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Fluhrer, Regina. "Zwei neuartige Aspartylproteasen BACE-1 und BACE-2." Diss., lmu, 2003. http://nbn-resolving.de/urn:nbn:de:bvb:19-14423.
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Wilson, D. M. "Platelet BACE Activity and its relationship to genetic variation at the BACE locus, in patients with different types of dementia." Thesis, Queen's University Belfast, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.517654.
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Strauss, Markus. "Funktionelle Analyse der humanen [beta]-Sekretase [Beta-Sekretase] (BACE)." [S.l.] : [s.n.], 2005. http://www.diss.fu-berlin.de/2005/45/index.html.
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Fuzaro, Junior Gilson [UNESP]. "Nível de atividade física, estado nutricional e níveis de BACE 1 e BACE 2 em idosos neurologicamente saudáveis e com doença de Alzheimer." Universidade Estadual Paulista (UNESP), 2015. http://hdl.handle.net/11449/138561.
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000863012.pdf: 1359589 bytes, checksum: a5d767aad97ebd041c16c340e5476d28 (MD5)A Doença de Alzheimer (DA) é neurodegenerativa, progressiva e causa comprometimento cognitivo em idosos. Além da terapia medicamentosa, alternativas não farmacológicas, como atividade física e orientação nutricional, podem auxiliar no tratamento da doença. A influência desses fatores em alguns biomarcadores, como as β-secretases, tem sido relacionada a alterações em alguns quadros da doença. Assim, o objetivo do presente estudo foi analisar o nível de atividade física, estado nutricional e níveis plaquetários de BACE 1 e BACE 2 em idosos com doença de Alzheimer nos estágios leve e moderado e em idosos cognitivamente preservados. Ainda, comparar grupos e a correlacionar estas variáveis. Para tanto, participaram do estudo 32 idosos com DA e 32 idosos hígidos. Para verificar o nível de atividade física os idosos utilizaram um acelerômetro e responderam ao questionário Baecke modificado para idosos. A avaliação do estado nutricional consistiu na coleta das medidas antropométricas: peso (kg), estatura (m), circunferências e pregas cutâneas. Também foi aplicada a Mini Avaliação Nutricional. Por meio de coleta sanguínea, foram analisados os níveis plaquetários de BACE 1 e BACE 2 dos grupos. Além disso, foram aplicados testes de rastreamento da função cognitiva, estagiamento da DA e sintomas depressivos dos participantes. Para análise dos dados, foi verificada a normalidade da amostra por meio do teste de Shapiro Wilk. Para dados paramétricos, foi utilizado o teste t de Student e correlação de Pearson, para dados não paramétricos, foi utilizado o teste U de Mann-Whitney e correlação de Spearman. Foi admitido um nível de significância de p<0,05. Os resultados indicam que houve diferença significativa nas médias de nível de atividade física, nas concentrações de BACE 1 e 2 e para a variável Mini Avaliação Nutricional entre os grupos, sendo que o grupo DA apresentou menor nível de atividade física...
Alzheimer's disease (AD) is a neurodegenerative, progressive and causes cognitive impairment in the elderly. Besides drug therapy, nonpharmacological alternatives such as physical activity and nutritional counseling, can help in treating the disease. The influence of these factors in some biomarkers such as β-secretase, has been related to changes in certain tables of the disease. The objective of this study was to analyze the level of physical activity, nutritional status and platelet levels of BACE BACE 1 and 2 in elderly patients with Alzheimer's disease in mild and moderate stages and cognitively preserved elderly. Also compare groups and to correlate these variables. To do so, participated in the study 32 elderly with AD and 32 healthy elderly. To check the level of physical activity the elderly used an accelerometer and the questionnaire Baecke modified for the elderly. The assessment of nutritional status consisted of the collection of anthropometric measurements: weight (kg), height (m), circumference and skinfold thickness. It has also been applied to Mini Nutritional Assessment. Through blood collection, platelet levels of BACE and BACE 1 of 2 groups were analyzed. Furthermore, screening tests were applied cognitive function, depressive symptoms and the staging of the attendees. For data analysis, the normality of the sample using the Shapiro-Wilk test was verified. For parametric data, we used the Student t test and Pearson's correlation to non-parametric data, the Mann-Whitney U test and Spearman correlation. It was admitted a significance level of p <0.05. The results indicate a significant difference in the average level of physical activity at concentrations of BACE 1 and 2 and the variable Mini Nutritional Assessment between the groups, with the DA group had lower levels of physical activity, higher concentrations of BACE and worse nutritional status. In addition, the Spearman test showed negative correlation between the...
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Fuzaro, Junior Gilson. "Nível de atividade física, estado nutricional e níveis de BACE 1 e BACE 2 em idosos neurologicamente saudáveis e com doença de Alzheimer /." Rio Claro, 2015. http://hdl.handle.net/11449/138561.
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Orientador: José Luiz Riani CostaBanca: Thays Martins Vital
Banca: Alexandre Gabarra de Oliveira
Resumo: A Doença de Alzheimer (DA) é neurodegenerativa, progressiva e causa comprometimento cognitivo em idosos. Além da terapia medicamentosa, alternativas não farmacológicas, como atividade física e orientação nutricional, podem auxiliar no tratamento da doença. A influência desses fatores em alguns biomarcadores, como as β-secretases, tem sido relacionada a alterações em alguns quadros da doença. Assim, o objetivo do presente estudo foi analisar o nível de atividade física, estado nutricional e níveis plaquetários de BACE 1 e BACE 2 em idosos com doença de Alzheimer nos estágios leve e moderado e em idosos cognitivamente preservados. Ainda, comparar grupos e a correlacionar estas variáveis. Para tanto, participaram do estudo 32 idosos com DA e 32 idosos hígidos. Para verificar o nível de atividade física os idosos utilizaram um acelerômetro e responderam ao questionário Baecke modificado para idosos. A avaliação do estado nutricional consistiu na coleta das medidas antropométricas: peso (kg), estatura (m), circunferências e pregas cutâneas. Também foi aplicada a Mini Avaliação Nutricional. Por meio de coleta sanguínea, foram analisados os níveis plaquetários de BACE 1 e BACE 2 dos grupos. Além disso, foram aplicados testes de rastreamento da função cognitiva, estagiamento da DA e sintomas depressivos dos participantes. Para análise dos dados, foi verificada a normalidade da amostra por meio do teste de Shapiro Wilk. Para dados paramétricos, foi utilizado o teste t de Student e correlação de Pearson, para dados não paramétricos, foi utilizado o teste U de Mann-Whitney e correlação de Spearman. Foi admitido um nível de significância de p<0,05. Os resultados indicam que houve diferença significativa nas médias de nível de atividade física, nas concentrações de BACE 1 e 2 e para a variável Mini Avaliação Nutricional entre os grupos, sendo que o grupo DA apresentou menor nível de atividade física...
Abstract: Alzheimer's disease (AD) is a neurodegenerative, progressive and causes cognitive impairment in the elderly. Besides drug therapy, nonpharmacological alternatives such as physical activity and nutritional counseling, can help in treating the disease. The influence of these factors in some biomarkers such as β-secretase, has been related to changes in certain tables of the disease. The objective of this study was to analyze the level of physical activity, nutritional status and platelet levels of BACE BACE 1 and 2 in elderly patients with Alzheimer's disease in mild and moderate stages and cognitively preserved elderly. Also compare groups and to correlate these variables. To do so, participated in the study 32 elderly with AD and 32 healthy elderly. To check the level of physical activity the elderly used an accelerometer and the questionnaire Baecke modified for the elderly. The assessment of nutritional status consisted of the collection of anthropometric measurements: weight (kg), height (m), circumference and skinfold thickness. It has also been applied to Mini Nutritional Assessment. Through blood collection, platelet levels of BACE and BACE 1 of 2 groups were analyzed. Furthermore, screening tests were applied cognitive function, depressive symptoms and the staging of the attendees. For data analysis, the normality of the sample using the Shapiro-Wilk test was verified. For parametric data, we used the Student t test and Pearson's correlation to non-parametric data, the Mann-Whitney U test and Spearman correlation. It was admitted a significance level of p <0.05. The results indicate a significant difference in the average level of physical activity at concentrations of BACE 1 and 2 and the variable Mini Nutritional Assessment between the groups, with the DA group had lower levels of physical activity, higher concentrations of BACE and worse nutritional status. In addition, the Spearman test showed negative correlation between the...
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Kobayashi, Dione T. "Behavioral and histochemical characterization of a novel BACE Knockout x PDAPP mouse model of Alzheimer's Disease : examination of potential effects of BACE inhibition on Alzheimer's Disease and the role of APP, Aβ and BACE in normal and pathological memory function." Thesis, University of Edinburgh, 2006. http://hdl.handle.net/1842/29204.
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This dissertation describes the phenotypic characterisation of a BACE knockout (KO) x PDAPP transgenic mouse line, utilising behavioural, histochemical, and pharmagologic methods. Several transgenic mouse models have been created that overexpress human mutant Amyloid Precursor Protein (hAPP) that reproduced many of the cognitive and histopathological features of AD. Recently, the β-site cleaving enzyme (BACE) responsible for the first proteolytic cleavage of APP has been characterised, and subsequent research has led to the propagation of BACE inhibition as a prime experimental strategy for AD therapy. Examining the behavioural and histological phenotypes of BACE KO animals on normal and hAPP overexpressing backgrounds is an effective way to assess whether the inhibition of BACE is a reasonable strategy for the treatment of AD. Behavioural studies were conducted using homozygous and hemizygous BACE KO mice, PDAPP mice, and BACE KO: PDAPP lines together with relevant controls. The results form the characterisation of the BACE KO x PDAPP mouse line indicate that the absolute loss of BACE and Aβ caused profound spatial memory deficits, sometimes greater even than that of hAPP mice alone. BACE KO was associated with spontaneous seizures as well as greater seizure activity in drug-induced seizure experiments. However, the partial hemizygous deletion of the BACE gene on a hAPP background appeared to improve spatial memory performance on certain measures and protect against drug-induced seizure responses relative to hAPP mice. The research described in this dissertation is consistent with the notion that, under certain circumstances, therapeutic inhibition of BACE may prove to be a valuable strategy for treatment of AD. These studies also support an important role for the APP processing pathway in “normal” learning and memory processes, possibly by regulating neuronal activity levels.
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Capell, Anja. "Funktionelle Charakterisierung von BACE, einer für die Alzheimer Krankheit relevanten Protease." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=976576228.
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Griffiths, Heledd Hâf. "Mechanisms of cellular prion protein regulation of the β-secretase, BACE." Thesis, University of Leeds, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.515339.
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Capell, Anja. "Funktionelle Charakterisierung von BACE, einer für die Alzheimer Krankheit relevanten Protease." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2005. http://dx.doi.org/10.18452/15321.
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Die Alzheimer Krankheit ist die häufigste Altersdemenz. Ein spezifisches pathologisches Merkmal der Alzheimer Krankheit ist die Amyloid-Ablagerung im Gehirn. Die Hauptkomponente der so genannten Amyloid-Plaques ist das Amyloid beta-Peptid (A-beta). A-beta entsteht durch sequenzielle proteolytische Spaltung aus einem membrangebundenen Vorläuferprotein, dem beta-APP (betaamyloid precursor protein). Die kürzlich identifizierte beta-Sekretase (BACE, beta-site APPcleaving enzyme) generiert den Schnitt am N-Terminus von A-beta. Es entsteht ein C-terminales, membrangebundenes beta-APP-Fragment, das beta-APP-CTF. Beta-APP-CTF ist das direkte Substrat für die gamma-Sekretase, die innerhalb der Membrandomäne schneidet, wodurch A-beta freigesetzt wird. In der vorliegenden Arbeit kann erstmalig gezeigt werden, dass BACE auf dem sekretorischen Transportweg aus dem Endoplasmatischen Retikulum (ER), über den Golgi-Apparat zur Zelloberfläche transportiert wird. Auf dem Transport wird BACE durch N-Glycosylierung und Propeptidabspaltung posttranslational modifiziert. BACE wird im ER N-glycosyliert und die mannosereichen Zucker werden auf dem Transport durch den Golgi-Apparat in Endoglycosidase H resistente Zucker des komplexen Typs modifiziert. Die Propeptidabspaltung, durch Furin oder furinähnliche Propeptidkonvertasen, findet unmittelbar vor dem Aufbau der komplexen Zucker statt. Ferner konnte gezeigt werden, dass der Transport von BACE die A-beta-Entstehung limitieren kann. In polarisierten Madin-Darby canine kidney (MDCK) Zellen wird BACE überwiegend zur apikalen Plasmamembran transportiert und damit entgegengesetzt zu seinem Substrat beta-APP. Der gegensätzliche Transport von BACE und beta-APP begrenzt die A-beta Entstehung. Wird der apikale Transport von beta-APP durch Deletion seines basolateralen Sortierungssignals erhöht, entsteht vermehrt A-beta. Der differenzielle Transport von BACE und beta-APP könnte ein Hinweis darauf sein, dass beta-APP nicht das physiologische Substrat von BACE ist.Alzheimer`s disease is the most common cause of progressive cognitive decline in the aged population. Pathologically Alzheimer`s disease is characterized by the invariant accumulation of senile plaques. Senile plaques are predominantly composed of the amyloid beta-peptide (A-beta), which is derived from the membrane bound beta-amyloid precursor protein (beta-APP) by sequential proteolytic cleavage. The recently identified beta-secretase (BACE) is responsible for the cleavage at the N-terminus of the A-beta domain. This cleavage generates membrane-bound beta-APP-Cterminal fragments (beta-APP-CTF) which are the immediate precursor for gamma-secretase cleavage and therefore for liberation of A-beta. The present work shows that BACE moves along the secretory pathway, while it undergoes post-translational modifications, which can be monitored by a significant increase in the molecular mass and cleavage of its pro-peptide. BACE becomes N-glycosylated within the ER and the increase in molecular mass is caused by complex N-glycosylation. The mature form of BACE is resistant to endoglycosidase H treatment; this indicates that BACE traffics through the Golgi. Furthermore the mature form of BACE does not contain the pro-peptide anymore. Pro-BACE is predominantly located within the endoplasmic reticulum. Pro-peptide cleavage occurs immediately before full maturation by furin or a furin-like proprotein convertase. Moreover traffic of BACE can limit A-beta generation. In the well established model system of polarized Madin-Darby canine kidney (MDCK) cells, the majority of BACE is sorted to the apical domain. Interestingly it has been shown previously that the substrate of BACE, beta-APP is transported to the basolateral surface of MCDK cells. Therefore, substantial amounts of BACE are targeted away from beta-APP to a non-amyloidogenic compartment, a cellular mechanism that limits A-beta generation. Upon deletion of the basolateral sorting signal of beta-APP, apically missorted beta-APP is processed by BACE. The differential targeting of BACE and its substrate beta-APP suggest that beta-APP might not be the major physiological substrate of BACE.
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Magnatti, Giorgia. "Discovery of BACE-1 inhibitors using an integrated computational and experimental approach." Thesis, University of Leeds, 2014. http://etheses.whiterose.ac.uk/8344/.
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There are numerous complementary approaches to facilitate the identification of novel inhibitors for biological targets, including high throughput screening and fragment-based drug discovery. Computational tools are often employed to predict binding pose and affinity of the new inhibitors. In this thesis an integrated computational and experimental approach to identify novel inhibitors is described. The approach involves the design of a virtual library of likely synthetically accessible lead-like molecules, followed by virtual high throughput screening (vHTS) against target protein. To exemplify the approach, BACE-1 was selected as an example target protein. BACE-1 is responsible for the formation of amyloidal plaque in brains affected by Alzheimer’s disease and therefore is a potential target for the treatment of the disease. A virtual library of lead-like molecules was generated based on diversity-oriented synthesis methods established in our laboratory. The library underwent virtual high throughput screening (vHTS) against BACE-1 by using eHiTS and two families of putative inhibitors were identified with high predicted ligand efficiency (cLE). The in silico approach employed to identify novel putative BACE-1 inhibitors is schematically represented as follows. [Unable to display image from abstract] A focused library based on the selected putative inhibitors was designed and synthesised, and biological activity was assessed via a fluorimetric assay. Structure-activity relationship (SAR) studies were conducted to rationalise the activity of the inhibitors and to confirm the validity of the integrated approach in identifying new inhibitors for biological targets. A novel series of BACE-1 inhibitors was identified and is herein described.
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Escudero-Lourdes, C., E. E. Uresti-Rivera, C. Oliva-González, M. A. Torres-Ramos, P. Aguirre-Bañuelos, and A. J. Gandolfi. "Cortical Astrocytes Acutely Exposed to the Monomethylarsonous Acid (MMA(III)) Show Increased Pro-inflammatory Cytokines Gene Expression that is Consistent with APP and BACE-1: Over-expression." SPRINGER/PLENUM PUBLISHERS, 2016. http://hdl.handle.net/10150/621476.
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Long-term exposure to inorganic arsenic (iAs) through drinking water has been associated with cognitive impairment in children and adults; however, the related pathogenic mechanisms have not been completely described. Increased or chronic inflammation in the brain is linked to impaired cognition and neurodegeneration; iAs induces strong inflammatory responses in several cells, but this effect has been poorly evaluated in central nervous system (CNS) cells. Because astrocytes are the most abundant cells in the CNS and play a critical role in brain homeostasis, including regulation of the inflammatory response, any functional impairment in them can be deleterious for the brain. We propose that iAs could induce cognitive impairment through inflammatory response activation in astrocytes. In the present work, rat cortical astrocytes were acutely exposed in vitro to the monomethylated metabolite of iAs (MMA(III)), which accumulates in glial cells without compromising cell viability. MMA(III) LD50 in astrocytes was 10.52 μM, however, exposure to sub-toxic MMA(III) concentrations (50-1000 nM) significantly increased IL-1β, IL-6, TNF-α, COX-2, and MIF-1 gene expression. These effects were consistent with amyloid precursor protein (APP) and β-secretase (BACE-1) increased gene expression, mainly for those MMA(III) concentrations that also induced TNF-α over-expression. Other effects of MMA(III) on cortical astrocytes included increased proliferative and metabolic activity. All tested MMA(III) concentrations led to an inhibition of intracellular lactate dehydrogenase (LDH) activity. Results suggest that MMA(III) induces important metabolic and functional changes in astrocytes that may affect brain homeostasis and that inflammation may play a major role in cognitive impairment-related pathogenicity in As-exposed populations.
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Westmeyer, Gil Gregor. "Identification of a BACE dimer and characterization of its biochemical and enzymatic properties." Diss., lmu, 2006. http://nbn-resolving.de/urn:nbn:de:bvb:19-59693.
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Schranner, Katharina. "Analyse der BACE-1-Regulation in der Alzheimer-Krankheit und im Down-Syndrom." Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-102663.
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Kalvodova, Lucie. "Reconstituting APP and BACE in proteoliposomes to characterize lipid requirements for β-secretase activity." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2006. http://nbn-resolving.de/urn:nbn:de:swb:14-1158242647401-41976.
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Proteolytic processing of the amyloid precursor protein (APP) may lead to the formation of the Abeta peptide, the major constituent of amyloid plaques in Alzheimer`s disease. The full-length APP is a substrate for at least 2 different (alpha and beta) proteases ("secretases"). The beta-secretase, BACE, cleaves APP in the first step of processing leading to the formation of the neurotoxic Abeta. BACE competes for APP with alpha-secretase, which cleaves APP within its Abeta sequence, thus precluding Abeta formation. It is thus important to understand how is the access of the alpha- and beta-secretase to APP regulated and how are the individual activities of these secretases modulated. Both these regulatory mechanisms, access to substrate and direct activity modulation, can be determined by the lipid composition of the membrane. Integral membrane proteins (like APP and BACE), can be viewed as solutes in a two-dimensional liquid membrane, and as such their state, and biological activity, critically depend on the physico-chemical character (fluidity, curvature, surface charge distribution, lateral domain heterogeneity etc.) of the lipid bilayer. These collective membrane properties will influence the activity of embedded membrane proteins. In addition, activity regulation may involve a direct interaction with a specific lipid (cofactor or co-structure function). Interactions of membrane proteins are furthermore affected by lateral domain organization of the membrane. Previous results had suggested that the regulation of the activity of the alpha- and beta-secretases and of their access to APP is lipid dependent, and involves lipid rafts. Using the baculovirus expression system, we have purified recombinant human full-length APP and BACE to homogeneity, and reconstituted them in large (~100nm, LUVs) and giant (10-150microm, GUVs) unilamellar vesicles. Using a soluble peptide substrate mimicking the beta-cleavage site of APP, we have examined the involvement of individual lipid species in modulating BACE activity in LUVs of various lipid compositions. We have identified 3 groups of lipids that stimulate proteolytic activity of BACE: 1.cerebrosides, 2.anionic glycerophospholipids, 3. cholesterol. Furthermore, we have co-reconstituted APP and BACE together in LUVs and demonstrated that BACE cleaves APP at the correct site, generating the beta-cleaved ectodomain identical to that from cells. We have developed an assay to quantitatively follow the beta-cleavage in proteoliposomes, and we have shown that the rate of cleavage in total brain lipid proteoliposomes is higher than in phosphatidylcholine vesicles. We have also studied partitioning of APP and BACE in GUVs between liquid ordered (lo) and liquid disordered (ld) phases. In this system, significant part of the BACE pool (about 20%) partitions into the lo phase, and its partitioning into lo phase can be further enhanced by cross-linking of membrane components. Only negligible fraction of APP can be found in the lo phase. We continue to study the behavior of co-reconstituted APP and BACE in GUVs The work presented in this thesis has yielded some interesting results and raised further questions. One of the important assignments of this project will in the next stage be the characterization of the impact of membrane domain organization on the beta-cleavage. Different domain arrangements that can be hypothesized in cell membranes can be modeled by varying the degree of phase fragmentation in proteoliposomes comprising reconstituted APP and BACE.
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Diercks, Katrin [Verfasser]. "Untersuchungen zur Funktion und Substratidentifikation der Alzheimer-relevanten Beta-Sekretase BACE-1 / Katrin Diercks." Kiel : Universitätsbibliothek Kiel, 2010. http://d-nb.info/1019983051/34.
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Adrian, Meredith Jenny. "Design and Synthesis of Inhibitors Targeting the Aspartic Proteases HIV-1 PR and BACE-1." Doctoral thesis, Stockholms universitet, Institutionen för organisk kemi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-29773.
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This thesis describes the synthesis of molecules designed for inhibition of two aspartic proteases, viral HIV-1 PR and human BACE-1. It also reports on the structure activity relationships of the targeted enzyme inhibitors. It is estimated that currently 33 million people are infected with HIV, the causative agent of AIDS. The virus targets T-lymphocytes and macrophages of the human immune system. The HIV-1 PR plays an important role in the viral replication, and by inhibiting the enzyme the disease progression can be slowed down or even halted. Herein is reported the design and synthesis of a series of HIV-1 PR inhibitors with novel P2 substituents of which several inhibit the enzyme in the nanomolar range. The aim of the second work was to further develop the inhibitors by the introduction of fluorine. Several attempts were performed to fluorinate different P2-substituents. Alzheimer’s disease (AD) is neurodegenerative, progressive and fatal disorder of the brain. It is associated with accumulation of plaques and tangles that cause impairment and functional decline of brain tissue which result in loss of memory and cognition. The plaques are mainly constituted of amyloid-β peptides that are generated in two steps from the amyloid precursor protein (APP). The cleavage sequence is initiated by the aspartic protease BACE-1, which makes the enzyme a key target in the effort of finding a therapy that aim to slow down the progression of AD. Herein are enclosed the development of two series of potent BACE-1 inhibitors. In the first work a synthetic strategy was developed to truncate a previously reported hydroxyethylene core structure in order to generate more drug-like inhibitors. This generated a series of truncated inhibitors where two amide bonds have been replaced with an ether - or alternatively a secondary amine linkage. A number of these inhibitors show potency against BACE-1. In the second part of the work the aim was investigate the effect of alterations in the P1 position. Five scaffolds with new P1 substituents were designed, synthesized and coupled with two different P2-P3 substituents. This resulted in a series of potent inhibitors that inhibit BACE-1 in the nanomolar range.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Submitted. Paper 2: Submitted. Paper 3: Manuscript.
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Renner, Lars. "Polymer Supported Lipid Bilayer Membranes for the Integration of Transmembrane Proteins." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2009. http://nbn-resolving.de/urn:nbn:de:bsz:14-ds-1241457489091-02157.
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This work reports on the successful formation of supported multicomponent lipid bilayer membranes (sLBMs) from natural occurring lipids as well as synthetic lipids on a set of polymer cushions consisting of alternating maleic acid copolymers. Maleic acid copolymers provide a versatile platform to adjust the physico-chemical behaviour by the choice of the comonomer unit. The formation of sLBMs was triggered by a transient reduction of the electrostatic repulsion between the polymer cushions and the lipid vesicles by lowering the solutions pH to 4. Upon formation the stability of sLBMs was not affected by subsequent variations of the environmental pH to 7.2. Even drastic changes in the environmental pH (between pH 2 and pH 9) did not lead to delamination and proved the stability of the polymer sLBM. The degree of hydrophilicity and swelling of the anionic polymer cushions was found to determine both the kinetics of the membrane formation and the mobility of the lipid bilayer with lipid diffusion coefficients in the range from 0.26 to 2.6 µm2 s-1. An increase in cushion hydrophilicity correlated with a strong increase in the diffusion coefficient of the lipids. This trend was found to correlate with the kinetics of bilayer formation in the process of vesicle spreading. The observations strongly support the important role of the support’s polarity for the fluidity of the sLBM, which is probably related to the presence of a water layer between support and bilayer. The investigated polymer cushions are considered to open new options for the in situ modulation of lipid bilayer membranes characteristics to match the requirements for the successful integration of functional transmembrane proteins (TMPs). As each cushion exhibits different physico-chemical properties, the resulting behaviour of the sLBMs and TMPs could be exactly adjusted to the specific requirements of biological samples. This is exemplarily shown by the integration of the TMP beta amyloid precursor protein cleaving enzyme (BACE). Integrated BACE was observed to be mobile on all polymer cushions. On the contrary, no lateral mobility of BACE was found in solid sLBM. Furthermore, the activity of integrated BACE was analysed by the cleavage of an amyloid precursor protein analogue. Remarkably, the polymer cushions did not only enhance the mobility but were also found to increase the activity of BACE by a factor of 1.5 to 2.5 in comparison to solid sLBM. From the obtained results it is obvious that even small cytoplasmic domains of transmembrane proteins might not be preserved upon the integration in silica sLBM. The observed beneficial effects of the utilised polymer cushions on the mobility and activity of transmembrane proteins motivate further studies to clarify the general applicability of the polymer platform. Altogether, this polymer platform provides valuable options to form sLBM with varying characteristics to reconstitute transmembrane proteins for a wide range of possible future applications in biologyDie vorliegende Arbeit beschreibt die Bildung von polymer unterstützten Lipiddoppelschichten zur Integration von transmembranen Proteinen. Das Polymerkissensystem besteht aus alternierenden Maleinsäurecopolymeren. Lipiddoppelschichten wurden durch die Steuerung der elektrostatischen Repulsion erzeugt: die Verringerung des pH-Wertes auf 4 wurde eine Erhöhung der adsorbierten Vesikelmenge auf den Polymeroberflächen induziert. Nach der erfolgten Bildung der Lipiddoppelschichten kann der pH-Wert beliebig variiert werden, ohne dass die Stabilität der Lipiddoppelschichten beeinflusst wird. Auch drastische Veränderungen des pH-Milieus (pH 2 - pH 9) führten zu keinen Veränderungen in der Membranintegrität. Der Grad der Hydrophilie und der Quellung der anionischen Polymerschichten beeinflusst sowohl die Bildung der Modellmembranen als auch die Mobilität der integrierten Lipidmoleküle. Dabei reichen die erzielten Lipiddiffusionskoeffizienten von 0.26 bis 2.6 µm2 s-1. Dabei ist die Mobilität direkt von der Hydrophilie des Substrates abhängig. Die beobachteten Ergebnisse zeigen deutlich die entscheidende Rolle der Polarität der verwendeten Substratoberflächen auf die Lipidmobilität, die sehr wahrscheinlich mit der Präsenz einer variablen Wasserschicht zusammenhängt. Die untersuchten Polymerkissen eröffnen neue Möglichkeiten für die insitu Modulierung der Charakteristika von Lipidschichten, um funktionale transmembrane Proteine zu integrieren. Aufgrund der unterschiedlichen physiko-chemischen Eigenschaften kann das Verhalten der Lipidschichten und der transmembranen Proteine nach den spezifischen Anforderungen des Modellsystems angepasst werden. Die funktionale Integration wurde am Beispiel des transmembranen Proteins BACE nachempfunden. Die Mobilität des integrierten BACE wurde auf allen Polymerkissen beobachtet. Im Gegensatz dazu wurde auf harten Substraten keine BACE Mobilität gefunden. Die Aktivität des integrierten BACE wurde durch die enzymatische Spaltung eines APP-Analogons nachgewiesen. Bemerkenswerteweise wurde ein Anstieg der BACE Aktivität auf den Polymerkissen um den Faktor 1,5 bis 2,5 im Vergleich zu den auf harten Substraten integrierten BACE beobachtet. Zusammenfassend, die verwendeten Polymerkissen bieten vielfältige Möglichkeiten Lipidschichten mit variierenden Eigenschaften für die Integration von transmembranen Proteinen zu erzeugen
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Brault, Marie Ève. "Développement d'un essai in vivo pour mesurer l'activité de BACE et son implication dans la maladie d'Alzheimer." Thesis, Université Laval, 2007. http://www.theses.ulaval.ca/2007/24433/24433.pdf.
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La protéine BACE (β-site APP Cleaving Enzyme) joue un rôle clé dans la production du peptide amyloïde β (Aβ) à l’origine de l’établissement de la maladie d’Alzheimer. À cause de son rôle central dans la maladie, BACE représente une cible potentielle dans le développement de thérapies. Récemment, un premier rôle physiologique pour BACE a été identifié, remettant en doute les approches thérapeutiques visant son inhibition. Des stratégies alternatives ciblant des modulateurs de l’activité de BACE pourraient représenter une approche plus sécuritaire pour traiter la maladie. Dans cette étude, nous avons tenté de développer un essai pour cribler des modulateurs de l’activité de BACE en utilisant deux systèmes différents : le système raporteur luciférase et un système basé sur le Bioluminescence Resonance Energy Transfert 2 (BRET2). Malgré les nombreuses optimisations réalisées, nous n’avons pas réussi à mettre au point un essai efficace permettant de cribler des modulateurs de l’activité de BACE.
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Wångsell, Fredrik. "Design and Synthesis of Aspartic and Serine Protease Inhibitors : Targeting the BACE-1 and the HCV NS3 Protease." Doctoral thesis, Uppsala universitet, Institutionen för läkemedelskemi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-108985.
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This thesis describes work done to design and synthesize protease inhibitors, with the intention of developing therapeutic agents for Alzheimer’s disease (AD) and the chronic liver condition caused by infection of the hepatitis C virus (HCV). AD is the most common form of dementia, and HCV infection is the primary reason for liver transplantation in industrialized countries. Today, these two illnesses affect 24 and 170 million people, respectively. It has been shown that the human aspartic protease BACE-1 plays an important role in the development of AD, and thus inhibition of BACE-1 may offer a way to improve the quality of life of individuals afflicted with the disease. Furthermore, it is known that the serine protease NS3 is a vital component in the replication of HCV. Several novel potent BACE-1 inhibitors encompassing different transition state mimics were prepared. First, a hydroxyethylene moiety encompassing a secondary hydroxyl group was evaluated as a transition state analogue, producing inhibitors in the low nanomolar range. Various tertiary hydroxyl isosteres were also investigated as the central core, with the aim of shielding the pivotal hydroxyl group. These transition state isosteres consisted of tertiary hydroxyl analogues of previously used secondary hydroxyl containing norstatine, statine, and hydroxyethylamine isosteres. Several tertiary hydroxyl-containing inhibitors were found to be active in the low micromolar range. In addition, two inhibitors were co-crystallized with the BACE-1 enzyme to provide X-ray crystal structures, which furnished valuable binding information for further design of improved BACE-1 inhibitors. The goal in the HCV NS3 protease inhibitor project was to design, synthesize and evaluate a novel hydroxycyclopentene bioisostere to the previously used acyl-hydroxyproline moiety. The investigation revealed that it was possible to synthesize inhibitors containing this new bioisostere that were potent in the low nanomolar range. Further optimization by rigidification of the most active inhibitor resulted in equipotent macrocyclic compounds.
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Sandgren, Veronica. "Design and Synthesis of Inhibitors Targeting BACE-1, an Aspartic Protease Involved in the Pathogenesis of Alzheimer’s Disease." Doctoral thesis, Linköpings universitet, Organisk Kemi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-76174.
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Alzheimer’s disease (AD) is the most common form of dementia, occurring in an estimated 24 million people worldwide. Accumulation of amyloid-b peptides leads to development of plaques in the brain, which eventually stimulates hyperphosphorylation of tau proteins leading to tangles. This is believed to play a crucial role in the pathology of AD. The amyloid-b peptides are formed when the amyloid precursor protein (APP) is cleaved first by the human aspartic protease BACE-1 and then by the protease g-secretase. BACE-1 catalyzes the ratelimiting step in this sequence, and hence it has emerged as an important therapeutic drug target. The research reported in this thesis is focused on the design and synthesis of BACE-1 inhibitors, where the synthetic work involves development of both acyclic and cyclic inhibitors. Initially, a series of linear inhibitors incorporating substituted cyclopentanes in the P2 position were synthesized and evaluated in an attempt to find a replacement for the widely used isophthalamide moiety, and this endeavor generated an inhibitor with activity in the nanomolar range. In the second study, a series of hydroxyethylene-based inhibitors with extended P1 substituents was synthesized and evaluated, which resulted in several truncated inhibitors also with activities in the nanomolar range. The third investigation targeted a series of P1-P3-linked hydroxyethylamine-based macrocyclic inhibitors and provided several highly potent compounds, however it did not deliver high cell permeability inhibitors. In addition, two inhibitors were co-crystallized with BACE-1 to provide X-ray crystal structures, which enabled analysis of the binding properties of these inhibitors. In the final study, the P2/P3 macrocyclic amide moiety and the P1-P3 ether oxygen bridge from the previous work were replaced with a keto functionality and a carbon, respectively, in an attempt to improve the permeability properties whilst maintaining the beneficial potencies of this class of macrocyclic inhibitors. The compounds synthesized did indeed display enhanced cell permeability properties, but this approach resulted in decreased potency. In short, this thesis presents several novel BACE-1 inhibitors, discusses the synthetic strategies, and reports biological data on the target compounds.
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Wångsell, Fredrik. "Design and Synthesis of Aspartic and Serine Protease Inhibitors targeting the BACE-1 and the HCV NS3 Protease /." Uppsala : Acta Universitatis Upsaliensis, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-108985.
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Barros, Carlos Vinícius de. "Qualidade de vida, dor e incapacidade funcional de idosos com lombalgia agudizada: análise dos dados do estudo BACE." Universidade Federal de Minas Gerais, 2014. http://hdl.handle.net/1843/BUOS-9KSHHJ.
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The Health Related Quality of Life (HRQoL) evaluation is essential in elderlies with worsened low back pain (LBP). The phenomena such as the population aging and feminization of the elderly arouse doubts about the elderly health facing the fact of their larger participation in the population. Therefore, the conditions that were previously young populations features have become prevalent among the elderlies. The worsened low back pain can be described in accordance of the pain intensity, the Disability, symptoms presence of pain irradiation to lower limbs (MMII) and prior history of back pain. This research aimed to analyze the studys data of Back Complaints in the Elderly (BACE) referring to the clinics characteristics of acute low back pain and the functional disability (Roland Morris Questionnaire - RDQ) in the elderly community and his influence on the awareness of the HRQoL using a generic instrument. The BACE study relates to a large study of the multicentric and longitudinal with the purpose of identifying the characteristics and the clinical course of the acute pain to the cronical pain on elderlies with low back pain living in countries as: Brazil, Australia and Netherland. The present study cut, in an observational transversal study drawing, a 302 elderlies sample provided from a database of BACE Brasil. The data selected were socio demographic, HRQoL (SF-36), depressive symptoms (CES-D), RDQ and the back pain characterization throughout the present pain intensity and with one week prior. The univariate analysis with the test t of student , detected significant statistic differences between elderlies with presence and absence of the irradiation on the domains of functional capability, physical aspects (PA), pain, social aspects, general state (GE) and vitality. Prior pain (low back pain in the past) showed statistics differences just in the PA domains, pain and GE (p<0,05). The correlation from Pearson between the functional performance, intensity of actual pain and prior pain And 8 domains Of the SF -36 were significant (p<0,05). The variable with the significant statistics differences in the test t and those variables that have some correlations also significant came in the linear regression models from type Stepwise to verify the how much ths variables explained the 8 domains from HRQoL from elderlies with low back pain. With the exception of the GS, the score of the RDQ influenced between 36% and 56% on the variation of the scores on the other domains of the HRQoL. The results of the present study demonstrate the functional incapability influence in the domains of the HRQoL from low back pain elderlies. These results indicate the importance of the physical evaluation parameters, functional capability and physical aspects, that can be modified, with important repercussions about the worsened low back pain elderlies life quality with similar features with the samples. In this context, the use of generic and specific instruments could facilitate the identification process of the compromised day activities in elderlies with low back pain and have help to the extent of clinical improvement and research interventions.A avaliação da qualidade de vida relacionada a saúde (QVRS) é essencial nos idosos com lombalgia agudizada. Os fenômenos como o envelhecimento populacional e a feminização da velhice despertaram dúvidas sobre a saúde do idoso diante da sua maior participação na população. Assim, as condições que eram anteriormente características na populações jovens tornaram-se prevalentes entre os idosos. A lombalgia agudizada pode ser descrita em termos da intensidade da dor, incapacidade, presença de sintomas de irradiação da dor para membros inferiores (MMII) e história de lombalgia anterior. O presente estudo buscou analisar os dados do estudo Back Complaitns in the Elderly (BACE) referentes às características clínicas da lombalgia aguda e de incapacidade funcional (Roland Morris Questionnaire - RDQ) no idoso comunitário e sua influência na percepção da QVRS utilizando um instrumento genérico. O estudo BACE trata-se um grande estudo multicêntrico e longitudinal com o objetivo de identificar as características e o curso clínico da dor aguda para a dor crônica de idosos com lombalgia residentes nos países Brasil, Australia e Holanda. O presente estudo recortou, em um desenho de estudo observacional transversal, uma amostra de 302 idosos provenientes do banco de dados do BACE Brasil. Foram selecionados os dados: sociodemográficos, QVRS (SF-36), sintomas depressivos (CES-D), RDQ e caracterização da lombalgia, através da intensidade da dor presente e com uma semana anterior, irradiação da dor para MMII, membro inferior de irradiação e história da dor anterior. A análise univariada com teste t de Student detectou diferenças estatisticamente significantes entre idosos com presença e ausência de irradiação nos domínios capacidade funcional, aspecto físico (AF), dor, aspectos sociais, estado geral (EG) e vitalidade. Dor anterior (lombalgia no passado) mostrou diferença estatística apenas nos domínios AF, dor e EG (p<0,05). As correlações de Pearson entre o desempenho funcional, intensidade da dor atual e pretérita e os oito domínios do SF-36 foram significantes (p<0,05). As variáveis com diferença estatisticamente significantes no teste t e aquelas variáveis com correlações também signicantes entraram nos modelos de regressão linear do tipo Stepwise para verificar o quanto essas variáveis explicavam os 8 domínios da QVRS. A incapacidade funcional causou grandes influências sobre a QVRS dos idosos com lombalgia agudizada. Com exceção do EG, o escore do RDQ influenciou entre 36% e 56% na variação dos escores nos demais domínios da QVRS. Os resultados do presente estudo demonstram a influência incapacidade funcional nos domínios da QVRS de idosos com lombalgia. Esses resultados indicam a importância da avaliação de parâmetros físicos, capacidade funcional e aspectos físicos, que podem ser modificados, com importantes repercussões sobre a qualidade de vida dos idosos com lombalgia agudizada com características semelhantes às da amostra. Nesse contexto, o uso de instrumentos genéricos e específicos poderia facilitar o processo de identificação das atividades diárias comprometidas no idosos com lombalgia e também auxiliar na medida da melhora clinica e dos resultados de intervenções.
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Mas, Henri. "L' expérience subjective du temps." Dijon, 1995. https://nuxeo.u-bourgogne.fr/nuxeo/site/esupversions/bc201956-b5af-443b-bace-1610d13f6dc3.
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L'expérience temporelle du sujet, en présence de l'énigme du temps, est à comprendre comme affirmation d'une orientation du sens. S'il peut s'agir la du sens de soi, cette thèse recherche d'abord à quelles conditions subjectives, puis objectives le temps et ses différents moments deviennent significatifs pour la personne. Elle repose sur deux présupposés : une durée biographique, qui sollicite le besoin d'unité, et une capacité inhérente d'évolution personnelle. Le problème de la conscience de soi est ici revisité. La présence active à soi-même est reconsidérée, selon l'axe d'une véritable dynamique temporelle intra-subjective. La perception du temps propre bénéficie d'une interprétation relativiste de l'"unité temporelle". Enfin, les attitudes temporelles sont éclairées par une mise en perspective, en partie psychologique, des projections du moi dans le temps. Leur analyse montre à quelles conditions éthiques la relation à la dramatique de la durée devient créatrice de sens pour le sujet. Première des grandes "formes" anthropologiquement constitutives de la notion du temps, l'instant est étudié comme le lieu où l'intention de sens interagit avec les manifestations les plus variées de la réification temporelle. La troisième partie de la thèse, limitée à une réflexion sur l'immédiateté vécue dans la culture contemporaine, traite des possibilités et des modalités d'expression libre du temps personnel ; par là-même, elle prépare d'une certaine manière à une écoute de ses diverses résonances socialesIn presence of the time enigma, the temporal experience of the subject is understook as the singular assertion of an orientation of the sense. Certainly, the sense of oneself is here at stake, but this dissertation tries to study in what subjective, then objective conditions time and its different moments become significant for the person. It rests on two premises : a biographical duration, appealing to the need of unity, and the personal ability to evolve. Here, the issue of self-awareness is revisited. The active presence to oneself is reconsidered according to the main line of a real intra-subjective temporal dynamic. The perception of "own time" is best understood thanks to a relativistic interpretation of "temporal unity". Lastly, temporal attitudes are enlightenedby a setting-off, partly psychological, of the projection of the self onto time. Besides, their analysis shows in what ethical conditions the relation to the drama of duration becomes creative of subjective meaning. First one of the great "forms" anthropologically constituent of the notion of time, the "instant" is studied as the place where the intention of sense interacts with the most varied expressions of temporal reification. The third part of the dissertation, considering especially contemporary immediacy, deals with the possibilities of free expression of personal duration
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Bäck, Marcus. "Design and Synthesis of Inhibitors Targeting the Hepatitis C Virus NS3 Serine Protease and the Aspartic Protease BACE-1." Doctoral thesis, Linköpings universitet, Organisk Kemi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-17850.
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This thesis describes the synthesis of molecules designed to inhibit the hepatitis C virus (HCV) NS3 serine protease and the human aspartic protease BACE-1, and it also reports the structure-activity relationships between potential inhibitors and the targeted enzymes. In addition, consideration is given to the class of enzymes known as proteases, as well as the question of why such enzymes can be regarded as suitable targets for developing drugs to combat diseases in general. Some strategies used to design protease inhibitors and the desired properties of such potential drug candidates are also briefly examined. Infection with HCV gives rise to a predominantly chronic disease that causes severe liver damage and ultimately leads to cirrhosis and liver cancer, and hence it represents the main factor underlying most of the liver transplants in the developed world. The HCV NS3 serine protease is essential for replication of the virus, and it has become one of the most widely exploited targets for developing anti-HCV inhibitors. The results presented here concern the design and synthesis of linear and macrocyclic NS3 protease inhibitors containing a novel trisubstituted cyclopentane moiety as an N-acyl-(4R)-hydroxyproline bioisostere. Several highly potent compounds were evaluated, including inhibitors with Ki and replicon EC50 values in the subnanomolar and the low nanomolar range, respectively. Alzheimer’s disease is a fatal neurodegenerative disorder of the brain. It is characterized by loss of memory and cognition, and is associated with accumulation of plaques and tangles that cause serious impairment and functional decline of brain tissues. The plaques consist mainly of amyloid-β fragments that are generated through two cleavages of amyloid precursor protein (APP). The enzyme responsible for the initial cleavage is the aspartic protease BACE-1 (beta-site APP-cleaving enzyme), which was explored in the current studies as a pharmaceutical target. The synthetic work comprised development of two series of BACE-1 inhibitors with different central core isosteres; a statine-based and a hydroxyethylene-based series. Highly potent inhibitors were produced by varying the substituents coupled to the statine-based central core. X-ray crystallography and molecular modeling enabled analysis of the binding properties of these compounds. In the second series a hydroxyethylene central core was decorated with more advanced P1 substituents with the aim of increasing the binding interactions with the S1 site. This resulted in inhibitors with more drug-like properties and activities in the low micromolar range.
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Bäck, Marcus. "Design and synthesis of inhibitors targeting the hepatitis C virus NS3 serine protease and the aspartic protease BACE-1 /." Linköping : Department of of Physics, Chemistry and Biology, Linköping University, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-17850.
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Clarke, H. E. "Altered heparan sulfate in ageing and dementia : a potential axis for the dysregulation of BACE-1 in Alzheimer's disease." Thesis, University of Liverpool, 2017. http://livrepository.liverpool.ac.uk/3006939/.
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Alzheimer’s disease (AD) is characterised by amyloid plaques composed of amyloid-beta (Aβ), the cleavage product of the amyloid precursor protein (APP) by the protease beta-secretase (BACE- 1). Heparan sulfate (HS) inhibits BACE-1 and holds potential as a new drug discovery target; in vivo HS may act as a brake on the generation of Aß via regulation of BACE-1. Previous work has identified the sulfate moieties in HS as key determinants in the efficacy of BACE-1 inhibition. Structural changes in HS are known to occur with ageing and we hypothesised that these changes could result in reduced BACE-1 inhibition and ultimately elevated production of Aβ. Strong anion exchange chromatography was used to assess disaccharide composition of HS from AD (n=20) and age-matched control (n=15) brain tissue. TaqMan® array profiling of HS-related genes was also carried out to explore expression levels of HS-related genes that may be responsible for downstream HS structural changes. HS purified from AD and age-matched control samples was assessed for its ability to inhibit BACE-1 using FRET-based BACE-1 activity assays and finally, manipulation of endogenous HS in HEKSweAPP cells with RNAi was carried out to explore the possibility of modulating generation of the toxic Aβ species. HS from AD tissue was found to carry a significantly decreased proportion of the di-sulfated ΔUA-GlcNS(6S) disaccharide vs. controls (p < 0.01) and increased levels of the lesser-sulfated ΔUAGlcNAc( 6S) unit vs. controls (p < 0.05). Furthermore, significantly more total HS was present within control brain tissue (122.3μg/100mg) vs. AD (78.6μg/100mg) (p < 0.01). TaqMan® array analysis revealed significant alteration in expression of HS biosynthetic genes with AD including upregulation of HS6ST1 (p < 0.05) and a strong trend for down regulation of HS6ST3, coupled with up regulation of SULF1. These changes may go some way to explain changes in the level of sulfation of HS particularly, 6-O sulfation, as observed by structural analysis. Most noticeably, BACE-1 activity assays revealed a significant reduction of BACE-1 inhibition efficacy by HS from AD patients (p < 0.05). In addition, knockdown of SULF1 in HEKSweAPP cells, which would be expected to elevate 6-O sulfation, generated a significant reduction in Aß. Our observation that AD brain HS contains fewer di-sulfated ΔUA-GlcNS(6S) disaccharides, alongside observed upstream gene expression changes, would be consistent with a less sulfated HS chain with reduced ability to inhibit BACE-1 thus generating more Aß as observed in AD. The observed reduction in BACE-1 inhibition efficacy by HS with AD confirms our hypothesis that structural changes in HS may contribute to modulating AD pathogenesis in patients. Finally, these studies support the idea that HS-based therapeutics might provide the basis for novel disease modifying drugs that could prove beneficial in future efforts to treat an underlying cause of AD.
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Ricote, Sandrine. "Elaboration et caractérisation du matériau d’électrolyte pour pile à combustible à conduction protonique : BaCe(0,9-x)ZrxY0,1 O3-delta." Dijon, 2008. http://www.theses.fr/2008DIJOS067.
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Le composé BaCe(0,9-x)ZrxY0,1 O3-delta (x=0 ; 0,3 ; 0,7 et 0,9) est étudié en tant que matériau d’électrolyte de pile à combustible à conduction protonique (PCFC). Des pastilles denses ont été fabriquées à partir de poudres synthétisées par chamottage, puis frittées à 1700°C. Elles ont été caractérisées chimiquement par ICP AES, morphologiquement par MEB, structuralement par DRX et Raman et mécaniquement par dilatométrie. L’insertion de protons après traitement sous atmosphère humide a été mise en évidence par profilométrie SIMS, XPS et DRX. La quantification des défauts protoniques entre 400°C et 600°C par mesure de la prise en eau a montré l’augmentation de la concentration protonique avec le taux de cérium et lorsque la température diminue. Grâce à des mesures en courant continu sous atmosphère humide, la conductivité totale a été décomposée en deux termes : une contribution de « type p » aux fortes pressions partielles en oxygène et une contribution ionique. L’étude de l’effet isotopique a révélé une contribution protonique significative à 500°C et 600°C. Lorsque le taux de cérium augmente, l’énergie d’activation, déterminée d’après les courbes d’Arrhenius obtenues par spectroscopie d’impédance, augmente et la résistivité des joints de grains par rapport au volume diminue. Une optimisation du procédé de mise en forme et de contrôle de la microstructure permettrait l’amélioration de ces résultats déjà prometteurs. Des tests de frittage par Spark Plasma Sintering (SPS) ont été réalisés sur des échantillons sans cérium, lesquels présentent des valeurs de conductivité plus importantes que les échantillons frittés conventionnellementBaCe(0. 9-x)ZrxY0. 1 O3-delta (x=0, 0. 3, 0. 7 et 0. 9) compounds have been studied as electrolyte material for protonic ceramic fuel cell (PCFC). The powders were synthesized by a solid state reaction, and sintered to form dense pellets at 1700°C. Chemical, morphological, structural and mechanical characterizations were performed on the samples, using respectively ICP AES, SEM, XRD, Raman and dilatometry. SIMS, XPS and XRD studies showed the insertion of protonic species in the samples, when treated in a moisturized atmosphere. Water uptake experiments provided quantification of the proton content between 400°C and 600°C: the protonic concentration increases with increasing cerium content and with decreasing temperature. The DC conductivity measured in wet atmosphere can be expressed as the sum of a p-type component, prominent at high oxygen partial pressure, and an ionic contribution. A study of the conductivity isotope effect revealed a significant protonic conductivity at 500°C and 600°C. When the cerium content increases, the activation energy, determined with the Arrhenius plots of the conductivity, increases and the resistivity of grain boundaries decreases compared to that of the bulk. An optimisation of the fabrication process and the control of the microstructure would improve these promising results. Spark Plasma Sintering (SPS) experiments have been performed on BaZr0. 9Y0. 1O3-delta samples, which exhibit higher conductivity values than the conventional sintered samples
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Barazza, Alessandra. "Lead structures for inhibition of drugable proteases cyclic statine-peptides for BACE-1 and selective bivalent constructs for MMP-9 /." [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=980404797.
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Capell, Anja [Verfasser], Christian [Gutachter] Haass, Gerd [Gutachter] Multhaup, and Peter-Micael [Gutachter] Kloetzel. "Funktionelle Charakterisierung von BACE, einer für die Alzheimer Krankheit relevanten Protease / Anja Capell ; Gutachter: Christian Haass, Gerd Multhaup, Peter-Micael Kloetzel." Berlin : Humboldt-Universität zu Berlin, 2005. http://d-nb.info/120807900X/34.
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Leopoldino, Amanda Aparecida Oliveira. "Correlação entre intensidade da dor, desempenho funcional e capacidade física em idosos com dor lombar agudizada: dados do estudo Bace Brasil." Universidade Federal de Minas Gerais, 2013. http://hdl.handle.net/1843/BUOS-9FCGXU.
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Population ageing is a reality and pain prevalence among elderly people is high, altering functional performance and physical capacity causing negative impact on their quality of life, this way, studies about back pain impact on elderly functionality must be encouraged. In this context, functional tests with clinical applicability that contemplate the categories exposed by the International Classification of Functioning, Disability and Health (ICF) and data from self-related instruments of pain and physical function are widely used. Therefore, the objective of this study was to verify if there is correlation between pain intensity measured by Numerical Pain Scale (NPS) and pain related to functional performance by the pain domain of Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index, between pain and physical capacity assessed by the Timed up and go (TUG) and gait speed test and between these two functional tests and Womac´s physical function domain in community-dwelling elderly with acute low back pain. This is a cross-sectional study, derived from an international consort - Back Complaints in the Elderly (BACE), among Brazil, Australia and the Netherlands. Subjects included in the study must be 60 years or older, have a new episode (crisis/reagudization) of low back pain in the last six weeks and those with cognitive impairment detectable by the Mini-Mental State Examination were excluded. Data analysis was conducted using Spearman´s Correlation Coefficient (r) for all outcome variables at a significance level of = 0.05. The sample was composed by 225 elderly with mean age of 68.1 (± 5.83) and mainly were women (86.7%). The mean score of current END was 4.73 and for the last seven days was 6.85, the mean score of WOMAC´s pain domain was 49.39 and the physical function domain mean score was 44.90. TUG´s mean value was 11.27 seconds and gait speed mean value was 1.01meters/second. Correlations between current END score and 7 days END score were o.53 and 0.45, respectively; correlations between TUG and gait speed and WOMAC´s physical function domain were 0.33 e -0.31, respectively, and correlations between current END and 7 days END and TUG and gait speed were 0.10; 0.23; -0.19 e -0.23, respectively. Our results showed relevant clinical results about pain and performance and physical capacity level of community-dwelling elderly with acute low back pain, allowing Physical Therapists and other health care professionals to better understand these outcomes and in this way, develop more assertive strategies to approach elder individuals with back pain.O envelhecimento populacional é uma realidade e a prevalência de dor entre idosos é alta, alterando o desempenho funcional e a capacidade física e causando impacto negativo na qualidade de vida, dessa forma, estudos sobre o impacto da dor lombar (DL) na funcionalidade de idosos devem ser incentivados. Nesse contexto, testes funcionais com aplicabilidade clínica que contemplem categorias propostas pela Classificação Internacional de Funcionalidade, Incapacidade e Saúde (CIF) e dados de instrumentos autorrelatados de dor e função física são bastante utilizados. Portanto, o objetivo deste estudo foi verificar se há correlação entre a intensidade da dor medida pela escala numérica de dor (END) e a dor relacionada ao desempenho funcional pelo domínio de dor do Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index, entre a dor e a capacidade física mensurada pelos testes Timed Up and Go (TUG) e velocidade de marcha (VM) usual e entre esses dois testes físico-funcionais e o domínio de função física do WOMAC em idosos comunitários com DL agudizada. Este é um estudo transversal, derivado de um consórcio internacional - Back Complaints in the Elderly (BACE), entre Brasil, Austrália e Holanda. Foram incluídos idosos com 60 anos e mais que relataram novo episódio (crise/reagudização) de DL nas últimas seis semanas e excluídos aqueles que apresentaram possível déficit cognitivo de acordo com o Miniexame do Estado Mental. Para análise dos dados, foi utilizado o coeficiente de correlação de Spearman (r) para todas as variáveis de desfecho e nível de significância = 0,05. A amostra total foi de 225 idosos com média de idade de 68,1 (± 5,83) anos e constituída por maioria de mulheres (86,7%). A média da END atual foi de 4,73 (± 3,08) e nos últimos 7 dias de 6,85 (± 2,66) pontos e a média da pontuação do domínio de dor do WOMAC foi de 49,39 (± 21,33) e de função física 44,90 (± 21,94) pontos. Foi observado no teste TUG o valor médio de 11,27 (± 2,61) segundos e no teste de VM 1,01 (± 0,22) metro/segundo. As correlações entre a END atual e a END há 7 dias e o domínio de intensidade de dor do WOMAC foram 0,53 e 0,45 respectivamente; as correlações entre o TUG e a VM e o domínio de função física do WOMAC foram 0,33 e -0,31, respectivamente e por fim as correlações entre a END atual e há 7 dias e os testes TUG e a VM foram de 0,10; 0,23; -0,19 e -0,23 respectivamente. Os resultados das correlações encontradas possibilitaram identificar achados clinicamente relevantes sobre a dor no desempenho e nível de capacidade física de idosos comunitários com DL agudizada, de tal forma que fisioterapeutas e outros profissionais da saúde possam compreender com maior clareza esses desfechos e, assim, desenvolver estratégias mais assertivas de intervenção para idosos com DL.
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Todd, S. A. "Beta-secretase activity in huaman blood platelets in patients and relationships to polymorphisms in BACE in Alzheimer's disease and control subjects." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492482.
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This study aimed to investigate whether there are differences in the ~-secretase activity in the platelets of Alzheimer's disease (AD) subjects and cognitively normal control subjects and to determine whether the concentration of cholesterol influences this activity. A further aim was to study whether the apolipoprotein (ApoE) £4 allele or polymorphisms in the ~-site amyloid precursor protein cleaving enzyme (BACE1) gene are associated with AD or with alterations in the ~-secretase activity in platelets. METHODS: Subjects with a diagnosis of AD (NINCDS - ADRDA) were recruited from a regional Memory Clinic. Control subjects with no evidence of cognitive impairment were also recruited. Blood samples were drawn for assay of ~-secretase activity and genetic analyses. Statistical analysis was performed using SPSS for Windows version 14, GraphPad version 4, and HaploView version 4. RESULTS: 399 SUbjects were recruited; 201 with probable AD and 198 controls. Mean platelet membrane ~-secretase activity was significantly higher in the AD group, compared to the control group. Age and serum cholesterol concentration were significantly higher in the AD group, but did not correlate with the platelet membrane ~-secretase activity. Platelet membrane cholesterol concentration was significantly lower in the AD group and was significantly positively IlI I, I I' I~ I I! ---------------------- correlated with the platelet membrane ~-secretase activity. ApoE £4 was strongly associated with AD but did not correlate with the platelet membrane ~-secretase activity. Variation in the BACE1 gene was not associated with AD and did not correlate with the platelet membrane ~-secretase activity. CONCLUSIONS: Platelet membrane ~-secretase activity is elevated in AD and is correlated with the platelet membrane cholesterol concentration. Common variants in the BACE1 gene do not influence the genetic susceptibility for AD in the NI population.
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Schuler, Jeffrey Thomas. "Forward Chemical Genetics Drug Screen Yields Novel Proteases and Proteolytic Inhibitors of HGF–induced Epithelial–Mesenchymal Transition." BYU ScholarsArchive, 2016. https://scholarsarchive.byu.edu/etd/6257.
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Hepatocyte Growth Factor (HGF)–induced Epithelial–Mesenchymal Transition (EMT) is a complex cellular pathway that causes epithelial cell scattering by breaking cell–cell contacts, eliminating apical–basal polarity, and replacing epithelial markers and characteristics with mesenchymal markers. Early EMT events include a brief period of cell spreading, followed by cell compaction and cell–cell contact breaks. A forward chemical genetics drug screen of 50,000 unique compounds measuring HGF–induced cell scattering identified 26 novel EMT inhibitors, including 2 proteolytic inhibitors. Here, we show that B5500–4, one of the EMT inhibitors from the screen, blocks HGF–induced EMT by a predicted blocking of the protease furin, in addition to secondarily blocking Beta–Secretase (BACE).We also show that MMP–12 and MMP–9 are required for HGF–induced EMT to progress. MMP–12 is required for cell contraction, and its inhibition produces a continuous cell spreading phenotype.We also demonstrate that both furin and BACE activity are required for HGF–induced EMT to proceed, but that they are involved in separate pathways. We show that BACE inhibition leads to a failure of cell spreading in early EMT, and that EphA2 is a member of this pathway. We also demonstrate that it is likely BACE2, and not BACE1 that is responsible for early cell spreading. Furin is also required for HGF–induced cell scattering, but does not play a role in the cell spreading process. These findings highlight the importance of proteolytic activity at the earliest stages of HGF–induced EMT.
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Lizzul-Jurse, Antoine. "Développement de nouvelles réactions de click in situ appliquées à la synthése d'inhibiteurs de la β-sécrétase." Thesis, Normandie, 2017. http://www.theses.fr/2017NORMR020.
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La synthèse contrôlée par la cible sous contrôle cinétique (Kinetic Target-Guided Synthesis, KTGS) est une approche relativement peu explorée, alternative à la chimie combinatoire traditionnelle,dans laquelle la protéine cible participe à la synthèse du ou de ses propres ligands. Ainsi, les travaux présentés dans la première partie de cette thèse ont pour principal objectif d'élargir l'éventail des réactions actuellement disponibles en KTGS grâce à la réaction d'aldolisation voire d'amidation, et ce en utilisant la β-sécrétase (BACE-1) comme cible biologique, qui est une enzyme étroitement impliquée dans la maladie d'Alzheimer. La seconde partie de cette thèse a été consacrée à la synthèse de marqueurs de masse fluorescents bioconjugables basés sur l'association d'un noyau coumarinique et d'une fonction phosphonium. Les deux générations présentées dans ce manuscrit ont entre autre permis de synthétiser une sonde FRET permettant de détecter l'activité enzymatique de la BACE-1, qui pourrait par ailleurs être un outil intéressant pour l'analyse des bruts réactionnels des réactions de click in situ,et diminuer les quantités d'enzyme engagées dans ces expériences. Enfin dans la dernière partie de cette thèse nous décrivons la mise au point de nouvelles réactions de conjugaison bio-orthogonale pour le marquage de molécules comportant une fonction aldéhyde. Nous avons ainsi développé d'une part une réaction trois composants via une séquence de condensation/Mannich/lactamisation et d'autre part une réaction d'oléfination de WittigThe kinetic target-guided synthesis (KTGS), is an underexplored alternative approach to combinatorial chemistry, in which the biological target is able to assemble its own inhibitors from a pool of fragments. Thus, the first part of this thesis aimed at extending the scope of the reactions available for the KTGS, by investigating the aldolisation and amidation reaction, using the β-secretase (BACE-1) as biological target, which is an enzyme narrowly involved in the Alzheimer's disease. The second part of this thesis was dedicated to the synthesis of bioconjagatable fluorophores containing a phosphonium group as mass tag associated to a coumarin core. Both generations presented in this manuscript allowed us, among other things, to synthesize a FRET probe that proved suitable for the determination of BACE-1 enzymatic activity. The utility of such a fluorogenic tool could be leveraged to facilitate the analysis of crude mixtures obtained during KTGS experiments, and lessen the amount of enzyme required in these experiments. Finally, in the last part of this thesis, we describe the development of two new bioorthogonal reactions allowing the selective labeling of molecules containing an aldehyde moiety : 1) a three component reaction involving a condensation/Mannich/lactamisation procedure, between an amine, an aldehyde and an enol partner; 2) a Wittig ligation between an aldehyde and a phosphonium bearing an active methylene
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Overhoff, Felix [Verfasser], and Axel [Akademischer Betreuer] Rominger. "Etablierung einer standardisierten Analyse longitudinaler Aβ-PET Scans zur effektiven Evaluation der BACE-Inhibition im transgenen Alzheimer-Mausmodell / Felix Overhoff ; Betreuer: Axel Rominger." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2021. http://d-nb.info/1235326047/34.
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Rochin, Leïla. "Le rôle des bêta-sécrétases dans la formation de fibres amyloïdes au cours de la mélanogenèse." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05T028/document.
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Dans l’épiderme, les mélanocytes participent à la protection de la peau contre les rayons ionisants du soleil en synthétisant un pigment, la mélanine, dans des compartiments apparentés aux lysosomes appelés melanosomes. La mélanogenèse est un processus séquentiel initié par la production de fibres amyloïdes dont la composante principale est la protéine PMEL. Ces fibres séquestrent la mélanine et permettent l’élimination d’intermédiaires toxiques produits lors de sa synthèse. La mélanogenèse et le phénotype pigmenté sont affectés lorsque le processus de formation des fibres est altéré. Les fibres résultent du clivage de PMEL dans les endosomes précurseurs des mélanosomes mais les protéases impliquées dans ce processus restent peu ou pas caractérisées. Afin de mieux comprendre les mécanismes de formation des fibres amyloïdes dérivées de PMEL, j’ai étudié le rôle de deux protéases : les Bêta-sécrétases BACE1 et BACE2. En combinant des techniques de biochimie, d’immunocytochimie et d’imagerie photonique et électronique, j’ai montré que la perte de l’expression de Bace2 in vivo (souris KO BACE2) ou sa déplétion (siRNA) dans une lignée de mélanocytes inhibent le clivage amyloïdogénique de PMEL et affectent à la fois la formation de fibres de PMEL dans les mélanosomes et la pigmentation. J’ai pu notamment reproduire in vitro le clivage spécifique de PMEL en utilisant une forme recombinante de BACE2. En parallèle, j’ai également étudié le rôle de BACE1 dans la mélanogenèse. Mes résultats indiquent que BACE1, bien que n’étant pas impliquée dans le clivage de PMEL, régulerait la maturation des mélanosomes précoces in vivo et in cellulo, en modulant les contacts entre mélanosomes et réticulum endoplasmique (RE). Dans les mélanocytes, BACE1 est présente dans le RE et interagit avec des protéines impliquées dans les contacts RE-endosomes. Ces contacts seraient cruciaux pour le transfert de molécules nécessaires à la maturation des mélanosomes. L’ensemble de ces résultats démontre un rôle pour chacune des Bêta-sécrétases dans le processus de mélanogenèse, levant le voile sur des processus clés liés à la biogenèse des mélanosomes. Par ailleurs, les fibres de PMEL constituant le modèle le plus abouti de l’amyloïdogenèse physiologique chez les mammifères, ces études pourraient à plus long terme aider à la compréhension de la formation des fibres amyloïdes pathologiques ; notamment dans la maladie d’Alzheimer où l’amyloïdogenèse d’APP est très similaire à celle de PMELIn the epidermis, melanocytes synthetize a pigment called melanin, in lysosome-related-organelles called melanosomes, in order to protect the skin against the ionizing radiations of the sun. Melanogenesis is a sequential process initiated by the formation of amyloid fibrils whose principal component is the protein PMEL. Those fibrils sequester the melanin pigment and allow the removal of toxic intermediates formed during its synthesis. Melanogenesis and the pigmented phenotype are affected when the process of fibrils formation is altered. Fibrils come from the processing of PMEL in endosome precursors of melanosomes but the proteases implicated in this process are not well characterized. In order to better understand the mechanisms implicated in the formation of the PMEL amyloid fibrils, I studied the role of two proteases: the Beta-secretases BACE1 and BACE2. Using a combination of biochemical, immunocytochemical methods and photonic and electronic imaging, I have shown that the loss of Bace2 expression in vivo (BACE2 KO mice) or its depletion (siRNA), in a melanocyte cell line, inhibit the amyloidogenic processing of PMEL and affect both the formation of the PMEL fibrils in melanosomes and pigmentation. I could reproduce in vitro the specific cleavage of PMEL by using a recombinant form of BACE2. In parallel, I have also studied the role of BACE1 in melanogenesis. My results indicate that BACE1, even though it is not implicated in PMEL processing, could regulate the maturation of early melanosomes in vivo and in cellulo, by modulating the contacts between melanosomes and endoplasmic reticulum (ER). In melanocytes, BACE1 is present in the ER and interacts with proteins implicated in ER-endosomes contacts. Those contacts would be crucial for the transfer of molecules that are necessary for melanosome maturation. All together those results demonstrate the role of both Beta-secretases in melanogenesis, and reveal key processes involved in melanosome biogenesis. Moreover, because PMEL fibrils are the most completed model of physiological amyloidogenesis in mammals, theses studies could help in the future the understanding of the formation of pathological amyloid fibrils; in particular in the Alzheimer’s disease where the amyloidogenesis of APP is very similar to the one of PMEL
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Völkel, Meike [Verfasser]. "Einfluß des β-site-APP-cleaving enzyme 1 (BACE 1) auf die synaptische Transmission und das Entladungsverhalten von CA1-Pyramidenzellen des Hippocampus / Meike Völkel." Kiel : Universitätsbibliothek Kiel, 2012. http://d-nb.info/1022796291/34.
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Kumar, Arun Babu. "Design, Synthesis and Evaluation of Novel Diazirine Photolabels with Improved Ambient Light Stability and Fluorous-Based Enrichment Capacity." Scholar Commons, 2012. http://scholarcommons.usf.edu/etd/4112.
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Photoaffinity labeling is a quintessential technique in studying and analyzing the interaction between a ligand and receptor. Diazirines are one of the important photo-labile moieties used in photoaffinity labeling due to their superior photo labeling characteristics. Herein, we report the investigations we conducted with diazirine photolabels on (a) photochemical aspects leading to enhancement of their ambient light stability and (b) equipping them with fluorous tags to enable fluorous enrichment of labeled proteins. Furthermore, we report a pilot study to develop BACE-1 inhibitors, which have potential to be developed into photoaffinity probes.
3-Trifluoromethyl-3-phenyldiazirine offers good selectivity and protection against pseudolabeling but due to its photo lability, it undergoes decomposition even under ambient light. Thus the laboratory handling, including synthesis, of 3-trifluoromethyl-3-phenyldiazirine is cumbersome and restricted under constant darkness. Herein, we have designed, synthesized and evaluated two photolabels with enhanced stability to ambient light conditions in addition to the good selectivity and protection against pseudolabeling as offered by 3-trifluoromethyl-3-phenyldiazirine. It was also found that the aqueous solubility, a vital physical property for a photolabel, was also improved in the modified ambient light stable photolabels.
Fluorous tags have found wide use in synthetic applications; herein we explore the possibility of its application in photoaffinity studies. We designed, synthesized and conducted photoactivation studies on two fluorous diazirine photolabels. The photoactivation studies unraveled an unanticipated photoreaction when the fluorous tag
was directly connected to the diazirine ring, yielding a fluorous alkene. The more practical photolabel of the two was chosen as the target specific photoaffinity labeling moiety for fluorous proteomics. Upon conducting photolabeling experiments under various conditions, we found that the strong hydrophobic character of the fluorous tag renders the photoaffinity label insoluble in aqueous solutions and significantly alters the binding mode and affinity of the photoaffinity label to its target receptor.
A library of 1,3-disubstituted 2-propanols was combinatorially prepared and tested as small molecule inhibitors of β-secretase (BACE-1). The initial screening of the 1,3-disubstituted 2-propanol library revealed a few low micromolar inhibitors for BACE-1. The compound that showed the best activity was chosen for further SAR studies, which resulted in a potent BACE-1 inhibitor with nanomolar inhibition. Investigation on the selectivity of these compounds for BACE-1 inhibition over cathepsin D revealed that these compound series possess very high selectivity. Furthermore, the physicochemical properties study showed that these compounds possessed the calculated parameters advantageous to cross the blood-brain barrier (BBB).
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Liliequist, Erik, and Martin Jonsson. "Knowledge Base : Back-end interface and possible uses." Thesis, KTH, Skolan för datavetenskap och kommunikation (CSC), 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-189145.
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This paper addresses two different aspects of the subject known as knowledge bases, or knowledge graphs. A knowledge base is defined as a comprehensive semantically organized machine-readable collection of universally relevant or domain-specific entities, classes, and facts. The objective of this paper is to explore how a knowledge base can be used to gain information about an entity. First we present one way to access information from the knowledge base using a back-end interface. This back-end interface takes simple parameters as input which are used to query the knowledge base. The main objective here is to be able to access the right entity, to be able to answers the questions correctly. After that follows a discussion about the need for knowledge bases and possible uses. The discussions will partly be based on results from our implementation, but also consider other similar implementation, and interviews with possible users in the business and society. We conclude that the back-end interface developed performs well enough, with a high precision, to be ran in an unsupervised system. Furthermore we realise that the interface can be improved in several ways by focusing on smaller domains of information. Several different possible uses have been identified. From these uses a market analysis has been done from which we conclude good market possibilities. Some of the key problems with implementing the interface regards the credibility of the information in the knowledge base. This is one of the main problems that needs to be solved to fully implement knowledge bases in business and society.Den här rapporten tar upp två olika områden som berör knowledge bases. En knowledge base definieras som en omfattande semantiskt organiserad maskinläslig samling av universellt relevanta eller domän-specifika entiteter, klasser, och fakta. Målet med rapporten är att undersöka hur en knowledge base kan användas för att få fram information om en entitet. Först presenteras ett tillvägagångsätt för kommunikation mot en knowledge base med hjälp av ett back-end gränssnitt. Back-end gränssnittet tar enkla parametrar som input och använder dessa för att köra en query mot en knowledge base. Huvudfokus i denna del kommer ligga i att få rätt svar på frågorna och kommer därmed att utvärderas utifrån det. Det andra området som arbetet berör är en diskussion kring hur knowledge bases kan integreras i samhället och näringslivet för att få ut en ökad nytta. Diskussionerna kommer att baseras på resultaten från den första delen av arbetet till viss del, men även andra liknande studier kommer vägas in för att ge ett bredare diskussionsunderlag. Utöver detta baseras också diskussionen på intervjuer med möjliga intressenter inom näringsliv och samhälle. Det utvecklade gränssnittet presterar på en nivå, med hög precision, som vi bedömer tillräcklig för implementering i oövervakade system. Dessutom har flertalet förbättringsområden identifierats. Huvudsakligen berör dessa att mer specifika implementationer kan få högre precision då specifikare kontroller kan genomföras. Flertal möjliga användningsområden har identifierats. Med dessa som grund har en marknadsanalys genomförts som pekar på goda förutsättningar för tekniken. Ett av det största problemen berör trovärdigheten i informationen i knowledge basen. Det är ett problem som måste lösas innan tekniken kan implementeras fullt ut i näringsliv och samhälle.
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Bertoldi, Karine. "Efeito do envelhecimento sobre a atividade de secretases e o perfil de exossomos circulantes : modulação pelo exercício físico." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2016. http://hdl.handle.net/10183/150934.
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As vias amiloidogênica e não-amiloidogênica, representadas pelas enzimas secretases como a enzima clivadora do sítio beta da APP (BACE) e a enzima conversora do fator de necrose tumoral-alfa (TACE) respectivamente, são responsáveis pela clivagem da proteína precursora amiloide (APP). Alterações no processamento da APP associadas ao acúmulo do peptídeo β-amiloide (Aβ) parecem estar relacionadas aos déficits cognitivos observados na doença de Alzheimer (DA), no entanto, estudos avaliando a maquinaria de processamento da APP durante o envelhecimento fisiológico são raros. O Aβ é formado através da clivagem da proteína precursora amiloide (APP) pela enzima BACE. Por outro lado, a APP pode ser clivada por secretases como a TACE gerando APPα, o qual é considerado neuroprotetor. Alguns estudos têm sugerido um envolvimento de vesículas denominadas exossomos no transporte de proteínas como o peptídeo Aβ além de um papel dos exossomos durante o estresse oxidativo e no processo de envelhecimento. No entanto, estudos avaliando a relação entre exossomos e marcadores oxidativos no envelhecimento ainda não foram realizados. Além disso, apesar de diversas evidências demonstrarem os efeitos benéficos do exercício físico, os efeitos exercidos sobre a modulação da atividade das secretases, especificamente TACE e BACE, e sobre o perfil dos exossomos durante o envelhecimento fisiológico têm sido pouco investigados. Portanto, o objetivo deste trabalho foi avaliar os efeitos do exercício físico sobre a atividade das secretases e sobre o perfil de exossomos circulantes em ratos durante o envelhecimento. Ratos Wistar de 3, 21 e 26 meses de idade foram divididos em sedentários e exercitados, o protocolo de exercício consistiu em 20 min/ dia durante 14 dias e após a última a sessão de exercício todos os animais foram submetidos ao teste da esquiva inibitória. As estruturas cerebrais e o sangue troncular foram coletados 1h (período da tarde) e 18 h (período da manhã) após a última sessão de exercício com o objetivo de avaliar os efeitos transitórios e tardios do protocolo de exercício. O hipocampo e o córtex pré-frontal foram dissecados e utilizados para quantificar o conteúdo de APP e avaliar a atividade das enzimas TACE e BACE. Os exossomos foram isolados do soro e utilizados para quantificar CD63, atividade da acetilcolinesterase (AChE), conteúdo de espécies reativas, atividade da superóxido dismutase (SOD) e conteúdo de Aβ.The amyloidogenic and non-amyloidogenic pathways, represented by secretases named β-site APP cleaving enzyme(BACE) and tumor necrosis factor-alpha converting enzyme (TACE), respectively, are responsible for amyloid protein precursor (APP) processing. APP cleavage modifications leading to increased β-amyloid (Aβ) peptide levels seem to be related to cognitive decline observed in Alzheimer disease (AD), however, works evaluating the APP processing machinery in the normal aging process are rarely studied. The Aβ is formed through APP cleavage by BACE enzyme, named amyloidogenic pathway. On the other hand, APP can be cleaved by a non-amyloidogenic pathway through secretase enzymes such as TACE producing APPα, which is a neuroprotective product. Some evidences suggested that extracellular vesicles named exosomes could carry proteins including the Aβ peptide between different cells. Yet, exosomes appear to be linked to oxidative stress and aging process. However, studies evaluating the relationship between exosomes and oxidative stress marks in the aging were not yet performed. The beneficial exercise impact in the aging process are widely described, nevertheless, its effects on secretase activities, specifically BACE and TACE, and exosome profile during normal aging remains understood. Therefore, the aim of this study was to evaluate the exercise effects on secretase activities and circulating exosomes profile in the aging process. Wistar rats (3-, 21- and 26-month-old) were divided into sedentary and exercised groups; the exercise protocol consisted in a daily moderate treadmill exercise (20 min each day during 2 weeks). After the last exercise sessions, all animals were subjected to inhibitory avoidance task. To identify transitory and delayed exercise effects, specifically 1 and 18 hours after the last exercise training session, hippocampi and prefrontal cortices as well as blood were obtained at different times of day, respectively, in the afternoon and early morning. The brain areas were used to quantify the APP content and BACE and TACE activities. The circulating exosomes were isolated from serum and used to quantify CD63, reactive species and Aβ content, besides AChE and superoxide dismutase (SOD) activities.
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新名, 芳有. "アミロイドカスケードに対する複数の薬理作用を有する化合物の同定とBACE-1の炎症条件下における機能の解明に関する研究." 京都大学 (Kyoto University), 2008. http://hdl.handle.net/2433/137170.
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Chiocco, Matthew J. "Beta-secretase transgenic mice effects of BACE1 and BACE2 on Alzheimer's disease pathogenesis /." Connect to text online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1111597750.
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Chiocco, Matthew J. "Beta-Secretase Trangenic Mice: Effects of BACE1 and BACE2 on Alzheimer's Disease Pathogenesis." Case Western Reserve University School of Graduate Studies / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=case1111597750.
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Carvalho, Tiago Gouveia. "A estrutura de capitais das PME europeias : análise da base de dados Bach." Master's thesis, Instituto Superior de Economia e Gestão, 2014. http://hdl.handle.net/10400.5/8366.
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Mestrado em Ciências EmpresariaisÉ costume dizer que as PME portuguesas estão descapitalizadas e necessitam cada vez mais de crédito para fazer face às suas necessidades de financiamento. Este trabalho tentará validar esta afirmação através da análise da base de dados BACH (Bank for the Accounts of Companies Harmonized). Esta base contém dados agregados das rubricas de balanço e rácios financeiros de empresas de dez países da União Europeia, para o período de 2000 até 2012. Vai-se utilizar variáveis e medidas de posição e dispersão de estatística descritiva para comparar os dados entre os países em cada setor de atividade económica da UE. Assim, será possível verificar, se as PME portuguesas encontram-se verdadeiramente com níveis de endividamento mais elevados, em relação aos outros países da UE. Vai-se também analisar, se existe ou não, convergência nos níveis de endividamento entre as PME dos vários países, em cada setor. E que tendência, os níveis de endividamento, apresentam em cada setor, durante o período observado. No final, constata-se que as PME portuguesas encontram-se com um dos maiores níveis de endividamento, variabilidade e com menor homogeneidade entre os valores.
It is a costume to say that portuguese SME are undercapitalized and increasingly need of credit to meet their financial needs. This paper attempts to validate this sentence by examining the database of BACH (Bank for the Accounts of Companies Harmonised). This database contains aggregate data of balance sheet items and financial ratios of companies belonging to ten EU countries, for the period of 2000 to 2012. By using variables and measures of position and dispersion of descriptive statistics, it will be possible to compare the data between the countries for each setor of economic activity in the EU. Therefore, it will be possible to verify, if the Portuguese SME, truly, have higher levels of debt, compared to other EU countries. Also it will be analyzed, whether or not exists, convergence in levels of debt among SME of the various countries, in each setor. And what trend, the levels of debt, present in each setor, during the observed period. In the end, it appears that Portuguese SME have one of the highest levels of debt, variability and less homogeneity among values.
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Alahmadi, Dimah. "Recommender systems based on online social networks : an Implicit Social Trust And Sentiment analysis approach." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/recommender-systems-based-on-online-social-networks-an-implicit-social-trust-and-sentiment-analysis-approach(ac03f7e5-4fc0-4c4a-bace-82188823eb84).html.
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Recommender systems (RSs) provide personalised suggestions of information or products relevant to user's needs. RSs are considered as powerful tools that help users to find interesting items matching their own taste. Although RSs have made substantial progress in theory and algorithm development and have achieved many commercial successes, how to utilise the widely available information on Online Social Networks (OSNs) has largely been overlooked. Noticing this gap in existing research on RSs and taking into account a user's selection being greatly influenced by his/her trusted friends and their opinions, this thesis proposes a novel personalised Recommender System framework, so-called Implicit Social Trust and Sentiment (ISTS) based RSs. The main motivation was to overcome the overlooked use of OSNs in Recommender Systems and to utilise the widely available information from such networks. This work also designs solutions to a number of challenges inherent to the RSs domain, such as accuracy, cold-start, diversity and coverage. ISTS improves the existing recommendation approaches by exploring a new source of data from friends' short posts in microbloggings. In the case of new users who have no previous preferences, ISTS maps the suggested recommendations into numerical rating scales by applying the three main components. The first component is measuring the implicit trust between friends based on their intercommunication activities and behaviour. Owing to the need to adapt friends' opinions, the implicit social trust model is designed to include the trusted friends and give them the highest weight of contribution in recommendation encounter. The second component is inferring the sentiment rating to reflect the knowledge behind friends' short posts, so-called micro-reviews. The sentiment behind micro-reviews is extracted using Sentiment Analysis (SA) techniques. To achieve the best sentiment representation, our approach considers the special natural environment in OSNs brief posts. Two Sentiment Analysis methodologies are used: a bag of words method and a probabilistic method. The third ISTS component is identifying the impact degree of friends' sentiments and their level of trust by using machine learning algorithms. Two types of machine learning algorithms are used: classification models and regressions models. The classification models include Naive Bayes, Logistic Regression and Decision Trees. Among the three classification models, Decision Trees show the best Mean absolute error (MAE) at 0.836. Support Vector Regression performed the best among all models at 0.45 of MAE. This thesis also proposes an approach with further improvement over ISTS, namely Hybrid Implicit Social Trust and Sentiment (H-ISTS). The enhanced approach applies improvements by optimising trust parameters to identify the impact of the features (re-tweets and followings/followers list) on recommendation results. Unlike the ISTS which allocates equal weight to trust features, H-ISTS provides different weights to determine the different effects of the two trust features. As a result, we found that H-ISTS improved the MAE to be 0.42 which is based on Support Vector Regression. Further, it increases the number of trust features from two to five features in order to include the influence of these features in rating predictions. The integration of the new approach H-ISTS with a Collaborative Filtering recommender system, in particular memory-based, is investigated next. Therefore, existing users with a history of ratings can receive recommendations by fusing their own tastes and their friends' preferences using the two type of memory-based methods: user-based and item-based. H-ISTSitem is the integration of H-ISTS and item-based which provides the lowest error at 0.7091. The experiments show that diversity is better achieved using the H-ISTSuser which is the integration of H-ISTS and user-based technique. To evaluate the performance of these approaches, two real social datasets are collected from Twitter. To verify the proposed framework, the experiments are conducted and the results are compared against the most relevant baselines which confirmed that RSs have been successfully improved using OSNs. These enhancements demonstrate the effectiveness and promises of the proposed approach in RSs.
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Diokh, Thérèse. "Développement des technologies mémoires "back-end" résistives à base d'oxydes pour application dans des "Systems on Chip" avancés." Thesis, Grenoble, 2013. http://www.theses.fr/2013GRENT048.
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Les mémoires résistives non volatiles à bases d'oxydes métalliques suscitent un intérêt croissant chez les industriels. Plus particulièrement, les mémoires non volatiles à base d'oxydes (OxRRAM) offrent des temps de programmation et d'accès très court, une faible consommation énergétique, un coût par bit très concurrentiel et une facilité de co-intégration dans le back-end avec du CMOS avancé. Ce travail de thèse a pour objectif le développement d'une mémoire OxRRAM facilement intégrable dans une technologie de fabrication CMOS avancée afin de montrer les avantages en vue de leur application dans des SoC. Une première étape fut la fabrication et l'analyse des cellules mémoires OxRRAM intégrant différents oxydes métalliques afin de choisir la solution la plus adaptée à être intégrée dans une technologie CMOS 65nm et 28nm. Des techniques de mesures dédiées ont été mises en place afin d'établir l'impact du diélectrique sur le fonctionnement de la mémoire OxRRAM en termes de polarisation, de temps de programmation, de courant de programmation et de mécanismes de transition. Des études statistiques et de fiabilité des différents états du point mémoire ont été aussi réalisées. La modélisation associée a permis de mieux comprendre les mécanismes de vieillissements et prédire des lois de durée de vie sous champ et en température des état écrit et effacé de la cellule OxRRAM. Les données expérimentales obtenues sur les cellules ont ensuite permis de concevoir et d'optimiser un circuit d'évaluation statistique de 16 Kbit en technologie CMOS 28nm en tenant compte de toutes les contraintes de design analogiqueOxide-based Resistive Random Acces Memories (OxRRAM) are nowadays considered among the most promising solutions for future generation of low-cost embedded non-volatile memories. The advantages of these memories are the scalability, low power consumption, high speed, complementary metal oxide semiconductor technology (CMOS) compatibility and ease of fabrication (the memory cell consisting of a Metal–Insulator– Metal (MIM) structure integrated in the back-end-of-line, plus an addressing element, i.e. a transistor or a diode) . The potential applications range from consumer – communications to automotive – industrial. This work deals with the development of an OxRRAM demonstrator into an advanced CMOS technology for System on Chip (SoC) application. We discuss the impact of different dielectrics materials (Ta2O5, ZrO2 and HfO2) and electrodes (Pt, Ti, TiN) on the memory performances and reliability in order to choose the best couple dielectric/electrode. We focus on the understanding of the memory switching physics that is involved in the programming of OxRRAM bit-cells. The failure and transition mechanism are presented for lifetime prediction. Some methodologies are presented in this PhD thesis for the optimization of the OxRRAM bit-cell performances and sizes according to a targeted Mutliple Time Programmable (MTP) memory application. We developed analog block systems to control and address the OxRRAM bit-cell taking to account the bipolar switching characteristics of the devices. Finally, these solutions are to be validated using a 1-kb OxRRAM demonstrator yet designed and fabricated in a logic 28-nm node CMOS technology. Keywords: Oxide Resistive memory (OxRRAM), High-k, MIM, CMOS, Characterization, Reliability, Modeling, Analog Design, Simulation
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Yitbarek, Baye Andarge. "Hydrogeological and hydrochemical framework of complex volcanic system in the Upper Awash River basin, Central Ethiopia : with special emphasis on inter-basins groundwater transfer between Blue Nile and Awash rivers." Poitiers, 2009. http://theses.edel.univ-poitiers.fr/theses/2009/Yitbarek-Baye-Andarge/2009-Yitbarek-Baye-Andarge-These.pdf.
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Une approche utilisant plusieurs méthodes convergentes a été mise en oeuvre pour étudier le cadre hydrogéologique du système aquifère volcanique fracturé et complexe du bassin supérieur du fleuve Awash situé sur le bord du Rift éthiopien. L'écoulement des eaux souterraines et les mécanismes de recharge des différents aquifères ont été étudiés à l'aide de méthodes conventionnelles de terrain, de l'hydrochimie, de l'hydrologie isotopique et de la modélisation numérique des flux souterrains. Des relations lithohydrostratigraphiques ont été établies à partir des logs lithologiques de forages exploratoires profonds. Les résultats montrent un modèle d'écoulement et des caractéristiques hydrauliques des différents aquifères volcaniques très complexes. La corrélation litho-hydrostratigraphique indique que l'aquifère basaltique inférieur, constitué de scories poreuses et perméables, est continu tout le long depuis le Nil Bleu jusqu'à la zone étudiée. L'analyse de la variation temporelle et spatiale des échantillons d’eau provenant d'endroits différents a révélé des interactions nettes entre l'eau souterraine et l'eau superficielle. De nouvelles évidences des transferts d'eau inter-bassins sont apparues. Deux aquifères basaltiques régionaux (l'aquifère supérieur et l'aquifère inférieur) ont été identifiés, montrant des signatures hydrochimiques et isotopiques bien distinctes. Dans la partie sud de la zone étudiée, l'aquifère supérieur et l'aquifère inférieur forment un système aquifère régional non confiné. Dans les parties nord et centrale du bassin au contraire, il apparaît que les deux systèmes sont séparés par un aquiclude régional, donnant lieu par endroits à des puits artésiens. Les eaux souterrainex provenant des puits d'exploration profonds (plus de 250 m) pénétrant l'aquifère basaltique inférieur et des puits situés au sud se sont révélées modérément mineralisées (TDS 400-650 mg/l), avec une composition isotopique stable, relativement moins enrichie et avec presque pas de tritium. Par contre, l'aquifère supérieur superficiel a une concentration ionique moins importante, davantage enrichie isotopiquement. Les résultats des différentes méthodes montrent clairement qu'il existe un transfert d'eau souterraine du nord du bassin adjacent du Nil Bleu vers le bassin supérieur du fleuve Awash. Les résultats convergent également pour attester de l'origine commune de la recharge et de la continuité hydraulique de l'aquifère basaltique inférieur exploité par des forages. Ceci peut avoir des implications pratiques capitales car l'existence d'importantes ressources d'eau souterraine en profondeur peut résoudre les problèmes d'approvisionnement de nombreuses villes, y compris la capitale, Addis Ababa. Ces résultats pourront aussi contribuer à mettre à jour d'autres aquifères régionaux le long des limites du rift dans des zones ayant une structure hydrogéologique similaire à celle du bassin supérieur du fleuve AwashIntegrated approach has been used to investigate the hydrogeological framework of a complex fractured volcanic aquifer system in the Upper Awash river basin located at the western shoulder of the Ethiopian rift. The groundwater flow system and mechanism of recharge of different aquifers have been studied using conventional hydrogeological field investigations, hydrochemistry, isotope hydrology and numerical groundwater flow modeling techniques. Litho-hydrostratigraphic relationships were constructed from lithologic logs obtained from exploratory drilling of deep boreholes. The result indicates quite complex flow pattern and hydraulic characteristics of the different volcanic aquifers. The litho-hydrostratigraphic correlation indicates that the permeable and porous scoraceous lower basaltic aquifer is extended laterally all the way from the Blue Nile Plateau to the study area. . The analysis of the temporal and spatial variation of water samples from different places revealed clear undwater-surface water interactions. New evidences have also emerged on the inter-basin groundwater transfer. Two distinct regional basaltic aquifers (Upper and lower) are identified showing distinct hydrochemical and isotopic signatures. In the southern part of the study area the upper and lower aquifers form one unconfined regional aquifer system. In the northern and central part of the basin, it appears that the two systems are separated by regional aquiclude forming confined aquifers, in places with artesian wells. The groundwater from the deep exploratory wells (>250m) tapping the lower basaltic aquifer and wells located in the south were found to be moderately mineralized (TDS: 400-600 mg/l), with relatively depleted stable isotope composition and with almost zero tritium. In contrast, the upper shallow aquifer has lesser ionic concentration, more isotopically enriched. Evidences from the different methods clearly indicate inter-basin groundwater transfer from the Blue Nile basin to the Upper Awash basin. The evidences also converge to testify common origin of recharge, presence of hydraulic connectivity for systems tapping the lower basaltic aquifer. This has enormous practical implication in finding large groundwater reserve at a greater depth that can solve the current water supply problems of the community including the capital Addis Ababa. It will also have important role in finding more regional aquifers along the plateau-rift margins in many areas having similar hydrogeological setup as the study area
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Tirano, Sauveur. "Intégration et caractérisation électrique d'éléments de mémorisation à commutation de résistance de type back-end à base d'oxydes métalliques." Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM4713/document.
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Cette thèse porte principalement sur la caractérisation électrique et la modélisation physique d'éléments mémoires émergents de type OxRRAM (Oxide Resistive Random Access Memory) intégrant soit un oxyde de nickel, soit un oxyde de hafnium. Une fois la maturité technologique atteinte, ce concept de mémoire est susceptible de remplacer la technologie Flash qui fait encore figure de référence. Les principaux avantages de la technologie OxRRAM reposent sur une très bonne compatibilité avec les filières CMOS, un faible nombre d'étapes de fabrication, une grande densité d'intégration et des performances attractives en termes de fonctionnement. Le premier objectif de ce travail concerne le diélectrique employé dans les cellules. Il s'agit d'apporter des éléments factuels permettant d'orienter un choix technologique sur la méthode d'élaboration de l'oxyde de nickel (oxydation thermique ou pulvérisation cathodique réactive) puis d'évaluer les performances de cellules à base d'oyxde de hafnium. Le second objectif est d'approfondir la compréhension des mécanismes physiques responsables du changement de résistance des dispositifs mémoire par une approche de modélisation physique des phénomènes opérant lors des phases d'écriture et d'effacement, sujet encore largement débattu dans la communauté scientifique. Le troisième objectif de cette thèse est d'évaluer, par le biais de caractérisations électriques, les phénomènes parasites intervenant dans les éléments mémoires de type 1R (élément résistif sans dispositif d'adressage) et, en particulier, la décharge capacitive apparaissant lors de leur programmation (opérations d'écriture)This work is focused on the electrical characterization and physical modeling of emerging OxRRAM memories (Oxide Resistive Random Access Memory) integrating nickel or hafnium oxide. After reaching maturity, this memory concept is likely to replace the Flash technology which is still a standard in the CMOS industry. The main advantages of resistive memories technology is their good compatibility with CMOS processes, a small number of manufacturing steps, a high integration density and their attractive performances in terms of memory operation. The first objective of this thesis is to provide enough informations allowing to orientate the elaboration process of the active nickel oxide layer (thermal oxidation, reactive sputtering) then to compare the performances of the fabricated cells with devices featuring a hafnium oxide layer. The second objective is to understand the physical mechanisms responsible of the device resistance change. A physical model is proposed allowing to apprehend SET and RESET phenomenon in memory devices, subject which is still widely debated in the scientific community. The third objective of this thesis is to evaluate electrical parasitic phenomenon observed in 1R-type memory elements (resistive element without addressing device), in particular the parasitic capacitance appearing during cell programming (writing operation)
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Lindberg, Erik, and Lukas Magnusson. "WEC Back-to-back Topology." Thesis, Uppsala universitet, Institutionen för teknikvetenskaper, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-351912.
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Böris, Elin, and Vendela Hall. "Developing a Methodology for Supplier Base Reduction : A Case Study at Dynapac GmbH." Thesis, Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-119334.
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Dynapac GmbH is a manufacturer of road construction equipment and has historically been acquired and merged with several companies, resulting in an expansion of their supplier base. Currently, they are experiencing a large supplier base within direct material causing a decrease in the effectiveness and efficiency in the management of the suppliers. Dynapac GmbH therefore wishes to lower the number of suppliers in order to obtain desired effects, such as cost savings, reduction of administrative workload, higher control, higher quality and improved communication with suppliers. The purpose of the study is therefore to develop a methodology that describes all the activities needed to successfully reduce the number of suppliers. At the moment, approximately 80 percent of the total purchasing budget is allocated to only 14 percent of the supplier base. The supplier base can therefore be assumed to consist of a high number of suppliers supplying only a few products with a low turnover. Based on this, it can be concluded that the supplier base includes several opportunities for supplier base reduction. The action of reducing the supplier base is perceived as being in line with the sourcing strategy as well as the business strategy and the needed support is therefore believed to be present in order to succeed with performing supplier base reduction. Based on existing research, a conceptual model for supplier base reduction was created. The current situation at Dynapac GmbH was thereafter analysed in order to enable a customization of the model. Interviews were held to obtain input regarding the model and the activities. The overall view on the model was positive and all activities were considered to be relevant to include. Possible customizations of the activities were discussed during the interviews, which resulted in a customized model consisting of activities with either two types of customizations: (1) defined variables or (2) developed processes. Lastly, the model was validated in a pilot test before it was reconfigured and handed over as a methodology. The finalized methodology included a thorough description on how to conduct supplier base reduction from beginning to end, consisting of 14 activities corresponding to five different phases. The first two phases intend to lay the basis for enabling a reduction of the supplier base and the third phase aims at implementing it in practice. The fourth phase consists of analysing the result of the implementation followed by the last phase with focus on continuous improvement of the supplier base.
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Johnson, Lisa Marie. "Back to back they faced each other." Thesis, University of Iowa, 2011. https://ir.uiowa.edu/etd/993.
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