In silico constraint-based strain optimization methods: the quest for optimal cell factories

Shifting from chemical to biotechnological processes is one of the cornerstones of 21st century industry. The production of a great range of chemicals via biotechnological means is a key challenge on the way toward a bio-based economy. However, this shift is occurring at a pace slower than initially expected. The development of efficient cell factories that allow for competitive production yields is of paramount importance for this leap to happen. Constraint-based models of metabolism, together with in silico strain design algorithms, promise to reveal insights into the best genetic design strategies, a step further toward achieving that goal. In this work, a thorough analysis of the main in silico constraint-based strain design strategies and algorithms is presented, their application in real-world case studies is analyzed, and a path for the future is discussed.

Project management under uncertainty: a study on solution methods

Project Management involves onetime endeavors that demand for getting it right the first time. On the other hand, project scheduling, being one of the most modeled project management process stages, still faces a wide gap from theory to practice. Demanding computational models and their consequent call for simplification, divert the implementation of such models in project management tools from the actual day to day project management process. Special focus is being made to the robustness of the generated project schedules facing the omnipresence of uncertainty. An "easy" way out is to add, more or less cleverly calculated, time buffers that always result in project duration increase and correspondingly, in cost. A better approach to deal with uncertainty seems to be to explore slack that might be present in a given project schedule, a fortiori when a non-optimal schedule is used. The combination of such approach to recent advances in modeling resource allocation and scheduling techniques to cope with the increasing flexibility in resources, as can be expressed in "Flexible Resource Constraint Project Scheduling Problem" (FRCPSP) formulations, should be a promising line of research to generate more adequate project management tools. In reality, this approach has been frequently used, by project managers in an ad-hoc way.

On the Hill estimator: a comparison of methods

Extreme value theory (EVT) deals with the occurrence of extreme phenomena. The tail index is a very important parameter appearing in the estimation of the probability of rare events. Under a semiparametric framework, inference requires the choice of a number k of upper order statistics to be considered. This is the crux of the matter and there is no definite formula to do it, since a small k leads to high variance and large values of k tend to increase the bias. Several methodologies have emerged in literature, specially concerning the most popular Hill estimator (Hill, 1975). In this work we compare through simulation well-known procedures presented in Drees and Kaufmann (1998), Matthys and Beirlant (2000), Beirlant et al. (2002) and de Sousa and Michailidis (2004), with a heuristic scheme considered in Frahm et al. (2005) within the estimation of a different tail measure but with a similar context. We will see that the new method may be an interesting alternative.

Comparing different methods to measure biofilm thickness: the techniques are: optical coherence tomography, confocal laser scanning microscopy and low load compression test

Dissertação de mestrado integrado em Engenharia Biomédica (área de especialização em Engenharia Clínica)

Finite integration methods for isospectral flows

In this paper we consider the approximate computation of isospectral flows based on finite integration methods( FIM) with radial basis functions( RBF) interpolation,a new algorithm is developed. Our method ensures the symmetry of the solutions. Numerical experiments demonstrate that the solutions have higher accuracy by our algorithm than by the second order Runge- Kutta( RK2) method.

Análise do ciclo de vida usando Lourenço modelo: caso da cidade de Damasco (1960-2015)

Dissertação de mestrado Internacional em Ambiente Construído Sustentável

Development of computational and experimental methods for biomass composition and evaluation of its impact in genome-scale models prediction

The use of genome-scale metabolic models has been rapidly increasing in fields such as metabolic engineering. An important part of a metabolic model is the biomass equation since this reaction will ultimately determine the predictive capacity of the model in terms of essentiality and flux distributions. Thus, in order to obtain a reliable metabolic model the biomass precursors and their coefficients must be as precise as possible. Ideally, determination of the biomass composition would be performed experimentally, but when no experimental data are available this is established by approximation to closely related organisms. Computational methods however, can extract some information from the genome such as amino acid and nucleotide compositions. The main objectives of this study were to compare the biomass composition of several organisms and to evaluate how biomass precursor coefficients affected the predictability of several genome-scale metabolic models by comparing predictions with experimental data in literature. For that, the biomass macromolecular composition was experimentally determined and the amino acid composition was both experimentally and computationally estimated for several organisms. Sensitivity analysis studies were also performed with the Escherichia coli iAF1260 metabolic model concerning specific growth rates and flux distributions. The results obtained suggest that the macromolecular composition is conserved among related organisms. Contrasting, experimental data for amino acid composition seem to have no similarities for related organisms. It was also observed that the impact of macromolecular composition on specific growth rates and flux distributions is larger than the impact of amino acid composition, even when data from closely related organisms are used.

Promising blood-derived biomarkers for estimation of the postmortem interval

A precise estimation of the postmortem interval (PMI) is one of the most important topics in forensic pathology. However, the PMI estimation is based mainly on the visual observation of cadaverous pheno- mena (e.g. algor, livor and rigor mortis) and on alternative methods such as thanatochemistry that remain relatively imprecise. The aim of this in vitro study was to evaluate the kinetic alterations of several bio- chemical parameters (i.e. proteins, enzymes, substrates, electrolytes and lipids) during putrefaction of human blood. For this purpose, we performed kinetic biochemical analysis during a 264 hour period. The results showed a significant linear correlation between total and direct bilirubin, urea, uric acid, transferrin, immunoglobulin M (IgM), creatine kinase (CK), aspartate transaminase (AST), calcium and iron with the time of blood putrefaction. These parameters allowed us to develop two mathematical models that may have predictive values and become important complementary tools of traditional methods to achieve a more accurate PMI estimation

Methods to solve the equations of motion

"Series title: Springerbriefs in applied sciences and technology, ISSN 2191-530X"

Integration methods in dynamic analysis

"Series title: Springerbriefs in applied sciences and technology, ISSN 2191-530X"

A critical evaluation of methods for the reconstruction of tissue-specific models

Under the framework of constraint based modeling, genome-scale metabolic models (GSMMs) have been used for several tasks, such as metabolic engineering and phenotype prediction. More recently, their application in health related research has spanned drug discovery, biomarker identification and host-pathogen interactions, targeting diseases such as cancer, Alzheimer, obesity or diabetes. In the last years, the development of novel techniques for genome sequencing and other high-throughput methods, together with advances in Bioinformatics, allowed the reconstruction of GSMMs for human cells. Considering the diversity of cell types and tissues present in the human body, it is imperative to develop tissue-specific metabolic models. Methods to automatically generate these models, based on generic human metabolic models and a plethora of omics data, have been proposed. However, their results have not yet been adequately and critically evaluated and compared. This work presents a survey of the most important tissue or cell type specific metabolic model reconstruction methods, which use literature, transcriptomics, proteomics and metabolomics data, together with a global template model. As a case study, we analyzed the consistency between several omics data sources and reconstructed distinct metabolic models of hepatocytes using different methods and data sources as inputs. The results show that omics data sources have a poor overlapping and, in some cases, are even contradictory. Additionally, the hepatocyte metabolic models generated are in many cases not able to perform metabolic functions known to be present in the liver tissue. We conclude that reliable methods for a priori omics data integration are required to support the reconstruction of complex models of human cells.

Automated network resilience optimization using computational intelligence methods

This paper presents an automated optimization framework able to provide network administrators with resilient routing configurations for link-state protocols, such as OSPF or IS-IS. In order to deal with the formulated NP-hard optimization problems, the devised framework is underpinned by the use of computational intelligence optimization engines, such as Multi-objective Evolutionary Algorithms (MOEAs). With the objective of demonstrating the framework capabilities, two illustrative Traffic Engineering methods are described, allowing to attain routing configurations robust to changes in the traffic demands and maintaining the network stable even in the presence of link failure events. The presented illustrative results clearly corroborate the usefulness of the proposed automated framework along with the devised optimization methods.

Microfluidic based on aqueous two-phase system for plasmidic DNA purification

Dissertação de mestrado em Bioquímica Aplicada (área de especialização em Biotecnologia)

Numerical methods in multibody system dynamics

"Series: Solid mechanics and its applications, vol. 226"