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.

Algorithms and tools for in silico design of cell factories

PhD thesis in Bioengineering

Algorithms and computational tools for metabolic flux analysis

PhD thesis in Biomedical Engineering

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.

Modelling and verifying smell-free architectures with the Archery language

Architectural (bad) smells are design decisions found in software architectures that degrade the ability of systems to evolve. This paper presents an approach to verify that a software architecture is smellfree using the Archery architectural description language. The language provides a core for modelling software architectures and an extension for specifying constraints. The approach consists in precisely specifying architectural smells as constraints, and then verifying that software architectures do not satisfy any of them. The constraint language is based on a propositional modal logic with recursion that includes: a converse operator for relations among architectural concepts, graded modalities for describing the cardinality in such relations, and nominals referencing architectural elements. Four architectural smells illustrate the approach.

A FEM-based model to study the behaviour of corroded RC beams shear repaired by NSM CFRP rods technique

This paper presents the main features of finite element FE numerical model developed using the computer code FEMIX to predict the near-surface mounted NSM carbon-fiber-reinforced polymer CFRP rods shear repair contribution to corroded reinforced concrete RC beams. In the RC beams shear repaired with NSM technique, the Carbon Fibre Reinforced Polymer (CFRP) rods are placed inside pre-cut grooves onto the concrete cover of the RC beam’s lateral faces and are bonded to the concrete with high epoxy adhesive. Experimental and 3D numerical modelling results are presented in this paper in terms of load-deflection curves, and failure modes for 4 short corroded beams: two corroded beams (A1CL3-B and A1CL3-SB) and two control beams (A1T-B and A1T-SB), the beams noted with B were let repaired in bending only with NSM CFRP rods while the ones noted with SB were repaired in both bending and shear with NSM technique. The corrosion of the tensile steel bars and its effect on the shear capacity of the RC beams was discussed. Results showed that the FE model was able to capture the main aspects of the experimental load-deflection curves of the RC beams, moreover it has presented the experimental failure modes and FE numerical modelling crack patterns and both gave similar results for non-shear repaired beams which failed in diagonal tension mode of failure and for shear-repaired beams which failed due to large flexural crack at the middle of the beams along with the concrete crushing, three dimensional crack patterns were produced for shear-repaired beams in order to investigate the splitting cracks occurred at the middle of the beams and near the support.

A FEM-based model to study the behaviour of corroded RC beams shear repaired by NSM CFRP rods technique

This paper presents the main features of finite element FE numerical model developed using the computer code FEMIX to predict the near-surface mounted NSM carbon-fiber-reinforced polymer CFRP rods shear repair contribution to corroded reinforced concrete RC beams. In the RC beams shear repaired with NSM technique, the Carbon Fibre Reinforced Polymer (CFRP) rods are placed inside pre-cut grooves onto the concrete cover of the RC beam’s lateral faces and are bonded to the concrete with high epoxy adhesive. Experimental and 3D numerical modelling results are presented in this paper in terms of load-deflection curves, failure modes and slip information of the tensile steel bars for 4 short corroded beams: two corroded beams (A1CL3-B and A1CL3-SB) and two control beams (A1T-B and A1T-SB), the beams noted with B were let repaired in bending only with NSM CFRP rods while the ones noted with SB were repaired in both bending and shear with NSM technique. The corrosion of the tensile steel bars and its effect on the shear capacity of the RC beams was discussed. Results showed that the FE model was able to capture the main aspects of the experimental load-deflection curves of the RC beams, moreover it has presented the experimental failure modes and FE numerical modelling crack patterns and both gave similar results for non-shear repaired beams which failed in diagonal tension mode of failure and for shear-repaired beams which failed due to large flexural crack at the middle of the beams along with the concrete crushing, three dimensional crack patterns were produced for shear-repaired beams in order to investigate the splitting cracks occurred at the middle of the beams and near the support.

Plastic-damage smeared crack model to simulate the behaviour of structures made by cement based materials

This work proposes a constitutive model to simulate nonlinear behaviour of cement based materials subjected to different loading paths. The model incorporates a multidirectional fixed smeared crack approach to simulate crack initiation and propagation, whereas the inelastic behaviour of material between cracks is treated by a numerical strategy that combines plasticity and damage theories. For capturing more realistically the shear stress transfer between the crack surfaces, a softening diagram is assumed for modelling the crack shear stress versus crack shear strain. The plastic damage model is based on the yield function, flow rule and evolution law for hardening variable, and includes an explicit isotropic damage law to simulate the stiffness degradation and the softening behaviour of cement based materials in compression. This model was implemented into the FEMIX computer program, and experimental tests at material scale were simulated to appraise the predictive performance of this constitutive model. The applicability of the model for simulating the behaviour of reinforced concrete shear wall panels submitted to biaxial loading conditions, and RC beams failing in shear is investigated.

Clustering barotrauma patients in ICU–A data mining based approach using ventilator variables

Lecture Notes in Computer Science, 9273

DOTA-based Ga(III) and Gd(III) chelates for medical imaging (PET, SPECT and MRI)

PhD Thesis in Sciences Specialization in Chemistry

Spatio-temporal modelling of environmental data

Programa Doutoral em Matemática e Aplicações.

Nanocomposites: the contribution of multiscale modelling to improve the dispersion levels

Tese de Doutoramento em Ciência e Engenharia de Polímeros e Compósitos

Development of procedures for the design, optimization and manufacturing of customized orthopaedic and trauma implants: Geometrical/anatomical modelling from 3D medical imaging

Tese de Doutoramento (Programa Doutoral em Engenharia Biomédica)

Feature Nets: behavioural modelling of software product lines

Software product lines (SPL) are diverse systems that are developed using a dual engineering process: (a)family engineering defines the commonality and variability among all members of the SPL, and (b) application engineering derives specific products based on the common foundation combined with a variable selection of features. The number of derivable products in an SPL can thus be exponential in the number of features. This inherent complexity poses two main challenges when it comes to modelling: Firstly, the formalism used for modelling SPLs needs to be modular and scalable. Secondly, it should ensure that all products behave correctly by providing the ability to analyse and verify complex models efficiently. In this paper we propose to integrate an established modelling formalism (Petri nets) with the domain of software product line engineering. To this end we extend Petri nets to Feature Nets. While Petri nets provide a framework for formally modelling and verifying single software systems, Feature Nets offer the same sort of benefits for software product lines. We show how SPLs can be modelled in an incremental, modular fashion using Feature Nets, provide a Feature Nets variant that supports modelling dynamic SPLs, and propose an analysis method for SPL modelled as Feature Nets. By facilitating the construction of a single model that includes the various behaviours exhibited by the products in an SPL, we make a significant step towards efficient and practical quality assurance methods for software product lines.

Development of a poly(L-Lactic acid) based drug release system

Dissertação de mestrado em Biofísica e Bionanossistemas