Tesis sobre el tema "Human-relevant"
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Stokes, Mark Geoffrey. "Task-relevant neural representations within the human brain". Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612317.
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Polischouk, Anya. "Molecular factors relevant to the radiosensitivity of human tumours /". Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-508-5.
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Tsai, Yu-Huan. "Investigating human neurolisteriosis with relevant host and bacterial partners". Paris 7, 2014. http://www.theses.fr/2014PA077232.
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Listeria mononocytogenes (Lm) est une bactérie pathogène qui traverse la barrière intestinale grâce à l'interaction entre sa protéine de surface InIA et la E-cadhérine (Ecad), pour disséminer dans l'hôte et induire la listériose. Lm peut également traverser la barrière hérnato-encéphalique et induire une neurolistériose, par un mécanisme encore inconnu. L'interaction InIA-Ecad est spécifique d'espèce, InIA ne reconnait pas la Ecad de souris mais interagit avec la Ecad humaine ainsi que la Ecad humanisée exprimée par des souris génétiquement modifiées générées au laboratoire. InlA a également été "murinisée" (InlAm) afin d'interagir avec la Ecad de souris. Nous avons montré qu'InlAm reconnait non seulement la Ecad murine, mais également, contrairement à In1A, la N-cadhérine (Ncad). Cette interaction InlAm-Ncad artéfactuelle induit la translocation de la bactérie à travers les cellules M villositaires, et s'accompagne d'une inflammation intestinale et de lésions de la barrière intestinale qui ne sont pas observées chez l'homme et les souris exprimant une Ecad humanisée. Nous avons utilisé le modèle de souris humanisées pour étudier la neurolistériose. Dans ce modèle, nous avons montré que les souches cliniques issus des complexes clonaux les plus associés aux cas de neurolistériose humaine sont plus virulents et induisent plus efficacement une neurolistériose que les souches d'autres complexes clonaux et que les souches de référence, non représentatives des souches cliniques. Grâce à l'utilisation combinée des souris humanisées et des souches cliniques appropriées, nous pouvons aujourd'hui étudier la pathogenèse de la neurolistériose après infection par voie orale et déterminer les mécanismes sous-jacentsListeria monocytogenes (Lm) is a bacterial foodbome pathogen that crosses the intestinal barrier via the interaction of its surface protein InIA with its receptor E-cadherin (Ecad), and disseminate within the host to induce listeriosis. Lm can cross the placental barrier in pregnant women resulting in abortion and fetal infection, and cross the blood-CNS barrier to cause neurolisteriosis via a so far unknown mechanism. InIA-Ecad interaction is species-specific, does not occur in wild-type (wt) mice, but does in humanized mice expressing humanized mouse Ecad. InIA has also been "murinized" (InlAm) to interact with mouse Ecad in wt mice. We have shown that InlAm not only interacts with mouse Ecad, but also uses N-cadherin (Ncad) as a receptor, whereas InIA does not. This unanticipated and artifactual InlAm-Ncad interaction promotes bacterial translocation across villous M cells, accompanying with intestinal inflammation and intestinal barrier damage, ail of which are not seen in humans and humanized mouse models permissive to In1A-Ecad interaction. The widely used reference strains are not representative of clinical isolates, based on MLST, a sequence-based typing method. We have shown in a humanized mouse model of listeriosis developed in the laboratory, that the isolates originating from the most prevalent clones responsible for human neurolisteriosis are more virulent and induce far more efficiently neurolisteriosis than isolates from other clonai complexes and reference strains. By use of the humanized mouse model and relevant human CNS isolates, we are investigating the pathogenesis of orally acquired neurolisteriosis, and deciphering the underlying mechanisms of neurolisteriosis
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Abdelmouti, Mai Mohamed Medhat Abdelhalim. "Engineering a genetically relevant zebrafish model of human uveal melanoma". Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/engineering-a-genetically-relevant-zebrafish-model-of-human-uveal-melanoma(6bc6f02b-8d80-4e6e-bc5b-72fab73b0788).html.
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Uveal melanoma (UM) is a sight and life-threatening malignancy of the human eye. The potential for progress in translational UM research is, however, hampered by the short supply of clinical samples due to its rarity and also the lack of an informative animal model which would allow experimental intervention to dissect the molecular machinery governing tumor development. Towards this end, we aimed to generate a genetically relevant model of human UM in zebrafish that can be used to study the roles of key genetic determinants in tumor initiation and progression in vivo and also establish a valuable resource for future preclinical studies. Given the pervasive role of Gαq proteins in driving UM pathogenesis, we engineered transgenic zebrafish to express oncogenic GNAQQ209P in the melanocyte lineage. This resulted in hyperplasia of uveal (choroidal) melanocytes, but with no evidence of malignant progression nor perturbation of RPE or skin melanocytes. However, combining expression of oncogenic GNAQQ209P with tp53 inactivation resulted in an earlier onset and even more extensive hyperplasia of choroidal melanocytes that then progressed to UM. While NRASQ61L and BRAFV600E potently stimulate ERK1/2-MAPK signalling pathway, immunohistochemical analysis revealed only sporadic immunoreactivity to phosphorylated ERK1/2 in hyperplastic choroidal lesions and also uveal tumors driven by oncogenic GNAQQ209P, in contrast to an abundant immunoreactivity in oncogenic HRASG12V-driven cutaneous tumors. Rather, ubiquitous positive staining for nuclear YAP was observed in GNAQQ209P-driven uveal tumor specimens. In keeping with a lesser role of GNAQ in regulating ERK1/2-MAPK signalling in UM, we showed that downregulation of oncogenic GNAQQ209P/L or inhibition of PLC-β in the majority of human UM cells expressing oncogenic GNAQQ209P/L barely affected ERK phosphorylation. In summary, this study demonstrates the insufficiency of oncogenic GNAQQ209P alone in driving UM development which only became evident with a second genetic hit involving tp53 inactivation. Our findings also demonstrate a weak correlation between oncogenic GNAQ mutations and sustained ERK1/2-MAPK activation, implying that ERK1/2 signalling is unlikely to be instrumental in the maintenance of GNAQQ209P-driven uveal tumors.
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Mant, Christine Andrea. "Background studies relevant to human papillomavirus type 16 vaccine development". Thesis, King's College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408673.
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Arber, Charles. "Generation of disease-relevant neurons from human pluripotent stem cells". Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/14670.
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This thesis describes investigations into exogenous factors that influence fate-choices during human pluripotent stem cell (PSC) differentiation in vitro. I describe novel growth factor environments and small molecule regimes that provide patterning signals enabling directed differentiation of human PSCs towards biomedically relevant neurons. I provide evidence that the TGFβ growth factor Activin can promote ventral telencephalic differentiation. Small adjustments in Activin administration can produce an over-representation of forebrain derived medium spiny neurons and cortical interneurons, with significance in Huntington’s disease and epilepsy respectively. Additionally, I manipulate the earliest growth factor environments of PSC differentiation to lead to broad changes in rostro-caudal patterning. Inhibiting FGF signalling leads to a midbrain-like phenotype that can be further differentiated towards a ventral midbrain dopaminergic fate, a cell type that degenerates in Parkinson’s disease. Our novel manipulations and differentiation protocols provide insights into early events in human development, which would otherwise be impossible to study. This logic can also be applied to investigate diseased states during human development and ageing via use of disease-specific cell lines. The mature neurons produced may provide a tool that can be applied to large-scale drug screening assays and toxicology testing as well as having the potential for cell based therapies in future years.
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Fuchs, Talia Leah. "Investigation and Implementation of Clinically Relevant Prognostic Biomarkers in Human Malignancies". Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/27973.
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The discovery and validation of prognostic biomarkers is a central focus of current medical research that underpins the practice of personalised medicine. In the field of surgical pathology, there is ample opportunity to identify histomorphological variables that can help guide therapeutic decision making. This thesis explores several novel pathological biomarkers in various malignancies, with the aim of translating knowledge gained at the basic science level into techniques applicable to routine diagnostic surgical pathology practice.
This thesis is broadly divided into four parts, each of which explores a novel prognostic tool through one or more studies published in peer-reviewed international pathology journals. First, the role of tumour infiltrating lymphocytes as a prognostic biomarker is examined in the contexts of colorectal carcinoma, triple negative breast carcinoma, and mesothelioma.
The second part of this thesis explores various prognostic factors in medullary thyroid carcinoma and proposes a novel histopathological grading scheme for predicting overall survival that can be easily implemented in routine surgical pathology practice.
The third part of the thesis explores existing grading systems for diffuse pleural mesothelioma and proposes a novel grading scheme that overcomes many of the limitations associated with other proposed systems.
The final chapter of this thesis examines a comprehensive range of prognostic markers in colorectal carcinoma to develop a novel prognostic tool for predicting five-year overall survival after primary tumour resection. This prognostic nomogram was constructed and validated using a large cohort of patients with detailed clinicopathological data, is user-friendly, and can be easily accessed online.
Each of these topics represents a practical application of our improved understanding of the mechanisms of tumour progression, with the aim of providing more detailed prognostic and predictive information to treating clinicians.
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Wagner, Andreas [Verfasser]. "Identification of process-relevant kinases in human amniotic production cells / Andreas Wagner". Ulm : Universität Ulm, 2019. http://d-nb.info/1192823958/34.
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Haas, Simone [Verfasser], Anton [Akademischer Betreuer] Cathomen y Stephan [Akademischer Betreuer] Ehl. "Tracing the specificity of CRISPR-Cas nucleases in clinically relevant human cells". Freiburg : Universität, 2019. http://nbn-resolving.de/urn:nbn:de:bsz:25-freidok-1514002.
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Haas, Simone Alexandra [Verfasser], Anton [Akademischer Betreuer] Cathomen y Stephan [Akademischer Betreuer] Ehl. "Tracing the specificity of CRISPR-Cas nucleases in clinically relevant human cells". Freiburg : Universität, 2019. http://d-nb.info/1233965611/34.
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Langenbrunner, Mary R. y Jamie Branam Kridler. "The Challenge of On-Line Human Services Courses: Keeping it Real and Relevant". Digital Commons @ East Tennessee State University, 2011. https://dc.etsu.edu/etsu-works/3481.
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Wu, Celina. "Dual agonist-antagonist functions of FTY720 influence neuroinflammation-relevant responses in human astrocytes". Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=110720.
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Astrocytes are the most abundant glia in the central nervous system (CNS), classically identified by their high expression of the intermediate filament, glial fibrillary acidic protein (GFAP). Astrocytes participate in a number of biochemical events important for CNS functions and play a dynamic role in regulating CNS injury/repair processes. In chronic inflammatory conditions such as multiple sclerosis (MS), astrocytes undergo pathophysiological changes that lead to a feature termed astrogliosis (Liberto, Albrecht et al. 2004; Sidoryk-Wegrzynowicz, Wegrzynowicz et al. 2011). Astrogliosis is common to MS lesions, and a novel therapeutic agent for MS, FTY720 (fingolimod, Gilenya™) demonstrates neuroprotective potential by inhibiting astrogliosis development (Choi, Gardell et al. 2011). FTY720 is an oral therapy recently approved for the treatment of MS, and is shown to readily access the CNS. There, it binds directly to sphingosine-1-phosphate receptors (S1PR) on astrocytes and the dynamics of S1PR signaling is shown to modulate astrocytic cellular responses that closely relate to MS pathology. This thesis examines the signaling and functional effects of FTY720 on primary human astrocytes. We used astrocytes derived from the human fetal CNS to explore neuroinflammation-relevant responses mediated by chronic (repeated daily) FTY720 administrations. FTY720 is known to initially acts as an agonist, activating S1PRs but also functions as an antagonist by promoting S1PR internalization and degradation; we examined whether these effects occurred in tandem. We report that receptors internalized by FTY720 can persist and continue to signal for an extended time period (hours). A single addition of FTY720 desensitizes the extracellular receptor-regulated phosphorylation (pERK) signaling response for >24 hours. Such refractory period for pERK signal transduction was maintained in astrocytes treated repeatedly (daily) with FTY720, otherwise the return of pERK activation was achieved by 72 hours following initial treatment. Moreover, receptor desensitization patterns correlated with the loss of proliferative responses induced by the natural ligand sphingosine-1-phosphate (S1P). We show that even under the condition of receptor desensitization (repeated daily administrations) FTY720 attenuated the capacity of the pro-inflammatory cytokine IL-1β, to activate calcium sensitive pathways. Repeated FTY720 treatments did not inhibit serum-induced pERK responses or the secretions of IL-6 and IP-10 in response to IL-1β activation. Our results indicate that daily FTY720 exposures can be a relevant regulator of neuro-inflammation by acting as a functional antagonist for external stimuli (natural ligand S1P) while sustaining internalized receptor-dependent agonist functions (inhibit IL-1β induced calcium mobilization).Les astrocytes sont les cellules gliales les plus abondantes du système nerveux central (SNC). Leur grande expression en filaments intermédiaires, la protéine acide fibrillaire gliale (GFAP), est une caractéristique permettant leur identification. Les astrocytes sont d'importants contributeurs aux événements biochimiques du SNC et jouent un rôle clé dans le processus de régulation des dommages et de la guérison du SNC. Sous des conditions d'inflammation chronique, tel la Sclérose en Plaques (SP), les astrocytes subissent des changements pathophysiologiques causant l'astrogliose (Liberto, Albrecht et al. 2004; Sidoryk-Wegrzynowicz, Wegrzynowicz et al. 2011). Ce mécanisme de cicatrisation est commun dans la SP et un nouvel agent thérapeutique, FTY720 (fingolimod, Gilenya™) démontre des effets protecteurs du SNC en prévenant l'évolution de l'astrogliose. (Choi, Gardell et al. 2011). FTY720 est un agent thérapeutique récemment approuvé pour traiter la SP. Il est administré oralement et a la capacité d'accéder au SNC. Une fois en place dans ce système, cet agent entre en contact direct avec le récepteur sphingosine-1-phosphate (S1PR) sur les astrocytes. Les réponses des astrocytes en réaction aux signaux générés par ce récepteur sont reliées à la pathologie de la SP. Cette thèse examine les signaux engendrés par FTY720 ainsi que ses fonctions sur les astrocytes humains primaires. Nous avons utilisé des astrocytes isolés à partir de SNC humains fœtaux pour examiner les réponses neuro-inflammatoires générées par l'administration quotidienne de FTY720. FTY720 agit initialement comme un agoniste en activant le récepteur S1P, mais il agit également comme un antagoniste en causant l'internalisation et la dégradation de ce récepteur. Nous avons examiné ces deux phénomènes de façon à savoir s'ils agissent en concert. Nous affirmons qu'un récepteur internalisé par FTY720 continue de générer des signaux pour une période de temps prolongée (heures). Une addition simple de FTY720 désensibilise l'astrocyte, pour une période de >24h, au signal de phosphorylation de ERK (pERK) qui est généré par le récepteur extracellulaire. Cette période réfractaire du signal de transduction de pERK fût maintenue dans les astrocytes traités quotidiennement avec FTY720, sinon le signal pERK reparaît 72 heures après le traitement initial. De plus, la désensibilisation du récepteur fût reliée à l'absence de réponse proliférative induite par le ligand naturel sphingosine-1-phosphate (S1P). Nous avons aussi démontré que le traitement quotidien des astrocytes avec FTY720 atténue la capacité de IL-1β à activer les voies moléculaires sensibles au calcium. Le traitement quotidien avec FTY720 n'inhibe pas les signaux de pERK lorsque les astrocytes sont stimulés à l'aide de sérum, ni la sécrétion de IL-6 ou de IP-10 lorsqu'ils sont stimulés avec IL-1β. Nos résultats suggèrent que l'exposition quotidienne à FTY720 agit comme un antagoniste aux stimuli extérieur (tel le ligand naturel S1P) ainsi qu'un agoniste lorsque le récepteur est internalisé (inhibe la mobilisation du calcium lorsqu'exposé à IL-1β).
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Kraus, Emma [Verfasser]. "Identification of small molecule inhibitors of clinically relevant human polyomavirus infections / Emma Kraus". Hamburg : Staats- und Universitätsbibliothek Hamburg Carl von Ossietzky, 2019. http://d-nb.info/1240835515/34.
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Stovall, Olin Scott. "Accounting for Human Resources: Implications for Theory and Practice". Thesis, University of North Texas, 2001. https://digital.library.unt.edu/ark:/67531/metadc3026/.
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Knowledge workers are an important resource for the typical modern business firm, yet financial reporting ignores such resources. Some researchers contend that the accounting profession has stressed reliability in order to make the accounting appear objective. Others concur, noting that accounting is an insecure profession and adopts strict rules when faced with uncertainty. Accountants have promulgated a strict rule to expense human resource costs, although many know that such resources have future benefits. Some researchers suggest that any discipline must modify its language in order to initiate change toward providing useful social ameliorations. If accounting theorists extend this idea to the accounting lexicon.s description of investments in human resources, investors and other accounting user groups might gain greater insight into how a firm fosters and nourishes human capital. I tested three hypotheses related to this issue by administering an experiment designed to assess financial analysts. perceptions about alternative financial statement treatments of human resources in an investment recommendation task. I predicted that (1) analysts' perceptions of the reliability (relevance) of the information they received would decrease (increase) as the treatment of human resources increasingly violated GAAP (became more current-oriented), (2) analysts exposed to alternative accounting treatments would report a lower likelihood of recommending that their clients invest in the company in the task, and (3) financial analysts who ranked reliability (relevance) as a more important information quality would be less (more) likely to recommend that their clients buy the stock represented in the case because the treatment of human resources on the financial statements violated GAAP (was more current-oriented) as compared to analysts who ranked reliability (relevance) as being lower (higher) in importance. Analysts receiving financial statements with accounting treatments of human resource costs that violated GAAP judged such information as less reliable and were also less likely to recommend that their clients buy the stock in the task than analysts receiving financial statements that conformed to GAAP. Also, analysts who perceived reliability as a more important information quality reacted more negatively to a replacement cost approach to accounting for human resources than participants who perceived reliability as being less important. A potential confounding explanation of the results is the varied language used in the audit opinions included with the treatment financial statements. Whether explained by the audit opinion language or the actual differences contained in the financial statements, the results suggest that an important user group, financial analysts, may be subject to the aura of objectivity suggested by Porter in 1995.
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Ayad, Nancy B. "Effects of Antidepressants on Human Mesenchymal Stem Cell Differentiation on Clinically Relevant Titanium Surfaces". VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4477.
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Selective Serotonin Reuptake Inhibitors (SSRIs) are the most frequently prescribed class of drugs worldwide and are implemented in the treatment of depression and other psychiatric disorders. SSRIs relieve depressive symptoms by modulating levels of the neurotransmitter serotonin in the brain. SSRIs block the function of the serotonin transporter, thereby increasing concentrations of extracellular serotonin. However, serotonin levels in the neurons of the brain only account for 5% while the remaining 95% is present outside the brain. Serotonin receptors and transporter are located on bone resident cells (mesenchymal stem cells (MSCs)), osteoblasts and osteoclasts, and serotonergic activity is believed to affect bone homeostasis. Consequently, alterations in serotonin levels by SSRI treatment have the potential to alter bone formation and remodeling. Clinical reports correlate increase risk of bone fractures and delayed bone healing with SSRI use. Metallic implants are commonly used as orthopedic and dental implants to fix bony defects. Surface modifications have been used to increase the level of bone to implant contact by controlling the differentiation of MSCs into an osteoblastic linage and facilitate bone production. However, it is not known if SSRIs can affect MSCs osteoblastic differentiation and bone remodeling signaling in response to microstructured biomaterials. The aims of this study were: 1) Investigate the effects of SSRIs on MSCs differentiation on microstructured titanium (Ti), 2) Determine the effects of SSRIs on bone remodeling signaling and osteoclast activation, and 3) Elucidate the effects of SSRIs on serotonin receptors and their effect on bone remodeling. To investigate this, human MSCs were grown on tissue culture polystyrene (TCPS), smooth Ti (PT) or microstructured Ti (SLA) surfaces under exposure to therapeutic concentrations of commonly prescribed antidepressants (SSRIs (fluoxetine, sertraline, paroxetine), Selective Norepinephrine Reuptake Inhibitor (SNRI) (duloxetine) and other regularly prescribed antidepressants (bupropion)) during differentiation toward osteoblasts. Osteoblastic differentiation was assessed in MSCs after treatment with the drugs (0.1μM, 1μM, 10μM) by alkaline phosphatase activity and osteocalcin levels. Antidepressant treatment decreased levels of MSC differentiation markers on microstructured Ti surfaces. Furthermore, treatment dose-dependently decreased protein levels secreted by MSCs which are important for bone formation (BMP2, VEGF, Osteoprotegerin), and increased those involved in bone resorption (RANKL). To determine the effect of SSRIs on bone remodeling signaling and osteoclast activation, human osteoclasts were either directly exposed to antidepressants or conditioned media obtained from MSCs treated with antidepressants on Ti surfaces, after which, enzymatic tartrate-resistant acid phosphatase (TRAP) activity was assessed. Antidepressants increased TRAP activity both directly and through treated MSCs, with the highest levels evident after treatment with conditioned media from MSCs on microstructured Ti surfaces. To elucidate the effects of serotonin receptors and their effect on bone remodeling, receptors were pharmacologically inhibited. Surface roughness decreased gene expression of HTR2A, HTR1B, and HTR2B, and antidepressant treatment increased their expression. Inhibition of HTR2A decreased RANKL protein levels, while inhibition of other serotonin receptors had no effect on RANKL or OPG levels. These studies suggest that antidepressants inhibit MSCs differentiation on microstructured Ti surfaces and increase levels of proteins associated with bone resorption. Additionally, our results showed that RANKL is regulated by serotonin receptor HTR2A. Taken together, our results suggest that antidepressants have a negative effect on osteoblastic differentiation, compromising bone formation and enhancing bone resorption, which can be detrimental to patients under orthopedic and dental treatment.
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Miranda, Benjamin H. "Development of a novel, clinically-relevant model for investigating factors that stimulate human hair growth". Thesis, University of Bradford, 2011. http://hdl.handle.net/10454/5731.
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Lack of hair due to alopecia or skin grafting procedures causes significant distress due to hair's role in social and sexual communication. Only limited pharmacological agents are currently available to stimulate hair growth; their development is hampered by inappropriate model systems. Most research involves large terminal scalp follicles rather than the clinical targets of tiny vellus or intermediate follicles. The overall aim of this thesis was to develop a novel model system based on intermediate hair follicles. Initially, intermediate follicles from female pre-auricular skin were characterised and compared to matched terminal follicles. Intermediate follicles were smaller, less pigmented, shorter and possessed a more 'tubular' bulb morphology than their more 'bulbous' terminal counterparts. Significant correlations were demonstrated between various hair follicle measurements and corresponding dermal papilla diameters. Isolated terminal follicles grew significantly more than intermediate hair follicles in organ culture for 9 days. Testosterone (10nM), the major regulator of human hair growth, increased only intermediate follicle growth; the anti-androgen, cyproterone acetate (1μM), prevented this stimulation, unlike the 5α-reductase type 2 inhibitor finasteride (40ng/ml). Immunohistochemistry demonstrated androgen receptor and 5α-reductase type 2 proteins in both follicle types, while quantitative real-time PCR and gene microarray analysis detected their increased gene expression in intermediate follicles. Thus, smaller intermediate follicles showed major morphological and gene expression differences to terminal follicles in vivo and retained significant, biologically-relevant differences in vitro in organ culture including androgen-responsiveness. Therefore, intermediate hair follicles offer a novel, exciting, more clinically relevant, albeit technically difficult, model for future investigations into hair growth.
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Srikanth, Priya. "Schizophrenia-Relevant DISC1 Interruption Alters Wnt Signaling and Cell Fate in Human iPSC-Derived Neurons". Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:23845068.
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The advent of human induced pluripotent stem cell (iPSC) technology has allowed for unprecedented investigation into the pathophysiology of human neurological and psychiatric diseases. Use of human iPSC-derived neural cells to study disease is complicated by the genetic heterogeneity of cell lines and diversity of differentiation protocols. Here, I address issues surrounding neuropsychiatric disease modeling with human iPSCs.
Dozens of published protocols exist to differentiate iPSCs into forebrain neuronal cultures. Among the factors that distinguish these methods are: use of small molecules, monolayer vs. aggregate culture, choice of plating substrates, method of NPC isolation, and glial co-culture. Each of these factors is evaluated here, creating a resource that directly compares a variety of differentiation procedures. The most efficient and reproducible method was an embryoid aggregate differentiation protocol, including aggregate plating onto a Matrigel substrate, enzymatic neural rosette selection, and neuronal dissociation and plating onto Matrigel.
This optimized protocol is used to model a schizophrenia-relevant mutation in human neural cells. Genetic and clinical association studies have identified disrupted-in-schizophrenia 1 (DISC1) as a strong candidate risk gene for major mental illness. DISC1 was initially associated with mental illness upon the discovery that its coding sequence is interrupted by a balanced chr(1;11) translocation in a Scottish family, in which the translocation cosegregates with psychiatric disorders. I investigate the functional and biochemical consequences of DISC1 interruption in human neurons using TALENs or CRISPR-Cas9 to introduce DISC1 frameshift mutations into iPSCs. I show that disease-relevant DISC1 targeting results in decreased DISC1 protein expression by nonsense-mediated decay, increases baseline Wnt signaling in neural progenitor cells, and causes a shift in neural cell fate. DISC1-dependent Wnt signaling and cell fate changes can be reversed by antagonizing the Wnt pathway during a critical window in neural progenitor development. These experiments suggest that DISC1-disruption increases Wnt signaling, which alters the balance and identity of neural progenitors, thereby subtly modifying cell fate.
These studies evaluate the use of multiple differentiation procedures in neural disease modeling, shed light on the roles of DISC1 during human brain development, and further our understanding of the pathogenesis of major mental illness.Medical Sciences
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Kong, Meardey. "Culturally Relevant Practices: A Case Study of NGOs Working in Cambodia to Combat Human Trafficking". Thesis, The University of Arizona, 2013. http://hdl.handle.net/10150/297629.
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Since Cambodia’s first democratic election in 1993, the monetary aid from international donors and non-governmental organizations (NGOS) flowing into the country has brought minimal positive outcomes. It has instead created a culture of aid dependency in conjunction with limited accountability and weakened governance. This exploratory case study aims to examine one particular organizational practice in relation to aid effectiveness and dependency - cultural sensitivity and competency or the relevant skills and knowledge each organization possesses to work with their specific population and context. Between June and August of 2012, semistructured interviews were conducted with eight individuals representing three international NGOs, one local NGO, and the Cambodian Royal Government. Questions were designed to gain a better understanding of the (1) responsibility of the Cambodian government in ensuring NGOs are equipped with culturally sensitive background/knowledge, (2) responsibility of the NGOs in ensuring their staffs are equipped with culturally sensitive background/knowledge, and (3) perception of cultural competency of NGOs in serving their beneficiaries. Preliminary findings showed that issues of cultural sensitivity and competency are a low priority among the Cambodian government and NGOs operating in the country, much less evidence of a system in place to address cultural competency in these organizations.
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Al, Tafif Abdullah. "PREDICTION OF HUMAN SYSTEMIC, BIOLOGICALLY RELEVANT PHARMACOKINETIC PROPERTIES BASED ON PHYSICOCHEMICAL PROPERTIES OF CALCIUM CHANNEL BLOCKERS". VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/2868.
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This research explored quantitative relationships (QSPKR) between different molecular descriptors and pertinent, systemic PK properties for 14 calcium channel blockers (CCB). Physicochemical properties (PC) such as molecular weight (MW), molar volume (MV), calculated logP (clogP), pKa, calculated logD7.4 (clogD), % ionized at pH 6.3 and pH 7.4, hydrogen bond donors (HBD), hydrogen bond acceptors (HBA), and number of rotatable bonds (nRot) were chosen as possible predictor variables for systemic PK properties for CCB, obtained from pertinent literature, assessing the PK of CCB after intravenous administration to healthy humans. All PC properties and molecular descriptors were computed using ACD-solubility/DB 12.01. Total body clearance (CLtot), steady-state volume of distribution (Vdss), total area under the plasma concentration-time profile (AUCoo), terminal half-life (t1/2), and fraction of drug excreted unchanged in urine (fe), if available, were obtained or derived from original references, exclusively from IV studies that administered CCB to healthy human volunteers. Several articles focused on drug interactions with grapefruit juice or the impact of renal/hepatic dysfunction, and in such cases, data from the healthy control group were used. Each study was evaluated for study design, PK sampling schedule, bioanalytical and PK analysis methods before inclusion into the final database. The assumption of linear systemic PK was verified by assessing AUCoo versus (IV) dose. Plasma protein binding information was collected from in-vitro experiments to obtain the fraction unbound in plasma (fu). Unbound volume of distribution at a steady state (Vdssu), unbound total (CLtotu), renal (CLrenu), and non-renal clearance (CLnonrenu) were estimated and compared with the relevant physiological references for Vdssu (plasma volume, blood volume, extracellular and intracellular spaces, total body water and body weight) and for the unbound clearances (liver blood flow, renal plasma flow, and glomerular filtration rate, GFR). Final PK property values were obtained by averaging across available studies. The distribution of both PC and PK properties were evaluated, and correlation matrices amongst PC properties were constructed to assess for collinearity. If two PC descriptors were found to be collinear, i.e. r, ≥ 0.8, only one of them was used in the final univariate analysis. Finally, univariate linear regression of all PK variables versus each molecular descriptor was performed; any relationship with p<0.05 and r2≥0.30 was considered to be statistically significant. The PC properties of the final 14 CCB were reasonably normally distributed with few exceptions. Overall, CCBs are small (MW range of 316-496 Da), basic and lipophilic (logD7.4 range of 1.5-5.1) molecules. On the other hand, for the PK properties, the distributions were found to be skewed with high standard deviations. Thus, all PK variables (except fu) were log-transformed. Although CCB are mostly highly plasma protein bound (fu range of 0.2-20%), they are characterized by extensive extravascular tissue distribution (Vdss range of 0.6-20.4 l/kg) and high, mainly metabolic, clearance (CLtot range of 3.7-131.7 ml/min/kg). Clevidipine is the only CCB undergoing extensive, extra-hepatic ester hydrolysis, responsible for the highest CLtot value. Urinary excretion for CCB is negligible. Amlodipine is a PK outlier due to its high Vdss (20.4 l/kg) and low CLtot (6.9 ml/min/kg, due to low hepatic extraction) with fu of 2%. Therefore, the final QSPKR analysis was performed including, as well as excluding amlodipine. Excluding amlodipine, the relationship between fu and logD7.4 was negative and significant (r2 of 0.4, n=12). The relationships between CLtotu, CLnonrenu and CLrenu and logD7.4 were found to be positive and significant (r2 between 0.6-0.7, n=3-12); none of the other PC variables affected any of the clearance terms. Although the relationship between Vdssu and logD7.4 was not significant (r2 of 0.25, n=12), it showed the expected positive slope. In fact, after removing bepridil (the remaining outlier in Vdssu), the relationship with logD7.4 became statistically significant (r2=0.46, n=11). The QSPKR obtained in this study for CCB, with logD7.4 being the main PC determinant for systemic PK properties, were similar to those previously reported for opioids, β-adrenergic receptor ligands and benzodiazepines. However, slope estimates for the relationships of CLnonrenu and CLtotu as a function of logD7.4 for CCB were higher compared to these previously studied compounds, which showed higher sensitivity, most likely as a result of their higher lipophilicity. Overall, lipophilicity measured as logD7.4 was found to be a statistically significant and plausible PC determinant for the biologically relevant systemic PK properties for CCB and other classes of drugs.
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Hamid, Umar Imran. "Use of clinically relevant human models to test novel therapies for the acute respiratory distress syndrome". Thesis, Queen's University Belfast, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.695362.
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In the current era, there are no effective therapies for the treatment of acute respiratory distress syndrome (ARDS) despite numerous clinical trials. Current strategies are aimed at improving pulmonary perfusion, recruitment of atelectatic alveoli and reducing iatrogenic injuries to the lung. The human models of ARDS give important information when testing potential drug therapies and serve as a bridge between experimental studies and phase 11/111 clinical trials. I was able to establish the ex vivo lung perfusion model and studied the effects of aspirin in reducing pulmonary inflammation produced by lipopolysaccharide (LPS). To translate the beneficial effect of aspirin on pulmonary inflammation seen in experimental models of ARDS into a phase I clinical trial, the healthy volunteer model of LPS inhalation was used. Aspirin in these human models of ARDS was shown to reduce the pulmonary makers of inflammation due to its anti-inflammatory properties, however further clinical studies will be required to establish its role as a potential drug therapy for ARDS.
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Kia, Richard. "Novel approaches using human induced pluripotent stem cells and microRNAs in the development of relevant human hepatocyte models for drug-induced liver injury". Thesis, University of Liverpool, 2014. http://livrepository.liverpool.ac.uk/2010059/.
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Drug-induced liver injury (DILI) remains a prominent cause of patient morbidity and mortality, partly due to the lack of relevant in vitro hepatic models for accurate screening for drug-induced hepatotoxicity at the early stages of drug development, and also the lack of sophisticated in vitro model systems to mechanistically understand the pathways that are perturbed following drug exposure. This thesis describes our endeavour to develop more relevant in vitro human hepatocyte models via novel investigative approaches using insights gained from the rapidly advancing research areas of human induced pluripotent stem cells and microRNAs (miRs). An emerging hepatic model is hepatocyte-like cells (HLCs) generated from human induced pluripotent stem cells (hiPSCs), though the functional phenotype of HLCs in general remains limited in comparison with the gold standard in vitro model of human primary hepatocytes (hPHs). As studies have shown that hiPSCs retain transient epigenetic memories of the donor cells despite cellular reprogramming with a resultant skewed propensity to differentiate towards the cell-type of origin, we evaluated the contribution of epigenetic memory towards hepatic differentiation by comparing HLCs generated from hPH- and non-hPH-derived hiPSC lines derived from a single donor. Our findings suggested that they were functionally similar, although comparison using hiPSC lines derived from other donors is still required to be conclusive. Although hPHs remain the gold standard in vitro model for DILI, they are commonly harvested from liver tissue of poor quality and rapidly lose their in vivo phenotype during extended in vitro culture, limiting its utility to acute toxicity studies only. Using an unbiased miR expression profiling approach, we identified a set of differentially-expressed miRs in dedifferentiating hPHs which are associated with many of the previously delineated perturbed pathways and biological functions. However, validation experiments are now required to confirm our findings from the bioinformatics analyses. Another approach taken to develop relevant and functional hepatic models includes efforts to better emulate the in vivo liver tissue environment by using complex hepatic models co-cultured with non-parenchymal cells. However, for the application of these models in the study of drug-induced toxicity, a hepatocyte-specific marker of hepatocyte perturbation is needed to discriminate non-specific cellular toxicity contributed by non-hepatocyte cell types present within the model. We demonstrated that the detection of miR-122 in cell culture media can be applied as a hepatocyte-enriched marker of toxicity in heterogeneous cultures of hepatic cells. In summary, this thesis describes our contribution towards the continuing efforts to develop new and improve on existing hepatic models for DILI by evaluating the contribution of epigenetic memory towards the functional phenotype of HLCs, delineating the changing miR profile of dedifferentiating hPHs, and introduced the concept of using miR-122 as a cell-type specific marker of hepatocyte perturbation with a potential to bridge in vitro and in vivo findings.
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Young, Ada. "Clinically relevant conventional dose of ionizing radiation enhances tumour cell migration in human breast cancer cell lines". Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/61247.
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It is estimated that >90% of cancer-related deaths are associated with the development and growth of tumour metastases. While tumour cell migration can be enhanced by high doses of ionizing radiation (IR) in vitro, the effect of lower, clinically relevant conventional IR doses on tumour cell migration and metastasis is unclear. I hypothesize that tumour cells that survive radiation therapy have a higher propensity to migrate in vitro and extravasate into the lungs in vivo, independent from radiation-induced changes in the solid tumour microenvironment.
Breast cancer cell lines treated with 2.3Gy IR were imaged in real-time over 72h to quantify changes in single cell migration. EMT statuses of cell lines were determined using Western blot and flow cytometry. We used conditioned medium from irradiated cells to determine whether cellular migration was influenced by secreted factors. TGF-β ELISAs were used to elucidate its role in enhancing cell migration after IR. Pre-irradiated and sham treated breast tumour cells were IV-injected into mice to examine changes in lung extravasation.
The mesenchymal MDA-MB-231 and LM2-4 cell lines treated with 2.3Gy of IR migrated a greater total distance and/or displaced further from the point of origin compared to untreated cells. No induction of EMT by 2.3Gy irradiation was observed, although MCF-7 cells migrated further from the point of origin after IR. Conditioned media from 2.3Gy treated tumour cells enhanced migration and displacement of untreated tumour cells. TGF-β ELISA analysis of supernatants from sham and 2.3Gy treated MDA-MB-231 cells revealed an almost two-fold increase in TGF-β1 72h post treatment. Chemokine antibody arrays revealed a number of up-regulated proteins after 2.3Gy treatment. 8 hours after IV injection, 2.3Gy pre-irradiated tumour cells was observed with enhanced lung colonization compared to sham controls.
IR dose of 2.3Gy are sufficient to enhance migration of both non-metastatic and metastatic breast cancer cell lines independent of EMT. By quantifying changes in the metastatic ability of tumour cells treated with a clinically relevant dose of radiation, my findings will help to determine whether there is a need for additional administration of targeted secondary therapy to minimize tumour cell dissemination.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate
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Hald, Rikke. "Generation and characterisation of a naive human antibody phage display library : a resource for clinically relevant reagents /". Cph. : Department of Pharmacology, The Danish University of Pharmaceutical Sciences, 2004. http://www.dfh.dk/phd/defences/rikkehald.htm.
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Scholz, Diana [Verfasser]. "Regulation of Alzheimer’s disease-relevant protein processing in human neurons of the LUHMES cell line / Diana Scholz". Konstanz : Bibliothek der Universität Konstanz, 2011. http://d-nb.info/1028742843/34.
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Varghese, Christy Susan [Verfasser] y Martin [Akademischer Betreuer] Müller. "Biological Characterization of the Diagnostically Relevant Human Papillomavirus 16 E1C Transcript / Christy Susan Varghese ; Betreuer: Martin Müller". Heidelberg : Universitätsbibliothek Heidelberg, 2020. http://d-nb.info/1204321841/34.
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Rubasha, Herbert. "Appreciating diversity : is the doctrine of margin of appreciation as applied in the European Court of Human Rights relevant in the African human rights system?" Diss., University of Pretoria, 2006. http://hdl.handle.net/2263/1228.
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"The purpose of this study is to interrogate the doctrine of margin of appreciation as applied in the European Court of Human Rights and establish amenable lessos to the African human rights system. As such, the author will be able to draw appropriate and informed recommendations on the prospects of the doctrine in African context. In other words, the study proceeds from the approach that 'diversity' alone is not enough to guarantee application of margin of appreciation. Rather, a variety of factors come into consideration while weighing whether margin of appreciation should be granted to states. Indeed, such benchmarks will inform the discourse of this study, while at the same time acknowledging that a comparative study between European and African systems cannot be possible. The premise for disqualifying a comparison assumes that margin of appreciation presupposes a democratic society. Thus, while the member states of the ECHR have attained high levels of human rights records, some of their counterparts in Africa are still marred by embarrassing human rights records." -- Preamble.
"Chapter one introduces the study and the context in which it is set. It highlights the basis and structure of the study. Chapter two makes reference to the connotation, origin and development of the doctrine of margin of appreciation. It discusses also contours and varying degrees of the doctrine's application with particular regard to respect of the rule of law. In addition, difficulties linked to the doctrine are highlighted. Chapter three highlights policy grounds underlying margin of appreciation in the European Court of Human Rights. It starts from most decisive policy grounds and moves to weaker ones. Chapter four examines the legal basis for application of the doctrine of margin of appreciation under the African Charter. It further notes the attitude of African states through their submissions claiming margin. The Prince case as the first of its kind to invoke margin of appreciation is discussed. Chapter five attempts to identify the defensibility and indefensibility of the doctrine in [the] African human rights system. Chapter six consists of a summary of the presentation and the conclusions drawn from the entire study." -- Introduction.Prepared under the supervision of Prof. Gilles Cistac at the Faculty of Law, Universidade Eduardo Mondlane, Maputo, Mocambique
Thesis (LLM (Human Rights and Democratisation in Africa)) -- University of Pretoria, 2006.
http://www.chr.up.ac.za/academic_pro/llm1/dissertations.html
Centre for Human Rights
LLM
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Sofy, Laura. "Establishing the Relevant Standards of Human Rights Protection under Dublin Regulation - A question of more than responsibility determination?" Thesis, Uppsala universitet, Juridiska institutionen, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-295234.
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Boriachek, Kseniia. "Next generation of human cancer diagnostics: Nanomaterial-based electrochemical sensors for clinically relevant exosomes and exosomal biomarkers analysis". Thesis, Griffith University, 2018. http://hdl.handle.net/10072/380570.
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Exosomes are 40-100 nm diameter membrane vesicles which are released from cells
and circulate in body fluids such as blood, urine, and saliva. Being encapsulated by a
lipid bilayer, these nanoscale vesicles carry a cargo of proteins, lipids, mRNA,
microRNA (miRNA) and transfer this cargo to recipient cells. Exosomes play an
important role in various biological processes such as intercellular signalling,
coagulation, inflammation, cellular homeostasis and involved in many pathological
conditions such as cancer progression and metastasis. Due to these unique properties,
exosomes are being pursued as promising biomarker source for diagnosis and prognosis
of various diseases. Despite excellent analytical performance of the conventional
methods for exosome analysis, most of them require large amount of input samples,
long assay time and cumbersome pre-processing steps. Therefore, the development of a
simple, sensitive and inexpensive platform that can be used for rapid quantification and
analysis of exosomes is of great importance to biology and medicine. This PhD project
endeavours to engineer such translational approaches to address the aforementioned
challenges for developing an inexpensive, rapid, sensitive and specific biosensor
platform. The thesis initially investigates the biogenesis, functions, diagnostic,
prognostic and therapeutic potential of exosomes an exosomal biomarkers followed by a
comprehensive study of recent progress in exosome analysis techniques including
conventional methods as well as electrochemistry-based approaches. We then report on
a simple electrochemical platform for detection of disease specific exosomes present in
cell culture media using commercially available extravidin-modified screen printed
electrodes. The assay has a two-step design, where initially total exosome population
was captured by a generic antibody and the disease specific exosomes were subpopulated
using a cancer-specific antibody. All the steps were performed on a single
extravidin-modified electrode and final quantification of disease-specific exosomes were done by differential pulse voltammetry readout. Subsequent to the development of
this proof of concept sensor, we attempted to address the increasing demand for
detecting low concentrations of disease-specific exosomes. Utilizing the capability of
quantum dots to serve as signal amplifiers, we next developed a highly sensitive
electrochemical approach enabled to detect 100 exo/μL and demonstrated the clinical
applicability via detecting disease-specific exosomes in serum samples derived from
patients with colon cancer of different stages. As not only exosomes themselves, but
also exosomal RNA showed a great promise as cancer biomarker, we also developed a
simple electrochemical approach for the detection of cancer-derived exosomal miRNAs
by selectively isolating the target miRNA using magnetic beads pre-functionalized with
the specific capture probes. The isolated targets were then directly adsorbed onto a gold
electrode surface and quantified via differential pulse voltametric readout. In our final
readout strategy, we developed a novel platform using nanoporous Au—NPFe2O3NC
nanocubes, which enable an efficient and easy exosome isolation with a subsequent
sensitive detection. To achieve this goal, we exploited the advantages of nanocubes such
as supermagnetism, high electrocatalytic and peroxidase-like activity. The approach
compromise both electrochemical (amperometric) and colorimetric (naked-eye) readout
strategies and was enable first to isolate the bulk exosome population and then
specifically detect choriocarcinoma-derived exosomes. All the readout platforms
reported in this thesis have shown excellent analytical performance with high specificity
and sensitivity. We also demonstrated the applicability of all assays in complex
biological samples including cohort of patient samples. We hope that in near future our
research efforts will be translated from lab settings to the point-of-care platform for
exosome analysis which could be used in clinical settings for improving patient care.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Environment and Sc
Science, Environment, Engineering and Technology
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Gudmundsson, Anders. "Studies on particle size-selective sampling of aerosols relevant for deposition in the human airways and onto the eyes". Lund : Dept. of Industrial Engineering, Division of Working Environment, Lund Institute of Technology, Lund University, 1995. http://books.google.com/books?id=XWZtAAAAMAAJ.
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Thomas, Andrew G. "On the plasticity of human mating strategies : experimental evidence for mating strategy change in response to evolutionarily relevant stimuli". Thesis, Swansea University, 2015. https://cronfa.swan.ac.uk/Record/cronfa41184.
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Evolutionary psychological theory explains the large variance found in humanmating behaviour through the use of a mating strategies perspective. Specifically, both sexes have short-term and long-term mating strategies containing sets of evolved psychological adaptations which guide mating effort. Individuals vary in their mating behaviour due to the differential activation of these two strategies which are thought to be activated conditionally. That is, an individual is hypothesized to engage in a short- term mating strategy over a long-term one in circumstances where, ancestrally, a short- term strategy would have led to the best fitness outcome. Despite a large body of evidence for the existence of mating strategies in humans, evidence for the ability to conditionally switch between strategies is less robust. To date, such evidence is either in the form of correlational studies, or experimental studies which demonstrate changes to behaviours only partly related to mating strategies. The aim of this thesis was to fill the gap in this literature by demonstrating that participants can change their mating strategies in response to evolutionarily relevant stimuli. A novel measure of mating strategies was developed in order to capture a participants’ propensity towards short- and long-term mating before and after exposure to cues hypothesized to have affected the effectiveness of the two mating strategies in the ancestral environment. These included cues related to a skewed local sex-ratio, self-perceived dominance, and environmental danger. Of the ten experimental hypotheses tested, support (or partial support) was found for seven and the experimental effects were typically small-to-medium in size. Thus, moderate support was found that humans are flexible in their mating strategy implementation and respond to evolutionarily relevant cues, although it was concluded that marked changes in an individual’s environment would be required for any lasting effect on their matingbehaviour to occur.
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Rademan, Janet Ellen. "The identification of contextually relevant health and well-being information needs for the youth through human-centered co-design". Thesis, Cape Peninsula University of Technology, 2015. http://hdl.handle.net/20.500.11838/2409.
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Thesis (MTech (Design))--Cape Peninsula University of Technology, 2015.Available health and well-being information is limited in communities with insufficient health care resources. This affects the community negatively on multiple levels in which the health and well-being needs of individuals are not satisfied. This research project explored the impact of human centred co-design, using tools such as health and well-being needs questionnaires including a health needs assessment as well as a quality of life scale. The aim was making accurate health and well-being information more accessible to the youth. The target group was Durbanville youth aged between 14 and 18 years. The sample included different ages ( = 15), races (79% White, 21% Coloured) and near equal gender distribution (55% female, 45% male). The sample (N = 33) was comprised of three groups: Group A, B, and C. A Human-Centered Design (HCD) framework was used during the project referring to the following three steps: Hear, Create, and Deliver. During the Hear phase, stories and inspiration from the participants were gathered. Group A (n = 10) completed a health and well-being information needs questionnaire. Group B (n = 15) discussed the topic, and created affinity diagrams. This was how the health and well-being status and information needs were established. During the Create phase; frameworks, opportunities, solutions, and prototypes were developed by the participants. Group B co-designed the concept prototype: a possible mobile application solution for practical access to health and well-being information. Group C (n = 8) provided feedback and input on the concept prototype and created storyboards to visually display scenarios in which they would use the mobile application. This step produced a youth-friendly health and well-being information service concept prototype. During the Deliver phase, the relevant health and well-being information solution was established as a youth-friendly health and well-being mobile application: WeHelp. Also, group A, B, and C were introduced to a similar existing resource named MobieG. Thus, the present study contributed directly to the participants’ health and well-being awareness. The research provided significant health and well-being insights. For example, the youth of Durbanville revealed extremely low scores on the emotional well-being domain. The data collected makes it possible for future researchers to create a practical, youth-friendly, health and well-being information service.
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Klein, Sebastian [Verfasser] y Elmar [Akademischer Betreuer] Heinzle. "Towards the assessment of human-relevant repeated dose toxicity using an in vitro systems toxicological approach / Sebastian Klein ; Betreuer: Elmar Heinzle". Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2017. http://d-nb.info/1152094742/34.
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Klein, Sebastian Verfasser] y Elmar [Akademischer Betreuer] [Heinzle. "Towards the assessment of human-relevant repeated dose toxicity using an in vitro systems toxicological approach / Sebastian Klein ; Betreuer: Elmar Heinzle". Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:291-scidok-ds-269362.
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Hey, Christina K. Mae. "Situating Critical Indigenous Worldview within Western Academic Traditions: Place-Based and Culturally-relevant Science Education for Human Empowerment and Environmental Sustainability". Diss., Virginia Tech, 2017. http://hdl.handle.net/10919/77577.
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Learning to value ourselves as uniquely endowed, understanding our irreplaceable fit into the social and environmental fabric, and becoming active agents woven into our communities will maximize our capacity for progressive change through empowerment. There are effective practices in orchestrating learning environments for empowerment that have ancient and proven roots but have become marginalized in contemporary education. These ways focus on fostering the development of unique gifts and group cohesion, as opposed the fostering of independence and competition, the latter being two ideologies not found in Nature when it is in balance and harmony. This reversal in paradigm will reclaim our ability to critically problem-solve and evoke transformative action by increasing the diversity of perspectives and talents focused on an endeavor. Central to this research is an exploration of the strategization involved in supporting cultural, cognitive, and creative capital—the gifts endowed to humankind that enable our co-evolution with this specific regions of this planet. This research explores methods not only of maintaining the integrity of Indigenous voice through the process of research and reporting but also of using science as a tool for building community through a sense of critical Indigenous identity. It is my hope that the data contained in this research will serve as a relevant, without being transferable, model of progressive educational approaches to ameliorate science education on a local, national, and global scale.Ph. D.
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Harrop, Ceri. "Biochemical, biophysical and network properties of mucins and mucus gels produced by human bronchial epithelial cells in response to disease-relevant mediators". Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.532253.
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Badri, Prajakta. "PREDICTION OF HUMAN SYSTEMIC, BIOLOGICALLY RELEVANT PHARMACOKINETIC (PK) PROPERTIES BASED ON QUANTITATIVE STRUCTURE PHARMACOKINETIC RELATIONSHIPS (QSPKR) AND INTERSPECIES PHARMACOKINETIC ALLOMETRIC SCALING (PK-AS)". VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/124.
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This research developed validated QSPKR and PK-AS models for predicting human systemic PK properties of three, preselected, pharmacological classes of drugs, namely opioids, β-adrenergic receptor ligands (β-ARL) and β-lactam antibiotics (β-LAs) using pertinent human and animal systemic PK properties (fu,, CLtot, Vdss, fe) and their biologically relevant unbound counterparts from the published literature, followed by an assessment of the effect of different molecular descriptors on these PK properties and on the PK-AS slopes for CLtot and Vdss from two species (rat and dog). Lipophilicity (log (D)7.4) and molecular weight (MW) were found to be the most statistically significant and biologically plausible, molecular properties affecting the biologically relevant, systemic PK properties: For compounds with log (D)7.4 > -2.0 and MW < 350 D (e.g., most opioids and β-ARL), increased log (D)7.4 resulted in decreased fu and increased Vdssu, CLtotu and CLnonrenu, indicating the prevalence of hydrophobic interactions with biological membrane/proteins. As result, the final QSPKR models using log (D)7.4 provided acceptable predictions for fu, Vdssu, CLtotu and CLnonrenu. CLnonrenu and CLtotu. For both the datasets, inclusion of drugs undergoing extrahepatic clearance worsened the QSPKR predictions. For compounds with log (D)7.4 < -2.0 and MW > 350 D (e.g., β-LA), increased MW (leading to more hydrogen bond donors/acceptors) resulted in a decrease in fu, likely indicating hydrogen bonding interactions with plasma proteins. In general, it was more difficult to predict PK parameters for β-LAs, as their Vdssu approached plasma volume and CLrenu and CLnonrenu were low - as a result of their high hydrophilicity and large MW, requiring specific drug transporters for distribution and excretion. The PK-AS analysis showed that animal body size accounted for most of the observed variability (r2> 0.80) in systemic PK variables, with single species methods, particularly those using dog, gave the best predictions. The fu correction of PK variables improved goodness of fit and predictability of human PK. There were no apparent effects of molecular properties on the predictions. CLren, CLrenu, CLnonren, and CLnonrenu were the most difficult variables to predict, possibly due to the associated interspecies differences in the metabolism, renal and hepatobiliary drug transporters.
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Lambrianides, A. "An investigation of the molecular basis of interactions between human monoclonal antibodies and antigens that are clinically relevant in systemic lupus erythematosus and the Antiphospholipid Syndrome". Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1444917/.
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Autontibodies to a wide variety of antigens are associated with systemic lupus erythematosus (SLE) and the Antiphospholipid Syndrome (APS). Previous studies have demonstrated the importance of somatic mutations and arginine residues in the complementarity determining regions (CDRs) of pathogenic anti-dsDNA and antiphospholipid antibodies. This thesis describes the study of two human monoclonal IgG antibodies, B3 (anti-DNA) and IS4 (antiphospholipid) that were derived from a patient with active SLE and primary APS respectively. I have demonstrated in-vitro expression and mutagenesis of B3 and IS4 and used this expression system to investigate the importance of the arginine residues in B3VH and IS4VH. The mutant heavy chains, as well as the wild-type VH were expressed with different light chains and the resulting antibodies assessed for binding to nucleosomes, alpha-actinin, cardiolipin (CL), phosphatidylserine (PS), beta-2-glycoprotein I (foGPI), and the N-terminal domain of p2GPI (Domain I) using direct binding assays. The results obtained have shown that the presence of arginine at position 53 in B3VH was essential but not sufficient for binding to dsDNA and nucleosomes. Conversely, the presence of this arginine reduced binding to alpha-actinin, pzGPI and Domain I of P2GPI. The fact that the arginine to serine substitution at position 53 in B3VH significantly alters binding of B3 to different clinically relevant antigens, but in opposite directions implies that this arginine residue plays a critical role in the affinity maturation of the antibody B3. Furthermore, of four arginine residues in IS4VH CDR3 substituted to serine, two at positions 100 and 100g reduced binding to all antigens, while two at positions 96 and 97 reduced binding to fcGPI but increased or decreased binding to CL and PS. Only one H/L chain combination bound neutral phospholipid and none bound dsDNA hence, these effects are particularly relevant to antigens important in APS. Therefore, my findings suggest that these four arginine residues have developed as a result of somatic mutations driven by an antigen containing both phospholipid and frGPI. These results extend our knowledge of the structure-function relationship of human anti-DNA and anti phospholipid antibodies and aid in our understanding of how these antibodies lead to pathogenicity and what we need to target in the future for possible therapies.
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Lisovsky, Irene. "Emergence of Nelfinavir and Lopinavir resistance relative to a clinically relevant human immunodeficiency virus type-1 single nucleotide polymorphism at position 36 in protease enzyme «in vitro»". Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=86996.
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The genetic differences and polymorphisms between HIV-1 subtype B and non-B subtypes have been well documented. Classically, however, antiretrovirals (ARVs), including protease inhibitors (PIs), have been designed based on structural and functional information obtained utilizing subtype B HIV-1. With the advent of antiretroviral therapy (ART) in developing countries and the emergence of non-B infections in developed countries, the impact of these polymorphisms must be evaluated in terms of ART efficacy.The 36th amino acid in the viral protease (PR) of B subtypes is Methionine (M), while non-B subtypes code for Isoleucine (I). I at position 36 is associated with PI resistance in subtype B HIV-1; therefore, we sought to investigate the effect of this single nucleotide polymorphism on emergence of resistance mutations and PI susceptibility in various HIV-1 subtypes in vitro. Our results indicate that the effect of this single nucleotide polymorphism appears to be subtype specific and PI specific.
Les différences génétiques (polymorphismes) entre les différents sous-types du VIH-1, soit B et non-B, sont bien documentées. Toutefois, les antirétroviraux incluant les inhibiteurs de la protéase, ont été conçus de façon structurelle et fonctionnelle en utilisant les informations obtenues à partir du sous-type B. L'impact des polymorphismes des différents sous-types du VIH-1 sur l'efficacité des antirétroviraux doit être évalué dû à l'émergence des infections de sous-types non-B dans les pays développés ainsi qu'avec l'arrivée de la thérapie antirétrovirale dans les pays en voie de développement.
Le 36e acide aminé de la protéase virale de sous-type B du VIH-1 est une méthionine. Cependant, cet acide aminé est remplacé par une isoleucine dans les sous-types non-B. La présence d'une isoleucine à la position 36 entraîne une résistance du VIH-1 sous-type B pour les inhibiteurs de la protéase. Nous avons examiné l'effet de ce polymorphisme sur les mutations de résistance dans les différents sous-types de VIH in vitro. Nos résultats indiquent que l'effet de ce polymorphisme serait différent selon le sous-type.
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Gottipati, Gopichand. "PREDICTION OF HUMAN SYSTEMIC, BIOLOGICALLY RELEVANT PHARMACOKINETIC (PK) PROPERTIES USING QUANTITATIVE STRUCTURE PHARMACOKINETIC RELATIONSHIPS (QSPKR) AND INTERSPECIES PHARMACOKINETIC ALLOMETRIC SCALING (PK-AS) APPROACHES FOR FOUR DIFFERENT PHARMACOLOGICAL CLASSES OF COMPOUNDS". VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3525.
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This research developed and validated QSPKR models for predicting in-vivo human, systemic biologically relevant PK properties (i.e., reflecting the disposition of the unbound drug) of four, preselected, pharmacological classes of drugs, namely, benzodiazepines (BZD), neuromuscular blocking agents (NMB), triptans (TRP) and class III antiarrhythmic agents (AAR), as well as PK allometric scaling (PK-AS) models for BZD and NMB, using pertinent human and animal systemic PK information (fu, CLtot, Vdss and fe) from published literature. Overall, lipophilicity (logD7.4) and molecular weight (MW) were found to be the most important and statistically significant molecular properties, affecting biologically relevant systemic PK properties, and the observed relationships were mechanistically plausible: For relatively small MW and lipophilic molecules, (e.g., BZD), an increase in logD7.4 was associated with a decrease in fu, an increase in Vdssu and CLnonrenu, suggesting the prevalence of nonspecific hydrophobic interactions with biological membranes/plasma proteins as well as hepatic partitioning/DME binding. Similar trends were observed in fu and Vdssu for intermediate to large MW, hydrophilic molecules (e.g., NMB). However, although similar trends were observed in fu and Vdssu for relatively hydrophilic, intermediate MW molecules (e.g., TRP), and a heterogeneous class (e.g., Class III AAR), logD7.4 and MW were found to be highly correlated, i.e., the indepdendent effects of logD7,4 and MW cannot be assessed NMB, TRP and Class III AAR show mechanistically diverse clearance pathways, e.g., hepatobiliary, extrahepatic, enzymatic/chemical degradation and renal excretion; therefore, effects of the logD7.4 and/or MW are note generalizable for any of the clearances across classes. PK-AS analyses showed that Vdssu and Vdss scaled well with body weight across animal species (including humans) for BZD. Overall, within the limitations of the methods (and the sample size), ‘acceptable’ predictions (i.e., within 0.5- to 2.0-fold error range) were obtained for Vdssu and Vdss for BZD (and fu correction resulted in improvement of the prediction); however, none of the CLtot predictions were acceptable, suggesting major, qualitative interspecies differences in drug metabolism, even after correcting for body weight (BW). NMB undergo little extravascular distribution owing to their relatively large MW and charged nature, and, as a result, a high percentage of acceptable predictions was obtained for Vdss (based on BW). Similarly, the prediction of CLren (based on BW and glomerular filtration rate, GFR) was acceptable, suggesting that NMB are cleared by GFR across species, and there are no interspecies differences in their tubular handling. On the other hand, CLtot (and/or CLnonren) could not be acceptably predicted by PK-AS, suggesting major differences in their clearance mechanisms across animal species.
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Leung, Man Ching. "Identification of human hair follicle antigens targeted in the presumptive autoimmune hair follicle disorder Alopecia Areata and their potential functional relevance In Vitro. Methods development for isolation and identification of Alopecia Areata-relevant human hair follicle antigens using a proteomics approach and their functional assessment using an Ex Vivo hair follicle organ culture model". Thesis, University of Bradford, 2008. http://hdl.handle.net/10454/4330.
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Alopecia areata (AA) is a putative autoimmune hair loss disorder. It mainly affects the scalp hair but can also involve body hair, and can also affect the nail and the eye. While there are may be several lines of evidence to support the autoimmune basis of AA, there is still very little information on the hair follicle autoantigen(s) involved in its pathogenesis. In this project, serum antibodies (AA=10, control=10) were used to immunoprecipitate AA-relevant target antigens from normal human scalp hair follicle extracts. These immunoprecipitates were analysed by LC-MALDI-TOF/TOF mass spectrometry for target protein identification. This part of the project involved substantial methods development. Trichohyalin was immunoprecipitated by all AA sera, but by only 5 normal sera. Importantly, the mean Mascot scores of the AA group was significantly higher than the normal group (p=0.005). Keratin 16 was also identified from immunoprecipitates as another potential AA-relevant target antigen. Functional studies by ex vivo whole hair follicle organ culture using commercial antibodies to trichohyalin and keratin 16 significantly inhibited hair fibre elongation compared to controls. Indirect immunofluorescence studies revealed that AA sera contained higher immunoreactivity against normal human scalp anagen hair follicles compared to normal sera. Immunoreactivities were mainly in the outer root sheath and inner root sheath, and less so to the medulla and hair bulb matrix. Double immunofluorescence studies of AA and normal serum with anti-trichohyalin antibody (AE15) revealed co-localisation of 9 of the AA sera antibodies with trichohyalin in the inner root sheath (mostly in Henle's, less in Huxley's/inner root sheath cuticle), but only weakly in 3 normal sera. This study supports the involvement of an antibody response to anagen-specific hair follicles antigens in AA. Moreover, there may be some evidence that these antibodies may have a pathogenic role.
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KATIA, CAPITANI. "Genome editing for clinically relevant mutations in genetic diseases and cancer". Doctoral thesis, Università di Siena, 2022. http://hdl.handle.net/11365/1211914.
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The present thesis concerns of two sections. The first one focuses on the application of Cluster Regularly Interspaced Short Palindromic Repeats (CRISPR) system as a tool for precise genome targeting and genome editing; the association between specific endonuclease and RNA guides complementary to the DNA target allows its targeting with single-nucleotide precision. CRISPR/Cas is able to perform Double-Strand Breaks (DSBs) at a target site which are soon repaired by cellular repairing mechanism, non-homologous end joining (NHEJ) or homology-directed repair (HDR).
The first part of my project aims to explore and demonstrate the efficacy of a personalized therapeutic approach based on the CRISPR/Cas9 technology associated with adeno-associated viral vectors (AAVs)s, a mutation-specific gene therapy to restore mutated genes in genetic diseases to their original sequence trough the HDR-mediated correction. I developed an mCherry/EGFP reporter cassette where the reporter gene bears a mutation-specific target. It connects the mCherry and the EGFP (out of frame) coding sequences. Due to a frameshift, the reactivation of the EGFP allows the visualization of cells in which Cas9 had targeted the mutation-specific sequence leading to the production of Indels. I worked to edit mutations involved in specific genetic diseases such as mutations in FOXG1 or in MECP2, which are responsible for Rett syndrome, in the IQSEC2 gene that causes an intellectual disability clinically related to the Rett syndrome and in COL4A3 and COL4A5 causing Alport syndrome.
In the second part of my study, I worked on developing a gene editing system aims to selective targeting to cancer cells while preserving the genetic integrity of normal cells. To this aim, I plan to exploit microhomology-mediated end joining (MMEJ) through Cas12a, an RNA-directed endonuclease that causes double-strand breaks with staggered ends, to insert in-frame the Herpes Simplex Virus –Thymidine Kinase suicide gene to trigger cell death. I designed and developed a construct to target a patient-specific single nucleotide variant within a coding sequence of the TP53 gene, from a patient with Chronic Lymphocytic Leukemia characterized by clonal expansion of clones bearing this TP53 mutation. I am able to detect the proper integration of the suicide gene sequence by analyzing the treated cells by fluorescence-activated cell sorting (FACS). Indeed, a green fluorescent protein (EGFP) sequence is linked to the TK by a 2A peptide system, thus green fluorescent cells are also the one expressing for the TK gene.
The second section of my thesis concerns the COVID-19 pandemic global crisis and the need to understand how best to study and treat COVID-19. A key focus is sharing and analyzing data to learn about the genetic determinants of COVID-19 susceptibility, severity, and outcomes. In particular, my work has been focused on the TLR7 gene that has been involved as an important pattern recognition receptor for the ssRNA of SARS-CoV-2. We demonstrate that rare loss-of-function variants in the TLR7 gene in young men with severe COVID-19 and with no prior history of major chronic diseases were associated with impaired TLR7 signaling and type I and II IFN responses.
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Owor, Maureen. "Making international sentencing relevant in the domestic context : lessons from Uganda". Thesis, University of Bristol, 2009. http://hdl.handle.net/1983/3d520048-dba7-4393-ba22-664923c079c3.
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This thesis is about achieving local procedural legitimacy through fair, culturally relevant sentencing procedures. Its scope, is reconciling international due process guarantees and a traditional notion of rights, in sentencing procedures of the International Criminal Court. My interest in this topic arose from the 2003 Uganda Law Reform Commission study on sentencing legislation reforms. There, participants regarded clan courts as functional in rural areas, because they had more informal, conciliatory sentencing processes than the ‘alien’ national courts. I later became aware that incorporation of traditional restorative processes may also help solve problems of legitimacy at the international level, as manifested in the case of Joseph Kony, discussed in Chapter 1 of this thesis. I then investigate whether the international sentencing framework could accommodate features of traditional restorative process despite incongruent standards, and if so, how this could be achieved. I argue that procedural rights ought to underpin this reconciliation, harnessing aims of international criminal justice with traditional restorative justice. Through my translation model, I propose small structural changes to international sentencing practice, and doctrinal reforms based on precedent. Using critical legal analysis and a small empirical study, the thesis demonstrates how translation could achieve just, culturally apposite sentencing outcomes. The International Criminal Tribunal for Rwanda and the Special Court for Sierra Leone provide insight into challenges to accommodating African normative standards. Nominal guidance from the African human rights mechanism and national courts, on an African notion of procedural fairness, further complicates this reconciliation. I conclude that we could translate laws across divergent legal systems, drawing from experiences of clan courts that assimilate legal structures and concepts from national courts. Major international instruments: Rome Statute 1998, United Nations International Covenant on Civil and Political Rights 1966 and the African Charter on Human and Peoples’ Rights 1981, are evaluated against this model.
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Bourgart, Etienne. "Métabolisme cutané et biomarqueurs d'exposition aux mélanges complexes d'hydrocarbures aromatiques polycycliques A realistic human skin model to study benzo[a]pyrene cutaneous absorption in order to determine the most relevant biomarker for carcinogenic exposure Solar simulated light exposure alters metabolization and genotoxicity induced by benzo[a]pyrene in human skin Influence of exposure dose, complex mixture, and ultraviolet radiation on skin absorption and bioactivation of polycyclic aromatic hydrocarbons". Thesis, Université Grenoble Alpes (ComUE), 2019. http://www.theses.fr/2019GREAS026.
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Les hydrocarbures aromatiques polycycliques (HAP) sont des cancérigènes ubiquitaires, produits en mélanges complexes dont la composition varie en fonction de la source d’émission. Classées substances prioritaires de par leur abondance et leur génotoxicité, l’exposition aux HAP des populations se fait notamment par voie cutanée au cours des activités professionnelles. La surveillance biologique de l’exposition (SBE) tient compte de l’absorption cutanée en plus de l’inhalation et identifie les situations d’exposition à risque. Pour estimer l’exposition au Benzo[a]pyrène (B[a]P), cancérogène certain pour l’homme, le dosage du 3-hydroxybenzo[a]pyrène (3-OHB[a]P) et du (±)trans-anti-B[a]P-tétraol (B[a]P-tétraol) a été récemment proposé. L’objectif de cette thèse était d’étudier l’absorption et le métabolisme cutanés du B[a]P mais aussi des mélanges d’HAP en vue de d’améliorer la compréhension de leur génotoxicité et de développer des biomarqueurs pertinents pour estimer les risques sanitaires. La première partie de ce travail a consisté au développement d’un modèle cutané ex vivo simple mais réaliste à partir d’explants de peau humaine. Après la mise au point des méthodes d’extraction et d’analyse adéquates, la toxico-cinétique et le métabolisme cutané de faibles doses de B[a]P ont été étudiés. La pénétration cutanée et le métabolisme du B[a]P sont inversement proportionnels à la dose appliquée. Cependant, les voies de métabolisation sont impactées différemment. Alors que la production du 3-OHB[a]P issu des voies de détoxication est dose-dépendante, la formation du B[a]P-tétraol, produit de l’hydrolyse du métabolite cancérogène ultime du B[a]P, est rapidement saturée. Le B[a]P-tétraol est donc le biomarqueur le plus pertinent pour estimer le risque cancérogène au B[a]P. De plus, la proportion de B[a]P non-métabolisé traversant la peau est extrêmement limitée indiquant que la toxicité de ce composé s’exprime essentiellement localement. La deuxième partie de ce travail a consisté en une synthèse bibliographique centrée sur la biotransformation de 7 autres HAP cancérogènes permettant d’identifier 16 métabolites d’intérêt commercialisés. In fine, le dosage de 10 de ces métabolites, impliqués dans les voies de bioactivation ou de détoxication de 5 HAP, a pu être développé en GC-MS/MS. Le dosage urinaire de ces nouveaux biomarqueurs devrait permettre d’améliorer la SBE des populations aux HAP cancérogènes. Dans la dernière partie de ce travail, l’impact de la composition de mélanges synthétiques ou industriels (extraits de brai de houille et de coke de pétrole) à différentes doses sur l’absorption et le métabolisme cutanés des HAP furent évalués en présence ou non de rayonnements ultraviolets (UV). La pénétration des HAP diminue quand la complexité du mélange et la dose augmentent. Alors que les UV amplifient la pénétration des HAP lors de l’application des mélanges industriels, ils n’ont pas d’effet sur le B[a]P appliqué seul ou sur les mélanges synthétiques. Leur bioactivation décroit sous l’influence des mélanges et des UV, provoquant une accumulation de HAP non-métabolisés dans la peau ce qui pourrait retarder la survenue des effets génotoxiques. A l’instar du B[a]P, la toxicité des autres HAP cancérogènes semble être essentiellement locale et dépendre du scénario d’exposition cutanée. Ce travail souligne l’importance de l’étude des mélanges du fait d’interactions plus complexes que de simples effets additifsPolycyclic aromatic hydrocarbons (PAH) are ubiquitous carcinogens emitted as complex mixtures whose composition depends on emission sources. Because of their abundance and genotoxicity, PAHs are classified as priority substances, to which people can be exposed via dermal absorption during occupational activities. Biomonitoring takes into account skin absorption as well as inhalation and allows the identification of hazardous exposure situations. To assess Benzo[a]pyrene (B[a]P) exposure, which is classified as carcinogenic to human, quantification of 3-hydroxybenzo[a]pyrene (3-OHB[a]P) and (±)trans-anti-B[a]P-tetrol (B[a]P-tetrol) was recently proposed. This PhD thesis aimed at studying the skin absorption and metabolism of B[a]P and PAH mixtures to improve the understanding of their genotoxicity and develop relevant biomarker for health risk assessment. The first part of this work consisted in developing a simple and realistic skin model from human skin explants. Further to the development of adequate extraction and analytical methods, cutaneous toxicokinetic and metabolism from low B[a]P doses were studied. B[a]P skin penetration and metabolism were inversely proportional to applied dose. Nevertheless, metabolic pathways are impacted differently. While 3-OHB[a]P production formed during detoxification was dose-dependent, the formation of B[a]P-tetrol, resulting from the hydrolysis of B[a]P ultimate carcinogenic metabolite, saturates rapidly. Therefore, B[a]P-tetrol is the most relevant biomarker for estimating B[a]P carcinogenic risk. In addition, unmetabolized B[a]P poorly diffused through skin indicating that B[a]P toxicity is mainly local. The second part of this work consisted of a literature review focusing on 7 other carcinogenic PAH biotransformation to identify 16 marketed metabolites of interest. In fine, GC-MS/MS analysis was developed for 10 previously identified metabolic intermediates that are either involved in bioactivation or detoxification pathways of 5 PAH. Urinary quantification of those new biomarkers should improve the biomonitoring of populations to carcinogenic PAH. Finally, we evaluated the impact of synthetic or industrial mixtures (coal tar pitch and petroleum coke extracts) composition at different doses on carcinogenic PAH skin absorption and metabolism combined or not with ultraviolet radiations (UVR). PAH penetration diminished when mixture complexity and dose increased. While UVR increased PAH penetration when industrial complex mixtures were applied, no effect was observed on pure B[a]P or synthetic mixtures. PAH bioactivation decreased with mixtures and UVR, inducing unmetabolized PAH accumulation in the skin which may delay the occurrence of genotoxic effects. Similarly to B[a]P, other carcinogenic PAH toxicity seems to be mainly local and depends on skin exposure scenario. This work underlines the importance of mixtures study owing to more complex chemical interactions than simple additive effects
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Alosaimi, Shatha Mobarak. "Leveraging Whole Genome Sequences to Compare Mutational Mechanism and Identify Medically Relevant Variation in African versus Non-African Descend Populations". Master's thesis, Faculty of Health Sciences, 2020. http://hdl.handle.net/11427/32191.
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Whole-Genome Sequencing (WGS) is ushering a new era in healthcare and research in identifying genetic variation in all populations. However, the African populations are still under-represented. Since African populations are being the most genetically diverse with high heterogeneity rate, we need to benchmark the Whole Genome Sequence (WGS) analysis pipeline to ensure reliable mutation detection. Therefore, it is essential to ensure that all steps of WGS downstream analysis are accurate, mainly the variant calling (VC). Current VC tools may produce falsepositive/negative results; such result may produce misleading conclusions in prioritisation of mutation, clinical relevancy and actionability of genes. With such many VC tools, two questions have arisen. Firstly, which tool has a high rate of sensitivity and precision in low either high coverage African sequences, given they have high genetic diversity and heterogeneity? Secondly, does the improvement of the VC result will advance the accuracy of detecting mutation and incidental finding (actionable genes) in African populations? In this project, a total of 100 DNA sequence samples was simulated (of which every 50 samples mimicked the genetics background of African and European, respectively) at different coverage (high and low). In particular, the sensitivity to discover polymorphisms was done by nine different VC tools. These tools were assessed in term of false positive/negative call rate given the simulated golden variants. Combining our result on sensitivity and positive predictive value (PPV). Lofreq performs best in African population data (sens=0.85, PPV=0.983, F-score=0.91) on high/low coverage data; as a result, we chose Lofreq to perform variant calling, and Gene-based annotation is performed to conduct in-sillico predication of mutation on publicly available data (the African Genome Variation and 1000 Genome Project). In doing so, we have leveraged WGS to examine and validate four of burden diseases in the African content, such as communicable diseases: HIV/AIDS, Malaria, Tuberculosis (TB), and Non-communicable diseases: such as Sickle cell disease, these diseases have uniquely shaped ethnic-specific and continental genomics variation and therefore provides unprecedented opportunities to map disease genes across the African continent. Moreover, the current actionable gene recommended by The American College of Medical Genetics and Genomics (ACMG) in the African population and update on additional African-specific actionable genes. Our result suggests African and African diaspora ethnic groups, particularly Bantu and Khoesan ethnics have gene diversity, high proportion of derived allele at low minor allele frequency (0.0 − 01) and the highest proportion of pathogenic variants within HIV, TB, Malaria, Sickle-Cell disease, while non-African ethnic groups including Latin America, Afro-Asiatic European related ethnic groups have high proportion of pathogenic variants within current actionable gene list. Overall, given the observed highest genetic diversity found in African ethnics and African diaspora related ethnics at these four Africa burden diseases and current actionable gene associated, our results support (1) the use of personalised medicine as beneficial to both African continent and worldwide; (2) a recommendation for African-specific actionable list of genes to further improve African and diaspora healthcare.
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Siegle, Greg Jeremy. "Cognitive and physiological aspects of attention to personally relevant negative information in depression /". Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1999. http://wwwlib.umi.com/cr/ucsd/fullcit?p9935457.
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Conradie, Johannes David. "Investigation of myostatin and relevant regulators during muscle regeneration after an acute bout of eccentric exercise". Thesis, Stellenbosch : Stellenbosch University, 2014. http://hdl.handle.net/10019.1/95947.
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Thesis (MSc)--Stellenbosch University, 2014.ENGLISH ABSTRACT: The aim of this study was to investigate the powerful muscle regulator, myostatin, and its regulators in response to an acute bout of plyometric training. The participants were recruited and screened by characterization by means of isometric force production tests, baseline blood creatine kinase levels and VO2 max results. The selected individuals (n=15) were subjected to a baseline muscle biopsy for comparative purposes. The study made use of plyometric jumping, as source of eccentric exercise, to serve as an exercise intervention after which muscle biopsies (4 hours post and 24 hours post) and blood draw (4 hours post, 24 hours post and 48 hours post) samples were taken. Maximal voluntary isometric contractions of the knee extensors were also measured immediately after the exercise protocol and after 1 week recovery. Creatine kinase (CK) analysis on the serum samples was used to conclude muscle damage. The muscle biopsy samples were used for protein quantification (Western blot) and gene expression assessment (semi-quantitative and real-time PCR). The results showed decreased force production immediately after eccentric exercise (p < 0.05), while returning back to baseline values at 1 week post exercise and CK results showed a significant increases at 4 hours (p<0.05), 24 hours (p<0.001) and 48 hours (p<0.01) after exercise. There were no significant differences in myostatin precursor protein (43 kDa), phosphorylated Smad2,3, Smad7 or activin receptor IIb in response to eccentric exercise. However, the follistatin protein was increased at both 4 hours and 24 hours after exercise (p<0.01). RNA analysis of the extracellular matrix (ECM) protein, decorin, revealed the existence of the splice variants A1 and A2 in human skeletal muscle. The RT-PCR analysis (n=4) of these variants showed no significant difference when comparing pre- to post-exercise. The decorin core protein was also investigated by means of antibody probing and results revealed the need for ABC chondroitinase enzyme treatment before immunoblotting of human skeletal muscle samples. The results concerning knee extensor force reduction and circulating creatine kinase showed the effectiveness of plyometric jumping in producing skeletal muscle damage in the lower limbs of unfit individuals, unaccustomed to eccentric exercise. In conclusion, myostatin, and its associated signalling cascade, are not activated in early muscle regeneration, but follistatin is increased during this phase possibly aiding and initiating the muscle repair process. Future studies: Variants of decorin are expressed in human skeletal muscle, increasing the complexity that should be taken into account in studies concerning the regulation of decorin in a human model. Investigation into myostatin protein at different post-translational levels needs more clarification. Published methods and materials used in different laboratories are not consistent and investigators should attempt to standardise protocols in order to compare results between studies more effectively. Of importance, these results show that the myostatin at protein level report different results compared to mRNA analysis and that more investigation into myostatin regulatory factors, with special reference to follistatin and decorin, is needed in future human models.
AFRIKAANSE OPSOMMING: Die doel van hierdie studie was om die kragtige spiere reguleerder, miostatin, en sy reguleerders in reaksie op 'n akute aanval van pliometriese spronge te ondersoek. Die deelnemers is gewerf en gekeur deur karakterisering deur middel van isometriese krag produksie toetse, basislyn bloed kreatien kinase vlakke en VO2maks resultate. Die geselekteerde individue (N = 15) is onderhewig aan 'n basislyn spierbiopsie vir vergelykende doeleindes. Die studie het gebruik gemaak van pliometriese spronge (essentriese spier aksie) as die oefening intervensie waarna spierbiopsie (4 uur na en 24 uur na) en bloed (4 uur na, 24 uur na en 48 uur na) monsters geneem is. Isometriese kontraksies van die knieverlengers is ook gemeet onmiddellik na die oefening protokol en na 1 week se herstel. Kreatine kinase (KK) ontleding van die serum monsters is gebruik om spierskade aftelei. Die spierbiopsie monsters was gebruik vir proteïen kwantifisering (Western klad) en die assessering van geen uitdrukking (semi-kwantitatiewe en real-time PCR). Die resultate het gewys dat krag produksie afgeneem het onmiddellik na essentriese oefening (p <0.05), terwyl dit terugkeer na die oorspronklike waardes 1 week na oefening en KK resultate toon 'n beduidende toename by 4 uur (p <0,05), 24 uur (p <0,001) en 48 uur (p <0,01) na oefening. Daar was geen betekenisvolle verskille in Miostatien voorloper proteïen (43 kDa), gefosforileerde Smad2,3, Smad7 of Activin reseptoor IIb in reaksie op essentriese oefening. Dit is egter die follistatien proteïen wat verhoog by beide 4 uur en 24 uur na oefening (p <0,01). RNS ontleding van die ekstrasellulêre matriks (ESM) proteïen, decorin, het die bestaan van die splitsing variante A1 en A2 in menslike skeletspier, aan die lig gebring. Die RT-PCR analise (n = 4) van hierdie variante het geen betekenisvolle verskille getoon wanneer voor met na-oefening vergelyk is. Die decorin kern proteïen is ook ondersoek deur middel van teenliggaam afhanklike metodes en resultate het die behoefte aan ABC chondroitinase ensiem behandeling voor immunokladding van menslike skeletspier monsters gesteun. Die resultate aangaande knieverlenger krag vermindering en sirkuleerende kreatien kinase het die doeltreffendheid van pliometriese spronge in die vervaardiging van skeletspier skade in die onderste ledemate van individue ongewoond aan essentriese oefening verseker. Ten slotte, Miostatien, en sy verwante sein kaskade, is nie geaktiveer vroeg in spier herstelling, maar follistatien is tydens hierdie fase verhoog en help moontlik met die aanvang van die spier herstel. Toekomstige studies: variante van decorin word uitgedruk in menslike skeletspier, wat die kompleksiteit aangaande decorin verhoog en dit is iets wat in ag geneem moet word in studies wat handel oor die regulering van decorin in mens modelle. Ondersoek na miostatien proteïen op verskillende na-translasie vlakke moet meer duidelikheid verkry. Gepubliseer metodes en materiaal wat gebruik word in verskillende laboratoriums is nie konsekwent en ondersoekbeamptes moet probeer om protokolle te standaardiseer sodat resultate van studies meer effektief kan vergelyk word. Van belang is, die resultate wys dat miostatien op proteïen vlak verskillende resultate vertoon in vergelyking met boodskapper-RNS ontleding en dat meer ondersoek na miostatien regulerende faktore, met spesiale verwysing na follistatien en decorin, nodig is in toekomstige menslike modelle.
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Gavaza, Takayedzwa. "Culturally-relevant augmented user interfaces for illiterate and semi-literate users". Thesis, Rhodes University, 2012. http://hdl.handle.net/10962/d1006679.
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This thesis discusses guidelines for developers of Augmented User Interfaces that can be used by illiterate and semi-literate users. To discover how illiterate and semi-literate users intuitively understand interaction with a computer, a series of Wizard of Oz experiments were conducted. In the first Wizard of Oz study, users were presented with a standard desktop computer, fitted with a number of input devices to determine how they assume interaction should occur. This study found that the users preferred the use of speech and gestures which mirrored findings from other researchers. The study also found that users struggled to understand the tab metaphor which is used frequently in applications. From these findings, a localised culturally-relevant tab interface was developed to determine the feasibility of localised Graphical User Interface components. A second study was undertaken to compare the localised tab interface with the traditional tabbed interface. This study collected both quantitative and qualitative data from the participants. It found that users could interact with a localised tabbed interface faster and more accurately than with the traditional counterparts. More importantly, users stated that they intuitively understood the localised interface component, whereas they did not understand the traditional tab metaphor. These user studies have shown that the use of self-explanatory animations, video feedback, localised tabbed interface metaphors and voice output have a positive impact on enabling illiterate and semi-literate users to access information.TeX
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Orendurff, Michael S. "Dynamic foot and ankle characteristics in functionally relevant gait performance in those with and without a pathology". Thesis, University of Roehampton, 2012. https://pure.roehampton.ac.uk/portal/en/studentthesis/dynamic-foot-and-ankle-characteristics-in-functionally-relevant-gait-performance-in-those-with-and-without-a-pathology(abd2dc9a-26a9-47fd-afcc-edee49360c64).html.
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The human ankle joint is hypothesized to be a primary controller of support, propulsion and steering during locomotion. A series of experiments were initiated to understand ankle plantarflexor muscle kinematics and kinetics in normal and pathological gait, and to define the specific locomotor demands of community ambulation. Additional experiments were then conducted to quantify the effects of walking speed on plantar pressures and centre of mass motion, to illuminate the role of the ankle in acceleration and deceleration during walking, and to examine how humans alter their kinematics and kinetics to turn. The results of these experiments provide support for the hypothesis that the ankle joint is important in a wide range of locomotor movements beyond walking straight ahead at constant speed. The ankle appears instrumental in adapting to different walking speeds, altering both the pressures on specific regions the plantar surface and the motion of the centre of mass across a range of speeds. The ankle also has subtle kinetic changes that appear to modulate acceleration and deceleration during single limb stance. For turning, the ankle plays a role during slowing into the turn and accelerating after the turn, but mediolateral shears appear to alter the trajectory of the body to negotiate a corner and the external hip rotators appear to rotate the trunk toward the new direction of travel. This work extends our understanding of the ankle in functionally relevant gait activities beyond simple straight-ahead walking at constant speed. The published papers included in this supporting statement have been cited by 180 different subsequent peerreviewed publications, suggesting that this work has had some impact on the field.
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Sinisalo, Johanna. "Interactions between humans and dogs : Neurobiological factors relevant for the treatment of exhaustion-related disorders". Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-11436.
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Increasing evidence illustrates an involvement of stress in a large variety of physical and mental illness. Together with the evolutionary development of the social behavior in humans, the traditional interpretations of the attachment theory and the social support theory underscores the importance of affection, belonging and appreciation for human well-being. Not only can an imbalanced stress system be the cause of severe pathological consequences, insufficient social contact can also hamper recovery. Frequent usage of animals in various settings steadily illustrates both physiological and psychological benefits on both the young and the old, the healthy and the ill. Through the study of neurobiological factors, with oxytocin as a central mediator of social behavior and its impact in turn on the stress- and cortisol system, this paper examines the possibility of animals to function as social support. The potential of animals to reduce the suffering in patients with stress related psychiatric disorders, such as the highly frequent exhaustion disorder, human-animal interactions might offer a non-invasive complementary tool to current treatment methods.
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Persson, Eva. "Drug Dissolution under Physiologically Relevant Conditions In Vitro and In Vivo". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Universitetsbiblioteket [distributör], 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7195.
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