Background and Purpose
Metabolic and vascular dysfunction are common features of obesity. Aryl hydrocarbon receptor (AhR) regulates lipid metabolism and vascular homeostasis, but whether vascular AhR ...are activated in obesity or have a protective and/or harmful effects on vascular function in obesity are unknown. Our study addresses whether AhR activation contributes to obesity‐associated vascular dysfunction and the mechanisms involved in these AhR effects.
Experimental Approach
Male AhR KO (Ahr−/−) and WT mice were fed either control or a HF (high‐fat) diet for 10 weeks. Metabolic and inflammatory parameters were measured in serum and adipose tissue. Vascular reactivity (isometric force) was evaluated using a myography. Endothelial NOS (eNOS) and AhR protein expression was determined by western blot, Cyp1A1 and Nos3 gene expression by RT‐PCR and.NO production was quantified by DAF fluorescence.
Key Results
HF diet increased total serum HDL and LDL, as well as vascular AhR protein expression and proinflammatory cytokines in the adipose tissue. HF diet decreased endothelium‐dependent vasodilation. AhR deletion protected mice from HF diet‐induced dyslipidaemia, weight gain and inflammatory processes. HF diet‐induced endothelial dysfunction was attenuated in Ahr−/− mice. Vessels from Ahr−/− mice exhibited a greater NO reserve. In cultured endothelial cells, lysophosphatidylcholine (LPC) a major component of LDL and oxidized LDL oxLDL) reduced Nos3 gene expression and NO production. Antagonism of the AhR inhibited LPC effects on endothelial cells and induced decreased endothelium‐dependent vasodilation.
Conclusion and Implications
AhR deletion attenuates HF diet‐induced dyslipidaemia and vascular dysfunction by improving eNOS/NO signalling. Targeting AhRs may prevent obesity‐associated vascular dysfunction.
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This study aimed to develop and evaluate bread with the use of pulp and flours of pequi, in partial replacement of water and wheat flour, to develop a bakery product with good technological, ...nutritional and sensorial qualities. The pequi husk and pulp flours were obtained by means of a thermal pre-treatment, oven drying and standardization of the dry material. Whereas, the bread formulation was defined through the baker's formulation. Besides, the dehydration process caused significant changes (p<0.05) in the L* value and chromaticity (C*), mainly of the flours (husk and pequi pulp), such changes are due to non-enzymatic oxidative processes and pigment degradation, especially carotenoids. The effect of the substitution of ingredients (wheat flour and water) by husk and pulp flours and pequi pulp contributed to the increase in lipid, crude fiber, nitrogen-free extract and energy value content. However, the substitution promoted changes in the attributes of color and textural properties, such as increased hardness, chewiness and cohesiveness. Nevertheless, all formulations showed good sensory acceptance and thus, pequi sweet breads can be implemented in school meals for contributing and meeting the nutritional recommendations established by the School Feeding Brazilian Program (PNAE).
One of the challenges of fault diagnosis is to verify diagnosability of systems with huge state space efficiently. Model checking approaches have the potential to analyze such systems efficiently. In ...this work, we propose a model checking approach to deal with the problem of the diagnosability verification. We define the diagnosability property in the transition system framework. To check this property, we describe it by using an unique linear temporal logic (LTL) formula. Our approach can be carried out in model checker tools for formal verification of models, such as SPIN and NuSMV. To illustrate the efficiency of our approach we perform some experiments. First, we consider a railway level crossing benchmark, comparing the results of our approach in SPIN and NuSMV with the results found using DESLab and Supremica tools. Then, we perform an exploratory statistical analysis comparing the average size of verifiers computed with our approach in SPIN with the average size of verifiers (it number of states plus transitions) computed with DESLab, which is a tool for diagnosability verification of Discrete Event Systems (DES) that uses the same foundation idea.
To assess the relationship between macular choroidal thickness (CT) measurements and retinal sensitivity (RS) in eyes with myopia and different stages of myopic maculopathy.
A masked, ...cross-sectional, and consecutive study involving patients with emmetropia/myopia (control group) and high myopia (HM) eyes. Automated choroidal thickness (CT) and manual outer retinal layer (ORL) thickness were acquired using swept-source optical coherence tomography, while retinal sensitivity (RS) assessed by microperimetry (MP3) in all regions of the macular Early Treatment Diabetic Retinopathy Study (ETDRS) grid. Comparisons were made between groups, and correlations were performed among these measurements, demographic and ocular parameters and myopic maculopathy classification.
A total of 37 (74 eyes) patients were included in the study. The mean age was 39 ± 13 years, and 28 patients (76%) were female. HM eyes exhibited inferior best-corrected visual acuity and a more advanced myopic maculopathy classification compared to the control group. The mean macular CT were 255 and 179 μm in the control and HM eyes (P < 0.001), respectively. In the HM eyes, superior ETDRS region presented the greatest values. Mean RS in control and HM groups was 28 and 24 dB (P = 0.001), respectively. Inner temporal followed by superior, were the regions of higher RS. Mean ORL thickness was 83 and 79 μm (P < 0.001), in the control and HM groups, respectively. The inner temporal ETDRS region presented the thickest measure. CT correlated significantly with RS (r = 0.41, P < 0.001) and ORL thickness, (r = 0.58, P < 0.001), which also correlated with RS (r = 0.40, P < 0.001). Spherical equivalent, axial length and myopic maculopathy stage were the parameters that most correlated with CT, RS and ORL thickness. For every 100 μm increase in thickening of CT there was an average increase of 3.4 μm in ORL thickness and 2.7 dB in RS. Myopic maculopathy classification demonstrated influence only with CT.
Myopia degree is related to ORL and choroidal thinning and deterioration of retinal sensitivity in some ETDRS regions of the macula. Choroidal thinning is associated to with a decline of retinal sensitivity, thinning of ORL, and worsening of myopic maculopathy classification, so new treatments are necessary to prevent myopia progression.
Malaria is a human parasitic disease distributed in many tropical countries and caused by various
species.
has the largest geographical distribution of the
species and is predominant in the Americas, ...including Brazil. Only a small number of
vaccine formulations have successfully reached clinical trials relative to their
counterparts. One of the candidate antigens for a blood-stage
vaccine is apical membrane antigen 1 (PvAMA-1). Due to the worldwide distribution of
parasites, a high degree of variability has been detected in this antigen sequence, representing a considerable challenge to the development of a universal vaccine against malaria. In this study, we evaluated how PvAMA-1 polymorphisms influence vaccine-derived immune responses in
malaria. To this end, we expressed 9 recombinant protein representatives of different PvAMA-1 allelic variants in the yeast
: Belem, Chesson I, Sal-1, Indonesia XIX, SK0814, TC103, PNG_05_ESP, PNG_62_MU, and PNG_68_MAS. After protein expression and purification, we evaluated the breadth of the immune responses derived from malaria-exposed individuals from the Amazon region. From 611 serum samples of malaria-exposed individuals, 53.68% of them reacted against the PvAMA-1 Belem through ELISA. Positive samples were further tested against recombinant proteins representing the other PvAMA-1 allelic variants. Whereas Sal-1, Chesson I and SK0814 variants were highly recognized by tested serum samples, Indonesia XIX, TC103, PNG_05_ESP, PNG_62_MU, and PNG_68_MAS were only slightly recognized. Moreover, polyclonal sera derived from C57BL/6 mice immunized with the PvAMA-1 Belem protein predominantly recognized Belem, Sal-1, Chesson I, SK0814, and Indonesia XIX through ELISA. Last, ELISA-based competition assays demonstrated that a previous interaction between anti-Belem polyclonal serum and Sal-1, Chesson I, SK0814, or Indonesia XIX proteins could further inhibit antibody binding to the Belem variant. Our human and mouse data suggest the presence of common epitopes or cross-reactivity between Belem, Sal-1, Chesson I, and SK0814 variants. Although the PvAMA-1 Belem variant induces strain-transcendent antibodies, PvAMA-1 variants from Thailand and Papua New Guinea may need to be included in a universal vaccine formulation to achieve protection against
malaria.
This chapter briefly describes the main results developed by the authors in the area of output feedback sliding mode control. For the sake of simplicity, the focus is maintained on uncertain ...single-input-single-output (SISO) nonlinear systems, although several results have been extended to the control of multi-input-multi-output (MIMO) systems. For the considered class of nonlinear systems, linear growth restriction on the unmeasured states is assumed, while less restrictive conditions are imposed to the growth of nonlinearities depending on the measured output. We present different tracking controllers for plants with arbitrary relative degree. We consider several approaches to overcome the relative degree obstacle: linear or variable structure lead filters, high-gain observers with constant or dynamic gain, global hybrid estimation schemes combining lead filters or observers with locally exact differentiators based on high-order sliding mode. Global or semi-global stability properties can be proved either for asymptotic exact tracking or for tracking within a small residual error. Some experimental results are presented to illustrate the applicability of the control schemes in real systems.
The collective motion of self-driven particles shows interesting novel phenomena such as swarming and the emergence of patterns. We have recently proposed a model for counterflowing particles that ...captures this idea and exhibits clogging transitions. This model is based on a generalization of the Fermi-Dirac statistics wherein the maximal occupation of a cell is used. Here we present a detailed study comparing synchronous and asynchronous stochastic dynamics within this model. We show that an asynchronous updating scheme supports the mobile-clogging transition and eliminates some mobility anomalies that are present in synchronous Monte Carlo simulations. Moreover, we show that this transition is dependent upon its initial conditions. Although the Gini coefficient was originally used to model wealth inequalities, we show that it is also efficient for studying the mobile-clogging transition. Finally, we compare our stochastic simulation with direct numerical integration of partial differential equations used to describe this model.
Multiple organ dysfunction is the most severe outcome of sepsis progression and is highly correlated with a worse prognosis. Excessive neutrophil extracellular traps (NETs) are critical players in ...the development of organ failure during sepsis. Therefore, interventions targeting NET release would likely effectively prevent NET-based organ injury associated with this disease. Herein, we demonstrate that the pore-forming protein gasdermin D (GSDMD) is active in neutrophils from septic humans and mice and plays a crucial role in NET release. Inhibition of GSDMD with disulfiram or genic deletion abrogated NET formation, reducing multiple organ dysfunction and sepsis lethality. Mechanistically, we demonstrate that during sepsis, activation of the caspase-11/GSDMD pathway controls NET release by neutrophils during sepsis. In summary, our findings uncover a novel therapeutic use for disulfiram and suggest that GSDMD is a therapeutic target to improve sepsis treatment.
•Inhibition of GSDMD with disulfiram abrogates NET formation, reducing multiple organ dysfunction and sepsis lethality.•Neutrophils from septic patients undergoing NETosis express GSDMD on the cell membrane and around typical NET structures.
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