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.

Simplified Mathematical Model for an Anaerobic Sequencing Batch Biofilm Reactor Treating Lipid-Rich Wastewater Subject to Rising Organic Loading Rates

This study proposes a simplified mathematical model to describe the processes occurring in an anaerobic sequencing batch biofilm reactor (ASBBR) treating lipid-rich wastewater. The reactor, subjected to rising organic loading rates, contained biomass immobilized cubic polyurethane foam matrices, and was operated at 32 degrees C +/- 2 degrees C, using 24-h batch cycles. In the adaptation period, the reactor was fed with synthetic substrate for 46 days and was operated without agitation. Whereas agitation was raised to 500 rpm, the organic loading rate (OLR) rose from 0.3 g chemical oxygen demand (COD) . L(-1) . day(-1) to 1.2 g COD . L(-1) . day(-1). The ASBBR was fed fat-rich wastewater (dairy wastewater), in an operation period lasting for 116 days, during which four operational conditions (OCs) were tested: 1.1 +/- 0.2 g COD . L(-1) . day(-1) (OC1), 4.5 +/- 0.4 g COD . L(-1) . day(-1) (OC2), 8.0 +/- 0.8 g COD . L(-1) . day(-1) (OC3), and 12.1 +/- 2.4 g COD . L(-1) . day(-1) (OC4). The bicarbonate alkalinity (BA)/COD supplementation ratio was 1:1 at OC1, 1:2 at OC2, and 1:3 at OC3 and OC4. Total COD removal efficiencies were higher than 90%, with a constant production of bicarbonate alkalinity, in all OCs tested. After the process reached stability, temporal profiles of substrate consumption were obtained. Based on these experimental data a simplified first-order model was fit, making possible the inference of kinetic parameters. A simplified mathematical model correlating soluble COD with volatile fatty acids (VFA) was also proposed, and through it the consumption rates of intermediate products as propionic and acetic acid were inferred. Results showed that the microbial consortium worked properly and high efficiencies were obtained, even with high initial substrate concentrations, which led to the accumulation of intermediate metabolites and caused low specific consumption rates.

The Coupled Aerosol and Tracer Transport model to the Brazilian developments on the Regional Atmospheric Modeling System (CATT-BRAMS) - Part 1: Model description and evaluation

We introduce the Coupled Aerosol and Tracer Transport model to the Brazilian developments on the Regional Atmospheric Modeling System (CATT-BRAMS). CATT-BRAMS is an on-line transport model fully consistent with the simulated atmospheric dynamics. Emission sources from biomass burning and urban-industrial-vehicular activities for trace gases and from biomass burning aerosol particles are obtained from several published datasets and remote sensing information. The tracer and aerosol mass concentration prognostics include the effects of sub-grid scale turbulence in the planetary boundary layer, convective transport by shallow and deep moist convection, wet and dry deposition, and plume rise associated with vegetation fires in addition to the grid scale transport. The radiation parameterization takes into account the interaction between the simulated biomass burning aerosol particles and short and long wave radiation. The atmospheric model BRAMS is based on the Regional Atmospheric Modeling System (RAMS), with several improvements associated with cumulus convection representation, soil moisture initialization and surface scheme tuned for the tropics, among others. In this paper the CATT-BRAMS model is used to simulate carbon monoxide and particulate material (PM(2.5)) surface fluxes and atmospheric transport during the 2002 LBA field campaigns, conducted during the transition from the dry to wet season in the southwest Amazon Basin. Model evaluation is addressed with comparisons between model results and near surface, radiosondes and airborne measurements performed during the field campaign, as well as remote sensing derived products. We show the matching of emissions strengths to observed carbon monoxide in the LBA campaign. A relatively good comparison to the MOPITT data, in spite of the fact that MOPITT a priori assumptions imply several difficulties, is also obtained.

Turbulent magnetic pumping in a Babcock-Leighton solar dynamo model

Context. The turbulent pumping effect corresponds to the transport of magnetic flux due to the presence of density and turbulence gradients in convectively unstable layers. In the induction equation it appears as an advective term and for this reason it is expected to be important in the solar and stellar dynamo processes. Aims. We explore the effects of turbulent pumping in a flux-dominated Babcock-Leighton solar dynamo model with a solar-like rotation law. Methods. As a first step, only vertical pumping has been considered through the inclusion of a radial diamagnetic term in the induction equation. In the second step, a latitudinal pumping term was included and then, a near-surface shear was included. Results. The results reveal the importance of the pumping mechanism in solving current limitations in mean field dynamo modeling, such as the storage of the magnetic flux and the latitudinal distribution of the sunspots. If a meridional flow is assumed to be present only in the upper part of the convective zone, it is the full turbulent pumping that regulates both the period of the solar cycle and the latitudinal distribution of the sunspot activity. In models that consider shear near the surface, a second shell of toroidal field is generated above r = 0.95 R(circle dot) at all latitudes. If the full pumping is also included, the polar toroidal fields are efficiently advected inwards, and the toroidal magnetic activity survives only at the observed latitudes near the equator. With regard to the parity of the magnetic field, only models that combine turbulent pumping with near-surface shear always converge to the dipolar parity. Conclusions. This result suggests that, under the Babcock-Leighton approach, the equartorward motion of the observed magnetic activity is governed by the latitudinal pumping of the toroidal magnetic field rather than by a large scale coherent meridional flow. Our results support the idea that the parity problem is related to the quadrupolar imprint of the meridional flow on the poloidal component of the magnetic field and the turbulent pumping positively contributes to wash out this imprint.

uvby-beta photometry of solar twins The solar colors, model atmospheres, and the T(eff) and metallicity scales

Aims. Solar colors have been determined on the uvby-beta photometric system to test absolute solar fluxes, to examine colors predicted by model atmospheres as a function of stellar parameters (T(eff), log g, [Fe/H]), and to probe zero-points of T(eff) and metallicity scales. Methods. New uvby-beta photometry is presented for 73 solar-twin candidates. Most stars of our sample have also been observed spectroscopically to obtain accurate stellar parameters. Using the stars that most closely resemble the Sun, and complementing our data with photometry available in the literature, the solar colors on the uvby-beta system have been inferred. Our solar colors are compared with synthetic solar colors computed from absolute solar spectra and from the latest Kurucz (ATLAS9) and MARCS model atmospheres. The zero-points of different T(eff) and metallicity scales are verified and corrections are proposed. Results. Our solar colors are (b - y)(circle dot) = 0.4105 +/- 0.0015, m(1,circle dot) = 0.2122 +/- 0.0018, c(1,circle dot) = 0.3319 +/- 0.0054, and beta(circle dot) = 2.5915 +/- 0.0024. The (b - y)(circle dot) and m(1,circle dot) colors obtained from absolute spectrophotometry of the Sun agree within 3-sigma with the solar colors derived here when the photometric zero-points are determined from either the STIS HST observations of Vega or an ATLAS9 Vega model, but the c(1,circle dot) and beta(circle dot) synthetic colors inferred from absolute solar spectra agree with our solar colors only when the zero-points based on the ATLAS9 model are adopted. The Kurucz solar model provides a better fit to our observations than the MARCS model. For photometric values computed from the Kurucz models, (b - y)(circle dot) and m(1,circle dot) are in excellent agreement with our solar colors independently of the adopted zero-points, but for c(1,circle dot) and beta circle dot agreement is found only when adopting the ATLAS9 zero-points. The c(1,circle dot) color computed from both the Kurucz and MARCS models is the most discrepant, probably revealing problems either with the models or observations in the u band. The T(eff) calibration of Alonso and collaborators has the poorest performance (similar to 140 K off), while the relation of Casagrande and collaborators is the most accurate (within 10 K). We confirm that the Ramirez & Melendez uvby metallicity calibration, recommended by Arnadottir and collaborators to obtain [Fe/H] in F, G, and K dwarfs, needs a small (similar to 10%) zero-point correction to place the stars and the Sun on the same metallicity scale. Finally, we confirm that the c(1) index in solar analogs has a strong metallicity sensitivity.

Cyclic variability of the circumstellar disk of the Be star zeta Tauri II. Testing the 2D global disk oscillation model

Context. About 2/3 of the Be stars present the so-called V/R variations, a phenomenon characterized by the quasi-cyclic variation in the ratio between the violet and red emission peaks of the HI emission lines. These variations are generally explained by global oscillations in the circumstellar disk forming a one-armed spiral density pattern that precesses around the star with a period of a few years. Aims. This paper presents self-consistent models of polarimetric, photometric, spectrophotometric, and interferometric observations of the classical Be star zeta Tauri. The primary goal is to conduct a critical quantitative test of the global oscillation scenario. Methods. Detailed three-dimensional, NLTE radiative transfer calculations were carried out using the radiative transfer code HDUST. The most up-to-date research on Be stars was used as input for the code in order to include a physically realistic description for the central star and the circumstellar disk. The model adopts a rotationally deformed, gravity darkened central star, surrounded by a disk whose unperturbed state is given by a steady-state viscous decretion disk model. It is further assumed that this disk is in vertical hydrostatic equilibrium. Results. By adopting a viscous decretion disk model for zeta Tauri and a rigorous solution of the radiative transfer, a very good fit of the time-average properties of the disk was obtained. This provides strong theoretical evidence that the viscous decretion disk model is the mechanism responsible for disk formation. The global oscillation model successfully fitted spatially resolved VLTI/AMBER observations and the temporal V/R variations in the H alpha and Br gamma lines. This result convincingly demonstrates that the oscillation pattern in the disk is a one-armed spiral. Possible model shortcomings, as well as suggestions for future improvements, are also discussed.

REPRODUCTIVE BIOLOGY AND FUNCTIONAL MATURITY IN FEMALES OF AEGLA FRANCA (DECAPODA: ANOMURA: AEGLIDAE)

We describe the reproductive period. fecundity, and average size at the onset of functional maturity of female Aegla franca, the northernmost distributed aeglid species. The reproductive period is markedly seasonal and takes place front May (austral mid-autumn) to August (late winter). Ovigerous females appear quite abruptly in the population by May, and this condition is observed in all adult females sampled regardless of their size. The average size at the onset of functional maturity in females, at which 50% of the females sampled during the reproductive period were considered adults, was 12.75 mm CL. The smallest post-ovigerous female measured 12.06 mm carapace length (CL). Mean fecundity (+/- S.D.) from 41 females bearing early and intermediate eggs was 129.1 +/- 32.2 and corresponded to a mean female CL of 14.11 mm. The elliptical-shaped eggs exhibited significant increase in size along the development stages. The third pair of pleopods bore higher number of eggs than the others. Compiled information regarding the reproductive period reported for aeglids revealed all increase in the breeding period length with latitude. The reproductive period tends to be shorter in localities under larger rainfall variation and smaller temperature variability than in sites with opposite climate conditions. Eggs tend to be fewer in number and larger in size towards lower latitudes. We present an hypothesis that stream water velocity might act as a major selective pressure during the early life history of fluvial aeglids with direct effect on the reproductive pattern.

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.

Melatonin treatment decreases c-fos expression in a headache model induced by capsaicin

The aim of the present work was to analyze c-fos response within the trigeminal nucleus caudalis (TNC) of pinealectomized rats and animals that received intraperitoneal melatonin, after intracisternal infusion of capsaicin, used to induce intracranial trigeminovascular stimulation. Experimental groups consisted of animals that received vehicle solution (saline-ethanol-Tween 80, 8:1:1, diluted 1:50) only (VEI, n = 5); animals that received capsaicin solution (200 nM) only (CAP, n = 6); animals submitted to pinealectomy (PX, n = 5); sham-operated animals (SH, n = 5); animals submitted to pinealectomy followed by capsaicin stimulation (200 nM) after 15 days (PX + CAP, n = 7); and animals that received capsaicin solution (200 nM) and intraperitoneal melatonin (10 mg/kg) (CAP + MEL, n = 5). Control rats, receiving vehicle in the cisterna magna, showed a small number of c-fos-positive cells in the TNC (layer I/II) as well as the sham-operated and pinealectomized rats, when compared to animals stimulated by capsaicin. On the other hand, pinealectomized rats, which received capsaicin, presented the highest number of c-fos-positive cells. Animals receiving capsaicin and melatonin treatment had similar expression of the vehicle group. Our data provide experimental evidence to support the role of melatonin and pineal gland in the pathophysiology of neurovascular headaches.

Exogenous Cx43 expression decrease cell proliferation rate in rat hepatocarcinoma cells independently of functional gap junction

Background: Gap junction intercellular communication (GJIC) is considered to play a role in the regulation of homeostasis because it regulates important processes, such as cell proliferation and cell differentiation. A reduced or lost GJIC capacity has been observed in solid tumors and studies have demonstrated that GJIC restoration in tumor cells contribute to reversion of the transformed phenotype. This observation supports the idea that restoration of the functional channel is essential in this process. However, in the last years, reports have proposed that just the increase in the expression of specific connexins can contribute to reversion of the malign phenotype in some tumor cells. In the present work, we studied the effects of exogenous Connexin 43 (Cx43) expression on the proliferative behavior and phenotype of rat hepatocarcinoma cells. Results: The exogenous Cx43 did not increase GJIC capacity of transfected cells, but it was critical to decrease the cell proliferation rate as well as reorganization of the actin filaments and cell flattening. We also observed more adhesion capacity to substrate after Cx43 transfection. Conclusion: Cx43 expression leads to a decrease of the growth of the rat hepatocellular carcinoma cells and it contributes to the reversion of the transformed phenotype. These effects were independent of the GJIC and were probably associated with the phosphorylation pattern changes and redistribution of the Cx43 protein.

Activation of endogenous p53 by combined p19Arf gene transfer and nutlin-3 drug treatment modalities in the murine cell lines B16 and C6

Background: Reactivation of p53 by either gene transfer or pharmacologic approaches may compensate for loss of p19Arf or excess mdm2 expression, common events in melanoma and glioma. In our previous work, we constructed the pCLPG retroviral vector where transgene expression is controlled by p53 through a p53-responsive promoter. The use of this vector to introduce p19Arf into tumor cells that harbor p53wt should yield viral expression of p19Arf which, in turn, would activate the endogenous p53 and result in enhanced vector expression and tumor suppression. Since nutlin-3 can activate p53 by blocking its interaction with mdm2, we explored the possibility that the combination of p19Arf gene transfer and nutlin-3 drug treatment may provide an additive benefit in stimulating p53 function. Methods: B16 (mouse melanoma) and C6 (rat glioma) cell lines, which harbor p53wt, were transduced with pCLPGp19 and these were additionally treated with nutlin-3 or the DNA damaging agent, doxorubicin. Viral expression was confirmed by Western, Northern and immunofluorescence assays. p53 function was assessed by reporter gene activity provided by a p53-responsive construct. Alterations in proliferation and viability were measured by colony formation, growth curve, cell cycle and MTT assays. In an animal model, B16 cells were treated with the pCLPGp19 virus and/or drugs before subcutaneous injection in C57BL/6 mice, observation of tumor progression and histopathologic analyses. Results: Here we show that the functional activation of endogenous p53wt in B16 was particularly challenging, but accomplished when combined gene transfer and drug treatments were applied, resulting in increased transactivation by p53, marked cell cycle alteration and reduced viability in culture. In an animal model, B16 cells treated with both p19Arf and nutlin-3 yielded increased necrosis and decreased BrdU marking. In comparison, C6 cells were quite susceptible to either treatment, yet p53 was further activated by the combination of p19Arf and nutlin-3. Conclusions: To the best of our knowledge, this is the first study to apply both p19Arf and nutlin-3 for the stimulation of p53 activity. These results support the notion that a p53 responsive vector may prove to be an interesting gene transfer tool, especially when combined with p53- activating agents, for the treatment of tumors that retain wild-type p53.

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.

The Coupled Aerosol and Tracer Transport model to the Brazilian developments on the Regional Atmospheric Modeling System (CATT-BRAMS) - Part 2: Model sensitivity to the biomass burning

We describe an estimation technique for biomass burning emissions in South America based on a combination of remote-sensing fire products and field observations, the Brazilian Biomass Burning Emission Model (3BEM). For each fire pixel detected by remote sensing, the mass of the emitted tracer is calculated based on field observations of fire properties related to the type of vegetation burning. The burnt area is estimated from the instantaneous fire size retrieved by remote sensing, when available, or from statistical properties of the burn scars. The sources are then spatially and temporally distributed and assimilated daily by the Coupled Aerosol and Tracer Transport model to the Brazilian developments on the Regional Atmospheric Modeling System (CATT-BRAMS) in order to perform the prognosis of related tracer concentrations. Three other biomass burning inventories, including GFEDv2 and EDGAR, are simultaneously used to compare the emission strength in terms of the resultant tracer distribution. We also assess the effect of using the daily time resolution of fire emissions by including runs with monthly-averaged emissions. We evaluate the performance of the model using the different emission estimation techniques by comparing the model results with direct measurements of carbon monoxide both near-surface and airborne, as well as remote sensing derived products. The model results obtained using the 3BEM methodology of estimation introduced in this paper show relatively good agreement with the direct measurements and MOPITT data product, suggesting the reliability of the model at local to regional scales.

Model Independent Tests of Skyrmions and Their Holographic Cousins

We describe a new exact relation for large N(c) QCD for the long-distance behavior of baryon form factors in the chiral limit. This model-independent relation is used to test the consistency of the structure of several baryon models. All 4D semiclassical chiral soliton models satisfy the relation, as does the Pomarol-Wulzer holographic model of baryons as 5D Skyrmions. However, remarkably, we find that the holographic model treating baryons as instantons in the Sakai-Sugimoto model does not satisfy the relation.

Charm and longitudinal structure functions within the Kharzeev-Levin-Nardi model

We use the Kharzeev-Levin-Nardi (KLN) model of the low x gluon distributions to fit recent HERA data on F(L) and F(2)(c)(F(2)(b)). Having checked that this model gives a good description of the data, we use it to predict F(L) and F(2)(c) to be measured in a future electron-ion collider. The results are similar to those obtained with the de Florian-Sassot and Eskola-Paukkunen-Salgado nuclear gluon distributions. The conclusion of this exercise is that the KLN model, simple as it is, may still be used as an auxiliary tool to make estimates for both heavy-ion and electron-ion collisions.