A New Mouse Model for Marfan Syndrome Presents Phenotypic Variability Associated with the Genetic Background and Overall Levels of Fbn1 Expression

Marfan syndrome is an autosomal dominant disease of connective tissue caused by mutations in the fibrillin-1 encoding gene FBN1. Patients present cardiovascular, ocular and skeletal manifestations, and although being fully penetrant, MFS is characterized by a wide clinical variability both within and between families. Here we describe a new mouse model of MFS that recapitulates the clinical heterogeneity of the syndrome in humans. Heterozygotes for the mutant Fbn1 allele mg Delta(loxPneo), carrying the same internal deletion of exons 19-24 as the mg Delta mouse model, present defective microfibrillar deposition, emphysema, deterioration of aortic wall and kyphosis. However, the onset of a clinical phenotypes is earlier in the 129/Sv than in C57BL/6 background, indicating the existence of genetic modifiers of MFS between these two mouse strains. In addition, we characterized a wide clinical variability within the 129/Sv congenic heterozygotes, suggesting involvement of epigenetic factors in disease severity. Finally, we show a strong negative correlation between overall levels of Fbn1 expression and the severity of the phenotypes, corroborating the suggested protective role of normal fibrillin-1 in MFS pathogenesis, and supporting the development of therapies based on increasing Fbn1 expression.

Renal denervation in an animal model of diabetes and hypertension: Impact on the autonomic nervous system and nephropathy

Background: The effects of renal denervation on cardiovascular reflexes and markers of nephropathy in diabetic-hypertensive rats have not yet been explored. Methods: Aim: To evaluate the effects of renal denervation on nephropathy development mechanisms (blood pressure, cardiovascular autonomic changes, renal GLUT2) in diabetic-hypertensive rats. Forty-one male spontaneously hypertensive rats (SHR) similar to 250 g were injected with STZ or not; 30 days later, surgical renal denervation (RD) or sham procedure was performed; 15 days later, glycemia and albuminuria (ELISA) were evaluated. Catheters were implanted into the femoral artery to evaluate arterial pressure (AP) and heart rate variability (spectral analysis) one day later in conscious animals. Animals were killed, kidneys removed, and cortical renal GLUT2 quantified (Western blotting). Results: Higher glycemia (p < 0.05) and lower mean AP were observed in diabetics vs. nondiabetics (p < 0.05). Heart rate was higher in renal-denervated hypertensive and lower in diabetic-hypertensive rats (384.8 +/- 37, 431.3 +/- 36, 316.2 +/- 5, 363.8 +/- 12 bpm in SHR, RD-SHR, STZ-SHR and RD-STZ-SHR, respectively). Heart rate variability was higher in renal-denervated diabetic-hypertensive rats (55.75 +/- 25.21, 73.40 +/- 53.30, 148.4 +/- 93 in RD-SHR, STZ-SHR-and RD-STZ-SHR, respectively, p < 0.05), as well as the LF component of AP variability (1.62 +/- 0.9, 2.12 +/- 0.9, 7.38 +/- 6.5 in RD-SHR, STZ-SHR and RD-STZ-SHR, respectively, p < 0.05). GLUT2 renal content was higher in all groups vs. SHR. Conclusions: Renal denervation in diabetic-hypertensive rats improved previously reduced heart rate variability. The GLUT2 equally overexpressed by diabetes and renal denervation may represent a maximal derangement effect of each condition.

Respiratory allergy to Blomia tropicalis: Immune response in four syngeneic mouse strains and assessment of a low allergen-dose, short-term experimental model

Background: The dust mite Blomia tropicalis is an important source of aeroallergens in tropical areas. Although a mouse model for B. tropicalis extract (BtE)-induced asthma has been described, no study comparing different mouse strains in this asthma model has been reported. The relevance and reproducibility of experimental animal models of allergy depends on the genetic background of the animal, the molecular composition of the allergen and the experimental protocol. Objectives: This work had two objectives. The first was to study the anti-B. tropicalis allergic responses in different mouse strains using a short-term model of respiratory allergy to BtE. This study included the comparison of the allergic responses elicited by BtE with those elicited by ovalbumin in mice of the strain that responded better to BtE sensitization. The second objective was to investigate whether the best responder mouse strain could be used in an experimental model of allergy employing relatively low BtE doses. Methods: Groups of mice of four different syngeneic strains were sensitized subcutaneously with 100 mu g of BtE on days 0 and 7 and challenged four times intranasally, at days 8, 10, 12, and 14, with 10 mu g of BtE. A/J mice, that were the best responders to BtE sensitization, were used to compare the B. tropicalis-specific asthma experimental model with the conventional experimental model of ovalbumin (OVA)-specific asthma. A/J mice were also sensitized with a lower dose of BtE. Results: Mice of all strains had lung inflammatory-cell infiltration and increased levels of anti-BtE IgE antibodies, but these responses were significantly more intense in A/J mice than in CBA/J, BALB/c or C57BL/6J mice. Immunization of A/J mice with BtE induced a more intense airway eosinophil influx, higher levels of total IgE, similar airway hyperreactivity to methacholine but less intense mucous production, and lower levels of specific IgE, IgG1 and IgG2 antibodies than sensitization with OVA. Finally, immunization with a relatively low BtE dose (10 mu g per subcutaneous injection per mouse) was able to sensitize A/J mice, which were the best responders to high-dose BtE immunization, for the development of allergy-associated immune and lung inflammatory responses. Conclusions: The described short-term model of BtE-induced allergic lung disease is reproducible in different syngeneic mouse strains, and mice of the A/J strain was the most responsive to it. In addition, it was shown that OVA and BtE induce quantitatively different immune responses in A/J mice and that the experimental model can be set up with low amounts of BtE.

Statistics of opinion domains of the majority-vote model on a square lattice

The existence of juxtaposed regions of distinct cultures in spite of the fact that people's beliefs have a tendency to become more similar to each other's as the individuals interact repeatedly is a puzzling phenomenon in the social sciences. Here we study an extreme version of the frequency-dependent bias model of social influence in which an individual adopts the opinion shared by the majority of the members of its extended neighborhood, which includes the individual itself. This is a variant of the majority-vote model in which the individual retains its opinion in case there is a tie among the neighbors' opinions. We assume that the individuals are fixed in the sites of a square lattice of linear size L and that they interact with their nearest neighbors only. Within a mean-field framework, we derive the equations of motion for the density of individuals adopting a particular opinion in the single-site and pair approximations. Although the single-site approximation predicts a single opinion domain that takes over the entire lattice, the pair approximation yields a qualitatively correct picture with the coexistence of different opinion domains and a strong dependence on the initial conditions. Extensive Monte Carlo simulations indicate the existence of a rich distribution of opinion domains or clusters, the number of which grows with L(2) whereas the size of the largest cluster grows with ln L(2). The analysis of the sizes of the opinion domains shows that they obey a power-law distribution for not too large sizes but that they are exponentially distributed in the limit of very large clusters. In addition, similarly to other well-known social influence model-Axelrod's model-we found that these opinion domains are unstable to the effect of a thermal-like noise.

A Markovian model market-Akerlof`s lemons and the asymmetry of information

In this work we study an agent based model to investigate the role of asymmetric information degrees for market evolution. This model is quite simple and may be treated analytically since the consumers evaluate the quality of a certain good taking into account only the quality of the last good purchased plus her perceptive capacity beta. As a consequence, the system evolves according to a stationary Markov chain. The value of a good offered by the firms increases along with quality according to an exponent alpha, which is a measure of the technology. It incorporates all the technological capacity of the production systems such as education, scientific development and techniques that change the productivity rates. The technological level plays an important role to explain how the asymmetry of information may affect the market evolution in this model. We observe that, for high technological levels, the market can detect adverse selection. The model allows us to compute the maximum asymmetric information degree before the market collapses. Below this critical point the market evolves during a limited period of time and then dies out completely. When beta is closer to 1 (symmetric information), the market becomes more profitable for high quality goods, although high and low quality markets coexist. The maximum asymmetric information level is a consequence of an ergodicity breakdown in the process of quality evaluation. (C) 2011 Elsevier B.V. All rights reserved.

Successful maintenance of a stingless bee population despite a severe genetic bottleneck

Stingless bees play an important ecological role as pollinators of many wild plant species in the tropics and have significant potential for the pollination of agricultural crops. Nevertheless, conservation efforts as well as commercial breeding programmes require better guidelines on the amount of genetic variation that is needed to maintain viable populations. In this context, we carried out a long-term genetic study on the stingless bee Melipona scutellaris to evaluate the population viability consequences of prolonged breeding from a small number of founder colonies. In particular, it was artificially imposed a genetic bottleneck by setting up a population starting from only two founder colonies, and continued breeding from it for a period of over 10 years in a location outside its natural area of occurrence. We show that despite a great reduction in the number of alleles present at both neutral microsatellite loci and the sex-determining locus relative to its natural source population, and an increased frequency in the production of sterile diploid males, the genetically impoverished population could be successfully bred and maintained for at least 10 years. This shows that in stingless bees, breeding from a small stock of colonies may have less severe consequences than previously suspected. In addition, we provide a simulation model to determine the number of colonies that are needed to maintain a certain number of sex alleles in a population, thereby providing useful guidelines for stingless bee breeding and conservation efforts.

Dignified death: Concept development involving nurses and doctors in Pediatric Intensive Care Units

The aim of this study was to develop the concept of the dignified death of children in Brazilian pediatric intensive care units (PICUs). The Hybrid Model for Concept Development was used to develop a conceptual structure of dignified death in PICUs in an attempt to define the concept. The fieldwork study was carried out by means of in-depth interviews with nine nurses and seven physicians working in PICUs. Not unexpectedly, the concept of dignified death was found to be a complex phenomenon involving aspects related to decisions made by the multidisciplinary team as well as those related to care of the child and the family. Knowledge of the concept`s dimensions can promote reflection on the part of healthcare professionals regarding the values and beliefs underlying their conduct in end-of-life situations. Our hope is that this study may contribute to theoretic and methodological development in the area of end-of-life care.

Neural network model for designing automotive devices using SMD LED

The advantages offered by the electronic component LED (Light Emitting Diode) have resulted in a quick and extensive application of this device in the replacement of incandescent lights. In this combined application, however, the relationship between the design variables and the desired effect or result is very complex and renders it difficult to model using conventional techniques. This paper consists of the development of a technique using artificial neural networks that makes it possible to obtain the luminous intensity values of brake lights using SMD (Surface Mounted Device) LEDs from design data. This technique can be utilized to design any automotive device that uses groups of SMD LEDs. The results of industrial applications using SMD LED are presented to validate the proposed technique.

On the accuracy of two-fluid model predictions for a particular gas-solid riser flow

Literature presents a huge number of different simulations of gas-solid flows in risers applying two-fluid modeling. In spite of that, the related quantitative accuracy issue remains mostly untouched. This state of affairs seems to be mainly a consequence of modeling shortcomings, notably regarding the lack of realistic closures. In this article predictions from a two-fluid model are compared to other published two-fluid model predictions applying the same Closures, and to experimental data. A particular matter of concern is whether the predictions are generated or not inside the statistical steady state regime that characterizes the riser flows. The present simulation was performed inside the statistical steady state regime. Time-averaged results are presented for different time-averaging intervals of 5, 10, 15 and 20 s inside the statistical steady state regime. The independence of the averaged results regarding the time-averaging interval is addressed and the results averaged over the intervals of 10 and 20 s are compared to both experiment and other two-fluid predictions. It is concluded that the two-fluid model used is still very crude, and cannot provide quantitative accurate results, at least for the particular case that was considered. (C) 2009 Elsevier Inc. All rights reserved.

Development of a Continuous Emulsion Copolymerization Process in a Tubular Reactor

This contribution describes the development of a continuous emulsion copolymerization processs for vinyl acetate and n-butyl acrylate in a tubular reactor. Special features of this reactor include the use of oscillatory (pulsed) flow and internals (sieve plates) to prevent polymer fouling and promote good radial mixing, along with a controlled amount of axial mixing. The copolymer system studied (vinyl acetate and butyl acrylate) is strongly prone to composition drift due to very different reactivity ratios. An axially dispersed plug flow model, based on classical free radical copolymerization kinetics, was developed for this process and used successfully to optimize the lateral feeding profile to reduce compositional drift. An energy balance was included in the model equations to predict the effect of temperature variations on the process. The model predictions were validated with experimental data for monomer conversion, copolymer composition, average particle size, and temperature measured along the reactor length.

DEVELOPMENT OF STATIC MIXERS FOR MISCIBLE FLUIDS IN LAMINAR FLOW WITH THE USE OF COMPUTATIONAL FLUID DYNAMICS (CFD)

Static mixers with improved performance were developed from CFD simulations in a stepwise approach. The relevant geometric features of simple mixer designs and the corresponding mixing mechanisms-laminar shear, elongational flow, and distributive mixing-were identified first. This information was used to formulate guidelines for the development of new geometries. The solid elements of the static mixer should: (a) provide restrictions to the flow; (b) deflect the flow; (c) be sequentially rotated around the flow direction to provide symmetry; (d) extend from the center of the pipe to the vicinity of the walls to avoid short-circuiting; and (e) distribute and remix the flow. Based on these guidelines, two improved mixer designs were developed: the DS A-I mixer has a good mixing efficiency and an acceptable pressure drop; the Fins 35 degrees mixer is more efficient and compact, but requires a larger pressure drop. Their performance indicates that their use is possible on industrial applications.

Stable Model Predictive Control for Integrating Systems with Optimizing Targets

This paper concern the development of a stable model predictive controller (MPC) to be integrated with real time optimization (RTO) in the control structure of a process system with stable and integrating outputs. The real time process optimizer produces Optimal targets for the system inputs and for Outputs that Should be dynamically implemented by the MPC controller. This paper is based oil a previous work (Comput. Chem. Eng. 2005, 29, 1089) where a nominally stable MPC was proposed for systems with the conventional control approach where only the outputs have set points. This work is also based oil the work of Gonzalez et at. (J. Process Control 2009, 19, 110) where the zone control of stable systems is studied. The new control for is obtained by defining ail extended control objective that includes input targets and zone controller the outputs. Additional decision variables are also defined to increase the set of feasible solutions to the control problem. The hard constraints resulting from the cancellation of the integrating modes Lit the end of the control horizon are softened,, and the resulting control problem is made feasible to a large class of unknown disturbances and changes of the optimizing targets. The methods are illustrated with the simulated application of the proposed,approaches to a distillation column of the oil refining industry.

On the solubility of proteins as a function of pH: Mathematical development and application

Thermodynamic relations between the solubility of a protein and the solution pH are presented in this work. The hypotheses behind the development are that the protein chemical potential in liquid phase can be described by Henry`s law and that the solid-liquid equilibrium is established only between neutral molecules. The mathematical development results in an analytical expression of the solubility curve, as a function of the ionization equilibrium constants, the pH and the solubility at the isoelectric point. It is shown that the same equation can be obtained either by directly calculating the fraction of neutral protein molecules or by integrating the curve of the protein average charge. The methodology was successfully applied to the description of the solubility of porcine insulin as a function of pH at three different temperatures and of bovine beta-lactoglobulin at four different ionic strengths. (C) 2011 Elsevier B.V. All rights reserved.

Valve friction and nonlinear process model closed-loop identification

Among several process variability sources, valve friction and inadequate controller tuning are supposed to be two of the most prevalent. Friction quantification methods can be applied to the development of model-based compensators or to diagnose valves that need repair, whereas accurate process models can be used in controller retuning. This paper extends existing methods that jointly estimate the friction and process parameters, so that a nonlinear structure is adopted to represent the process model. The developed estimation algorithm is tested with three different data sources: a simulated first order plus dead time process, a hybrid setup (composed of a real valve and a simulated pH neutralization process) and from three industrial datasets corresponding to real control loops. The results demonstrate that the friction is accurately quantified, as well as ""good"" process models are estimated in several situations. Furthermore, when a nonlinear process model is considered, the proposed extension presents significant advantages: (i) greater accuracy for friction quantification and (ii) reasonable estimates of the nonlinear steady-state characteristics of the process. (C) 2010 Elsevier Ltd. All rights reserved.

Effects of 7-Epiclusianone on Streptococcus mutans and Caries Development in Rats

The aim of this study was to evaluate the effects of 7-epiclusianone (7-epi) on specific virulence attributes of Streptococcus mutans in vitro and on development of dental caries in vivo. 7-Epi was obtained and purified from fruits of Rheedia brasiliensis. We investigated its influence on surface-adsorbed glucosyltransferase (Gtf) B activity, acid production, and viability of S. mutans in biofilms, as well as on caries development using a rodent model. 7-Epi (100 mu g/mL) significantly reduced the activity of surface-adsorbed GtfB (up to 48.0 +/- 1.8 of inhibition at 100 mu g/mL) and glyco-lytic pH-drop by S. mutans in biofilms (125 and 250 mu g/mL) (vs. vehicle control, p < 0.05). In contrast, the test compound did not significantly affect the bacterial viability when compared to vehicle control (15% ethanol, p > 0.05). Wistar rats treated topically with 7-epi (twice daily, 60-s exposure) showed significantly smaller number of and less severe smooth-and sulcal-surface carious lesions (p < 0.05), without reducing the S. mutans viable population from the animals` dental biofilms. In conclusion, the natural compound 7-epiclusianone may be a potentially novel pharmacological agent to prevent and control dental caries disease.