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1
Conceicao, Viviane. "Genome-Wide Host Gene Expression Analysis Before and After the Initiation of Highly Active Antiretroviral Therapy And Natural Control of HIV in Therapy Naïve HIV+ Non-Progressors." Thesis, The University of Sydney, 2013. http://hdl.handle.net/2123/9384.
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Since its discovery 25 years ago, the HIV virus has infected more than 34 million people in the world; the infection caused by this virus has led the world to its most terrible pandemic, and the greatest global health crises of our times. The host-virus interaction and natural history of the disease are influenced by the distinctive interface the virus has with each infected individual. The infection with HIV-1 is characterized by the destruction of CD4+ T-cells during the typical course of the infection, but HIV has the arsenal to infect practically all the major blood leukocytes. Taken from these observations, it is apparent that HIV has the innate ability to subvert and manipulate the host gene machinery at the transcriptomic level. The highly active anti-retroviral therapy (HAART) consists of a combination of powerful drugs, which serve as potent defence mechanism against the ways in which the HIV virus attacks the human bod y. Although these drugs are not able to rid the body of HIV virus, they can significantly delay the onset of AIDS and reduce the incidence of opportunistic infections, morbidity and mortality related to HIV infection. After the introduction of HAART treatment, it is observed that most patients with good adherence respond to HAART, which is defined by a decrease of plasma viral load to undetectable levels and an immune reconstitution with a significant increase of CD4+ T cell levels. Around 30% of the patients fail to achieve this response and continue to express high plasma viral load and low CD4+ T cell numbers. In contrast, some rare HIV+ patients maintain below detectable levels of plasma viremia without the treatment. These are termed long-term nonprogressors(LTNPs), less commonly called elite controllers. These rare individuals are infected with HIV, but have the natural ability to control the infection with the strength of their immune system. Many of th ese patients have been HIV positive for 30 years or more and! off the rapy for the entire duration of their infection, showing high CD4+T cells counts and no progression to the disease. In this context, it is important to mention that the genomic basis of this natural effective immunological control of viremia in LTNPs, as opposed to drug-mediated control of HIV, remains unknown. The development of high throughput microarray platforms and bioinformatic platforms to visualize and analyse the complex dataset has enabled considerable progress in the field of viral genomics, and also the visualization of host-virus interactions at the molecular level. In chapter III, we carried out a comparative genome-wide (encompassing all 25,000 human genes) pharmacogenomic study using whole primary peripheral blood mononuclear cells (PBMC) derived from 14 HIV+ patients at two time points: pre-HAART (TP-1 with detectable viremia) and post (TP2: below detectable level (BDL) of plasma HIV <40 copies of HIV RNA/mL plasma), to ascertain how genomically distinct viremic phase is from the phase in which virus is fully controlled with HAART. Another goal was to define the underlying pharmacogenomic basis of HIV control during HAART. In the second study shown in Chapter IV, we compared the two time points against the 9 LTNPs to unravel the genomic basis of natural control of viremia in therapy naïve LTNPs showing below detectable levels of viremia (<20 copies of HIV RNA/mL plasma) and high and stable CD4+T cell counts. Genomic RNA extracted from the PBMCs was used in genome-wide microarray analysis, using HT-12v3 Illumina chips. Quantile normalization was performed to normalize the data and inter-patient variability. Illumina®BeadStudio Data Analysis Software wa s used to obtain differentially expressed (DE) genes. Only the significant genes with p value <0.01 and FDR of <5% (for the comparison between TP1 and TP2) and FDR <1% (for the comparison between LTNP vers us TP1 and LTNP versus TP2) were considered appropriate for ! analysis . Pathway analysis was performed in MetaCoreTM from GeneGo, Inc to derive functional annotations. Functionally significant genes were validated by quantitative real time PCR. Between TP1 and TP2, 234 genes were differentially expressed. Within these genes, 212 were down-regulated and 22 upregulated. Between the comparison between LTNP vs TP1, 965 genes were differently expressed (706 genes were up-regulated and 259 genes were down-regulated), and when LTNP was compared to the TP2 group, we found 1181 DE genes (with 727 genes up-regulated and 454 genes downregulated). In the first part of this study, comparing the TP1 and TP2 only, we found that of the top 10 pathways, 8 belonged to the immune response system. This was the most significant pathway up-regulated in TP1 when compared to TP2. This comprised of genes that were involved in antiviral action of interferon (IFN) and their signalling function, antiviral response, dendritic cell maturation a nd migration, and cell metabolism. Map folder and enrichment analysis corroborated with our findings, thereby confirming an intrinsic role of the immune, inflammatory and interferon response family-related genes during HIV viremia in the absence of treatment. But a closer examination of this contrast also showed a mirror down-regulation of genes involved in innate and adaptive immunity, inflammation, apoptosis and antiviral functions. This directly implies a functional relevance of these pathways, through their modulation in TP1 and TP2 stages. Although these data are intuitive and expected, such analysis has never been performed before. The second part of this study, on comparisons between LTNP and TP1 and LTNP against TP2, we show the first evidence demonstrating that the natural control of HIV in LTNP is guided by the genes enriched in the immune response, cytoskeleton remodelling, apoptosis and T cell signalling pathways. Another striking ob servation was that, even though the LTNP and TP2 groups maintai ned BDL of plasma viremia (<40 copies), the LTNP group was genomically distinct from the TP2, which controlled viremia with HAART. This highlights the qualitative distinction and critical role of enriched pathways in natural control of viremia in the LTNPs. Seventeen genes encompassing all these pathways were validated by q-PCR, which showed consistent trends between microarray and q-RT PCR. One gene in particular, the thrombospondin (THBS1) (R2= 0.942) was identified as a biomarker in our study, discriminating between viremic patients and LTNPs at the genomic (R2= 0.942, p<2.654e.08) and proteomic levels (p<0.003761). The levels of expression of THBS1 showed excellent correlation with plasma viremia (R2=0.81557;p<.0.0003761), the first description of such an important protein. This is the most unique finding of this work, which has significance in HIV disease prognostics and diagnostics, in addition to predicting the strength of the ho st immune system, as evident from its down-regulation and low expression in the natural controllers. Overall, through these analyses, we have shown that, although there are common set of key genes associated with HIV at all stages, each stage also showed unique molecular signatures. This was demonstrated with the identification of molecular signatures for the control of virus with HAART therapy, as well as for the natural control of HIV in LTNPs. Especially for the LTNPs, the downregulation of the apoptosis was the most significant feature, which may have important implications in therapy, especially in the context of using apoptosis as a target for future therapies.
2
van, Bockel David John Clinical School St Vincent's Hospital Faculty of Medicine UNSW. "Qualitative analysis of T-cell repertoire for relevance to non-progressive HIV infection." Publisher:University of New South Wales. Clinical School - St Vincent's Hospital, 2008. http://handle.unsw.edu.au/1959.4/41304.
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Cytotoxic T-lymphocytes are important for the control of viral replication during HIV infection, however the magnitude and breadth of HIV-specific CD8+ T-cell response does not correlate well. The purpose for this study was the examination of the HLA-B*2705-specific CD8+ T-cell response to the KRWIILGLNK (KK10) epitope as a definitive model of immune control over HIV replication. The breadth of the T-cell receptor (TCR) repertoire was determined for an association between the qualitative nature of this response and immune escape and therefore, disease progression. Methodology was developed and validated for TCR repertoire analysis in formaldehyde fixed antigen-specific CD8+ T-cells. The TCR repertoire for the KK10-specific CD8+ T-cell response was defined in cross-section and longitudinally for 6 HLA-B*2705+ patients. Comparison was made to cognate HLA-A*0201 CMV NV9 and HLA-B*2705 EBV RL9-specific CD8+ T-cell populations using the Simpson??s diversity index and the Morisita-Horn similarity index for standardized repertoire analysis. HLA-B*2705 KK10-specific TCR repertoire was not found to be a determinant of control. Greater clonotype variation was found within CMV-specific CD8+ T-cell populations, suggesting an association with reactivation of CMV and disease state. An association was found between KK10-specific population diversity and the prevalence of cognate KK10 epitope in vivo. Cross-reactivity observed for dominant KK10-specific clonotypes suggested that avidity of CD8+ T-cells was important for in vivo survival. Phenotype and function was tested through multiparameter analysis of HIV and CMV-specific CD8+ T-cells. Increased frequency of CD127 (IL-7R) and Bcl-2 expression within dominant populations was suggestive of selective advantage. Division of dominant and sub-dominant CMV-specific CD8+ T-cell populations into ??early?? and ??late?? differentiation phenotypes indicated virus-specific mechanisms of clonotype turn over. No simple association of TCR expression was found for HIV and CMV-specific CD8+ T-cells with published examples of definitive TCR bias. Over-represented TCR ??-chain families of patients were found in association with public clonotypes. Convergent recombination of TCR genes was demonstrated as a mechanism for the prevalence of shared clonotypes. Standardized assessment of T-cell repertoire successfully identified mechanisms of antigen-specific CD8+ T-cell recruitment. A substantial increase in sample numbers is required before this methodology can be used to accurately demonstrate the importance of TCR repertoire usage in the control of human viral infection.
3
Bignami, F. "L'ESPOSIZIONE AD HIV-1 INFLUENZA LA RISPOSTA IMMUNITARIA CD4-MEDIATA ALTERANDO IL PROFILO D'ESPRESSIONE DEI MICRORNA CELLULARI." Doctoral thesis, Università degli Studi di Milano, 2010. http://hdl.handle.net/2434/150033.
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MicroRNAs (miRNAs) are small single-strand non-coding RNAs that repress gene expression by inhibiting translation. MiRNAs are known to inhibit HIV-1 expression interfering with viral mRNAs. In order to better understand how HIV-related alterations in cellular physiology and immunologic control function, 3 classes of patients (éLTNP, Naive and multiply exposed to HIV-1 uninfected subjects, named MEU) were enrolled, from whom blood CD4+ cells were purified. In this cellular subtype the expression levels of 377 miRNAs were analyzed by TaqMan real-time PCR-based arrays. Only miRNAs expressed in 70% of patients of at least one class and of at least 1 log10 variation from healthy controls were selected. A similar analysis had also been performed in primary culture of CD4+T cells and monocyte-macrophages infected by R5 strains and in CD4+ cells exposed to recombinant and natural gp120 molecules in vitro. In all experiments, expression levels of Dicer and Drosha, two enzymes involved in miRNA biogenesis, were evaluated by real-time PCR.
Similar miRNA profiles were detected in the CD4+ cells from éLTNP and Naive, although these infected patients had different parameters such as viral and proviral loads, infection time and CD4+ T cell number. Moreover, a complex down-regulation of miRNA was observed in the CD4+ cells from MEU subjects. This indicates that the only HIV-1 antigen exposure can modulate cellular programming process of CD4+ cells. Three up-regulated (miR-203, 449a, 502-5p) and five down-regulated (miR-329, 337-5p, 379, 503, 518d-3p) miRNAs, modulated in all patient classes, defined a HIV-1 signature. By hierarchical clustering of the miRNA profile, éLTNP clustered with Naive patients, whereas all MEU subjects grouped together; this suggests that miRNA expression may discriminate between infected and uninfected individuals. By statistical analysis, 16 miRNAs significantly differentiated éLTNP and Naive from MEU, while only the miR-155 discriminated éLTNP from Naive. Of these, 9 were involved in viral replication and/or in immune response.
Computational studies suggested that target genes of altered miRNAs are involved in a lot of cellular processes and in binding/catalytic activity. According to the Dicer and Drosha expression, that was down-regulated in all patient classes, a correlation was observed between miRNA and the two enzymes expression. In contrast, no differences were observed in CD4+ cells infected in vitro or exposed to gp120 molecules. This suggests that there is a complex regulation of miRNA expression after HIV exposure, not only due to the miRNA biogenesis.
The miRNA expression analysis in CD4+ cells exposed to gp120 molecules showed a modulation of 66 miRNAs; only 42% of these showed the same levels of expression, suggesting that the remaining percentage of miRNAs was modulated by other gp120 epitopes. When the gp120 was neutralized with mAbs, only 1/3 of altered miRNAs were reverted to the expression of non exposed controls. This indicates the existence of epitopes (other than the CD4 binding domain) capable of inducing a miRNA modulation. Finally, the miRNA expression analysis highlights that 5 miRNAs (miR-34c-p, 518f, 452, 202 and 487b) could have a role in HIV-CD4+ cell binding.
In conclusion, in light of these results, it can be supposed that the altered miRNA profile is due to the constant HIV exposure of CD4+ cells through a bystander phenomenon rather than a direct effect. Therefore it can be assumed that only the exposure to gp120 molecules can leave a signature in immune cells.
4
Parnicza, Justin W. "WV LTAP PMS integrating GIS with PMS software /." Morgantown, W. Va. : [West Virginia University Libraries], 2010. http://hdl.handle.net/10450/10848.
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Thesis (M.S.)--West Virginia University, 2010.Title from document title page. Document formatted into pages; contains ix, 97 p. : ill. (some col.), col. maps. Includes abstract. Includes bibliographical references (p. 51).
5
Arend, Marcos Osmar. "Lente Toroidal de Plasma (LTP)." Pontif?cia Universidade Cat?lica do Rio Grande do Sul, 2016. http://tede2.pucrs.br/tede2/handle/tede/7003.
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This paper proposes the use of plasma lenses to replace the classical solid dielectric lens for focusing the electromagnetic wave, with application in theaters of military operations. The results are shown for an array of plasma elements constituting a directional antenna with innovative features. One of the major advantages is the reduced cross section presented to the electromagnetic wave emitted by a radar system, minimizing the detection probability in specific operational bands, thus maximizing the invisibility of the proposed system.
Este trabalho prop?e o uso de lentes de plasma em substitui??o ? cl?ssica lente diel?trica s?lida para focaliza??o de ondas-eletromagn?ticas, com aplica??o em teatros de opera??es militares. Os resultados s?o demonstrados em um arranjo de elementos de plasma, constituindo uma antena direcional de aracter?sticas inovadoras. Um dos principais diferenciais se refere ? reduzida se??o transversal apresentada ? onda eletromagn?tica emitida por sistemas de radar (RCS), minimizando em determinadas bandas de opera??o a probabilidade de detec??o, maximizando, portanto, a invisibilidade do sistema proposto.
6
Lack, Jeremy David. "The solution structure and surface properties of TB3 of LTBP-1." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249190.
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Steer, Ruth. "Investigations of the extracellular deposition of latent TGF-beta binding protein-1 (LTBP-1)." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/investigations-of-the-extracellular-deposition-of-latent-tgfbeta-binding-protein1-ltbp1(41e0ee4f-5030-4333-8a52-e0d21d1fc649).html.
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LTBP-1 is a large extracellular glycoprotein that is a component of the large latent TGF-β complex. The extracellular sequestration of latent TGF-β in the extracellular matrix (ECM) is fundamental to the regulation of TGF-β bioavailability and activity. LTBP-1 is described to contribute to the regulation of TGF-β bioavailability through mediating the extracellular sequestration of newly secreted latent TGF-β with fibrillin microfibrils in the ECM. However it is not well understood how LTBP-1, and thus latent TGF-β, becomes deposited into the ECM. Previous work by our group suggested that LTBP-1 interactions with the glycosaminoglycan heparan sulphate (HS) at the cell-matrix interface might facilitate the association of LTBP-1 with fibrillin microfibrils. Using recombinant LTBP-1 fragments and mutants, LTBP-1 interaction with HS have been fine-mapped. Deposition of a LTBP-1 HS-binding mutant, and of LTBP-1 when HS was depleted, was studied in cell cultures; findings presented here demonstrate that HS may not be critical for the deposition of LTBP-1 into the ECM. Contributions of fibrillin and fibronectin to LTBP-1 deposition were investigated, and data presented here support published findings that fibrillin is not always required for LTBP-1 deposition. In addition, the dependency of LTBP-1 deposition upon fibronectin was suggested to differ between different cell types (epithelial and mesenchymal). How LTBP-1 may be stabilised within the ECM through crosslinking by tissue transglutaminase was investigated using recombinant fragments and cell culture studies. Tissue transglutaminase was found to promote the extracellular incorporation of LTBP-1, and novel cross-links within LTBP-1, and between LTBP-1 and fibrillin-1, but not LTBP-1 and fibronectin, were identified. Additionally, results indicated that LTBP-1 was present in extremely high molecular weight assemblies in the ECM of cultured fibroblasts. Collectively, these results have contributed to current knowledge of how LTBP-1 becomes deposited into the ECM. They indicate that the deposition of LTBP-1 is not underpinned by HS, may be cell type-specific, and that LTBP-1 may potentially self-assemble extracellularly into homotypic structures that may associate with fibrillin microfibrils.
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Evans, Gary Lee. "The induction of long-term potentiation attenuates kainic acid-induced excitotoxicity." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/777.
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The activation of N-methyl-D-aspartate glutamate receptors (NMDARs) is required for the long term potentiation (LTP) and long term depression (LTD) of excitatory synaptic transmission at hippocampal CA1 synapses, and plays an important role in learning and memory. In addition, it is accepted that the over-activation of NMDARs leads to the neurotoxicity associated with stroke and other neurodegenerative disorders. Thus, the NMDAR provides a logical starting point to investigate a possible relationship between synaptic plasticity and the cell-signalling pathways which ultimately determine neuronal fate. Research in our lab has indicated that NR2A-containing NMDARs are essential for LTP induction whereas NR2B-containing NMDARs are crucial for the production of LTD in vitro, and the results of this study support these findings in the anaesthetized rat. Furthermore, using the kainic acid (KA) model of neurotoxicity, this research has explored the opposing roles that activity-dependent synaptic plasticity, through different NMDAR subtypes, can play in determining neuronal outcome in an excitotoxic environment. In these experiments, it is shown that (1) the induction of LTP using high-frequency stimulation (HFS) promotes the phosphorylation of Akt, which plays a critical role in controlling cell survival and apoptosis, (2) the induction of LTP using HFS attenuates kainic acid (KA) induced neurodegeneration while the induction of LTD using low-frequency stimulation (LFS) has no incremental effect on the degree of cell death resulting from exposure to KA, (3) the blockade of NR2B-containing NMDARs using Ro25-6981 attenuates KA-induced neurodegeneration while the blockade of NR2A-containing NMDARs using NVP-AAM077 does not influence KA-induced neurotoxicity, (4) pre-treatment with NR2A antagonists blocks both the induction of LTP and its neuroprotective effect against KA while NR2B antagonists neither block the induction of LTP nor the neuroprotection that this can provide against KA, (5) the administration of NR2A antagonists after the induction of LTP has no effect on the expression of LTP or its neuroprotective effect against KA, and (6) pre-treatment with a high dose (2.4mg/kg) of NVP-AAM077 leads to the induction of LTD rather than LTP as a result of HFS. Altogether this research supports the hypothesis that the production of LTP via the activation of NR2A-containing NMDARs protects neurons against excitotoxic neuronal death by promoting cell survival signalling. Furthermore, because NR2A antagonists applied after the production of LTP do not block neuroprotection, it can be concluded that LTP itself, and not NR2A activation, is responsible for this neuroprotective effect.
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Yan, Yi. "The role of Akt in AMPA receptor insertion and LTP." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/31741.
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It has been widely accepted that long-term potentiation (LTP) in the hippocampal CA1
region mostly results from increased insertion of post-synaptic α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptors (AMPARs). The previous
study in our lab has shown that activation of phosphatidylinositol 3-kinase (PI3K) by
selective stimulation of synaptic N-methyl-D-aspartate receptors (NMDARs) is required
for the increased cell surface expression of AMPARs and the consequent LTP. However,
the following signaling pathways still remain unknown. In the present study, the
involvement of Akt, the primary downstream protein kinase of PI3K, was examined with
a combination of electrophysiological, biochemical and molecular biological techniques.
The study found that Akt is required for the post-synaptic AMPAR insertion and LTP.
Furthermore, the threonine 840 (Thr840) on GluRl C-tail was identified as a novel Akt
phosphorylation site, suggesting a potential mechanism by which Akt contributes to
AMPAR incorporation and LTP.Medicine, Faculty of
Graduate
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Lu, You Ming. "Signaling cascades underlying two different forms of LTP in hippocampus." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0007/NQ41219.pdf.
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Barrag��n, Guti��rrez Jos�� Eduardo. "An��lisis de factibilidad de una empresa dedicada al dise��o de experiencias." Thesis, Universidad de las Am��ricas Puebla, 2012. http://catarina.udlap.mx/u_dl_a/tales/documentos/ltn/barragan_g_je/.
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del, Moral S��nchez Jos�� Luis, and Salinas Diego Armando Torres. "Desarrollo de Estrategias para Empresas Basadas en Sistemas de Simulac����n Din��mica." Thesis, Universidad de las Am��ricas Puebla, 2011. http://catarina.udlap.mx/u_dl_a/tales/documentos/ltn/del_m_jl/.
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De, La Rosa Morales Rafael Alfredo. "Evaluaci��n del impacto de los portales web de gobierno estatal en M��xico." Thesis, Universidad de las Am��ricas Puebla, 2012. http://catarina.udlap.mx/u_dl_a/tales/documentos/ltn/de_l_ra/.
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Jain, Saurabh. "LTCP-RC: RTT compensation technique to scale high-speed protocol in high RTT links." Texas A&M University, 2005. http://hdl.handle.net/1969.1/2528.
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In this thesis, we propose a new protocol named Layered TCP with RTT Compensation
(LTCP-RC, for short). LTCP-RC is a simple modification to the congestion
window response of the high-speed protocol, Layered TCP (LTCP). In networks characterized
by large link delays and high RTTs, LTCP-RC makes the LTCP protocol
more scalable. Ack-clocked schemes, similar to TCP, suffer performance problems
like long convergence time and throughput degradation, when RTT experienced by
the flow increases. Also, when flows with different RTTs compete, the problem of
unfairness among competing flows becomes worse in the case of high-speed protocols.
LTCP-RC uses an RTT Compensation technique in order to solve these problems.
This thesis presents a general framework to decide the function for RTT Compensation
factor and two particular design choices are analyzed in detail. The first
algorithm uses a fixed function based on the minimum RTT observed by the flow.
The second algorithm uses an adaptive scheme which regulates itself according to
the dynamic network conditions. Evaluation of the performance of these schemes is
done using analysis and ns-2 simulations. LTCP-RC exhibits significant performance
improvement in terms of reduced convergence time, low drop rates, increased utilization
in presence of links with channel errors and good fairness properties between
the flows,. The scheme is simple to understand, easy to implement on the TCP/IP
stack and does not require any additional support from the network resources. The choice of parameters can be influenced to tune the RTT unfairness of the scheme,
which is not possible in TCP or other high-speed protocols. The flexible nature of
the analysis framework has laid the ground work for the development of new schemes,
which can improve the performance of the window based protocols in high delay and
heterogeneous networks.
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Langlais, Valentin. "Contrôle de l'activité des récepteurs NMDA par la D-sérine : rôle des récepteurs astrocytaires EphB3 et CB1." Thesis, Bordeaux, 2016. http://www.theses.fr/2016BORD0211/document.
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Les astrocytes sont des partenaires clés des neurones. Dans l’hippocampe, et tout particulièrement au niveau des synapses CA3-CA1, en libérant la D-sérine, ces cellules gliales régulent l’activité des récepteurs glutamatergiques de type N-methyl-D-aspartate (NMDA) et de ce fait la mémoire synaptique, aussi connue sous le nom de plasticité synaptique à long terme. Cependant, le signal synaptique à l’origine de la libération de la D-sérine par les astrocytes reste à ce jour méconnu. De par des données rapportées dans la littérature nous nous sommes tout particulièrement intéressés aux récepteurs astrocytaires aux ephrins de type B3 (EphB3) et aux endocannabinoïdes de type 1 (CB1). Pour ce faire nous avons principalement utilisé une approche électrophysiologique sur des tranches aiguës d’hippocampe de souris adulte. Dans une première étude, nos données indiquent que l’activation des récepteurs EphB3 augmente la présence de D-sérine synaptique et en conséquence l’activité des récepteurs NMDA synaptiques. A l’inverse, leur inhibition diminue à la fois l’activité des récepteurs NMDA synaptiques et la potentialisation à long-terme qui en dépend (LTP ; une forme de plasticité synaptique à long terme). L’interaction EphB3-ephrinB3 contrôle donc la LTP en contrôlant la disponibilité en D-sérine synaptique. Dans une seconde étude, nous avons utilisé un modèle transgénique permettant d’inhiber l’expression des récepteurs CB1 astrocytaires (souris GFAP-CB1-KO). Nous avons découvert que la suppression de ces récepteurs diminue la disponibilité en D-sérine synaptique. De plus, nos travaux montrent que les récepteurs CB1 astrocytaires sont nécessaires à l’induction de la LTP via la D-serine. En conclusion, ces travaux de Thèse révèlent que les récepteurs astrocytaires EphB3 et CB1 régulent les fonctions dépendantes des récepteurs NMDA via le contrôle qu’ils exercent sur la disponibilité en D-sérineAstrocytes are key partners of neurons. In the hippocampus, and more particularly at CA3-CA1 synapses, by releasing D-serine, these glial cells regulate the activity of synaptic Nmethyl-D-aspartate (NMDA) receptors and thus synaptic memory, also known as long-term synaptic plasticity. Yet, the synaptic signal inducing D-serine release by astrocytes is still unknown. Based on interesting data from the literature we have investigated the role of the astrocytic receptors for ephrinB3 (EphB3) and endocannabinoids (CB1). To this end we used electrophysiological approaches on acute hippocampal slices of adult mice. In a first study, our data indicate on one hand that the activation of EphB3 receptors increases synaptic D-serine availability and in consequences the activity of synaptic NMDA receptor activity. On the other hand, inhibition of EphB3 receptors induces a decrease of synaptic NMDA receptor activity as well as the induction of the long-term potentiation (LTP; a form of long-term plasticity). Thus, EphB3-ephrinB3 interaction controls LTP induction through the availability of synaptic D-serine. In a second study, we used a transgenic model allowing the inhibition of CB1 receptors expression in astrocytes (GFAP-CB1-KO mice). We discovered that their deletion reduced synaptic D-serine availability. Our work shows that astrocytic CB1 receptors are necessary for LTP induction via this D-serine. All together, this PhD work reveals that astrocytic EphB3 and CB1 receptors regulate synaptic NMDA receptor functions through the control of D-serine availability
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Esteves, Ingrid de Miranda. "Caracterização das alterações na via hipocampo-córtex pré-frontal medial em modelo farmacológico da doença de Alzheimer." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/17/17140/tde-26082016-110343/.
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Severas altera¸c~oes no metabolismo energ´etico, no consumo de glicose e na sinaliza¸c~ao de insulina cerebral est~ao presentes na doen¸ca de Alzheimer (DA). O modelo animal da DA obtido pela administra¸c~ao intracerebroventricular de estreptozotocina (STZ-icv) em ratos induz um estado de resist^encia `a insulina no c´erebro associado `a disfun¸c~oes colin´ergicas e a d´eficits cognitivos, tornando-o um dos poucos modelos experimentais da forma espor´adica da DA. Este trabalho tem como objetivo caracterizar, neste modelo, as disfun¸c~oes sin´apticas na via hipocampo - c´ortex pr´e-frontal medial (CA1-CPFm) e testar se o tratamento com nicotina ´e capaz de prevenir as disfun¸c~oes sin´apticas e reverter os preju´?zos cognitivos induzido pelo STZ-icv. Para isso, ratos Wistar receberam STZ e foram submetidos a 20 dias de tratamento com nicotina. Dois dias depois, foram realizados nos animais teste de campo aberto e de reconhecimento de objeto. Em seguida os animais foram anestesiados com uretana para que os registros eletrofisiol´ogicos fossem realizados. Um eletrodo foi utilizado para estimular CA1 com pulso pareado e potenciais de campo p´os-sin´apticos (fPSP1) e sua facilita¸c~ao (fPSP2) foram registradas por um eletrodo no CPFm. Ap´os 30 minutos de linha de base, uma estimula¸c~ao em alta frequ^encia foi aplicada para induzir a potencia¸c~ao de longa dura¸c~ao (LTP), seguido de mais quatro horas de registro. Outro grupo experimental foi realizado para avaliar o efeito de longo prazo da STZ-icv e do tratamento com nicotina. Neste grupo, testes comportamentais e eletrofisiol´ogicos foram realizados 60 dias ap´os o fim do tratamento. Independentemente do tempo, os resultados indicam que a STZ produziu uma redu¸c~ao na indu¸c~ao e na manuten¸c~ao da LTP, mas a facilita¸c~ao por pulso pareado (PPF = fPSP2 / fPSP1) mostra que a STZ prejudica a plasticidade pr´e-sin´aptica apenas a curto prazo. O tratamento com nicotina atenua a disfun¸c~ao na LTP induzida pela STZ. Al´em disso, apenas o tratamento de nicotina tamb´em ´e capaz de reduzir a plasticidade pr´e-sin´aptica no grupo controle dois dias ap´os o fim do tratamento. Estes resultados tamb´em est~ao associados com os dados comportamentais, uma vez que a nicotina reverteu os d´eficits de mem´oria de reconhecimento nos animais STZ mas manteve o comportamento explorat´orio reduzido. Sugerimos com isso que o sistema colin´ergico, que desempenha um papel importante em fun¸c~oes cognitivas e na LTP, est´a afetado nos animais injetados com STZ e o tratamento cr^onico com nicotina consegue reduzir os danos na plasticidade sin´aptica e comportamentais, induzidos pela STZ.Severe abnormalities in brain glucose/energy metabolism and insulin signaling have been documented to play an important role in early stage of alzheimer disease (AD) pathology. Intracerebroventricular administration (icv) of streptozotocin (STZ) in rats can induce an insulin-resistant brain state associated with cholinergic dysfunctions and memory impairments, which make it a suitable experimental model of the sporadic form of AD. The present work aimed to extend the characterization of this model by probing synaptic plasticity dysfunctions in the medial prefrontal cortex (mPFC)- hippocampal (CA1) pathway and test if nicotine can prevent synaptic dysfunction and revert cognitive impairment induced by icv STZ. Here, Wistar rats received bilateral microinjection of STZ and were submitted to 20 days of nicotine treatment. After 2 days of withdrawing the subjects were submitted to open field and object recognition tests. After that, animals were anesthetized with urethane for electrophysiological tests. A twisted bipolar electrode was used to stimulate posterior-dorsal hippocampus (CA1/subiculum) with paired-pulse. Basal field post-synaptic potentials (fPSP1) and facilitated responses (fPSP2) were recorded by a monopolar electrode in the medial mPFC. After 30min of baseline, high frequency stimulation was applied to induce long-term potentiation (LTP) and additional four hours of electrophysiological recordings was performed. Another experimental group was performed to evaluate the long term effect of both icv STZ and nicotine treatment. In this group behavioral and electrophysiological tests were performed with 60 days after chronic treatment. Independently of time, our results indicate that STZ produced a significant decrease in the induction and maintenance of LTP, but paired pulse facilitation (PPF = fPSP2/fPSP1) shows that only the short-term pre-synaptic plasticity was impaired after STZ injection. The nicotine treatment attenuates the STZ-induced LTP dysfunction in the CA1-mPFC pathway. However, just the nicotine treatment (in control group) can reduce pre-synaptic plasticity two days after chronic treatment. These results are also associated with behavioral data, since nicotine treatment reversed the deficits in recognition memory of STZ animals but maintained the reduced exploratory behavior. We suggest that the brain cholinergic system, which plays a role in cognition function and LTP, is affected in STZ injected animals and chronic treatment with nicotine can attenuate the STZ-induced synaptic plasticity and behavioral dysfunctions.
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Cho, Taesup. "Neural stem cell transplantation : neuroprotection and LTP-induced facilitation of neurogenesis." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/36960.
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Transplantation of neural progenitor cells (NPC) constitutes a putative therapeutic maneuver for use in treatment of neurodegenerative diseases. At present, effects of NPC transplantation in the Alzheimer’s disease (AD) brain are largely unknown and a primary objective of this work is to demonstrate possible efficacy of NPC administration in an AD animal model. The benefits of transplantation could involve a spectrum of effects including replacement of endogenous neurons, conferring neuroprotection with enhancement of neurotrophic factors, and diminishing levels of neurotoxic agents. Additionally, since chronic inflammation is a characteristic property of the AD brain, I considered NPC transplantation could have a particular utility in inhibiting ongoing inflammatory reactivity. Accordingly, intra-hippocampal transplantation of NPC has been examined for efficacy in attenuating inflammatory responses and conferring neuroprotection in the hippocampus. These findings indicate efficacy for NPC transplantation with effects consistent with cellular actions to attenuate inflammatory reactivity. Synaptic plasticity, such as long-term potentiation (LTP), is thought to play a critical role in modification of neuronal circuitry in learning and memory, but the role in neurogenesis is not well known. A critical aspect of my study was to examine potential roles of N-methyl-D-aspartate receptor (NMDAR)-dependent LTP in promoting neurogenesis by facilitating proliferation/survival and neuronal differentiation of endogenous NPCs in the dentate gyrus (DG) and exogenously transplanted neural stem cells (NSCs) in the CA1. I found that LTP induction significantly facilitates proliferation/survival and neuronal differentiation of endogenous NPCs and exogenously transplanted NSCs in the hippocampus. These effects were eliminated by a NMDAR competitive antagonist, CPP. Accordingly, chemical LTP stimulation reproduced enhanced proliferation/survival and neuronal differentiation of NSCs when co-cultured with hippocampal neurons. These effects were eliminated by a NMDAR competitive antagonist, D-APV and inhibited by the tyrosine kinase inhibitor, K252a. ELISA and biotinylation results revealed that NMDAR-mediated LTP facilitates the release of a neurotrophic factor, BDNF. The conditioned media from cLTP-induced hippocampal neurons were sufficient to activate the BDNF receptor, TrkB. Overall, my results suggest that NMDAR-dependent LTP plays a critical role in neurogenesis and may contribute to the utility of NSC transplantation as an effective cell therapy for a variety of neurodegenerative diseases.
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Romberg, Carola. "Hippocampal LTP and spatial learning in glutamate receptor subunit-deficient mice." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.442569.
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Hashimoto, Kenji. "Occurrence of dentate granule cell LTP without proximal dendritic Ca2+ increase." Kyoto University, 2004. http://hdl.handle.net/2433/147498.
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De, Pasquale Roberto. "Visual discrimination learning and LTP-like changes in primary visual cortex." Doctoral thesis, Scuola Normale Superiore, 2009. http://hdl.handle.net/11384/85939.
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Svensson, Markus. "Modeling Pavement Performance based on Data from the Swedish LTPP Database : Predicting Cracking and Rutting." Licentiate thesis, KTH, Väg- och banteknik, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-119863.
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The roads in our society are in a state of constant degradation. The reasons for this are many, and therefore constructed to have a certain lifetime before being reconstructed. To minimize the cost of maintaining the important transport road network high quality prediction models are needed. This report presents new models for flexible pavement structures for initiation and propagation of fatigue cracks in the bound layers and rutting for the whole structure. The models are based on observations from the Swedish Long Term Pavement Performance (LTPP) database. The intention is to use them for planning maintenance as part of a pavement management system (PMS). A statistical approach is used for the modeling, where both cracking and rutting are related to traffic data, climate conditions, and the subgrade characteristics as well as the pavement structure.QC 20130325
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Filosa, Alessandro. "Neuron-glia communication via EphA4-ephrinA3 modulates LTP through glial glutamate transport." Diss., lmu, 2010. http://nbn-resolving.de/urn:nbn:de:bvb:19-116043.
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Liotta, Agustin [Verfasser]. "Impact of disinhibition and neuromodulation in hippocampal oscillations and LTP / Agustin Liotta." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2012. http://d-nb.info/1026991412/34.
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Richards, David Andrew. "On the role of arachidoic acid in long term potentation." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286684.
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Phillips, Keith Geoffrey. "Role of nitric oxide and somatic action potentials in a GluR1 independent LTP." Thesis, Cardiff University, 2010. http://orca.cf.ac.uk/55048/.
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Studies in GluRl knockout mice have shown that neocortical LTP consist of both pre- and post-synaptic components that rely on nitric oxide and GluRl respectively (Hardingham and Fox, 2006). Given that GluRl knockout also show hippocampal LTP (Hoffmann et al., 2002) I hypothesised that the residual LTP might depend on nitric oxide. I have found that hippocampal LTP can be induced in GluRl knockout with purely orthodromic stimuli in mature mice (>8weeks) and that a theta-burst protocol was effective at inducing LTP while 100Hz stimulation was not. I found that only theta-burst stimulation produced reliable post-synaptic spikes, while 100Hz stimulation produced relatively few spikes. Inhibition of post-synaptic somatic spikes with local TTX application prevented LTP in the GluRl knockout mice. Theta-burst induced LTP in GluRl knockout was almost entirely nitric oxide dependent and involved both nitric oxide synthase 1 and nitric oxide synthase 3 isoforms. Finally, I also found that somatic spike production was also necessary for a nitric oxide dependent form of LTP in wild-type mice, which made up approximately 50% of the potentiation at 2 hours post-tetanus. I conclude that nitric oxide dependent LTP can be produced by physiologically relevant theta-burst stimuli because this protocol evokes reliable action potentials. Since this form of activity occurs during learning it could be relevant to memory formation in GluRl knockout and wild-type mice.
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Lefort, Julie. "Role of cerebellar LTP at parallel fiber : Purkinje cell synapses in spatial navigation." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066151/document.
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La navigation spatiale peut être subdivisée en deux processus: la construction d’une représentation mentale de l’espace à partir de l’exploration de l’environnement d'une part, et l’utilisation de cette représentation de façon à produire le trajet le plus adapté pour rejoindre le lieu souhaité d'autre part. Lors de l’exploration de l’environnement, des informations externes et des informations de mouvement propre (i.e. vestibulaires et proprioceptives) sont combinées pour former la carte cognitive. Depuis longtemps des études suggèrent que le cervelet participe à la navigation spatiale mais son rôle a souvent été confiné à l’exécution motrice. Notre équipe a étudié des souris mutantes L7-PKCI présentant un déficit de plasticité synaptique de type dépression à long terme (DLT) au niveau des synapses entre fibres parallèles et cellules de Purkinje du cortex cérébelleux. Ces travaux ont montré que les souris présentent à la fois un déficit dans l'optimisation de la trajectoire mais également dans le maintien de la carte cognitive formée dans l'hippocampe. En effet, les propriétés de décharge des cellules de lieu de l'hippocampe sont affectées chez ces souris exclusivement lorsque celles-ci doivent naviguer en se reposant sur les informations provenant de leur mouvement propre, c'est à dire quand elles explorent l'environnement dans le noir. A ces mêmes synapses, une plasticité de type potentialisation à long terme (PLT) a été observée et permet (avec la DLT) la modulation bidirectionelle de l’efficacité synaptique. La plasticité bidirectionnelle est un processus clé dans les modèles théoriques de type « filtre adaptatif » de traitement de l’information par le cervelet. Selon ces modèles, l’absence de PLT ou DLT devrait affecter de façon similaire la plasticité bidirectionnelle et conduire ainsi à des déficits comparables. Pour tester cette hypothèse, nous avons étudié les conséquences fonctionnelles d’un déficit de type PLT au niveau de la même synapse entre fibre parallèle et cellule de Purkinje. Nous avons utilisé la lignée transgénique L7-PP2B, spécifiquement déficitaire pour cette plasticité.Malgré un léger déficit moteur révélé exclusivement sur le rotarod, les capacités de navigation des souris L7-PP2B ne sont pas affectées dans une tâche de navigation en labyrinthe aquatique de type piscine de Morris. Les propriétés des cellules de lieu de l’hippocampe des souris L7-PP2B ont ensuite été caractérisées lors de l’exploration d’une arène circulaire dans différentes conditions environnementales. Contrairement à celles des souris L7-PKCI, les propriétés des cellules de lieux des souris L7-PP2B ne sont pas affectées lorsque les souris ne peuvent utiliser que les informations de mouvement propre pour s’orienter, c'est à dire dans le noir. Par contre, les cellules de lieux des souris L7-PP2B présentent une instabilité en l’absence de toute manipulation d’indice environnemental, dans 23% des sessions d’enregistrement. Cette instabilité, absente chez les souris contrôles, se manifeste de façon imprévisible dans un environnement familier et est caractérisée par une rotation angulaire cohérente de l’ensemble des cellules de lieux enregistrées. Ces données suggèrent qu’en l’absence de PLT cérébelleuse la représentation spatiale de l’hippocampe n’est pas ancrée de façon stable aux indices externes proximaux. Ces résultats, associés à ceux des souris L7-PKCI indiquent que le cervelet contribue de manière complexe à la fois à la représentation spatiale hippocampique et aux capacités de navigation et que DLT et PLT jouent probablement des rôles différents dans ces processusSpatial navigation can be divided into two processes: building a spatial representation from the environment exploration and using this representation to produce an adapted trajectory toward a goal. During the environment exploration, external and self-motion information (i.e. vestibular and proprioceptive) are combined to form the spatial map. It has long been suggested that the cerebellum participates in spatial navigation but its role has often been confined to motor execution. Our team has studied L7-PKCI mice which lack a plasticity mechanism (long term depression (LTD)) at parallel fiber-Purkinje cell synapses in the cerebellar cortex. These works have shown that L7-PKCI mice present a deficit in trajectory optimization as well as in the maintenance of the cognitive map in the hippocampus. Indeed in these mice, the firing properties of hippocampal place cells are affected specifically when mice have to rely on self-motion information, i.e. when exploring the environment in the dark.A these same synapses, another type of plasticity (long term potentiation (LTP)) has been described, and allows (with LTD) the bidirectional modulation of the synaptic efficiency. Bidirectional plasticity is a key element of the ‘adaptive filter’ theoretical models of cerebellar information processing. According to these models, a lack of LTP or LTD should similarly affect bidirectional plasticity and result in comparable deficits. To test this prediction, we investigated the functional consequences of a deficit of LTP at parallel fiber-Purkinje cell synapses using the L7-PP2B mice model, specifically impaired for this plasticity.In spite of a mild motor adaptation deficit, revealed on the rotarod task, spatial learning of L7-PP2B mice was not impaired in the watermaze task. Hippocampal place cell properties of L7-PP2B mice were characterized during exploration of a circular arena, following different experimental manipulations. In contrast to mice lacking cerebellar LTD, place cells properties of L7-PP2B mice were not impaired when mice had to rely on self-motion cues, i.e. in the dark. Surprisingly, L7-PP2B place cells displayed instability in the absence of any proximal cue manipulation in 23 % of the recording sessions. This instability occurred in an unpredictable way in a familiar environment and was characterized each time by a coherent angular rotation of the whole set of recorded place cells. These data suggest that, in the absence of cerebellar LTP, hippocampal spatial representation cannot be reliably anchored to the proximal cue. These results along with those from L7PKCI mice, indicate that the cerebellum contributes to both hippocampal representation and subsequent navigation abilities and that LTP and LTD are likely to play different roles in these processes
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Aya, Rino. "Regeneration of elastic fibers by three-dimensional culture on a collagen scaffold and the addition of latent TGF-β binding protein 4 to improve elastic matrix deposition." Kyoto University, 2016. http://hdl.handle.net/2433/215396.
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Park, Pojeong. "Calcium-permeable AMPA receptors are required for PKA-dependent LTP at hippocampal CA1 synapses." Thesis, University of Bristol, 2017. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.720854.
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Luckett, Suzanne. "Purification and characterisation of SFTI-1 and LTP from sunflower seeds (Helianthus annuus l.)." Thesis, University of Bristol, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322251.
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Ditto, Andrew J. "DNA-LPEI complexes encapsulated in LTP nanospheres as a non-viral gene therapy vector." University of Akron / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=akron1165596983.
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Ditto, Andrew. "DNA-LPEI complexes encapsulated in LTP nanospheres as a non-viral gene therapy vector." Akron, OH : University of Akron, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=akron1165596983.
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Thesis (M.S.)--University of Akron, Dept. of Biomedical Engineering, 2006."December, 2006." Title from electronic thesis title page (viewed 12/31/2008) Advisor, Yang Yun; Committee members, Stephanie Lopina, Steven Schmidt; Department Chair, Daniel Sheffer; Dean of the College, George K. Haritos; Dean of the Graduate School, George R. Newkome. Includes bibliographical references.
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Alessi, Nicola. "Modifiche al protocollo di trasporto LTP per migliorarne le prestazioni in presenza di perdite elevate." Bachelor's thesis, Alma Mater Studiorum - Università di Bologna, 2016. http://amslaurea.unibo.it/10314/.
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La presente tesi si pone come obiettivo quello di analizzare il protocollo LTP (in particolare in ION) e proporre dei miglioramenti utili al caso in cui siano presenti perdite elevate. Piu in dettaglio, una prima parte introduttiva motiva l'inefficacia del TCP/IP in ambito interplanetario e introduce l'architettura DTN Bundle Protocol (Cap.1). La tesi prosegue con la descrizione delle specifiche del protocollo LTP (Cap.2), in particolar modo evidenziando come un bundle venga incapsulato in un blocco LTP, come questo sia successivamente diviso in tanti segmenti LTP e come questi vengano successivamente inviati con il protocollo UDP o con un protocollo analogo. Viene quindi presentata un'approfondita analisi delle penalizzazioni dovute alle perdite dei segmenti LTP, sia di tipo dati che di segnalazione (Cap. 3). Quest'analisi permette di dimostrare la criticita degli effetti delle perdite, in particolare per quello che riguarda i segmenti LTP di segnalazione. Mentre in presenza di perdite basse tali effetti hanno in media un impatto minimo sul tempo di consegna di un blocco LTP (quindi del bundle in esso contenuto), in quanto avvengono raramente, in presenza di perdite elevate rappresentano un collo di bottiglia per il tempo di consegna di un blocco LTP. A tal proposito sono state proposte alcune modifiche che permettono di migliorare le prestazioni di LTP (Cap. 4) compatibilmente con le specifiche RFC in modo da garantire l'interoperabilita con le diverse implementazioni del protocollo. Successivamente nel Cap. 5 viene mostrato come sono state implementate le modifiche proposte in ION 3.4.1. Nel capitolo finale (Cap. 6) sono presenti i risultati numerici relativi ad alcuni test preliminari eseguiti confrontando la versione originale del protocollo con le versioni modificate contenenti i miglioramenti proposti. I test sono risultati molto positivi per elevate perdite, confermando cosi la validita dell'analisi e dei miglioramenti introdotti.
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Barmashenko, Gleb. "Läsionsinduzierte Änderungen der intrazellulären Kalziumkonzentration und der LTP von Neuronen im visuellen Kortex der Ratte." [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=963996037.
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Siemer, Helge. "Über die Beteiligung des Transkriptionsfaktors CREB im Modell der Langzeitpotenzierung (LTP) im Hippocampus der Ratte." [S.l.] : [s.n.], 2001. http://www.diss.fu-berlin.de/2002/303/index.html.
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Kucharczyk, Lilianna Stanislawa Verfasser], and Robert [Akademischer Betreuer] [Bähring. "LTP in conventional and conditional Arc/Arg3.1 KO mice / Lilianna Stanislawa Kucharczyk ; Betreuer: Robert Bähring." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2020. http://d-nb.info/1215292473/34.
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Kucharczyk, Lilianna Stanislawa [Verfasser], and Robert [Akademischer Betreuer] Bähring. "LTP in conventional and conditional Arc/Arg3.1 KO mice / Lilianna Stanislawa Kucharczyk ; Betreuer: Robert Bähring." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2020. http://d-nb.info/1215292473/34.
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Ionescu, Marius Anton. "L' activation éosinophilique dans les lymphomes T cutanés primitifs." Paris 7, 2003. http://www.theses.fr/2003PA077056.
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Kemp, Nicola. "Mechanisms underlying the induction of long-term depression in the CA1 region of the hippocampus." Thesis, University of Bristol, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300704.
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Dinger, Katharina [Verfasser]. "Structural and functional analysis of LTBP 4 as a factor of pathogenesis in the development of pulmonary emphysema / Katharina Dinger." Berlin : Freie Universität Berlin, 2017. http://d-nb.info/1129685616/34.
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Sá, Júnior Euridson de. "Mercado secundário de títulos públicos: microestrutura, liquidez e spread de compra e venda para o mercado de LTNs no Brasil." reponame:Repositório Institucional do FGV, 2007. http://hdl.handle.net/10438/1773.
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Previous issue date: 2007-08-30T00:00:00ZThis work comprises two parts. First part, it discusses and compares liquidity and market microstructure aspects from government securities in some countries as Brazil, Chile, Mexico, Korea, Poland and United States. The analyses uses some microstructure dimensions like the liquidity from secondary market (bid and ask spread, turnover to average outstanding stock and most important maturity), the efficiency costs, infrastructure and transparency from primary and secondary market and the market security. The goal is to describe the microstructure of secondary markets from theses countries and to compare with the microstructure of Brazilian secondary markets. Despite of low tenor from government securities the Brazilian secondary market presents microstructure like those countries that suggested other reasons avoiding enlarge tenors from prefixed securities. The second part of this work examines the liquidity of the local secondary market for the Brazilian government securities between 2003 to 2006 and the determinants of realized bid-ask spreads for secondary market of the LTNs – Letras do Tesouro Nacional between 2005 to 2006. The spreads were calculated from daily basis with high frequency database for 30 minutes period and one-day period. Overall, the liquidity is an important determinant of the realized bid-ask spread for the LTN market. Specifically, the bid-ask spread decreases when the volume increases. The bid-ask spread increases in the remaining-time-to-maturity of LTN. LTNs up to 30 days tenor presented average bid-ask spreads around 1 cents of reais (1.89 bp) and LTNs with two years tenor presented average bid-ask spreads around 54 cents of reais (3.84 bp) for 30 minutes period and 81 cents of reais (5.72 bp) for one day period. The econometric tests were performed based on a model presented by Chakravarty e Sarkar (1999) applied to USA bonds markets for the years 1995 to 1997. The tests were estimated by Generalized Method of Moments (GMM) technique. Our estimation and evaluation of liquidity measures for the Brazilian government securities market reveal that the simple bid-ask spread is a useful measure for assessing and tracking liquidity.
Este trabalho está dividido em dois ensaios. O primeiro ensaio examina aspectos da liquidez do mercado secundário de títulos públicos no Brasil no período 2003 a 2006 e os determinantes do spread de compra e venda no mercado secundário de LTN - Letra do Tesouro Nacional no período 2005 a 2006. Os spreads foram calculados com base em dados diários de alta freqüência, para períodos de 30 minutos e de um dia. Em linhas gerais, a liquidez é um determinante importante no cálculo do spread. Especificamente os spreads diminuem quando os volumes ofertados aumentam. No caso dos prazos de vencimento, os spreads aumentam quando os prazos se ampliam. LTNs com prazos de vencimentos até 30 dias apresentaram spreads de 1 centavo de reais (1.89 bp) enquanto que LTNs com prazos acima de dois anos apresentaram spreads médios em torno de 54 centavos de reais (3.84 bp) para intervalos de 30 minutos e 81 centavos de reais (5.72 bp) para intervalos de um dia. Os testes econométricos foram realizados com base em um modelo apresentado por Chakravarty e Sarkar (1999) e aplicado ao mercado americano de bonds no período de 1995 e 1997. Os testes foram feitos utilizando-se a técnica do Método dos Momentos Generalizados (GMM). Os resultados confirmam o spread de compra e venda como medida importante no acompanhamento da liquidez. O segundo ensaio compara aspectos da liquidez e da microestrutura do mercado de títulos públicos em alguns paises como Brasil, Chile, México, Coréia, Singapura, Polônia e Estados Unidos. A análise utiliza algumas dimensões da microestrutura como a liquidez do mercado secundário (spread de compra e venda, giro do estoque de títulos e vencimentos mais negociados), os custos de eficiência, a estrutura e transparência do mercado primário e secundário e, por último, a segurança do mercado. O objetivo é comparar as características e o funcionamento dos mercados secundários desses paises e, confrontar com a realidade do mercado brasileiro face ao desenvolvimento da microestrutura. Apesar da falta de alongamento dos prazos dos títulos públicos, o mercado secundário no Brasil apresenta aspectos da microestrutura semelhantes aos paises em consideração o que sugere a existência de outros fatores fora a microestrutura que limitam o aumento dos prazos. Os resultados do primeiro ensaio ajudam nas comparações dos demais paises. Como resultado, encontramos que embora a liquidez do mercado secundário de títulos públicos no Brasil concentra-se em papéis de prazo menor, este fato provavelmente não se deve a questões de microestrutura do mercado.
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Ximing, LI. "Insights into Delivery of Somatic Calcium Signals to the Nucleus During LTP Revealed by Computational Modeling." Ohio University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou152236301476345.
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Moreno, Pérez Nuria. "Fenotipos de alergia alimentaria por sensibilización a proteínas transferidoras de lípidos (LTP) en adultos del área mediterránea." Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/665226.
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Introducción: Las proteínas transferidoras de lípidos (LTP) son la causa más frecuente de alergia alimentaria y anafilaxia inducida por alimentos en adultos en el área mediterránea. Existe una gran variabilidad en el perfil de reconocimiento molecular frente a estas proteínas y distintos grados de gravedad en su expresión clínica. El objetivo principal de este estudio fue identificar si en la alergia alimentaria por sensibilización a LTP se pueden identificar patrones comunes o clústers en función de parámetros clínicos y del perfil de reconocimiento molecular a alérgenos alimentarios y polínicos.
Métodos: Se incluyeron pacientes adultos con sensibilización a LTP de melocotón a los que se le realizó una anamnesis dirigida con recogida de variables demográficas y de las características de la reacción inicial y de las reacciones presentadas tras la ingesta de alimentos vegetales, así como la determinación del perfil de sensibilización molecular. A un subgrupo de pacientes se les realizó prueba de exposición controlada con placebo y/o prueba de frotamiento con un protocolo de interpretación de los resultados estandarizados. La receta de enmascaramiento utilizada fue diseñada a base de zumo comercial de melocotón y validada por medio del test del triángulo en voluntarios sanos. Se realizaron análisis estadísticos de agrupaciones que permitieran identificar características comunes de los diferentes fenotipos.
Resultados: Se incluyeron 306 pacientes de los que un 84% fueron diagnosticados de Síndrome LTP (SLTP). Globalmente la forma de presentación más frecuente fue el síndrome de alergia oral y en un tercio de los casos la reacción se produjo en presencia de cofactores. Los alimentos principalmente implicados en este SLTP fueron: el melocotón, que produjo sobre todo urticaria de contacto, la nuez, que indujo síntomas de anafilaxia y la lechuga, más frecuentemente relacionada con reacciones exacerbadas por cofactor. La gravedad de las reacciones y la edad de presentación de los síntomas se relacionaron de manera significativa con el alimento implicado en la primera reacción alérgica, predominando las reacciones locales en la infancia cuando el alimento implicado era el melocotón y las reacciones sistémicas en la edad adulta con cualquier otro alimento vegetal. El análisis de las variables clínicas y de los alimentos permitió diferenciar 2 “clústers”. El “clúster” 1 se caracterizaba por presentar reacciones más graves al “debut” y en el momento del diagnóstico con un mayor número de alimentos vegetales, principalmente nuez, pipa de girasol, castaña, cacahuete, guisante y altramuz. En este grupo el alimento responsable de la primera reacción no solía ser melocotón, mientras que en el “clúster” 2 los pacientes acostumbraban a presentar reacciones leves con un menor número de alimentos vegetales y debutaban con alergia a melocotón. Además en el presente estudio, fue validada una receta a base de zumo comercial de melocotón cuantificado en Pru p 3, en un grupo de 32 voluntarios sanos y posteriormente utilizada en una prueba de exposición oral enmascarada con placebo en un subgrupo de 25 pacientes del estudio.
Conclusiones: En alergia a LTP de pacientes adultos de nuestra área de influencia se diferencian dos “clústers” de pacientes con características diferenciales, uno de presentación leve y debut con melocotón y otro grave, con inicio como clínica sistémica con múltiples alimentos vegetales. Además, se ha validado la primera receta con zumo de melocotón comercial, cuantificado en Pru p 3 para pruebas de exposición oral con melocotón controladas con placebo y se ha demostrado la utilidad de un protocolo estandarizado para interpretar los resultados de dicha prueba y el test de frotamiento.Background: Lipid transfer proteins (LTP) are the main cause of food allergy and food-induced anaphylaxis in adults in the Mediterranean area. There is a high variability of the molecular recognition profile against LTP and different degrees of severity in their clinical expression. The aim of this study was to identify whether in food allergy induced by LTP sensitization common patterns or cluster can be identified according to clinical parameters and molecular recognition profile to food and pollen allergens. Methods: Sensitized adults to peach LTP were included and underwent to a guided medical anamnesis collecting demographics variables and characteristics of the first allergic reaction to any plant-food and allergic reactions suffered upon plant-food ingestion, as well as the molecular recognition profile. A subgroup of patients underwent to double-blind placebo controlled peach challenge and/or peach rubbing test by means of standardized protocol and interpretation of the results. The masking recipe was designed and made with peach commercial juice and validated by means of a triangle sensory test in healthy volunteers. Cluster statistical analyses were carried out to identify common characteristics of the different phenotypes. Results: 306 patients were included, of which 84% were diagnosed with lipid transfer protein Syndrome (LTPS). Overall the most common clinic expression was oral allergy syndrome (OAS) and in one third of the patients the reaction occurred in presence of cofactors. The most implicated plant-food in this LTPS were: peach, that primarily caused contact urticaria, walnut that induced anaphylaxis and lettuce, mostly related to reactions induced by cofactors. The severity of the reactions and the age of clinical appearance were significantly related to the culprit plant-food that caused the first allergic reaction, mainly local reactions in the childhood when peach was the culprit food, and systemic reactions in the adulthood when any other plant-food were involved. The clinical and food variables analysis allowed to differentiate 2 clusters. Cluster 1 was characterized by more severe allergic reactions at onset and at diagnosis with a greater number of plant-food, mainly walnut, sunflower, chestnut, peanut, pea and lupine. In this group the plant-food involved in the first allergic reaction used not to be peach, while in cluster 2 patients used to suffer milder reactions with a lower number of plant-foods and their onset were with peach. Furthermore, in the present study, a recipe made with peach commercial juice and quantified in Pru p 3 was validated in a subgroup of 32 volunteers and subsequently used in an placebo controlled oral food challenge in a subgroup of 25 patients of the study. Conclusions: 2 clusters of patients can be differentiated in LTP allergy in adults in our area of influence with distinguishing features, one “mild” with peach at the onset, and other “severe”, starting with systemic reactions with plant-foods different from peach. Besides, the first commercial peach juice recipe quantified in Pru p 3, has been validated to perform placebo controlled oral food challenges, and the utility of a standardized protocol to interpret the results of oral challenges and rubbing test has been demonstrated.
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Brown, Christopher Martin. "Intracellular mechanisms of stress-induced LTP impairment : a signalling pathway triggered by corticosterone in the rat hippocampus." Thesis, University of Bristol, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.715798.
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Whitcomb, Daniel. "Alpha-beta1-42 of LTP is mediated by a signaling pathway involving caspase-3, Akt1 GSK-3beta." Thesis, University of Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.550333.
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Amyloid-f31--42 (Af3) is considered a major mediator of the cognitive impairments that are seen in Alzheimer's disease, the leading form of dementia and a growing world-wide health problem. In vitro, Af3 treatment of hippocampal brain slices impairs long-term potentiation and enhances long- term depression, forms of synaptic plasticity, and as such serve to provide cellular correlates of this action. However, the mechanisms underlying these effects are not fully understood. In this thesis the mechanisms underlying the Aj3-mediated dysregulation of synaptic plasticity are therefore explored. Exogenously applied Aj3 was first confirmed to inhibit an NMOAR-dependent form of L TP in the hippocampus (in both acute hippocampal slices and cultured hippocampal slices) and the characteristics of the inhibition of L TP by Aj3 were examined. Next, the inhibition of L TP was found to be reliant on the activation and function of caspases, which themselves have recently been implicated in a newly characterised mechanism of L TO. Finally, evidence is provided showing that this mechanism forms part of a signalling cascade that likely reflects the cleavage and inactivation of Akt-1 by caspases, liberating GSK-3j3 from inhibition - a key L TO-signalling mechanism. These results are best explained by a mechanism whereby the exogenous application of Aj3 causes the induction of L TO signalling. The consequence of which is to inhibit LTP.
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Müller, Volker. "Entwicklung einer kompetetiven PCR zur Quantifizierung der mRNA von TGF-beta-1 und LTBP-1 in Fettspeicherzellen der Leber von Rattus norvegicus." [S.l.] : [s.n.], 2001. http://archiv.ub.uni-marburg.de/diss/z2001/0306/.
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Niggemeyer, Marie Nicola. "Einfluss experimentell modifizierter LTBP-4-Genexpression auf das Expressionsprofil von TGF-[beta]1 [TGF-Beta1], p21 und c-myc in HEK293T Zellen." Berlin mbv, 2007. http://d-nb.info/987696262/04.
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Niggemeyer, Marie Nicola [Verfasser]. "Einfluss experimentell modifizierter LTBP-4-Genexpression auf das Expressionsprofil von TGF-β1, p21 und c-myc in HEK293T Zellen / Marie Nicola Niggemeyer." Berlin : Freie Universität Berlin, 2008. http://d-nb.info/1022697587/34.
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Klusacsek, Katrin [Verfasser]. "Analyse der differentiellen Genexpression der Tumorsuppressorgene TGF-beta1-3 und deren Bindungsproteine LTBP-1, -3 und -4 in caninen Mammatumoren / Katrin Klusacsek." Berlin : Freie Universität Berlin, 2008. http://d-nb.info/1022642650/34.
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Bareiss, Max. "Effectiveness of Intersection Advanced Driver Assistance Systems in Preventing Crashes and Injuries in Left Turn Across Path / Opposite Direction Crashes in the United States." Thesis, Virginia Tech, 2019. http://hdl.handle.net/10919/96570.
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Intersection crashes represent one-fifth of all police reported traffic crashes and one-sixth of all fatal crashes in the United States each year. Active safety systems have the potential to reduce crashes and injuries across all crash modes by partially or fully controlling the vehicle in the event that a crash is imminent. The objective of this thesis was to evaluate crash and injury reduction in a future United States fleet equipped with intersection advanced driver assistance systems (I-ADAS). In order to evaluate this, injury risk modeling was performed. The dataset used to evaluate injury risk was the National Automotive Sampling System / Crashworthiness Data System (NASS/CDS). An injured occupant was defined as vehicle occupant who experienced an injury of maximum Abbreviated Injury Scale (AIS) of 2 or greater, or who were fatally injured. This was referred to as MAIS2+F injury. Cases were selected in which front-row occupants of late-model vehicles were exposed to a frontal, near-, or far-side crash.
Logistic regression was used to develop an injury model with occupant, vehicle, and crash parameters as predictor variables. For the frontal and near-side impact models, New Car Assessment Program (NCAP) test results were used as a predictor variable. This work quantitatively described the injury risk for a wide variety of crash modes, informing effectiveness estimates.
This work reconstructed 501 vehicle-to-vehicle left turn across path / opposite direction (LTAP/OD) crashes in the United States which had been originally investigated in NMVCCS. The performance of thirty different I-ADAS system variations was evaluated for each crash. These variations were the combinations of five Time to Collision (TTC) activation thresholds, three latency times, and two different intervention types (automated braking and driver warning). In addition, two sightline assumptions were modeled for each crash: one where the turning vehicle was visible long before the intersection, and one where the turning vehicle was only visible after entering the intersection. For resimulated crashes which were not avoided by I-ADAS, a new crash delta-v was computed for each vehicle. The probability of MAIS2+F injury to each front row occupant was computed.
Depending on the system design, sightline assumption, I-ADAS variation, and fleet penetration, an I-ADAS system that automatically applies emergency braking could avoid 18%-84% of all LTAP/OD crashes. An I-ADAS system which applies emergency braking could prevent 44%-94% of front row occupants from receiving MAIS2+F injuries. I-ADAS crash and injured person reduction effectiveness was higher when both vehicles were equipped with I-ADAS. This study presented the simulated effectiveness of a hypothetical intersection active safety system on real crashes which occurred in the United States, showing strong potential for these systems to reduce crashes and injuries.
However, this crash and injury reduction effectiveness made the idealized assumption of full installation in all vehicles of a future fleet. In order to evaluate I-ADAS effectiveness in the United States fleet the proportion of new vehicles with I-ADAS was modeled using Highway Loss Data Institute (HLDI) fleet penetration predictions. The number of potential LTAP/OD conflicts was modeled as increasing year over year due to a predicted increase in Vehicle Miles Traveled (VMT). Finally, the combined effect of these changes was used to predict the number of LTAP/OD crashes each year from 2019 to 2060. In 2060, we predicted 70,439 NMVCCS-type LTAP/OD crashes would occur. The predicted number of MAIS2+F injured front row occupants in 2060 was 3,836. This analysis shows that even in the long-term fleet penetration of Intersection Active Safety Systems, many injuries will continue to occur. This underscores the importance of maintaining passive safety performance in future vehicles.M.S.
Future vehicles will have electronic systems that can avoid crashes in some cases where a human driver is unable, unaware, or reacts insufficiently to avoid the crash without assistance. The objective of this work was to determine, on a national scale, how many crashes and injuries could be avoided due to Intersection Advanced Driver Assistance Systems (I-ADAS), a hypothetical version of one of these up-and-coming systems. This work focused on crashes where one car is turning left at an intersection and the other car is driving through the intersection and not turning. The I-ADAS system has sensors which continuously search for other vehicles. When the I-ADAS system determines that a crash may happen, it applies the brakes or otherwise alerts the driver to apply the brakes. Rather than conduct actual crash tests, this was simulated on a computer for a large number of variations of the I-ADAS system. The basis for the simulations was real crashes that happened from 2005 to 2007 across the United States. The variations that were simulated changed the time at which the I-ADAS system triggered the brakes (or alert) and the simulated amount of computer time required for the I-ADAS system to make a choice. In some turning crashes, the car cannot see the other vehicle because of obstructions, such as a line of people waiting to turn left across the road. Because of this, simulations were conducted both with and without the visual obstruction. For comparison, we performed a simulation of the original crash as it happened in real life. Finally, since there are two cars in each crash, there are simulations when either car has the I-ADAS system or when both cars have the I-ADAS system. Each simulation either ends in a crash or not, and these are tallied up for each system variation. The number of crashes avoided compared to the number of simulations run is crash effectiveness. Crash effectiveness ranged from 1% to 84% based on the system variation. For each crash that occurred, there is another simulation of the time immediately after impact to determine how severe the impact was. This is used to determine how many injuries are avoided, because often the crashes which still happened were made less severe by the I-ADAS system. In order to determine how many injuries can be avoided by making the crash less severe, the first chapter focuses on injury modeling. This analysis was based on crashes from 2008 to 2015 which were severe enough that one of the vehicles was towed. This was then filtered down by only looking at crashes where the front or sides were damaged. Then, we compared the outcome (injury as reported by the hospital) to the circumstances (crash severity, age, gender, seat belt use, and others) to develop an estimate for how each of these crash circumstances affected the injury experienced by each driver and front row passenger. A second goal for this chapter was to evaluate whether federal government crash ratings, commonly referred to as “star ratings”, are related to whether the driver and passengers are injured or not. In frontal crashes (where a vehicle hits something going forwards), the star rating does not seem to be related to the injury outcome. In near-side crashes (the side next to the occupant is hit), a higher star rating is better. For frontal crashes, the government test is more extreme than all but a few crashes observed in real life, and this might be why the injury outcomes measured in this study are not related to frontal star rating. Finally, these crash and injury effectiveness values will only ever be achieved if every car has an I-ADAS system. The objective of the third chapter was to evaluate how the crash and injury effectiveness numbers change each year as new cars are purchased and older cars are scrapped. Early on, few cars will have I-ADAS and crashes and injuries will likely still occur at roughly the rate they would without the system. This means that crashes and injuries will continue to increase each year because the United States drives more miles each year. Eventually, as consumers buy new cars and replace older ones, left turn intersection crashes and injuries are predicted to be reduced. Long into the future (around 2050), the increase in crashes caused by miles driven each year outpaces the gains due to new cars with the I-ADAS system, since almost all of the old cars without I-ADAS have been removed from the fleet. In 2025, there will be 173,075 crashes and 15,949 injured persons that could be affected by the I-ADAS system. By 2060, many vehicles will have I-ADAS and there will be 70,439 crashes and 3,836 injuries remaining. Real cars will not have a system identical to the hypothetical I-ADAS system studied here, but systems like it have the potential to significantly reduce crashes and injuries.
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Schütze, Mareice [Verfasser]. "Malignitätsassoziierte Proteinexpressionsprofile von Derlin-1, TGF-β [TGF-beta], LTBP-4, p27 und RAD51 in metastasierenden Mammatumoren des Hundes / vorgelegt von Mareice Schütze." Berlin : mbv, Mensch-und-Buch-Verl, 2010. http://d-nb.info/1013050827/34.
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