Dissertations / Theses on the topic 'MSG rats'

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Fundação Araucária
Hypothalamic obesity (HyO) is a severe condition without any effective therapy. Bariatric operations appear as an alternative treatment, but the effects of this procedure are controversial. Here, we investigated the effects of duodenal-jejunal bypass (DJB) upon lipid profile and expression of main genes, protein and transcription factors involved in hepatic lipid metabolism pathways in HyO rats. During the first 5 days of life, male newborn Wistar rats received a subcutaneous injection of monosodium glutamate (MSG) [4 g/kg body weight (BW), HyO group]. Control (CTL) group received saline [1.25 g/kg BW]. At 90 days of age, HyO rats were randomly submitted to DJB or sham operations forming HyO DJB and HyO Sham group, respectively. Six months after DJB, obesity parameters, lipids levels, and expression of genes and protein in the liver were verified. HyO Sham rats displayed obesity, hyperinsulinemia, insulin resistance, hypertryglyceridemic and presented higher free fatty acids (FFA) levels and hepatic triglyceride (TG) content. Also, HyO Sham animals enhanced acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN) and stearoyl-CoA desaturase-1 (SCD-1) mRNA levels and ACC and FASN protein in the liver. Carnitine palmitoyltransferase-1a (CPT-1a) and microsomal TG transfer protein (MTTP) were down-regulated in HyO Sham rats. DJB operation normalized serum insulin, TG and FFA levels and hepatic TG content, without changing obesity in these animals. In addition, DJB reduced mRNA levels of liver pyruvate kinase (LPK), ACC, SCD-1, acyl-CoA oxidase (ACO) and carbohydrate response elemento-binding protein (ChREBP). ACC and FASN protein expression were normalized in HyO DJB animals. DJB reduces de-novo lipogenesis and improves hepatic TG content in HyO DJB rats, indicating that this surgery is efficient in the resolution of nonalcoholic fatty liver disease (NAFLD) in HyO.
A obesidade hipotalâmica (OH) é uma condição severa que não apresenta nenhuma terapia eficaz. Cirurgias bariátricas têm surgido como uma alternativa de tratamento, porém, os efeitos deste procedimento são controversos. No presente trabalho, investigamos os efeitos da derivação duodeno-jejunal (DDJ) sobre o perfil lipídico e sobre a expressão gênica de proteínas e fatores de transcrição envolvidos em vias do metabolismo lipídico hepático em ratos com OH. Durante os cinco primeiros dias de vida, ratos Wistar neonatos receberam uma injeção subcutânea de glutamato monossódico (MSG) [4 g/kg de peso corporal, grupo OH]. O grupo controle (CTL) recebeu solução salina [1,25 g/kg de peso corporal]. Aos 90 dias de idade, os ratos OH foram aleatoriamente submetidos à pseudo-cirurgia (PC) ou à DDJ, formando os grupos OH PC e OH DDJ, respectivamente. Seis meses após a DDJ, foram verificados, os parâmetros de obesidade, concentração de lipídios e expressão gênica e proteica no fígado. Ratos OH PC apresentaram obesidade, hiperinsulinemia, resistência à insulina, hipertrigliceridemia, concentrações elevadas de ácidos graxos livres (AGL) e do conteúdo de triglicerídeo (TG) hepático. Também, os animais OH PC tiveram aumento na quantidade de mRNA da acetil-CoA carboxilase (ACC), ácido graxo sintetase (FASN) e estearoil-CoA desaturase-1 (SCD-1) e da expressão proteica da ACC e FASN no fígado. A expressão gênica da carnitina palmitoil-transferase-1a (CPT-1a) e da proteína de transferência de triglicerídeos microssomal (MTTP) foram menores no fígado do grupo OH PC. A cirurgia de DDJ normalizou a concentração de insulina, AGL e TG séricos e o conteúdo de TG hepático, sem alterar a obesidade nesses animais. Além disso, a DDJ reduziu a expressão do mRNA da piruvato quinase hepática (LPK), ACC, SCD-1, acil-CoA oxidase (ACO) e da proteína de ligação do elemento responsivo à carboidratos (ChREBP). A expressão proteica de ACC e FASN foi normalizada em animais OH DDJ. A DDJ reduz a lipogênese de novo e melhora o conteúdo de TG hepático em ratos OH DDJ, indicando que esta cirurgia é eficiente na resolução da doença hepática gordurosa não alcoólica (DHGNA) na OH.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Background and Objective: Periodontal disease is a chronic disease that affects a major population part and has been associated with systemic changes. As a result, its relationship with obesity and atherosclerosis, it is a matter of concern for the health system.The aim of this study was to evaluate the behavior of periodontal tissues and abdominal aorta artery in rats with hypothalamic obesity associated with experimental periodontitis. Material and Methods: Twenty-eight male Wistar rats were divided , initially, into 2 groups that were subjected to intradermal injections of 4G/kg of solution of Monosodium glutamate (MSG) and 1,25G/kg/day of saline solution (group CTL)in the cervical region, in the first 5 days of life. At 70 days, the groups were subdivided into 2 another groups, where was induced periodontitis with the ligation placing in 1s lower molars; creating in this way 4 groups: control group without ligation (CTL); control group with ligation (CTL Lig); group MSG without ligation (MSG); group MSG with ligation (MSG Lig). After 100 days the rats were weighed and the naso-anal lenght was measured, so the index of Lee was determined and, then, the animals were sacrificed. Gingival tissue and abdominal aorta samples, as well as the hemi-jaws were withdrawn for immunological, morphological and radiographic analysis. Results: The interleukin-6 concentration in gingival tissue was significant in CTL Lig group, being that the Tumor Necrosis Factor-alpha concentration in the abdominal aorta is higher in groups with experimental periodontitis (p< 0.05). Both the x-ray analysis as the histology showed a lower alveolar bone loss in the MSG Lig, group when compared to the CTL Lig group (p< 0.05). In the abdominal aorta morphometric analysis there was statistically significant 48 difference in the measurement of the artery wall diameter, being the largest diameter observed in the MSG Lig group (p< 0.05). Conclusion: Therefore, this study suggests that the periodontitis in association with the hypothalamic obesity may contribute to the increase of the width of the abdominal aorta walls, as well as the hypothalamic obesity may exert a protective effect on alveolar bone loss.
Objetivo: O objetivo desse trabalho foi avaliar o comportamento de tecidos periodontais e da artéria aorta abdominal em ratos com obesidade hipotalâmica associada a periodontite experimental. A doença periodontal é uma doença crônica que afeta grande parte da população e tem sido associada a alterações sistêmicas. Sendo assim, sua relação com a obesidade e a aterosclerose, é motivo de preocupação para o sistema de saúde. Metodologia: Vinte e oito ratos Wistar foram divididos, inicialmente, em 2 grupos que foram submetidos a injeções intradérmicas na região cervical de 4g/kg/dia de solução de Glutamato Monossódico (grupo MSG) e 1,25g/kg/dia de solução salina (grupo CTL), nos primeiros 5 dias de vida. Aos 70 dias, esse grupos foram subdivididos em outros 2 grupos, onde foi induzida a periodontite com a colocação de ligadura nos 1ºs molares inferiores; originando-se assim 4 grupos: grupo controle sem ligadura (CTL); grupo controle com ligadura (CTL Lig); grupo MSG sem ligadura (MSG); grupo MSG com ligadura (MSG Lig). Aos 100 dias os ratos foram pesados e mensurados o comprimento naso-anal, assim o índice de Lee foi determinado e, então, os animais foram sacrificados. Amostras de tecido gengival e da aorta abdominal, bem como as hemi-mandíbulas foram retiradas para análises imunológicas, morfológicas e radiográficas. Resultados: A concentração de interleucina-6 no tecido gengival foi significante no grupo CTL Lig, sendo a concentração do Fator de Necrose Tumoral alfa na aorta abdominal maior nos grupos com periodontite induzida (p<0.05). Tanto a análise radiográfica quanto a histológica demonstrou uma menor perda óssea alveolar no grupo MSG Lig, quando comparado ao grupo CTL Lig (p<0.05). Na análise morfométrica da aorta abdominal houve diferença estatisticamente significante na mensuração do diâmetro das paredes da artéria, sendo o maior diâmetro observado no grupo MSG Lig (p<0.05). Conclusion: Logo, este estudo sugere que a periodontite em associação com a obesidade hipotalâmica pode contribuir para o aumento da largura das paredes da aorta abdominal, bem como a obesidade hipotalâmica pode exercer um efeito protetor sobre a perda óssea alveolar.

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Among the several organic alterations arising from obesity, chronic inflammation is associated with the balance of cytokines TNF-α, IL-1β, IL-6, IL-2, IFNg, IL-4 and IL-10, and there is evidence the amino acid taurine (Tau) has anti-inflammatory effect. Therefore, this study investigated the inflammatory profile in plasma and retroperitoneal adipose tissue of MSG-obese rats, supplemented or not, with the TAU. Male Wistar rats received subcutaneous injections of MSG (4mg/kg body weight/day) or hyperosmotic saline during the first 5 days of life, composing the control (CON) and MSG groups. After 21 days, half of each group received TAU 2.5% in drinking water, and separated into 04 groups: CON, CON with TAU (CTAU), MSG and MSG with TAU (MTAU). At 120 days of age, the animals were euthanized. The MSG rats showed an increase in Lee Index, retroperitoneal and perigonadal fat pads deposition, insulin and triglycerides plasmatic concentrations and HOMA-IR, when compared to CON animals, showing that the treatment with MSG led to obesity. The TAU supplementation attenuated retroperitoneal fat deposition, as well as TG concentration. The MSG treatment did not alter the expression of JNK and IκBα. However, the supplementation with TAU increased 61% the expression of IkBα in CTAU group compared to the CON and 107% in the MTAU animals compared to the MSG. The expression of TNF-α, IL-1β and IL-6 in the retroperitoneal adipose tissue were similar in the four groups of animals, as well as plasma concentrations of TNF-α, IL-1β, IL-6, IL-2, IFNγ, IL-4 and IL-10. It is possible to conclude that neonatal treatment with MSG does not influence the inflammatory profile of the animals. We also conclude that the TAU increased 61% of IkBα protein expression in the control group and 107% in the MSG-obese animals, without affecting the inflammatory cytokines. Thus we suggest that TAU can exert their anti-inflammatory effects in adipose tissue, via NF-kB
Dentre as várias alterações orgânicas decorrentes da obesidade, está o processo inflamatório crônico associado ao balanço das citocinas TNF-α, IL-1β, IL-6, IL-2, IFNγ, IL-4 e IL-10, e, há evidências de que o aminoácido taurina (TAU) possui efeito anti-inflamatório. Assim, neste trabalho investigamos o perfil inflamatório plasmático e do tecido adiposo retroperitoneal de ratos obesos-MSG, suplementados ou não, com o aminoácido TAU. Ratos Wistar receberam injeções subcutâneas de MSG (4mg/kg de peso corporal/dia) ou salina hiperosmótica, durante os primeiros 5 dias de vida e foram distribuídos nos grupos MSG e CON, respectivamente. Após os 21 dias de vida, metade de cada grupo recebeu 2,5% de TAU na água de beber, sendo separados nos grupos CON, CON + TAU (CTAU), MSG e MSG + TAU (MTAU). Aos 120 dias de vida os animais foram eutanasiados. Ratos MSG apresentaram obesidade acompanhada de hipertrigliceridemia e resistência à insulina (RI). Todavia, não afetou a expressão de IκBα e JNK. A suplementação com TAU aumentou 61% a expressão do IkBα no grupo CTAU em relação ao grupo CON e 107% nos animais MTAU em comparação com os obesos-MSG. As expressões de TNF-α, IL-1β e IL-6 no tecido adiposo retroperitoneal foram semelhantes nos 4 grupos de animais estudados, assim como as concentrações plasmáticas do TNF-α, IL-1β, IL-6, IL-2, IFNγ, IL-4 e IL-10. É possível concluir que o tratamento neonatal com MSG não influencia o perfil inflamatório dos animais. Concluímos também que a TAU aumentou a expressão proteica do IkBα nos animais controle e MSG, sem afetar as citocinas inflamatórias. Desta forma sugerimos que a TAU possa exercer seus efeitos anti-inflamatórios no tecido adiposo, via NF-κB

Intermedin (IMD) is a peptide hormone discovered in 2004 belonging to the calcitonin/calcitonin gene-related peptide superfamily. It signals through a Gprotein coupled receptor by the coupling of a calcitonin receptor-like receptor (CRLR) and one of the receptor activity-modifying proteins (RAMPs) 1-3. Due to its similarity to adrenomedullin in structure and functions, IMD is also known as adrenomedullin 2 (ADM2). Among members of the superfamily, IMD shares the highest degree of homology with ADM, which is a multifunctional vasodilator ubiquitously expressed in various tissues and organs and has been studied by our group for its reproductive functions. It is hypothesized that IMD may be present in the reproductive systems of the rat and exert some effects on reproductive functions. The objectives of this study were to investigate the expression of IMD and its receptor components in the male and female reproductive systems of the rat, the changes in expression across the oestrous cycle, and its effect on uterine contraction. The gene expression levels of Imd and its receptor components and peptide levels of IMD were measured by RT-PCR and enzyme immunoassay respectively. The effect of IMD on the uterine contraction was studied by the organ bath technique. Imd mRNA and IMD levels were detected in the testis, epididymis, ventral prostate, coagulating gland, and seminal vesicle of the male rat and the ovary, oviduct, and uterus of the female rat, suggesting possible roles for IMD in both the male and female reproductive systems. In the male, the Imd mRNA levels were the highest in the seminal vesicle but lowest in the testis and the epididymis and IMD peptide levels were the highest in the coagulating gland but lowest in the epididymis. In the female, the Imd mRNA and IMD peptide levels were the highest in the oviduct and the uterus respectively while both the Imd and IMD levels were the lowest in the ovary. Imd mRNA and IMD levels displayed cyclic changes in various female reproductive tissues across the oestrous cycle. In the ovary, positive immunostaining was detected in the follicles and corpora lutea with more staining in the latter. The Imd mRNA level was significantly higher at prooestrus than dioestrus while the IMD peptide level was significantly higher at metoestrus than dioestrus. In the oviduct, the Imd mRNA level was the lowest at dioestrus but the IMD peptide level was the highest at dioestrus. Positive immunostaining was observed in the ciliated epithelial cells. Uterine Imd mRNA level was the highest at prooestrus while the IMD level was the highest at dioestrus. IMD was found in the luminal and glandular epithelia. IMD significantly reduced the uterine contraction amplitude and frequency but not the basal tone. CGRP receptor antagonist hCGRP8-37 and ADM receptor antagonist hADM22-52 partially abolished the inhibitory effect of IMD on uterine contraction while the IMD specific receptor antagonist hIMD17-47 completely blocked the actions. Enzyme inhibitors of NO (L-NAME) and PI3K (Wortmannin) pathways diminished the IMD-mediated effects on uterine contraction while cAMP/PKA blocker KT5720 had no effect.
published_or_final_version
Physiology
Master
Master of Philosophy

Oxytocin release within the brain modulates several social behaviours in animals and humans. Moreover, low central oxytocin content has been linked to neuropsychiatric disorders, such as anxiety and autism. The exogenous administration of oxytocin has been proposed for therapeutic treatment, but oxytocin does not cross the blood-brain barrier (BBB) in physiologically significant amounts. An alternative approach to oxytocin administration is to stimulate central oxytocin release using melanocortins. Central administration of the naturally occurring melanocortin, α-MSH, has been shown to trigger somatodendritic oxytocin release in vitro. Unfortunately, endogenous melanocortins also do not penetrate the BBB in neuroactive amounts. In this study, I investigated whether systemic administration of synthetic melanocortin receptor 3/4 (MC3/4) agonist, Melanotan-II (MT-II), affects oxytocin neuronal activity and secretion in anaesthetised rats. I hypothesised that systemic administration of MT-II directly (centrally) acts on magnocellular oxytocin neurones to trigger somatodendritic oxytocin release from neurones of the supraoptic nucleus (SON) of the hypothalamus in vivo. Firstly, using double immunohistochemistry against Fos protein, a widely used marker for neural activity, and oxytocin, I showed that intravenous (i.v.; 1 mg/kg), but not intranasal (1 and 30 μg rat), administration of MT-II markedly induced Fos expression in magnocellular oxytocin neurones of the SON and paraventricular nuclei (PVN) of the hypothalamus, and this response was prevented by prior intracerebroventricular (i.c.v.) administration of the melanocortin antagonist, SHU-9119 (1 μg rat). In addition, brain areas receiving peripheral inputs which are involved in the regulation of oxytocin and vasopressin release were also analysed, showing that i.v. MT-II significantly increased Fos expression in the nucleus tractus solitarii (NTS), but not in circumventricular organs of the anteroventral third ventricle (AV3V) region. MT-II-induced Fos in the NTS was not prevented by the i.c.v. melanocortin antagonist. Then, using in vivo electrophysiology, I investigated whether i.v. administration of MT-II affects the electrical activity of SON neurones. Extracellular single-unit recordings from identified magnocellular neurones of the SON showed that MT-II significantly increased the firing rate in oxytocin neurones, however, no significant changes in firing rate were detected in vasopressin neurones. Finally, in vivo oxytocin release experiments showed that i.v. administration of MT-II did not trigger somatodendritic oxytocin release within the SON as measured by microdialysis and subsequent radioimmunoassay. Interestingly, the i.c.v. administration of MT-II (1 μg rat) also failed to trigger oxytocin release within the SON. The analysis of oxytocin content in plasma revealed that the change in oxytocin concentration was significantly greater in i.v. MT-II injected rats compared to vehicle-injected rats. Taken together, these results show that after i.v., but not intranasal, administration of MT-II, the activity of magnocellular neurones of the SON is increased. As previous studies showed that SON oxytocin neurones are inhibited in response to direct application of melanocortin agonists, the actions of i.v. MT-II are likely to be mediated, at least in part, indirectly by activation of inputs from the caudal brainstem.

Within these studies the properties of a high repetition rate (≤ 25,000 Hz) Nd:YVO4 laser were investigated with a view to improving the throughput and quality of information obtained from MALDI MS data collected in continuous raster sampling mode. Initially, the nature of the laser beam profile was investigated and a novel fluorometric method developed for imaging these profiles. Analysis of thin film samples of α-cyano-4-hydroxycinnamic acid (CHCA) and lipid standard phophatidylcholine (PC) 34:1 were carried out. Under most conditions a lower repetition rate and slow stage raster speed were found to be optimal. However, in tissue based investigations repetition rates of 5-10 kHz and faster raster speeds were found to increase the detected ion intensity. Subsequent to this, the use of para-nitroaniline (PNA) as an effective matrix for high-repetition rate laser MALDI MSI applications was investigated and compared to CHCA. PNA was found to provide high quality MSI data, comparable to or better than that obtained with CHCA. The utility of CHCA and PNA were then investigated for the repeat analysis of single tissue sections with a view to increasing the amount of information obtained. Up to five analyses of the same tissue section were demonstrated. Repeat analysis was then applied to the acquisition of both lipid and protein data from a single tissue section using multiple matrices and tissue washing.

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The growing number of overweight and obesity has led to an increase in the number of patients with insulin resistance and diabetes mellitus type 2. MSG obese rats were glucose intolerant, insulin resistant and theirs pancreatic islets secrete more insulin in response to glucose. Subdiafragmatic vagotomy changes the response of islets to glucose and improves glucose homeostasis, supporting the hypothesis that an unbalance of autonomic nervous system with increased parasympathetic nervous system (PNS) action but a decreased sympathetic nervous system function. Studies showed that the PNS is also involved in β-cell proliferation. Therefore, we investigated of PNS participation, using a subdiafragmatic vagal denervation, upon pancreatic β-cell function and mass regulation, and the body glucose control disruption in MSG-obese rats. For this, Male Wistar rats received during the first five days of life monosodium glutamate (MSG) or saline. Subdiaphragmatic vagotomy was performed at 30 days of life. At 90 days of age, we verified static insulin secretion, pancreas morphometric, ERK expression in islets, glucose homeostasis and lipidis. The MSG treatment caused obesity at 90 days of life. MSG rats presented lower body weight and nasoanal length, increased Lee index and fat depots, normoglycemia, hyperinsulinemia, dyslipidemia, glucose intolerance and insulin resistance when compared to CTL. Vagotomy performed at 30-days of age prevented obesity, fat deposition in the liver and ameliorated glucose tolerance and insulin sensitivity in adult MVAG rats in relation to MSG rats. Islets from MSG rats secreted more insulin at stimulatory glucose concentrations than CTL islets. Histological analysis showed that pancreatic islets from MSG rats were lower with a reduction in β-cell area without modification in α-cell content when compared with CTL. Also, MSG group presented an increased number of pancreatic islets per mm2, with higher number of islets, which may contributes to the higher islet and β-cell relative mass in the MSG pancreas. These effects were associated with enhanced proliferation in MSG group. The number of MVAG pancreatic islet were less than MSG. Vagotomoy performed at 30-days of age, reduced islet and β-cell area in the pancreas from 90-days old CVAG rats. Finally, the relative islet and β-cell mass in MVAG and CVAG rats was similar to CTL. Here we verified if ERK was involved in β-cell replication in MSG rats, but presented no alteration. We demonstrate for the first time that adult MSG rats showed enhanced pancreatic β-cell proliferation which contributes to the higher islet insulin secretion in response to glucose. The vagus nerve is the main factor involved in such a process, since vagotomy performed at 30 days of age prevented islet morphological alterations in adult MVAG rats. Possibly this increase PNS activity in MSG endocrine pancreas is responsible to hyperinsulinemia that enhanced fat storage, damaged glucose homeostasis and insulin action in MSG obesity.
O crescente número de pessoas com sobrepeso e obesidade tem levado ao aumento no número de pacientes com resistência à insulina (RI) e portadores do Diabetes mellitus tipo 2. Ratos obesos MSG são intolerantes à glicose (Gli), RI e suas ilhotas pancreáticas secretam mais insulina em resposta à concentrações de Gli. A vagotomia subdiafragamática altera a responsividade das ilhotas à Gli e melhora a homeostase glicêmica nestes animais, sugerindo um desbalanço do sistema nervoso autonômico, com aumento do tônus parassimpático e redução do simpático. Estudos demonstram que o sistema nervoso parassimpático (SNP) possui efeito na proliferação das células β-pancreáticas. Desta forma, investigamos a participação do SNP, através da vagotomia subdiafragmática, no metabolismo energético e na proliferação das ilhotas e de células β-pancreáticas de ratos obesos-MSG. Para isto, ratos Wistar machos receberem durante os cinco primeiros dias de vida glutamato monossódico (grupo MSG) ou salina (grupo CTL). A vagotomia subdiafragmática foi realizada aos 30 dias de vida formando os grupos MVAG e CVAG. Aos 90 dias, verificamos a secreção estática de insulina, homeostase glicêmica e lipídica, morfometria do pâncreas e conteúdo proteico da ERK nas ilhotas. Ratos MSG apresentaram redução do peso corporal e comprimento nasoanal, aumento do índice de Lee e acúmulo de gordura, normoglicêmia, hiperinsulinemia, dislipidemia, intolerância à Gli e RI comparados aos CTL. A vagotomia realizada aos 30 dias de vida preveniu obesidade, acúmulo de gordura no fígado e melhorou a tolerância à Gli e a sensibilidade à insulina em ratos MVAG adultos em relação aos ratos MSG. As ilhotas dos animais MSG secretaram mais insulina quando estimulada pela Gli, em relação aos animais CTL. As análises histológicas mostram que as ilhotas pancreáticas dos animais MSG são menores com redução da área das células β sem alteração nas células α em relação aos CTL. O grupo MSG apresenta um aumento do número das ilhotas por mm2, que pode estar contribuindo com o aumento da massa relativa das ilhotas e das células β. Esse efeito está associado ao aumento da proliferação no grupo MSG. O número de ilhotas foi menor nos MVAG em relação aos MSG. A vagotomia realizada aos 30 dias de vida reduziu a área das ilhotas e das células β aos 90 dias de vida nos animais CVAG. Finalmente, a massa relativa das ilhotas e da células β no MVAG e CVAG foram similares ao CTL. Verificamos se a ERK estava envolvida na proliferação das células β nos ratos MSG, porém não apresentaram alterações desta proteína. Pela primeira vez demonstramos que ratos MSG apresentam aumento da proliferação das células β que contribui com o aumento da secreção de insulina em resposta à Gli. O nervo vago é o principal fator envolvido neste processo, visto que a vagotomia realizada aos 30 dias de vida preveniu as alterações morfológicas das ilhotas nos ratos MVAG adultos.

There is a growing evidence of the potential health benefits of a diet rich in fruits and vegetables. National nutritional guidelines advise the consumption of at least five portions (400 g ) of these foods per day with the goal being a reduction in the levels of coronary heart disease (CHD) strokes and certain cancers. The beneficial properties of fruit and vegetables may be ascribed, in part to the presence of antioxidants and recent attention in this regard has focused on phenolic and polyphenolic compounds. These compounds are present in a wide variety of commonly consumed foods and beverages. Onions are a rich source of the polyphenolic flavonol quercetin-4′-glucoside. For this compound to have some health effects it must be absorbed and reach target organs in a concentration and form where they can exert an effect. To-date interest has focussed on the levels of the intact quercetin aglycone circulating in plasma and excreted in urine. However, it is now known that quercetin does not circulate in the plasma as the parent compound or the aglycone. However, at the outset of this project, the exact form(s) and concentration of metabolites circulating in plasma were unknown. The need to know what compounds are actually circulating, and at what concentration, is important if in vitro studies are to be made into the mechanisms by which quercetin could, potentially, exert a health benefit. The reasons why these issues have not been addressed are due to a number of factors. The main methodology used in studies into absorption, distribution, metabolism and excretion or (A.D.M.E) as it is know in the drug industry, is by use of chromatography coupled to various detection systems. This can range from a simple isocratic single pump linked to a single wavelength absorbance detector, to a gradient pumping system with an autoinjector linked in series to a diode array absorbance detector and mass spectrometer. The latter instruments, although initially expensive are now becoming more affordable. The original methodology used to determine the level of quercetin in plasma involved hydrolysis of the quercetin conjugates back to the aglycone. The information, which is lost by using this hydrolysis method, is vital if we are to gain a better understanding of the A.D.M.E process. There have been a large number of feeding studies carried out using onions or the flavonol contained in them. However, very little additional information was gained after the initial investigations. The objectives of the studies presented in this thesis were to develop methodology to identify and quantify the major metabolites of quercetin in man after ingestion of onions. This would initially require the use of radiolabelled [2-14C]quercetin-4´-glucoside fed to rats to facilitate the development of the method. Having successfully developed methods that would work both in rats and in man, it was of great interest to establish the fate of the complete dose of [2-14C]quercetin-4´-glucoside in rats. In Chapter 2 radiolabelled quercetin-4´-glucoside was used as a tracer to follow the metabolism of the compound as it was acted on by the digestive system of the rat. After 1 h 93% of the ingested dose was recovered in the gastrointestinal tract (GIT). Analysis using HPLC with a photodiode array (PDA) detector in series with a radioactivity monitor connected to an electrospray ion trap mass spectrometer facilitated the separation, quantification and partial identification of 18 out of 19 metabolites. The 1 h sample was part of a larger study that investigated the fate of the radiolabelled compounds up to 5 h after dosing. The latter samples formed part of another study not reported on in this thesis. Having developed the methodology, using the radiolabelled compound, it was then applied to a feed of onions to healthy human volunteers to determine if metabolite detection, identification and quantification could be carried out without the use of the radioactive tracer. In Chapter 3 plasma samples collected 1 h after a feed of onions and urine collection from 0-4 h post feed were used to test if the method could be transferred to a non labelled assay. A total of 22 metabolites plus the parent compound were identified. The metabolic profile of the plasma and urine showed marked differences, again pointing to major post absorption metabolism. The successful transfer of the method from the initial radiolabelled study to the onion feed allowed pharmacokinetic data to be obtained from all plasma samples taken over a 24 h period, along with the 0-24 h urine samples. In Chapter 4 it was seen that the metabolites are both rapidly absorbed and excreted, with plasma levels returning almost back to baseline by 6 h. The total excretion in urine accounted for 4.5% of the ingested dose. These results were controversial, as the pioneer of this field had published that the elimination half life of quercetin was of the order of 18 h. The differences between the two methods employed are discussed in Chapters 3 and 4. The fact that only 4.5% could be accounted for in this study, which was in agreement with other studies, leaves the question of what happens to the other 95.5%. It is possible that the potential health benefit attributed to this compound may have nothing to do with the parent compound but could be coming from something in the other 95.5%. Studies using patients who have undergone an ileostomy have been used to provide further information into what happens to the majority of the dose. By collecting the ileal fluid after a flavonol feed the amount of intact compound can be measured in ileal fluid (Hollman et al., 1995b; Walle et al., 2000). This work and some results from a similar trial study are discussed in Chapter 4, with regard to the process of metabolite absorption and formation. The only way to follow the parent compound throughout its passage through the body is by use of a labelled compound. In Chapter 5 a second feed of [2-14C]quercetin-4´-glucoside, which focuses on the overall fate of the compound, has samples collected for up to 72 h. The fate of the dose was monitored both in terms of the level of radioactivity excreted and found in the tissues and also the identity of the radioactive compounds detected in these samples. In Chapter 5 the results from this study and what impact they could have on quercetin’s potential ability to be the compound responsible for the health benefits are discussed.

Firstly, changes in peripheral section of oxytocin and α-MSH, and changes in oxytocin and α-MSH neurone activity were studied in male rats during copulation. Intromission increased plasma concentration of both oxytocin and α-MSH and Fos expression in neurones in the SON and in the PVN and in the accurate nucleus was increased, confirming the similarities between oxytocin and α-MSH in their involvement in male sexual behaviour. The putative interaction between oxytocin and α-MSH was then investigated by studying at which central or peripheral level this interaction would occur. Oxytocin antagonist iv-injection had no effect on the increase of oxytocin and α-MSH secretion during intromission, suggesting that peripheral oxytocin does not regulate peripheral α-MSH secretion. However, oxytocin administered centrally to non-mating conscious rates decreased plasma α-MSH concentration, suggesting that central oxytocin may regulate α-MSH peripheral secretion. These studies therefore support an interaction between central oxytocin and α-MSH. Then, the effects of central α-MSH on oxytocin secretion and neuronal activity were investigated. Central administration of α-MSH induced Fos expression in magnocellular oxytocin neurones in the SON and in the PVN but had no effect on parvocellular oxytocin neurons in the PVN. Α-MSH directly administered onto the SON induced a strong increase in Fos expression in oxytocin neurones in the SON. These studies indicate that α-MSH modulates directly the activity on selected oxytocin neurones and that consequently, αMSH may regulate some specific oxytocin effects and not others. However, central administration of α-MSH decreased oxytocin secretion from the pituitary gland. This illustrates that Fos induction does not necessarily reflect excitation of the neurones. Finally, MC4R antagonist centrally administered reduced the Fos expression induced at intromission in magnocellular oxytocin neurones but had no effect on the Fos expression in the parvocellular neurones.

A madeira é um material de fonte renovável, porém com grande variabilidade em suas propriedades mecânicas, devendo ser adequadamente avaliadas e caraderizadas para o correto uso. Uma forma de avaliar estas propriedades é através de ensaios não destrutivos, que não danificam o material. Dentre os vários métodos de classificação destaca-se a classificação mecânica por tensões (MSR), a qual é um efetivo sistema de classificação e avaliação de peças estruturais de madeira, devido sua alta produtividade, podendo todas as peças produzidas serem avaliadas e certificadas. O processo de classificação por meio de ensaios não destrutivos, objetiva determinar os valores do modulo de elasticidade (MOE) e sua correlação com os módulos de resistência a flexão(MOR). A alta produção anual de peças estruturais do gênero pínus spp no Brasil e o conhecimento tecnológico de suas propriedades, tomará sua utilização viável na construção civil em maior escala. Este trabalho avalia a influência da velocidade de ensaio e a intensidade da carga aplicada, nos valores do módulo dinâmico, correlacionando este com os módulos de elasticidade estático e o modulo de resistência à flexão, considerando a classificação visual das peças ensaiadas. Os resultados mostram que a espécie pinus spp deve ser classificada visualmente e mecanicamente para o correto uso estrutural
Wood is a material of renewable source, however with great variability in their mechanical properties and must becharaderized for it\'s corred use and in arder to determine these properties using non-destrudive tests. Among this tests, stands out the Machine Stress Rating (MSR), which is a effedive system of grading and assessment of strudurallumber, due their high produdivity, ali being able to the produced pieces be assessed and certifled. The process of grading by means of non-destrudive test, objedive to determine the values of MOE and correlate them with MOR values. The annual high production of strudural piaces of pinus spp in Brazil, with the technologic knowledge of their properties, made their utilization feasible in the civil construdion in great scale. This work propose the study of mechanical stress grading for this specie, correlating the values of the dynamic modulus obtained in the MSR, analysing the influence of the speed and test and the intensity of the force applied, with the static modulus and the modulus of rupture. The results showed that in order to use pinus spp to structural purpose the lumber must be visually and mechanically graded.

The purpose of this study was to extract galvanized steel wire reinforcement coupons from mechanically stabilized earth (MSE) walls along I-15 and determine the rate of corrosion that has taken place since Phase I, which was conducted by Gerber and Billings (2010). The galvanized steel reinforcement analyzed in this study has been in place for 19 to 20 years at the time of extraction. A total of 85 coupons were extracted and laboratory analysis was performed to determine the thickness of remaining zinc galvanization on each coupon. Soil samples were obtained from each one-stage wall extraction location to determine moisture content for correlation with corrosion. After laboratory testing was performed, the measured zinc coating thickness was compared to that determined in Phase I. An average corrosion rate of approximately 0.032 oz/ft²/year has occurred since Phase I. According to the AASHTO (2017) design corrosion rate of 0.35 oz/ft²/year for the first two years and 0.09 oz/ft²/year until the depletion of the zinc, the zinc coating would have been completely depleted after 16 years. Based on the results of laboratory testing, the initial galvanization coating was likely greater than the specified thickness of 2.0 oz/ft² (86 μm). The zinc galvanization is corroding at a slower rate than the AASHTO design rate. The AASHTO design rate for depletion of zinc coating and subsequent corrosion of the steel reinforcement is conservative for the corrosion conditions present in the MSE wall reinforcement coupons tested. The integrity of the steel reinforcement that is currently in place is not likely to be compromised by corrosion.

In this paper we deal with the `strength' of ill-posedness for ill-posed linear operator equations Ax = y in Hilbert spaces, where we distinguish according_to_M. Z. Nashed [15] the ill-posedness of type I if A is not compact, but we have R(A) 6= R(A) for the range R(A) of A; and the ill-posedness of type II for compact operators A: From our considerations it seems to follow that the problems with noncompact operators A are not in general `less' ill-posed than the problems with compact operators. We motivate this statement by comparing the approximation and stability behaviour of discrete least-squares solutions and the growth rate of Galerkin matrices in both cases. Ill-posedness measures for compact operators A as discussed in [10] are derived from the decay rate of the nonincreasing sequence of singular values of A. Since singular values do not exist for noncompact operators A; we introduce stability rates in order to have a common measure for the compact and noncompact cases. Properties of these rates are illustrated by means of convolution equations in the compact case and by means of equations with multiplication operators in the noncompact case. Moreover using increasing rearrangements of the multiplier functions specific measures of ill-posedness called ill-posedness rates are considered for the multiplication operators. In this context, the character of sufficient conditions providing convergence rates of Tikhonov regularization are compared for compact operators and multiplication operators.

O estudo investigou a ação sensibilizadora à insulina da glimepirida (Gp), em ratos MSG, resistentes à insulina. Animais controle (C) e MSG, e tratados (CG e MSG/G) ou não com Gp, foram submetidos a ITT; análise do GLUT4 no tecido adiposo (TAB), EDL, sóleo e coração; ensaios de translocação e captação de glicose/incorporação ao glicogênio no sóleo; dosagem do glicogênio e p-GSK3 no fígado. No TAB, mRNA e proteína GLUT4 se elevaram nos MSG, o que foi revertido pela Gp, efeito importante para não agravar a obesidade. No sóleo, o mRNA aumentou nos MSG, mas a proteína GLUT4 foi igual a C, e se elevou com a Gp. Sob estímulo insulínico, GLUT4 em membranas plasmáticas aumentou em ratos C e MSG/G. Captação de glicose e incorporação ao glicogênio muscular no sóleo, conteúdo de glicogênio e de p-GSK3 no fígado foram menores nos MSG. A Gp aumentou a expressão/translocação de GLUT4 em músculo de ratos MSG, melhorando a captação de glicose e glicogeniogênese neste tecido. Estes efeitos, mais o aumento da glicogeniogênese hepática, conferem à Gp ação sensibilizadora à insulina.
The study investigated the insulin sensitizer action of the glimepiride (Gp) in insulin- resistant MSG rats. Control (C) and MSG animals, non-treated or treated with Gp (CG and MSG/G) were submitted to ITT; GLUT4 analysis in adipose tissue (WAT), EDL, soleus and heart; GLUT4 translocation assays and glucose uptake/glycogen incorporation in soleus; glycogen and p-GSK3 analysis in the liver. In WAT, GLUT4 mRNA and protein increase in MSG rats was abolished by Gp, an effect important to avoid the aggravation of the obesity. In MSG soleus, GLUT4 mRNA increased but protein was similar to C, elevating after Gp. Under insulin stimulation, GLUT4 in plasma membrane increased in C and MSG/G only. Glucose uptake and incorporation to muscular glycogen in soleus, and glycogen/p-GSK-3 content in the liver were all lower in MSG rats. Gp increased GLUT4 expression/translocation in MSG muscle, improving glucose uptake and glycogenesis in this tissue. These effects, added to the higher hepatic glycogenesis confer the Gp its insulin sensitizer action.

ITC/USA 2007 Conference Proceedings / The Forty-Third Annual International Telemetering Conference and Technical Exhibition / October 22-25, 2007 / Riviera Hotel & Convention Center, Las Vegas, Nevada
The accuracy of channel estimation plays a crucial role in the demodulation of data symbols sent across an unknown wireless medium. In this work a new analytical expression for the channel estimation error of a multiple input multiple output (MIMO) system is obtained when the wireless medium is continuously changing in the temporal domain. Numerical examples are provided to illustrate our findings. Space-time (ST) coding using Continuous Phase Modulation (CPM) has spectral advantages relative to linear modulations. In spite of the spectral benefits, Space-Time Trellis Codes (STTC) using the CPM implementation of Minimum Shift Keying (MSK) scheme has inherent inphase and quadrature interference, when the received complex baseband signal is the input into the matchfilter to remove the shaped sinusoid pulses. In this paper a novel optimum transmitting and detecting structure for STTC-MSK is proposed. Treating the Alamouti scheme as an outer code, each STTC MSK waveform frame is immediately followed by the orthogonal conjugate waveform frame at the transmit side. At the receiver first orthogonal wave forming is applied, then a new time-variant yet simple trellis structure of the STTC-MSK signals is developed. This STTC-MSK detector is absolutely guaranteed to be I/Q interference-free and still keeps a smaller computation load compared with STTC-QPSK. Simulations are made over quasi-static AWGN fading channel. It is shown that our detector for ST-MSK has solved the I/Q interference problem and has around 2.8 dB gain compared with the Alamouti Scheme and 3.8 dB gain for bit error rate at 5 X 10^(-3) in a 2 by 1 Multiple Input Single Output system.

This study investigated the beneficial potential effects of grape pomaces obtained after winemaking of different Mediterranean grape varieties from crude materials to their in vivo effectiveness. Grapes and their respective grape pomaces from six different V. vinifera L. cultivar were studied namely Grenache (from two different locations [GRE1 and GRE2]), Syrah (from two different locations [SYR1 and SYR2]), Carignan (CAR), Mourvèdre (MOU), Counoise (COU) and Alicante (ALI) grape varieties from the Rhône Valley. The comparison of several wine industry by-products with their respective grapes provided evidence that pomace remaining at the end of the winemaking process can be very rich sources of antioxidants. The quantitative and qualitative distribution of polyphenols by HPLC-PDA-Fluo-MS in grape pomaces showed significant differences through varieties and vintages varying from 15% to 70% of polyphenols extracted. Seeds from Grenache (GRE1), Syrah (SYR1) and skins from Syrah (SYR1), Carignan and Alicante were of particular interest because of their higher polyphenol contents in terms of flavan-3-ols (monomers, dimers and trimers) up to 8.7 mg/g DW and anthocyanins (glycosides, acetylated and coumaroylated derivatives up to 17.40, 1.57 and 2.38 mg/g DW, respectively). The investigation of aqueous and hydro-alcoholic 70% extracts of seeds from Carignan and Syrah (SYR1) and skins from Carignan and Alicante was carried out as they contained high levels of total phenols and antioxidant activity. Several extracts, were tested in order to evaluate their in vivo biological effects on hypertension using a spontaneously hypertensive rat (SHR) model. A series of different grape pomace extracts were tested in association with verapamil. All in vivo experiments demonstrated that some grape pomace extracts administrated with or without co-ingestion with verapamil possessed an anti-hypertensive activity. This was evident with GRE1 (EA70) seed pomace extract, SYR1 (EA70) seed pomace extract, ALI (EA70) skin pomace extract administrated alone and with GRE1 (EA70) seed pomace extract, SYR1 (EAQ) seed pomace extract, ALI (EA70) skin pomace extract and SYR2 (EAQ) skin pomace extract administrated in association with verapamil. Grape pomace extracts with or without co-ingestion with verapamil were absorb as phase II metabolites mainly including glucuronide, O-methyl glucuronide, sulfate, and O-methyl sulfate derivatives of (epi)catechin which arise from the metabolism of monomeric flavan-3-ols. The detection by HPLC-PDA-Fluo-MSn and GC-MS of microbial-derived metabolites of flavan-3-ols, hydroxyphenyl-γ-valerolactones in their glucuronide and sulfate forms confirmed the absorption of metabolites derived from both monomeric and polymeric flavan-3-ols from grape pomace extracts and subsequent post-absorption conjugation. Numerous metabolites derived from further microbial degradation of hydroxyvalerolactones were also detected. The urinary excretion of these metabolites accounted for a larger proportion of the total polyphenol ingested than phase II metabolites of monomeric flavan-3-ols, indicating the important role of intestinal bacteria in the metabolism of polymerized procyanidins. All these metabolites may have exerted biological effects during the period in which they circulated in the bloodstream. This study constitutes the first step of assessing grape pomace as an enhancer of the verapamil, an anti-hypertensive drug. Substantial levels of polyphenols, especially flavan-3-ols, procyanidins and anthocyanins, remain in pomace after the winemaking process in quantities sufficient to exert anti-hypertensive effects. In addition, according to the extract used and its composition, it is feasible to modulate anti-hypertensive effects by amplifying or decreasing polyphenols and/or verapamil absorption.

[EN] Alcohol abuse is one of the most alarming issues for the health authorities. It is estimated that at least 23 million of European citizens are affected by alcoholism causing a cost around 270 million euros. Excessive alcohol consumption is related with physical harm and, although it damages the most of body organs, liver, pancreas, and brain are more severally affected. Not only physical harm is associated to alcohol-related disorders, but also other psychiatric disorders such as depression are often comorbiding. As well, alcohol is present in many of violent behaviors and traffic injures. Altogether reflects the high complexity of alcohol-related disorders suggesting the involvement of multiple brain systems. With the emergence of non-invasive diagnosis techniques such as neuroimaging or EEG, many neurobiological factors have been evidenced to be fundamental in the acquisition and maintenance of addictive behaviors, relapsing risk, and validity of available treatment alternatives. Alterations in brain structure and function reflected in non-invasive imaging studies have been repeatedly investigated. However, the extent to which imaging measures may precisely characterize and differentiate pathological stages of the disease often accompanied by other pathologies is not clear. The use of animal models has elucidated the role of neurobiological mechanisms paralleling alcohol misuses. Thus, combining animal research with non-invasive neuroimaging studies is a key tool in the advance of the disorder understanding. As the volume of data from very diverse nature available in clinical and research settings increases, an integration of data sets and methodologies is required to explore multidimensional aspects of psychiatric disorders. Complementing conventional mass-variate statistics, interests in predictive power of statistical machine learning to neuroimaging data is currently growing among scientific community. This doctoral thesis has covered most of the aspects mentioned above. Starting from a well-established animal model in alcohol research, Marchigian Sardinian rats, we have performed multimodal neuroimaging studies at several stages of alcohol-experimental design including the etiological mechanisms modulating high alcohol consumption (in comparison to Wistar control rats), alcohol consumption, and treatment with the opioid antagonist Naltrexone, a well-established drug in clinics but with heterogeneous response. Multimodal magnetic resonance imaging acquisition included Diffusion Tensor Imaging, structural imaging, and the calculation of magnetic-derived relaxometry maps. We have designed an analytical framework based on widely used algorithms in neuroimaging field, Random Forest and Support Vector Machine, combined in a wrapping fashion. Designed approach was applied on the same dataset with two different aims: exploring the validity of the approach to discriminate experimental stages running at subject-level and establishing predictive models at voxel-level to identify key anatomical regions modified during the experiment course. As expected, combination of multiple magnetic resonance imaging modalities resulted in an enhanced predictive power (between 3 and 16%) with heterogeneous modality contribution. Surprisingly, we have identified some inborn alterations correlating high alcohol preference and thalamic neuroadaptations related to Naltrexone efficacy. As well, reproducible contribution of DTI and relaxometry -related biomarkers has been repeatedly identified guiding further studies in alcohol research. In summary, along this research we demonstrate the feasibility of incorporating multimodal neuroimaging, machine learning algorithms, and animal research in the advance of the understanding alcohol-related disorders.
[ES] El abuso de alcohol es una de las mayores preocupaciones de las autoridades sanitarias en la Unión Europea. El consumo de alcohol en exceso afecta en mayor o menor medida la totalidad del organismo siendo el páncreas e hígado los más severamente afectados. Además de estos, el sistema nervioso central sufre deterioros relacionados con el alcohol y con frecuencia se presenta en paralelo con otras patologías psiquiátricas como la depresión u otras adicciones como la ludopatía. La presencia de estas comorbidades demuestra la complejidad de la patología en la que multitud de sistemas neuronales interaccionan entre sí. El uso imágenes de resonancia magnética (RM) han ayudado en el estudio de enfermedades psiquiátricas facilitando el descubrimiento de mecanismos neurológicos fundamentales en el desarrollo y mantenimiento de la adicción al alcohol, recaídas y el efecto de los tratamientos disponibles. A pesar de los avances, todavía se necesita investigar más para identificar las bases biológicas que contribuyen a la enfermedad. En este sentido, los modelos animales sirven, por lo tanto, a discriminar aquellos factores únicamente relacionados con el alcohol controlando otros factores que facilitan el desarrollo del alcoholismo. Estudios de resonancia magnética en animales de laboratorio y su posterior evaluación en humanos juegan un papel fundamental en el entendimiento de las patologías psiquatricas como la addicción al alcohol. La imagen por resonancia magnética se ha integrado en entornos clínicos como prueba diagnósticas no invasivas. A medida que el volumen de datos se va incrementando, se necesitan herramientas y metodologías capaces de fusionar información de muy distinta naturaleza y así establecer criterios diagnósticos cada vez más exactos. El poder predictivo de herramientas derivadas de la inteligencia artificial como el aprendizaje automático sirven de complemento a tradicionales métodos estadísticos. En este trabajo se han abordado la mayoría de estos aspectos. Se han obtenido datos multimodales de resonancia magnética de un modelo validado en la investigación de patologías derivadas del consumo del alcohol, las ratas Marchigian-Sardinian desarrolladas en la Universidad de Camerino (Italia) y con consumos de alcohol comparables a los humanos. Para cada animal se han adquirido datos antes y después del consumo de alcohol y bajo dos condiciones de abstinencia (con y sin tratamiento de Naltrexona, una medicaciones anti-recaídas usada como farmacoterapia en el alcoholismo). Los datos de resonancia magnética multimodal consistentes en imágenes de difusión, de relaxometría y estructurales se han fusionado en un esquema analítico multivariable incorporando dos herramientas generalmente usadas en datos derivados de neuroimagen, Random Forest y Support Vector Machine. Nuestro esquema fue aplicado con dos objetivos diferenciados. Por un lado, determinar en qué fase experimental se encuentra el sujeto a partir de biomarcadores y por el otro, identificar sistemas cerebrales susceptibles de alterarse debido a una importante ingesta de alcohol y su evolución durante la abstinencia. Nuestros resultados demostraron que cuando biomarcadores derivados de múltiples modalidades de neuroimagen se fusionan en un único análisis producen diagnósticos más exactos que los derivados de una única modalidad (hasta un 16% de mejora). Biomarcadores derivados de imágenes de difusión y relaxometría discriminan estados experimentales. También se han identificado algunos aspectos innatos que están relacionados con posteriores comportamientos con el consumo de alcohol o la relación entre la respuesta al tratamiento y los datos de resonancia magnética. Resumiendo, a lo largo de esta tesis, se demuestra que el uso de datos de resonancia magnética multimodales en modelos animales combinados en esquemas analíticos multivariados es una herramienta válida en el entendimiento de patologías
[CAT] L'abús de alcohol es una de les majors preocupacions per part de les autoritats sanitàries de la Unió Europea. Malgrat la dificultat de establir xifres exactes, se estima que uns 23 milions de europeus actualment sofreixen de malalties derivades del alcoholisme amb un cost que supera els 150.000 milions de euros per a la societat. Un consum de alcohol en excés afecta en major o menor mesura el cos humà sent el pàncreas i el fetge el més afectats. A més, el cervell sofreix de deterioraments produïts per l'alcohol i amb freqüència coexisteixen amb altres patologies com depressió o altres addiccions com la ludopatia. Tot aquest demostra la complexitat de la malaltia en la que múltiple sistemes neuronals interactuen entre si. Tècniques no invasives com el encefalograma (EEG) o imatges de ressonància magnètica (RM) han ajudat en l'estudi de malalties psiquiàtriques facilitant el descobriment de mecanismes neurològics fonamentals en el desenvolupament i manteniment de la addició, recaiguda i la efectivitat dels tractaments disponibles. Tot i els avanços, encara es necessiten més investigacions per identificar les bases biològiques que contribueixen a la malaltia. En aquesta direcció, el models animals serveixen per a identificar únicament dependents del abús del alcohol. Estudis de ressonància magnètica en animals de laboratori i posterior avaluació en humans jugarien un paper fonamental en l' enteniment de l'ús del alcohol. L'ús de probes diagnostiques no invasives en entorns clínics has sigut integrades. A mesura que el volum de dades es incrementa, eines i metodologies per a la fusió d' informació de molt distinta natura i per tant, establir criteris diagnòstics cada vegada més exactes. La predictibilitat de eines desenvolupades en el camp de la intel·ligència artificial com la aprenentatge automàtic serveixen de complement a mètodes estadístics tradicionals. En aquesta investigació se han abordat tots aquestes aspectes. Dades multimodals de ressonància magnètica se han obtingut de un model animal validat en l'estudi de patologies relacionades amb el consum d'alcohol, les rates Marchigian-Sardinian desenvolupades en la Universitat de Camerino (Italià) i amb consums d'alcohol comparables als humans. Per a cada animal es van adquirir dades previs i després al consum de alcohol i dos condicions diferents de abstinència (amb i sense tractament anti-recaiguda). Dades de ressonància magnètica multimodal constituides per imatges de difusió, de relaxometria magnètica i estructurals van ser fusionades en esquemes analítics multivariats incorporant dues metodologies validades en el camp de neuroimatge, Random Forest i Support Vector Machine. Nostre esquema ha sigut aplicat amb dos objectius diferenciats. El primer objectiu es determinar en quina fase experimental es troba el subjecte a partir de biomarcadors obtinguts per neuroimatge. Per l'altra banda, el segon objectiu es identificar el sistemes cerebrals susceptibles de ser alterats durant una important ingesta de alcohol i la seua evolució durant la fase del tractament. El nostres resultats demostraren que l'ús de biomarcadors derivats de varies modalitats de neuroimatge fusionades en un anàlisis multivariat produeixen diagnòstics més exactes que els derivats de una única modalitat (fins un 16% de millora). Biomarcadors derivats de imatges de difusió i relaxometria van contribuir de distints estats experimentals. També s'han identificat aspectes innats que estan relacionades amb posterior preferències d'alcohol o la relació entre la resposta al tractament anti-recaiguda i les dades de ressonància magnètica. En resum, al llarg de aquest treball, es demostra que l'ús de dades de ressonància magnètica multimodal en models animals combinats en esquemes analítics multivariats són una eina molt valida en l'enteniment i avanç de patologies psiquiàtriques com l'alcoholisme.
Cosa Liñán, A. (2017). Analytical fusion of multimodal magnetic resonance imaging to identify pathological states in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/90523
TESIS

Une population discrète de neurones localisés dans le noyau arqué synthétise la proopiomélanocortine (POMC) et sécrète le neuropeptide alpha-melanocyte-stimulating hormone (α-MSH). Le but du présent travail était de déterminer les mécanismes ioniques qui sous-entendent la libération de l'α-MSH et de rechercher l'implication éventuelle de certains neurotransmetteurs dans la régulation de l'activité des neurones à POMC. En utilisant la technique de périfusion de tranches d'hypothalamus de rat, nous montrons que la libération d'α-MSH induite par une concentration dépolarisante de potassium met en jeu des canaux calciques voltage-dépendants de type N et T. Le GABA inhibe la libération d'α-MSH via l'activation de récepteurs GABA#A, et cet effet est modulé par les benzodiazépines de type central. Des expériences in vivo indiquent que le GABA et les benzodiazépines exercent également un effet inhibiteur sur l'expression du gène de la POMC. Le neuropeptide tyrosine (NPY) inhibe la liberation d'α-MSH induite par le potassium, via l'activation des récepteurs Y2 couplés à une protéine G sensible à la pertussis toxine. L'administration chronique de NPY par voie intracérébroventriculaire entraîne une réduction du contenu hypothalamique en α-MSH dans l'hypothalamus ce qui suggère que le NPY pourrait également bloquer la synthèse de la POMC dans les neurones hypothalamiques

Thesis (Ph. D.)--Materials Science and Engineering, Georgia Institute of Technology, 2008.
Committee Chair: Dr. Joe K. Cochran; Committee Co-Chair: Dr. Thomas H. Sanders; Committee Member: Dr. John Elton; Committee Member: Dr. Meilin Liu; Committee Member: Dr. Robert F. Speyer.

Ambitionen med studien är att öka förståelsen för hur elever agerar i de fall vuxna inte styr deras val. Vår fråga gäller huruvida elever väljer vad de ska göra beroende på vad de har för intresse eller vem de vill vara med. Således är syftet med studien att undersöka hur elever resonerar kring sina fria val av aktiviteter på raster och i fritidshem, samt vilka faktorer som kan spela in när dessa val görs. Undersökningen har gjorts i form av en gruppintervju med fem medverkande elever ur årskurs tre. Gruppintervjun har spelats in och transkriberats för att sedan analyseras med den hermeneutiska cirkeln som struktur. Analysen av det empiriska materialet har gjorts med Pierre Bourdieus teorier om att människors handlande styrs av den kontext de befinner sig i.Analysen är uppdelad i två teman som är direkt kopplade till studiens två frågeställningar. Dessa frågeställningar rör hur elever resonerar kring sina val av aktiviteter och vilka begränsningar som framkommer i dessa. Resultatet pekar på att trender på skolgården, relationer mellan elever och lust till specifika aktiviteter är faktorer som är avgörande i elevers val av aktivitet. De begränsande faktorer som respondenterna talar om, eller faktorer som gör att elever väljer bort aktiviteter, är personals styrning, platsspecifika regler och elever från högstadiet. Den övergripande slutsatsen är att elever i de flesta fall väljer vänner före intresse.

Nowadays there is research into molten salt reactors. The use of chlorine-based salts, which would be more available than known fluoride salts, is envisaged. The subject of research is not only the chemical and physical properties of chloride salts, but also their behavior in the neutron field and the influence of neutron balance inside the reactor. Many properties can also be determined using calculations that draw information from scientific nuclear libraries (endf). The purpose of this work is to compare important nuclear libraries with each other, and also to compare the reaction rates calculated from the library data with the reaction rates obtained by self-measurement. The preview will include a description of the necessary activities associated with the preparation of measurements, instructions for compiling the computer program NJOY and the process of the measurement itself. At the end of the work will be summarized the results and statements of which nuclear library is the closest in its values to the results of experiments.

We give an upper bound for the norm distance of (0,1) -valued Markov-exchangeable random variables to mixtures of distributions of Markov processes. A Markov-exchangeable random variable has a distribution that depends only on the starting value and the number of transitions 0-0, 0-1, 1-0 and 1-1. We show that if, for increasing length of variables, the norm distance to mixtures of Markov processes goes to 0, the rate of this convergence may be arbitrarily slow. (author's abstract)
Series: Forschungsberichte / Institut für Statistik

Les modèles cosmologiques prédisent que la composante dominante de la masse de l'Univers est sous forme de matière noire (DM). L'étude des propriétés statistiques et topologiques de sa distribution représente donc un point clé de la cosmologie moderne et, puisqu'elle n'est pas directement observable, nous proposons de sonder sa distribution en utilisant le milieu intergalactique comme traceur. Celui-ci est constitué d'un gaz diffus qui suit de façon très précise la distribution de DM. En observant un quasar lointain, la présence de ce gaz se manifeste par une série de raies d'absorption le long de la ligne de visée: c'est la forêt Lyman-alpha. De plus, si nous disposons d'un groupe de quasars avec des séparations angulaires faibles, on peut interpoler l'information que nous avons le long des lignes devisée afin de reconstruire le champ en trois dimensions. Nous testons cette méthode de reconstruction de manière quantitative à l'aide d'outils statistiques et topologiques qui nous renseignent sur les propriétés de connexité de la distribution du gaz. En utilisant des simulations hydrodynamiques, nous comparons les propriétés des champs reconstruits avec celles du champ de départ afin de comprendre sous quelles conditions celles-ci sont préservées par l'inversion. Les résultats de nos analyses soulignent le potentiel très prometteur de cette méthode de reconstruction. La future génération de télescopes de type ELT devraient permettre d'observer un nombre de sources lointaines suffisamment élevé pour que des reconstructions de bonne qualité puissent être faites. La distribution de la DM pourra alors être mesurée avec une bonne précision
Cosmological models predict that the mass of the Univers is dominated by a non-collisional and non-baryonic component: the so-called dark matter (DM). Thus, studying the statistical and topological properties of its spatial distribution is a key issue in cosmology. Since this component can not be directly observed, we propose to probe its distribution by using the Intergalactic Medium as a tracer. Simulations support the idea that this low-density gas follows the potential wells of the DM in a very precise way. When looking at a distant quasar, the presence of this gas results in a series of absorption features along the line of sight: the so-called Lyman-alpha forest. Moreover, when a group of quasars with small angular separations is available, then it is possible to interpolate the information provided by the Lyman-alpha forest, in order to recover the three dimensional density field, by using sophisticated inversion methods. In this thesis we test the result of this inversion method in a quantitative way, by using some statistical and topological tools which give information about the connectivity properties of the distribution. Hydrodynamical simulations are used to compare the properties of the original field with those of the recovered field. The aim is to understand under which conditions the inversion preserves the global topology of the field. The results of our analysis show the very promising power of the inversion procedure. Future observations with the next generation of Extremely Large Telescopes (ELT) should be able to observe a number of sources sufficiently high to allow this kind of reconstruction to be performed with accurate precision

Extended spectrum β-lactamases or ESBLs, which are derived from non-ESBL precursors by point mutation of β-lactamase genes (bla), are spreading rapidly all over the world and have caused considerable problems in the treatment of infections caused by bacteria which harbour them. The mechanism of this resistance is not fully understood and a better understanding of these mechanisms might significantly impact on choosing proper diagnostic and treatment strategies. Previous work on SHV β-lactamase gene, blaSHV, has shown that only Klebsiella pneumoniae strains which contain plasmid-borne blaSHV are able to mutate to phenotypically ESBL-positive strains and there was also evidence of an increase in blaSHV copy number. Therefore, it was hypothesised that although specific point mutation is essential for acquisition of ESBL activity, it is not yet enough, and blaSHV copy number amplification is also essential for an ESBL-positive phenotype, with homologous recombination being the likely mechanism of blaSHV copy number expansion. In this study, we investigated the mutation rate of non-ESBL expressing K. pneumoniae isolates to an ESBL-positive status by using the MSS-maximum likelihood method. Our data showed that blaSHV mutation rate of a non-ESBL expressing isolate is lower than the mutation rate of the other single base changes on the chromosome, even with a plasmid-borne blaSHV gene. On the other hand, mutation rate from a low MIC ESBL-positive (≤ 8 µg/mL for cefotaxime) to high MIC ESBL-positive (≥16 µg/mL for cefotaxime) is very high. This is because only gene copy number increase is needed which is probably mediated by homologous recombination that typically takes place at a much higher frequencies than point mutations. Using a subinhibitory concentration of novobiocin, as a homologous recombination inhibitor, revealed that this is the case.

La mise en place de la membrane glomerulaire (mbg) au cours de la nephrogenese chez le rat a ete etudie par des techniques biochimiques, cytoimmunologiques et structurales. Toutes les macromolecules de la mbg (collagene iv, laminine, fibronectine, pgags) sont detectees par immunofluorescence des le stade precoce de la nephrogenese. La filtration renale ne commenceq u'au 18**(e) jour de la gestation alors que la nibg n'est encore constituee que par une lame base (epitheliale). Les proprietes d'ultrafiltration ne deviennent effectives qu'a partir du jour 20 lorsque la mbg acquiert sa structure tripartite apres coalescence des 2 lames basales. La fonction d'ultrafiltration glomerulaire requiert une proportion precise et une organisation particuliere des principales macromolecules de la mbg

Hot wire anemometers have been used in several wind velocity sensors deployed in Mars. They are based in keeping the temperature of a surface at a constant value, above the ambient. This is done by means of a heater controlled with an electronic system. The cooling rate of each point at the sensor surface can be used to calculate the wind velocity and direction. However, due to turbulent fluctuations, the cooling rate is not constant even in the case of constant velocity. Moreover, RANS simulations cannot estimate such fluctuations as they only provide an estimation of the averaged flow field. The goal of this work has been to estimate such fluctuations and the e↵ect they might have on the sensor readings. To do so, the turbulent cooling rate (Nusselt number) of a sensor with a generic shape, under the typical conditions to be find in Mars, has been simulated using high performance LES (Large Eddy Simulation) simulations and compared with RANS and URANS simulations.

In this thesis work, automatic recognition algorithms for digital modulated signals are surveyed. Feature extraction and classification algorithm stages are the main parts of a modulation recognition system. Performance of the modulation recognition system mainly depends on the prior knowledge of some of the signal parameters, selection of the key features and classification algorithm selection. Unfortunately, most of the features require some of the signal parameters such as carrier frequency, pulse shape, time of arrival, initial phase, symbol rate, signal to noise ratio, to be known or to be extracted. Thus, in this thesis, features which do not require prior knowledge of the signal parameters, such as the number of the peaks in the envelope histogram and the locations of these peaks, the number of peaks in the frequency histogram, higher order moments of the signal are considered. Particularly, symbol rate and signal to noise ratio estimation methods are surveyed. A method based on the cyclostationarity analysis is used for symbol rate estimation and a method based on the eigenvector decomposition is used for the estimation of signal to noise ratio. Also, estimated signal to noise ratio is used to improve the performance of the classification algorithm. Two methods are proposed for modulation recognition: 1) Decision tree based method 2) Bayesian based classification method A method to estimate the symbol rate and carrier frequency offset of minimum-shift keying (MSK) signal is also investigated.

La malnutrition liée au vieillissement est souvent accompagnée de nombreux dérèglements et dysfonctionnements métaboliques, notamment la perturbation de l'homéostasie énergétique (installation de l’insulinorésistance), la fragilité, la diminution de la masse musculaire et les troubles de la réponse immunitaire. Ainsi, la manipulation nutritionnelle, au cours du vieillissement, est considérée comme l'une des solutions possible pour prévenir et traiter ces troubles. Parmi les substances nutritives qui ont été largement étudiées, la composition en protéines (acides aminés), la qualité des lipides (AGPI n-3) et les micronutriments (vitamine D).L’objectif de cette thèse consiste à déterminer l’impact de la dénutrition et d’évaluer le potentiel d'une des formules de réalimentation contenant un mélange à haute teneur en protéines solubles du lait, associées à de la matière grasse laitière, enrichie en acides gras polyinsaturés de la famille omega 3 (précurseur ALA et DHA) et en vitamine D sur la composition en acides gras (AG) du plasma, des globules rouges et du cerveau ainsi que ses conséquences sur les marqueurs du statut inflammatoire, la réponse hépatique à l’insuline, l'expression de gènes impliqués dans la régulation de l'homéostasie énergétique et l’inflammation hypothalamique, chez des rats âgés préalablement soumis à une restriction alimentaire. Dans un premier temps, nous avons montré que la restriction alimentaire de trois mois, non carencée en ALA, induit une perte importante en omega3 (ALA et dérivés LCn-3) alors que le dérivé ARA de la série n-6 est peu modifié, conduisant ainsi à une élévation du statut pro-inflammatoire exprimé sous forme d’une augmentation du ratio ARA/LCn-3.Toutefois, les quatre semaines de réalimentation, notamment avec la formule contenant le mélange matière grasse laitière, colza et DHA, associé à de la caséine ou des protéines solubles du lait, restaure 1/ les valeurs de DHA du cerveau non restaurées par un régime contrôle de renutrition, 2/ augmente les valeurs des dérivés LCn-3 (EPA, DHA) à des niveaux supérieurs à ceux d’un régime contrôle non dénutris et de renutrition. Cette augmentation s’accompagne d’une réduction des valeurs d’ARA, induisant une baisse drastique dans le plasma et les globules rouges du ratio ARA/EPA. Ces formules montrent pour la première fois qu’elles peuvent induire une réduction très importante du statut inflammatoire par rapport à celui observé généralement chez les vieux rats et pourrait présenter un intérêt beaucoup plus général en prévention des pathologies associées au vieillissement, liées ou non à la dénutrition.Dans un second temps, nous avons montré que la restriction alimentaire de trois mois entraîne 1/ une augmentation de l’expression du récepteur à l'insuline dans l'hypothalamus, le foie et le tissu adipeux, accompagnée d'une augmentation du facteur pro-inflammatoire TNFα dans l’hypothalamus. Cependant, la réalimentation de quatre semaines entraîne 2/ un gain de poids similaire et maintient l’insulinosensibilité hépatique. En effet, nous avons montré, pour la première fois, qu’une réalimentation avec les régimes comportant le mélange MGLA/colza/DHA, permettrait 3/ d’augmenter la prise alimentaire et de diminuer l’inflammation hypothalamique, notamment, avec la formule complète contenant un mélange de haute teneur en protéines solubles de lait, associée à la matière grasse laitière /colza/DHA et enrichie en vitamine D
Malnutrition related to aging is often accompanied by many metabolic disorders, including the disruption of energy homeostasis (installation of insulin resistance), fragility, decreased muscle mass and immune response deficiency. Thus, the nutritional manipulation, during aging, is considered to be a solution to prevent these disorders or to treat and limit damages. Amongst the nutrients that have been widely studied, we find the quality of proteins (or amino acids), of lipids (n-3 PUFA) and micronutrients (vitamin D).The aim of this thesis is to determine the impact of undernutrition and assess the potential of the refeeding formulas containing a high content of soluble protein of milk, associated with milk fat enriched with omega3 polyunsaturated fatty acids (ALA precursor and DHA) and vitamin D, on the fatty acid (FA) of the plasma, red blood cells and brain and its consequences on markers of inflammatory status, the hepatic response to insulin, the expression of genes involved in the regulation of energy homeostasis as well as hypothalamic inflammation, in old rats previously submitted for food restrictionAs a first step, our results showed that the dietary restriction of three months, despite being only moderately ALA deficient, induced a drastic loss omega3 (ALA and derivatives LCn-3), whereas a weak increase of ARA derived from n-6 series is observed, leading to a rise of the pro-inflammatory state expressed as an increase in the ratio ARA/LCn-3.However, we have shown that the four-week-refeeding formulas containing a blend of dairy-fat, rapeseed and DHA associated with casein or milk soluble proteins, restored 1 / DHA values of the brain not previously restored by the refeeding control diet, 2 /increases the values of LCn-3 derivatives (EPA, DHA) to levels above those obtained with the control non-malnourished and refeeding diets. This increase was accompanied by a reduction in ARA values, leading to a drastic drop in plasma and red blood cells ratio ARA / EPA. These formulas show for the first time that they can induce a very significant reduction of inflammatory status compared to that usually seen in old rats and could therefore present a more general interest in prevention of ageing diseases associated or not to undernutrition.In a second step, our results showed that dietary restriction of three months resulted 1/increased expression of the insulin receptor in the hypothalamus, liver and adipose tissue, accompanied by an increase of the proinflammatory factor TNF in the hypothalamus. However, the four-weeks-refeeding produces 2/ a similar weight gain and maintains hepatic insulin sensitivity. Indeed, we showed, for the first time, that refeeding, with diets containing the blend of dairy-fat / rapeseed / DHA, would 3/ increase food intake and decrease the hypothalamic inflammation, especially with the full formula containing a mixture of high content of soluble milk proteins, associated with dairy-fat / rapeseed / DHA fortified with vitamin D

Doppler radar wind profilers are already widely used to measure atmospheric winds throughout the free troposphere and stratosphere. Several methods have been developed to quantify atmospheric turbulence with such radars, but to date they have remained largely un-tested; this thesis presents the first comprehensive validation of one such method. Conventional in-situ measurements of turbulence have been concentrated in the surface layer, with some aircraft and balloon platforms measuring at higher altitudes on a case study basis. Radars offer the opportunity to measure turbulence near continuously, and at a range of altitudes, to provide the first long term observations of atmospheric turbulence above the surface layer. Two radars were used in this study, a Mesosphere-Stratosphere-Troposphere (MST) radar, at Capel Dewi, West Wales, and the Facility for Ground Based Atmospheric Measurements (FGAM) mobile boundary layer profiler. In-situ measurements were made using aircraft and tethered-balloon borne turbulence probes. The spectral width method was chosen for detailed testing, which uses the width of a radar's Doppler spectrum as a measure of atmospheric velocity variance. Broader Doppler spectra indicate stronger turbulence. To obtain Gaussian Doppler spectra (a requirement of the spectral width method), combination of between five and seven consecutive spectra was required. Individual MST spectra were particularly non-Gaussian, because of the sparse nature of turbulence at its observation altitudes. The width of Gaussian fits to the Doppler spectrum were compared to those from the `raw' spectrum, to ensure that non-atmospheric signals were not measured. Corrections for non-turbulent broadening, such as beam broadening, and signal processing, were investigated. Shear broadening was found to be small, and the errors in its calculation large, so no corrections for wind shear were applied. Beam broadening was found to be the dominant broadening contribution, and also contributed the largest uncertainty to spectral widths. Corrected spectral widths were found to correlate with aircraft measurements for both radars. Observing spectral widths over time periods of 40 and 60 minutes for the boundary layer profiler and MST radar respectively, gave the best measure of turbulence intensity and variability. Median spectral widths gave the best average over that period, with two-sigma limits (where sigma is the standard deviation of spectral widths) giving the best representation of the variability in turbulence. Turbulent kinetic energies were derived from spectral widths; typical boundary layer values were 0.13 m 2.s (-2) with a two-sigma range of 0.04-0.25 m 2.s (-2), and peaked at 0.21 m 2.s (-2) with a two-sigma range of 0.08-0.61 m 2.s (-2). Turbulent kinetic energy dissipation rates were also calculated from spectral widths, requiring radiosonde measurements of atmospheric stability. Dissipation rates compared well width aircraft measurements, reaching peaks of 1x10 (-3) m 2.s (-3) within 200 m of the ground, and decreasing to 1-2x10 (-5) m 2.s (-3) near the boundary layer capping inversion. Typical boundary layer values were between 1-3x10 (-4) m 2.s (-3). Those values are in close agreement with dissipation rates from previous studies.

Millennium Development Goal 1 (MDG 1) on halving extreme poverty is measured with the international poverty line. The purpose of the study is to evaluate the measurement of MDG 1 by reviewing the robustness of the international poverty line and some of its national sub-reports. There are at least two problems in assessing a reliable poverty line, namely what constitutes extreme poverty and what kind of life situation this refers to. Through a qualitative content analysis, the study shows that the selected national reports lack a reliable reference for human dietary energy requirements pivotal for estimating a fair threshold for food needs. In the case that a reliable source was used, the activity level was prone to a wide range of interpretations and lacked procedural consistency.  The FAO (2011) has presented minimum dietary energy requirements that are below the references used in the national reports, which could shift the poverty line. The study also shows that the concept of “extreme poverty” has been used inconsistently. MDG 1 identifies extreme poverty as the inability to meet basic food- and non-food needs. The international poverty line is based on a myriad of national poverty lines ranging from minimum- to generous needs, where extreme poverty is defined as people barely having enough for the food component alone. These two variables create obstacles in setting a reliable international poverty line. A small shift in the international poverty line changes the poverty rates substantially, making it difficult for poverty programs and MDG 1 in truly identifying the people in most need of help.

Elements of continuous variation such as tremolo, vibrato and portamento enable dimensions of their own in expressive melodic music in styles such as in Indian Classical Music. There is published work on parametrically modeling some of these elements individually, and to apply the modeled parameters to automatically generated musical notes in the context of machine musicianship, using simple rule-based mappings. There have also been many systems developed for generative musical accompaniment using probabilistic models of discrete musical elements such as MIDI notes and durations, many of them inspired by computational research in linguistics. There however doesn't seem to have been a combined approach of parametrically modeling expressive elements in a probabilistic framework. This documents presents a real-time computational framework that uses a multi-attribute trie / n-gram structure to model parameters like frequency, depth and/or lag of the expressive variations such as vibrato and portamento, along with conventionally modeled elements such as musical notes, their durations and metric positions in melodic audio input. This work proposes storing the parameters of expressive elements as metadata in the individual nodes of the traditional trie structure, along with the distribution of their probabilities of occurrence. During automatic generation of music, the expressive parameters as learned in the above training phase are applied to the associated re-synthesized musical notes. The model is aimed at being used to provide automatic melodic accompaniment in a performance scenario. The parametric modeling of the continuous expressive elements in this form is hypothesized to be able to capture deeper temporal relationships among musical elements and thereby is expected to bring about a more expressive and more musical outcome in such a performance than what has been possible using other works of machine musicianship using only static mappings or randomized choice. A system was developed on Max/MSP software platform with this framework, which takes in a pitched audio input such as human singing voice, and produces a pitch track which may be applied to synthesized sound of a continuous timbre. The system was trained and tested with several vocal recordings of North Indian Classical Music, and a subjective evaluation of the resulting audio was made using an anonymous online survey. The results of the survey show the output tracks generated from the system to be as musical and expressive, if not more, than the case where the pitch track generated from the original audio was directly rendered as output, and also show the output with expressive elements to be perceivably more expressive than the version of the output without expressive parameters. The results further suggest that more experimentation may be required to conclude the efficacy of the framework employed in relation to using randomly selected parameter values for the expressive elements. This thesis presents the scope, context, implementation details and results of the work, suggesting future improvements.

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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
A patogênese do melasma, especialmente o papel dos queratinócitos e fibroblastos no desenvolvimento e manutenção da doença não é bem compreendida. Alterações dérmicas como dano estrutural à zona de membrana basal, melanócitos em pêndulo, elastose solar, celularidade, proliferação vascular, além da expressão de mediadores inflamatórios, fatores de crescimento, expressão epitelial de melanocortina e receptores dos hormônios sexuais; sugerem interação entre a unidade epidermo-melânica e a derme na fisiopatologia do melasma. A pigmentação melânica da pele pode ser estimulada por diferentes vias de sinalização, sendo a radiação ultravioleta, citocinas dérmicas e inflamação epidérmica, os modelos mais usuais. Neste estudo, objetivamos comparar a morfologia nuclear e a textura da cromatina entre queratinócitos basais no melasma facial e pele adjacente, investigar a ativação das diferentes vias de estímulo à pigmentação, além do envolvimento da derme, com foco na zona de membrana basal e colágeno, no melasma facial. Para a sua execução, foram coletados pares de biópsias faciais (2mm) de mulheres adultas com melasma e de pele adjacente (<2 cm). Processaram-se para coloração de PAS e picrosirius red; imunofluorescência para p53, p38, IL- 1α, αMSH, MC1R e COX2; imunoistoquímica para Melan-Acontracorada com PAS; Microscopia Eletrônica de Transmissão, além de cultura primária de fibroblastos para real-timePCR array e marcação para SA-β-gal. Foram avaliados: núcleos de queratinócitos da camada basal quanto à morfometria nuclear e textura da cromatina; quantificada a intensidade de fluorescência nos compartimentos da epiderme e derme; avaliadas organelas citoplasmáticas e zona de membrana basal; além do colágeno dérmico e densidade de melanócitos: totais e em pêndulo. Em relação à pele adjacente sem melasma: núcleos de queratinócitos basais da epiderme com melasma facial apresentaram índices morfométricos e textura da cromatina alterados; houve aumento da expressão epitelial de αMSH e MC1R, sem diferença quanto ao p53, p38, IL1α e COX2; houve maior número de organelas citoplasmáticas e melanossomas em estágios de maturação maiores nos queratinócitos e melanócitos; áreas danificadas na zona de membrana basal com presença de microvesículas adjacentes à membrana basal; maior número de melanócitos em pêndulo; colágeno dérmico desestruturado. Entre os fibroblastos, houve maior marcação para SA-β-gal e expressão alterada dos genes COL4A1, IL6, ESR2, DKK3, CCL2, WIF1, WNT3A, HGF, IL1B, MMPs 1-7-9 no melasma. As alterações encontradas nos queratinócitos, na derme e zona de membrana basal, sugerem que o fenótipo do melasma pode resultar de alterações em toda unidade epidermo-melânica, não somente de uma hipertrofia dos melanócitos, as vias inflamatórias da epiderme e dependentes de p53 não se mostraram proeminentes, além de ser identificado um possível papel do processo de reparo/dano da derme e da senescência de fibroblastos na patogênese da doença.
The melasma pathogenesis, specially the role of keratinocytes and fibroblast in the disease development and maintenance are not completely understood. Dermal alterations such as basal membrane structural damage, pendulous melanocytes, solar elastosis, cellularity, vascular proliferation, in addition to the expression of inflammatory mediators, grow factors, epithelial melanocortin and sexual hormones receptors, suggest there is an interaction between the epidermal melanin unit and dermis in melasma physiopathology. The melanin skin pigmentation can be stimulated by different signaling pathways. UVR, dermal cytokines and epidermal inflammation are the most common models. These study aims to compare the nuclear morphology and chromatin texture in basal keratinocytes between melasma and adjacent skin, to investigate the activation of different pigmentation signaling pathways, and the dermal involvement, focusing on basal membrane zone and collagen. Therefore, facial skin biopsies (2 mm) from women were taken from melasma and normal skin (<2 cm apart) and processed for PAS and picrosirius red; immunofluorescence for p53, p38, IL-1α, αMSH, MC1R and COX2, immunohistochemistry for Melan-A counterstaining with PAS, and transmission electronic microscopy. Furthermore, primary fibroblast culture for real-timePCRarray and SA-β-gal staining. The nuclei of basal keratinocytes were evaluated as nuclear morphometry and chromatin texture; the fluorescence intensity was quantified in the epidermis and dermis; cytoplasm organelles and basal membrane zone were evaluated; in addition to dermal collagen and melanocytes density: total and pendulous. Regarding adjacent healthy skin, the melasma skin showed alterations in morphometric index and chromatin texture; there was greater epithelial expression of αMSH and MC1R, but without difference for p53, p38, IL1α and COX2; cytoplasm organelles and melanossomas in higher maturity were in greater number in keratinocytes and melanocytes; there were commoner damaged areas in basal membrane zone, presence of microvesicules adjacent to basal membrane; and higher number of pendulous melanocyte; dermal collagen was less structured. There were greater SA-β-gal staining and altered expression of COL4A1, IL6, ESR2, DKK3, CCL2, WIF1, WNT3A, HGF, IL1B, MMPs 1-7-9 genes in melasma fibroblasts.The alterations presented in keratinocytes, dermis and basal membrane zone suggest the melasma phenotype can result from alteration in entire epidermal melanin unit, not just hypertrophic melanocytes, the epidermal inflammatory pathways and p53 dependents do not show prominence, in addition to the possible role of the repair/ damage process identified at dermis and fibroblast senescence in the melasma pathogenesis.
FAPESP: 12/09233-5
FAPESP: 12/05004-1

Les progrès de la recherche sur le cancer du sein dépendent de la disponibilité d’outils appropriés, comme les lignées cellulaires qui peuvent être implantées chez des souris immunocompétentes. La souche de souris C57Bl/6 est la plus étudiée et c’est la seule pour laquelle certaines variantes génétiques sont disponibles. Étant donné qu'aucune lignée cellulaire de carcinome mammaire à récepteurs hormonaux positifs de souche C57Bl/6 n'est disponible, nous avons décidé d'établir des lignées cellulaires de ce type. Nous avons induit des cancers du sein chez des souris C57BL/6 femelles en utilisant un analogue synthétique de la progestérone combiné à un agent endommageant l'ADN. Des lignées cellulaires ont été établies à partir de ces tumeurs et sélectionnées pour leur positivité au niveau du double récepteur (estrogène + progestérone), ainsi que pour leur transplantabilité chez les femelles C57BL/6. Parmi plusieurs lignées, une lignée cellulaire, que nous avons appelée MD5, remplissait ces critères et a permis l'établissement de tumeurs mal différenciées et très prolifératives. Ces tumeurs ont réduit leur croissance (sans toutefois régresser) lors du traitement par des antagonistes des récepteurs d’œstrogènes, ainsi que par une chimiothérapie à base d'anthracylines. Cependant, ce dernier effet n'a pas été influencé par la déplétion des lymphocytes T et, en outre, ces tumeurs n'ont pas répondu au blocage de PD-1, ce qui suggère que les tumeurs MD5 sont immunologiquement froides. En conclusion, les cellules MD5, dérivées des animaux C57BL/6, constituent un modèle de cancer du sein à récepteurs hormonaux positifs de mauvais pronostic
Progress in breast cancer research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best explored mouse strain, C57Bl/6, is also the only one for which multiple genetic variants are available. Driven by the fact that no hormone receptor-positive C57Bl/6-derived mammary carcinoma cell lines are available, we decided to establish such cell lines. Breast cancers were induced in female C57BL/6 mice using a synthetic progesterone analogue combined with a DNA damaging agent. Cell lines were established from these tumors and selected for dual (estrogen + progesterone) receptor positivity, as well as transplantability into C57BL/6 females. One cell line, which we called MD5,fulfilled these criteria and allowed for the establishment of poorly differentiated, highly proliferative, immune cold tumors. Such tumors reduced their growth (though did not regress) upon treatment with estrogen receptor antagonists, as well as with anthracyline-based chemotherapy. However, the latter effect was not influenced by T cell depletion and MD tumors failed to respond to PD-1 blockade, suggesting that they are immunologically cold. In conclusion, C57BL/6-derived MD5 cells constitute a model of poor prognosis hormone receptor-positive breast cancer

碩士
國立中央大學
電機工程研究所
91
In the development of third mobile telecommunication systems, attention for the realization of mobile systems, which are able to integrate high, medium and low rate transmission is increasing day by day. But because that the pseudo-noise sequences are not exactly orthogonal, signal will suffer from the interference called Multiple Access Interference (MAI). In this thesis, we analyze and simulate different kinds of interference cancellation (IC) schemes to overcome MAI in multi-rate MPG DS/CDMA. Among ICs, we can see the advantage and disadvantage of traditional parallel interference cancellation (PIC) 、 groupwise parallel interference cancellation (GPIC) and groupwise serial interference cancellation (GSIC). Two kinds of groupwise hybrid interference cancellation (GHIC) by combining GSIC and GPIC is also considered. It can improve the disadvantage of PIC 、GPIC and GSIC. The simulation results show that the performance enhancement can be achieved through weighting factors and Improved IC technique.

碩士
國立臺灣大學
物理學研究所
106
This study is the use of 128-channel whole brain magnetoencephalography (MEG) for animal auditory response. MEG is built up with superconducting quantum interference devices(SQUIDs) which are made up by superconductors. By using its high sensibility of magnetic measurement, we could use measure the electromagnetic signals generated by biological stimulations of neurotransmission. Therefore, there are merits for both the humanities and bioscience-related researches. Because the whole brain magnetometer system is designed to measure human brain signals, the resolution obtained after contrast imaging is limited, and the signal source can’t be accurately expressed in the animal body. So the improvement from the front and back-end computing parts is performed for smaller signal measurement and calculation. In this study, the calibration of the pre-positioning was performed under the existing hardware application of the graph instrument system. In this case, we can measure the signal of the animal body more accurately, image the measured signal and use it to reverse the algorithm coordinates of signal sources. The improvement of the positioning calibration and inversion algorithm is applied for animals which require high spatial resolution. According to the time of appearance of auditory stimulus-induced P9 waveforms and the location of nerve activation, we can see that the auditory stimulations from the left and right ears reveal symmetrical brain distributions for the activated nerves, and has no obviously different effects on the timing of evoked responses. Moreover, the intensity and position of the equivalent current dipole(ECD) are deduced from the inversions of the iso-field contour mapping. The minimum-norm estimation (MNE) and the minimum range after introducing the parameters with source iteration of minimum norm (SIMN) are compared. It is found that SIMN can get more concentrated and accurate data than that by using MNE. On the other hand, the magnetic field induced by a current circuit is measured by the coil arrays to simulate a future magnetic image detection system. This is a preconditioning for the development of a SQUID-array magnetic image sensing system.

Normal cellular behaviour in multicellular organisms is achieved by tight control of signaling pathway networks. The mitogen-activated protein kinase (MAPK) signaling cascade is one of these signaling networks, that when deregulated can lead to cellular transformation. Activation of the RAS-RAF-MEK-MAPK (ERK) signal transduction pathway or the SAPK2/p38 pathway results in the activation of mitogen- and stress-activated protein kinases 1 and 2 (MSK1/2). Subsequently, MSKs go on to phosphorylate histone H3 at Ser10 and Ser28.Here, we demonstrate that the activities of ERK and MSK1, but not p38, are elevated in Hras-transformed cells (Ciras-3) relative to these activities in the parental 10T1⁄2 cells. Analyses of the subcellular distribution of MSK1 showed that the H3 kinase was similarly distributed in Ciras-3 and 10T1/2 cells, with most MSK1 being present in the nucleus. In contrast to many other chromatin modifying enzymes, MSK1 was loosely bound in the nucleus and was not a component of the nuclear matrix. Our results provide evidence that oncogene-mediated activation of the RAS-MAPK signal transduction pathway elevates the activity of MSK1, resulting in the increased steady-state levels of phosphorylated H3, which may contribute to the chromatin decondensation and aberrant gene expression observed in oncogene-transformed cells. Furthermore, upon activation of the ERK and p38 MAPK pathways, the MSK1/2- mediated nucleosomal response, including H3 phosphorylation at serine 28 or 10, is coupled with the induction of immediate-early gene transcription. The outcome of this response, varying with the stimuli and cellular contexts, ranges from neoplastic transformation to neuronal synaptic plasticity. Here, we used sequential co-immunoprecipitation assays and chromatin immunoprecipitation (ChIP) assays on mouse fibroblast 10T1/2, Ciras-3 and MSK1 knockdown 10T1/2 cells to show that H3 serine 28 and 10 phosphorylation leads to promoter remodeling. MSK1, in complexes with phospho-serine adaptor 14-3-3 proteins and BRG1 (the ATPase subunit of the SWI/SNF remodeler) is recruited to the promoter of target genes by transcription factors such as ELK-1 or NFκB. Following MSK1-mediated H3 phosphorylation, BRG1 associates with the promoter of target genes via 14-3-3 proteins, which act as scaffolds. The recruited SWI/SNF remodels nucleosomes at the promoter of immediate-early genes enabling the binding of transcription factors like JUN and the onset of transcription. Since RAS-MAPK activated MSKs mediate H3 phosphorylation that is required for expression of various immediate-early gene products involved in cellular transformation, inhibition of MSK activity may be a therapeutic target that could be exploited in cancers with upregulated RAS-MAPK signaling.

Error-control codes, which are being extensively used in communication systems, have found themselves very useful in data storage as well during the past decade. This thesis deals with two types of codes for data storage, one pertaining to the issue of privacy and the other to reliability. In many scenarios, user accessing some critical data from a server would not want the server to learn the identity of data retrieved. This problem, called Private Information Retrieval (PIR) was rst formally introduced by Chor et al and they gave protocols for PIR in the case where multiple copies of the same data is stored in non-communicating servers. The PIR protocols that came up later also followed this replication model. The problem with data replication is the high storage overhead involved, which will lead to large storage costs. Later, Fazeli, Vardy and Yaakobi, came up with the notion of PIR code that enables information-theoretic PIR with low storage overhead. In the rst part of this thesis, construction of PIR codes for certain parameter values is presented. These constructions are based on a variant of conventional Reed-Muller (RM) codes called binary Projective Reed-Muller (PRM) codes. A lower bound on block length of systematic PIR codes is derived and the PRM based PIR codes are shown to be optimal with respect to this bound in some special cases. The codes constructed here have smaller block lengths than the short block length PIR codes known in the literature. The generalized Hamming weights of binary PRM codes are also studied. Another work described here is the implementation and evaluation of an erasure code called Coupled Layer (CL) code in Ceph distributed storage system. Erasure codes are used in distributed storage to ensure reliability. An additional desirable feature required for codes used in this setting is the ability to handle node repair efficiently. The Minimum Storage Regenerating (MSR) version of CL code downloads optimal amount of data from other nodes during repair of a failed node and even disk reads during this process is optimum, for that storage overhead. The CL-Near-MSR code, which is a variant of CL-MSR, can efficiently handle a restricted set of multiple node failures also. Four example CL codes were evaluated using a 26 node Amazon cluster and performance metrics like network bandwidth, disk read and repair time were measured. Repair time reduction of the order of 3 was observed for one of those codes, in comparison with Reed Solomon code having same parameters. To the best of our knowledge, such large gains in repair performance have never been demonstrated before.

This dissertation designs linear transceivers for the multiuser downlink in multiple-input multiple-output (MIMO) systems. The designs rely on an uplink/downlink duality for the mean squared error (MSE) of each individual data stream. We first consider the design of transceivers assuming channel state information (CSI) at the transmitter. We consider minimization of the sum-MSE over all users subject to a sum power constraint on each transmission. Using MSE duality, we solve a computationally simpler convex problem in a virtual uplink. The transformation back to the downlink is simplified by our demonstrating the equality of the optimal power allocations in the uplink and downlink. Our second set of designs maximize the sum throughput for all users. We establish a series of relationships linking MSE to the signal-to-interference-plus-noise ratios of individual data streams and the information theoretic channel capacity under linear minimum MSE decoding. We show that minimizing the product of MSE matrix determinants is equivalent to sum-rate maximization, but we demonstrate that this problem does not admit a computationally efficient solution. We simplify the problem by minimizing the product of mean squared errors (PMSE) and propose an iterative algorithm based on alternating optimization with near-optimal performance. The remainder of the thesis considers the more practical case of imperfections in CSI. First, we consider the impact of delay and limited-rate feedback. We propose a system which employs Kalman prediction to mitigate delay; feedback rate is limited by employing adaptive delta modulation. Next, we consider the robust design of the sum-MSE and PMSE minimizing precoders with delay-free but imperfect estimates of the CSI. We extend the MSE duality to the case of imperfect CSI, and consider a new optimization problem which jointly optimizes the energy allocations for training and data stages along with the sum-MSE/PMSE minimizing transceivers. We prove the separability of these two problems when all users have equal estimation error variances, and propose several techniques to address the more challenging case of unequal estimation errors.

A group of small GTPases consist of over twenty protein families in the super class P-loop. It has a very diverse cell functions. Small GTPases regulate the formation of vesicular follicles, cytoskeleton and nuclear transport. They participate also on cell proliferation and signaling. The aim of my work is to find important amino acids that define family and distinguish each other. I focus on families Arf, Rab, Ran, Ras and Rho. At the Rho family I am also devoted to classes Rho, Rac and Cdc42. Amino acids are identified using bioinformatic programs selected Consurf and Sca5. The objective is also to test P2RANK specialized tool developed at the Charles University in Prague that predict ligand binding sites from protein structure in different families. Founding amino acids can have a big role in the functional divergence of individual families and classes of small GTPases and can be the basis for future study example for the proliferation of cancerous cells. 1.1 Keywords Powered by TCPDF (www.tcpdf.org)

Multiple Sequenzalignments (MSAs) von homologen Proteinen sind nützliche Werkzeuge, um kompensatorische Mutationen zwischen nicht-konservierten Residuen zu charakterisieren. Die Identifizierung dieser Residuen in MSAs ist eine wichtige Aufgabe um die strukturellen Grundlagen und molekularen Mechanismen von Proteinfunktionen besser zu verstehen. Trotz der vielen Anzahl an Literatur über kompensatorische Mutationen sowie über die Sequenzkonservierungsanalyse für die Erkennung von wichtigen Residuen, haben vorherige Methoden meistens die biochemischen Eigenschaften von Aminosäuren nicht mit in Betracht gezogen, welche allerdings entscheidend für die Erkennung von kompensatorischen Mutationssignalen sein können. Jedoch werden kompensatorische Mutationssignale in MSAs oft durch das Rauschen verfälscht. Aus diesem Grund besteht ein weiteres Problem der Bioinformatik in der Trennung signifikanter Signale vom phylogenetischen Rauschen und beziehungslosen Paarsignalen. Das Ziel dieser Arbeit besteht darin Methoden zu entwickeln, welche biochemische Eigenschaften wie Ähnlichkeiten und Unähnlichkeiten von Aminosäuren in der Identifizierung von kompensatorischen Mutationen integriert und sich mit dem Rauschen auseinandersetzt. Deshalb entwickeln wir unterschiedliche Methoden basierend auf klassischer- und quantum Informationstheorie sowie multiple Testverfahren. Unsere erste Methode basiert auf der klassischen Informationstheorie. Diese Methode betrachtet hauptsächlich BLOSUM62-unähnliche Paare von Aminosäuren als ein Modell von kompensatorischen Mutationen und integriert sie in die Identifizierung von wichtigen Residuen. Um diese Methode zu ergänzen, entwickeln wir unsere zweite Methode unter Verwendung der Grundlagen von quantum Informationstheorie. Diese neue Methode unterscheidet sich von der ersten Methode durch gleichzeitige Modellierung ähnlicher und unähnlicher Signale in der kompensatorischen Mutationsanalyse. Des Weiteren, um signifikante Signale vom Rauschen zu trennen, entwickeln wir ein MSA-spezifisch statistisches Modell in Bezug auf multiple Testverfahren. Wir wenden unsere Methode für zwei menschliche Proteine an, nämlich epidermal growth factor receptor (EGFR) und glucokinase (GCK). Die Ergebnisse zeigen, dass das MSA-spezifisch statistische Modell die signifikanten Signale vom phylogenetischen Rauschen und von beziehungslosen Paarsignalen trennen kann. Nur unter Berücksichtigung BLOSUM62-unähnlicher Paare von Aminosäuren identifiziert die erste Methode erfolgreich die krankheits-assoziierten wichtigen Residuen der beiden Proteine. Im Gegensatz dazu, durch die gleichzeitige Modellierung ähnlicher und unähnlicher Signale von Aminosäurepaare ist die zweite Methode sensibler für die Identifizierung von katalytischen und allosterischen Residuen.

This doctoral thesis focuses on the evaluation of the World Bank (WB) performance in delivering development aid to the Least Developed Countries (LDCs). For this purpose, an extensive research was performed to analyze a set of 790 Implementation Completion and Results reports for key economic and financial indicators. Results of this research provide various insights for the appraisal and the results stage of project delivery of the LDCs in different continents. In the final part of the economic and financial analysis the minimum Social Return on Investment (SROI) of the LDCs including all project costs was calculated. This SROI ratio outcome of 1 and 1.06 in the weighted and 1.3 and 1.72 in the unweighted case indicate that projects delivered by the WB have a positive effect on the poor countries. In the second part of this research project the data set of the ICR reports was qualitatively researched for negative ratings according to 3 core assessment categories for the overall project performance: Sustainability, bank performance and borrower performance. As a result the most critical categories respectively risks were outlined. In conclusion, the research analyses and findings support the general demand to provide even more development assistance to poor countries.:Table of Tables and Figures List of Equations List of Abbreviations 1 Introduction 1.1 Introduction to the Topic 1.2 Assessing Poverty Problems and Achieving Economic Growth 1.3 Millennium Development Goals 1.4 Development Aid 2 Research Approach 2.1 Objective 2.2 Structure 2.3 Least Developed Countries 2.4 World Bank 2.5 Data Access and Relevance 2.5.1 Data Basis 2.5.2 Implementation Completion and Results Reports 2.5.3 Project Types 2.6 Term “Performance” 2.7 Study and Research Questions 2.8 Challenges of this Doctoral Thesis 2.9 Contribution of this Thesis 3 Economic and Financial Analysis 3.1 SROI Concept 3.1.1 SROI Definition 3.1.2 SROI Process and Impact Map 3.1.3 Cost-Benefit-Analysis 3.1.4 SROI Calculation 3.2 SROI of World Bank Projects 3.2.1 Purpose of the Cost-Benefit-Analysis 3.2.2 Indicators of the SROI Calculation 3.2.2.1 Net Present Value 3.2.2.2 Capital and Recurring Costs 3.2.2.3 Project Dates and Duration 3.2.2.4 NPV-horizon 3.2.2.5 Discount Rate 3.2.3 Types of NPV-Cost-Ratios 3.2.3.1 Pro-Rata-Capital-Costs Ratio 3.2.3.2 Total-Capital-Costs Ratio 3.2.3.3 Pro-Rata-Capital plus Recurring-Costs Ratio 3.2.3.4 Total-Capital plus Recurring-Costs Ratio 3.2.4 Calculation of the proper SROI Ratio 3.2.5 Portfolio Analysis 3.2.6 Sensitivity Analysis 3.3 Additional Economic and Financial Indicators 3.3.1 Economic Rate of Return 3.3.2 Benefit-Cost-Ratio 3.3.3 Net Benefit 3.3.4 Financial Net Present Value 3.3.5 Financial Rate of Return 4 Results of the Economic and Financial Analysis 4.1 Analysis Approach and Setup 4.2 NPV Outcomes at the Appraisal Stage 4.2.1 Appraisal NPVs of the LDCs 4.2.2 Appraisal NPV Continent Comparison 4.3 NPV Outcomes of the Result Stage 4.3.1 Result NPVs of the LDCs 4.3.2 Result NPV Continent Comparison 4.4 Appraisal vs. Result NPVs 4.4.1 Results of the LDCs 4.4.2 Continent Comparison 4.5 Economic Rate of Return Result Values 4.5.1 Results of the LDCs 4.5.2 Continent Comparison 4.6 Additional Economic and Financial Indicator Result Values 4.6.1 Benefit-Cost-Ratio and Net Benefit 4.6.2 Financial Net Present Value and Financial Rate of Return 4.7 Overall Project Performance 4.7.1 Definition 4.7.2 Overall Project Performance Ratings 4.7.3 Outcome Calculation for Non-Financial Indicator Projects 4.7.4 Verification of Outcomes and Conclusion 4.8 NPV-Cost-Ratios and SROI Calculation 4.8.1 NPV-Cost-Ratios of the ICR Reports 4.8.1.1 Overall Results 4.8.1.2 Continent Comparison 4.8.2 Standardized NPV-Cost-Ratios 4.8.2.1 Overall Results 4.8.2.2 Continent Comparison 4.8.3 Calculating the Minimum SROI Ratio 4.8.3.1 Overall Results of the Capital SROI Ratio 4.8.3.2 Continental Comparison of the Capital SROI Ratio 4.8.3.3 Overall Results of the Minimum SROI Ratio 4.8.3.4 Continental Comparison of the Minimum SROI Ratio 4.8.4 Making Meaning of the Results 4.9 Summary and Conclusion 5 Qualitative Data Analysis 5.1 Content Analysis 5.2 Sustainability 5.2.1 Sustainability Rating Definition 5.2.2 Sustainability Rating Categories 5.3 Bank Performance 5.3.1 Bank Performance Definition 5.3.2 Bank Performance Categories 5.4 Borrower Performance 5.4.1 Borrower Performance Definition 5.4.2 Borrower Performance Categories 6 Results of the Qualitative Data Analysis 6.1 Sustainability 6.1.1 Quantitative Assessment of Sustainability Ratings 6.1.2 Outcome of the Content Analysis 6.1.2.1 Types of Reasons 6.1.2.2 Overall Results 6.1.2.3 Results in Haiti 6.1.2.4 Continent Comparison 6.1.3 Excursus: Positive NPV Projects 6.1.4 Summary and Conclusion 6.2 Bank Performance 6.2.1 Quantitative Assessment of Bank Performance Ratings 6.2.2 Outcome of the Content Analysis 6.2.2.1 Types of Reasons 6.2.2.2 Overall Results 6.2.2.3 Results in Haiti 6.2.2.4 Continent Comparison 6.2.3 Summary and Conclusion 6.3 Borrower Performance 6.3.1 Quantitative Assessment of Borrower Performance Ratings 6.3.2 Outcome of the Content Analysis 6.3.2.1 Types of Reasons 6.3.2.2 Overall Results 6.3.2.3 Results in Haiti 6.3.2.4 Continent Comparison 6.3.3 Summary and Conclusion 7 Overall Summary and Conclusion 8 Critical Acclaim and Recommendations 9 Outlook and Future Research List of Appendices Appendix References