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1
Liu, Ka-yuet. "Pathways to Suicidal Behaviour : A Mechanism-Based Approach." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.504109.
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Graciotti, Michele. "An integrated approach to unravelling malaria cell signalling pathways." Thesis, University of Leicester, 2013. http://hdl.handle.net/2381/27739.
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In the current thesis we analyse protein phosphorylation pathways in P. falciparum, the protozoa responsible for the most virulent form of malaria in order to both understand the role and scope of this protein modification in the parasite, and to explore its feasibility as a new drug target. With the aim to map phosphorylation pathways controlled by P. falciparum Casein Kinase 2 (PfCK2), we developed a new chemical-biological approach based on γ-modified ATP analogues bearing reporting groups on the transferred phosphate in order to selectively tag CK2 substrates. Despite being able to efficiently synthesise a small set of analogues, the data presented here shows that the P-N linkage bond between the nucleotide and the tag is stable during the assay conditions but not during the product analysis due to its acidic liability (e.g. with HPLC, MALDI); suggesting that a different type of linkage should be chosen in the future. Detailed characterisation studies of the parasite PfCK2 presented here showed a number of important features differing from human CK2. Docking analyses with a CK2 inhibitor showed that the PfCK2 ATP binding pocket is smaller than human CK2 due to the presence of Val116 and Leu45 which in the human kinase are replaced by more bulky isoleucine residues: Ile120 and Ile49. The difference between the human and parasite CK2 orthologues extends further to mechanisms of activation and regulation. Shown here is the autophosphorylation of PfCK2 that, unlike the human orthologue, occurs within subdomain I at Thr63. This autophosphorylation is essential for full catalytic activity. In addition we also showed that Thr63 phosphorylation regulates the interaction between the calalytic α-subunit and the regulatory β2-subunit. Here, we also presented evidence for tyrosine phosphorylated proteins in parasite infected red blood cells. PfCK2 can act as a dual specificity kinase phosphorylating P. falciparum Minichromosome Maintenance protein 2 (PfMCM2) on Tyr16 in vitro. It is therefore possible that PfCK2 may contribute to tyrosine phosphorylation within the parasite. Finally, we also reported a study regarding MCM2-Ser13 phosphorylation which successfully identified PfCK1 as the kinase responsible for this event.
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Magliarelli, Helena. "Uncovering ubiquitylation pathways in liver metabolism by a proteomic approach." Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ083/document.
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Chez les vertébrés, le foie est un des organes majeurs du métabolisme en étant le siège de la régulation de différentes voies du métabolisme qui contrôlent l’homéostasie du glucose et des lipides. En se basant sur des travaux de recherche récents suggérant que le système de conjugaison de l'ubiquitine est engagé en réponse à différents signaux métaboliques, nous avons réalisé une analyse protéomique globale dans le but d’identifier des protéines ubiquitylées dans le foie de souris soumises á un protocole de jeûne – re-nourrissage. Parmi les 117 protéines différemment ubiquitylé sur le jeûne ou le re-nourrissage, nous avons identifié complément 3 (C3) dans le foie de souris réalimentées. Nous avons observé qu'un produit d'activation de C3, C3a, est ubiquitylé dans les hépatocytes primaires traités avec les médias riches en nutriments. Ainsi, nous proposons que l'ubiquitination de C3 joue un rôle dans la régulation des fonctions inflammatoires ou métaboliques de C3 dans le foieIn vertebrates, the liver has developed to be a major metabolic organ able to control glucose and lipid homeostasis. It activates or inhibits specific pathways in a regulated manner, depending on the metabolic state of our organism. Based on the emerging experimental evidence suggesting that the ubiquitin conjugation system is engaged in response to different metabolic cues, we conducted a global proteomic analysis to identify metabolic pathways modified by ubiquitylation. To this end, we used livers of mice subjected to a fasting – refeeding protocol. Amongst the 117 proteins differentially ubiquitylated upon fasting or refeeding conditions, we identified complement 3 (C3) to be ubiquitinated in livers of refed mice. We observed that an activation product of C3, C3a, is ubiquitylated in primary hepatocytes treated with nutrient-rich media. Thus, we suggest that the ubiquitylation of C3 plays a role in the regulation of inflammatory or metabolic functions of C3 in the liver
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Flores, Ricardo, Yiting Li, Alexander Yu, Jianhe Shen, Pulivarthi Rao, Serrine Lau, Marina Vannucci, Ching Lau, and Tsz-Kwong Man. "A systems biology approach reveals common metastatic pathways in osteosarcoma." BioMed Central, 2012. http://hdl.handle.net/10150/610101.
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BACKGROUND:Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. The survival rate of patients with metastatic disease remains very dismal. Nevertheless, metastasis is a complex process and a single-level analysis is not likely to identify its key biological determinants. In this study, we used a systems biology approach to identify common metastatic pathways that are jointly supported by both mRNA and protein expression data in two distinct human metastatic OS models.RESULTS:mRNA expression microarray and N-linked glycoproteomic analyses were performed on two commonly used isogenic pairs of human metastatic OS cell lines, namely HOS/143B and SaOS-2/LM7. Pathway analysis of the differentially regulated genes and glycoproteins separately revealed pathways associated to metastasis including cell cycle regulation, immune response, and epithelial-to-mesenchymal-transition. However, no common significant pathway was found at both genomic and proteomic levels between the two metastatic models, suggesting a very different biological nature of the cell lines. To address this issue, we used a topological significance analysis based on a "shortest-path" algorithm to identify topological nodes, which uncovered additional biological information with respect to the genomic and glycoproteomic profiles but remained hidden from the direct analyses. Pathway analysis of the significant topological nodes revealed a striking concordance between the models and identified significant common pathways, including "Cytoskeleton remodeling/TGF/WNT", "Cytoskeleton remodeling/Cytoskeleton remodeling", and "Cell adhesion/Chemokines and adhesion". Of these, the "Cytoskeleton remodeling/TGF/WNT" was the top ranked common pathway from the topological analysis of the genomic and proteomic profiles in the two metastatic models. The up-regulation of proteins in the "Cytoskeleton remodeling/TGF/WNT" pathway in the SaOS-2/LM7 and HOS/143B models was further validated using an orthogonal Reverse Phase Protein Array platform.CONCLUSIONS:In this study, we used a systems biology approach by integrating genomic and proteomic data to identify key and common metastatic mechanisms in OS. The use of the topological analysis revealed hidden biological pathways that are known to play critical roles in metastasis. Wnt signaling has been previously implicated in OS and other tumors, and inhibitors of Wnt signaling pathways are available for clinical testing. Further characterization of this common pathway and other topological pathways identified from this study may lead to a novel therapeutic strategy for the treatment of metastatic OS.
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Rosen, Seth D. "Pathways to prevention? evaluating the United Kingdom's approach to counter-radicalization /." Connect to Electronic Thesis (CONTENTdm), 2010. http://worldcat.org/oclc/645628208/viewonline.
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Burrowes, Jodie Anne. "A functional attributes approach to secondary succession pathways in New Zealand." Thesis, University of Canterbury. Department of Biological Sciences, 1999. http://hdl.handle.net/10092/4822.
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While for many years we have been attempting to conserve the remaining natural
areas in New Zealand, interest has recently increased in the possibility of restoring
degraded areas back to (predominantly) native vegetation. Knowledge of probable
secondary succession pathways for such areas would assist their management. A
method to describe, and thus compare, succession pathways would help determine the
strongest influences on the succession process. If this method did not use plant
species, but species grouped according to shared characteristics, comparison of
succession pathways between places with different floras would be possible.
This thesis is the first use of the functional attributes method to describe succession
pathways for New Zealand vegetation. The method was first tested by a quantitative
comparison of species and functional attributes data for two New Zealand sites, using
ordination and correlation analyses. The results supported the hypothesis that
conversion of the data from species to functional attributes will permit, by use of
ordination analysis, recovery of the same rank-order of sites in a successional
sequence, using field data from New Zealand vegetation. The second test was a
qualitative assessment of the method, using four New Zealand sites, involving
comparisons between regeneration sequences in the literature, and those generated by
functional attributes information. The regeneration sequence generated from
functional attributes information was found to approximately reproduce the sequence
predicted or observed by researchers for the study sites.
The results were very encouraging, and showed that the functional attributes method
has potential for representing succession pathways in New Zealand sites. The
potential of the method as a land management tool, including modelling responses to
introduced species, is discussed. The next step would be the development of a
computer model, allowing multiple sequences to be quickly generated with different
disturbance regimes and initial vegetation.
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Kruse, Colin Peter Singer. "Data-Enabled Approach to Characterize Dynamic Regulatory Pathways in Two Kingdoms." Ohio University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1573746719306039.
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Dondelinger, Frank. "Machine learning approach to reconstructing signalling pathways and interaction networks in biology." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/7850.
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In this doctoral thesis, I present my research into applying machine learning techniques for reconstructing species interaction networks in ecology, reconstructing molecular signalling pathways and gene regulatory networks in systems biology, and inferring parameters in ordinary differential equation (ODE) models of signalling pathways. Together, the methods I have developed for these applications demonstrate the usefulness of machine learning for reconstructing networks and inferring network parameters from data. The thesis consists of three parts. The first part is a detailed comparison of applying static Bayesian networks, relevance vector machines, and linear regression with L1 regularisation (LASSO) to the problem of reconstructing species interaction networks from species absence/presence data in ecology (Faisal et al., 2010). I describe how I generated data from a stochastic population model to test the different methods and how the simulation study led us to introduce spatial autocorrelation as an important covariate. I also show how we used the results of the simulation study to apply the methods to presence/absence data of bird species from the European Bird Atlas. The second part of the thesis describes a time-varying, non-homogeneous dynamic Bayesian network model for reconstructing signalling pathways and gene regulatory networks, based on L`ebre et al. (2010). I show how my work has extended this model to incorporate different types of hierarchical Bayesian information sharing priors and different coupling strategies among nodes in the network. The introduction of these priors reduces the inference uncertainty by putting a penalty on the number of structure changes among network segments separated by inferred changepoints (Dondelinger et al., 2010; Husmeier et al., 2010; Dondelinger et al., 2012b). Using both synthetic and real data, I demonstrate that using information sharing priors leads to a better reconstruction accuracy of the underlying gene regulatory networks, and I compare the different priors and coupling strategies. I show the results of applying the model to gene expression datasets from Drosophila melanogaster and Arabidopsis thaliana, as well as to a synthetic biology gene expression dataset from Saccharomyces cerevisiae. In each case, the underlying network is time-varying; for Drosophila melanogaster, as a consequence of measuring gene expression during different developmental stages; for Arabidopsis thaliana, as a consequence of measuring gene expression for circadian clock genes under different conditions; and for the synthetic biology dataset, as a consequence of changing the growth environment. I show that in addition to inferring sensible network structures, the model also successfully predicts the locations of changepoints. The third and final part of this thesis is concerned with parameter inference in ODE models of biological systems. This problem is of interest to systems biology researchers, as kinetic reaction parameters can often not be measured, or can only be estimated imprecisely from experimental data. Due to the cost of numerically solving the ODE system after each parameter adaptation, this is a computationally challenging problem. Gradient matching techniques circumvent this problem by directly fitting the derivatives of the ODE to the slope of an interpolant. I present an inference procedure for a model using nonparametric Bayesian statistics with Gaussian processes, based on Calderhead et al. (2008). I show that the new inference procedure improves on the original formulation in Calderhead et al. (2008) and I present the result of applying it to ODE models of predator-prey interactions, a circadian clock gene, a signal transduction pathway, and the JAK/STAT pathway.
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Ghinescu, Rodica. "A modeling-based approach for investigating multiple processing pathways in simple visual tasks /." free to MU campus, to others for purchase, 2004. http://wwwlib.umi.com/cr/mo/fullcit?p3164509.
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Alles, Marie Chehani Clinical School St Vincent's Hospital Faculty of Medicine UNSW. "A bioinformatics approach to discovery of estrogen-responsive genetic pathways in breast cancer." Awarded by:University of New South Wales. Clinical School - St Vincent's Hospital, 2008. http://handle.unsw.edu.au/1959.4/41513.
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Breast cancers fall into two major classes depending on their estrogen receptor (ER) status. ER+ and ER- tumors have very different molecular phenotypes, and may have distinct cells of origin. ER- tumors generally fail to respond to endocrine therapy and have a poorer prognosis. To develop a comprehensive understanding of the gene networks active in ER+ compared to ER- breast cancers, we performed a meta-analysis of Grade 3 breast cancers from five published datasets. A measure of association with ER status taking into account intra- and inter-study variability was calculated for every probe set. The meta-analysis revealed that ER-/Grade 3 tumors show increased expression of proliferation-associated functional categories when compared to ER+/Grade 3 tumors. Using Gene Set Enrichment Analysis we show that transcript levels of direct transcriptional targets of ER are lower in ER- tumors, but that expression of other estrogen-induced genes is higher in ER- tumors. Transcript levels of both direct and other targets of the estrogen-regulated MYC gene and the E2F family of genes are significantly higher in ER- tumors. The increased expression of targets of MYC and E2F is particularly pronounced in the "basal" subgroup of ER- tumors. This suggests that a study assessing the association of these genes with clinical outcome in ER- patients is warranted, but is not currently feasible due to lack of suitable publicly available data. The contribution of genes regulated or bound by estrogen, MYC or E2F to increased risk of relapse in ER+ tamoxifen-treated patients was assessed in a pilot study using Cox proportional hazards models and Gene Set Enrichment Analysis. The high expression of several gene sets containing genes induced by estrogen and/or MYC and direct targets of MYC and E2F was correlated with poor outcome in these patients. We conclude that over-expression or constitutive activation of MYC, possibly in conjunction with elevated E2F activity, may lead to the induction of a set of genes characteristic of the estrogen response thereby contributing to increased proliferation in ER- breast tumors, particularly in the basal subgroup. A pilot survival study indicated that MYC- and E2F-activity may play a role in tamoxifen-resistance.
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Harris, Danielle Arlanda. "A typological approach to exploring pathways for rapists, child molesters and incest offenders." College Park, Md. : University of Maryland, 2004. http://hdl.handle.net/1903/1448.
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Thesis (M.A.) -- University of Maryland, College Park, 2004.Thesis research directed by: Dept. of Criminology and Criminal Justice. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Humphrys, Elka Suzanne. "Understanding the pathways to oesophageal and stomach cancer diagnosis : a multi-methods approach." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/289397.
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Increasing symptom awareness, encouraging help-seeking, and facilitating timely referral are key for improving cancer outcomes, particularly for cancers such as oesophageal and gastric (stomach), where five-year survival is less than 20%. In this research, I used multiple methods to explore factors that influence timely diagnosis of these cancers from a patient's perspective, with a particular focus on health literacy (accessing, understanding and using health information, and navigating healthcare systems). I started by exploring current knowledge in this field before conducting a systematic review investigating health literacy in the timely diagnosis of symptomatic cancer. Literature was searched from January 1990-May 2017 using six bibliographic databases. I screened 2304 titles/abstracts, assessed 26 full-text papers and included three, although they were methodologically weak, therefore limiting the conclusions. To examine pathways to diagnosis for oesophageal and gastric cancer, I conducted a questionnaire study of newly diagnosed patients across two hospitals in the East and North East of England. 127 participants were recruited (39.6% recruitment rate), aged 44-96 (median 71); 102 male (80%). Most had oesophageal cancer (n=102, 80%); 64 (50%) of the total cohort were late-stage at diagnosis. Common pre-diagnostic symptoms varied between cancers (oesophageal: difficulty swallowing (n=66, 65%), painful swallowing (n=55, 54%); gastric: fatigue/tiredness (n=20, 80%), weight loss (n=13, 52%)). The questionnaire included two domains (engagement, understanding) of the Health Literacy Questionnaire with participants demonstrating high health literacy (mean 4.18 and 4.28, score 1-5). The median time from noticing the trigger symptom (prompting help-seeking) to diagnosis was 81 days (IQR 45-137.5, n=107). Twenty-six participants were purposively sampled, from questionnaire respondents, for face-to-face interviews (aged 55-88, 18 male, 15 with oesophageal cancer). I undertook thematic analysis to explore participant accounts of their pathways to diagnosis, identifying that the symptom nature was important for appraisal, while health literacy ability influenced the health system interval. Descriptions of 'heartburn', 'reflux' and 'indigestion' differed between participants, suggesting these terms may introduce uncertainty in relation to symptom experience. This is the first study to explore the role of health literacy in the timely diagnosis of symptomatic cancer, and pathways to diagnosis for oesophageal and gastric cancers, from a patient's perspective. Findings provide important insights for the development of targeted awareness campaigns and strategies enhancing GP symptom exploration.
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Song, Guang. "A motion planning approach to protein folding." Texas A&M University, 2003. http://hdl.handle.net/1969.1/337.
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Protein folding is considered to be one of the grand challenge problems in biology. Protein folding refers to how a protein's amino acid sequence, under certain physiological conditions, folds into a stable close-packed three-dimensional structure known as the native state. There are two major problems in protein folding. One, usually called protein structure prediction, is to predict the structure of the protein's native state given only the amino acid sequence. Another important and strongly related problem, often called protein folding, is to study how the amino acid sequence dynamically transitions from an unstructured state to the native state. In this dissertation, we concentrate on the second problem. There are several approaches that have been applied to the protein folding problem, including molecular dynamics, Monte Carlo methods, statistical mechanical models, and lattice models. However, most of these approaches suffer from either overly-detailed simulations, requiring impractical computation times, or overly-simplified models, resulting in unrealistic solutions.
In this work, we present a novel motion planning based framework for studying protein folding. We describe how it can be used to approximately map a protein's energy landscape, and then discuss how to find approximate folding pathways and kinetics on this approximate energy landscape. In particular, our technique can produce potential energy landscapes, free energy landscapes, and many folding pathways all from a single roadmap. The roadmap can be computed in a few hours on a desktop PC using a coarse potential energy function. In addition, our motion planning based approach is the first simulation method that enables the study of protein folding kinetics at a level of detail that is appropriate (i.e., not too detailed or too coarse) for capturing possible 2-state and 3-state folding kinetics that may coexist in one protein. Indeed, the unique ability of our method to produce large sets of unrelated folding pathways may potentially provide crucial insight into some aspects of folding kinetics that are not available to other theoretical techniques.
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Nawfal, Saadi Failali. "An open source approach to Sweden's energy system : A review of future energy pathways." Thesis, KTH, Energisystemanalys, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-147363.
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This paper discusses the development of an energy systems model for Swedenconsidering electricity, heat and direct fossil fuel consumption in the residential,industrial and transport sectors as well as the energy interaction with the other Nordiccountries and its impact on the Swedish energy system. The model is developed in theOpen source energy modelling system (OSeMOSYS) (Mark Howells 2011) andshowcases potential energy investment options for Sweden in the next four decades(2010-2050). It considers different scenarios and provides a technology neutralassessment of how Sweden can invest in energy infrastructure in the most judiciousway. The paper also describes the new user interface developed called ANSWEROSeMOSYS.The paper further discusses the results of the different scenarios. Thebusiness as usual scenario shows an inclination towards investments in nuclear power.Further scenarios consider the gradual phasing out of the use of oil in CHP plants andnuclear power as well as new energy policies and tax reforms. The paper discusses theseresults in detail and demonstrates how Sweden could improve its energy infrastructureconsidering different policy implications and constraints put up by the availability andfeasibility of different resources. Finally, the prospect of wider stakeholder engagementbased on this model is discussed. Building on the open-source nature of the model,inputs and modifications from research institutes, energy modelling experts,government bodies, as well as the wider public will be incorporated into the model. Thesource code and modelling data will be made publicly available.
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Giraudo, Maeva. "Response of a lepidopteran pest to xenobiotics : exploring transduction pathways by a transcriptomic approach." Nice, 2010. http://www.theses.fr/2010NICE4023.
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Les insectes herbivores ont développé des mécanismes de détoxication des toxines de plantes qu’ils ingèrent, notamment grâce à l’expression de cytochrome P450. Les P450 métabolisent les xénobiotiques, et chez les vertébrés, les récepteurs nucléaires qui contrôlent leur induction sont bien connus. Nous avons montré chez Drosophila que peu de P450 répondent aux xénobiotiques et que le CYP6A2 montre un pattern d’expression similaire au CYP2 chez les mammifères qui est induit par les récepteurs nucléaires CAR/PXR. Chez le ravageur polyphage Spodoptera frugiperda, nous avons réalisé une analyse transcriptomique et montré que les patterns de genes différentiellement exprimés dans le midgut et dans les cellules Sf9 de cet insecte, étaient spécifiques pour chacun des xénobiotiques, suggérant de multiples mécanismes de transduction. Des analyses par qRT-PCR ont montré que les toxines de plantes sont de forts inducteurs de P450 in vivo, avec peu d’effets in vitro. Une étude des effets de deux insecticides mimant des hormones, le méthoxyfenozide et le méthoprene, dans les cellules Sf9 a montré que ces deux composés induisent un arrêt du cycle cellulaire. Nous avons cloné SfHR96, un récepteur nucléaire orthologue des xénosenseurs CAR/PXR chez les vertébrés, et observé que ce récepteur est exprimé constitutivement dans tous les tissus et les stades de développement. Nous avons initié l’étude de la fonction de SfHR96 par des techniques de RNAi in vitro, et in vivo grâce à l’expression de mutants dominant négatifs dans des vers à soie transgéniques. Nous formons l’hypothèse que SfHR96 dimérise avec ultraspiracle (USP), l’orthologue chez les insectes du récepteur RXR des vertébrésHerbivorous insects have developed detoxification mechanisms to metabolically inactivate the plant toxins that they ingest, mainly based on cytochrome P450 expression. P450s are induced by and metabolize xenobiotics, and for vertebrates, the nuclear receptors that control P450s induction are well understood. We have shown in Drosophila that only small subsets of P450s are inducible by xenobiotics and that the specific CYP6A2 showed pattern of induction similar to that of mammalian CYP2 genes that are induced by PXR/CAR nuclear receptors. In the polyphagous pest Spodoptera frugiperda (Lepidoptera, Noctuidae) we studied gene expression by a transcriptomic analysis of and found that the patterns of differentially transcribed genes in the midgut and in the derived Sf9 cells of this insect were specific to each chemical tested, suggesting multiple, partially overlapping transduction mechanisms. QRT-PCR analysis showed that the plant toxins were the strongest inducers of a small number of P450s in vivo, with moderate effects in vitro. Specific focus on the effects of two hormone mimics, methoxyfenozide and methoprene, in Sf9 cells showed that they both induced cell cycle arrest. We have cloned SfHR96, a nuclear receptor ortholog of the vertebrate xenosensors CAR and PXR. We found that this receptor is not inducible by xenobiotics and is expressed constitutively in all tissues and developmental stages. Strategies to demonstrate the function of SfHR96 by inactivation in vitro by RNAi and in vivo with dominant negative mutants in transgenic silkworms have been initiated. We hypothesize that SfHR96 dimerizes with ultraspiracle (USP), the insect ortholog of vertebrate RXR
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Szwalbe, Agnieszka J. "A combined chemical and biological approach towards elucidating fungal maleidride and xanthone biosynthetic pathways." Thesis, University of Bristol, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.715739.
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Streicher, Kai Nino. "Sustainable energy system pathways : Development and assessment of an indicator-based model approach to enhance sustainability of future energy technology pathways in Germany (SEnSys)." Thesis, Linköpings universitet, Institutionen för tema, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-111564.
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After the nuclear fallout in Japan, Germany decided to back out from nuclear energy while at the same time changing the energy supply from fossil to renewable sources. This elaborate plan, known as Energiewende, will require significant economic and structural efforts that will have profound impacts on the environment and society itself. It is therefore crucial to identify possible technological pathways that can lead to a renewable energy supply, while reducing negative impacts on a holistic scope. In order to analyse alternative energy technology scenarios in Germany, this thesis focuses on the development of an indicator-based numerical Sustainable Energy Systems (SEnSys) model approach. Other than previous approaches, the SEnSys model considers full aggregated impacts of technological pathways leading to future configurations. With the help of an exemplary case study on two alternative energy technology scenarios (Trieb1 and Trieb2), the feasibility of the SEnSys model in evaluating sustainability is subsequently assessed. The results can affirm the findings of previous studies concerning lower economic and environ- mental impacts for scenario Trieb2, with small shares of renewable energy imports, compared to scenario Trieb1 based on only local but fluctuating renewables. Additionally, the results are in accordance with other relevant studies, while offering new valuable insights to the topic. Given a comprehensive revision of the identified uncertainties and limitations, it can be stated that the SEnSys model bares the potential for further analysing and improving sustainability of energy technology scenarios in Germany and other countries.
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Fletcher, Donald George. "The viability of energy plantations in Thailand : an energy system approach using alternative conversion pathways." Thesis, University of Oxford, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236249.
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Pathak, Ashutosh K. "A proteomics based approach of IgE-receptor mediated signalling pathways in a mast cell line." Thesis, University of Sheffield, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.427236.
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Jalil, Vega Francisca Alejandra. "Development of a systems approach for studying decarbonisation pathways of heat demand in the UK." Thesis, Imperial College London, 2018. http://hdl.handle.net/10044/1/61337.
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In the UK, 45% of the total energy demand in 2016 was used for heating purposes, 68% of which was supplied by natural gas. Credible alternatives for decarbonising heat include district heating combined with low carbon heat sources, heat electrification using heat pumps (with a decarbonised electricity system), or hydrogen-fuelled heat technologies. Adoption of these technologies must proceed alongside network infrastructure investment and developments in the broader energy system, such as increased renewable power generation. At the time of writing, no systematic framework exists that trades off individual building and district heat supply technologies and their associated infrastructures at high spatial resolutions. This work formulates and applies such framework. It presents a mixed integer linear optimisation model that decides on investments and operation of gas, electricity, heat, and hydrogen technologies and associated network infrastructures, for supplying commercial and domestic heat and electricity demands in spatially-resolved urban areas, minimising the net present cost through 2050. This model is implemented to study four key issues related to heat decarbonisation: Comparing different temperature heat networks for decarbonising heat; the effect of spatial resolution in outcomes of energy systems models for heat; the role of hydrogen in heat decarbonisation pathways in the UK; and the sensitivity of heat decarbonisation outcomes to uncertainty in techno-economic parameters. Results show that adoption of heat technologies depends, among several factors, on linear heat density, zone-to-zone connectivity, and scenario-specific techno-economic assumptions such as technology, fuels, or electricity prices. Linear heat density adoption thresholds were found for individual technologies. Medium and high temperature heat networks were adopted in high and medium/high linear heat density zones, respectively. Hydrogen boilers were adopted when enabling gas networks to be retrofitted to transport hydrogen. Finally, spatial resolution was shown to be a determining factor for finding cost-effective heat decarbonisation pathways through energy systems models.
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Turkington, Richard Calvin. "A systems biology approach to define pathways of oxaliplatin and 5-fluorouracil resistance in colorectal cancer." Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.580110.
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The discovery of underlying mechanisms of drug resistance and the development of novel agents to target these pathways is a priority for patients with advanced colorectal cancer (CRC). The aim of this study was to identify novel targets whose knock-down is important in mediating sensitivity to 5-FU and oxaliplatin in Kras wild type and mutant CRC models. Materials and Methods. Transcriptional profiling (Almac Diagnostics Colorectal Cancer Disease Specific Array'") of pre-treatment metastatic CRC liver biopsies and oxaliplatin/5-FU resistant HCTl16 cell lines followed by Pathway Analysis and Gene Set Enrichment Analysis (GSEA) were used to identify individual genes from novel drug-sensitivity pathways for incorporation into a RNAi screen. Results. We identified panels of genes whose expression is altered (acutely and basally) between sensitive and 5-FU- or oxaliplatin-resistant models. The significant pathways involved in 5-FU/oxaliplatin resistance included Cell Cycle, Focal Adhesion, Insulin and MAPK signalling. In the MAPK pathway, we found that FGFR4 silencing potently increased apoptosis in Kras wild type and mutant CRC cells, and this was further enhanced when FGFR4 siRNA was combined with 5-FU or oxaliplatin. FGFR4 inhibition completely inhibited migration of Kras mutant HCTl16 cells and we found that FGFR4 silencing resulted in strong inhibition of ST A T3 activity in Kras mutant, but not Kras wild type, CRC cells. Conclusions. This study demonstrates the utility of microarray expression data, obtained from pre-clinical and clinical samples, and analyzed by pathway and Gene Set Enrichment Analysis to identify pathways of oxaliplatin/5-FU sensitivity in CRC. In addition FGFR4 inhibition in combination with 5-FU or oxaliplatin could represent a novel treatment strategy for Kras mutant and wild type CRC tumours. We are currently investigating FGFR4 small molecule inhibitors in preclinical in vitro and in vivo models.
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Budisavljevic, Sanja. "Anatomy of the perisylvian language pathways in the living human brian : a diffusion tensor imaging approach." Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/anatomy-of-the-persisylvian-language-pathways-in-the-living-human-brian(ea7aa2ab-85fd-4a3d-8d8b-86c88c516c41).html.
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Language is a unique human ability influenced by genetic, cultural and social factors. Decades of research in the field have identified those brain networks that have made the development of language in humans possible. This PhD thesis introduces three studies that aim to explore the anatomy of the perisylvian language pathways (three segments of the arcuate fasciculus) both in healthy and pathological condition, using dffusion tensor imaging tractography. First study examined typical developmental trajectories of the perisylvian language network in a normative data of 101 subjects (age range: 9-49 years). After observing how these pathways mature across life span, second study investigated how these are influenced by genes and environment in a sample of 43 adult twin pairs (26 monozygotic and 17 dizygotic pairs). The results showed that perisylvian language pathways exhibit distinct maturational patterns and vary in respect to genetic control that guides this process. Familial effects played an important role for those tracts that lateralised early in life (frontal lobe connections), whereas those tracts that continue to remodel throughout adolescence (temporo-parietal connections) were driven more by unique environmental effects. While the first two studies explored anatomy of perisylvian language pathways in healthy population, third study examined neural correlates in a pathological condition that affects language processing. This study included 61 adults with autism spectrum disorder and 61 matched neurotypical controls. Localised abnormalities were identified in the left perisylvian language pathways in people with autism spectrum disorder and an association was found between these white matter abnormalities and severity of past language deficits. In conclusion, these findings may be important to furthering our knowledge of the anatomy of the perisylvian language pathways in healthy population. Also, they may facilitate our understanding of possible biological mechanisms that underpin language dysfunction in psychiatric disorders, and lead to new approaches for early diagnosis and treatment.
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Tikkanen, Jussi M. "Identification and inhibition of specific pathways leading to transplant obliterrative bronchiolitis an experimental approach in the rat." Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/tikkanen2/.
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Elderbrock, Evan. "Revealing Promising Pathways for Increasing Urban Ecosystem Services: An Approach Combining Stakeholder Priorities with Ecosystem Service Quantification." Thesis, University of Oregon, 2019. http://hdl.handle.net/1794/24232.
Full textAbstract:
Urban development diminishes the delivery of ecosystem services (ES), defined as benefits from ecological processes and functions critical to human health and well-being. Land-use planners and environmental managers are increasingly familiar with the concept of ES; however, methods for incorporating ES into urban planning are underdeveloped. While previous reports have identified the combination of ES quantification and stakeholder engagement as necessary for increasing the delivery of ES, methods of implementation remain unexplored. To address this disparity, this study combines ES quantification with perspectives from multiple stakeholders to identify specific land cover conversion scenarios that increase the delivery of ES in the Friendly Area Neighborhood of Eugene, Oregon and compares each conversion scenario using an informed weighting system. The result is a method, with potential for use by researchers and public officials, to quantify the delivery of ES, identify stakeholders’ ES priorities, and assess the benefits associated with green infrastructure development.2020-01-11
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Chidgey, Laura Louise. "An integrated approach to unravel the effect pathways of endocrine disrupting chemicals on the developing zebrafish, Danio rerio." Thesis, University of Exeter, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.496171.
Full textAbstract:
Over the last two decades, a wide range of chemicals in the aquatic environment have been shown to elicit disruptive effects on the endocrine system and, in turn, alter physiological function. However, the underlying mechanisms for these effects remain largely elusive. In this thesis, a molecular approach (using DNA microarrays and RTPCR) was employed to investigate the mechanistic basis for estrogenic disruption in ling the zebrafish (Danio rerio) as a model species.
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Conzelmann, Holger. "Mathematical modeling of biochemical signal transduction pathways in mammalian cells a domain-oriented approach to reduce combinatorial complexity /." [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:93-opus-38819.
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Roberts, Sean Anthony. "A GENE THERAPY APPROACH TO THE INHIBITION OF HIV-1 REPLICATION BY RESTORATION OF INNATE ANTIVIRAL DEFENSE PATHWAYS." Diss., Temple University Libraries, 2010. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/99935.
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Microbiology and ImmunologyPh.D.
Since it emerged as an infectious agent in 1981, the human immunodeficiency virus type 1 (HIV-1) is continually disseminated and remain fatal to the majority of those infected. Strategies including highly active retroviral therapies (HAART) with nucleoside analogues and protease inhibitors have shown limited success in therapy due to the virus' ability to evolve rapidly at every replication cycle as a consequence of it's highly error prone reverse transcriptase, generating resistant retroviral strains and in addition to latent HIV-1 reservoirs. Thirty years of research efforts to find a cure or to generate a vaccine has been met with failure. It is, therefore, of necessity to broaden our paradigm of therapy for the treatment and eventual cure of HIV-1 infection. In this study, I look beyond the current anti-retroviral strategies and instead rely on the mammalian host immune system to inhibit HIV-1 replication through molecular genetic manipulation. Here, we approach the inhibition of HIV-1 replication by up-regulation of the innate antiviral pathway that is natural to mammalian cells. HIV-1 derived self-inactivating lentiviral (SIN) vectors were designed and constructed to deliver the antiviral payloads of two antiviral enzymes, p68 kinase (PKR) and 2'-5' oligoadenlyate synthetase (2-5OAS), to target cell, SupT1 lymphoblastoid cells and CD4+ T lymphocytes under the control of a constitutive cytomegalovirus (CMV) promoter. These data here demonstrates a significant inhibition of HIV-1 replication in cells transduced with the anti HIV-1 transgenes PKR and 2-5OAS as determined by HIV-1 induced syncytia formation and HIV-1 p24 antigen capture assay. Furthermore, here demonstrated is an increase up-regulation of PKR and 2-5OAS 96 hr post cell transduction in all the clones when compared to pHIV empty vector control. These results demonstrate that the over-expression of PKR and 2-5OAS can inhibit HIV-1 replication and also confirm the involvement of PKR and 2-5OAS in the IFN-associated antiviral pathway against HIV-1 infection.
Temple University--Theses
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Ni, Ying. "A Machine Learning Approach to Predict Gene Regulatory Networks in Seed Development in Arabidopsis Using Time Series Gene Expression Data." Thesis, Virginia Tech, 2016. http://hdl.handle.net/10919/81463.
Full textAbstract:
Gene regulatory networks (GRNs) provide a natural representation of relationships between regulators and target genes. Though inferring GRN is a challenging task, many methods, including unsupervised and supervised approaches, have been developed in the literature. However, most of these methods target non-context-specific GRNs. Because the regulatory relationships consistently reprogram under different tissues or biological processes, non-context-specific GRNs may not fit some specific conditions. In addition, a detailed investigation of the prediction results has remained elusive. In this study, I propose to use a machine learning approach to predict GRNs that occur in developmental stage-specific networks and to show how it improves our understanding of the GRN in seed development.
I developed a Beacon GRN inference tool to predict a GRN in seed development in Arabidopsis based on a support vector machine (SVM) local model. Using the time series gene expression levels in seed development and prior known regulatory relationships, I evaluated and predicted the GRN at this specific biological process. The prediction results show that one gene may be controlled by multiple regulators. The targets that are strongly positively correlated with their regulators are mostly expressed at the beginning of seed development. The direct targets were detected when I found a match between the promoter regions of the targets and the regulator's binding sequence. Our prediction provides a novel testable hypotheses of a GRN in seed development in Arabidopsis, and the Beacon GRN inference tool provides a valuable model system for context-specific GRN inference.Master of Science
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Hueso, González Andrés. "Pathways to Sustainability in Community-Led Total Sanitation. Experiences from Madhya Pradesh and Himachal Pradesh." Doctoral thesis, Editorial Universitat Politècnica de València, 2013. http://hdl.handle.net/10251/31520.
Full textAbstract:
Community-Led Total Sanitation (CLTS) es un enfoque de saneamiento basado en la facilitación participativa para que las comunidades rurales analicen su situación sanitaria y los riesgos de la defecación al aire libre. Así, se genera un deseo por parte de la
comunidad de pasar a la acción y convertirse en un lugar libre de defecación al aire libre (ODF - open defecation free). El enfoque CLTS ha demostrado ser más efectivo que enfoques pasados y se ha expandido rápidamente por todo el mundo. En la India,
donde se concentran más de la mitad de los defecadores al aire libre del mundo, el CLTS se enfrenta a ciertas dificultades, principalmente debido a la incompatibilidad con la campaña de saneamiento del gobierno indio, pero existen algunas áreas dónde sí
ha podido ser introducido con cierto éxito. Por otro lado, existen evidencias de comunidades ¿tanto en India como en otros
lugares¿ que vuelven a defecar al aire libre después de haber sido declaradas ODF. Esto plantea preguntas importantes en relación a la sostenibilidad de los resultados del CLTS.
Para arrojar luz sobre estas cuestiones, esta tesis pretende explorar cómo contribuyó la introducción del CLTS en Madhya Pradesh (MP) y Himachal Pradesh (HP) al saneamiento sostenible, teniendo en cuenta tanto el proceso político que determinó la
intervención en lo local, como losmecanismos a través de los que dicha intervención contribuyó al saneamiento sostenible. Para
ello, utilizo un marco analítico inspirado en el Pathways Approach, donde la sostenibilidad es entendida desde una perspectiva
dinámica y nomativa (que se mantenga el estatus ODF con mayor justicia social) y donde se da relevancia a los procesos políticos
entorno a la sostenibilidad, incluyendo narrativas, agentes e intereses políticos. Utilizo tres casos de estudio: Khandwa district
(MP), Mandi district (HP) y Budni block (MP). La metodología es predominantemente cualitativa, basada en entrevistas a todos
los niveles administrativos y en trabajo de campo intensivo, incluyendo visitas cortas a múltiples comunidades y estudios en
profundidad en una comunidad en cada caso de estudio.
Las evidencias varían para cada caso. En Khandwa district, el CLTS fue introducido en 2007. Pero debido a la presión por parte
del estado (MP) para conseguir premios de saneamiento y los intereses creados a nivel local, se acabó utilizando un enfoque
mixto, con herramientas participativas del CLTS, pero basado en la construcción de letrinas subsidiadas. El desigual progreso
inicial no se mantuvo, y muchas familias volvieron a defecar al aire libre al cabo de un tiempo. Las principales causas fueron la
falta de apropiación, la baja calidad de construcción y la falta de interés tras la obtención de los premios y el traslado administrativo de quienes lideraron la introducción del CLTS. En Mandi district, con una política estatal (HP) favorable y el apoyo de una
ONG local, autoridades motivadas con el saneamiento iniciaron en 2006 una campaña inspirada en los principios del CLTS, pero
usando teatro comunitario y visitas puerta a puerta en lugar de las herramientas del CLTS. El uso de letrinas creció radicalmente
y se ha mantenido, cambiando la percepción social sobre el saneamiento. En Budni block (MP), un impulsor del CLTS se convirtió
en máxima autoridad administrativa del bloque. Su experiencia y el apoyo de UNICEF contrarrestaron intereses opuestos y permitieron la puesta en marcha a finales de 2010 de una campaña coherente con el CLTS. Se realizaron facilitaciones en numerosas comunidades, que formaron comités de saneamiento para hacer sus comunidades ODF. Aunque aún en una fase inicial, se
pudo observar que la campaña estaba contribuyendo al cambio de comportamiento colectivo en una parte considerable de las
comunidades.
Cabe extraer una serie de conclusiones a partir de estas evidencias. En primer lugar, la campaña de saneamiento de la India se
implementa de forma vertical y sin tener en cuenta la demanda local, en contra de las directrices oficiales. Esto se debe a intereses de distintos actores: clientelismo político, inercia tecnocrática o rendición de cuentas mal orientada. Todo ello afecta también al CLTS, haciendo complicada su introducción a escala: los intereses opuestos pueden dar lugar a enfoques mixtos y resultados pobres. Pero cuando los agentes que impulsan el CLTS tienen el poder y el compromiso suficientes, son capaces de lograr
intervenciones coherentes, con sobresalientes resultados. Lo que hace que las intervenciones sean exitosas es que las comunidades se apropien del problema del saneamiento, trabajen en comités para acabar con la defecación al aire libre y logren hacer
prevalecer la perspectiva colectiva sobre el saneamiento. La facilitación mediante CLTS ¿pero también otras herramientas basadas en las emociones, como el teatro comunitario¿ pueden movilizar a un grupo de personas para formar un comité. Sin embargo, se trata solo de un primer paso dentro del largo y difícil proceso de cambiar la perspectiva social de saneamiento, por lo que
dicho comité necesitará un apoyo adecuado. Además, las comunidades suelen presentar diversidad y fuertes brechas sociales,
faltando pues un sentimiento de unidad. Así, la inclusión de todos los grupos en la facilitación y en los comités se convierte en
un elemento crucial para alcanzar a toda la comunidad. De la misma manera, no se puede dar por descontado que las familias
más necesitadas vayan a recibir ayuda de otras familias, sino que se deberá promover. Finalmente, se ha observado que por
falta de apoyo técnico existen de diseños de letrina ineficientes que afectan a la sostenibilidad y pueden provocar riesgos sanitarios. En cualquier caso, cuando la perspectiva colectiva de saneamiento se asienta en una comunidad, muchos de los desafíos
que aparecen reciben una respuesta adecuada.Hueso González, A. (2013). Pathways to Sustainability in Community-Led Total Sanitation. Experiences from Madhya Pradesh and Himachal Pradesh [Tesis doctoral]. Editorial Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/31520
Alfresco
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Balfour, Liezl. "Implementation and evaluation of a clinical pathway for non-invasive ventilation in critical care : a person-centred practice development approach." Thesis, University of Pretoria, 2020. http://hdl.handle.net/2263/79586.
Full textAbstract:
Introduction: Non-invasive ventilation (NIV) is an alternative method for
providing safe mechanical ventilatory assistance to adult patients
presenting with acute respiratory failure. Internationally the utilisation of
NIV has increased by 400% during the past decade. The clinical pathway
for NIV was collaboratively developed by the multidisciplinary team in the
critical care unit in 2012, but implementation into practice did not realise
as anticipated. As the burden of chronic disease rises in South Africa, the
healthcare system is under pressure to provide evidence-based and costeffective
care to more patients. Avoiding endotracheal intubation reduces
the patient’s risk of complications which lengthens the hospitalisation
period and the cost of hospitalisation. The utilisation of clinical pathways
in the South African context is limited.
Aim: The overall aim of the study was implementation and evaluation of
the outcomes of a person-centred clinical pathway for non-invasive
ventilation in the critical care unit.
Research methodology: Mixed method design through a personcentred
practice development approach utilising emancipatory action
research. Several data collection methods are used throughout the
phases of the study. A critical realist worldview was held which
incorporated the principles of a person-centred approach through
collaboration, inclusion and participation. The study was conducted in
three interdependent and interrelated phases. During Phase 1, the
culture of the critical care units was assessed using a validated 37-item
questionnaire to establish the perceptions of the critical care nurses
related to evidence implementation. A total of twenty-three registered
nurses participated. Additionally, the content of the clinical pathway was
adapted following a rigorous literature review in collaboration with the
internal facilitators and validated via a Delphi with critical care experts.
Phase 2 was dedicated to the collaborative development of an implementation strategy for the implementation of the clinical pathway in
the critical care unit. During Phase 3, the outcomes of the implementation
of the clinical pathway for NIV was evaluated.
Findings: The collaborative utilisation of a person-centred practice
development approach for the implementation and evaluation of the
clinical pathway for NIV, aided the researcher in identifying moral injury
amongst critical care nurses, which inhibits the implementation of
research evidence into practice.Thesis (PhD)--University of Pretoria, 2020.
Nursing Science
PhD
Unrestricted
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Zodda, Erika. "Characterization of Endothelial Cells dysfunction associated to Acute Myocardial Infarction: modulation of metabolic pathways as a new therapeutic approach." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/668403.
Full textAbstract:
The endothelium plays a pivotal role in the development of cardiovascular disease (CVD) and emerging evidence indicates that pathological blood vessel responses and endothelial dysfunction are associated with metabolic alterations in endothelial cells (ECs).
This project aims at performing a complete characterization of the metabolic profiles of an endothelial pathological Acute Myocardial Infarction (AMI) model of 8 patients. The results discussed throughout this thesis are part of this attempt, and brought to the identification of the insights and causes of the AMI pathology, as a consequence of the metabolic alterations related to the endothelium dysfunction which occurs in patients.
Due to patients variability, finding a single and clear mechanism among all is quite hard to grasp. However, we have been able to find some metabolic feature to be exploited as possible biomarker for the identification of this CVD. Patients cells presented a low proliferation rate and unveiled a dependence to mitochondrial metabolism, which results in an increased ROS-oxidative stress. Consequently, these cells express increased level of glutathione that supplies the antioxidant defense and prevent ROS (Reactive oxygen species) accumulation. Glutamine seems to play a key role in this AMI model; first of all it is necessary for these cells to display a proper mitochondrial function and in addition, it is required for the synthesis of glutathione as antioxidant against the high level of ROS detected. Additionally, finding a higher content of glutaminase C (GAC) in patients, has opened the possibility that these cells rely more on glutaminase reaction for their survival, and this dependence gathered with the augmented need to neutralize the acidic pH , which results from the increased lactate production, by the ammonia molecules released from glutamine metabolism. This findings point that in AMI model is occurring a metabolic adaptation similar to the Warburg effect, usually described in cancer cells.
In the frame of finding the same origin among different pathologies ,in the second part of this work we focused on the crosstalk between dysfunctional endothelium and tumor microenvironment. Moreover, nowadays there is an increasing interest in supporting the existence of a link between cardiovascular pathologies and cancer.
One of the wide possibilities which lies these two lethal morbidities is a an alteration of the DNA repair system, crucial for the recovery of the healthy cells against the diseased ones, when a pathological event takes place. Through this study we found that: alternative splicing governs cell‐type regulated expression of variant forms of mRNAs and their encoded proteins that exert differential function. So, employing cancer cell model in which distinct tumor cell subpopulations display differentiated epithelial or mesenchymal phenotype, we have identified alternatively spliced mRNAs with potential impact on the self‐renewal capacities of these cell subpopulations. More in details, among all the genetic characters which can be involved in this process, we provide evidences that RAP80 (UIMC1), an adaptor protein with critical functions in homology-dependent DNA repair (HDR), is expressed as alternatively spliced isoforms in epithelial and mesenchymal cells, as a function of ESRP1/2 expression. More specifically, we have found that the ratio of expression of a full-length isoform to a short isoform of RAP80 is significantly higher in epithelial cells than mesenchymal cells in a prostate cancer cell model for EMT. RAP80 contains a region required for interaction with Abraxas , a core component of the BRCA1-A complex involved in DNA-damage repair. We propose that the ratio of full-length RAP80 to the short isoform lacking AIR is a new mechanism for the regulation of HDR mediated by BRCA1. A higher long/short RAP80 isoform ratio will favor, and lower ratios will counter, the recruitment of BRCA1-A complexes to DSBs.
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Hamza, Maissa. "Exploring barriers and pathways to data protection by design within IT companies : An integrated approach based on experts’ perspectives." Thesis, Umeå universitet, Institutionen för informatik, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-141457.
Full textAbstract:
The European General Data Protection Regulation (GDPR) will soon come into force, it is a regulation which spells out increased compliance demands for data protection by design. Failure to comply can lead to huge financial penalties, something IT companies controlling and processing personal data should not ignore. As the one-year countdown begins, studies have revealed under-preparedness of organizations affected by the GDPR. None of the studies so far has offered an integrated overview of the barriers faced by IT companies to embrace data protection by design. This study aims to help fill this gap and to investigate. A study based on expert’s knowledge has been carried out, using an integrated approach. Five experts from advocacy, legal and IT industry were interviewed, aiming to answer the following research question: “What are the barriers for IT companies to embrace data protection by design and how should these barriers be overcome?” An integrated overview of the barriers will then be presented, which includes the managerial, engineering and legal obstacles. The study goes on to present pathways to embrace data protection by design. A key contribution to this study is that managerial, legal and engineering barriers have shown to be directly interconnected and influence on each other. As such a much broader view must be undertaken to fully understand the different barriers that face IT companies in embracing data protection by design.
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Martin, Lee. "An Intersectional Approach to Earlier Interventions within the Criminal Justice System in the UK : An Analysis of Two Governmental Documents." Thesis, Linköpings universitet, Tema Genus, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-157738.
Full textAbstract:
This thesis seeks to explore how two governmental documents discuss earlier preventions of criminality. The two documents analyzed are the Female Offender Strategy and The Government’s Approach to Crime Prevention. The first of these documents main aim is to provide a more gender sensitive approach to the criminal justice system within the United Kingdom and the latter document does not explicitly differ between the genders. The analysis will be carried out with the use of feminist pathways theory and through an intersectional lens, in order to demonstrate how the two documents discuss earlier prevention of criminality. By utilizing the methodology of What’s the Problem Represented to be (WPR) the aim is to demonstrate who benefits from the documents and who is relegated to the sidelines. Neither of the two documents demonstrate a strategy or policy which takes into account the many varying identities which exist amongst the inmate population of the criminal justice system.
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O'Donnell, Melissa. "Towards prevention - a population health approach to child abuse and neglect : health indicators and the identification of antecedent causal pathways." University of Western Australia. School of Paediatrics and Child Health, 2009. http://theses.library.uwa.edu.au/adt-WU2010.0029.
Full textAbstract:
[Truncated abstract] The primary aims of this thesis were to investigate health indicators of child maltreatment, as well as pathways into the child protection system using routinely collected government databases, enabling a preventative health approach to child abuse and neglect. This thesis aims to improve understanding of the trends in child maltreatment and the factors, at the child and family level, which increase or reduce vulnerability to child maltreatment so more effective prevention policies and practices can be developed. This project uses longitudinal de-identified population data from the Western Australian Government Departments of Child Protection, Health and Disability Services. These data contained information on demographic, clinical, social and child protection outcomes of children and their families. Record linkage of administrative data was undertaken to: investigate health indicators of abuse and neglect using Hospital Morbidity data to enable the monitoring of population trends in abuse and neglect; compare proportion of cases obtained using health indicators with the Department of Child Protection data, and describe the physical, psychological and social characteristics of abused and/or neglected children and families. Statistical techniques utilised include logistic and Cox regression to investigate risk of adverse child outcomes, taking into account potential confounding and time to event. The main findings include: There has been an increase in assault and maltreatment related hospital admissions over the last 25 years. ... There has been a marked increase in the birth prevalence of Neonatal Withdrawal Syndrome (NWS) in Western Australia over the last 25 years, from 1 per 10,000 live births in 1980, to 31 per 10,000 live births in 2005. Specific maternal characteristics associated with having a child with NWS are identified and these children have an increased risk of child protection involvement. A population level analysis of child and parental factors determined the estimated increase in risk of substantiated child maltreatment for child intellectual disability, parental admissions for mental health, substance use, and assault, as well as greater socio-economic disadvantage. Conclusions This is the first body of research which has extensively used longitudinal, population level linked health and child protection data to investigate health indicators of child abuse and neglect and antecedent causal pathways. Monitoring injuries and conditions associated with child abuse and neglect in routinely collected data and using multiple sources of ascertainment are important initiatives in child maltreatment surveillance. Health indicators of child abuse and neglect are not subject to the same definitional and policy issues as child protection data and therefore provide a more valid comparison over time and between jurisdictions. The identification of factors which increase vulnerability for children and families to child maltreatment is essential in the implementation of prevention strategies including universal public health approaches as well as the identification of at-risk families for targeted intervention.
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Ferreira, Catarina Domingues. "WNT/ß-catenin and Hedgehog signaling pathways as therapeutic targets in B cell neoplasms." Master's thesis, Universidade de Aveiro, 2018. http://hdl.handle.net/10773/22676.
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Mestrado em Bioquímica - Métodos BiomolecularesAs neoplasias de células B são caracterizadas por um grupo heterogéneo de doenças que incluem linfomas de células B e doenças de células plasmáticas, entre outras. O mieloma múltiplo (MM) é uma neoplasia maligna originada pela proliferação de células plasmáticas monoclonais que permanece incurável. Esta proliferação de células plasmáticas malignas no microambiente da medula óssea produz proteína monoclonal no sangue ou na urina e está associada a sinais malignos. Representa aproximadamente 1% das doenças neoplásicas e 10% a 15% das neoplasias hematológicas. O linfoma difuso de grandes células B (DLBCL) é a forma mais comum de linfoma não-Hodgkin, representando 31% dos linfomas não-Hodgkin, e sendo fatal se não for tratado. DLBCL é um linfoma agressivo e de crescimento rápido que pode surgir nos gânglios linfáticos ou fora do sistema linfático, no trato gastrointestinal, testículos, tiroide, pele, mama, osso ou cérebro. A ativação inadequada de vias de sinalização embrionárias, como WNT/β-catenina e Hedgehog, vias críticas de autorrenovação das células estaminais e diferenciação das células hematopoiéticas, tem sido implicada nestas neoplasias de células B. Neste sentido, essas vias podem constituir potenciais novos alvos terapêuticos para tratar o MM e o DLBCL. O objetivo principal deste estudo foi avaliar o potencial terapêutico de inibidores das vias WNT/β-catenina e Hedgehog, respetivamente IWR-1 e vismodegib, isolados e em combinação um com o outro, usando linhas celulares de MM e DLBCL. Para avaliar o efeito dos inibidores IWR-1 e vismodegib no MM e no DLBCL foram utilizadas linhas celulares H929 (MM) e FARAGE (DLBCL), submetidas a diferentes concentrações dos inibidores. A atividade metabólica foi avaliada utilizando o ensaio de resazurina, a morte celular por microscopia ótica (coloração de May-Grunwald) e citometria de fluxo (FC) (marcação com anexina V/7-AAD e quantificação de BCL-2 e caspases, proteínas relacionadas com a apoptose). A análise do ciclo celular foi avaliada por FC, utilizando a solução PI/RNAse. Também por FC, foi avaliada a expressão de β-catenina e ERK fosforilado, moléculas relacionadas com as vias de sinalização WNT/β-catenina e HH. Os resultados mostraram que IWR-1 e vismodegib reduziram a atividade metabólica celular de modo dependente do tempo, da linha celular e da concentração, em monoterapia ou em combinação. O IC50 do IWR-1 nas células H929 e Farage foi de 40 μM e 75 μM, respetivamente, enquanto que o IC50 do vismodegib foi de 70 μM para as células H929 e 57 μM para as células Farage, após 24 horas de tratamento. Estes resultados mostram que as células H929 são mais sensíveis ao IWR-1 e, contrariamente, as células Farage são mais sensíveis ao vismodegib. Estes compostos induzem a morte celular predominantemente por apoptose e induzem bloqueio do ciclo celular em G1. Em conclusão, os resultados sugerem que IWR-1 e vismodegib são potenciais novas terapias direcionadas que poderão ser eficientes no tratamento de MM e DLBCL. No entanto, IWR-1 é mais indicado para a terapêutica do MM e o vismodegib para a terapêutica do DLBCL.
B-cell neoplasms are characterized by a heterogeneous group of diseases that include, B-cell lymphomas and plasma cell disorders, among others. Multiple myeloma (MM) is a malignant neoplasm originated by proliferation of monoclonal plasma cells that remains incurable. This clonal proliferation of malignant plasma cells occurs in the bone marrow microenvironment, leads to the production of monoclonal protein in the blood or urine and is associated with malignant signals. It accounts for approximately 1% of neoplastic diseases and 10% to 15% of hematologic neoplasms. Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma, representing 31% of the non-Hodgkins lymphomas, being fatal if untreated. DLBCL is an aggressive, fast-growing lymphoma, that can arise in lymph nodes or outside of the lymphatic system, in the gastrointestinal tract, testicles, thyroid, skin, breast, bone, or brain. Inappropriate activation of conserved embryonic signaling pathways, such as WNT/β-catenin and Hedgehog (HH), critical for stem cell self-renewal and differentiation of hematopoietic cells, has been implicated in these B-cell neoplasms. In this sense, these pathways may constitute new potential therapeutic targets to treat MM and DLBCL. The main goal of this study was to evaluate the therapeutic potential of a WNT/ β-catenin and a Hedgehog inhibitor, respectively, the IWR-1 and vismodegib, alone and in combination, using MM and DLBCL cell lines. To evaluate the effect of IWR-1 and vismodegib in MM and in DLBCL, H929 (MM) and FARAGE (DLBCL) cell lines were submitted to different concentrations of the inhibitors. Metabolic activity was evaluated using resazurin assay and cell death was evaluated by optical microscopy (May-Grunwald staining) and flow cytometry (FC) (Annexin V/7-AAD staining and by quantification of BCL-2 and caspases expression, apoptosis-related proteins). Cell cycle analysis was evaluated by FC, using a PI/RNAse solution. Also by FC the expression of β-catenin and phosphorylated ERK, molecules related to the WNT/β-catenin and HH signaling pathways, were tested. Results showed that IWR-1 and vismodegib reduced cell metabolic activity in a time-, cell line- and dose-dependent manner, when administrated in monotherapy or in combination. The IC50 of IWR-1 in H929 and Farage cells was 40 μM and 75 μM, respectively, and the IC50 of vismodegib was 70 μM for H929 cells and 57 μM in Farage cells, after 24h of treatment. These results show that H929 cells are more sensitive to IWR-1 and, contrarily, Farage cells are more sensitive to vismodegib. These compounds induce cell death mainly by apoptosis and showed an arrest in cell cycle at G1. In conclusion, results suggest that IWR-1 and vismodegib are potential new targeted therapies that could be efficient in MM and DLBCL treatment in the future. However, IWR-1 is more indicated for MM therapy and vismodegib for DLBCL therapy
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Kunkel, Joseph. "A Systems Approach for Dissecting Integrated Signaling Pathways: TORC1 and Ras/PKA Regulation of Glucose Induced Growth Control in S. cerevisiae." Diss., The University of Arizona, 2015. http://hdl.handle.net/10150/578637.
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One of the leading aims of systems biology is the complete delineation of the organization and architecture of signaling networks. Within this aim, characterizing integrated circuits is a particular challenge. Integrated circuits are the sites of information multiplexing, where input from multiple sources are combined into a single output or channel. A number of quantitative methods for analyzing epistasis within integrated pathways have been developed, with limited success. Here I present Expression Component Analysis, a novel approach for determining quantitative epistasis within an integrated signaling circuit, and describe the application of Expression Component Analysis in analyzing an interesting and important integrated signaling circuit in the model eukaryote, S.cerevisiae.
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Samakinde, Chris Adesola. "An integrated approach to understanding the geological controls on gas escape and migration pathways in offshore northern Orange Basin, South Africa." University of the Western Cape, 2017. http://hdl.handle.net/11394/6132.
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Philosophiae Doctor - PhD (Earth Science)The use of an integrated approach in science has gained more prominence recently because it is thorough and provides a dynamic perspective from which scientific problems can be investigated and solutions proffered. Here, an integrated approach (Litho and seismic stratigraphy, structural modelling, Seismic attributes analyses and 3D numerical simulation of hydrocarbon generation and migration) were used to investigate geological controls (faults and stratigraphic features) on hydrocarbon migration pathways and suggest prospective areas within the Block 1 of Orange Basin, South Africa.
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Ormsmith, Michael. "AN EXPLANATORY MIXED-METHODS APPROACH TO TRACING “CAREER PATHWAYS” POLICY IN VIRGINIA: HOW SCHOOL COUNSELORS AND STUDENT DEMOGRAPHICS INFLUENCE IMPLEMENTATION FIDELITY." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3308.
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This explanatory mixed-methods policy analysis describes how school counselors' thoughts and attitudes contribute to the implementation fidelity of the Academic and Career Plan (ACP) policy in a suburban Virginia school division. A quantitative survey investigated counselor thoughts about the policy, implementation behaviors, and counselor ideas about equity issues related to providing college and career planning services to at risk students. Counselor interviews were conducted to provide deeper insight about the street level implementation practices and beliefs of counselors. Findings reveal that counselors place substantial value in the ACP policy and think the process is useful for connecting student interests and postsecondary goals to high school programs of study. Counselors implement the ACP policy with high fidelity because the policy incorporates counselor beliefs such as integrating the career pathway model into the course selection process. Counselors report spending more time assisting higher socioeconomic groups with college planning which results in less time for supporting at risk students. Findings indicate that counselors recognize the need at risk students have for additional support during postsecondary planning but are inhibited by the demands of higher socioeconomic groups. Finally, implications for school leaders related to improving counselor services to at risk students are discussed.
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Pollen, Claudia Mvula. "An analysis of women's agency in the Zambian floriculture industry using a global production network approach : mechanisms and pathways for agency." Thesis, University of Leeds, 2017. http://etheses.whiterose.ac.uk/18867/.
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The study of women integrated in export markets in developing countries since the rise and spread of neo-liberalism over the past two and half decades attracted wide-ranging interest and scholarship, with findings identifying both the positive and negative effects of such integration for women. On the one hand, the gender literature identifies women as agents operating under complex traditional and institutional constraints, while on the other hand, development economists aiming at improving the wage gap have called for resources to be deployed to improve women’s lives. Examining the ways and circumstances of women’s working life in the Zambian floricultural industry has transformed into an inquiry into women’s agency. While substantial scholarship has uncovered the strategies (e.g. bargaining) that women use to attain certain outcomes (voice in the home or organising at work), the literature on GPNs and on gender in particular has remained largely silent on the processes underlying, and leading to, the outcomes sought. Therefore, the premise underlying this thesis was to establish that regardless of what women did, they did not operate in a vacuum, rather, their workplaces were part of a wider international community of global production processes integrated vertically and horizontally. Thus, uncovering the processes and strategies women used required framing the question within this broader framework. This thesis places the understanding of women’s agency within the broader context of Global Production Networks (GPNs). I argue that women rationalise their actions and decisions to work by deploying a range of strategies such as negotiations and bargaining, while drawing upon an array of resources through networks in the community and the workplace in the course of their work cycle. This suggests women do not simply do, rather they assess, strategize and then proceed with a course of action to reposition themselves so that what is observed as women’s actions is a product of the culmination of different processes i.e. Conception, gestation and delivery.
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Menon, Nikhila. "Mobility and pathways to autonomy of women : a study of informal workers in fisheries sector in Kerala, India." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/mobility-and-pathways-to-autonomy-of-women-a-study-of-informal-workers-in-fisheries-sector-in-kerala-india(fef45318-9e2d-4936-a9cd-33c16e81d60d).html.
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Mobility and Pathways to Autonomy of Women: A study of informal workers in fisheries sector in Kerala, India Mobility defined as the freedom and ability to move has intrinsic and instrumental values in promoting human development. Paid work which involves mobility associated with work can be a ‘capability-enhancing’ experience when such mobility improves opportunities and enhances freedoms. However, the existing studies have neither examined nor measured mobility with its multiple domains for women. My thesis fills this gap in research by exploring the multiple domains of gendered mobility by measuring mobility as a single construct and analysing whether mobility is a ‘capability’ for women workers which improves autonomy and agency. It is inter-disciplinary as it is situated at the confluence of development studies, human geography and sociological disciplines. The following features of the thesis make it unique in the development studies discipline. First, the contextual setting is unique as it is based in Kerala, which is a socially progressive state in India. The thesis unearths the underlying structural constraints in the Kerala model of social development for transformation of women workers under patriarchy. It is a comparative study which examines the household autonomy and agency of two types of informal women workers in the post-harvest fisheries, namely ‘peeling workers’ linked to production chains and ‘fish vendors’ who are self-employed. Second, the capability approach provides the theoretical framework for the analysis of mobility of women as capability and it introduces a new concept of ‘transformational mobility’. By examining mobility using the Rasch Rating Scale Model (RSM) for the first time in development studies, the thesis operationalises capability measurement by introducing the measurement scale of mobility of women workers which empirically delineates the multiple domains of mobility based on the constraints faced by women. Third, the mixed methods research design using survey data and qualitative interviews of women workers provide better insight and contextual understanding of women’s work. An innovative method, namely, the Crisp set Qualitative Comparative Analysis (CsQCA), explores the causal mechanisms that bring about ‘transformational mobility’ in women workers. The thesis empirically proves the significance of social and human capital factors like caste, low education of spouse and marital status along with the underlying patriarchal structures that determine pathways to transformational mobility and decision making of women. Lastly, the qualitative analysis using classic grounded theory contributes to the emergence of substantive theories for women workers which reflect contrasting agentic behaviour of peeling workers and fish vendors in the context of Kerala. The lack of collective agency among peeling workers questions the claims of Kerala model of development in improving the agency of women. The findings confirm that work mobility associated with informal low paid work is not necessarily a capability for women in fisheries.
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Philipp, Oliver [Verfasser], Ina [Gutachter] Koch, and Heinz D. [Gutachter] Osiewacz. "Age-dependent processes and molecular pathways of the fungal ageing model "Podospora anserina": A bioinformatics approach / Oliver Philipp ; Gutachter: Ina Koch, Heinz D. Osiewacz." Frankfurt am Main : Universitätsbibliothek Johann Christian Senckenberg, 2017. http://d-nb.info/1148548254/34.
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Pesta, Racheal Pesta. "Assessing Ethno-Racial Differences in the Pathways from School Exclusion to Criminal Offending: A Theoretically Integrative Approach to Understanding the School to Prison Pipeline." University of Akron / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=akron1503042662677665.
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Armant, Olivier. "A genomic approach to study the molecular pathways of differentiation regulated by the proneural genes Mash 1 and Ngn 2 during development of the mouse telencephalon." Université Louis Pasteur (Strasbourg) (1971-2008), 2005. https://publication-theses.unistra.fr/public/theses_doctorat/2005/ARMANT_Olivier_2005.pdf.
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Les principales phases cellulaires de la neurogenèse chez les mammifères sont aujourd'hui bien décrites. Toutefois les mécanismes moléculaires à l'origine de la diversité des neurones produis à partir d'une population restreinte de cellules souches neurales ne sont toujours pas correctement compris. L'activité proneurale de certains facteurs de transcriptions à domaine bHLH (" basic Helix Loop Helix ") a été conservée au cours de l'évolution de la Drosophile aux mammifères, et démontré comme essentielle pour la différentiation des cellules souches neurales en neurones. Ma thèse porte sur l'étude au niveau transcriptionnel des voies moléculaires régulées par les facteurs proneuraux Neurogénines et Mash1 lors de la différenciation du télencéphale de la souris. Je démontre tout d'abord que les gènes proneuraux sont capables d'instruire un programme de différenciation spécifique de sous-types neuronaux. En effet, lors des phases précoces du développement du cortex cérébral, les gènes Ngn1 et Ngn2 régulent de manière positive un phénotype neuronal de type glutamatergique tout en inhibant le phénotype subcortical GABAergique spécifiquement induit par Mash1. Ce travail m'a également permis d'identifier des gènes cibles directs des facteurs proneuraux. En particulier de nombreux gènes impliqués dans la voie de signalisation Notch, notamment les gènes de la famille Delta, sont vraisemblablement directement régulés par Mash1 dans le télencéphale. Enfin, l'analyse génomique du programme de différentiation régulé par les gènes proneuraux fourni un outil remarquable pour la découverte de nouveaux gènes potentiellement impliqués dans la différentiation de population neuronales ayant des fonctions importantes et affectés dans certaines maladies neurologiques. Je décris ici une analyse fonctionnelle préliminaire de deux gènes, Delta like homologue 1 et Nemo like kinase, régulés dans le télencéphale par les facteurs proneurauxThe main cellular steps of neurogenesis start to be well established in mammals. But the molecular mechanisms leading to the neuronal diversity produced from a reduced population of neural stem cells are still not understood. The proneural activity of several transcription factors of the bHLH (basic Helix Loop Helix) family is conserved through evolution from Drosophila to mammals and play crucial roles to instruct the differentiation of neurons from neural stem cells. I have studied, at the transcriptional level, the molecular pathways regulated by proneural factors Neurogenins and Mash1 during development of the mouse telencephalon. First, I show that in parallel to the activation of a generic neuronal differentiation programme, proneural genes specify different neuronal subtype identities. Indeed, during the early phase of cortical development Ngn1 and Ngn2 induce a glutamatergic fate, while in the same time inhibit the subcortical GABAergic phenotype regulated by Mash1. I show also the characterisation of target genes directly regulated by proneural genes. In particular numerous genes from the Delta family, involved in the Notch signalling pathway, are presumably directly regulated by Mash1 in the telencephalon. Finally the genome wide analysis of the neuronal differentiation pathways regulated by proneural genes provide a very efficient tool for the discovery of new genes putatively involved in the differentiation of neuronal populations, and potentially affected in neurological diseases. I describe in this work preliminary results for the functional analysis of two genes, Delta like 1 and Nemo like kinase, regulated in the telencephalon by proneural genes
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Joglekar, Shachi [Verfasser], Jane [Akademischer Betreuer] Parker, Ulf-Ingo [Akademischer Betreuer] Flügge, and Renier van der [Akademischer Betreuer] Hoorn. "Dissection of EDS1-dependent and salicylic acid-independent defence signalling pathways in Arabidopsis thaliana: a chemical biology approach / Shachi Joglekar. Gutachter: Jane Parker ; Ulf-Ingo Flügge ; Renier van Der Hoorn." Köln : Universitäts- und Stadtbibliothek Köln, 2014. http://d-nb.info/1079321594/34.
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Reiff, Caroline. "Genes, pathways & transcription factors involved in probiotic mediated resolution of gut inflammation in IL10-KO mice, an animal model of inflammatory bowel disease : an integrated gene, protein and bioinformatics approach." Thesis, University of Aberdeen, 2010. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=158244.
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Genes, pathways & transcription factors involved in probiotic mediated resolution of gut inflammation in IL10-KO mice an animal model of Inflammatory Bowel Disease. An integrated Gene, Protein and Bioinformatics Approach The IL10-KO mouse is a model of human inflammatory bowel disease (IBD), used to study host microbial interactions and potential therapeutics. Affymetrix microarray and proteomics analysis on colon of WT and IL10-KO mice and cecum of IL10-KO and WT mice orally administered with and without probiotic VSL#3 was performed and identified signalling pathways and transcription factors relevant to gut inflammation and anti-inflammatory probiotics. Results were validated by Real-time PCR, immunocytochemistry, proteomics, histopathology and via pathway signature analysis of publicly available microarray data. Changes in metabolically active bacteria in response to VSL#3 were assessed with DGGE. Inflammation in IL10-KO mice was characterised by up-regulation of immune/inflammatory and down-regulation of lipid/xenobiotic metabolism and PPAR signalling. VSL#3 resolved inflammation in the cecum inducing down-regulation of genes in immune/inflammatory pathways, decrease in the number of CCL5 positive T cells and up-regulation of galectin2, known to trigger apoptosis of T cells. VSL#3 induced up-regulation of PPARα/PPAR signalling and lipid/xenobiotic metabolism, antagonistic to NFB signalling and reduced metabolically active bifidobacteria. Analysis of publicly available data showed results were relevant to human IBD, indicated that antigen processing/presentation is up-regulated early on during development of colitis in IL10-KO mice, identified the potential of PPARα/PPAR signalling to induce down-regulation of CCL5, CD3 & antigen processing/presentation, and the potential of the xenobiotic metabolism to induce down-regulation of cytokine-cytokine interaction & mitosis. As VSL#3 treatment of IL10-KO mice induced up-regulation of PPARα/PPAR signalling and xenobiotic metabolism these results provide a possible mechanistic explanation for the VSL#3 induced down-regulation of CCL5, CD3, antigen processing/presentation, cytokine-cytokine interaction and mitosis in the cecum of VSL#3 treated IL10-KO mice.
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Spohn, Marius [Verfasser], and Evi [Akademischer Betreuer] Stegmann. "Exploiting gene regulation as an approach to identify, analyze and utilize the biosynthetic pathways of the glycopeptide ristomycin A and the zincophore [S,S]-EDDS in Amycolatopsis japonicum / Marius Spohn ; Betreuer: Evi Stegmann." Tübingen : Universitätsbibliothek Tübingen, 2017. http://d-nb.info/1167310691/34.
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Lee, Mark N. "Genomic Approaches to Dissect Innate Immune Pathways." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10692.
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The innate immune system is of central importance to the early containment of infection. When receptors of innate immunity recognize molecular patterns on pathogens, they initiate an immediate immune response by inducing the expression of cytokines and other host defense genes. Altered expression or function of the receptors, the molecules that mediate the signal transduction cascade, or the cytokines themselves can predispose individuals to infectious or autoimmune diseases. Here we used genomic approaches to uncover novel components underlying the innate immune response to cytosolic DNA and to characterize variation in the innate immune responses of human dendritic cells to bacterial and viral ligands. In order to identify novel genes involved in the cytosolic DNA sensing pathway, we first identified candidate proteins that interact with known signaling molecules or with dsDNA in the cytoplasm. We then knocked down 809 proteomic, genomic, or domain-based candidates in a high-throughput siRNA screen and measured cytokine production after DNA stimulation. We identified ABCF1 as a critical protein that associates with DNA and the known DNA-sensing components, HMGB2 and IFI16. We also found that CDC37 regulates stability of the signaling molecule, TBK1, and that chemical inhibition of CDC37 as well as of several other pathway regulators (HSP90, PPP6C, PTPN1, and TBK1) potently modulates the innate immune response to DNA and to retroviral infection. These proteins represent potential therapeutics targets for infectious and autoimmune diseases that are associated with the cytosolic DNA response. We also developed a high-throughput functional assay to assess variation in responses of human monocyte-derived dendritic cellsto LPS (receptor: TLR4) or influenza (receptors: RIG-I and TLR3), with the goal to ultimately map genetic variants that influence expression levels of pathogen-responsive genes. We compared the variation in expression between the dendritic cells of 30 different individuals, and within paired samples from 9 of these individuals collected several months later. We found genes that have significant inter- vs. intra-individual ariation in response to the stimuli, suggesting that there is a substantial genetic component underlying variation in these responses. Such variants may help to explain differences between individuals’ risk for infectious, autoimmune, or other inflammatory diseases.
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Merrick, Christine. "A synthetic biology approach to metabolic pathway engineering." Thesis, University of Glasgow, 2015. http://theses.gla.ac.uk/6383/.
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Microbial biosynthesis of commodity compounds offers a cheaper, greener and more reliable method of production than does chemical synthesis. However, engineering metabolic pathways within a microbe for biosynthesis of a target compound is a complicated process: levels of gene expression, protein stability, enzyme activity, and metabolic flux must be balanced for high productivity without compromising host cell viability. A major rate-limiting step in engineering microbes for optimum biosynthesis of a target compound is DNA assembly, as current methods can be cumbersome and costly. This study aimed to develop a new, synthetic biology tool for rapid DNA assembly that can be applied to engineering and optimizing metabolic pathways for the microbial biosynthesis of commodity compounds. The potential of using serine site-specific recombinases as synthetic biology tools to assemble DNA was investigated and a new DNA assembly method, Serine Integrase Recombinational Assembly (SIRA), using PhiC31 integrase was established. It was demonstrated that SIRA can clone DNA parts ranging in size from 71 bp to 12.7 kb, assemble as many as five DNA parts in a one-pot reaction, facilitate targeted post-assembly modification of an assembled construct and generate variation between DNA constructs in a single assembly reaction. SIRA was used to generate variation between constructs containing genes of the violacein biosynthesis pathway, the lycopene biosynthesis pathway, or the DXP pathway for isoprenoid biosynthesis in E. coli. By studying the phenotypes and genotypes of the constructs generated, it was possible to identify rate-limiting steps within these pathways. Finally, a lycopene-producing in vivo biosensor screen was developed in E. coli to screen DNA assemblies, made with SIRA, encoding genes from the DXP pathway, for enhanced isoprenoid production. By optimizing the expression conditions for assemblies of DXP pathway genes that enhanced isoprenoid production and genes for lycopene biosynthesis in E. coli, 35.78 mg lycopene per gram dry cell weight was obtained - the highest recorded level of lycopene produced from engineering of the DXP pathway alone in E. coli.
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Sefer, Lea. "Targeting the Hedgehog pathway in disease : a structural biology approach." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:e08a7c23-7d30-4d49-8f6e-e0b5c265bdfb.
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The Hedgehog (Hh) pathway is a morphogen pathway essential for proper embryonic development of all bilaterians that remains active in adults where it contributes to tissue homoeostasis. Malfunction of the pathway results in developmental defect, while constitutive activation was correlated with multiple cancers. The Hh pathway is a validated cancer drug target with two FDA approved inhibitors targeting the Hh GPCR signal transducer Smoothened. This thesis focuses on two alternative Hh targets, the Sonic Hh (ShhN) morphogen and its acyltransferase Skinny Hh. In Chapter 2, the aim was to structurally characterise a complex between ShhN and its only small-molecule inhibitor Robotnikinin using in silico docking and crystallography. The results revealed that the most likely binding site of Robotnikinin is the pseudo-active site of ShhN and that the interactions involve the His134-Ser136 loop. In Chapter 3, the aim was to identify novel ShhN inhibitors using crystallographic fragment-based screening of 1,200 unique fragments. The screening resulted in 13 potential hits, 5 of which were found within the ion binding cleft. In Chapter 4, the aim was to validate the obtained hits and conduct preliminary structure activity relationship (SAR) assays. Based on the results, FRG 155 was identified as the preferred hit that bound to the the ShhN pseudo-active site with low micromolar affinity. Preliminary SAR identified positive and negative features of the fragment. In Chapter 5, the aim was to structurally and functionally characterise Skinny Hh. Protocols for successful expression and purification of milligram quantities of thermostable and active Skinny Hh were developed, providing a platform for crystallisation and drug screening. The first luminal loop of Skinny Hh was found to be essential for the activity of Skinny Hh. In summary, alternative Hh pathway targets, ShhN and Skinny Hh, were characterised using structural biology approaches and will contribute to the development of novel inhibitors with the application in Hh ligand-dependent tumours.
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van, Bueren Kelly Leanne. "Genomic and transcriptomic approaches to pathways affected in DiGeorge syndrome." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1444221/.
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This thesis describes the identification and characterisation of genes important in development of the pharyngeal apparatus and heart, the major structures affected in DiGeorge syndrome (DGS). DGS is characterised by craniofacial, cardiovascular, thymus and parathyroid defects. It is most commonly caused by heterozygous deletion of a 3Mb region of chromosome 22ql 1 encompassing at least 30 genes. Haploinsufficiency of the TBX1 transcription factor is considered to be the major underlying cause of this syndrome. Animal models of DiGeorge syndrome have demonstrated the importance of Tbxl in pharyngeal and heart development and therefore, identifying the downstream targets of Tbxl is of vital importance in understanding the development of these systems. This project was aimed at identifying cell autonomous effects of Tbxl by isolating Tbxl-lacZ expressing cells and comparing the gene expression profiles of Tbxl null and heterozygous cells by microarray analysis. Validation of the downregulated gene, Hesl has been further investigated by the characterisation of pharyngeal and heart defects in mice carrying null alleles of this potential Tbxl target. In addition, BAC recombineering was also conducted to generate a transgenic mouse carrying a GFP-labelled, reversible, mutant Tbxl allele. This modified Tbxl allele should provide the basis for further enrichment of Tbxl targets by allowing isolation of Tbxl-expressing cells from transgenic mice and subsequent restoration of Tbxl function by cre-mediated recombination. Furthermore, in order to identify other pathways important in heart development, DGS patients with atypical chromosome rearrangements were analysed. This approach led to the identification of a potentially disrupted gene, HIC2, whose function was analysed using gene trap mouse models and which was shown to play a role in heart development. Overall these experiments have led to the elucidation of novel genes and genetic pathways affected in DGS and have contributed to a better understanding of the mechanisms controlling morphogenesis of the pharyngeal apparatus and heart.