://hdl.handle.net/10803/315463.
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Los pequeños ARNs son ARNs cortos no codificantes que regulan la expresión génica en la mayoría de eucariotas. Las plantas tienen dos clases de pequeños ARNs, los microARNs (miRNAs) y los pequeños ARNs de interferencia (siRNAs), que se diferencian por su biogénesis y su modo de acción.
Actualmente se estima que las pérdidas debidas a patógenos y plagas alcanzan el 50-80%, siendo uno de los factores limitantes de la producción y causando graves pérdidas económicas. Tenemos pues la necesidad de mejorar el conocimiento de los mecanismos de defensa y desarrollar nuevas estrategias para la protección de los cultivos. Con el fin de ampliar los conocimiento en este sector, se han llevado a cabo estudios con Arabidopsis y arroz, los dos sistemas modelo usados en genómica funcional en plantas dicotiledóneas y monocotiledóneas.
En el primer capítulo, se analizaron las alteraciones en la acumulación de pequeños ARNs, incluyendo miRNAs, en respuesta al tratamiento con elicitores en plantas de Arabidopsis. Entre los miRNAs regulados por elicitores se encuentra miR168, que regula ARGONAUTE1, el componente principal del complejo RISC (RNA-induced silencing complex) de la maquinaria de funcionamiento de miRNAs. Los microarrays permitieron, además de analizar miRNAs conocidos, la identificación de un pequeño ARN incorrectamente anotado como miRNA en el registro miRBase. Se demostró que este pequeño ARN es un pequeño ARN heterocromático (hc-siRNA) denominado siRNA415.
En el segundo capítulo, se usaron librerías de secuenciación masiva de pequeños ARNs para la identificación global de miRNAs de arroz regulados por elicitores fúngicos. Esto permitió también describir 9 miRNAs no caracterizados previamente. Combinando dichas librerías con el análisis de nuestros degradomas, se identificaron sus respectivos targets y se observó la existencia de redes reguladoras enriquecidas en miRNAs regulados por elicitores. Específicamente, se identificó un número importante de miRNAs y sus genes diana, implicados en las rutas de biosíntesis de pequeños ARNs, incluyendo miRNAs, hc-siRNAs y “trans-acting siRNAs” (ta-siRNAs). Así mismo se presentan evidencias de miRNAs y sus genes diana implicados en la señalización mediada por hormonas así como en la interacción entre rutas hormonales, demostrando así un gran potencial en la regulación de la inmunidad del arroz. Asimismo se describe la regulación de genes de arroz que contienen “Conserved-Peptide upstream Open Reading Frame” (CPuORF) mediada por miRNAs. Esto sugiere la existencia de una red reguladora nueva que integra la función de miRNAs y CPuORF en plantas. El conocimiento adquirido en este estudio ayudará al la comprensión de los mecanismos de defensa mediados por miRNAs, así como a desarrollar estrategias apropiadas a la protección del arroz.
En el tercer capítulo, se uso la combinación de herramientas bioinformáticas y experimentales para el análisis de miRNAs policistrónicos en arroz, observando la existencia de 23 loci con la habilidad de formar la típica estructura de horquilla de los precursores de miRNAs. Se presentan evidencias experimentales de 7 miRNAs policistrónicos que contienen tanto miRNAs homólogos como miRNAs no homólogos. Se demostró también un patrón de conservación en diferentes especies de arroz (Oryza sativa) cuyo genoma es AA, no presente en especies primitivas de arroz.
Conjuntamente, los resultados obtenidos en este trabajo apoyan la idea que los miRNAs pueden ser considerados como componentes de la respuesta de las plantas a la infección por patógenos, posiblemente actuando como nodos de regulación de diferentes procesos fisiológicos durante la adaptación de las plantas a la infección.Small RNAs (sRNAs) are short non-coding RNAs that guide gene silencing in most eukaryotes. Plants have two main classes of sRNAs, microRNAs (miRNAs) and small interfering RNAs (siRNAs), which are distinguished by their mode of biogenesis and mechanisms of action. In this day and age, crop losses due to pathogens and pests are estimated from 50% to 80%, factors limiting crop production and causing important economical losses. There is then an imperative need to improve our knowledge in defense mechanisms and to develop novel strategies for crop protection. To improve the understanding in this field, we carried out studies in Arabidopsis and rice plants, the two model systems used for functional genomic studies in dicot and monocot plant species. In the first chapter, we analyzed alterations on the accumulation of smRNAs in response to elicitor treatment, including miRNAs, in Arabidopsis plants. Among the elicitor-regulated miRNAs was miR168 which regulates ARGONAUTE1, the core component of the RNA-induced silencing complex involved in miRNA functioning. In addition to known miRNAs, microarray analysis allowed the identification of an elicitor-inducible small RNA that was incorrectly annotated as a miRNA in the miRBase registry. We demonstrated that this smRNA, is a heterochromatic-siRNA (hc-siRNA) named as siRNA415. In the second chapter, we used deep sequencing of small RNA libraries for global identification of rice miRNAs that are regulated by fungal elicitors. We also describe 9 previously uncharacterized miRNAs. Combined small RNA and degradome analyses revealed regulatory networks enriched in elicitor-regulated miRNAs supported by the identification of their corresponding target genes. Specifically, we identified an important number of miRNA/target gene pairs involved in small RNA pathways, including miRNA, heterochromatic and trans-acting siRNA pathways. We present evidence for miRNA/target gene pairs implicated in hormone signaling and cross-talk among hormone pathways having great potential in regulating rice immunity. Furthermore, we describe miRNA-mediated regulation of Conserved-Peptide upstream Open Reading Frame (CPuORF)-containing genes in rice, which suggests the existence of a novel regulatory network that integrates miRNA and CPuORF functions in plants. The knowledge gained in this study will help in understanding the underlying regulatory mechanisms of miRNAs in rice immunity and develop appropriate strategies for rice protection. In the third chapter, we used a combination of bioinformatic tools and experimental analyses for the discovery of new polycistronic miRNAs in rice, revealing 23 loci with the ability to form the typical hairpin structure of miRNA precursors in which two or more mature miRNAs mapped along the same structure. Evidence is presented on the polycistronic nature of 7 miRNA precursors containing homologous or non-homologous miRNA species. We also demonstrated a pattern of conservation in the genome of rice (Oryza sativa) species that have an AA genome, but not in primitive rice species. Collectivelly, results obtained in this work support the notion that miRNAs might be considered as components of the plant response to pathogen infection, possible acting as regulatory nodes of different physiological processes during plant adaptation to infection conditions.
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Sermersheim, Matthew Alan. "MG53 is a Novel Regulator of Inflammation and Innate Immunity." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu157121945938419.
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Kotha, Jayaprakash. "Molecular mechanism of tetraspanin CD9 mediated cell motility." View the abstract Download the full-text PDF version, 2007. http://etd.utmem.edu/ABSTRACTS/2007-010-Kotha-index.html.
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Thesis (Ph.D. )--University of Tennessee Health Science Center, 2007.Title from title page screen (viewed on July 16, 2007). Research advisor: Lisa K. Jennings, Ph.D. Document formatted into pages (xiv, 150 p. : ill.). Vita. Abstract. Includes bibliographical references (p.130-150).
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Bai, Pengfei. "Dissecting the Layered Rice Innate Immunity at the Molecular, Genetic, and Metabolomic Levels." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1525780095074052.
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Lindgren, Malin. "Molecular and functional characterization of the insect hemolymph clot." Doctoral thesis, Stockholm : Department of Molecular Biology and Functional Genomics, Stockholm University, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-7310.
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Talebian, Fatemeh. "CD200-CD200R Interaction in Tumor Immunity." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1331913293.
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Mayer, Oren Michael. "Trigger Factor, Mycobacterium tuberculosis' Double-Edged Sword| Immunity to a Mycobacteriophage at the Cost of Virulence." Thesis, Yeshiva University, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10306458.
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The struggle for survival between phages and their bacterial hosts is best exemplified by the diverse mechanisms bacteria utilize to block phage infection, and the methods phages use to surmount them. Mycobacteriophage DS6A is unique amongst the more than 8000 identified mycobacteriophages in that its host range is restricted to mycobacteria that are members of the Mycobacterium tuberculosis Complex (MTBC). However, the molecular mechanism for this specificity remains unknown. To study the relationship DS6A has to both MTBC and non-tuberculous mycobacteria (NTMs), we generated two novel recombinant DS6A shuttle phasmids containing fluorescent reporter mVenus. These phages were utilized to clearly demonstrate that 50 years of previous scientific dogma was incorrect, and DS6A can in fact infect NTM mycobacteria to a wide range of degrees. Work teasing out the mechanisms of resistance is underway. Additionally, we identified the chaperone trigger factor (Tig; Rv2462c) to be required for a productive DS6A infection in Mtb. Interestingly, no host range mutants have been generated that can overcome this resistance to plaguing. Deleting tig did not affect the lysis profile of any of the other >30 mycobacteriophages able to infect Mtb. Susceptibility of Mtb Δ tig to DS6A infection was rescued by complementation of tig on an integrating plasmid. DS6A fluorophage infection of Mtb Δ tig induced high levels of detectable fluorescence, suggesting Tig is not required for the adsorption of phage or introduction of DS6A DNA. Additionally assays determined that Tig was not involved in transcriptional or translational activation. However, deleting tig did yield an additional phenotype in Mtb; significant attenuation in both immunocompetent and immunocompromised mice. Lipidome and secretome assays showed stark differences between the lipid makeup and secreted protein profiles of the tig mutant versus the WT that could explain the cause of attenuation. For Mtb, the loss of tig is a double edged sword; total resistance to DS6A is afforded in the clonal population, but at the cost of virulence in eukaryotic hosts.
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Dhar, Jayeeta. "Suppression of Pulmonary Innate Immunity by Pneumoviruses." Cleveland State University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=csu1479673989904175.
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Viljakainen, L. (Lumi). "Evolutionary genetics of immunity and infection in social insects." Doctoral thesis, University of Oulu, 2008. http://urn.fi/urn:isbn:9789514289286.
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Abstract In social insects a major cost of social life is the high number of pathogens found in large societies and the greater likelihood of transmission of pathogens among closely related individuals. The aim of this thesis was to investigate the effect of high pathogen pressure on the molecular evolution of genes involved in the innate immune system in social insects. In addition, the transmission dynamics of the intracellular bacteria Wolbachia in wood ants was examined. By comparing DNA sequences from diverse species of ants and honeybees it was shown that the immune genes in hymenopteran social insects have evolved rapidly. However, by using codon-based likelihood models of evolution positive selection was detected in only two ant genes. This may reflect behaviourally based colony-level defences that can reduce selective pressure on the immune genes. The transmission modes of Wolbachia were studied by comparing DNA sequence variation of the bacteria with that of the host ants. First, it was found that all the studied ants carry Wolbachia. Second, Wolbachia have been transmitted both vertically from mother to offspring and horizontally between individuals of the same as well as of different speciesTiivistelmä Yhteiskuntahyönteisten (muurahaiset, ampiaiset, mehiläiset ja termiitit) ekologisen menestyksen kääntöpuolena on ollut jatkuva riesa taudinaiheuttajista, joita suurissa yhteisöissä tavataan runsaammin kuin yksittäin elävissä eliöissä. Taudinaiheuttajien tuoman paineen myötä yhteiskuntahyönteisille on kehittynyt käyttäytymiseen perustuvia puolustusmekanismeja täydentämään kaikille monisoluisille eliöille yhteistä synnynnäistä, fysiologista immuniteettia. Nämä puolustusmekanismit ovat todiste siitä, että taudeilla on ollut suuri merkitys yhteiskuntahyönteisten käyttäytymisen evoluutiossa. Toisaalta taudinaiheuttajien vaikutuksista synnynnäiseen immuunipuolustukseen tiedetään hyvin vähän. Väitöstutkimuksen ensisijainen kohde oli taudinaiheuttajien merkitys yhteiskuntahyönteisten synnynnäisen immuunipuolustuksen evoluutiossa. Tutkimuksessa tarkasteltiin, miten immuunijärjestelmän geenit ovat ajan mittaan muuttuneet. Tulokset osoittivat että muutoksia, jotka johtavat proteiinien aminohappojen vaihtumiseen on tapahtunut tiuhempaan tahtiin muurahaisilla ja mehiläisillä kuin yksittäin elävällä banaanikärpäsellä. Merkkejä erityisen voimakkaasta luonnonvalinnasta löydettiin kuitenkin yllättävän pienestä määrästä geenejä. Tämä voi johtua siitä, että käyttäytymiseen perustuvat puolustusmekanismit lieventävät taudinaiheuttajien vaikutusta synnynnäiseen immuunipuolustukseen. Väitöstutkimukseen sisältyi myös hyönteisten solunsisäisen bakteerin, Wolbachian, siirtymismekanismien kartoitus kekomuurahaisilla. Wolbachia on loinen, joka siirtyy yleensä äidiltä jälkeläisille munasolussa. Leviäminen voi tapahtua myös horisontaalisesti lajitoverien ja jopa eri lajien edustajien kesken. Geenisekvensseihin perustuvassa tutkimuksessa kaikista muurahaisista löytyi Wolbachia-bakteereja, ja samasta yksilöstä saattoi löytyä useaa eri bakteerikantaa. Koska muurahaislajien väliset geneettiset erot olivat paljon suurempia kuin erot niissä elävien bakteerien välillä, voitiin päätellä että bakteerien pääasiallinen leviämistapa tutkituilla muurahaisilla on ollut horisontaalinen
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Borge-Renberg, Karin. "Communicate or die : signalling in Drosophila immunity." Doctoral thesis, Umeå : Univ, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1817.
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Calil, Iara Pinheiro. "Characterization of transcriptionally active atwwp1 nuclear bodies that confer partial immunity against begomoviruses." Universidade Federal de Viçosa, 2017. http://www.locus.ufv.br/handle/123456789/11661.
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Conselho Nacional de Desenvolvimento Científico e Tecnológico
Begomovírus bipartidos (Familía Geminiviridae) - grupo de vírus de DNA que se replica no núcleo de células infectadas – codifcam a proteína de movimento NSP (nuclear shuttle protein) que facilita a translocação do DNA viral do núcleo para o citoplasma, através dos poros nucleares. O tráfego intracelular do complexo NSP- DNA é assessorado pela proteína NIG (NSP-interacting GTPase), localizada no compartimento citoplasmático celular. Nesta investigação, é descrita a caracterização de AtWWP1, uma proteína dotada de dois domínios WW, identificada por sua interação com NIG. No capítulo II foi demonstrado que AtWWP1 forma corpos nucleares (NBs) por meio de seu domínio WW e é capaz de relocar NIG do citoplasma para o núcleo, confinando-a em corpos nucleares. Portanto, a interação AtWWP1-NIG, mediada pelo domínio WW de AtWWP1, pode interferir com o papel pro-viral de NIG durante a infecção o qual é associado à sua localização citoplasmática. Consistente com essa hipótese, a perda de função de AtWWP1 em Arabidopsis resulta em aumento de suscetibilidade em resposta à infecção por begomovírus, ao passo que a superexpressão de AtWWP1 confere tolerância à infecção viral. Entretanto, a função antiviral de AtWWP1-NB pode ser antagonizada durante a infecção viral, uma vez que foi observado um decréscimo ou desorganização dos corpos nucleares de AtWWP1 em células infectadas. Os dados apresentados no capítulo II demonstraram que AtWWP1 se organiza em estruturas subnucleares as quais conferem imunidade intrínseca contra infecção por begomovírus. Contudo, a função molecular dos corpos nucleares de AtWWP1 não foi elucidada. No capítulo III, foi demonstrado que AtWWP1 co-localiza em corpos nucleares com a proteína CDKC2, cuja função celular é associada à transcrição e processamento de RNA. CDKC2 modula o estado de fosforilação do domínio C- terminal da RNA polimerase II (CTD-RNAPII). Foi demonstrado que AtWWP1 também interage com CTD-RNAPII em NBs. Os corpos nucleares de AtWWP1 foram desfeitos ou reorganizados em corpos nucleares maiores após tratamentos com inibidores de transcrição e fosforilação; tal comportamento se assemelha ao observado em CDKC2-NBs, cuja organização dinâmica dos corpos nucleares depende do status transcricional da célula. Como evidência adicional de seu papel na transcrição celular, foi demonstrado que AtWWP1 possui capacidade de ligação a DNA e que seus NBs estão associados à região de eucromatina. Consistente com os resultados previamente obtidos, a alteração nos níveis transcricionais de AtWWP1 em linhagens transgênicas resultou no enriquecimento de fatores de transcrição diferencialmente expressos. Coletivamente, os dados obtidos neste trabalho demonstram que AtWWP1 forma corpos nucleares correspondentes a sítios ativos de expressão gênica ou de processamento de RNA acoplado à transcrição.
As DNA viruses, which replicate in the nucleus of infected cells, the bipartite begomoviruses (Geminiviridae family) encode the nuclear shuttle protein to facilitate the translocation of viral DNA from the nucleus to the cytoplasm via nuclear pores. This intracellular trafficking of NSP-DNA complexes is accessorized by the NSP- interacting GTPase (NIG) at the cytosolic side. Here, we report the characterization of AtWWP1, a WW domain-containing protein, identified as a NIG partner. In the chapter II, we demonstrated that AtWWP1 forms nuclear bodies (NBs) via its WW domains and relocates NIG from the cytoplasm to the nucleus where it is confined to AtWWP1-NBs.Therefore, the NIG-AtWWP1 interaction, which also occurs via the WW domains, may interfere with the NIG pro-viral function that is associated with its cytosolic localization. Consistent with this hypothesis, loss of AtWWP1 function debilitates further the plant upon begomovirus infection and overexpression of AtWWP1 confers tolerance to begomovirus. The antiviral function of AtWWP1-NBs, however, may be antagonized by viral infection, which was demonstrated to induce either a decrease in the number or disruption of AtWWP1-NBs. Our data established that AtWWP1 organizes nuclear structures as nuclear foci, which provide intrinsic immunity against begomovirus infection. Nevertheless, the underlying biochemical function of these AtWWP1-NBs has yet to be elucidated. In Chapter III, we demonstrated that AtWWP1-NB co-localizes with CDKC;2-NB, which has been shown to be involved in transcription and RNA processing. Like CDKC2, which modulates the phosphorylation status of RNA polymerase II C-terminal domain (CTD-RNA pol II), we showed that AtWWP1 interacts with CTD-RNA pol II within NBs. AtWWP1-NBs were disintegrated into diffuse pattern or converted to larger structures upon treatment with transcriptional inhibitors, a feature that resembles the CDKC2-NB dynamic organization, which depends on the transcriptional status of the cells. As further evidence for a role in transcription, we also demonstrated that AtWWP1 displays DNA binding activity and AtWWP1-NBs associate with active chromatin regions. Accordingly, the manipulation of the AtWWP1 levels promoted an enrichment of differentially expressed transcriptional factors in transgenic lines. Collectively, our data establish that the nuclear bodies formed by AtWWP1 are associated with active gene expression or co-transcriptional RNA processing.
Os anexos impressos estão na ordem invertida em relação à versão digital, mas não compromete o conteúdo.
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Uvell, Hanna. "Signaling and transcriptional regulation of antimicrobial peptide genes in Drosophila melanogaster." Doctoral thesis, Stockholm : Department of Molecular Biology and Functional Genomics, Stockholm university, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-1051.
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Kuriakose, Shiby. "Molecular regulation of Trypanosoma congolense-induced proinflammatory cytokine production in macrophages and its modulation by diminazene aceturate (Berenil)." PLOS, Frontiers in Immunology, Elsevier, Sage, 2016. http://hdl.handle.net/1993/31677.
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African trypanosomiasis remains a major health problem to both humans and animals due to lack of effective treatment or vaccine to control the disease. Animal trypanosomiasis is considered one of the most important diseases affecting livestock production and agricultural development in sub-Saharan Africa. Although the use of trypanocides remain the most important method for controlling the disease in animals, the mechanisms of action of these compounds are not completely known. The overall aim of this thesis is to decipher the molecular mechanisms involved in Trypanosoma congolense-induced cytokine production and how this is modulated by the trypanocide, Diminazene aceturate (Berenil).
First, I investigated the molecular and biochemical mechanisms of action of Berenil to determine whether in addition to trypanolytic effect, it exerts a modulatory effect on the host immune system. Although it is known that T. congolense infection in mice is associated with increased production of pro-inflammatory cytokines by macrophages, the intracellular signaling pathways leading to the production of these cytokines remain unknown. Therefore, I investigated the innate receptors and intracellular signaling pathways that are involved in T. congolense-induced pro-inflammatory cytokine production in macrophages. Next I further determined whether the inhibitory effect of Berenil on proinflammatory cytokine production in macrophages is specific to T. congolense.
I found that Berenil treatment significantly reduced the immune activation and proinflammatory cytokine production in infected mice suggesting that in addition to its direct trypanolytic effect, Berenil also modulates the host immune response to the parasite. Next, I show that T. congolense induced pro-inflammatory cytokine production in macrophages is dependent on phosphorylation of mitogen-activated protein kinase (MAPK) and signal transducer and activation of transcription (STAT) proteins in a TLR2-dependent manner. I further show that Berenil treatment downregulates T. congolense as well as LPS induced cytokine production by affecting the phosphorylation of MAPK and STAT proteins.
Collectively, the results from this thesis provide novel insights into T. congolense-induced activation of the innate immune system and modulation of host immune response by Berenil. These findings are significant and could help in developing newer and better therapeutic strategies against the disease, in particular, and inflammatory responses in general.October 2016
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Sutiwisesak, Rujapak. "Natural Polymorphism of Mycobacterium tuberculosis and CD8 T Cell Immunity." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1076.
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Coevolution between Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, and the human host has been documented for thousands of years. Interestingly, while T cell immunity is crucial for host protection and survival, T cell antigens are the most conserved region of the Mtb genome. Hypothetically, Mtb adapts under immune pressure to exploit T cell responses for its benefit from inflammation and tissue destruction for ultimately transmission.
EsxH, a gene encoding immunodominant TB10.4 protein, however, contains polymorphic regions corresponding to T cell epitopes. Here, I present two complementary analyses to examine how Mtb modulates TB10.4 for immune evasion. First, I use a naturally occurring esxH polymorphic clinical Mtb isolate, 667, to investigate how A10T amino acid exchange in TB10.4 affect T cell immunity. To verify and identify the cause of the immunological differences, I construct isogenic strains expressing EsxHA10T or EsxHWT. In combination with our recent finding that TB10.44-11-specific CD8 T cells do not recognize Mtb-infected macrophages, we hypothesize that TB10.4 is a decoy antigen as it distracts host immunity from inducing other potentially protective responses. I examine whether an elimination of TB10.44-11-specific CD8 T cell response leads to a better host protective immunity. The studies of in vivo infection and in vitro recognition in this dissertation aim to provide a better understanding of the counteraction between immune evasion and protective immunity.
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Lee, Seung-Hwan. "From Cmv1 to Ly49h: Molecular genetics, haplotype analysis and transgenesis to characterize innate immunity to cytomegalovirus." Thesis, University of Ottawa (Canada), 2004. http://hdl.handle.net/10393/29133.
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In mice, natural resistance to infection with murine cytomegalovirus (MCMV) is controlled by a dominant chromosome 6 locus, Cmv1, which is expressed at the level of Natural killer (NK) cells. To characterize the molecular mechanism underlying MCMV-resistance, our laboratory initiated a positional cloning approach for the identification of Cmv1, and localized the host resistance locus to a 0.35 cM genetic interval, corresponding to 1.6 Mb genomic DNA.
This dissertation presents the results leading to the cloning and characterization of the Cmv1 gene. First, I constructed a transcription map for the Cmv1 interval, which included 19 genes comprising the full Ly49 gene cluster and other novel candidate genes. In an attempt to narrow down the localization of Cmv1, I determined haplotypes in the vicinity of the Cmv1 interval in a panel of 17 inbred mice strains. This approach demonstrated the presence of three major classes of independent haplotypes. Close inspection of allele sharing among those haplotypes excluded Ly49e, Ly49f and Ly49d as Cmv1 candidates.
As an alternative approach to cloning Cmv1, I took advantage of a recombinant inbred strain, the BXD-8 strain. The BXD-8 line was of particular interest because it is susceptible to MCMV infection while harboring an MCMV-resistance C57BL/6 haplotype at Cmv1. Using STS content and PFGE analysis, I showed the presence of a 23 kb deletion in BXD-8. Subsequent gene expression analysis of the full Ly49 gene cluster revealed that the deletion of Ly49h is associated with MCMV susceptibility in BXD-8 mice.
Finally, to test the role of Ly49h in host resistance to MCMV infection, I introduced the Ly49h gene into a susceptible background. Investigation of Ly49h gene expression by RT-PCR and FRCS analysis demonstrated a strong correlation between the level of Ly49h mRNA and protein expression and the control of MCMV replication, providing conclusive evidence of the allelism between Cmv1 and Ly49h.
In conclusion, I identified the Ly49h gene encoding a NK activation receptor as Cmv1 supporting a specific role for NK cells in antiviral immunity. Transgenic mice expressing Ly49H will be instrumental for understanding of mechanism of NK mediated resistance and possible pleiotropic effects of Cmv1.
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Read, Amanda. "Study of molecular mechanisms underlying persistent Bartonella infections : interactions with erythrocytes and circumnavigation of host immunity." Thesis, University of Liverpool, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417971.
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Pednekar, Lina. "Understanding cellular and molecular interactions of gC1qR, a receptor for the globular domain of complement protein C1q." Thesis, Brunel University, 2013. http://bura.brunel.ac.uk/handle/2438/13876.
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gC1qR was originally discovered as a C1q receptor specific to the globular head domain of C1q, the first subcomponent of the classical pathway of complement activation. During the same period, calreticulin (CRT), formerly called as cC1qR, was described as a receptor for the collagen region of C1q and collectins. Although much work has been carried out with relation to CRT-CD91 complex, the biological implications and structure-function studies of C1q-gC1qR interaction has not been further explored. With passage of time since 1994, it has become evident that gC1qR is also a multi-functional pattern recognition receptor that can recognise pathogens in addition to acting as a modulator of inflammation at the site of injury or infection. In this thesis, a recombinant form of gC1qR using a T7 promotor expression system was expressed and examined for its interaction with individual globular head modules of C1q A, B and C chains (ghA, ghB and ghC, respectively). A number of single residue substitution mutants of ghA, ghB and ghC modules were also analysed for their interaction with gC1qR in order to map complementary binding sites. Concomitant expression of gC1qR and C1q in the adherent monocytes with, and without proinflammatory stimuli was analysed by qPCR in order to establish autocrine/paracrine basis of C1q-gC1qR interaction. In addition, experiments were carried out to examine if C1q-mediated anti-lymphoproliferative effect can be altered by gC1qR. Subsequently, using the wild type and mutants of ghA, ghB and ghC modules, the interaction of DC-SIGN and SIGN-R, a newly discovered partner of C1q and gC1qR on the dendritic cell surface, was examined. Experiments are underway to understand how a trimolecular complex involving C1q, gC1qR and DC-SIGN participate during HIV-1 infection. Structure-function studies involving gC1qR and HCV core protein and HIV-1 gp41 have also been carried out to localise domains of gC1qR responsible for viral pathogenesis. The last chapter dwells on a newly discovered ability of gC1qR to upregulate bradykinin 1 receptor on the endothelial cell surface, thus its role in altering vascular permeability and the contact system. The thesis describes (1) localisation of interacting sites between C1q and gC1qR and their togetherness in co-expression under pro-inflammatory conditions and possibly suppression of immune cell proliferative response; (2) localisation of complementary binding sites between DC-SIGN, gC1qR and C1q and its possible implications in HIV-1 infection and antigen presenting cells such as dendritic cells; (3) localisation of interacting sites between gC1qR and HCV core protein as well as HIV-1 gp41 peptides with potential to propose a therapeutic peptide; and (4) ability of gC1qR to upregulate bradykinin 1 and 2 receptors on endothelial cells and its newly identified function as a modifier of inflammation.
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Go, Yun Young. "MOLECULAR AND GENOMIC APPROACHES TO UNDERSTANDING HOST-VIRUS INTERACTIONS IN SHAPING THE OUTCOME OF EQUINE ARTERITIS VIRUS INFECTION." UKnowledge, 2011. http://uknowledge.uky.edu/gradschool_diss/840.
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Equine arteritis virus (EAV) is the causal agent of equine viral arteritis, a disease of equids. During natural outbreaks of the disease, EAV can cause abortion in pregnant mares and persistent infection in stallions. Understanding how host cellular proteins interact with viral RNA and viral proteins, as well as their role in viral infection, will enable better characterization of the pathogenesis of EAV and establishment of persistent infection in stallions. Accordingly, we hypothesized that both viral factors and host genetically related factors could influence the outcome of EAV infection in horses. To test this hypothesis, we first combined contemporary molecular biology techniques with dual color flow cytometric analysis to characterize the interactions of viral structural proteins and the equine peripheral blood mononuclear cells in vitro. Results from this study demonstrated that interactions between GP2, GP3, GP4, GP5 and M envelope proteins of EAV play a major role in determining the CD14+ monocyte tropism while the tropism of CD3+ T lymphocytes is determined by GP2, GP4, GP5 and M envelope proteins but not the GP3 protein. Secondly, a genome wide association study using SNP genotyping identified a common haplotype associated with the in vitro CD3+ T lymphocyte/resistance to EAV infection among four breeds of horses. Subsequently, these studies were extended to establish a possible correlation between the in vitro susceptibility of CD3+ T lymphocytes to EAV and establishment of persistent infection in stallions. Interestingly, carrier stallions with susceptible CD3+ T lymphocyte phenotype to EAV may represent those at higher risk of becoming persistently infected. Finally, the precise effect of EAV on the immune system of horses, innate and humoral immunity, was studied. Horses were shown to mount a strong humoral antibody response to nonstructural proteins (nsps) 2, 4, 5 and 12 of EAV, whereas nsps 1, 2 and 11 suppressed the type I interferon production. The data presented in this dissertation suggest new directions for future EAV research using genomic and proteomic approaches to study host cell factors involved in EAV attachment and entry and establishment of persistent infection in the stallions.
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Xu, Dan. "Cellular Immunity in Recombinant Adeno-Associated Virus Vector Mediated Gene Therapy." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1313504203.
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Magale, Hussein Issak. "Interaction of PfEMP1 with the Human Immune System and the Prospect of PfEMP1-based Vaccine for Malaria." Thesis, The University of Arizona, 2016. http://hdl.handle.net/10150/613366.
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Malaria is a leading cause of death in some developing countries. The malaria parasite has been around for over a century, and has coevolved with humans. Coming up with an effective vaccine for P. falciparum will save millions of lives and reduce the morbidity and mortality of malaria globally. Understanding the role of exported parasite proteins i.e PfEMP1 a virulence factor and major cause of malarial pathogenesis, has been of great interest to vaccine researchers in the last decade. The focus of this review is to provide a literature review on PfEMP1s, their interaction with the human immune system, and their role in helping P. falciparum parasite to evade the immune system. This review will primarily focus on the intra-erythrocytic stage, which is the stage that results in the symptoms of malaria. A review is necessary to understand the antigenic variation of PfEMP1s, and how PfEMP1s challenge the different arms of the immune response, both the innate and adaptive. This review is unique in touching on the major parts of the immune system's interaction with the PfEMP1 antigen. Furthermore, the review explores the discussion of future research and therapeutic opportunities based on our knowledge of PfEMP1 antigens.
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Bernard, Miriam. "Molecular interactions between the kelp saccharina latissima and algal endophytes." Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS105.
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Des algues brunes endophytes envahissent les tissus des laminariales, avec des effets potentiellement négatifs sur leur hôte. Des études moléculaires ont permis d'identifier deux genres, Laminarionema et Laminariocolax, dominant la diversité de ces endophytes. Une étude épidémiologique par qPCR a montré une forte prévalence de l'endophyte Laminarionema elsbetiae chez Saccharina latissima, avec des variations saisonnières et locales. En laboratoire, la présence de L. elsbetiae induit des réponses physiologiques différentes chez S. latissima, son hôte principal, et chez Laminaria digitata, un hôte occasionnel. Une approche transcriptomique a révélé des réponses moléculaires différentes chez les deux hôtes et l'endophyte, en lien avec les mécanismes de reconnaissance et de défense des deux partenaires. Ces spécificités du dialogue moléculaire lors des premières étapes de l'interaction pourraient expliquer la variabilité des profils d'infection observés dans les populations naturellesEndophytic brown algae invade stipes and fronds of kelps with potential negative effects for their hosts. The molecular diversity of kelp endophytes was investigated and a majority of the isolated endophytes belonged to the genera Laminarionema and Laminariocolax. Using a qPCR approach, a high prevalence of the endophyte Laminarionema elsbetiae was detected in natural Saccharina latissima populations, but with seasonal and geographical variations. Co-cultivation experiments showed different physiological responses of the main host, S. latissima, and an occasional host, Laminaria digitata, to L. elsbetiae. A transcriptomic approach revealed important differences between the molecular responses of the two kelps, related to the recognition of the endophyte and subsequent defence reactions. These specific differences in the molecular cross-talk during the early steps of the interaction could explain the variability of natural infection patterns in kelp species
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Turner, Matthew L. "The effect of bacterial pathogen-associated molecular patterns and metabolism on innate immunity in the bovine endometrium." Thesis, Swansea University, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.678484.
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Sang, Yongming. "Porcine innate antiviral immunity : host defense peptides and toll-like receptors." Diss., Manhattan, Kan. : Kansas State University, 2008. http://hdl.handle.net/2097/960.
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Brown, Tanya. "Phenomenological and Molecular Basis of the Cnidarian Immune System." FIU Digital Commons, 2017. http://digitalcommons.fiu.edu/etd/3468.
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Coral reefs are one of the most diverse ecosystems on the planet due partially to the habitat structure provided by corals. Corals are long lived organisms that can live for hundreds of years and as a result growth of many species is very slow. As a result of this, recovery of corals from disease outbreaks is very slow and difficult and therefore the ecosystem is deteriorating rapidly. Due to this increase in disease and its detrimental effect on coral reefs, it has become imperative to study how corals respond to disease outbreaks. The response of the coral to pathogens is believed to be controlled by the innate immune system. However, the immune pathways and components of these pathways used by cnidarians to combat pathogens are still rudimentary. This work showed that C3 and heat shock protein 70 are components of the coral immune system that positively respond to disease occurrence. As disease out breaks become more frequent, the question has arisen as to whether cnidarians have homologs to of the adaptive immune system that allow them to respond more rapidly to subsequent encounters with the same bacterium. In the cnidarian model system Exaiptasia pallida, immune priming occurs up to one month after the initial sub lethal exposure to the pathogen. This transient form of priming could be the result of host energy allocation in place of establishing long term immune priming which could be too energetically costly. Cnidarians may only activate priming during summer months, when ocean temperatures and bacterial load are high. Specificity of immune priming in E. pallida requires further investigation with more bacterial pathogens. In this dissertation, one bacterial strain shows specificity while the other does not. Furthermore, the priming response involves many pathways which include pathogen recognition, inflammation, and activation of NF-κB. The discovery of immune priming in a sea anemone shows that this phenomenon evolved earlier in the tree of life than previously thought. Additionally, identification of priming in E. pallida is suggestive of its presence in corals which would allow for potential vaccinations of vulnerable corals.
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Iracheta-Vellve, Arvin. "Innate Immunity As Mediator of Cell Death and Inflammation in Alcoholic Liver Disease." eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/960.
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Central driving forces in the pathogenesis of liver disease are hepatocyte death and immune cell-driven inflammation. The interplay between outcomes, stemming from these two major cell types, is present from the earliest ethanol exposure, and are both determinants in advanced stages of liver disease particularly in alcoholic liver disease (ALD). The complexities associated with advanced ALD are many and therapies are limited. Due to the liver’s role in ethanol metabolism and filtering gut-derived products, it is becoming increasingly clear that innate immunity plays a central role in triggering activation of cell death and inflammatory pathways in ALD. We identified interferon regulatory factor 3 (IRF3) activation as a mediator of hepatocyte death as the first event after ethanol exposure, and the inflammasome as a protein complex responsible for the subsequent inflammatory cascade, driven by the NLRP3 inflammasome.
Our novel findings in murine samples and human patients with alcoholic hepatitis demonstrate that ethanol-induced inflammasome activity results in Caspase-1-mediated pyroptosis and extracellular ASC aggregates in the liver and circulation. Pyroptosis can be abrogated by therapeutic inhibition of inflammasome components, NLRP3 or Caspase-1. Taken together, the event leading to mtDNA release into the cytoplasm is the inception of the pathogenesis of ALD, triggering hepatocyte death, culminating in a pro-inflammatory cascade driven by the NLRP3 inflammasome and pyroptotic release of ASC.
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Chatelain, Philippe Guillaume [Verfasser]. "On the emergence and molecular characteristics of LRR-RLKs and LRR-RLPs in plant immunity / Philippe Guillaume Chatelain." Tübingen : Universitätsbibliothek Tübingen, 2019. http://d-nb.info/1227539851/34.
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Kinuthia, Wanja. "The molecular mechanism of immune evasion by the eggs and larvae of the Endoparasitoid Venturia canescens in its host, Ephestia kühniella /." Title page, table of contents and summary only, 1996. http://web4.library.adelaide.edu.au/theses/09PH/09phk56.pdf.
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