Evaluation of state of the art numerical integration schema

Tese de mestrado integrado. Engenharia Química. Faculdade de Engenharia. Universidade do Porto. 201

Novel approaches for effective design of controlled drug release systems, employing hybrid semi-parametric mathematical systems

The controlled release of a drug from a carrier into a medium over a defined period of time is referred to as Controlled Drug Release (CDR). A major challenge for a sustainable and reproducible CDR is the unintentional initial burst, which occurs in the first hours/days of immersion and during which a large amount of drug is released. Also it can have deleterious effects on the host. Burst release happens with both small drug molecules and large proteins and for both drug-loaded PLGA micro- and nanoparticles. Particle design can, in principal, be used to control the amount of burst but no systematic methods are to date available and the design process is governed by trial and error. One reason might be that the available models for burst release do not explicitly account for the particle design parameters. This thesis proposes novel methodologies that allow for rational design of drug-loaded PLGA micro- and nanoparticles. It is divided in three main parts. Firstly, a quantitative analysis of the physicochemical factors that impact on the amount of burst release and the burst release rate using partial least squares and decision tree methods is performed. The factors with the greatest impact are selected for the subsequent modelling activities. Next, a bootstrap aggregated hybrid model (HM) is developed, which can successfully predict the cumulative drug release of an independent set of CDR experiments. Lastly, a new rational design method is presented for the optimization of the formulation characteristics of protein-loaded PLGA nanoparticles. The method is successfully applied to design the carrier of a mock-protein, α- chymotrypsin, yielding a close to desired release profile. The method can also help to judge upon the similarity of the mock protein with a target protein in terms of their similarities in burst release behavior. This thesis proposes the first rational PLGA particle design method requiring only the specification of the drug and the desired burst release profile. The application of the method can be expected to significantly reduce the time for PLGA particle development. With the increasing availability of CDR data the predictive power of the method can be further improved towards a systematic and reliable tool. The engine of the method is the hybrid model which links the release profile to the design parameters and is the first of its kind in drug release modeling

Microbiome and Autism

Background: Autism Spectrum Disorders (ASD) are a group of neurologic conditions that affect behavior, communication, and social interaction in children and adults all over the world. Several recent studies correlate these disorders with alterations of the gut microbiome due to the possible imbalance of the gut-brain axis. This possible connection opens new avenues to explore the unknown areas of ASD pathogenesis and the new opportunities for managing this disorder. The goal of this systematic review is to analyze the existing knowledge on microbiome changes in ASD and to understand its importance in the biological and behavioral context of ASD patients. Methods: A systematic search covering the topics of ASD and microbiome was performed on PubMed and completed on October 7, 2019. Twenty-eight articles were included and their quality was assessed. The data extracted for analysis was related to the participants characteristics, the study type and method of analysis, the instrument used to diagnose ASD and the main outcomes of said investigation. Results: Most of the reviewed studies found microbiome changes in ASD patients in comparison with neurotypical subjects. However, there was no specific pattern of bacterial changes found. The studies focused mostly on Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria. Out of all these phyla, the only one that exhibited a clear trend in ASD subjects was Firmicutes, mainly the order Clostridiales and Clostridium species, with a documented increase in ASD subjects in ten studies. Conclusion: This review suggests that there is an altered microbiome in ASD. However, the current analysis was not able to establish a set of bacterial changes characteristic to this pathology. Nevertheless, the gut-brain axis relationship seems to be one worth pursuing in hopes to establish a clear pathophysiological path to this disorder.As Perturbações do Espetro Autista (PEA) são um conjunto de condições neurológicas que afetam a comunicação e a interação social, com padrões repetitivos e restritivos de comportamento e hipo ou hiper-reactividade a estímulos sensoriais e ambientais. Estas condições são definidas pela sua clínica, visto que a sua patogénese não se encontra ainda esclarecida. Existem fatores genéticos e ambientais implicados na génese das PEA, e também múltiplas comorbilidades com destaque para os distúrbios gastrointestinais. A elevada prevalência destes distúrbios em crianças com PEA leva à hipótese de que, para além de meras comorbilidades, estes possam ser parte do mecanismo causal desta patologia. Assim, através da teoria do “gut-brain axis” ou eixo intestino-cérebro, é possível estabelecer uma ligação entre estas duas componentes da PEA. O eixo intestino-cérebro define-se como o conjunto de interações nervosa, endócrina e imunológica que se estabelece entre o SNC e o trato GI. Um elemento fundamental desta comunicação é a microbiota, o conjunto de bactérias e outros microrganismos que residem num particular nicho biológico, neste caso o trato intestinal humano. No meio intestinal, estas bactérias produzem metabolitos essenciais para a sinalização endócrina e imunológica, comunicando também com o SNC através de recetores do nervo vago. O microbioma intestinal é também promotor da motilidade, produtor de vitaminas e tem um efeito protetor contra organismos patogénicos entéricos. No entanto, quando em desequilíbrio ou disbiose, pode produzir toxinas que atingem o SNC. Esta revisão sistemática procurou explorar a relação entre as alterações no microbioma humano e a patogénese da PEA. Foi realizada uma pesquisa na base de dados PubMed usando a expressão: “(("Autistic Disorder"[Mesh]) OR ("Autism Spectrum Disorder"[Mesh])) AND (("Microbiota"[Mesh]) OR ("Gastrointestinal Microbiome"[Mesh]))”. Os critérios de inclusão foram: estudos observacionais ou de intervenção, realizados em indivíduos com PEA e com referência à sua relação com a microbiota intestinal, redigidos em inglês. Foram também incluídos estudos referidos nas referências das revisões sistemáticas e meta-analises englobadas na pesquisa inicial. A qualidade dos estudos foi avaliada segundo os critérios STROBE e TREND e os principais dados extraídos foram: o número de participantes do estudo, o tipo de estudo e a metodologia usada, o/os instrumento/os usados para diagnosticar PEA e os principais resultados obtidos. Usando as recomendações do PRISMA (Preferred Reporting for Systematic Reviews and Meta-Analysis) foram incluídos 28 estudos nesta revisão. Foram estudadas 1169375 crianças com idades compreendidas entre 1 e 18 anos. Os estudos foram divididos em 3 grupos para facilitar a sua análise e discussão: “Standard comparison”, “Comparison by exposure variables” e "Comparison after intervention”. O primeiro grupo comparava linearmente o microbioma de indivíduos com PEA com o de sujeitos neurotípicos. O segundo reunia os estudos de coorte que procuravam verificar o impacto de variáveis que alterariam o microbioma, segundo os autores, para concluir se essa exposição teria influência num posterior diagnóstico de PEA. O último grupo reunia os estudos de intervenção com suplementos ou probióticos em crianças com PEA. A maioria dos estudos revelou uma diferença significativa entre o microbioma dos indivíduos com PEA e o dos controlos, mas as diferenças registadas não foram constantes entre estudos, com a notável exceção da ordem Clostridiales e da espécie Clostridium, que demostrou um notável aumento nos indivíduos com PEA. No primeiro grupo de estudos, apenas 2 em 18 consideraram que não havia uma divergência entre os microbiomas. No entanto, os próprios estudos foram realizados em condições bastante diferentes: 9 comparavam as crianças com PEA com os seus irmãos neurotípicos, enquanto os restantes 11 usaram controlos da comunidade; apenas 2 estudos abordaram a micobiota; um estudo analisou crianças e mães como uma unidade em termos de distribuição destes microrganismos e outro estudo recolheu os seus dados usando biopsias retais, ao invés de amostras fecais, por exemplo. Em relação aos estudos de coorte, não foi encontrada nenhuma relação causal entre os fatores testados (parto por cesariana, uso de antibióticos nos primeiros anos de vida) e a incidência de PEA. Os estudos de intervenção demostraram um efeito positivo da suplementação e probióticos na alteração da composição do microbioma, mas estes efeitos nem sempre se revelaram a nível sintomático. Assim, foi verificada uma diferença não negligenciável entre o microbioma de um indivíduo com PEA e o microbioma neurotípico. Esta conclusão pode ser uma base para futura pesquisa nesta aérea, através de um estudo que procure uniformizar os fatores que influenciam a microbiota e as suas condições de desenvolvimento

Soil management in Brazilian states: comparative analyzes of Physical and Monetary Soil Nutrient Balance in 2005 and 2015

Intensive agricultural production tends to stimulate the outflow of nutrients from the soil, requiring producers to properly manage the soil to avoid reducing fertility in the following crops. Thus, the objective was to estimate the annual monetary balance of nutrients in the soil of six Brazilian states that present the highest consumption of inorganic fertilizers in the years 2005 and 2015. The Annual Balance of Nutrients in Soil was used to calculate the physical and monetary balance of nutrients, in the main crops of these States, by quantifying the export of N, P, K from the soil by plants and the insertion of nutrients, through the application of fertilizers, fertigation, and biological fixation. The monetary balance of N, P and K added for the six states was positive and increased by 114% between 2005 and 2015, however, the balance of P for the state of Paraná was negative in 2015 reaching R$ 1,769.17. The balances and Mato Grosso, Rio Grande do Sul, and Paraná were higher concerning Goiás, São Paulo, and Minas Gerais. Except for Paraná, related to P, there was no positive depreciation of the associated NPK nutrients. The different flows, in the comparison among states, are caused by the different dynamics of land use, mainly in the size of the corn and soybean cultivation area

Analysis of flux data sets

Deutscher Akademischer Austausch Dienst, Reference number: 6818.Background: Non-negative linear combinations of elementary flux modes (EMs) describe all feasible reaction flux distributions for a given metabolic network under the quasi steady state assumption. However, only a small subset of EMs contribute to the physiological state of a given cell. Results: In this paper, a method is proposed that identifies the subset of EMs that best explain the physiological state captured in reaction flux data, referred to as principal EMs (PEMs), given a pre-specified universe of EM candidates. The method avoids the evaluation of all possible combinations of EMs by using a branch and bound approach which is computationally very efficient. The performance of the method is assessed using simulated and experimental data of Pichia pastoris and experimental fluxome data of Saccharomyces cerevisiae. The proposed method is benchmarked against principal component analysis (PCA), commonly used to study the structure of metabolic flux data sets. Conclusions: The overall results show that the proposed method is computationally very effective in identifying the subset of PEMs within a large set of EM candidates (cases with ~100 and ~1000 EMs were studied). In contrast to the principal components in PCA, the identified PEMs have a biological meaning enabling identification of the key active pathways in a cell as well as the conditions under which the pathways are activated. This method clearly outperforms PCA in the interpretability of flux data providing additional insights into the underlying regulatory mechanisms.publishersversionpublishe

Primavera: arroz precoce 'agulhinha' para os cerrados de Rondonia.

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