Spontaneous healing of Mycobacterium ulcerans lesions in the guinea pig model

Buruli Ulcer (BU) is a necrotizing skin disease caused by Mycobacterium ulcerans infection. BU is characterized by a wide range of clinical forms, including non-ulcerative cutaneous lesions that can evolve into severe ulcers if left untreated. Nevertheless, spontaneous healing has been reported to occur, although knowledge on this process is scarce both in naturally infected humans and experimental models of infection. Animal models are useful since they mimic different spectrums of human BU disease and have the potential to elucidate the pathogenic/protective pathway(s) involved in disease/healing. In this time-lapsed study, we characterized the guinea pig, an animal model of resistance to M. ulcerans, focusing on the macroscopic, microbiological and histological evolution throughout the entire experimental infectious process. Subcutaneous infection of guinea pigs with a virulent strain of M. ulcerans led to early localized swelling, which evolved into small well defined ulcers. These macroscopic observations correlated with the presence of necrosis, acute inflammatory infiltrate and an abundant bacterial load. By the end of the infectious process when ulcerative lesions healed, M. ulcerans viability decreased and the subcutaneous tissue organization returned to its normal state after a process of continuous healing characterized by tissue granulation and reepethelialization. In conclusion, we show that the experimental M. ulcerans infection of the guinea pig mimics the process of spontaneous healing described in BU patients, displaying the potential to uncover correlates of protection against BU, which can ultimately contribute to the development of new prophylactic and therapeutic strategies.

Dynamic interface model for masonry walls subjected to high strain rate out-of-plane loads

The present study proposes a dynamic constitutive material interface model that includes non-associated flow rule and high strain rate effects, implemented in the finite element code ABAQUS as a user subroutine. First, the model capability is validated with numerical simulations of unreinforced block work masonry walls subjected to low velocity impact. The results obtained are compared with field test data and good agreement is found. Subsequently, a comprehensive parametric analysis is accomplished with different joint tensile strengths and cohesion, and wall thickness to evaluate the effect of the parameter variations on the impact response of masonry walls.

A bio-inspired computational model for motion detection

Tese de Doutoramento (Programa Doutoral em Engenharia Biomédica)

An integrated model for simulation of construction phasing of arch concrete dams

Dissertação de mestrado integrado em Civil Engineering

Tapping the wealth of microbial data in high-throughput metabolic model reconstruction

Genome-scale metabolic models are valuable tools in the metabolic engineering process, based on the ability of these models to integrate diverse sources of data to produce global predictions of organism behavior. At the most basic level, these models require only a genome sequence to construct, and once built, they may be used to predict essential genes, culture conditions, pathway utilization, and the modifications required to enhance a desired organism behavior. In this chapter, we address two key challenges associated with the reconstruction of metabolic models: (a) leveraging existing knowledge of microbiology, biochemistry, and available omics data to produce the best possible model; and (b) applying available tools and data to automate the reconstruction process. We consider these challenges as we progress through the model reconstruction process, beginning with genome assembly, and culminating in the integration of constraints to capture the impact of transcriptional regulation. We divide the reconstruction process into ten distinct steps: (1) genome assembly from sequenced reads; (2) automated structural and functional annotation; (3) phylogenetic tree-based curation of genome annotations; (4) assembly and standardization of biochemistry database; (5) genome-scale metabolic reconstruction; (6) generation of core metabolic model; (7) generation of biomass composition reaction; (8) completion of draft metabolic model; (9) curation of metabolic model; and (10) integration of regulatory constraints. Each of these ten steps is documented in detail.

On modified simple reacting spheres kinetic model for chemically reactive gases

Versão dos autores para esta publicação.

Association between LDL-C, Non HDL-C, and Apolipoprotein B Levels with Coronary Plaque Regression

Background:Previous reports have inferred a linear relationship between LDL-C and changes in coronary plaque volume (CPV) measured by intravascular ultrasound. However, these publications included a small number of studies and did not explore other lipid markers.Objective:To assess the association between changes in lipid markers and regression of CPV using published data.Methods:We collected data from the control, placebo and intervention arms in studies that compared the effect of lipidlowering treatments on CPV, and from the placebo and control arms in studies that tested drugs that did not affect lipids. Baseline and final measurements of plaque volume, expressed in mm3, were extracted and the percentage changes after the interventions were calculated. Performing three linear regression analyses, we assessed the relationship between percentage and absolute changes in lipid markers and percentage variations in CPV.Results:Twenty-seven studies were selected. Correlations between percentage changes in LDL-C, non-HDL-C, and apolipoprotein B (ApoB) and percentage changes in CPV were moderate (r = 0.48, r = 0.47, and r = 0.44, respectively). Correlations between absolute differences in LDL-C, non‑HDL-C, and ApoB with percentage differences in CPV were stronger (r = 0.57, r = 0.52, and r = 0.79). The linear regression model showed a statistically significant association between a reduction in lipid markers and regression of plaque volume.Conclusion:A significant association between changes in different atherogenic particles and regression of CPV was observed. The absolute reduction in ApoB showed the strongest correlation with coronary plaque regression.

Left Atrial Volume Determinants in Patients with Non-Ischemic Dilated Cardiomyopathy

Background:Left atrial volume (LAV) is a predictor of prognosis in patients with heart failure.Objective:We aimed to evaluate the determinants of LAV in patients with dilated cardiomyopathy (DCM).Methods:Ninety patients with DCM and left ventricular (LV) ejection fraction ≤ 0.50 were included. LAV was measured with real-time three-dimensional echocardiography (eco3D). The variables evaluated were heart rate, systolic blood pressure, LV end-diastolic volume and end-systolic volume and ejection fraction (eco3D), mitral inflow E wave, tissue Doppler e´ wave, E/e´ ratio, intraventricular dyssynchrony, 3D dyssynchrony index and mitral regurgitation vena contracta. Pearson´s coefficient was used to identify the correlation of the LAV with the assessed variables. A multiple linear regression model was developed that included LAV as the dependent variable and the variables correlated with it as the predictive variables.Results:Mean age was 52 ± 11 years-old, LV ejection fraction: 31.5 ± 8.0% (16-50%) and LAV: 39.2±15.7 ml/m2. The variables that correlated with the LAV were LV end-diastolic volume (r = 0.38; p < 0.01), LV end-systolic volume (r = 0.43; p < 0.001), LV ejection fraction (r = -0.36; p < 0.01), E wave (r = 0.50; p < 0.01), E/e´ ratio (r = 0.51; p < 0.01) and mitral regurgitation (r = 0.53; p < 0.01). A multivariate analysis identified the E/e´ ratio (p = 0.02) and mitral regurgitation (p = 0.02) as the only independent variables associated with LAV increase.Conclusion:The LAV is independently determined by LV filling pressures (E/e´ ratio) and mitral regurgitation in DCM.

A foundation model for marxian breakdown theories based on a new falling rate of profit mechanism (Long version)

The paper presents a foundation model for Marxian theories of the breakdown of capitalism based on a new falling rate of profit mechanism. All of these theories are based on one or more of "the historical tendencies": a rising capital-wage bill ratio, a rising capitalist share and a falling rate of profit. The model is a foundation in the sense that it generates these tendencies in the context of a model with a constant subsistence wage. The newly discovered generating mechanism is based on neo-classical reasoning for a model with land. It is non-Ricardian in that land augmenting technical progress can be unboundedly rapid. Finally, since the model has no steady state, it is necessary to use a new technique, Chaplygin's method, to prove the result.

A foundation model for marxian breakdown theories based on a new falling rate of profit mechanism.

The paper presents a foundation model for Marxian theories of the breakdown of capitalism based on a new falling rate of profit mechanism. All of these theories are based on one or more of ?the historical tendencies?: a rising capital-wage bill ratio, a rising capitalist share and a falling rate of profit. The model is a foundation in the sense that it generates these tendencies in the context of a model with a constant subsistence wage. The newly discovered generating mechanism is based on neo-classical reasoning for a model with land. It is non-Ricardian in that land augmenting technical progress can be unboundedly rapid. Finally, since the model has no steady state, it is necessary to use a new technique, Chaplygin?s method, to prove the result.

Fungi, bacteria and soil pH: the oxalate-carbonate pathway as a model for metabolic interaction

The oxalatecarbonate pathway involves the oxidation of calcium oxalate to low-magnesium calcite and represents a potential long-term terrestrial sink for atmospheric CO2. In this pathway, bacterial oxalate degradation is associated with a strong local alkalinization and subsequent carbonate precipitation. In order to test whether this process occurs in soil, the role of bacteria, fungi and calcium oxalate amendments was studied using microcosms. In a model system with sterile soil amended with laboratory cultures of oxalotrophic bacteria and fungi, the addition of calcium oxalate induced a distinct pH shift and led to the final precipitation of calcite. However, the simultaneous presence of bacteria and fungi was essential to drive this pH shift. Growth of both oxalotrophic bacteria and fungi was confirmed by qPCR on the frc (oxalotrophic bacteria) and 16S rRNA genes, and the quantification of ergosterol (active fungal biomass) respectively. The experiment was replicated in microcosms with non-sterilized soil. In this case, the bacterial and fungal contribution to oxalate degradation was evaluated by treatments with specific biocides (cycloheximide and bronopol). Results showed that the autochthonous microflora oxidized calcium oxalate and induced a significant soil alkalinization. Moreover, data confirmed the results from the model soil showing that bacteria are essentially responsible for the pH shift, but require the presence of fungi for their oxalotrophic activity. The combined results highlight that the interaction between bacteria and fungi is essential to drive metabolic processes in complex environments such as soil.

Family relationships and learning experiences in anxious vs. non-anxious families: Are there differences ?

L'objectif principal de ce travail était d'explorer les relations parent-enfant et les processus d'apprentissage familiaux associés aux troubles anxieux. A cet effet, des familles ayant un membre anxieux (la mère ou l'enfant) ont été comparées avec des familles n'ayant aucun membre anxieux. Dans une première étude, l'observation de l'interaction mère-enfant, pendant une situation standardisée de jeu, a révélé que les mères présentant un trouble panique étaient plus susceptibles de se montrer verbalement contrôlantes, critiques et moins sensibles aux besoins de l'enfant, que les mères qui ne présentaient pas de trouble panique. Une deuxième étude a examiné les perceptions des différents membres de la famille quant aux relations au sein de la famille et a indiqué que, par comparaison aux adolescents non-anxieux, les adolescents anxieux étaient plus enclins à éprouver un sentiment d'autonomie individuelle diminué par rapport à leurs parents. Finalement, une troisième étude s'est intéressée à déterminer l'impact d'expériences d'apprentissage moins directes dans l'étiologie de l'anxiété. Les résultats ont indiqué que les mères présentant un trouble panique étaient plus enclines à s'engager dans des comportements qui maintiennent la panique et à impliquer leurs enfants dans ces comportements, que les mères ne présentant pas de trouble panique. En se basant sur des recherches antérieures qui ont établi une relation entre le contrôle parental, la perception de contrôle chez l'enfant et les troubles anxieux, le présent travail non seulement confirme ce lien mais propose également un modèle pour résumer l'état actuel des connaissances concernant les processus familiaux et le développement des troubles anxieux. Deux routes ont été suggérées par lesquelles l'anxiété pourrait être transmise de manière intergénérationnelle. Chacune de ces routes attribue un rôle important à la perception de contrôle chez l'enfant. L'idée est que lorsque les enfants présentent une prédisposition à interpréter le comportement de leurs parents comme hors de leur contrôle, ils seraient plus enclins à développer de l'anxiété. A ce titre, la perception du contrôle représenterait un tampon entre le comportement de contrôle/surprotection des parents et le trouble anxieux chez l'enfant. - The principal objective of the present work was to explore parent-child relationships and family learning processes associated with anxiety disorders. To this purpose, families with and without an anxious family member (mother or child) were compared. In a first study, observation of mother-child interaction, during a standard play situation, revealed that mothers with panic disorder were more likely to display verbal control and criticism, and less likely to display sensitivity toward their children than mothers without panic disorder. A second study examined family members' perceptions of family relationships and indicated that compared to non-anxious adolescents, anxious adolescents were more prone to experience a diminished sense of individual autonomy in relation to their parents. Finally a third study was interested in determining the effect of less direct learning experiences in the aetiology of anxiety. Results indicated that mothers with panic disorder were more likely to engage in panic-maintaining behaviour and to involve their children in this behaviour than mothers without panic disorder. Based on previous research showing a relationship between parental control, children's perception of control, and anxiety disorders, the present work not only further adds evidence to support this link but also proposes a model summarizing the current knowledge concerning family processes and the development of anxiety disorders. Two pathways have been suggested through which anxiety may be intergenerationally transmitted. Both pathways assign an important role to children's perception of control. The idea is that whenever children have a predisposition towards interpreting their parents' behaviour as beyond of their control, they may be more prone to develop anxiety. As such, perceived control may represent a buffer between parental overcontrolling/overprotective behaviours and childhood anxiety disorder.

NEUROPATHOPHYSIOLOGICAL MECHANISMS IN GLUTARIC ACIDURIA TYPE I: 3-HYDROXYGLUTARIC ACID LEADS TO AMMONIA INCREASE AND NON-APOPTOTIC CELL DEATH

A 3D in vitro model of rat organotypic brain cell cultures in aggregates was used to investigate neurotoxicity mechanisms in glutaric aciduria type I (GA-I). 1 mM glutarate (GA) or 3-hydroxyglutarate (3OHGA) were repeatedly added to the culture media at two different time points. In cultures treated with 3OHGA, we observed an increase in lactate in the medium, pointing to a possible inhibition of Krebs cycle and respiratory chain. We further observed that 3OHGA and to a lesser extend GA induced an increase in ammonia production with concomitant decrease of glutamine concentrations, which may suggest an inhibition of the astrocytic enzyme glutamine synthetase. These previously unreported findings may uncover a pathogenic mechanism in this disease which has deleterious effects on early stages of brain development. By immunohistochemistry we showed that 3OHGA increased non-apoptotic cell death. On the cellular level, 3OHGA and to a lesser extend GA led to cell swelling and loss of astrocytic fibers whereas a loss of oligodendrocytes was only observed for 3OHGA. We conclude that 3OHGAwas the most toxic metabolite in our model for GA-I. 3OHGA induced deleterious effects on glial cells, an increase of ammonia production, and resulted in accentuated cell death of non-apoptotic origin.

A musculoskeletal shoulder model based on pseudo-inverse and null-space optimization.

The goal of the present work was assess the feasibility of using a pseudo-inverse and null-space optimization approach in the modeling of the shoulder biomechanics. The method was applied to a simplified musculoskeletal shoulder model. The mechanical system consisted in the arm, and the external forces were the arm weight, 6 scapulo-humeral muscles and the reaction at the glenohumeral joint, which was considered as a spherical joint. The muscle wrapping was considered around the humeral head assumed spherical. The dynamical equations were solved in a Lagrangian approach. The mathematical redundancy of the mechanical system was solved in two steps: a pseudo-inverse optimization to minimize the square of the muscle stress and a null-space optimization to restrict the muscle force to physiological limits. Several movements were simulated. The mathematical and numerical aspects of the constrained redundancy problem were efficiently solved by the proposed method. The prediction of muscle moment arms was consistent with cadaveric measurements and the joint reaction force was consistent with in vivo measurements. This preliminary work demonstrated that the developed algorithm has a great potential for more complex musculoskeletal modeling of the shoulder joint. In particular it could be further applied to a non-spherical joint model, allowing for the natural translation of the humeral head in the glenoid fossa.

Productivity, Preferences and UIP deviations in an Open Economy Business Cycle Model

We show that a flex-price two-sector open economy DSGE model can explain the poor degree of international risk sharing and exchange rate disconnect. We use a suite of model evaluation measures and examine the role of (i) traded and non-traded sectors; (ii) financial market incompleteness; (iii) preference shocks; (iv) deviations from UIP condition for the exchange rates; and (v) creditor status in net foreign assets. We find that there is a good case for both traded and non-traded productivity shocks as well as UIP deviations in explaining the puzzles.