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1
Hosker, Harold Stephen Ronald. "Alveolar macrophage and blood monocyte function in small cell lung cancer." Thesis, University of Newcastle Upon Tyne, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241364.
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Leszczyńska, Katarzyna. "Signalling and function of the small Rho GTPase RhoJ in endothelial cells." Thesis, University of Birmingham, 2011. http://etheses.bham.ac.uk//id/eprint/1495/.
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RhoJ is an endothelial expressed Rho GTPase, and its knock-down impairs endothelial cell (EC) migration and tubulogenesis, increases stress fibre (SF) and focal adhesion (FA) numbers. This work aimed to determine the intracellular localisation of RhoJ, identify its binding partners, test how it is activated and further explore its function in ECs. Endogenous RhoJ localised to FAs and overexpression of its active mutant (daRhoJ) promoted EC migration, and diminished FA and SF numbers. In addition to FAs, overexpressed RhoJ localised also to endosomes and RhoJ knock-down slightly delayed transferrin recycling. Vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF-2) and thrombin activated RhoJ in ECs. PAK-interacting exchange factor β (βPIX) and G protein-coupled receptor kinase-interacting target 1 (GIT1), which promote FA disassembly, were identified as RhoJ-binding partners. RhoJ co-localised with these proteins in ECs, and βPIX knock-down and to a lesser extent GIT1 knock-down reduced RhoJ localisation to FAs. Overexpression of daRhoJ increased the amount of GIT1 and βPIX in FAs, and increased the total amount of the βPIX protein in ECs. In conclusion, RhoJ localises to FAs, promotes EC migration, regulates FA and SF numbers, interacts with βPIX and GIT1 and is activated by pro-angiogenic factors.
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Norville, Phillip. "Small colony variants in Staphylococcus aureus and other species : antibiotic selection, antimicrobial susceptibility, and biofilm formation." Thesis, Cardiff University, 2011. http://orca.cf.ac.uk/17713/.
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Staphylococcus aureus is one of the leading causes of hospital acquired infections. The ability of S. aureus to acquire resistance to a diverse range of antimicrobial compounds, results in limited treatment options, particularly in methicillin-resistant S. aureus. A mechanism by which S. aureus develops reduced susceptibility to antimicrobials is through the formation of small colony variants (SCVs). Reduced antimicrobial susceptibility in S. aureus SCVs is not related to ‘classical’ mechanisms of resistance, but occurs as a direct result of the development of the SCV phenotype. S. aureus SCVs are frequently associated with defects in the bacterial electron transport chain and these defects are responsible for the characteristics associated with the SCV phenotype. This study aimed to investigate and characterise the selection of S. aureus SCVs in the presence of various antibiotics and also to examine their biofilm forming capabilities. Four members of the aminoglycoside family of antibiotics were shown to select for S. aureus SCVs. In addition, a broad range (X 0.25 MIC – X 4 MIC) of aminoglycoside concentrations were shown to select for S. aureus SCVs. Characterisation of these isolates revealed that differences in auxotrophy, biochemical profiles, carotenoid production, haemolysis, levels of intracellular ATP, mutation frequency and reversion rate were present. Members of the tetracycline family of antibiotics were also shown to select for S. aureus SCVs. Tetracycline selected S. aureus SCVs show attenuated catalase, coagulase and heamolysis activity and reduced production of extracellular DNase and lipase and reduced susceptibility to various antimicrobial agents. As SCVs have been linked to persistent and recurrent infections their ability to form biofilms was also investigated. A range of S. aureus SCVs isolated from various backgrounds were shown to form greater biofilms in comparison to parent strains, which was attributed to increased production of polysaccharide intracellular adhesin. In addition S. aureus SCV biofilms displayed a more pronounced reduction in antimicrobial susceptibility, which was attributed to a reduction in antimicrobial penetration through SCV biofilms. Limited discovery of novel antibiotics in recent years and the observation that S. aureus SCVs can be selected for by various antimicrobial compounds highlights the need for novel antimicrobial compounds. Accordingly, an investigation into the susceptibility of S. aureus to various plant compounds was undertaken. Both S. aureus SCVs and parent strains showed susceptibility to five plant antimicrobials tested, of which SCVs were more susceptible to cinnamon bark, green tea and oregano. Resistance to these plant antimicrobials could not be induced and synergistic relationships between certain plant antimicrobials and antibiotics were demonstrated. Finally, formation of SCVs in bacterial species other than S. aureus was examined. Gentamicin induced SCV selection in Escherichia coli, Pseudomonas aeruginosa and S. epidermidis as well as chloroamphenicol and ciprofloxacin in E. coli and tetracycline in S. epidermidis. SCVs from these bacterial species shared common characteristics associated with the SCV phenotype including altered growth and biochemical profiles, auxotrophy for compounds involved in electron transport, reduction in expression of virulence factors and reduced antimicrobial susceptibility. Additionally all SCVs showed an increased capacity to form biofilms. The ability of certain antibiotics to select for SCVs and their increased capacity to form biofilms suggest that SCV are an important adaptation to aid survival and persistence in times of stress. Reduced susceptibility to commonly used antibiotics in SCVs signifies that the development of new antimicrobial compounds is required. Harnessing naturally occurring plant antimicrobials and their synergistic relationship with antibiotics may offer a novel approach to treating antibiotic resistant infections whilst overcoming antibiotic selection for SCVs.
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Masjedi, Mohsen. "Physiological inflammation of the small intestine during weaning in the rat /." Title page, table of contents and summary only, 1998. http://web4.library.adelaide.edu.au/theses/09PH/09phm3973.pdf.
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Ismail, Jaidaa. "Testing BCL2A1 Small Molecule Inhibitors in Fluorescence Polarization Assays." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595846503840908.
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Chen, Xi. "Design and synthesis of small molecule inhibitors of coagulation FXIIa." Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/53481/.
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Blood coagulation factors, factor XII (FXII), plasma kallikrein (PK), factor XI (FXI), and high-molecular-weight kininogen (HMWK), are four proteins that are involved in the plasma contact activation system (CAS) and kallikrein-kinin system (KKS). FXII is the initiation point of the intrinsic pathway of blood coagulation and is also the link between procoagulant and proinflammatory reactions. A number of inhibitors for blood coagulation factors have been approved for clinical usage. These inhibitors not only show inhibitory activities against thrombosis, but also disrupt haemostasis causing excessive bleeding. Contrasted with other coagulation proteases, the deficiency in FXII, instead of causing excessive bleeding, only reduces thrombus formation in blood coagulation. This unique property has made FXII a potential target for the treatments of thrombosis. FXII inhibitors such as aptamers, antibodies and peptides have been reported. Due to their limitations, some inhibitors have poor selectivity or weak binding affinity. Some inhibitors (biopolymers) have pharmaceutical problems. A chemically synthesised FXII inhibitor, with high selectivity is of great importance. The current lack of small molecule FXII inhibitors is limiting efforts to fully understand and validate FXII as a drug target. This project aims to design and synthesise a novel class of 1, 2, 5-tri-substituted benzene urea compounds as potent FXIIa inhibitors. Using Lossen rearrangement, a total of 134 urea compounds were chemically synthesised in this project. All compounds were biologically tested against activated factor XII (FXIIa). Detailed structure-activity relationships (SAR) information was obtained by functional enzyme assays (FXIIa). The range of activity of urea lead compounds in series is between 5.7 μM and 182.0 μM. The urea compound (127) bearing a benzamidine functional group (4-((2-(3-(2-(Pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)ureido)ethyl)sulfonamido)benzamidine) had the most potent inhibition against FXIIa (α-FXIIa: 5.7 ± 0.1 μM; β-FXIIa: 5.9 ± 0.2 μM). The top 25 most potent inhibitors were selected and were biologically tested for their selectivity between FXIIa and activated factor X (FXa). There are four out of 25 compounds showed their activities against FXa in a range between 1.9 ± 0.6 μM and 141.7 ± 16.5 μM. The selectivity between FXa and FXIIa was rationalised by serine protease-ligand crystal structure (FXa-rivaroxaban complex) and computational modelling simulation (FXIIa-hybrid model). In conclusion, potent FXIIa inhibitors were identified. The present study provides a rationale for further development of FXIIa inhibitors for the treatment of thrombosis and the investigation of selectivity between FXIIa and factor Xa (FXa).
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Hartlage, Alex S. "T CELL IMMUNITY IN A SMALL ANIMAL SURROGATE OF HEPATITIS C VIRUS INFECTION." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1584101091684162.
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Moghaddami, Mahin. "Characterization of isolated lymphoid aggregations in the mucosa of the small intestine /." Title page, abstract and contents only, 1999. http://web4.library.adelaide.edu.au/theses/09PH/09phm6959.pdf.
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Thesis (Ph.D.)--University of Adelaide, Dept. of Microbiology and Immunology, 1999.<br>Errata & addenda tipped in behind back end paper. Copies of author's previously published articles in pocket on back end-paper. Bibliography: leaves 147-194.
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Guo, Weihong, and 郭衛紅. "The immune mechanisms and novel immunosuppressive approaches in experimental small bowel transplantation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hub.hku.hk/bib/B3124175X.
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Jezierski, Anna W. "Crosstalk of E-cadherin and small GTPase Rap1 coordinates the clonality of human embryonic stem cells." Thesis, University of Ottawa (Canada), 2009. http://hdl.handle.net/10393/28089.
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Human embryonic stem cells (hESCs) are pluripotent cells, capable of giving rise to all three germ layers while maintaining their ability to proliferate indefinitely in culture. However, little is known regarding the microenvironmental cues that govern hESC self-renewal, particularly the challenge of clonal propagation following single cell dissociation. Increasing evidence suggests that intracellular pathways that coordinate E-cadherin-mediated cell-cell and integrin-mediated cell-ECM adhesions, are indispensable for the maintenance and self-renewal of hESCs. I have demonstrated that a potential crosstalk between small GTPase Rap1 and E-cadherin coordinates the colony formation and self-renewal of hESCs. I demonstrate that Rap1 expression kinetically decreases following the dissociation-induced disruption of E-cadherin mediated cell-cell adhesion compared to adherent hESCs. Inhibition of Rap1 with GGTI-298 completely abolishes the colony formation and self-renewal capacity of dissociated hESCs, whereas ectopic expression of Rap1 augments colony formation and survival. Addition of a potential activator of Rap1, Bombesin, inhibited dissociation-induced loss of Rap1 in hESCs and subsequently enhanced their survival, clonal propagation and self-renewal. Given the considerable extracellular and intracellular activators of Rap1, this work may provide an intracellular target to improve hESCs maintenance and self-renewal and provide new insights into the mechanisms regulating clonality and self-renewal.
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Randrian, Violaine. "Role of myosin IIA in the small intestine immunosurveillance by dendritic cells." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB038/document.
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Plusieurs méthodes de capture antigénique ont été décrites dans l’intestin grêle, surtout en cas d’infection: échantillonnage direct par les cellules dendritiques (DC), capture par les macrophages qui délivrent ensuite l’antigène aux DC du stroma, passage des antigènes à travers les cellules caliciformes. Des travaux antérieurs in vitro dans le laboratoire ont montré l’importance de la myosine IIA dans la coordination de la migration des DC avec la capture et de l’apprêtement antigénique. L’objectif de ma thèse était de combiner plusieurs méthodes d’imagerie telle que la microscopie intravitale, la microscopie confocale ex vivo et l’immunofluorescence sur tissus à la cytométrie en flux pour déterminer l’impact de la myosine IIA sur la capture antigénique in vivo. Cette étude montre que les DC patrouillent en permanence dans l’épithélium de l’intestin grêle, y compris hors conditions infectieuses. Elles sont recrutées dans la lamina propria (LP) et pénètrent dans l’épithélium par transmigration à travers la membrane basale qui sépare ces deux compartiments. La myosine IIA est indispensable à la transmigration de CD103+CD11b+DC. Ces événements de transmigration surviennent plus fréquemment dans les parties proximales de l’intestin grêle, duodénum and jéjunum, que dans l’iléon. Chez les souris adultes, ces DC ne sont pas recrutées sous l’influence du microbiote mais sont sensibles au rétinal, un métabolite de la vitamine A qu’elles transforment en une molécule active l’acide trans-rétinoïque (AtRA). D’après notre analyse transcriptomique, les DC intra-épithéliales constituent une population homogène dont le profil est distinct de celui de leurs homologues de la LP. Elles sont enrichies en ARN des voies liées à l’apprêtement antigénique, l’autophagie et les lysosomes. Ces résultats suggèrent qu’elles ont une fonction différente des CD103+CD11b+DC de la LP: elles n’agissent pas sur la prolifération ni la différenciation des lymphocytes T mais contrôlent spécifiquement l’effectif des lymphocytes intra-épithéliaux CD8+αβ. Ces découvertes reflètent l’importance de l’épithélium comme première ligne de défense contre les pathogènes. Elles soulèvent également de nouvelles questions concernant la régulation de la réponse immune dans l’épithélium et les interactions mutuelles entre la lumière intestinale, l’épithélium et le stroma des villosités<br>Several routes for antigen capture have been described in the small intestine, mainly upon pathogenic infection: direct sampling by Dendritic Cells (DCs), sampling by macrophages that deliver antigens to DCs in the stroma, antigenic passage through goblet cells. Previous in vitro work in the lab showed that myosin IIA is essential to coordinate antigen uptake and processing with DC migration. The objective of my thesis was to combine several imaging methods including intravital microscopy, ex vivo confocal microscopy and immunofluorescence on gut tissue to flow cytometry in order to unravel the impact of myosin IIA on DC physiology in vivo. My work shows that CD103+CD11b+ DCs, which are unique to the gut, constantly patrol the epithelium of the small intestine at steady state: they are recruited from the lamina propria (LP) and penetrate into the epithelium by transmigrating through the basal membrane that separates these two compartments. DC transmigration requires myosin IIA in vivo. Remarkably, we found that DC transmigration into the epithelium occurs mainly in the upper parts of the small intestine, the duodenum and the jejunum, but is not observed in the ileum. DC transmigration does not require the gut microbiota but relies on retinal, a vitamin A metabolite of that they convert into its active form all-trans retinoic acid (AtRA). Strikingly, single cell RNA-seq showed that intra-epithelial CD103+CD11b+ DCs constitute a homogenous cell population with a distinct transcriptomic signature from their LP counterpart. They are enriched with RNA related to antigen presentation, autophagy and lysosome pathways. Our results further suggest that these cells have a different function from LP CD103+CD11b+ DCs, as they do not significantly impact proliferation or differentiation of T helper lymphocytes but control the CD8+αβ intraepithelial lymphocytes (IELs) pool. These findings highlight the importance of the epithelial tissue as a first line of defense against pathogens in the upper parts of the small intestine. They also raise new questions about the regulation of the immune response in the epithelium and the mutual influences between lumen, epithelium and intestinal lamina propria
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Thompson, Fiona Marie. "Activation of the mucosal immune system and growth of the small intestine at weaning /." Title page, abstract and contents only, 1994. http://web4.library.adelaide.edu.au/theses/09PH/09pht4677.pdf.
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Lucera, Mark B. "Lysine Acetylation and Small Molecule Epigenetic Inhibition Reveal Novel Mechanisms Controlling Cellular Susceptibility to HIV-1 Infection." Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1448969829.
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Lu, Jingwei. "Development of Effective Immunotherapy for Ovarian Cancer Using Adoptive gamma-delta T Cells and Small Targeting Molecules." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1366380793.
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Li, Xiaosong. "The mechanism study of novel approaches to control chronic allograft rejection in rat orthotopic small bowel transplantation." Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B36395778.
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Horwath, Michael C. "Changing the Fate of Histoplasma Capsulatum-infected Cells with Small Molecules: Investigation of Zinc Modifying Agents and the Antioxidant Ferrostatin-1." University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin151635627882887.
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Corbet, Marlene. "Exploiting the helminth-derived immunomodulator, ES-62 and its small molecule analogues to dissect the mechanisms underpinning the development of the pathogenic phenotype of synovial fibroblasts in autoimmune arthritis." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8007/.
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Parasitic helminths are able to survive within their hosts due to their ability to dampen immune responses by secreting molecules with anti-inflammatory and tissue repair properties. Reflecting this, there is increasing evidence of an inverse correlation between parasitic worm infection and the incidence of allergic and autoimmune disorders on a global scale. Such epidemiological evidence has led to the “hygiene hypothesis” which postulates that the recent rapid eradication of parasitic worms in developed countries has resulted in unbalanced hyper-reactive immune systems and consequently, inflammatory disease. As “worm therapy” per se is not ideal, this in turn triggered the idea that exploiting the ability of helminth-derived “immunomodulators” to dampen pathological host inflammation would potentially allow identification of the key pathogenic events in models of human inflammatory disease and hence provide a starting point for development of new and safer therapeutics. Consistent with this, as a serendipitous side-effect of its anti-inflammatory actions, ES-62, a phosphorylcholine (PC)-containing glycoprotein secreted by the filarial nematode, Acanthocheilonema viteae exhibits therapeutic potential in mouse models of inflammatory disorders such as asthma, lupus and rheumatoid arthritis (RA). RA is a chronic autoimmune inflammatory disorder that affects 1 % of the population in industrialized countries, with no known cure. This disorder causes joint destruction and leads to reduced mobility and disability. Deregulation of T cell activation has long been considered to be a major force driving inflammation and thus to date, therapies have focused on systemic anti-inflammatory treatments, which generally leave individuals immunosuppressed and open to infection. Thus, interest has begun to focus on the role(s) that synovial fibroblasts (SF) in the joint play in the early onset of the disease, the maintenance of established inflammation and even in the spread of disease to unaffected joints. This reflects that despite not being part of the immune system, SF produce pro-inflammatory cytokines during the pathogenesis of RA and also directly mediate joint destruction by secreting matrix metalloproteinases (MMPs) that damage cartilage and bone. Indeed, there is increasing evidence that the local pro-inflammatory environment pertaining in the joints drives SF to become 3 imprinted pathogenic aggressors that initiate, drive and spread joint inflammation and bone resorption during development of collagen-induced arthritis (CIA), a mouse model of RA. Intriguingly, therefore, whilst it is established that protection afforded by ES-62 against joint inflammation and bone destruction in CIA is associated with reduced production of the pathogenic cytokine, IL-17 by and CD4+ T cells, recent evidence suggested that ES-62 could also act directly to suppress the aggressive hyper-inflammatory phenotype of SF in the joint. The molecular mechanisms involved were not defined but interestingly, given that SF express the ES-62 target TLR4 and are the only cells in the joint to express the IL-22 receptor, the parasite product appeared to harness the inflammation-resolving and/or tissue repair actions of IL-22 to suppress SF responses during the established phase of disease. Thus the core goal of this thesis was to advance our fundamental understanding of how SF become imprinted pathogenic aggressors that initiate, drive and spread joint inflammation and bone resorption in the CIA mouse model, as a surrogate for the pathogenic events in the joints in RA. In particular, the primary major aim was to investigate the impact of the local pro-inflammatory environment pertaining during disease, specifically focusing on the signalling and epigenetic mechanisms by which IL-17 and IL-22 potentially (counter)regulate the pathogenic phenotype of SF. Complementing this, another major aim was to establish whether ES-62 acted directly to modulate the phenotype of SF and thus, to identify the key mechanisms by which ES-62 could prevent SF from promoting inflammation and bone destruction and in this way render them insensitive to pro-inflammatory signals. From a therapeutic point of view, being a large immunogenic molecule, ES-62 is not suitable for use in the clinic and thus candidate small molecule analogues (SMAs) of ES-62, based around its active PC moiety have been designed, some which mimic its therapeutic potential in a variety of inflammatory disorders. Thus, it was also important to address whether ES-62 and its SMAs were similarly able to affect SF and prevent their pathogenicity. These studies revealed that the microenvironment of the joint during induction and progression of CIA did indeed result in remodelling of the epigenetic landscape of SF and that such cell reprogramming was associated with the acquisition of a hyperinflammatory, tissue destructive phenotype. Such 4 reprogramming could be recapitulated in vitro, at least in part, by chronic exposure of normal SF to pro-inflammatory cytokines such as IL-17 and IL-1 pathogenic mediators that are found at high levels in the arthritic joint. Such reprogramming was dependent on ERK and STAT3 signalling converging on miR-155-mediated regulation of inflammatory networks via global DNA hypomethylation. ES-62 was able to counteract this by suppressing the levels of ERK, STAT3 and miR-155 signalling but rather surprisingly, this did not result in abrogation of this hypomethylated epigenetic landscape. Rather, whereas the SMA 12b appeared to act simply by preventing/reversing global DNA demethylation to suppress the induction of genes that drive pathogenesis in CIA, ES-62 induced further global DNA hypomethylation and modulation of the epigenetic landscape by inducing HDAC1: collectively these findings suggested that ES-62 might additionally induce (homeostatic) inflammation-resolving and tissue repair genes that would have translational impact in established disease. In any case, these studies suggest that the proposal to use the global DNA methylation status of RA patients as a biomarker of disease should be treated with caution.
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Li, Xiaosong, and 李小松. "The mechanism study of novel approaches to control chronic allograft rejection in rat orthotopic small bowel transplantation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B36395778.
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Gatbonton-Schwager, Tonibelle N. "Biological and Chemical Analysis of Small Molecule Activators of Anti-inflammatory and Antioxidant Nrf2-Keap1 Signaling." Case Western Reserve University School of Graduate Studies / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1390560628.
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Koch, William J. "Initial Characterization of a Multifaceted Small Molecule and Its Efficacy for the Treatment of Type 1 Diabetes Mellitus." Ohio University / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1617098329334351.
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Charrier, Mélinda. "Caractérisation phénotypique et fonctionnelle de sous-populations Natural Killer (NK) chez des patients atteints d’un cancer bronchique non à petites cellules et impact d’une vaccination avec des exosomes de cellules dendritiques (Dex) autologues." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS438.
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Depuis peu, l’immunothérapie a émergé comme une nouvelle stratégie chez les patients atteint de Cancer Bronchique Non à Petites Cellules (CBNPC), confirmant ainsi le rôle du système immunitaire dans cette maladie. Malgré ces nouveaux traitements (thérapies ciblées, immunothérapie), les taux de réponses restent faibles avec un impact modeste sur la survie globale. Des biomarqueurs sont donc nécessaire pour définir les populations cibles de ces traitements. Une des pistes explorées est le statut immunitaire des patients, en effet celui-ci a un impact pronostic et pourrait influencer la réponse aux traitements standards tels que la chimiothérapie, les thérapies ciblées et même l’immunothérapie. Parmi les cellules du système immunitaire, les cellules Natural Killer (NK) auraient un rôle effecteur dans le CBNPC. Il est maintenant clairement établit que les cellules NK favorisent la mise en place d’une immunité adaptative fonctionnelle et efficace. Ainsi une altération des fonctions NK pourrait être un mécanisme associé à l’échappement à l’immunité adaptative de la tumeur. Dans notre première étude, nous avons mis en évidence que les exosomes de cellules dendritiques stimulaient les cellules NK via NKp30, cette activité étant associée à un gain de survie sans progression chez des malades inopérables porteurs d’un CBNPC avancé. Notre second projet a révélé, pour la première fois, un rôle pronostic des transcrits de NCR3 (gène de NKp30) chez des patients naïfs de tout traitement. L’activation des cellules NK via NKp30 pourrait être une stratégie efficace d’immunomodulation chez les patients atteints de CBNPC avancé. Ces travaux confirment le rôle important des cellules NK dans le CBNPC avancé<br>Recently, immunotherapy has emerged as a new strategy in Non-Small Cell Lung Cancer (NSCLC) patients, confirming the key role of the immune system in this disease. Despite these new treatments (targeted therapies, immunotherapy), response rates remain low with a modest impact on overall survival. Biomarkers are needed to define the target population of these treatments. One of the options explored is the immune status; indeed the immune status of cancer patients has a prognosis impact and may influence the response to standard treatments such as chemotherapy, targeted therapies and even immunotherapy. Among the immune cells, Natural Killer cells (NK) have an effector role in NSCLC. It is now established that NK cells can promote a functional and efficient adaptive immunity. Therefore, an impaired NK functions could be a mechanism associated with the escape from adaptive immunity of the tumor. In our first study, we demonstrated that exosomes from dendritic cells stimulated NK cells through NKp30, this activity is being associated with improved survival in advanced NSCLC. Our second project has revealed, for the first time, a independent prognostic role of NCR3 transcript (NKp30 gene) for naïve advanced NSCLC. Activation of NK cells via NKp30 could be an effective strategy for immunomodulation in advanced NSCLC patients. These studies confirm a major role of NK cells in advanced NSCLC
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Lemmey, Andrew Bruce. "Effects of insulin-like growth factors (IGFS) on recovery from gut resection in rats : a thesis submitted to the University of Adelaide, South Australia for the degree of Doctor of Philosophy." 1992, 1993. http://web4.library.adelaide.edu.au/theses/09PH/09phl554.pdf.
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Includes bibliographical references (leaves 159-213) Shows that IGF-I peptides are effective in diminishing post-surgical catabolism and enhancing adaptive gut hyperplasia in rats recovering from massive small bowel resection.
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Ou, Gangwei. "Human intestinal epithelial cells in innate immunity : interactions with normal microbiota and pathogenic bacteria." Doctoral thesis, Umeå : Umeå University, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-18388.
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Nistler, Ryan J. "Small RNA Regulation of the Innate Immune Response: A Role for Dicer in the Control of Viral Production and Sensing of Nucleic Acids: A Dissertation." eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/834.
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All organisms exist in some sort of symbiosis with their environment. The food we eat, air we breathe, and things we touch all have their own microbiota and we interact with these microbiota on a daily basis. As such, we employ a method of compartmentalization in order to keep foreign entities outside of the protected internal environments of the body. However, as other organisms seek to replicate themselves, they may invade our sterile compartments in order to do so. To protect ourselves from unfettered replication of pathogens or from cellular damage, we have developed a series of receptors and signaling pathways that detect foreign bodies as well as abnormal signals from our own perturbed cells. The downstream effector molecules that these signaling pathways initiate can be toxic and damaging to both pathogen and host, so special care is given to the regulation of these systems. One method of regulation is the production of endogenous small ribonucleic acids that can regulate the expression of various receptors and adaptors in the immune signaling pathways. In this dissertation, I present work that establishes an important protein in small ribonucleic acid regulation, Dicer, as an essential protein for regulating the innate immune response to immuno-stimulatory nucleic acids as well as regulating the productive infection of encephalomyocarditis virus. Depleting Dicer from murine embryonic fibroblasts renders a disparate type I interferon response where nucleic acid stimulation in the Dicer null cells fails to produce an appreciable interferon response while infection with the paramyxovirus, Sendai, induces a more robust interferon response than the wild-type control. Additionally, I show that Dicer plays a vital role in controlling infection by the picornavirus, encephalomyocarditis virus. Encephalomyocarditis virus fails to grow efficiently in Dicer null cells due to the inability for the virus to bind to the outside of the cell, suggesting that Dicer has a role in modulating viral infection by affecting host cellular protein levels. Together, this work identifies Dicer as a key protein in viral innate immunology by regulating both the growth of virus and also the immune response generated by exposure to pathogen associated molecular patterns. Understanding this regulation will be vital for future development of small molecule therapeutics that can either modulate the innate immune response or directly affect viral growth.
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Bloom, Connor. "The Feasibility of Whole-Blood-System Genotyping: A Case Study using the San Diego Blood Bank." Scholarship @ Claremont, 2019. https://scholarship.claremont.edu/cmc_theses/2110.
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Over the past several decades and increasingly in recent years, blood transfusions in the United States have plummeted as surgery has gotten more precise and less invasive. Alongside this decrease in general transfusions has been an increase in specific blood products for patients whose immune systems require special treatment. Simultaneously, trends in healthcare in the United States have incentivized regional hospitals to join large conglomerates. These coexisting factors have left regional blood banks, traditionally economically viable, in much weakened states. This thesis was born out of an initial curiosity to discover whether or not genetic science, and genotyping in particular, could benefit small regional blood banks by allowing them to bring down their costs of pre-transfusion blood testing or offer new products. I focus on the San Diego Blood Bank (SDBB) as a case study of the larger blood banking industry. In the course of this research, economic factors were taken into consideration as well as social and health. A minor question that was also discussed was whether genotyping not only help regional blood banks survive fiscally but also open the gateway to better patient outcomes and lower costs nationally of blood transfusions and their associated costs. Feasibility analyses and financial modeling suggest support for genotyping blood donors and transfusion recipients in order to more perfectly match blood transfusions through extended antigen matching.
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Galvao, Flávio Henrique Ferreira. "Modelo experimental de doença do enxerto versus hospedeiro após transplante de intestino delgado." Universidade de São Paulo, 1998. http://www.teses.usp.br/teses/disponiveis/5/5132/tde-13072011-171433/.
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A doença do enxerto versus hospedeiro (DEVH) é uma grave complicação do transplante de órgãos sólidos, com alta mortalidade. Seu estudo tem sido limitado pela carência de modelos experimentais apropriados. Descreve-se um modelo de DEVH baseado no aumento do quimerismo, sua evolução clínica, histopatológica, do número das células quiméricas, do perfil das citocinas e da tolerância imunológica. Ratos Lewis (LEW) foram submetidos a transplante simultâneo de intestino delgado e medula óssea provenientes de ratos ACI (grupo de estudo - E) ou LEW (grupo controle - C), tratados com FK-506 (1 mg/Kg/dia) entre o 0 e 13o PO, e uma dose semanal daí por diante. Os ratos foram divididos nos seguintes grupos: E1- 6 ratos sacrificados no 120o PO. E2- 8 ratos após apresentarem sinais clínicos graves de DEVH entre o 189o e o 271o PO. Como controle, ratos LEW foram receptores dos mesmos tipos de enxertos provenientes de ratos LEW, submetidos à mesma imunossupressão e foram assim divididos: C1- 6 ratos sacrificados no 120o PO, C2- 5 ratos sacrificados entre o 223o e o 270o PO. A citometria de fluxo foi realizada para quantificar a porcentagem das células linfóides de ACI doadores no sangue periférico nos E1, E2 em 6 períodos: 30o PO, 65o PO, 95o PO, 120o PO, 160o PO, 200o PO. Os animais foram examinados 2 vezes por semana à procura de sinais de DEVH (rash cutâneo, perda de peso, de pelo e hiperqueratose). No sacrifício dos animais do grupo E1 e C1, foram colhidas amostras de língua (LI), de linfonodos cervicais (LC), intestino delgado do receptor e do enxerto para análise das citocinas IL-2, IL-4, IL-6, IL-10, IFN-gama e TNF-alfa por meio da reação em cadeia da polimerase. Em todos os grupos foram também colhidas amostras destes órgãos para histopatologia e nos animais do grupo E2 linfonodos cervicais foram processados para análise da reatividade celular por meio da reação mista dos linfócitos (MLR). A evolução clínica e histopatológica foi graduada de 0 a 3 de acordo com a severidade dos sintomas e do infiltrado mononuclear das amostras. Os ratos dos grupos E1 e E2 iniciaram sinais da DEVH entre o 84o e 115o PO. Os ratos dos grupos C1 e C2 não apresentaram evidência de DEVH. Amostras de LI e LC dos ratos do grupo E1 apresentaram alterações histopatológicas grau 2 e do grupo E2 apresentaram alterações histopatológicas grau 3, respectivamente. Nenhuma alteração histopatológica foi encontrada nos ratos do grupo controle e em amostras do ID. Nenhuma alteração histopatológica foi encontrada no intestino delgado do receptor e do enxerto. O aumento da porcentagem de células do doador no sangue periférico do receptor foi progressivo chegando a 5,4±2.3% no 10o período, 21±4,6% no 3o período e 39,3±4% no 6o período. IL-2, IL-6, IL-10, IFN-gma e TNF-alfa estiveram aumentados em língua e IL-4, IL-6, IL-10, IFN-gama e TNF-alfa em linfonodos cervicais. Os linfócitos de ratos do grupo E2 mostraram hiporreatividade aos de ratos ACI e hiperreatividade aos de ratos PVG (terceira parte) denotando tolerância imunológica. Neste modelo experimental há uma inexorável evolução imunológica para DEVH; existe correlação direta entre o aumento do quimerismo em sangue periférico e da expressão de citocinas em língua e linfonodos cervicais e a severidade da DEVH, além da indução de tolerância imunológica do rato do grupo E2 quimérico ao rato ACI normal.<br>Graft-versus-host disease (GVHD) has been a major concern after small bowel transplantation (SBTX) and the lack of suitable experimental models has limited the study of GVHD after solid organ transplantation. Here we describe a re1evant experimental model of GVHD after fully allogeneic SBTX based on chimerism augmentation, its clinical and histophatological evolution, cytokine involvement, responsible donor cell and immunologic tolerance analysis. LEW rat recipients received orthotopic SBTX and simultaneous donor bone marrow cell infusion (250x106), from ACI rats (experimental group - E) or LEW (control group C). FK-506 was administered dayly at a dose of 1 mg/kg on day 0 to 13, then continued as a weekly injection of same dose until the experimental end point. The recipients were divided in the following groups: E1 - 6 rats sacrificed at 120° POD. E2 - 8 rats sacrificed with critical GVHD between DPO 189 to 271. LEW recipient of LEW grafts, under the same immunossupression were used as control and divided as: C1 - 6 rats sacrificed at POD 120; C2- 5 rats sacrificed between 223 and 270 POD the number of donor cell in the recipient circulation was determined by flowcytometry in 6 pos-operative time: 30, 65, 95, 120, 160, 200. The rats were analyzed twice a week for body weigh and searching for signs of GVHD (cutaneous rush, hiperkeratosis and loss of hair and body weigh). At the sacrificed, samples from tongue (TG), cervical lymph node (CLN), donor (SBD) and recipient (SBR) small bowel were taken from all animals for histophatology and from E1 and C1l animals for IL-2, IL-4, IL-6, IL-10, IFN-gama e TNF-alfa cytokines analysis using reverse transcription polymerase chain reaction. Samples from cervical lynph nodes of 5 animals from group E2 were used for mixed lymphocyte reaction for tolerance analysis. The clinical and histophatological evolution of the disease were evaluated from degree 0 to 3 according to the severity. GVHD in E1 and E2 animals started between 84 and 115 POD. Histophatological analysis of TG and CLN showed that E1 animals present GVHD grade 2 and E2 animals grade 3. The increase of donors cells in the recipient circulation was progressive and account for 5.4± 2.3% at POD 30, 21.4±4.6% at POD 95 and 39.3±4% at POD 200. IL-4, IL-6, IL-10, IFN-gama e TNF-alfa were upregulated in CLN and IL-2, IL-6, IL-10, IFN-gama e TNF-alfa were upregulated in TG when compared with the respective controls. The lymphocytes from E2 group showed hyporeactivety to lymphocytes of normal ACI and hypereactivety to those of PVG, meaning tolerance. No cytokines alteration was noted in SBD neither SBR. Animals from group C1 and C2 did not present any sign of disease. This result show that GVHD is a inexoravel evolution under the experimental conditions of this study and the evolution of the disease is near correlated with the augmentation of the donor cells in the recipient circulation and upregulation of cytokines gene expression in target organs. Tolerance to the same donor strain lynphocytes was also noted.
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Perroud, Junior Mauricio Wesley 1971. "Avaliação de viabilidade, tolerância e segurança da vacina com células dendríticas autológas maduras em pacientes com carcinoma de pulmão não pequenas células avançado = Assessment of feasibility, safety and tolerance of mature autologous dendritic cells vaccine in patients with advanced non-small cell lung carcinoma." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310256.
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Orientador: Lair Zambon<br>Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas<br>Made available in DSpace on 2018-08-21T10:28:19Z (GMT). No. of bitstreams: 1
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Previous issue date: 2012<br>Resumo: Os resultados terapêuticos globais do carcinoma de pulmão não pequenas células em estádio avançado são bem limitados. A imunoterapia com células dendríticas foi desenvolvida como uma nova estratégia para o tratamento de câncer de pulmão. O objetivo deste estudo foi avaliar a viabilidade, segurança e respostas imunológicas em pacientes com carcinoma de pulmão não pequenas células tratados com vacina autóloga de células dendríticas maduras pulsadas com antígenos. Cinco pacientes HLA-A2 com carcinoma de pulmão não pequenas células inoperável (estádio III ou IV) foram selecionados para receber duas doses de 5 x 107 de células dendríticas administradas por vias subcutânea e intravenosa, duas vezes em intervalos de duas semanas. A segurança, tolerabilidade e respostas imunológica e tumoral à vacina foram avaliadas pela evolução clínica e laboratorial, ensaio de linfoproliferação e critérios de RECIST, respectivamente. A dose utilizada para a imunoterapia demonstrou ser segura e bem tolerada. O ensaio de linfoproliferação mostrou uma melhora na resposta imune específica após a imunização, com uma resposta significativa após a segunda dose (p = 0,001). Esta resposta não foi persistente e houve uma tendência à redução após duas semanas da segunda dose da vacina. Dois pacientes apresentaram uma sobrevida quase duas vezes maior que a média esperada e foram os únicos que expressaram os antígenos tumorais HER-2 e CEA Apesar do pequeno tamanho da amostra, os resultados sobre o tempo de sobrevida, resposta imune, segurança e tolerabilidade, combinado com os resultados de outros estudos, são animadores para a condução de um estudo clínico com doses múltiplas em pacientes com câncer de pulmão que foram submetidos a tratamento cirúrgico, seguindo as diretrizes do Cancer Vaccine Clinical Trial Working Group<br>Abstract: Overall therapeutic outcomes of advanced non-small-cell lung cancer (NSCLC) are poor. The dendritic cell (DC) immunotherapy has been developed as a new strategy for the treatment of lung cancer. The purpose of this study was to evaluate the feasibility, safety and immunologic responses in use in mature, antigen-pulsed autologous DC vaccine in NSCLC patients. Five HLA-A2 patients with inoperable stage III or IV NSCLC were selected to receive two doses of 5x107 DC cells administered subcutaneous and intravenously two times at two week intervals. The safety, tolerability and immunologic and tumor responses to the vaccine were evaluated by the clinical and laboratorial evolution, lymphoproliferation assay and RECIST's criteria, respectively. The dose of the vaccine has shown to be safe and well tolerated. The lymphoproliferation assay showed an improvement in the specific immune response after the immunization, with a significant response after the second dose (p = 0.001). This response was not long lasting and a tendency to reduction two weeks after the second dose of the vaccine was observed. Two patients had a survival almost twice greater than the expected average and were the only ones that expressed HER-2 and CEA together. Despite the small sample size, the results on the survival time, immune response, and safety and tolerability, combined with the results of other studies, are encouraging to the conduction of a large clinical trial with multiples doses in patients with early lung cancer who underwent surgical treatment, following the guidelines of the Cancer Vaccine Clinical Trial Working Group<br>Doutorado<br>Clinica Medica<br>Doutor em Ciências
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Cerf-Bensussan, Nadine. "Etude des lymphocytes intraepitheliaux de l'intestin chez l'homme et le rat." Paris 7, 1987. http://www.theses.fr/1987PA077045.
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"Loss of LKB1 Leads to Alteration of the Immune Microenvironment in Non-Small Cell Lung Cancer." Master's thesis, 2015. http://hdl.handle.net/2286/R.I.29807.
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abstract: The majority of non-small cell lung cancer (NSCLC) patients (70%) are diagnosed with adenocarcinoma versus other histological subtypes. These patients often present with advanced, metastatic disease and frequently relapse after treatment. The tumor suppressor, Liver Kinase B1, is frequently inactivated in adenocarcinomas and loss of function is associated with a highly aggressive, metastatic tumor (1). Identification of the mechanisms deregulated with LKB1 inactivation could yield targeted therapeutic options for adenocarcinoma patients. Re-purposing the immune system to support tumor growth and aid in metastasis has been shown to be a feature in cancer progression (2). Tumor associated macrophages (TAMs) differentiate from monocytes, which are recruited to the tumor microenvironment via secretion of chemotaxic factors by cancer cells. We find that NSCLC cells deficient in LKB1 display increased secretion of C-C motif ligand 2 (CCL2), a chemokine involved in monocyte recruitment. To elucidate the molecular pathway regulating CCL2 up-regulation, we investigated inhibitors of substrates downstream of LKB1 signaling in A549, H23, H2030 and H838 cell lines. Noticeably, BAY-11-7082 (NF-κB inhibitor) reduced CCL2 secretion by an average 92%. We further demonstrate that a CCR2 antagonist and neutralizing CCL2 antibody substantially reduce monocyte migration to NSCLC (H23) cell line conditioned media. Using an in vivo model of NSCLC, we find that LKB1 deleted tumors demonstrate a discernible increase in CCL2 levels compared to normal lung. Moreover, tumors display an increase in the M2:M1 macrophage ratio and increase in tumor associated neutrophil (TAN) infiltrate compared to normal lung. This M2 shift was significantly reduced in mice treated with anti-CCL2 or a CCR2 antagonist and the TAN infiltrate was significantly reduced with the CCR2 antagonist. These data suggest that deregulation of the CCL2/CCR2 signaling axis could play a role in cancer progression in LKB1 deficient tumors.<br>Dissertation/Thesis<br>Masters Thesis Biology 2015
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Shaheen, Tanzia. "Screening lead small molecules for cytokine induction in a human whole blood assay informs candidate adjuvant selection." Thesis, 2018. https://hdl.handle.net/2144/31282.
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BACKGROUND: The human immune system is comprised of various cells that function to fight infection while also avoiding harmful inflammatory and autoimmune responses. The immune system consists of the innate and adaptive immune responses. While the adaptive immune response is involved in the late phase of infection and plays a role in generating classic T and B-cell based immunological memory, the innate immune response is the first line of defense and plays a role in early recognition of foreign substances and induction of an inflammatory response. Although the innate immune response is a natural and inborn response, it varies with age. Human newborns in particular are immunologically distinct due to their polarized T helper type 2 (Th2) cell response and increased anti-inflammatory cytokine production. While these adaptations protect the fetus from rejection by the mother, they lead to increased susceptibility of newborns to infection. While immunization is the most promising strategy to combat this increased susceptibility of newborns, the responses of newborns to different vaccines are impaired as a result of their functionally distinct immune system. For this reason, there have been efforts to develop and incorporate adjuvants into vaccines in order to enhance the immune response of newborns and young infants, who suffer the greatest burden of infectious diseases.
OBJECTIVE: The objective of this thesis is to determine which compound(s) in a small molecule library (compound 037 family) that had been identified based on a high throughput TNF-α screen of human primary mononuclear cells activates immune cells and has the potential to act as effective vaccine adjuvants.
METHODS: Human cord blood was collected from 7 healthy term newborns after Cesarean section and peripheral blood was collected from the arms of 15 healthy adult volunteers between the ages of 18 and 60. The blood was processed and the compounds of the small molecule library were tested via whole blood assays and enzyme-linked immunosorbent assays (ELISAs) to measure production of pro-inflammatory cytokines, specifically tumor necrosis factor (TNF) and interleukin-1β (IL-1β). The responses of the compounds were further characterized by measuring additional cytokines and chemokines via a 41-plex cytokine multiplex assay.
RESULTS: It was determined that at the top two concentrations that were tested (3.7 μM and 11.0 μM), certain compounds of the 037 family induced TNF and IL-1β production comparable to that produced by R848, an already established adjuvant. The compounds with the most activity depended on which cytokine was being produced as well as the age group (newborn vs. adult). Results of the 41-plex cytokine multiplex showed that while there is no clear indication of which group of cytokines are produced after stimulation with these compounds, there was increased production of certain chemokines, especially in adults.
CONCLUSIONS: The difference in activity of the compounds in the 037 family suggests that the functional groups might play a role in enhancing activity of certain compounds. The increased production of chemokines after stimulation with these compounds suggests that the compounds might activate pathways different from TLR7/8 but still results in an inflammatory response. More work needs to be done in order to identify the receptors and pathways that these compounds activate.
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Masjedi, Mohsen. "Physiological inflammation of the small intestine during weaning in the rat / by Mohsen Masjedi." Thesis, 1998. http://hdl.handle.net/2440/19349.
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Erratum is pasted onto back end-paper.<br>Bibliography: leaves 164-207.<br>xvii, 207, [26] leaves, [23] leaves of plates : ill. (chiefly col.) ; 30 cm.<br>Explores the hypothesis that physiological inflammation in the small intestine and the mesenteric lymph node is upregulated during the weaning period. Aims to determine changes in the number, phenotype, and activation status (using interleukin-2 receptor expression) of intraepithelial lymphocytes, lamina propria lymphocytes, mucosal mast cells, and mesenteric lymph node cells from preweaning to post weaning rats.<br>Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1998
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Thompson, Fiona Marie. "Activation of the mucosal immune system and growth of the small intestine at weaning / by Fiona Marie Thompson." Thesis, 1994. http://hdl.handle.net/2440/21494.
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Contains errata sheet in back pocket.<br>Bibliography: leaves 167-211.<br>xviii, 211, [8] leaves, [4] leaves of plates : ill. (some col.) ; 30 cm.<br>Explores the hypothesis that growth of the small intestine at weaning is promoted by an activated mucosal immune system in the gut. Tests by observing rats, guinea pigs and human infants.<br>Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1995?
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"Distribution and frequency of myeloid and t cell populations in the small intestine of newborn and weaned calves." Thesis, 2011. http://hdl.handle.net/10388/etd-07282011-105745.
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The development of mucosal dendritic cells (DCs) in cattle is poorly understood and an
analysis of myeloid cells in the bovine small intestine is required to increase our knowledge in this area. The phenotype, frequency and distribution of mucosal myeloid and lymphoid lamina propria leukocytes (LPL) and intraepithelial leukocytes (IEL) in the ileum and jejunum of newborn calves (3-5 weeks old) were analyzed using flow cytometry and immunohistochemistry (IHC). LPL and IEL were isolated through the use of chemical and enzymatic incubations. Costaining with a CD45-specific monoclonal antibody allowed us to exclude all non-leukocytic cells from our analysis of IEL and LPL. The morphology of CD45+CD11c+MHC Class II+ cells isolated from the lamina propria (LP) of ileum and jejunum showed myeloid characteristics, validating the use of CD11c and MHC Class II co-expression to identify myeloid cells.
Regional differences in the frequency and number of leukocytes isolated from the IEL and LP compartments of the ileum and jejunum were analyzed in newborn calves. The CD11cHiCD14+ and CD335+ NK cell populations were significantly more abundant in the ileum than the jejunum. IHC was then used to identify the distribution of myeloid cells within the intestine. This analysis confirmed the presence of a variety of myeloid cell populations within the LP. Furthermore, CD11c+ cells were uniquely distributed within the jejunal, but not the ileal
IEL compartment. In contrast, CD11b+ cells were present in the ileal, but absent from the jejunal, IEL compartment. A comparison of myeloid cell populations isolated from jejunum and blood dentified distinct mucosal DC populations, such as CD11c+CD13+ cells, which were present in he jejunum but absent from blood.
The phenotype, frequency and distribution of IEL and LPL in the ileum and jejunum of weaned calves (6 months old) were then investigated. Significant regional differences were observed when comparing mucosal T cell populations with CD8+ and γδ T cells more abundant in the ileum and CD4+ T cells more abundant in the jejunum. Proportionally, there were no significant differences between the frequency and number of myeloid populations in the two regions. IHC was, once again, used to confirm these unique distributions of cells within each region. CD11b+ cells were present in the LP of both the ileum and jejunum, although a small number of CD11b+ cells were found in the ileal epithelium. CD4+ T cells were restricted to the LP, while CD8+ and γδ T cells were restricted to the IEL compartment.
Significant age-related changes were observed when comparing mucosal leukocyte populations in the ileum and jejunum of newborn and 6 month old calves. In the ileum there was an age-related enrichment of CD8+ and γδ T cells, while in the jejunum there was enrichment in CD4+ and CD8+ T cells. In contrast, total myeloid (CD11c+MHC Class II+) cells number remained unchanged but there was a significant age-related enrichment of DC subpopulations (CD13, CD26, CD205).
In conclusion, the ileum and jejunum of the newborn calf was populated by diverse myeloid subpopulations, some of which were distinct from myeloid subpopualtions identified in blood. Furthermore, the total number of CD11cHiMHC Class II+ myeloid cells isolated from a 10
cm segment of intestine did not change with age. If neonatal DCs are functionally equivalent to
DCs present in weaned calves then the neonatal mucosal immune system appears to have an equivalent capacity to acquire and present antigens acquired from diet, commensal microflora, or pathogens. The one limitation to this conclusion may be the marked difference in the distribution of intraepithelial DC and macrophage distribution when comparing newborn and weaned calves.
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Katsman, Yulia. "Improved Mouse Models for the Study of Treatment Modalities using Sulfur-containing Small-molecular-Weight Molecules for Passive Immune-mediated Thrombocytopenia." Thesis, 2009. http://hdl.handle.net/1807/18786.
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Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by
autoantibody-mediated platelet destruction. To test the efficacy of novel sulfur compounds as
alternative treatments for ITP, we used a mouse model of passive immune thrombocytopenia
(PIT). Using this model, the platelet nadir could not be maintained, with platelet counts rising
after day 4, despite daily anti-platelet antibody administration. We examined reticulated platelet
counts by flow cytometry, and found increased thrombopoiesis in the bone marrow to be at least
partially responsible for this platelet rebound. Consequentially, two improved mouse models of
PIT were developed, where the platelet rebound is circumvented. The first model employs sublethal
total body gamma-irradiation in combination with daily antibody administration, while the
second model employs gradual escalation of the daily antibody dose. Finally, we show that none
of the tested candidate compounds show efficacy in elevating platelet counts in vivo, likely due
to their limited solubility.
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(8623374), Shishir Poudyal. "A COMBINED GENETIC AND CHIMERIC ANALYSIS OF THE FLAVIVIRAL NON-STRUCTURAL PROTEINS." Thesis, 2020.
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<p>A successful flaviviral life cycle involves several coordinated events between viral proteins and host factors. The polyprotein processing at the surface of the ER membrane results in the formation of several replication proteins that bring about changes in the ER membrane making it permissive for viral genome amplification. Non-structural proteins 4A (NS4A) and non-structural protein 4B (NS4B) are two of the most important integral membrane proteins of DENV that are essential part of the viral replicase complex. The cleavage at NS4A-2K-NS4B is temporally and spatially regulated. The cleavage at the N-terminal of 2K is carried out by viral NS2B/3 protease while host signalase cleaves on the C-terminal side at the ER lumen to give rise to a mature NS4B protein. This thesis primarily focuses on demonstrating the function of 2K as an independent peptide rather than simply a signal sequence, and the role 2K plays, when present as 2K-NS4B vs NS4B. Moreover, this thesis has attempted to explore the function of transmembrane domains (TMDs) in replication separating them from their membrane anchor function. This thesis will also describe the development of a ZIKV replicon and its use in screening small molecule inhibitors in the last chapter.</p><p>In Chapter 2 of the thesis, we established 2K as an independent, information carrying peptide rather than just a signal peptide. A strategy involving chimeric virus generation and mutational analysis supported the notion that 2K is rather unique and important for viral replication and infectious particle production. Using an interserotypic 2K chimeric virus, it was established that the 2Ks of DENV are serotype specific, however, they are interchangeable with a huge fitness cost in infectious particle production. We further showed that individual amino acid residues towards then end of h-region and C-terminus of the 2K peptide affect viral replication and infectious particle production. Moreover, it was shown that the 2K peptide consists of a highly conserved ‘DNQL’ region at its N-terminal that plays an important role in viral replication.</p><p>Chapter 3 details the mechanistic aspect of the effects observed in interserotypic 2K chimeric viruses. The interserotypic chimeric viruses were comparable to wild type in replication, however, they were deficient in infectious particle production early in the life cycle. The major change to be noted in the chimeric viruses was the absence of signalase cleavage at the 2K-NS4B junction. We demonstrated that in a virus infected system, 2K-NS4B and NS4B populations are always present which led us to look for any specific functions of the cleaved vs uncleaved 2K-NS4B protein. Using a transcomplementation system where NS4B was presented in the absence of 2K, we showed that particle production can be rescued in the interserotypic 2K chimeric viruses. It was further concluded using NS4B truncations that the property of NS4B to rescue particle production was concentrated in the ER luminal loop. Further, alanine scanning mutagenesis of the conserved residues of ER loop resulted in pinpointing T198 and its involvement in the early stages of viral packaging.</p><p>Chapter 4 examined the role of TMDs of NS4A and NS4B and attempted to define their roles separately from their membrane anchoring functions. Several interserotypic TMD chimeric viruses were generated to address the function of these domains. We concluded that TMD1 and TMD3 of NS4A could be replaced with partial success across the DENV serotypes, whereas, TMD2 was serotype specific. The specificity of TMD2 of NS4A is not contributed by a single amino acid and should be a function of the secondary structure formed by TMD2 as it sits on the inner leaflet of the ER membrane. We demonstrated the variable roles different TMDs of NS4B play in viral replication using a similar strategy of reverse genetics of chimeric viruses. TMD1 of NS4B was replaceable with no to minimal effect, whereas, the remaining four showed variable effect upon substitution. More importantly, we demonstrated how the reorientation of TMD5 of NS4B post NS2B/3 cleavage might vary in different serotypes of DENV using revertant virus obtained from the TMD5 interserotypic chimera. Analysis of interserotypic cytosolic and ER luminal loop chimeras of NS4B pointed to functional conservation of the cytosolic loop between DENV-2 and DENV-3, whereas, the remaining cytosolic loops and the ER loops showed variable level of defects upon substitution, suggesting their functions in serotype-dependent manner.</p><p>Chapter 5 describes the construction and characterization of a ZIKV replicon system and use of it to screen several small molecule inhibitors of the flaviviruses MTase. Several small molecule inhibitors of flavivirus N-7-MTase were designed/synthesized in Dr. Arun K Ghosh’s lab which would target the extra pocket unique to the flavivirus SAM-binding site. We analyzed the docking of a set of these compounds into MTase domain of NS5 of ZIKV, DENV and YFV and screened them for their ability to inhibit replication of ZIKV, DENV and YFV. A huge variation in the activity profile of these compounds were observed against different flaviviruses even though these compounds were targeted against the highly conserved MTase domain of flavivirus NS5. GRL-002- and GRL-004-16-MT specifically inhibited ZIKV replication with low micromolar IC<sub>50</sub> value, while these compounds showed little to no effect on DENV and YFV.<b> </b>On the other hand, compounds GRL-007-, GRL-0012- and GRL-0015-16-MT demonstrated a dual inhibitory effect against DENV and YFV albeit the CC<sub>50</sub> values of the GRL-012 and GRL-015 were concerning. Compounds GRL-007-16-MT showed broad spectrum activity against ZIKV, DENV and YFV even though it was slightly cytotoxic to Vero cells. Moreover, GRL-002-16 was inhibitory to YFV while ineffective against DENV, whereas, GRL-016-16 had the opposite effect. Our results reveal the differential efficacies of the small molecule inhibitors targeting N-7-MTase. The experimental data suggests these compounds have different cytotoxicities in different cell lines and the compounds act in a virus-specific way. Nonetheless, we were able to shortlist some potent compounds for future modifications.</p>
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Lemmey, Andrew Bruce. "Effects of insulin-like growth factors (IGFS) on recovery from gut resection in rats : a thesis submitted to the University of Adelaide, South Australia for the degree of Doctor of Philosophy / by Andrew Bruce Lemmey." 1992. http://hdl.handle.net/2440/21638.
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xxiii, 222 leaves : ill., plates ; 30 cm.<br>Title page, contents and abstract only. The complete thesis in print form is available from the University Library.<br>Shows that IGF-I peptides are effective in diminishing post-surgical catabolism and enhancing adaptive gut hyperplasia in rats recovering from massive small bowel resection.<br>Thesis (Ph.D.)--University of Adelaide, Dept. of Animal Science, 1992
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Cherukommu, Shirisha. "Role of GSK-3 and T-bet in anti-tumor immunity." Thesis, 2021. http://hdl.handle.net/1866/25645.
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Le facteur de transcription T-bet joue un rôle central dans la régulation de la différenciation des lymphocytes T. La protéine tyrosine kinase, la glycogène synthase kinase 3 (GSK-3), inhibe l'activation des lymphocytes T et contrôle l'expression de leurs récepteurs inhibiteurs PD-1 et LAG- 3. Bien que l'inhibition de GSK-3 puisse augmenter l'expression de T-bet, l'interrelation entre T-bet et GSK-3 dans l'immunité tumorale est inconnue. Dans cette étude, nous montrons que les souris knock-out T-bet (Tbet - / -) sont compromises dans leur capacité à contrôler la croissance des cellules tumorales du mélanome B16. Cependant, l'injection d'une petite molécule inhibitrice (SMI) de GSK-3 inverse cette condition compromise entraînant le contrôle de la croissance tumorale similaire à celle observée chez les souris de type sauvage. Un examen de Tbet - / - a montré une perte de cellules dendritiques (DC) et de cellules leucocytes polymorphonucléaires (PMN) potentiellement suppressives et de lymphocytes tumoraux T (TILs) CD4 + accompagnée d'une augmentation de cellules T CD8 +. L'analyse viSNE (avancé tSNE) a en outre montré une réduction de la population effectrice expérimentée à l'antigène dans les TILs CD8 + chez Tbet -/-. Cette population est marquée par la réduction de CD44. L'inhibition de GSK-3 n'a montré aucun effet sur la perte de DC, TILs CD4 +, PMN et les TILs CD8 + ainsi que l’expression de Granzyme B (GZMB) sur les cellules T CD8 +. La seule exception était une augmentation mineure néanmoins statistiquement significative du facteur de transcription Eomesdermin (Eomes) dans les TILs CD8 +. L'étude démontre un effet compensatoire inattendu de l'inhibition de GSK-3 sur la perte de T-bet. Il reste à élucider la nature complète du parcours de cette compensation.<br>The transcription factor T-bet plays a central role in regulating T-cell differentiation, while the protein tyrosine kinase, glycogen synthase kinase 3 (GSK-3) inhibits T-cell activation and controls the expression of inhibitory receptors PD-1 and LAG-3 on T-cells. Although GSK-3 inhibition can increase T-bet expression, the inter-relationship between T-bet and GSK-3 in tumor immunity is unknown. In this study, we show that T-bet knock-out (Tbet-/-) mice are compromised in their ability to control the growth of the B16 melanoma tumor cells. However, the injection of a small molecule inhibitor (SMI) of GSK-3 reverses this compromised condition resulting in the control of tumor growth similar to that seen in wild type mice. An examination of Tbet-/- showed a loss of dendritic cells (DC) and potentially suppressive polymorphonuclear leucocytes (PMN) and CD4+ cell tumor infiltrating lymphocytes (TILs) accompanied by an increase in CD8+ cells. viSNE analysis (advanced tSNE- t-Distributed Stochastic Neighbor Embedding) further showed a reduction of antigen experienced effector marker CD44 in CD8+ TILs in Tbet-/-. GSK-3 inhibition showed no effect on the loss of DCs, CD4+ TILs or the presence of PMNs or CD8+ T-cells or the loss of Granzyme B (GZMB) on CD8+ cells. The one exception was a minor but statistically significant increase in the transcription factor Eomesodermin (Eomes) in CD8+ TILs. The study demonstrates an unexpected compensatory effect of GSK-3 inhibition on the loss of T-bet. The full nature of the pathway that accounts for this compensation remains to be elucidated.
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Mwanthi, Muithi. "PAK1's regulation of eosinophil migration and implications for asthmatic inflammation." Thesis, 2013. http://hdl.handle.net/1805/3786.
Texto completoResumen
Indiana University-Purdue University Indianapolis (IUPUI)<br>More than 300 million people world-wide suffer from breathlessness, wheezing, chest tightness, and coughing characteristic of chronic bronchial asthma, the global incidence of which is on the rise. Allergen-sensitization and challenge elicits pulmonary expression of chemoattractants that promote a chronic eosinophil-rich infiltrate. Eosinophils are increasingly recognized as important myeloid effectors in chronic inflammation characteristic of asthma, although few eosinophil molecular signaling pathways have successfully been targeted in asthma therapy. p21 activated kinases (PAKs), members of the Ste-20 family of serine/threonine kinases, act as molecular switches in cytoskeletal-dependent processes involved in cellular motility. We hypothesized that PAK1 modulated eosinophil infiltration in an allergic airway disease (AAD) murine model. In this model, Pak1 deficient mice developed reduced inflammatory AAD responses in vivo with notable decreases in eosinophil infiltration in the lungs and broncho-alveolar lavage fluids (BALF). To test the importance of PAK1 in hematopoietic cells in AAD we used complementary bone marrow transplant experiments that demonstrated decreased eosinophil inflammation in hosts transplanted with Pak1 deficient bone marrow. In in vitro studies, we show that eotaxin-signaling through PAK1 facilitated eotaxin-mediated eosinophil migration. Ablating PAK1 expression by genetic deletion in hematopoietic progenitors or siRNA treatment in derived human eosinophils impaired eotaxin-mediated eosinophil migration, while ectopic PAK1 expression promoted this migration. Together these data suggest a key role for PAK1 in the development of atopic eosinophil inflammation and eotaxin-mediated eosinophil migration.