As infecções por Streptococcus pneumoniae (pneumococo) ainda desafiam os sistemas de saúde em todo mundo. Este é um estudo observacional, de seguimento retrospectivo, que avaliou aspectos microbiológicos e clínicos das cepas de pneumococo isoladas de pacientes com doença invasiva pneumocócica (DIP) isolados nos Departamentos Regionais de Saúde (DRS) de Araraquara, Barretos, Franca e Ribeirão Preto, em um período de 16 anos (1998-2013). As informações foram obtidas junto ao Instituto Adolfo Lutz e, no banco de dados do Hospital das Clínicas de Ribeirão Preto (HCRP). Analisou-se 796 linhagens, com predominio do gênero masculino (58,9%), da faixa etária de 20 a menores de 60 anos de idade (32,2%) e do período de 2003 a 2010 (60,2%). As DIPs mais comuns foram a meningite (45,7%) e a pneumonia (45,0%). Quanto aos sorotipos mais frequentes, observou-se em 83,3%: 14, 3, 19F, 1, 6A, 6B, 23F, 9V, 18C, 19A, 12F, 4, 7F, 5, 22F, 11A, 8, 9N, 10A e 15C, sendo o 14 o mais comum nos quatro DRS estudados. Os sorotipos 14, 3 e 19F foram mais frequentes na meningite, enquanto os sorotipos 14, 3 e 1 na pneumonia. Após 2010, verificou-se diminuição dos sorotipos 14, 1, 23F e 5 e aumento de 12F, 11A e 8, não contidos na vacina. A resistência à penicilina foi de 14,8%, sendo 3,0% resistência intermediária e 11,8% de resistência plena. Para ceftriaxona, 5,3% foram não sensíveis. A sensibilidade ao cloranfenicol, eritromicina e ceftriaxona manteve-se acima dos 90%, no período estudado. O maior nível de resistência foi observado para Sulfametoxazol/trimetoprim (49,4%). Destaca-se o aumento dos sorotipos 12F, 11A e 8 após a vacinação, considerando que nenhum deles compõe as vacinas conjugadas disponíveis. Observou-se variabilidade de resistência entre os diferentes sorotipos de pneumococo. A DIP mais frequente nos pacientes cadastrados no HCRP foi a pneumonia (67,8%), seguida da meningite (22,9%) tendo como sorotipos mais frequentes 14, 6A, 23F, 1, 3, 18C, 19F, 12F, 4,9V, 6B e 19A. Destes pacientes 67,5% apresentaram cura sem sequelas, 6,9% tiveram algum tipo de sequela e 25,6% evoluíram para óbito. A pneumonia causou 18,2% dos óbitos, principalmente na faixa etária de 20 a menores de 60 anos de idade. Os sorotipos 12F, 14, 18C, 9V, 18A, 19A e 23F foram responsáveis por 64,9% dos óbitos por meningite, enquanto os sorotipos 3, 14, 9V, 6B, 23F e 19F estiveram envolvidos em 63,4% das mortes por pneumonia. Entre os pacientes que morreram 68,2% tinham algum tipo de comorbidade, sendo HIV/AIDS, alcoolismo e câncer as mais comuns. A faixa etária com 60 anos ou mais foi a mais significativa (OR=4,2) para o insucesso, independente da presença de comorbidade. A presença do sorotipo 18C foi fator de risco significativo tanto na análise bruta (OR=3,8), quanto ao ajustar por comorbidade (OR=5,0) ou ajustada por idade (OR=5,4). O mesmo ocorreu para o sorotipo 12F (respectivamente, OR=5,1, OR=5,0 e OR=4,7). Observou-se alterações na circulação de alguns sorotipos de pneumococo no período pós VPC10. Ressalta-se a importância da continuidade da vigilância das DIPs, afim de determinar oscilações clínicas e microbiológicas da doença. Além disto, na era das vacinas conjugadas, o contínuo monitoramento sobre a distribuição de sorotipos na população é necessário para a avaliação do impacto e adequação da imunização / Infections by Streptococcus pneumoniae (pneumococcus) are still a challenge to health systems worldwide. An observational retrospective study was developed to assess microbiological and clinical aspects of pneumococcus strains isolated from patients with invasive pneumococcal diseases (IPD) which were isolated in the Regional Health Departments (DRS) of Araraquara, Barretos, Franca and Ribeirão Preto, in a period of 16 years (1998-2013). Data were obtained at the Adolfo Lutz Institute and in databases of the Clinics Hospital of Ribeirão Preto (HCRP). A total of 796 strains were analyzed, with prevalence of male individuals (58.9%), aged between 20 and 60 years (32.2%), and in the period between 2003 and 2010 (60.2%). The most common IPD were meningitis (45.7%) and pneumonia (45.0%). Regarding the most frequent serotypes, in 83.3% they were: 14, 3, 19F, 1, 6A, 6B, 23F, 9V, 18C, 19A, 12F, 4, 7F, 5, 22F, 11A, 8, 9N, 10A and 15C, with 14 being the most common in the four DRS studied. Serotypes 14, 3 and 19F were more frequent in meningitis, whereas serotypes 14, 3 and 1 were more frequent in pneumonia. After 2010, there was a decrease in serotypes 14, 1, 23F and 5, and an increase in 12F, 11A and 8, which are not included in the vaccine. Resistance to penicillin was 14.8%, with 3.0% being intermediate, and 11.8% full resistance. For ceftriaxone, 5.3% were not sensitive. Sensitivity to chloramphenicol, erythromycin and ceftriaxone remained over 90% in the studied period. The highest level of resistance was observed for Sulfamethoxazole/trimethoprim (49.4%). It is noteworthy that there was an increase in the s serotypes 12F, 11A and 8 after vaccination, considering that none of them make up the combined vaccines available. Resistance varied among the different serotypes of pneumococcus. The most frequent IPD in the patients registered in the HCRP was pneumonia (67.8%), followed by meningitis (22.9%), with the most frequent serotypes being 14, 6A, 23F, 1, 3, 18C, 19F, 12F, 4, 9V, 6B and 19A. Of these patients, 67.5% were cured without sequela, 6.9% had some sort of sequela and 25.6% evolved to death. Pneumonia caused 18.2% of the deaths, mainly in the age range between 20 and 60 years. Serotypes 12F, 14, 18C, 9V, 18A, 19A and 23F were responsible for 64.9% of the deaths by meningitis, whereas serotypes 3, 14, 9V, 6B, 23F and 19F were involved in 63.4% of the deaths by pneumonia. Among the patients who died, 68.2% had some sort of comorbidity, with HIV/AIDS, alcoholism and cancer being the most common. The age range over 60 years was the most significant (OR=4.2) for failure, regardless of the presence of a comorbidity. The presence of serotype 18C was a significant risk factor both in the gross analysis (OR=3.8), and in the adjustment as for comorbidity (OR=5.0) or age (OR=5.4). This was also true for the serotype 12F (respectively, OR=5.1, OR=5.0 and OR=4.7). There were alterations in the circulation of some pneumococcus serotypes in the period after VPC10. it is emphasized the importance of continued monitoring of DIPs, in order to determine clinical and microbiological fluctuations of the disease. In addition, in the era of combined vaccines, it is necessary to keep monitoring the distribution of serotypes in the population to assess the impact and adequacy of immunization

On considère le problème de contrôle optimal de temps minimal pour des systèmes affine et mono-entrée en dimension finie, avec conditions initiales et finales fixées, où le contrôle scalaire prend ses valeurs dans un intervalle fermé. Lors de l'application d'une méthode de tir pour résoudre ce problème, on peut rencontrer des obstacles numériques car la fonction de tir n'est pas lisse lorsque le contrôle est bang-bang. Pour ces systèmes, dans le cas bang-bang, un concept théorique de temps conjugué a été défini, toutefois les algorithmes de calcul direct sont difficiles à appliquer. En outre, les questions théoriques et pratiques de la théorie du temps conjugué sont bien connues dans le cas lisse, et des outils efficaces de mise en oeuvre sont disponibles. On propose une procédure de régularisation pour laquelle les solutions du problème de temps minimal dépendent d'un paramètre réel positif suffisamment petit et sont définis par des fonctions lisses en temps, ce qui facilite l'application de la méthode de tir simple. Sous des hypothèses convenables, nous prouvons un résultat de convergence forte des solutions du problème régularisé vers la solution du problème initial, lorsque le paramètre réel tend vers zéro. Le calcul des temps conjugués pour les trajectoires localement optimales du problème régularisé est standard. Nous prouvons, sous des hypothèses appropriées, la convergence du premier temps conjugué du problème régularisé vers le premier temps conjugué du problème de contrôle bang-bang initial, quand le paramètre réel tend vers zéro. Ainsi, on obtient une procédure algorithmique efficace pour calculer les temps conjugués dans le cas bang-bang. / In this thesis we consider a minimal time control problem for single-input control-affine systems in finite dimension with fixed initial and final conditions, where the scalar control take values on a closed interva1. When applying a shooting method for solving this problem, one may encounter numerical obstacles due to the fact that the shooting function is non smooth whenever the control is bang-bang. For these systems a theoretical concept of conjugate time has been defined in the bang-bang case, however direct algorithms of computation are difficult to apply. Besides, theoretical and practical issues for conjugate time theory are well known in the smooth case, and efficient implementation tools are available. We propose a regularization procedure for which the solutions of the minimal time problem depend on a small enough real positive parameter and are defined by smooth functions with respect to the time variable, facilitating the application of a single shooting method. Under appropriate assumptions, we prove a strong convergence result of the solutions of the regularized problem towards the solution of the initial problem, when the real parameter tends to zero. The conjugate times computation of the locally optimal trajectories for the regularized problem falls into the standard theory. We prove, under appropriate assumptions, the convergence of the first conjugate time of the regularized problem towards the first conjugate time of the initial bang-bang control problem, when the real parameter tends to zero. As a byproduct, we obtain an efficient algorithmic way to compute conjugate times in the bang-bang case.

As infecções por Streptococcus pneumoniae (pneumococo) ainda desafiam os sistemas de saúde em todo mundo. Este é um estudo observacional, de seguimento retrospectivo, que avaliou aspectos microbiológicos e clínicos das cepas de pneumococo isoladas de pacientes com doença invasiva pneumocócica (DIP) isolados nos Departamentos Regionais de Saúde (DRS) de Araraquara, Barretos, Franca e Ribeirão Preto, em um período de 16 anos (1998-2013). As informações foram obtidas junto ao Instituto Adolfo Lutz e, no banco de dados do Hospital das Clínicas de Ribeirão Preto (HCRP). Analisou-se 796 linhagens, com predominio do gênero masculino (58,9%), da faixa etária de 20 a menores de 60 anos de idade (32,2%) e do período de 2003 a 2010 (60,2%). As DIPs mais comuns foram a meningite (45,7%) e a pneumonia (45,0%). Quanto aos sorotipos mais frequentes, observou-se em 83,3%: 14, 3, 19F, 1, 6A, 6B, 23F, 9V, 18C, 19A, 12F, 4, 7F, 5, 22F, 11A, 8, 9N, 10A e 15C, sendo o 14 o mais comum nos quatro DRS estudados. Os sorotipos 14, 3 e 19F foram mais frequentes na meningite, enquanto os sorotipos 14, 3 e 1 na pneumonia. Após 2010, verificou-se diminuição dos sorotipos 14, 1, 23F e 5 e aumento de 12F, 11A e 8, não contidos na vacina. A resistência à penicilina foi de 14,8%, sendo 3,0% resistência intermediária e 11,8% de resistência plena. Para ceftriaxona, 5,3% foram não sensíveis. A sensibilidade ao cloranfenicol, eritromicina e ceftriaxona manteve-se acima dos 90%, no período estudado. O maior nível de resistência foi observado para Sulfametoxazol/trimetoprim (49,4%). Destaca-se o aumento dos sorotipos 12F, 11A e 8 após a vacinação, considerando que nenhum deles compõe as vacinas conjugadas disponíveis. Observou-se variabilidade de resistência entre os diferentes sorotipos de pneumococo. A DIP mais frequente nos pacientes cadastrados no HCRP foi a pneumonia (67,8%), seguida da meningite (22,9%) tendo como sorotipos mais frequentes 14, 6A, 23F, 1, 3, 18C, 19F, 12F, 4,9V, 6B e 19A. Destes pacientes 67,5% apresentaram cura sem sequelas, 6,9% tiveram algum tipo de sequela e 25,6% evoluíram para óbito. A pneumonia causou 18,2% dos óbitos, principalmente na faixa etária de 20 a menores de 60 anos de idade. Os sorotipos 12F, 14, 18C, 9V, 18A, 19A e 23F foram responsáveis por 64,9% dos óbitos por meningite, enquanto os sorotipos 3, 14, 9V, 6B, 23F e 19F estiveram envolvidos em 63,4% das mortes por pneumonia. Entre os pacientes que morreram 68,2% tinham algum tipo de comorbidade, sendo HIV/AIDS, alcoolismo e câncer as mais comuns. A faixa etária com 60 anos ou mais foi a mais significativa (OR=4,2) para o insucesso, independente da presença de comorbidade. A presença do sorotipo 18C foi fator de risco significativo tanto na análise bruta (OR=3,8), quanto ao ajustar por comorbidade (OR=5,0) ou ajustada por idade (OR=5,4). O mesmo ocorreu para o sorotipo 12F (respectivamente, OR=5,1, OR=5,0 e OR=4,7). Observou-se alterações na circulação de alguns sorotipos de pneumococo no período pós VPC10. Ressalta-se a importância da continuidade da vigilância das DIPs, afim de determinar oscilações clínicas e microbiológicas da doença. Além disto, na era das vacinas conjugadas, o contínuo monitoramento sobre a distribuição de sorotipos na população é necessário para a avaliação do impacto e adequação da imunização / Infections by Streptococcus pneumoniae (pneumococcus) are still a challenge to health systems worldwide. An observational retrospective study was developed to assess microbiological and clinical aspects of pneumococcus strains isolated from patients with invasive pneumococcal diseases (IPD) which were isolated in the Regional Health Departments (DRS) of Araraquara, Barretos, Franca and Ribeirão Preto, in a period of 16 years (1998-2013). Data were obtained at the Adolfo Lutz Institute and in databases of the Clinics Hospital of Ribeirão Preto (HCRP). A total of 796 strains were analyzed, with prevalence of male individuals (58.9%), aged between 20 and 60 years (32.2%), and in the period between 2003 and 2010 (60.2%). The most common IPD were meningitis (45.7%) and pneumonia (45.0%). Regarding the most frequent serotypes, in 83.3% they were: 14, 3, 19F, 1, 6A, 6B, 23F, 9V, 18C, 19A, 12F, 4, 7F, 5, 22F, 11A, 8, 9N, 10A and 15C, with 14 being the most common in the four DRS studied. Serotypes 14, 3 and 19F were more frequent in meningitis, whereas serotypes 14, 3 and 1 were more frequent in pneumonia. After 2010, there was a decrease in serotypes 14, 1, 23F and 5, and an increase in 12F, 11A and 8, which are not included in the vaccine. Resistance to penicillin was 14.8%, with 3.0% being intermediate, and 11.8% full resistance. For ceftriaxone, 5.3% were not sensitive. Sensitivity to chloramphenicol, erythromycin and ceftriaxone remained over 90% in the studied period. The highest level of resistance was observed for Sulfamethoxazole/trimethoprim (49.4%). It is noteworthy that there was an increase in the s serotypes 12F, 11A and 8 after vaccination, considering that none of them make up the combined vaccines available. Resistance varied among the different serotypes of pneumococcus. The most frequent IPD in the patients registered in the HCRP was pneumonia (67.8%), followed by meningitis (22.9%), with the most frequent serotypes being 14, 6A, 23F, 1, 3, 18C, 19F, 12F, 4, 9V, 6B and 19A. Of these patients, 67.5% were cured without sequela, 6.9% had some sort of sequela and 25.6% evolved to death. Pneumonia caused 18.2% of the deaths, mainly in the age range between 20 and 60 years. Serotypes 12F, 14, 18C, 9V, 18A, 19A and 23F were responsible for 64.9% of the deaths by meningitis, whereas serotypes 3, 14, 9V, 6B, 23F and 19F were involved in 63.4% of the deaths by pneumonia. Among the patients who died, 68.2% had some sort of comorbidity, with HIV/AIDS, alcoholism and cancer being the most common. The age range over 60 years was the most significant (OR=4.2) for failure, regardless of the presence of a comorbidity. The presence of serotype 18C was a significant risk factor both in the gross analysis (OR=3.8), and in the adjustment as for comorbidity (OR=5.0) or age (OR=5.4). This was also true for the serotype 12F (respectively, OR=5.1, OR=5.0 and OR=4.7). There were alterations in the circulation of some pneumococcus serotypes in the period after VPC10. it is emphasized the importance of continued monitoring of DIPs, in order to determine clinical and microbiological fluctuations of the disease. In addition, in the era of combined vaccines, it is necessary to keep monitoring the distribution of serotypes in the population to assess the impact and adequacy of immunization

Estudos realizados e recomendados pela OMS e UNICEF, indicam alta prevalência de infecções pneumocócicas e meningocócicas, sobretudo em crianças abaixo dos dois anos de idade. O Streptococcus pneumoniae é um dos agentes mais frequentes de pneumonia, otite média aguda (OMA), meningite e sinusite em crianças. O número global de mortes em crianças menores de cinco anos de idade causadas por pneumonia foi de 8,8 milhões, em 2008. O Ministério da Saúde, devido ao alcance de bons resultados com soroconversão por imunização, indicou a implantação das vacinas antipneumocócica 10-valente e meningocócica C conjugadas no calendário vacinal das crianças menores de dois anos de idade. Na presente pesquisa, conduziu-se um estudo transversal com componente retrospectivo desenvolvido nas redes de Atenção Básica e Hospitalar de Guaranésia, cidade de pequeno porte do interior do estado de Minas Gerais. Objetivou-se avaliar o impacto da vacinação na ocorrência de doenças respiratórias em lactentes, considerando o período anterior e posterior à introdução da vacina antipneumocócica 10-valente, no Programa Nacional de Imunização. Na análise estatística definiu-se o período entre 2009 e 2012. O método de estudo adotado foi o um estudo transversal aninhado em uma série temporal, sendo observado que no período pós introdução da vacina antipneumocócica 10 valente conjugada houve uma redução de 40% na prevalência de pneumonia adquirida na comunidade, com diferença estatística entre os dois períodos . Confirmou-se que a oscilação sazonal tem interferência nas doenças estudadas. Em relação ao sexo, constatou-se que o masculino tem predomínio sobre o feminino quanto ao acometimento por pneumonia. Foi observado que o sexo masculino apresentou 28% mais chance de PNM. Em relação à otite média aguda e à rinossinusite, a variável sexo não apresentou predomínio entre elas. Os dados estatísticos, considerando a razão de prevalência (RP = 1,96 (IC95%: 1,52 2,53); p <0,05), sugeriram que não vacinar está associado com a ocorrência de PNM. Constatou-se que a prevalência de PNM foi 70% menor (RP 0,30 (IC95%: 0,24 0,37); p<0,05) nas crianças com vacina em dia comparando-se àquelas com a vacina em atraso, ou seja, manter vacina em dia sugere proteção contra PNM. No entanto, houve 53% menos OMA entre não vacinados do que entre vacinados (RP = 0,47 (IC95%: 0,35 0,64); p<0,05). Diante dos resultados encontrados, pode-se concluir que a vacinação antipneumocócica 10-valente está associada com redução dos casos de pneumonia adquirida na comunidade em lactentes. / Studies and recommended by WHO and UNICEF, indicate a high prevalence of pneumococcal and meningococcal infections, especially in children under two years of age. Streptococcus pneumoniae is one of the most frequent agents of pneumonia, acute otitis media (AOM), meningitis and sinusitis in children. The overall number of deaths in children under five years of age caused by pneumonia was 8.8 million in 2008. The Ministry of Health due to reach good results with seroconversion by immunization, indicated the implementation of pneumococcal vaccines 10- meningococcal C conjugate and brave in the immunization schedule of children under two years of age. In this research, conducted a cross-sectional study with retrospective component developed in primary care networks and Hospital Guaranésia, small town in the state of Minas Gerais. This study aimed to assess the impact of vaccination on the incidence of respiratory diseases in infants, considering the time before and after the introduction of the vaccine pneumococcal 10-valent, the National Immunization Program. Statistical analysis defined the period between 2009 and 2012. The adopted method of study was a cross-sectional study nested in a time series, it was observed that in the post introduction period of pneumococcal vaccine conjugate 10 brave there was a 40% reduction in the prevalence of community-acquired pneumonia, with statistical difference between the two periods. It was confirmed that the seasonal oscillation has interference in the diseases. With regard to gender, it was found that the male is predominant over females in relation to involvement by pneumonia. It was observed that men had 28% more chance of pneumonia. In relation to acute otitis media and sinusitis, sex does not showed a predominance among them. Statistical data, considering the prevalence ratio (PR = 1.96 (95% CI: 1.52 to 2.53), p <0.05), suggested that not vaccinating is associated with the occurrence of pneumonia. It was found that the prevalence of pneumonia was 70% lower (PR 0.30 (95% CI: 0.24 to 0.37), p <0.05) in children with day vaccine is compared to those of the vaccine in delay, ie to keep day suggests vaccine protection against pneumonia. However, there were 53% fewer of AOM than for unvaccinated vaccinated (OR = 0.47 (95% CI: 0.35 to 0.64); p <0.05). Considering the results, it can be concluded that vaccination pneumococcal 10-valent is associated with reduction of cases of community-acquired pneumonia in infants.

Stimuli responsive coatings offer a versatile method by which to manipulate interfacial interactions of proteins in a desired way. However, there exists little guidance as to how the structure of a responsive polymer coating influences adsorption of proteins. In this dissertation, the adsorption behavior of immuglobulin G (IgG) on poly (N-isopropylacryamide) (PNIPAAm) hydrogel coatings was investigated as a function of film thickness. PNIPAAm exhibits a hydrophilic to hydrophobic transition above a critical temperature of ~32°C in aqueous solutions. In this research, through the use of quartz crystal microbalance with dissipation (QCM-D) it was observed that the adsorption was thickness dependent and became non-reversible as the temperature was decreased. Interestingly, QCM-D results also suggested a similar amount of protein adsorption on both hydrated and dehydrated PNIPAAm surfaces. A rigid film analysis using Sauerbrey equation revealed a multi-layer formation on the collapsed PNIPAAm coatings. Although it is allegedly reported that PNIPAAm favors adsorption above the critical temperature due to hydrophobic interactions, there have been several studies that reported adsorption of proteins below the critical temperature. To better understand the QCM-D results, hydrodynamic shear force assays in a spinning disk configuration were performed in order to quickly measure and quantify adhesion of polystyrene (PS) probe spheres (10μm) to the PNIPAAm coatings in both the solvated (hydrophilic) and collapsed (hydrophobic) state. The influence of polymer coating thickness, polymer chain cross-link density, microsphere concentration and adsorption time on the adhesion characteristics of the coatings was investigated in relation with volume phase transition of the polymer coatings. A series of experiments on quantification of the temperature dependent adhesion of proteins adsorbed on surface attached PNIPAAm coatings of thicknesses was performed as the surface chemistry was switched from hydrophilic to hydrophobic. First, adhesion of polystyrene (PS) microspheres on PNIPAAm coatings was quantified in order to have a guideline for temperature dependent adhesion performance of these coatings. PS particles were subjected to a range of detachment shear stresses through hydrodynamic flow in a spinning disk configuration. These experiments provide an indirect method to determine the force of adhesion since it is proportional to the hydrodynamic force. Model protein, IgG, was then linked to PS microspheres and the mean adhesion strength of the IgG coated PS microspheres were determined through the detachment shear stresses. The influence of PS deposition time, PS bead concentration, PNIPAAm coating thickness and PNIPAAm cross-link density on the adhesion strength were addressed. The results indicated that in the collapsed state, the adhesion of bare hydrophobic PS microspheres depends strongly on coating thickness. For hydrophilic charged PS microspheres the adhesion was always higher on the hydrated PNIPAAm surfaces and appeared not to be strongly affected by the increase in PNIPAAm coating thickness. The adhesion of IgG was higher on the collapsed PNIPAAm surfaces and the adhesion trend did not significantly change as the PNIPAAm film thickness was increased. For PNIPAAm coatings with the cross-link density reduced by factor of 10, the adhesion was again higher on the collapsed PNIPAAm surface and scaled linearly with thickness. Moreover, the influence of thickness became prominent at the higher thickness values (165 nm-185 nm). In addition, the adhesion of carboxylated microspheres on PNIPAAm did not reach equilibrium and increased linearly with microsphere deposition time. A study on the sensing characteristics of PNIPAAm coatings in response to heavy metal ions was also conducted in this dissertation. The temperature-dependent swelling behavior of poly(N-isopropylacrylamide) and tripeptide Gly-Gly-His/poly(NIPAAm) conjugate hydrogel coatings were investigated using a quartz crystal microbalance with dissipation (QCM-D) while in contact with NaCl, ZnCl2, NiCl2, and CuCl2 solutions. To fabricate the tripeptide conjugated gels, precursor gels of poly(NIPAAm-co-3-aminopropylmethacrylamide[3.5 mole%]) were synthesized via free radical polymerization. The metal binding tripeptide, Gly-Gly-His, was subsequently synthesized in the gel via a Merrifield solid phase peptide synthesis (SPPS) technique, in which the amino group of the copolymer gel provided a functional site to support peptide synthesis. It was found that the logarithm of the transition temperature of the tripeptide Gly-Gly-His/poly(NIPAAm) conjugate hydrogel was proportional to the ionic strength, showing two distinct regions at low and high ionic strengths for the divalent ions. In the low ionic strength regime, the salting out constants were 0.08 M-1, 0.07 M-1, and 0.06 M-1 for Cu2+, Ni2+, and Zn2+, respectively, which follows the known trend for binding of the ions to Gly-Gly-His. In the high ionic strength region, when the metal-ion binding sites in the tripeptide conjugate hydrogel were saturated, the salting out constants were similar to the salting out constants associated with pure poly(NIPAAm).

Polypropionate marine natural products have emerged as a class of compounds that display a high degree of structural diversity. Specifically, metabolites such as that reported as tridachiahydropyrone (7), isolated from sacoglossan molluscs, display novel ring systems. The introductory chapter gives some background on tridachione marine natural products and outlines the isolation of metabolites from several species of sacoglossan mollusc. Chapter One also gives examples of the utility of the tandem conjugate addition-Dieckmann condensation approach being applied to the synthesis of these compounds. Chapter Two describes the development of the tandem conjugate addition-Dieckmann condensation and subsequent trans methylation approach to cyclohexenone rings. The synthetic strategy utilised chiral, functionalised cyclohexenone rings as synthons in the formation of bicyclic ring systems, so development of the carbocyclic ring formation was of vital importance to the overall strategy. Examples are given which confirm the viability of the proposed synthetic route to cyclohexenones such as 91, 92 and 104 from the reaction of [alpha,beta]-unsaturated carbonyl compounds 39 and 59 with dialkyl and dialkenyl Gilman cuprates. Chapter Three describes the incorporation of chiral cyclohexenone 117 into the bicyclic framework of model compound 105, analogous to the marine natural product reported as tridachiahydropyrone (7). The chapter explores the use of cyclohexenone precursor 43 that contained the total carbon framework of the bicyclic core of the desired pyrone. Once again, a tandem conjugate addition-cyclisation reaction was employed using a dialkyl Gilman cuprate, followed by trans methylation to give the requisite cyclohexenone synthon 117. A novel Eaton’s reagent-promoted intramolecular cyclisation of acid 122 to pyrone 123 was then effected. Subsequent O-methylation afforded [alpha]-methoxy-[beta]-methyl-[gamma]-pyrone 105 as a single enantiomer, which had the identical core structure to the natural product. The structure, including relative stereochemistry of 105, was confirmed by single crystal X-ray analysis. Chapter Four builds on the previous two chapters and describes the conjugate addition-cyclisation with a higher order Gilman cuprate derived from vinyl bromide 44, which would deliver the vinyl side-chain required for the synthesis of reported natural product 7. The same acyclic precursor 43 as used in Chapter Three was cyclised and methylated to yield yet another cyclohexenone synthon 41. A single crystal X-ray analysis of related alcohol 162 confirmed the relative stereochemistry and structure. Another novel P2O5-mediated intramolecular cyclisation was achieved to give pyrone 168 and O-methylation provided a compound with the reported structure of natural product 7 as a single enantiomer. The structure of synthetic 7 was established unequivocally through extensive NMR studies. Comparisons of spectral data confirmed that natural tridachiahydropyrone was not the same as synthetic compound 7, so revision of the assigned natural product structure is warranted. Several other analogues were also synthesised using this methodology, highlighting the versatility of the method under development.

<p>Vid analys av vattenprover tagna från t.ex. ett vattendrag betäms halten av olika ämnen. Dessa halter är ofta beroende av vattenföringen. Det är av intresse att ta reda på om observerade förändringar i halterna beror på naturliga variationer eller är orsakade av andra faktorer. För att undersöka detta har föreslagits en statistisk tidsseriemodell som innehåller okända parametrar. Modellen anpassas till uppmätta data vilket leder till ett underbestämt ekvationssystem. I avhandlingen studeras bl.a. olika sätt att säkerställa en unik och rimlig lösning. Grundidén är att införa vissa tilläggsvillkor på de sökta parametrarna. I den studerade modellen kan man t.ex. kräva att vissa parametrar inte varierar kraftigt med tiden men tillåter årstidsvariationer. Det görs genom att dessa parametrar i modellen regulariseras.</p><p>Detta ger upphov till ett minsta kvadratproblem med en eller två regulariseringsparametrar. I och med att inte alla ingående parametrar regulariseras får vi dessutom ett partiellt regulariserat minsta kvadratproblem. I allmänhet känner man inte värden på regulariseringsparametrarna utan problemet kan behöva lösas med flera olika värden på dessa för att få en rimlig lösning. I avhandlingen studeras hur detta problem kan lösas numeriskt med i huvudsak två olika metoder, en iterativ och en direkt metod. Dessutom studeras några sätt att bestämma lämpliga värden på regulariseringsparametrarna.</p><p>I en iterativ lösningsmetod förbättras stegvis en given begynnelseapproximation tills ett lämpligt valt stoppkriterium blir uppfyllt. Vi använder här konjugerade gradientmetoden med speciellt konstruerade prekonditionerare. Antalet iterationer som krävs för att lösa problemet utan prekonditionering och med prekonditionering jämförs både teoretiskt och praktiskt. Metoden undersöks här endast med samma värde på de två regulariseringsparametrarna.</p><p>I den direkta metoden används QR-faktorisering för att lösa minsta kvadratproblemet. Idén är att först utföra de beräkningar som kan göras oberoende av regulariseringsparametrarna samtidigt som hänsyn tas till problemets speciella struktur.</p><p>För att bestämma värden på regulariseringsparametrarna generaliseras Reinsch’s etod till fallet med två parametrar. Även generaliserad korsvalidering och en mindre beräkningstung Monte Carlo-metod undersöks.</p> / <p>Statistical analysis of data from rivers deals with time series which are dependent, e.g., on climatic and seasonal factors. For example, it is a well-known fact that the load of substances in rivers can be strongly dependent on the runoff. It is of interest to find out whether observed changes in riverine loads are due only to natural variation or caused by other factors. Semi-parametric models have been proposed for estimation of time-varying linear relationships between runoff and riverine loads of substances. The aim of this work is to study some numerical methods for solving the linear least squares problem which arises.</p><p>The model gives a linear system of the form <em>A</em><em>1x1</em><em> + A</em><em>2x2</em><em> + n = b</em><em>1</em>. The vector <em>n</em> consists of identically distributed random variables all with mean zero. The unknowns, <em>x,</em> are split into two groups, <em>x</em><em>1</em><em> </em>and <em>x</em><em>2</em><em>.</em> In this model, usually there are more unknowns than observations and the resulting linear system is most often consistent having an infinite number of solutions. Hence some constraint on the parameter vector x is needed. One possibility is to avoid rapid variation in, e.g., the parameters<em> x</em><em>2</em><em>.</em> This can be accomplished by regularizing using a matrix <em>A</em><em>3</em>, which is a discretization of some norm. The problem is formulated</p><p>as a partially regularized least squares problem with one or two regularization parameters. The parameter <em>x</em><em>2</em> has here a two-dimensional structure. By using two different regularization parameters it is possible to regularize separately in each dimension.</p><p>We first study (for the case of one parameter only) the conjugate gradient method for solution of the problem. To improve rate of convergence blockpreconditioners of Schur complement type are suggested, analyzed and tested. Also a direct solution method based on QR decomposition is studied. The idea is to first perform operations independent of the values of the regularization parameters. Here we utilize the special block-structure of the problem. We further discuss the choice of regularization parameters and generalize in particular Reinsch’s method to the case with two parameters. Finally the cross-validation technique is treated. Here also a Monte Carlo method is used by which an approximation to the generalized cross-validation function can be computed efficiently.</p>

Controlling interactions in synthetic polymers as precisely as in proteins would have a strong impact on polymer science. Advanced structural and functional control can lead to rational design of, integrated nano- and microstructures. To achieve this, properties of monomer sequence defined oligopeptides were exploited. Through their incorporation as monodisperse segments into synthetic polymers we learned in recent four years how to program the structure formation of polymers, to adjust and exploit interactions in such polymers, to control inorganic-organic interfaces in fiber composites and induce structure in Biomacromolecules like DNA for biomedical applications. / Die Kontrolle von Wechselwirkungen in synthetischen Polymersystemen mit vergleichbarer Präzision wie in Polypeptiden und Proteinen hätte einen dramatischen Einfluss auf die Möglichkeiten in den Polymer- und Materialwissenschaften. Um dies zu erreichen, werden im Rahmen dieser Arbeit Eigenschaften von Oligopeptiden mit definierter Monomersequenz ausgenutzt. Die Integration dieser monodispersen Biosegmente in synthetische Polymere erlaubt z. B. den Aufbau von Peptid-block-Polymer Copolymeren. In solchen sogenannten Peptid-Polymer-Konjugaten sind die Funktionalitäten, die Sekundärwechselwirkungen und die biologische Aktivität des Peptidsegments präzise programmierbar. In den vergangen vier Jahren konnte demonstriert werden, wie in Biokonjugatsystemen die Mikrostrukturbildung gesteuert werden kann, wie definierte Wechselwirkungen in diesen Systemen programmiert und ausgenutzt werden können und wie Grenzflächen zwischen anorganischen und organischen Komponenten in Faserkompositmaterialien kontrolliert werden können. Desweiteren konnten Peptid-Polymer-Konjugate verwendet werden, um für biomedizinische Anwendungen DNS gezielt zu komprimieren oder Zelladhäsion auf Oberflächen zu steuern.

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Vid analys av vattenprover tagna från t.ex. ett vattendrag betäms halten av olika ämnen. Dessa halter är ofta beroende av vattenföringen. Det är av intresse att ta reda på om observerade förändringar i halterna beror på naturliga variationer eller är orsakade av andra faktorer. För att undersöka detta har föreslagits en statistisk tidsseriemodell som innehåller okända parametrar. Modellen anpassas till uppmätta data vilket leder till ett underbestämt ekvationssystem. I avhandlingen studeras bl.a. olika sätt att säkerställa en unik och rimlig lösning. Grundidén är att införa vissa tilläggsvillkor på de sökta parametrarna. I den studerade modellen kan man t.ex. kräva att vissa parametrar inte varierar kraftigt med tiden men tillåter årstidsvariationer. Det görs genom att dessa parametrar i modellen regulariseras. Detta ger upphov till ett minsta kvadratproblem med en eller två regulariseringsparametrar. I och med att inte alla ingående parametrar regulariseras får vi dessutom ett partiellt regulariserat minsta kvadratproblem. I allmänhet känner man inte värden på regulariseringsparametrarna utan problemet kan behöva lösas med flera olika värden på dessa för att få en rimlig lösning. I avhandlingen studeras hur detta problem kan lösas numeriskt med i huvudsak två olika metoder, en iterativ och en direkt metod. Dessutom studeras några sätt att bestämma lämpliga värden på regulariseringsparametrarna. I en iterativ lösningsmetod förbättras stegvis en given begynnelseapproximation tills ett lämpligt valt stoppkriterium blir uppfyllt. Vi använder här konjugerade gradientmetoden med speciellt konstruerade prekonditionerare. Antalet iterationer som krävs för att lösa problemet utan prekonditionering och med prekonditionering jämförs både teoretiskt och praktiskt. Metoden undersöks här endast med samma värde på de två regulariseringsparametrarna. I den direkta metoden används QR-faktorisering för att lösa minsta kvadratproblemet. Idén är att först utföra de beräkningar som kan göras oberoende av regulariseringsparametrarna samtidigt som hänsyn tas till problemets speciella struktur. För att bestämma värden på regulariseringsparametrarna generaliseras Reinsch’s etod till fallet med två parametrar. Även generaliserad korsvalidering och en mindre beräkningstung Monte Carlo-metod undersöks. / Statistical analysis of data from rivers deals with time series which are dependent, e.g., on climatic and seasonal factors. For example, it is a well-known fact that the load of substances in rivers can be strongly dependent on the runoff. It is of interest to find out whether observed changes in riverine loads are due only to natural variation or caused by other factors. Semi-parametric models have been proposed for estimation of time-varying linear relationships between runoff and riverine loads of substances. The aim of this work is to study some numerical methods for solving the linear least squares problem which arises. The model gives a linear system of the form A1x1 + A2x2 + n = b1. The vector n consists of identically distributed random variables all with mean zero. The unknowns, x, are split into two groups, x1 and x2. In this model, usually there are more unknowns than observations and the resulting linear system is most often consistent having an infinite number of solutions. Hence some constraint on the parameter vector x is needed. One possibility is to avoid rapid variation in, e.g., the parameters x2. This can be accomplished by regularizing using a matrix A3, which is a discretization of some norm. The problem is formulated as a partially regularized least squares problem with one or two regularization parameters. The parameter x2 has here a two-dimensional structure. By using two different regularization parameters it is possible to regularize separately in each dimension. We first study (for the case of one parameter only) the conjugate gradient method for solution of the problem. To improve rate of convergence blockpreconditioners of Schur complement type are suggested, analyzed and tested. Also a direct solution method based on QR decomposition is studied. The idea is to first perform operations independent of the values of the regularization parameters. Here we utilize the special block-structure of the problem. We further discuss the choice of regularization parameters and generalize in particular Reinsch’s method to the case with two parameters. Finally the cross-validation technique is treated. Here also a Monte Carlo method is used by which an approximation to the generalized cross-validation function can be computed efficiently.