Dissertations / Theses on the topic 'Protein microarray'
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1
Klenkar, Goran. "Protein Microarray Chips." Doctoral thesis, Linköping : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-8904.
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Zhou, Ye. "Microcontact printing for protein microarray applications /." Linköping : Univ, 2004. http://www.bibl.liu.se/liupubl/disp/disp2004/tek886s.pdf.
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Voelker, Alden Earl. "Selective Fusion-Tag-Catalyzed Protein Immobilizations for Microarray and Biosensor Applications." Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1370448393.
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Bove, Elia <1978>. "Identification of surface protein complexes of Streptococcus pyogenes through protein microarray technology." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2009. http://amsdottorato.unibo.it/1686/2/BoveElia_Tesi.pdf.
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A systematic characterization of the composition and structure of the bacterial cell-surface proteome and its complexes can provide an invaluable tool for its comprehensive understanding. The knowledge of protein complexes composition and structure could offer new, more effective targets for a more specific and consequently effective immune response against a complex instead of a single protein. Large-scale protein-protein interaction screens are the first step towards the identification of complexes and their attribution to specific pathways. Currently, several methods exist for identifying protein interactions and protein microarrays provide the most appealing alternative to existing techniques for a high throughput screening of protein-protein interactions in vitro under reasonably straightforward conditions. In this study approximately 100 proteins of Group A Streptococcus (GAS) predicted to be secreted or surface exposed by genomic and proteomic approaches were purified in a His-tagged form and used to generate protein microarrays on nitrocellulose-coated slides. To identify protein-protein interactions each purified protein was then labeled with biotin, hybridized to the microarray and interactions were detected with Cy3-labelled streptavidin. Only reciprocal interactions, i. e. binding of the same two interactors irrespective of which of the two partners is in solid-phase or in solution, were taken as bona fide protein-protein interactions. Using this approach, we have identified 20 interactors of one of the potent toxins secreted by GAS and known as superantigens. Several of these interactors belong to the molecular chaperone or protein folding catalyst families and presumably are involved in the secretion and folding of the superantigen. In addition, a very interesting interaction was found between the superantigen and the substrate binding subunit of a well characterized ABC transporter. This finding opens a new perspective on the current understanding of how superantigens are modified by the bacterial cell in order to become major players in causing disease.
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Bove, Elia <1978>. "Identification of surface protein complexes of Streptococcus pyogenes through protein microarray technology." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2009. http://amsdottorato.unibo.it/1686/.
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A systematic characterization of the composition and structure of the bacterial cell-surface proteome and its complexes can provide an invaluable tool for its comprehensive understanding. The knowledge of protein complexes composition and structure could offer new, more effective targets for a more specific and consequently effective immune response against a complex instead of a single protein. Large-scale protein-protein interaction screens are the first step towards the identification of complexes and their attribution to specific pathways. Currently, several methods exist for identifying protein interactions and protein microarrays provide the most appealing alternative to existing techniques for a high throughput screening of protein-protein interactions in vitro under reasonably straightforward conditions. In this study approximately 100 proteins of Group A Streptococcus (GAS) predicted to be secreted or surface exposed by genomic and proteomic approaches were purified in a His-tagged form and used to generate protein microarrays on nitrocellulose-coated slides. To identify protein-protein interactions each purified protein was then labeled with biotin, hybridized to the microarray and interactions were detected with Cy3-labelled streptavidin. Only reciprocal interactions, i. e. binding of the same two interactors irrespective of which of the two partners is in solid-phase or in solution, were taken as bona fide protein-protein interactions. Using this approach, we have identified 20 interactors of one of the potent toxins secreted by GAS and known as superantigens. Several of these interactors belong to the molecular chaperone or protein folding catalyst families and presumably are involved in the secretion and folding of the superantigen. In addition, a very interesting interaction was found between the superantigen and the substrate binding subunit of a well characterized ABC transporter. This finding opens a new perspective on the current understanding of how superantigens are modified by the bacterial cell in order to become major players in causing disease.
6
Qureshi, Aaron M. "A combinatorial design of a protein-binding DNA microarray." College Park, Md. : University of Maryland, 2004. http://hdl.handle.net/1903/2081.
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Thesis (M.S.) -- University of Maryland, College Park, 2004.Thesis research directed by: Dept. of Mathematics. 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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Sundberg, Mårten. "Protein microarrays for validation of affinity binders." Licentiate thesis, KTH, Proteomik, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-48256.
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Is specificity an important issue regarding affinity reagents? What about the validation of affinity reagents today, is it good enough? This depends on the application and the producer of the reagent. Validation should be the most important marketing argument that can be found.Today there is a continuous growth of both the number of affinity reagents that are produced and the different types of affinity reagents that are developed. In proteomics they become more and more important in exploring the human proteome. Therefore, validated affinity reagents should be on top of every proteomic researcher’s list. How should this be accomplished?Better international agreements on how affinity reagents should be tested to be regarded as functional reagents are needed. One of the most important issues is the specificity of the affinity reagent. An international standard for which specific validation that is needed for different kinds of applications would be very useful.In this thesis, it is shown that the protein microarray platform that was established within the HPA project at KTH is a very good tool to determine the specificity of different affinity binders.In the first study, the production of mono-specific antibodies for tissue profiling in the Human Protein Atlas (HPA) project is presented. The section describing the use of protein microarrays for validation of the antibodies is relevant for this thesis. The implementation of protein microarrays in the HPA workflow was an important addition, because a deeper insight of the specificity of all the antibodies produced were now available.In a second study, bead based arrays were compared to planar protein microarrays used in the HPA project. In this study, 100 different bead identities were coupled with 100 different antigens and mixed together to generate an array. The correlation between the two types of assays was very high and the conclusion was that the methods can be used as backup to each other.A third study was a part of an international initiative to produce renewable affinity binders against proteins containing SH2 domain. Here, the HPA protein microarrays were modified to analyze different types of reagents produced at six laboratories around the world. Monoclonal antibodies, single chain fragment and fibronectin scaffolds were tested as well as mono-specific antibodies. It was shown to be possible to adapt protein microarrays used in the HPA project to validate other kinds of affinity reagents.QC 20111117
Development and applications of protein microarrays
The Swedish Human Proteome Resource (HPR) program
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Scietti, Luigi Angelo Domenico <1986>. "Exploring host-pathogen interactions through protein microarray. Large-scale protein microarray analysis revealed novel human receptors for the staphylococcal immune evasion protein FLIPr and for the neisserial adhesin NadA." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amsdottorato.unibo.it/6994/1/Luigi_Scietti_PhD_thesis_final.pdf.
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Adhesion, immune evasion and invasion are key determinants during bacterial pathogenesis. Pathogenic bacteria possess a wide variety of surface exposed and secreted proteins which allow them to adhere to tissues, escape the immune system and spread throughout the human body. Therefore, extensive contacts between the human and the bacterial extracellular proteomes take place at the host-pathogen interface at the protein level. Recent researches emphasized the importance of a global and deeper understanding of the molecular mechanisms which underlie bacterial immune evasion and pathogenesis. Through the use of a large-scale, unbiased, protein microarray-based approach and of wide libraries of human and bacterial purified proteins, novel host-pathogen interactions were identified.
This approach was first applied to Staphylococcus aureus, cause of a wide variety of diseases ranging from skin infections to endocarditis and sepsis. The screening led to the identification of several novel interactions between the human and the S. aureus extracellular proteomes. The interaction between the S. aureus immune evasion protein FLIPr (formyl-peptide receptor like-1 inhibitory protein) and the human complement component C1q, key players of the offense-defense fighting, was characterized using label-free techniques and functional assays.
The same approach was also applied to Neisseria meningitidis, major cause of bacterial meningitis and fulminant sepsis worldwide. The screening led to the identification of several potential human receptors for the neisserial adhesin A (NadA), an important adhesion protein and key determinant of meningococcal interactions with the human host at various stages. The interaction between NadA and human LOX-1 (low-density oxidized lipoprotein receptor) was confirmed using label-free technologies and cell binding experiments in vitro.
Taken together, these two examples provided concrete insights into S. aureus and N. meningitidis pathogenesis, and identified protein microarray coupled with appropriate validation methodologies as a powerful large scale tool for host-pathogen interactions studies.
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Scietti, Luigi Angelo Domenico <1986>. "Exploring host-pathogen interactions through protein microarray. Large-scale protein microarray analysis revealed novel human receptors for the staphylococcal immune evasion protein FLIPr and for the neisserial adhesin NadA." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amsdottorato.unibo.it/6994/.
Full textAbstract:
Adhesion, immune evasion and invasion are key determinants during bacterial pathogenesis. Pathogenic bacteria possess a wide variety of surface exposed and secreted proteins which allow them to adhere to tissues, escape the immune system and spread throughout the human body. Therefore, extensive contacts between the human and the bacterial extracellular proteomes take place at the host-pathogen interface at the protein level. Recent researches emphasized the importance of a global and deeper understanding of the molecular mechanisms which underlie bacterial immune evasion and pathogenesis. Through the use of a large-scale, unbiased, protein microarray-based approach and of wide libraries of human and bacterial purified proteins, novel host-pathogen interactions were identified.
This approach was first applied to Staphylococcus aureus, cause of a wide variety of diseases ranging from skin infections to endocarditis and sepsis. The screening led to the identification of several novel interactions between the human and the S. aureus extracellular proteomes. The interaction between the S. aureus immune evasion protein FLIPr (formyl-peptide receptor like-1 inhibitory protein) and the human complement component C1q, key players of the offense-defense fighting, was characterized using label-free techniques and functional assays.
The same approach was also applied to Neisseria meningitidis, major cause of bacterial meningitis and fulminant sepsis worldwide. The screening led to the identification of several potential human receptors for the neisserial adhesin A (NadA), an important adhesion protein and key determinant of meningococcal interactions with the human host at various stages. The interaction between NadA and human LOX-1 (low-density oxidized lipoprotein receptor) was confirmed using label-free technologies and cell binding experiments in vitro.
Taken together, these two examples provided concrete insights into S. aureus and N. meningitidis pathogenesis, and identified protein microarray coupled with appropriate validation methodologies as a powerful large scale tool for host-pathogen interactions studies.
10
Riba, Michela. "Mitochip, microarray of human mitochondrial protein genes, development and applications." Thesis, Open University, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599927.
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Burger, Jürgen [Verfasser], and Gerald A. [Akademischer Betreuer] Urban. "Automated system for the cell-free protein microarray synthesis and the label-free molecule-protein interaction analysis." Freiburg : Universität, 2017. http://d-nb.info/1148929290/34.
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Vaglenov, Kiril Aleksandrov Petrenko V. A. "Development and study of phage-based microarray and dot-blot." Auburn, Ala., 2007. http://repo.lib.auburn.edu/Send%2002-04-08/VAGLENOV_KIRIL_37.pdf.
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Hlatshwayo, Nkosikhona Rejoyce. "Comparison of protein binding microarray derived and ChIP-seq derived transcription factor binding DNA motifs." Thesis, Rhodes University, 2015. http://hdl.handle.net/10962/d1017907.
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Transcription factors (TFs) are biologically important proteins that interact with transcription machinery and bind DNA regulatory sequences to regulate gene expression by modulating the synthesis of the messenger RNA. The regulatory sequences comprise of short conserved regions of a specific length called motifs . TFs have very diverse roles in different cells and play a very significant role in development. TFs have been associated with carcinogenesis in various tissue types, as well as developmental and hormone response disorders. They may be responsible for the regulation of oncogenes and can be oncogenic. Consequently, understanding TF binding and knowing the motifs to which they bind is worthy of attention and research focus. Various projects have made the study of TF binding their main focus; nevertheless, much about TF binding remains confounding. Chromatin immunoprecipitation in conjunction with deep sequencing (ChIP-seq) techniques are a popular method used to investigate DNA-TF interactions in vivo. This procedure is followed by motif discovery and motif enrichment analysis using relevant tools. Protein Binding Microarrays (PBMs) are an in vitro method for investigating DNA-TF interactions. We use a motif enrichment analysis tools (CentriMo and AME) and an empirical quality assessment tool (Area under the ROC curve) to investigate which method yields motifs that are a true representation of in vivo binding. Motif enrichment analysis: On average, ChIP-seq derived motifs from the JASPAR Core database outperformed PBM derived ones from the UniPROBE mouse database. However, the performance of motifs derived using these two methods is not much different from each other when using CentriMo and AME. The E-values from Motif enrichment analysis were not too different from each other or 0. CentriMo showed that in 35 cases JASPAR Core ChIP-seq derived motifs outperformed UniPROBE mouse PBM derived motifs, while it was only in 11 cases that PBM derived motifs outperformed ChIP-seq derived motifs. AME showed that in 18 cases JASPAR Core ChIP-seq derived motifs did better, while only it was only in 3 cases that UniPROBE motifs outperformed ChIP-seq derived motifs. We could not distinguish the performance in 25 cases. Empirical quality assessment: Area under the ROC curve values computations followed by a two-sided t-test showed that there is no significant difference in the average performances of the motifs from the two databases (with 95% confidence, mean of differences=0.0088125 p-value= 0.4874, DF=47) .
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Wei, Shuai. "Protein-Surface Interactions with Coarse-Grain Simulation Methods." BYU ScholarsArchive, 2013. https://scholarsarchive.byu.edu/etd/3943.
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The interaction of proteins with surfaces is a major process involved in protein microarrays. Understanding protein-surface interactions is key to improving the performance of protein microarrays, but current understanding of the behavior of proteins on surfaces is lacking. Prevailing theories on the subject, which suggest that proteins should be stabilized when tethered to surfaces, do not explain the experimentally observed fact that proteins are often denatured on surfaces. This document outlines several studies done to develop a model which is capable of predicting the stabilization and destabilization of proteins tethered to surfaces. As the start point of the research, part of this research showed that the stability of five mainly-alpha, orthogonal-bundle proteins tethered to surfaces can be correlated to the shape of the loop region where the tether is placed and the free rotation ability of the part of proteins near surfaces. To test the expandability of the protein stability prediction pattern derived for mainly-alpha, orthogonal-bundle proteins, same analysis is performed for proteins from other structure motifs. Besides the study in these small two-state proteins, a further analysis of surface-induced change of folding mechanism is also studied with a multi-state lysozyme protein 7LZM. The result showed that by tethering a protein on a surface, the melting temperature of a part of the protein changed, which leads to an avoidance of the meta-stable state. Besides the change of folding mechanism, by tethering the lysozyme protein to a certain site, the protein could both keep a stable structure and a good orientation, allowing active sites to be available to other proteins in bulk solution. All the work described above are done with a purely repulsive surface model which was widely used to roughly simulate solid surfaces in protein microarrays. For a next-level understanding of protein-surface interactions, a novel coarse-grain surface model was developed, parameterized, and validated according to experimental results from different groups. A case study of interaction between lysozyme protein 7LZM and three types of surfaces with the novel model has been performed. The results showed that protein stabilities and structures are dependent on the types of surfaces and their different hydrophobicities. This result is consistent with previously published experimental work.
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Xu, Yangqing. "A filtration-based protein microarray platform for proteomics and biomedical applications : development and kinetic studies." Diss., Georgia Institute of Technology, 2002. http://hdl.handle.net/1853/20233.
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Mahaye, Ntombikayise. "A central enrichment-based comparison of two alternative methods of generating transcription factor binding motifs from protein binding microarray data." Thesis, Rhodes University, 2013. http://hdl.handle.net/10962/d1003049.
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Characterising transcription factor binding sites (TFBS) is an important problem in bioinformatics, since predicting binding sites has many applications such as predicting gene regulation. ChIP-seq is a powerful in vivo method for generating genome-wide putative binding regions for transcription factors (TFs). CentriMo is an algorithm that measures central enrichment of a motif and has previously been used as motif enrichment analysis (MEA) tool. CentriMo uses the fact that ChIP-seq peak calling methods are likely to be biased towards the centre of the putative binding region, at least in cases where there is direct binding. CentriMo calculates a binomial p-value representing central enrichment, based on the central bias of the binding site with the highest likelihood ratio. In cases where binding is indirect or involves cofactors, a more complex distribution of preferred binding sites may occur but, in many cases, a low CentriMo p-value and low width of maximum enrichment (about 100bp) are strong evidence that the motif in question is the true binding motif. Several other MEA tools have been developed, but they do not consider motif central enrichment. The study investigates the claim made by Zhao and Stormo (2011) that they have identified a simpler method than that used to derive the UniPROBE motif database for creating motifs from protein binding microarray (PBM) data, which they call BEEML-PBM (Binding Energy Estimation by Maximum Likelihood-PBM). To accomplish this, CentriMo is employed on 13 motifs from both motif databases. The results indicate that there is no conclusive difference in the quality of motifs from the original PBM and BEEML-PBM approaches. CentriMo provides an understanding of the mechanisms by which TFs bind to DNA. Out of 13 TFs for which ChIP-seq data is used, BEEML-PBM reports five better motifs and twice it has not had any central enrichment when the best PBM motif does. PBM approach finds seven motifs with better central enrichment. On the other hand, across all variations, the number of examples where PBM is better is not high enough to conclude that it is overall the better approach. Some TFs bind directly to DNA, some indirect or in combination with other TFs. Some of the predicted mechanisms are supported by literature evidence. This study further revealed that the binding specificity of a TF is different in different cell types and development stages. A TF is up-regulated in a cell line where it performs its biological function. The discovery of cell line differences, which has not been done before in any CentriMo study, is interesting and provides reasons to study this further.
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Zhou, Jerry. "Discovery and application of colorectal cancer protein markers for disease stratification." Thesis, The University of Sydney, 2013. http://hdl.handle.net/2123/10400.
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Colorectal cancer (CRC) is a major cause of cancer mortality. Whereas some patients respond well to therapy, others do not, and thus more precise methods of CRC stratification are needed. The intracellular protein expression from 28 CRC primary tumours and corresponding normal intestinal mucosa was analysed using saturation-DIGE/MS and Explorer antibody microarrays. Changes in protein abundance were identified at each stage of CRC. Proteins associated with proliferation, glycolysis, reduced adhesion, endoplasmic reticulum stress, angiogenesis, and response to hypoxia represent changes to CRC and its microenvironment during development. Molecular changes in CRC cells and their microenvironment can be incorporated into clinic-pathological data to help sub-classify tumours and personalise treatment. DotScan antibody microarray analysis was used to profile the surface proteome of cells derived from 50 CRC samples and corresponding normal intestinal mucosa. Fluorescence multiplexing enabled the analysis of two different sub-populations of cells from each sample: EpCAM+ cells (CRC cells or normal epithelial cells in normal mucosa) and CD3+ T-cells (tumour-infiltrating lymphocytes). Unsupervised hierarchical clustering of the CRC and T-cell surface profiles defined four clinically relevant clusters, which showed some correlation with histopathological and clinical characteristics such as cancer cell differentiation, peri-tumoural inflammation and stimulation of infiltrating T-cells. The observed relationship between the surface antigen expression profiles of patients’ CRC cells and their corresponding tumour infiltrating T-cells suggests that CRC surface proteins may play a direct role in influencing the activity (and hence surface protein expression) of neighbouring T-cells and/or vice versa. We conclude that the application of surface profiling may provide improved patient stratification, allowing more reliable prediction of disease progression and patient outcome.
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Beeton-Kempen, Natasha. "P450 biochips : development of a protein microarray platform for investigating cytochrome P450 clinical drug metabolism." Doctoral thesis, University of Cape Town, 2010. http://hdl.handle.net/11427/10103.
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Includes bibliographical references (leaves 224-243).This thesis describes the development of a novel cytochrome P450 array format, the P450 Biochip that allows quantitative and truly high-throughput measurement of cytochrome P450-mediated turnover reactions in sub-nanolitre volumes.
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Cavanna, T. C. L. "Microarray expression analysis of metastasising sarcoma cells implies a role for protein 4.1b in metastasis." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1445352/.
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The identification of the genes underlying the mechanisms of metastasis is of great interest, since metastatic disease is the major cause of death in cancer patients. To investigate the possible mechanisms of metastasis, I used an inbred rat sarcoma model and analysed four related cell populations with significant differences in their ability to shed metastases when subcutaneously injected into inbred rats (P < 0.01). I characterised the motility and morphology of the four cell populations and found that the metastatic cells had a stronger chemotactic response to PDGF/IGF, migrated faster, and had fewer stress fibres, than the non-metastastic cells. Next I performed microarray analysis to investigate the gene expression differences underlying the progression to the metastatic phenotype. I examined gene expression in the cultured cells, and in the tumours that formed after subcutaneous injection of the cells into rats. In this way, I was able to identify genes whose expression was significantly changed with metastatic potential, both in cultured cells and in primary tumours. Twenty-three genes were differentially expressed more than 2.5-fold in metastatic cells (P < 0.05). The gene encoding protein 4.IB was down-regulated in the metastatic cells. To investigate the possible function of 4.IB, I reduced its expression in non-metastatic cells by RNA interference (RNAi). Cells with reduced 4. IB expression displayed an altered F-actin morphology, with a loss of stress fibres compared to control cells. The stress fibre phenotype was rescued by transfection of an RNAi-resistant 4. IB cDNA, showing that the effect was specific. I also found that the 4. IB RNAi cells migrated at twice the speed of the wild-type cells. I conclude that the loss of 4.IB in the metastatic cells causes a significant loss of actin stress fibres and increase in cell speed, and thus plays a role in progression to metastatic phenotype.
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Ye, Albert Shanbuo. "Development and Application of Lysate Microarray Technology for Quantitative Analysis of Human Disease." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11024.
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Reductionist biology has yielded tremendous insight into the basis of biochemistry and genetic disease. However, the remarkable failure of reductionist biology to explain complex problems, especially cancer, has led to the development of systems biology. The vast complexity of biological systems remains the most difficult problem in biology today. In order to understand this complexity, we need tools to massively multiplex measurements of a signaling network. Therefore, we developed lysate microarray technology to fill this need. In this work, we discuss three ways in which lysate microarrays were applied to human disease. In the first work, we discuss a key stage in malaria development. The liver-stage malaria parasite represents a promising target for intervention, and we present the first use of lysate microarray technology as a screening tool for host-parasite interactions in an infectious disease. We identified three cancer-related pathways that are modified in malaria infection, and studied the p53 pathway in depth. Our finding that the parasite downregulates p53 and that treatment with Nutlin-3 strongly decreases parasite load may lead to the development of a prophylactic malaria vaccine. In the second work, we began by screening drug combinations and varying dosing schedule in triple-negative breast cancers (TNBCs). We systematically explored stimulation space and collected a large lysate microarray dataset, which was used for statistical analysis. We identified a sensitization effect when a growth factor signaling inhibitor was presented before a genotoxic agent. This sensitization was generalizable among a subset of TNBCs and may generally be important for cancers driven by growth factor signaling, as we found the effect extends to nonTNBC cancers. We hope this data will be useful in guiding cancer treatment strategies in patients. In the third work, we study the changing role of the DNA Damage Response (DDR) as a cell line evolves towards cancer. We used the MCF10A progression series and studied how these cell lines respond to genotoxic agents. We identified differences in cell fates after treatment, and collected a large lysate microarray dataset for statistical analysis. Early analysis of the data indicates gross rewiring within the DDR between the MCF10A cell lines.
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Wang, Chen. "From network to pathway: integrative network analysis of genomic data." Diss., Virginia Tech, 2011. http://hdl.handle.net/10919/77121.
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The advent of various types of high-throughput genomic data has enabled researchers to investigate complex biological systems in a systemic way and started to shed light on the underlying molecular mechanisms in cancers. To analyze huge amounts of genomic data, effective statistical and machine learning tools are clearly needed; more importantly, integrative approaches are especially needed to combine different types of genomic data for a network or pathway view of biological systems. Motivated by such needs, we make efforts in this dissertation to develop integrative framework for pathway analysis. Specifically, we dissect the molecular pathway into two parts: protein-DNA interaction network and protein-protein interaction network. Several novel approaches are proposed to integrate gene expression data with various forms of biological knowledge, such as protein-DNA interaction and protein-protein interaction for reliable molecular network identification.
The first part of this dissertation seeks to infer condition-specific transcriptional regulatory network by integrating gene expression data and protein-DNA binding information. Protein-DNA binding information provides initial relationships between transcription factors (TFs) and their target genes, and this information is essential to derive biologically meaningful integrative algorithms. Based on the availability of this information, we discuss the inference task based on two different situations:
(a) if protein-DNA binding information of multiple TFs is available:
based on the protein-DNA data of multiple TFs, which are derived from sequence analysis between DNA motifs and gene promoter regions, we can construct initial connection matrix and solve the network inference using a constraint least-squares approach named motif-guided network component analysis (mNCA). However, connection matrix usually contains a considerable amount of false positives and false negatives that make inference results questionable. To circumvent this problem, we propose a knowledge based stability analysis (kSA) approach to test the conditional relevance of individual TFs, by checking the discrepancy of multiple estimations of transcription factor activity with respect to different perturbations on the connections. The rationale behind stability analysis is that the consistency of observed gene expression and true network connection shall remain stable after small perturbations are applied to initial connection matrix. With condition-specific TFs prioritized by kSA, we further propose to use multivariate regression to highlight condition-specific target genes. Through simulation studies comparing with several competing methods, we show that the proposed schemes are more sensitive to detect relevant TFs and target genes for network inference purpose. Experimentally, we have applied stability analysis to yeast cell cycle experiment and further to a series of anti-estrogen breast cancer studies. In both experiments not only biologically relevant regulators are highlighted, the condition-specific transcriptional regulatory networks are also constructed, which could provide further insights into the corresponding cellular mechanisms.
(b) if only single TF's protein-DNA information is available:
this happens when protein-DNA binding relationship of individual TF is measured through experiments. Since original mNCA requires a complete connection matrix to perform estimation, an incomplete knowledge of single TF is not applicable for such approach. Moreover, binding information derived from experiments could still be inconsistent with gene expression levels. To overcome these limitations, we propose a linear extraction scheme called regulatory component analysis (RCA), which can infer underlying regulation relationships, even with partial biological knowledge. Numerical simulations show significant improvement of RCA over other traditional methods to identify target genes, not only in low signal-to-noise-ratio situations and but also when the given biological knowledge is incomplete and inconsistent to data. Furthermore, biological experiments on Escherichia coli regulatory network inferences are performed to fairly compare traditional methods, where the effectiveness and superior performance of RCA are confirmed.
The second part of the dissertation moves from protein-DNA interaction network up to protein-protein interaction network, to identify dys-regulated protein sub-networks by integrating gene expression data and protein-protein interaction information. Specifically, we propose a statistically principled method, namely Metropolis random walk on graph (MRWOG), to highlight condition-specific PPI sub-networks in a probabilistic way. The method is based on the Markov chain Monte Carlo (MCMC) theory to generate a series of samples that will eventually converge to some desired equilibrium distribution, and each sample indicates the selection of one particular sub-network during the process of Metropolis random walk. The central idea of MRWOG is built upon that the essentiality of one gene to be included in a sub-network depends on not only its expression but also its topological importance. Contrasted to most existing methods constructing sub-networks in a deterministic way and therefore lacking relevance score for each protein, MRWOG is capable of assessing the importance of each individual protein node in a global way, not only reflecting its individual association with clinical outcome but also indicating its topological role (hub, bridge) to connect other important proteins. Moreover, each protein node is associated with a sampling frequency score, which enables the statistical justification of each individual node and flexible scaling of sub-network results. Based on MRWOG approach, we further propose two strategies: one is bootstrapping used for assessing statistical confidence of detected sub-networks; the other is graphic division to separate a large sub-network to several smaller sub-networks for facilitating interpretations. MRWOG is easy to use with only two parameters need to be adjusted, one is beta value for performing random walk and another is Quantile level for calculating truncated posteriori mean. Through extensive simulations, we show that the proposed scheme is not sensitive to these two parameters in a relatively wide range. We also compare MRWOG with deterministic approaches for identifying sub-network and prioritizing topologically important proteins, in both cases MRWG outperforms existing methods in terms of both precision and recall. By utilizing MRWOG generated node/edge sampling frequency, which is actually posteriori mean of corresponding protein node/interaction edge, we illustrate that condition-specific nodes/interactions can be better prioritized than the schemes based on scores of individual node/interaction. Experimentally, we have applied MRWOG to study yeast knockout experiment for galactose utilization pathways to reveal important components of corresponding biological functions; we also applied MRWSOG to study breast cancer patient prognostics problems, where the sub-network analysis could lead to an understanding of the molecular mechanisms of antiestrogen resistance in breast cancer.
Finally, we conclude this dissertation with a summary of the original contributions, and the future work for deepening the theoretical justification of the proposed methods and broadening their potential biological applications such as cancer studies.Ph. D.
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Filipponi, Luisa, and n/a. "New micropatterning techniques for the spatial addressable immobilization of proteins." Swinburne University of Technology, 2006. http://adt.lib.swin.edu.au./public/adt-VSWT20060905.113858.
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Bio-microdevices are miniaturised devices based on biologically derived components
(e.g., DNA, proteins, and cells) combined or integrated with microfabricated substrates.
These devices are of interest for numerous applications, ranging from drug discovery, to
environmental monitoring, to tissue engineering. Before a bio-microdevice can be fully
developed, specific fabrication issues need to be addressed. One of the most important
is the spatial immobilization of selected biomolecules in specific micro-areas of the
device. Among the biomolecules of interest, the controlled immobilization of proteins to
surfaces is particularly challenging due to the complexity of these macromolecules and
their tendency to lose bioactivity during the immobilization step. The present Thesis
reports on three novel micropatterning techniques for the spatial immobilization of
proteins with bioactivity retention and improved read-out of the resulting micropatterns.
The technologies developed are based on three different micropatterning approaches,
namely 1) direct-writing UV laser microablation (proLAB), 2) a novel microcontact
printing method (�CPTA) and 3) a replica molding method combined with bead selfassembly
(BeadMicroArray). The first two technologies, proLAB and �CPTA, are an
implementation of existing techniques (laser ablation and �CP, respectively), whereas
the third, i.e., the BeadMicroArray, is a totally new technique and type of patterning
platform.
'ProLAB' is a technology that uses a micro-dissection tool equipped with a UV laser
(the LaserScissors�) for ablating a substrate made of a layer of ablatable material, gold,
deposited over a thin polymer layer. The latter layer is transparent to the laser but
favours protein adsorption. In the present work microchannels were chosen as the
structure of interest with the aim of arranging them in 'bar-codes', so to create an
'information-addressable' microarray. This platform was fabricated and its application
to specific antigen binding demonstrated.
The second technique that was developed is a microstamping method which exploits the
instability of a high-aspect ratio rubber stamp fabricated via soft-lithography. The
technique is denominated microcontact printing trapping air (�CPTA) since the collapsing of a rubber stamp made of an array of micro-pillars over a plane glass surface
resulted in the formation of a large air gap around the entire array. The method can be
successfully employed for printing micro-arrays of proteins, maintaining biological
activity. The technique was compared with robotic spotting and found that microarrays
obtained with the �CPTA method were more homogeneous and had a higher signal-tonoise
ratio.
The third technique developed, the BeadMicroArray, introduces a totally new platform
for the spatial addressable immobilization of proteins. It combines replica molding with
microbead self-assembling, resulting in a platform where diagnostic beads are entrapped
at the tip of micropillars arranged in a microarray format. The fabrication of the
BeadMicroArray involves depositing functional microbeads in an array of V-shaped
wells using spin coating. The deposition is totally random, and conditions were
optimised to fill about half the array during spin coating. After replica molding, the
resulting polymer mold contains pyramid-shaped posts with beads entrapped at the very
tip of the post. Thanks to the fabrication mode involved, every BeadMicroArray
fabricated contains a unique geometric code, therefore assigning a specific code to each
microarray. In the present work it was demonstrated that the functionality of the beads
after replica molding remains intact, and that proteins can be selectively immobilized on
the beads, for instance via biorecognition. The platform showed a remarkable level of
selectively which, together with an efficient blocking towards protein non-specific
adsorption, lead to a read-out characterized by a very good signal-to-noise. Also, after
recognition, a code was clearly visible, therefore showing the encoding capacity of this
unique microarray.
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Gry, Marcus. "Global expression analysis of human cells and tissues using antibodies." Doctoral thesis, Stockholm : Bioteknologi, Kungliga Tekniska högskolan, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-9116.
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Mohsenchian, Atefeh. "Biomarker discovery for ALS by using affinity proteomica." Thesis, KTH, Skolan för bioteknologi (BIO), 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-149440.
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Nhat, Nguyen Thi Duy. "Stationary and temporal structure of antibody titer distributions to human influenza A virus in southern Vietnam." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:f8eba4e1-9c68-4750-bfed-e6f0de8dd2de.
Full textAbstract:
Seroepidemiology aims to understand population-level exposure and immunity to infectious disease. Serological results are normally presented as binary outcomes describing the presence or absence of antibody, despite the fact that many assays measure continuous quantities. A population's antibody titers may include information on multiple serological states - naiveté, recent infection, non-recent infection, childhood infection - not just seropositivity or seronegativity. In the first part of this thesis, I investigate 20,152 general-population serum samples from southern Vietnam collected between 2009 and 2013 from which I report antibody titers to the influenza virus HA1 protein using a continuous titer measurement from a protein microarray assay. I describe titer distributions to subtypes 2009 H1N1 and H3N2, and using a model selection approach for mixture distributions, I determine that 2009 H1N1 is best described by four titer subgroups while H3N2 is best described by three titer subgroups. For H1N1, my interpretation is that the two highest-titer subgroups correspond to recent and historical infection, which is consistent with pandemic attack rates. For H3N2 however, right-censoring of titers makes interpretations difficult to validate. To move beyond this stationary interpretation of titers, I developed two methods for analyzing this serum collection as a time series. First, I attempted to analyze mixture categories in individual time windows. This approach did not lead to a consistent temporal picture of titer change; results differed by site and were sensitive to assumptions in the mixture fitting. Second, I attempted to fit a hybrid-dynamical model with free incidence parameters. This inference was robust to parameter assumptions, consistent across sites, and in agreement with the incidence reported in Vietnam's influenza surveillance network. In addition, my new approach showed evidence that there was a second silent wave of the 2009 influenza pandemic that was not recorded in national surveillance, which is this thesis' main novel result.
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Shrestha, Om Kumar. "The effect of LMNA mutations on the lamin IG-fold structure and muscle gene expression." Thesis, University of Iowa, 2012. https://ir.uiowa.edu/etd/3383.
Full textAbstract:
Mutations in the human LMNA gene encoding A-type lamins cause a collection of diseases termed laminopathies, including several types of muscular dystrophy. Lamins are intermediate filaments, which line the inner membrane of nuclear envelope. Lamins maintain the nuclear shape and regulate gene expression through interactions with chromatin. Heterozygous mutations LMNA, which result in single amino acid substitutions within the C-terminal Ig-fold domain, were identified in patients with muscular dystrophy. These substitutions were modeled in Drosophila and found to cause muscle defects. We have taken a multi-disciplinary approach to understanding the molecular basis of these muscle defects. Using Nuclear Magentic Resonance (NMR) and Circular Dischroism (CD) we determined that the amino acid substitutions cause perturbations of the tertiary, but not secondary, structure of the Ig-fold. Microarray analysis of RNA isolated from muscle revealed that mutant lamins cause cause mis-regulation of genes involved oxidative stress and neuromuscular junction function. Collectively, these data demonstrate that perturbations within the lamin Ig-fold cause changes in gene expression, providing insights on pathways involved in pathogenesis and identifying new potential therapeutic targets.
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Silk, Rhiannon Nicola. "Studies into host macrophage transcriptional control by the African Swine Fever Virus protein A238L." Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/4808.
Full textAbstract:
African swine fever virus (ASFV) is a large double-stranded DNA virus which causes a lethal haemorrhagic fever in domestic pigs. This virus primarily infects cells from the monocyte/macrophage lineage and its ability to manipulate the function of these cells is key to the pathogenesis of this disease. ASFV encodes several proteins involved in immune evasion. One of these proteins, A238L, has been shown to inhibit host macrophage gene transcription. This protein has been shown to interact with several cellular proteins involved in signal transduction: a serine/threonine protein phosphatase, calcinerurin (CaN), the transcription factor NF-кB, and most recently the transcriptional co-activator CREB binding protein (CBP/P300). However its exact mechanism of action is not fully understood. Previous work has been limited to the investigation of individual signaling pathways and/or the expression of individual host genes. The aim of this study was to investigate the global effect of A238L on host macrophage gene transcription and also to carry out further investigation into the mechanism by which this protein functions. To determine the global effect of A238L on host macrophage gene transcription differential gene expression between porcine cells expressing A238L and control cells was examined using a porcine oligonucleotide microarray. These results demonstrated that A238L was a potent inhibitor of host macrophage gene expression. Functional characterisation of the annotated genes showed that a large proportion of A238L down-regulated genes are typically induced in response to cell stress. Significantly, genes regulated by the I kappa B kinase (IKK), mitogen-activated protein kinase (MAPK) and janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways were all shown to be down regulated by A238L. Genes associated with the MAPK pathways were particularly enriched. The transcription of A238L-regulated genes is controlled by numerous different transcription factors, including NF-кB. All of the transcription factors identified interact with the transcription co-activator CBP/P300. This provides a common link between these factors, and indicates that A238L may target CBP/P300 to inhibit gene transcription. This observation supports recent work demonstrating that A238L interacts with and inhibits CBP/P300 function. To explore the potential mechanisms involved in the nuclear localisation of A238L, ASFV-infected Vero cells, expressing A238L under the control of its own promoter, were examined under a range of conditions using confocal microscopy. The results demonstrated that A238L was actively imported into the nucleus and exported by a CRM 1 mediated pathway, although a pool of A238L protein remained in the cytoplasm. Sequence analysis of A238L identified the presence of two putative nuclear localisation signals (NLS-1 and NLS-2). NLS-2 was located within A238L’s CaN docking motif. Mutation of these motifs indicated that both NLS-1 and NLS-2 are active and exhibit functional redundancy. Mutation of the CaN docking motif alone, in the presence of intact NLS-2, resulted in a dramatic increase in the nuclear localisation of A238L. These results are consistent with a model in which A238L functions within both the nucleus and the cytoplasm and suggest that binding of CaN to A238L masks NLS-2, contributing to the cytoplasmic retention of A238L.
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Habibi, Golareh. "Y-box binding protein-1 (YB-1) is a bio-marker of aggressiveness in breast cancer and is a potential target for therapeutic intervention." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/911.
Full textAbstract:
Early detection is one of the most important factors for successful treatment of cancer. Currently, scientists are searching for molecular markers that can help identify and predict outcome and chance of recurrence in patients. In this study, we demonstratet he potential impact of Y-Box binding protein-1 (YB-1) as a marker of aggressiveness and cancer recurrence in breast malignancies by screening one of the largest tissue microarrays in North America.
YB-1 is an oncogenic transcription/translation factor, which is over-expressed in the majority of malignancies, including breast cancer. In the cohort of 4049 primary breast tumours, we show that YB-1 is a strong marker of aggressiveness, poor survival and cancer recurrence in all subtypes of human breast cancer with a particularly high frequency of expression in the ER negative basal-like and HER-2 breast cancer subtypes. This suggests that targeting YB-1 may provide a new avenue for therapeutic intervention in these breast cancers that are currently challenging to treat. Cox regression multivariate analysis indicates that YB-1 is second only to nodal status as a strong independent prognostic marker for poor outcome and relapse compared to established clinico-pathological biomarkers, including tumour size, age, grade, ER and HER-2 status. This finding suggests that YB-1 has great potential to be in a priority list of biomarkers for identifying the patients with a higher risk of relapse and poor outcome. Subsequently, we find an association between YB-1 and urokinase Plasminogen Activator (uPA) expression in the basal-like subtype. We then show that YB-1 is involved in the regulation of uPA expression. More importantly, silencing YB-1 or uPA results in a significant reduction in cancer cell invasion. As there are no commercially available YB-linibitors we examine the efficacy of BMS-536924, a small molecule inhibitor for activated IGF-1R/IR on SUM149 cells. We demonstrate that activated IGF-1R is associated with poor survival in primary breast tumours and, that BMS-536924 reduces uPA expression through inhibition YB-1 in SUM149 cells.
We therefore conclude that YB-1 is a bio-marker for poor survival and relapse. We also indicate that YB-1 has potential use as a molecular marker in a clinical setting. Inhibiting YB-1 may provide an ideal opportunity for targeted therapy in breast cancer.
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Calicchio, Rosamaria. "High-throughput transcriptional analysis of the endothelial alterations in preeclampsia identifies JDP2 (Jun dimerization protein 2) as a novel actor in hypoxia sensing." Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05T060/document.
Full textAbstract:
La prééclampsie est une maladie humaine qui affecte 3-8 % des grossesses dans le monde, cliniquement définie par l’apparition de novo d’une hypertension et d’une protéinurie. La cause initiale de la maladie semble être liée à un défaut de vascularisation placentaire, ce qui entraine des cycles d'hypoxie – ré-oxygénation, une ischémie placentaire et la libération de débris placentaires dans la circulation maternelle. Ces derniers sont responsables d'une activation endothéliale généralisée, exacerbée par un état pro-coagulant et pro-inflammatoire. Pour mieux caractériser la réponse des cellules endothéliales aux facteurs plasmatiques présent dans la circulation maternelle des femmes prééclamptiques , nous avons choisi une approche à l’échelle du génome entier pour évaluer le profil d'expression génique (grâce à des puces d’expression) de la lignée de cellules endothéliales humaines de la veine ombilicale (HUVEC) cultivée avec du plasma prééclamptique, comparée au profil de cellules cultivées avec du plasma humain provenant de grossesses normales. Cette étude nous a permis d'identifier différents gènes modulés dont celui codant la protéine de dimérisation Jun 2 (JDP2, diminué près de trois fois) qui pourrait être responsable d'une partie des modifications transcriptomiques trouvées. De façon intéressante en effet, inhiber JDP2 par une approche de siRNA régule significativement à la baisse (entre autres) l'expression du VEGF, imitant ainsi les effets du plasma prééclamptique sur les HUVEC. Dans la dernière partie de mon projet, nous nous sommes particulièrement concentrés sur l'impact de l’inhibition de JDP2 sur des gènes induits par l'hypoxie. La tension partielle basse en oxygène modifie l'expression génique par l'intermédiaire de la stabilisation du facteur de transcription HIF- 1a. En fait, dans un état hypoxique, HIF- 1a échappe à la dégradation par le protéasome, il forme alors des hétérodimères avec ARNT (HIF- 1ß) et induit l'expression de gènes ayant un élément de réponse à l’hypoxie (HRE) dans leur promoteur. L'induction de l'expression du VEGF dans des conditions d’hypoxie constitue un des premiers modèles de l’effet de l’hypoxie sur l’expression génique et c’est également un des mieux caractérisés. Afin d'évaluer le rôle de JDP2 sur l'expression du VEGF, et plus généralement sur des gènes cible de l’hypoxie, nous avons cultivé des cellules HUVEC dans des conditions de normoxie et d’hypoxie. Les mêmes conditions ont été utilisées en association avec la transfection de siRNA contre JDP2. En conclusion, dans des conditions d’hypoxie, l’inhibition de JDP2 a un impact négatif sur l'expression du VEGF. De plus, JDP2 semble être un médiateur essentiel de l'expression génique induite par l'hypoxie, car il est nécessaire à une activité complète de promoteur contenant des HRE (démontré dans des essais luciférase)Preeclamspia is a unique human disorder which affects 3-8% of pregnancies worldwide, clinically defined as the new onset of hypertension and proteinuria. The root cause of the disease seems to be linked to a defect of placental vascularization, which enhances cycles of hypoxia –reoxygenantion, placental ischemia and the release of placental debris into maternal circulation. The latter ones are responsible for a widespread endothelial activation, exacerbated pro-coagulable and pro-inflammatory state. To best characterize the response of endothelial cells to the plasma factors present in maternal circulation of preeclamptic women, we chose a genome –wide approach in order to evaluate the gene expression profile of Human Umbilical Vein Endothelial Cells (HUVEC) line cultivated with preeclamptic plasma, compared to cells cultivated with human plasma coming from normal pregnancies. This study allows us to identify the gene Jun Dimerization Protein2 (JDP2) which could be responsible for part of transcriptomic modifications. Interestingly inhibiting JDP2 by the use of siRNA significantly down- regulates VEGF expression, thus mimicking the effects of preeclamptic plasma on HUVEC. In the last part of my project we focus specifically on the impact of JDP2 knock down on hypoxia- induced genes. Low oxygen tension modifies gene expression via the stabilization of the transcription factor HIF-1a. In fact under hypoxic condition, HIF-1a escapes from proteasomal degradation, it forms heterodimers with ARNT (HIF- 1ß) and induces the expression of genes having a Hypoxia Responsive Element (HRE) in their promoter. One of the first and best characterized models of the effect of hypoxia on gene expression is the induction of VEGF expression under hypoxic condition. In order to evaluate the contribution of JDP2 to VEGF expression, and more generally to hypoxia target genes, we cultivate HUVEC in normoxic and hypoxic condition. The same conditions were used in association with transfection of siRNA against JDP2. In conclusion, under hypoxic condition, JDP2 down- regulation has a negative impact on VEGF expression. Moreover, JDP2 seems to be an essential mediator of hypoxia –induced gene expression, since it is necessary for a full HRE promoter activity (demonstrated by Luciferase assays)
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Zhang, Jing. "Design and implementation of DNA-Directed Immobilisation (DDI) glycoarrays for probing carbohydrate-protein interactions." Phd thesis, Ecole Centrale de Lyon, 2010. http://tel.archives-ouvertes.fr/tel-00605541.
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Yang, Zhugen. "3D-Microstructured Protein Chip for Cancer Diagnosis." Phd thesis, Ecole Centrale de Lyon, 2012. http://tel.archives-ouvertes.fr/tel-00780192.
Full textAbstract:
Protein microarrays are becoming powerful tools to screen and identify tumor markers for cancer diagnosis, because of the multiplex detection and minute volume of sample requirement. Due to the diversity and variation in different cancers, no single tumor marker is sensitive and specific enough to meet strict diagnostic criteria. Therefore, a combination of tumor markers is required to increase sensitivity and to establish distinct patterns to increase specificity. To obtain reliable tests, the development of reproducible surface chemistry and immobilization procedure are crucial steps in the elaboration of efficient protein microarrays. In this thesis, 3D micro-structured glass slides were functionalized with various surface chemistries like silane monolayer (amino, epoxy and carboxy), and polymer layers of Jeff amine, chitosan, carboxymethyl dextran (CMD), maleic anhydride-alt-methyl vinyl ether copolymer (MAMVE) for physical adsorption or covalent binding with proteins. Surface characterizations, such as X-ray photoelectron spectroscopy (XPS) and Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), confirmed the monolayer/polymer grafting on the glass slides. Colorimetric assay for determining amine density of three aminated surfaces demonstrated that APDMES had more grafting density than Jeffamine and chitosan. Contact angle measurements show that polymer surfaces were more hydrophilic than monolayer surfaces due to the increasing dosages of polar functional groups. Moreover, the parameters such as additives and pH of spotting buffer, probe concentration, blocking procedures etc, were optimized for tumor marker detection. Under the optimized conditions, antibody microarrays were validated with purified tumor antigens. The best analytical performances obtained for each tumor antigen tested were strongly dependent on functionalized surfaces, e.g. MAMVE exhibited best analytical performances for CEA andHsp60 while NHS leads to best results for PDI and CA19-9. Besides, the implemented antibody microarrays were applied to tumor marker detection from colorectal cancer sera. This evaluation shows the interest to combine several tumor markers on the same surface and the combination of tumor markers on their specific surface lead to remarkably increase the positive responses of tested cancer sera (even up to 100 %). A second type of microarrays (tumor-associated antigens - TAA microarrays) was designed to discriminate breast cancer patients from healthy donors through the detection of tumor autoantibodies. This study included a cohort of 29 breast cancer patients' and 28 healthy donors' sera. A panel of fiveTAAs (Hsp60, p53, Her2, NY-ESO-1 and Hsp70) immobilized on their respective optimized surface chemistry allowed to specifically detect over 82% of breast cancer patients.
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Gagni, P. "DEVELOPMENT OF NOVEL HIGH PERFORMANCE PROTEIN MICROARRAYS FOR DIAGNOSTIC APPLICATIONS." Doctoral thesis, Università degli Studi di Milano, 2015. http://hdl.handle.net/2434/249493.
Full textAbstract:
Several application of protein microarray technology in diagnostics have been published and a limited number of protein microarrays is currently available on the In Vitro Diagnostics (IVD) market. Albeit several advantages, related to the miniaturization, the multiplexing capability and the possibility of integrating the immunoassays in biosensing devices, microarrays may still lack of specificity or sensitivity. To overcome these limitations and expand the use of protein microarray platform in diagnostics, the present PhD research aimed at developing innovative approaches to increase the assay specificity and sensitivity, reaching very low detection limits, that are compatible with the use of the proposed devices in diagnostics. Furthermore, the use of protein microarrays has been applied to the characterization of emerging biomarkers: exosomes.
First of all, surface immobilized hydrogels have been investigated as reagent reservoir for microarray reagents. They have been demonstrated to store reagents in a dry form, stable over days, in a format easy to transport and to preserve. Moreover, they also acted as chambers able to physically separate analytes or reagents which may cross-react with proteins on the printed arrays. In this way the solution was prevented from spreading over the surface and the assays provided sentitive performances, comparable to standard static incubations.
In further studies, the complementarity of information provided by fluorescence-based, label-free IRIS and SP-IRIS microarray platforms has been applied to develop immunoassays useful in the diagnostics of Neurodegenerative Disorders. Specifically, two different assay formats have been exploited. The first part of the work focused on the development of a classical sandwich immunoassay able to detect physiological concentrations of Amyloid-beta peptides, biomarkers for Alzheimer’s disease, in both artificial cerebrospinal fluid and real human samples.
The second study was aimed at extending the concept of protein microarrays to extracellular vesicles (i.e., exosomes) detection through surface antigen-antibodies recognition. In this innovative application, the nanoparticles were detected with label-free IRIS (total biomass measurements) and SP-IRIS (particle counting and size distribution). In addition, individual particles were incubated with gold-labeled antibodies to identify biomarkers expressed on their surface.
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Bae, Kyounghwa. "Bayesian model-based approaches with MCMC computation to some bioinformatics problems." Texas A&M University, 2005. http://hdl.handle.net/1969.1/2396.
Full textAbstract:
Bioinformatics applications can address the transfer of information at several stages
of the central dogma of molecular biology, including transcription and translation.
This dissertation focuses on using Bayesian models to interpret biological data in
bioinformatics, using Markov chain Monte Carlo (MCMC) for the inference method.
First, we use our approach to interpret data at the transcription level. We propose
a two-level hierarchical Bayesian model for variable selection on cDNA Microarray
data. cDNA Microarray quantifies mRNA levels of a gene simultaneously so has
thousands of genes in one sample. By observing the expression patterns of genes under
various treatment conditions, important clues about gene function can be obtained.
We consider a multivariate Bayesian regression model and assign priors that favor
sparseness in terms of number of variables (genes) used. We introduce the use of
different priors to promote different degrees of sparseness using a unified two-level
hierarchical Bayesian model. Second, we apply our method to a problem related to
the translation level. We develop hidden Markov models to model linker/non-linker
sequence regions in a protein sequence. We use a linker index to exploit differences
in amino acid composition between regions from sequence information alone. A goal
of protein structure prediction is to take an amino acid sequence (represented as
a sequence of letters) and predict its tertiary structure. The identification of linker
regions in a protein sequence is valuable in predicting the three-dimensional structure.
Because of the complexities of both models encountered in practice, we employ the
Markov chain Monte Carlo method (MCMC), particularly Gibbs sampling (Gelfand
and Smith, 1990) for the inference of the parameter estimation.
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Wang, Yemin. "Role of tumour suppressor ING3 in melanoma pathogenesis." Thesis, University of British Columbia, 2009. http://hdl.handle.net/2429/3850.
Full textAbstract:
The type II tumour suppressor ING3 has been shown to modulate transcription, cell cycle control, and apoptosis. To investigate the putative role of ING3 in melanoma development, we examined the expression of ING3 in 58 dysplastic nevi, 114 primary melanomas, and 50 metastatic melanomas with tissue microarray and immunohistochemistry. Overall ING3 was reduced in metastatic melanomas compared with dyslastic nevi and primary melanomas. Reduced nuclear ING3 staining also correlated with melanoma progression, increased cytoplasmic ING3 level, tumour location at sun-exposed sites, and a poorer disease-specific 5-year survival of patients with primary melanoma. Multivariate analysis revealed that nuclear ING3 staining can independently predict patient outcome in primary melanomas. In melanoma cells, ING3 expression was rapidly induced by UV irradiation. Using stable clones of melanoma cells overexpressing ING3, we showed that ING3 significantly promoted UV-induced apoptosis. Unlike its homologues ING1b and ING2, ING3-enhanced apoptosis upon UV irradiation was independent of functional p53. Furthermore, ING3 did not affect the expression of mitochondrial proteins but increased the cleavage of Bid and caspases. Moreover, ING3 upregulated Fas expression and ING3-mediated apoptosis was blocked by inhibiting caspase-8 or Fas activation. Knockdown of ING3 expression decreased UV-induced apoptosis remarkably, suggesting that ING3 plays a crucial role in cellular response to UV radiation. To explore how ING3 is deregulated in advanced melanomas, we examined ING3 expression in metastatic melanoma cells and found that ING3 was downregulated due to a rapid protein turnover in these cells. Further studies demonstrated that ING3 undergoes degradation via the ubiquitin-proteasome pathway. We also demonstrate that ING3 interacts with the SCF (Skp1/Cul1/Roc1/Skp2) E3 ligase complex. Knockdown of Cul1 or Skp2 significantly stabilized ING3 in melanoma cells. In addition, lysine residue 96 is essential for ING3 ubiquitination as its mutation to arginine completely abrogated ING3 turnover and enhanced ING3-stimulatd apoptosis upon UV irradiation. Taken together, ING3 is deregulated in melanomas as a result of both nucleus-to-cytoplasm shift and rapid degradation. The level of ING3 in the nucleus may be an important marker for human melanoma progression and prognosis. Restoration of ING3 expression significantly sensitizes melanoma cells to UV radiation through the activation of Fas/caspase-8 pathway.
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Sundberg, Mårten. "Mass Spectrometry and Affinity Based Methods for Analysis of Proteins and Proteomes." Doctoral thesis, Uppsala universitet, Analytisk kemi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-259623.
Full textAbstract:
Proteomics is a fast growing field and there has been a tremendous increase of knowledge the last two decades. Mass spectrometry is the most used method for analysis of complex protein samples. It can be used both in large scale discovery studies as well as in targeted quantitative studies. In parallel with the fast improvements of mass spectrometry-based proteomics there has been a fast growth of affinity-based methods. A common challenge is the large dynamic range of protein concentrations in biological samples. No method can today cover the whole dynamic range. If affinity and mass spectrometry-based proteomics could be used in better combination, this would be partly solved. The challenge for affinity-based proteomics is the poor specificity that has been seen for many of the commercially available antibodies. In mass spectrometry, the challenges are sensitivity and sample throughput. In this thesis, large scale approaches for validation of antibodies and other binders are presented. Protein microarrays were used in four validation studies and one was based on mass spectrometry. It is shown that protein microarrays can be valuable tools to check the specificity of antibodies produced in a large scale production. Mass spectrometry was shown to give similar results as Western blot and Immunohistochemistry regarding specificity, but did also provide useful information about which other proteins that were bound to the antibody. Mass spectrometry has many applications and in this thesis two methods contributing with new knowledge in animal proteomics are presented. A combination of high affinity depletion, SDS PAGE and mass spectrometry revealed 983 proteins in dog cerebrospinal fluid, of which 801 were marked as uncharacterized in UniProt. A targeted quantitative study of cat serum based on parallel reaction monitoring showed that mass spectrometry can be an applicable method instead of ELISA in animal proteomic studies. Mass spectrometry is a generic method and has the advantage of shorter and less expensive development costs for specific assays that are not hampered by cross-reactivity. Mass spectrometry supported by affinity based applications will be an attractive tool for further improvements in the proteomic field.
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Wei, Shuai. "The Structure and Stability of Alpha-Helical, Orthogonal-Bundle Proteins on Surfaces." BYU ScholarsArchive, 2010. https://scholarsarchive.byu.edu/etd/2323.
Full textAbstract:
The interaction of proteins with surfaces is a major problem involved in protein microarrays. Understanding protein/surface interactions is key to improving the performance of protein microarrays, but current understanding of the behavior of proteins on surfaces is lacking. Prevailing theories on the subject, which suggest that proteins should be stabilized when tethered to surfaces, do not explain the experimentally observed fact that proteins are often denatured on surfaces. In an attempt to develop some predictive capabilities with respect to protein/surface interactions, it was asked in previous works if the stabilization/destabilization of proteins on surfaces could be correlated to secondary structure and found that no link existed. However, further investigation has revealed that proteins with similar tertiary structure show predictable stabilization patterns. In this research, it is reported how five, alpha-helical, orthogonal-bundle proteins behave on the surface compared to the bulk. By measuring stabilization using melting temperatures and the Gibbs energies of folding, it is shown that the stability of proteins tethered to surfaces can be correlated to the shape of the loop region where the tether is placed and the free rotation ability of the part of proteins near surfaces. It is also shown that any destabilization that occurs because of the surface is an enthalpic effect and that surfaces always stabilize proteins entropically. Furthermore, the entropical stabilization effect comes from unfolded states of the tethered protein, while the enthalpical destabilization effect is from the folded states of protein. A further analysis of surface induced change of folding mechanism is also studied with a multi-state protein 7LZM in this research. The result showed that by tethering a protein on a surface, the melting temperature of part of the protein changed, which leads to a miss of state.
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Le, Thi Thuy Trang. "Molecular and functional characterisation of an osmotin gene from the resurrection plant Tripogon loliiformis." Thesis, Queensland University of Technology, 2018. https://eprints.qut.edu.au/115835/1/Thi%20Thuy%20Trang_Le_Thesis.pdf.
Full textAbstract:
Abiotic stresses such as drought, salinity, and extreme temperature are significant challenges hindering the capacity of agriculture to meet the food demands of an increasing global population. This thesis characterises an osmotin gene (TlOsm) from a naturally-tolerant plant for use in the development of stress-adapted crops. The efficacy of TlOsm to improve stress tolerance was assessed and compared with two osmotins from stress-sensitive (rice) species. The results demonstrate the potential of TlOsm to improve tolerance against cold, drought, and salinity stress and highlighted the higher efficacy of genes from naturally-tolerant species.
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Gu, Jinghua. "Novel Monte Carlo Approaches to Identify Aberrant Pathways in Cancer." Diss., Virginia Tech, 2013. http://hdl.handle.net/10919/51950.
Full textAbstract:
Recent breakthroughs in high-throughput biotechnology have promoted the integration of multi-platform data to investigate signal transduction pathways within a cell. In order to model complicated dynamics and heterogeneity of biological pathways, sophisticated computational models are needed to address unique properties of both the biological hypothesis and the data. In this dissertation work, we have proposed and developed methods using Markov Chain Monte Carlo (MCMC) techniques to solve complex modeling problems in human cancer research by integrating multi-platform data. We focus on two research topics: 1) identification of transcriptional regulatory networks and 2) uncovering of aberrant intracellular signal transduction pathways.
We propose a robust method, called GibbsOS, to identify condition specific gene regulatory patterns between transcription factors and their target genes. A Gibbs sampler is employed to sample target genes from the marginal function of outlier sum of regression t statistic. Numerical simulation has demonstrated significant performance improvement of GibbsOS over existing methods against noise and false positive connections in binding data. We have applied GibbsOS to breast cancer cell line datasets and identified condition specific regulatory rewiring in human breast cancer.
We also propose a novel method, namely Gibbs sampler to Infer Signal Transduction (GIST), to detect aberrant pathways that are highly associated with biological phenotypes or clinical information. By converting predefined potential functions into a Gibbs distribution, GIST estimates edge directions by learning the distribution of linear signaling pathway structures. Through the sampling process, the algorithm is able to infer signal transduction directions which are jointly determined by both gene expression and network topology. We demonstrate the advantage of the proposed algorithms on simulation data with respect to different settings of noise level in gene expression and false-positive connections in protein-protein interaction (PPI) network.
Another major contribution of the dissertation work is that we have improved traditional perspective towards understanding aberrant signal transductions by further investigating structural linkage of signaling pathways. We develop a method called Structural Organization to Uncover pathway Landscape (SOUL), which emphasizes on modularized pathways structures from reconstructed pathway landscape. GIST and SOUL provide a very unique angle to computationally model alternative pathways and pathway crosstalk. The proposed new methods can bring insight to drug discovery research by targeting nodal proteins that oversee multiple signaling pathways, rather than treating individual pathways separately. A complete pathway identification protocol, namely Infer Modularization of PAthway CrossTalk (IMPACT), is developed to bridge downstream regulatory networks with upstream signaling cascades. We have applied IMPACT to breast cancer treated patient datasets to investigate how estrogen receptor (ER) signaling pathways are related to drug resistance. The identified pathway proteins from patient datasets are well supported by breast cancer cell line models. We hypothesize from computational results that HSP90AA1 protein is an important nodal protein that oversees multiple signaling pathways to drive drug resistance. Cell viability analysis has supported our hypothesis by showing a significant decrease in viability of endocrine resistant cells compared with non-resistant cells when 17-AAG (a drug that inhibits HSP90AA1) is applied.
We believe that this dissertation work not only offers novel computational tools towards understanding complicated biological problems, but more importantly, it provides a valuable paradigm where systems biology connects data with hypotheses using computational modeling. Initial success of using microarray datasets to study endocrine resistance in breast cancer has shed light on translating results from high throughput datasets to biological discoveries in complicated human disease studies. As the next generation biotechnology becomes more cost-effective, the power of the proposed methods to untangle complicated aberrant signaling rewiring and pathway crosstalk will be finally unleashed.Ph. D.
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Fredriksson, Simon. "Proximity Ligation : Transforming protein analysis into nucleic acid detection through proximity-dependent ligation of DNA sequence tagged protein-binders." Doctoral thesis, Uppsala University, Department of Genetics and Pathology, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2691.
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A novel technology for protein detection, proximity ligation, has been developed along with improved methods for in situ synthesis of DNA microarrays. Proximity ligation enables a specific and quantitative transformation of proteins present in a sample into nucleic acid sequences. As pairs of so-called proximity probes bind the individual target protein molecules at distinct sites, these reagents are brought in close proximity. The probes consist of a protein specific binding part coupled to an oligonucleotide with either a free 3’- or 5’-end capable of hybridizing to a common connector oligonucleotide. When the probes are in proximity, promoted by target binding, then the DNA strands can be joined by enzymatic ligation. The nucleic acid sequence that is formed can then be amplified and quantitatively detected in a real-time monitored polymerase chain reaction. This convenient assay is simple to perform and allows highly sensitive protein detection. Parallel analysis of multiple proteins by DNA microarray technology is anticipated for proximity ligation and enabled by the information carrying ability of nucleic acids to define the individual proteins. Assays detecting cytokines using SELEX aptamers or antibodies, monoclonal and polyclonal, are presented in the thesis.
Microarrays synthesized in situ using photolithographic methods generate impure products due to damaged molecules and interrupted synthesis. Through a molecular inversion mechanism presented here, these impurities may be removed. At the end of synthesis, full-length oligonucleotides receive a functional group that can then be made to react with the solid support forming an arched structure. The 3’-ends of the oligonucleotides are then cleaved, removing the impurities from the support and allowing the liberated 3’-hydroxyl to prime polymerase extension reactions from the inverted oligonucleotides. The effect of having pure oligonucleotides probes compared to ones contaminated with shorter variants was investigated in allele specific hybridization reactions. Pure probes were shown to have greater ability to discriminate between matched and singly mismatched targets at optimal hybridization temperatures.
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Shi, Liu. "Elaboration of protein microarrays for rapid screening and quantification of breast cancer biomarkers." Thesis, Ecully, Ecole centrale de Lyon, 2015. http://www.theses.fr/2015ECDL0024/document.
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Le cancer du sein demeure un problème de santé publique majeure dans le monde. Afin d'améliorer les chances de survie et la qualité de vie des femmes, il est nécessaire d’effectuer le diagnostic à un stade précoce et d’appliquer le traitement. Dans ce contexte, un des objectifs de cette thèse est de développer des puces à protéines pour le diagnostic et le pronostic du cancer du sein. Parmi les nombreux marqueurs biologiques potentiels, des recherches récentes ont montré que des anticorps anti-heat shock proteins (anti-HSPs) sont associés à la genèse tumorale. Ces anticorps seraient donc de bons biomarqueurs diagnostiques et pronostiques pour le cancer du sein. Par conséquent, nous avons élaboré une puce à antigènes afin de détecter les anticorps anti-HSP dans le sérum de 50 patients atteints de cancer du sein et de 26 témoins sains. Nos résultats indiquent clairement que la la détection multiplex d’une combinaison d'anticorps anti-HSP permet de discriminer les patients atteints de cancer du sein des témoins sains avec une sensibilité de 86% et une spécificité de 100%. Ensuite, nous avons élaboré une puce à anticorps pour doser la concentration de l'activateur du plasminogène de type urokinase (uPA) et de son inhibiteur principal (PAI-1) dans 16 extraits cytosoliques de tissus tumoraux. uPA et PAI-1 sont décrits comme étant de bons biomarqueurs pronostiques et prédictifs du cancer du sein. De faibles taux de uPA (≤3 ng / mg de protéine) et PAI-1 (≤14 ng / mg de protéine) sont associés à un faible risque de récidive et pas de bénéfice d’une chimiothérapie pour les patients atteints de cancer du sein. Les résultats obtenus à partir de puces à anticorps étaient surface dépendante par rapport aux résultats obtenus sous forme ELISA. En outre, l'utilisation de nos puces à anticorps nécessite 25 fois moins de volume d'échantillon par rapport à un dosage ELISA, résolvant ainsi les principales limites de la méthode ELISA. Enfin, nous avons déterminé et optimisé les paramètres influençant les performances des puces à protéines, comme par exemple la chimie de surface, la durée expérimentale, la concentration des solutions, etc. Nous avons également étudié les conditions de stockage à la fois pour des surfaces chimiquement fonctionnalisées et pour les puces à protéines. Les résultats ont montré que les puces à protéines conservent leur activité biologique jusqu’à trois mois de stockageBreast cancer becomes the most common cancer among women. In order to improve women's chances of survival and life quality, to be diagnosed at an early stage and to receive correct treatment are the most promising ways. In this context, we aim at developing an antigen microarray for screening serological biomarkers to diagnose breast cancer patients as early as possible. Among numerous potential biomarkers, recent researches showed that antibodies against heat shock proteins (HSPs) are associated with tumor genesis and would be good diagnostic and prognostic biomarkers for breast cancer. Therefore, we used customized antigen microarray to screen anti-HSP antibodies in 50 breast cancer patients and 26 healthy controls. Our results indicated clearly that combining multiplex detection of anti-HSPs antibodies could discriminate breast cancer patients from healthy controls with sensitivity 86% and specificity 100%. Then, we elaborated an antibody microarray to detect the concentration of urokinase type plasminogen activator (uPA) in 16 cytosolic extracts of breast tummor tissue. uPA is good prognostic and predictive biomarker for breast cancer, low levels of uPA (≤3 ng/mg of protein) is associated with low risk of recurrence and no benefit of chemotherapy for breast cancer patients, and vice versa. Our results showed that the results obtained from our antibody microarray were surface dependent compared with the results obtained from ELISA. Furthermore, the use of our antibody microarray requires 25 times less sample volume compared with ELISA kit, thus solving the main limitations of ELISA. Finally, we determined and optimized the parameters which affected the performances of protein microarray, e.g. microarray surface chemistry, experimental duration, the concentration of solutions, etc. Furthermore, we studied the storage conditions for both chemically functionalized microarray surface as well as printed protein microarray. Results showed that our protein microarrays retain efficient biological activity for at least 3 month of storage
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Awakura, Yasuo. "Microarray-based identification of CUB-domain containing protein 1 as a potential prognostic marker in conventional renal cell carcinoma." Kyoto University, 2009. http://hdl.handle.net/2433/124251.
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Shahryarhesami, Soroosh [Verfasser], and Christoph [Akademischer Betreuer] Michalski. "Detection of bacteria and virus-associated Pancreatic Ductal Adenocarcinoma by cell-free protein microarray / Soroosh Shahryarhesami ; Betreuer: Christoph Michalski." Heidelberg : Universitätsbibliothek Heidelberg, 2020. http://d-nb.info/1208975218/34.
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Lundberg, Emma. "Bioimaging for analysis of protein expression in cells and tissues using affinity reagents." Doctoral thesis, Stockholm : School of biotechnology, Royal institute of technology, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-4862.
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Mandelli, Andrea Paola. "Unfolding the immune response against Staphylococcus aureus-mediated systemic sequelae of skin recurrences." Doctoral thesis, Università di Siena, 2022. http://hdl.handle.net/11365/1203731.
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Staphylococcal protein A (SpA) is a surface-associated virulence factor of Staphylococcus aureus (S. aureus) which binds human immunoglobulins via both Fc and Fab fragment masking the pathogen to the host immune system. This activity interacts with the normal maturation of the host immune system during an infection and allows S. aureus to cause recurrent infections as, for example, skin recurrences. Skin recurrences are not only bothersome superficial infections that require continuous treatments, but may also evolve in more complicated and systemic complications. Immunization with SpA protects animals against S. aureus systemic infections unmasking the pathogen to the host immune system, which turns out to recognize bacterial antigens otherwise hidden by SpA activity.
The aim of this project was to assess the protective effect of SpAmut against skin recurrences and systemic complications in a mouse model of Skin and Soft Tissues Infections (SSTIs) set up in C57BL/6 mice, which are naturally susceptible to re-infections with S. aureus. Vaccination with SpAmut adjuvanted with AS01 (SpAmut/AS01) was able to limit bacterial spreading from the skin through the blood, abrogating S. aureus infiltration to the kidneys (target for systemic disease). S. aureus-specific protein microarrays were used to compare sera of mice vaccinated with SpAmut/AS01 and then infected with those of mice only infected for their ability to recognize a selection of S. aureus antigens. Vaccination with SpAmut/AS01 was able to unmask several S. aureus antigens to the immune system during SSTIs in mice. Interestingly, mice infected with S. aureus did not develop measurable antibodies against the mutated version of SpA, whereas infection in vaccinated mice significantly increased the avidity of antibodies against SpAmut induced by previous immunization. Furthermore, only sera from vaccinated and infected mice allowed internalization of S. aureus by human phagocytes in vitro, suggesting a functional role in mediating the in vivo observed protection.
Overall, these data support the essential role of vaccination with SpA, an immunomodulator antigen of S. aureus, in the induction of a functional specific antibody response during recurrences, contributing to the control of systemic bacterial dissemination, one of the main complications developed during S. aureus-mediated SSTIs.
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Pokorny, Morgan R. "The role of Y-box binding protein 1 in prostate cancer." Thesis, Queensland University of Technology, 2013. https://eprints.qut.edu.au/65556/1/Morgan_Pokorny_Thesis.pdf.
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This thesis examined the possible role of Y-box binding protein 1 (YBX1) in prostate cancer aggression and spread. Novel roles were uncovered for YBX1 in the regulation of several genes previously implicated in prostate cancer, as well as showing an effect for YBX1 in increasing tumour cell invasion and movement and reciprocal regulation of androgen-regulated gene networks. In addition, it was found that Y-box 1 regulated several other well-known cancer genes implicated in breast and other cancers. The work performed in this thesis has strengthened the foundations for pursuing YBX1 as a possible central target molecule in prostate cancer therapeutics.
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Kibat, Janek Norman [Verfasser], and Gerhard [Akademischer Betreuer] Winter. "Development of a protein microarray platform for the characterization of antibodies and quantitative immunoassays / Janek Norman Kibat ; Betreuer: Gerhard Winter." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1167683161/34.
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Chan, Steven Man Cheong. "Protein microarray technology for profiling signaling patwhays [sic] : insights into pro-oncogenic notch signaling in T cell acute lymphoblastic leukemia /." May be available electronically:, 2006. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
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Guida, Marianna <1981>. "Fosfoproteomica e terapia personalizzata: utilizzo di una piattaforma Reverse Phase Protein Microarray per predire la risposta del paziente alla farmacoterapia." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2011. http://amsdottorato.unibo.it/3246/1/tesi_completa.pdf.
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Guida, Marianna <1981>. "Fosfoproteomica e terapia personalizzata: utilizzo di una piattaforma Reverse Phase Protein Microarray per predire la risposta del paziente alla farmacoterapia." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2011. http://amsdottorato.unibo.it/3246/.
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Malone, Michael Harold. "Using Gene Expression Profiling to Understand the Mechanism of Glucocorticoid-Induced Apoptosis in Lymphoid Malignancies." Case Western Reserve University School of Graduate Studies / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=case1112296162.
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