Breakdown of the blood-retinal barrier (BRB), as occurs in diabetic retinopathy and other chronic retinal diseases, results in vasogenic edema and neural tissue damage, causing vision loss. Vasoinhibins are N-terminal fragments of prolactin that prevent BRB breakdown during diabetes. They modulate the expression of some transient receptor potential (TRP) family members, yet their role in regulating the TRP vanilloid subtype 4 (TRPV4) remains unknown. TRPV4 is a calcium-permeable channel involved in barrier permeability, which blockade has been shown to prevent and resolve pulmonary edema. We found TRPV4 expression in the endothelium and retinal pigment epithelium (RPE) components of the BRB, and that TRPV4-selective antagonists (RN-1734 and GSK2193874) resolve BRB breakdown in diabetic rats. Using human RPE (ARPE-19) cell monolayers and endothelial cell systems, we further observed that (i) GSK2193874 does not seem to contribute to the regulation of BRB and RPE permeability by vasoinhibins under diabetic or hyperglycemic-mimicking conditions, but that (ii) vasoinhibins can block TRPV4 to maintain BRB and endothelial permeability. Our results provide important insights into the pathogenesis of diabetic retinopathy that will further guide us toward rationally-guided new therapies: synergistic combination of selective TRPV4 blockers and vasoinhibins can be proposed to mitigate diabetes-evoked BRB breakdown.

Trabecular bone, rather than being considered as a homogeneous material, must be analysed as a structure of interconnected beam and plate-like elements. The arrangement and morphology of these elements depend on the specific tissue studied as well as on the physiology of the individual. It is therefore impossible to define the mechanical properties trabecular bone in general. To estimate the properties of an individual structure, flexible numerical models must be developed, which allow the calculation of elastic constants and resistance of tissue previously characterised by non-destructive observation. Voxel-based modelling of structures observed by X-ray microtomography is computation intensive. Here, synthetic 2D-microstructures are analysed, constructed as a collection of Voronoi-cells obtained from the observation of plane sections of cancellous bone. The effect of architecture (vertebra and femur), bone density and loss of trabecular connectivity was researched. The study confirms findings of earlier experimental and numerical studies relating to the effect of these parameters; the technique is efficient in terms of experimental effort and numerical analysis. Consequently, the use of synthetic microstructures based on a Voronoi-cell approximation of the real bone architecture may be a promising approach for the prediction of the mechanical properties of trabecular bone.

No abstract

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Forging is a widely used manufacturing process, and its design and modeling are important to reducing production costs, increasing die lifespan, and improving the mechanical properties of the final product. In this study, the forging process of a connecting rod was modeled using 3D coupled Eulerian Lagrangian (CEL) analysis by FEM. The methodology adopted achieved to determine a preform geometry that reduces final flash and forging load, while ensuring complete filling of the stamp. Starting from the final geometry, the final die was designed. After the first result for an approximately 27% of flash, the material distribution was adjusted decreasing it at the regions where the flash was too large. After an iterative method was applied to determine better preform, a proposal was found that reduced forging force by approximately 42% and the percentage of flash volume by 64% in comparison with the first one. A final flash of about 10% is considered a good objective to reach. Lower values may cause many iterations, not a significant difference in forging loads, the risk of an unfilled die, and complex preform geometries.

Forging is a widely used manufacturing processes and its design and modeling are important to reducing production costs, increasing die lifespan and improving the mechanical properties of the final product. In this study, the forging process of a connecting rod was modeled using 3D Coupled Eulerian Lagrangian (CEL) analysis by FEM. The methodology adopted achieved to determine a preform geometry that reduces final flash and forging load, while ensuring complete filling of the stamp. Starting from the final geometry, the final die was designed. After the first result for an approximately 27% of flash, it was adjusted the material distribution decreasing it at the regions where the flash was too large. After an iterative method was applied to determine better preform, a proposal was found that reduced forging force by approximately 42% and the percentage of flash volume by 64% in comparison with the first one. A final flash of about 10% is considered a good objective to reach. Lower values may cause many iterations, not a significant difference in forging loads, the risk of an unfilled die and complex preform geometries.

No abstract