Mature grains of wild-type (WT) and low phytic acid 1-1 (lpa 1-1) mutant from corn (Zea mays L.) were studied for total phosphorus (total P), phytic acid-phosphorus (PA-P), and mineral cations. Whole grain PA-P in lpa 1-1 was reduced 61.6% compared to WT whereas whole grain total P remained constant. Scutellum and root-shoot axis PA-P was 91.6% and 3.6% of WT whole-grain amounts respectively, compared to 89.3% and 4.0% in lpa 1-1. Relative partitioning of PA-P between the scutellum and root-shoot axis was not altered in lpa 1-1 mutant embryos as compared to WT. In lpa 1-1 the total P was slightly decreased in the scutella and increased in both root-shoot axes and rest-of-grain fractions. Whole grain Mg, Fe, and Mn amounts were higher in lpa 1-1 grains than in WT grains; K and Zn were similar, and Ca was lower. The lpa 1-1 whole grains and embryos contained 1/3 higher Fe than WT. For both grain types all measured metallic elements, except Ca, were more concentrated in embryos than the rest-of-grain fractions. Studies showed that WT grains contained larger globoids than lpa 1-1 grains in both scutellum and aleurone layer cells. This globoid size reduction reflected the PA-P decrease. Most lpa 1-1 aleurone globoids were non-spherical and lpa 1-1 scutellum globoids were clusters of spheres while both scutellum and aleurone globoids of WT were discrete spheres. The lpa 1-1 mutation had an impact on the globoid formation. X-ray analyses of scutellum and aleurone layer globoids from both grain types revealed major amounts of P, K, and Mg and traces of Ca, Fe, and Zn. Analysis demonstrated lower P, K and Mg and higher Ca, Fe and Zn in aleurone globoids than scutellum globoids. Both grain types contained almost no mineral nutrient stores in the starchy endosperm, whereas the scutellum was the major site of PA-P and mineral nutrient deposition. / Thesis / Master of Science (MSc)

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

This thesis consists of four chapters. Chapter 1 focuses on theoretical results on high-order laplacian-based regularization in function estimation. We studied the iterated laplacian regularization in the context of supervised learning in order to achieve both nice theoretical properties (like thin-plate splines) and good performance over complex region (like soap film smoother). In Chapter 2, we propose an innovative static path-planning algorithm called m-A* within an environment full of obstacles. Theoretically we show that m-A* reduces the number of vertex. In the simulation study, our approach outperforms A* armed with standard L1 heuristic and stronger ones such as True-Distance heuristics (TDH), yielding faster query time, adequate usage of memory and reasonable preprocessing time. Chapter 3 proposes m-LPA* algorithm which extends the m-A* algorithm in the context of dynamic path-planning and achieves better performance compared to the benchmark: lifelong planning A* (LPA*) in terms of robustness and worst-case computational complexity. Employing the same beamlet graphical structure as m-A*, m-LPA* encodes the information of the environment in a hierarchical, multiscale fashion, and therefore it produces a more robust dynamic path-planning algorithm. Chapter 4 focuses on an approach for the prediction of spot electricity spikes via a combination of boosting and wavelet analysis. Extensive numerical experiments show that our approach improved the prediction accuracy compared to those results of support vector machine, thanks to the fact that the gradient boosting trees method inherits the good properties of decision trees such as robustness to the irrelevant covariates, fast computational capability and good interpretation.

京都大学 / 新制・課程博士 / 博士(薬学) / 甲第23847号 / 薬博第854号 / 新制||薬||242(附属図書館) / 京都大学大学院薬学研究科薬学専攻 / (主査)教授 金子 周司, 教授 土居 雅夫, 教授 竹島 浩 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

The mechanisms that regulate the differentiation of stem cells (SCs) into cardiomyocytes are still unclear and the role of endogenous molecules on this process remains unexplored. One such molecule is the bioactive phospholipid lysophosphatidic acid (LPA) which accumulates in the myocardium following acute infarction and exerts multiple biological functions, including the regulation of cell growth and differentiation as well as cell survival (Tigyi et al., 2003; Sengupta, et al., 2004). Experiments were therefore carried out in this thesis to reveal whether LPA can induce the differentiation of stem cells into cardiomyocytes and to identify the signalling mechanisms that mediate this effect. All experiments were carried out in the mouse P19 carcinoma stem cell line. Treatments with LPA in the absence and presence of various pharmacological compounds were conducted in embryoid bodies (EBs) formed from the P19 cells in sterile Petri dishes over 4 days. The EBs were subsequently transferred into 6-well cell culture plates and cultured for specific time points. Lysates were generated and subjected to western blotting for expression of cardiac- specific myosin light chain -1v (MLC-1v). To look at the expression of LPA receptors (LPAR1-LPAR5) experiments were carried out by RT-PCR using specific primers for each LPA receptor and the role of the latter in mediated responses to LPA were examined in the presence of the LPAR 1/3 antagonist, Ki16425, or the LPAR 4 receptor blocker suramin. In addition, experiments were carried out investigating the role of Gαi and specific signalling pathways that may be involved in the differentiation of P19 cells. These were carried out using potent inhibitors/antagonists of Gαi inhibitor (Pertussis toxin), PI3K inhibitor (LY294002), Akt inhibitor (Akt inhibitor XIII), PKC inhibitor (Bisindolylmaleimide I BIM-I), ROCK inhibitor (Y-27632), p38-MAPK inhibitor (SB203580) and ERK1/2 inhibitor (PD98059). Further experiments were carried out to establish whether the presence of LPA results in the phosphorylation of the targeted kinases. These studies were however limited to Akt, p38 MAPK and ERK1/2. Incubation of cells with LPA resulted in the differentiation of P19 cells into cardiomyocytes as reflected by the induction of MLC-1v. The latter increased significantly above basal in a time-dependent manner, reaching a maximum 10 days after plating EBs in 6-well plates. The induction of MLC-1v was more pronounced in cells incubated with 5 μM LPA at 6 days but showed little concentration differences at day 12. RT-PCR analysis confirmed the expression of LPA receptors 1 to 4 but not 5. Pre-incubating cells with suramin and Ki16425 concentration-dependently inhibited MLC-1v expression with 0.05 mg/ml and 10 μM respectively, virtually abolishing the expression of MLC-1v. Additionally, inhibitors of LPAR1/3 and LPAR4 receptors and all the signalling inhibitors except SB203580 abolished the phosphorylation of ERK1/2. Similarly, p38 MAPK activation was completely abolished by LPAR1/3 and LPAR4 receptor antagonists, Interestingly, only LY294002 (5 μM) and Y27632 (10 μM) abolished the LPA induced activation of p38 MAPK while SB203580, BIM-I, Akt inhibitor XIII and PD95080 caused no significant changes to the phosphorylation of p38 MAPK. In conclusion, the studies carried out in this thesis have shown that LPA can induce P19 stem cells to differentiate into cardiomyocytes and they are linked to the well characterised LPA receptors (LPAR1/3 and 4). These receptors are coupled to downstream signalling pathways of which those involving the ROCK, PI3K, PKC and/or Akt may be critical, and may converge on ERK1/2. Inhibition of any of these pathways has the potential to suppress differentiation. In contrast, signalling leading to p38 activation may potentially suppress differentiation but this needs further clarification.

Submitted by Maike Costa (maiksebas@gmail.com) on 2017-07-07T15:09:57Z No. of bitstreams: 1 arquivototal.pdf: 1854233 bytes, checksum: 535d273c615cebce265419e27f74439a (MD5) / Made available in DSpace on 2017-07-07T15:09:57Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 1854233 bytes, checksum: 535d273c615cebce265419e27f74439a (MD5) Previous issue date: 2016-10-17 / Ouabain is a cardiotonic steroid initially described as a substance of plant origin. In 1991, the endogenous production of higher mammals was identified and since then their physiological actions have been studied. Work of our group have demonstrated that ouabain modulates the acute inflammatory response induced by different phlogistic agents, also being able to interfere negatively in inflammatory profile triggered by Leishmania (L.) amazonensis. Acute lung injury (ALI) is a serious inflammatory disease characterized by acute inflammation, extensive accumulation of polymorphonuclear leukocytes and accumulation of proinflammatory mediators, which culminates with diffuse alveolar damage and which may cause the patient died due to severe hypoxemia. There is no data in the literature on the effects of ouabain in ALI. Objectives: Evaluate the immunomodulatory effect of ouabain in a murine model of ALI induced by LPS. Methods: BALB / c mice were treated intraperitoneally with ouabain at a dose of 0.56 mg / kg for a period of three consecutive days, 1 hour after the last treatment the animals were challenged intranasally with 40μl of an LPS solution (2 5 mg / kg); 24 hours after challenge, the animals were euthanized, the collected biological sample and inflammatory parameters, including cell migration, protein exudates, cytokine production, TLR4 expression and histopathological changes were then evaluated. Data were analyzed by PRISMA software. Results: The treatment with ouabain decreased total leukocytes migration to the inflamed site (48,84%), this event associated with decreased neutrophil migration (70,71%) and independent of macrophage migration. The ouabain also decreased the exudate protein in the broncho-alveolar region (26,32%) and production of the cytokines TNF-α (14,80%), IL-6 (47,07%) and IL1-β (33,59%), however this reduction in the production of these mediators was not related to the expression of TLR4. Additionally, the ALI histopathology changes were also reduced by treatment with ouabain. Conclusions: The results show that ouabain has anti-inflammatory action in ALI induced by LPS. / A Ouabaína é um esteroide cardiotônico inicialmente descrito como uma substância de origem vegetal. Em 1991, a sua produção endógena por mamíferos superiores foi identificada e desde então suas ações fisiológicas vêm sendo estudadas. Trabalhos do nosso grupo demonstraram que a ouabaína modula a resposta inflamatória aguda induzida por diferentes agentes flogísticos, sendo também capaz de interferir negativamente no perfil inflamatório desencadeado pela Leishmania (L.) amazonensis. A lesão pulmonar aguda (LPA) é uma doença inflamatória caracterizada por inflamação aguda e extenso acúmulo de polimorfonucleares e de mediadores pró-inflamatórios, que culmina com dano alveolar difuso podendo levar o paciente a óbito por hipoxemia severa. Não há dados na literatura sobre os efeitos da ouabaína na LPA. Objetivos: Avaliar o efeito imunomodulador de ouabaína em modelo murino de LPA induzida por LPS. Métodos: Camundongos BALB/c machos foram tratados via intraperitoneal com ouabaína na dose de 0,56 mg/Kg por um período de três dias consecutivos, 1h após o último tratamento os animais foram desafiados via intranasal com LPS (2,5 mg/Kg); 24h após o desafio, os animais foram eutanásiados, as amostras biológicas coletadas e os parâmetros inflamatórios, incluindo migração celular, exsudato proteico, produção de citocinas, expressão de TLR4 e alterações histopatológicas foram então avaliados. Os dados foram analisados pelo software PRISMA. Resultados: O tratamento com a ouabaína diminuiu a migração de leucócitos totais para o sítio inflamado (48,84%), evento este, associado a diminuição da migração de neutrófilos (70,7%) e independente da migração de macrófagos. Ouabaína também diminuiu o exsudato proteico na região bronco-alveolar (26,32%) e a produção das citocinas TNF-α (14,80%), IL-6 (47,07%) e IL1-β (33,59%), entretanto essa redução na produção desses mediadores não mostrou relação com a expressão do TLR4. Adicionalmente, as alterações histopatológicas características da LPA também foram reduzidas pelo tratamento com ouabaína. Conclusões: Os resultados obtidos demonstram que ouabaína possui ação anti-inflamatória na LPA induzida por LPS.

Made available in DSpace on 2017-07-10T18:34:01Z (GMT). No. of bitstreams: 1 Marlowa Zachow.pdf: 1273004 bytes, checksum: 081277ea29c172abe5d0122c9c704ac4 (MD5) Previous issue date: 2012-12-04 / This research aims to analyze the impact that the association of companies of Information Technology of Paraná has on their competitiveness. The process of globalization has brought the need for companies of all sizes move to compete with multinational giants, especially in this line of business. An alternative was the creation of a local productive arrangement, encouraged by governmental and nongovernmental organizations. Through the results of the survey found that companies know that the joint actions could enhance or improve competitiveness. It was noticed that there was a considerable growth in terms of turnover and number of employees after the association. Entrepreneurs realize the advantages it has for being part of the arrangement, noting among these advantages the issue of personnel training and training. It was also noticed that the arrangement researched is very young, because it had its foundation in 2008. There is plenty to evolve, realizing the need to attract more businesses to the arrangement, as well as other priority action plans that address all activities of information technology and communication. / Esta pesquisa tem por objetivo analisar o impacto que a associação das empresas de Tecnologia da Informação do Oeste do Paraná tem sobre a competitividade das mesmas. O processo de globalização trouxe a necessidade das empresas de qualquer porte em passar a competir com gigantes multinacionais, especialmente nesse ramo de atuação. Uma alternativa encontrada foi a criação de um arranjo produtivo local, incentivado por instituições governamentais e não governamentais. Através dos resultados da pesquisa constatou-se que as empresas sabem que as ações conjuntas melhoram ou poderiam melhorar a competitividade. Percebeu-se que houve um crescimento considerável em termos de faturamento e número de funcionários após a associação. Os empresários percebem as vantagens que tem por fazerem parte do arranjo, destacando entre essas vantagens a questão da capacitação de pessoal e treinamento. Percebeu-se ainda que o arranjo pesquisado é muito jovem, pois teve sua fundação em 2008. Há muito para evoluir, percebendo-se a necessidade de atrair mais empresas para o arranjo, bem como priorizar outros planos de ação que contemplem todas as atividades de tecnologia da informação e comunicação.

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Statistical heterogeneity refers to differences among results of studies combined in a meta-analysis beyond that expected by chance. On the one hand, excessive heterogeneity can diminish power to discover genetic signals; on the other, moderate heterogeneity can reveal important biological differences among studies. Given its double-edged nature, this thesis dissects heterogeneity in genetic association meta-analyses from three vantage points. First, a novel multi-variant statistic, M is proposed to detect genome-wide (systematic) heterogeneity patterns in genetic association meta-analyses. This was motivated by the limited availability of appropriate methodology to measure the impact of heterogeneity across genetic signals, since traditional metrics (Q, I² and T²) measure heterogeneity at individual variants. Second, given that meta-analyses comprising small numbers of studies typically report imprecise summary effect estimates; GWAS-derived empirical heterogeneity priors are used to improve precision in estimation of average genetic effects and heterogeneity in smaller meta-analyses (e.g. ≤ 10 studies). Third, a critical evaluation of the Han-Eskin random-effects model shows how it can identify small effect heterogeneous loci overlooked by traditional fixed and random-effects methods. This work draws attention to the existence of genome-wide heterogeneity patterns, to reveal systematic differences among the ascertainment criteria of participating studies in a meta-analysis of coronary disease (CAD) risk. Furthermore, simulation studies with the Han-Eskin random-effects model revealed inflated genetic signals at small effect loci when heterogeneity levels were high. However, it did reveal an additional CAD risk variant overlooked by traditional meta-analysis methods. We therefore recommend a holistic approach to exploring heterogeneity in meta-analyses which assesses heterogeneity of genetic effects both at individual variants with traditional statistics and across multiple genetic signals with the M statistic. Furthermore, it is critically important to review forest plots for small effect loci identified using the Han-Eskin random-effects model amidst moderate-to-high heterogeneity (I² ≥ 40%).

<p>Functional impairment is increasingly prevalent among middle-aged and older adults, with 2 in 5 adults over the age of 65 having some form of disability, the majority being limitations on mobility. Many older adults are able to maintain functional capacity well into later life, but the factors that contribute to high levels of function and the mechanisms by which they operate are unclear, although prior work has demonstrated the importance of social relationships for health. Guided by principles from the life course perspective and perspectives on social connectedness, this dissertation examined the role of social connectedness across the life course as a predictor of functional capacity in adulthood. I used existing longitudinal data from the national Midlife in the United States (MIDUS) study to pursue three central aims.</p> <p><br></p> <p>First, Paper 1 compared theoretical and data-driven approaches to classifying life course relationships, including multiple dimensions of social connectedness at different time points across the life course. Results showed that the data-driven approach (i.e., latent profile analysis) was a stronger predictor of functional limitations than the theoretical approach and revealed relationship trajectories consistent with life course cumulative processes. Second, using the profiles obtained from Paper 1, Paper 2 probed the association between life-course social connectedness and functional limitations by examining the potential mediating role of candidate biological and behavioral mechanisms, and moderation by socioeconomic status (SES). Paper 2 findings suggested that observed differences in later-life functional limitations based on life-course social connectedness can be at least partially explained by physical activity, but do not vary by SES. Contrary to hypotheses, inflammation was not a significant mediator. Third, Paper 3 used monozygotic twin data and within-family analyses to sharpen the focus on potential causal associations between life-course social connectedness and adult functional status. Results suggested that the association is likely driven by genetic and/or shared environmental influences. </p> <p><br></p> <p>Taken together, these results add to our understanding of social connectedness and health and address important gaps in the literature. These findings are used to generate theory- and intervention-relevant insights into the successful maintenance of health, independence, and function across the lifespan.</p>