RESUMEN
In crystalline materials, dislocations are three-dimensional lattice distortions that systematically distort twin interfaces that they encounter. This results in dislocation dissociation events and changes in the atomic structure of the interface. The manner in which the interface distorts drive the product of the dissociation event, and consequently, the incident dislocation core and the magnitude and relative direction of the Burgers vector govern these slip-twin interaction phenomena. Recent characterization studies using transmission electron microscopy as well as advanced molecular dynamic simulations have shown that slip dislocations, whether striking or struck by a {10 1 ¯ 2} twin boundary, dissociate into a combination of twinning disconnections, interfacial disclinations (facets), jogs, and other types of dislocations engulfed inside the twin domains, called transmuted dislocations. While twinning disconnections were found to promote twin propagation, the dislocations incorporated inside the twin are of considerable importance to hardening and damage initiation as they more significantly obstruct slip dislocations accommodating plasticity of the twins. In this work, the dislocation transmutation event and its effect on hardening is captured using a dislocation density based hardening model contained in a visco-plastic self-consistent mean-field model. This is done by allowing the twins to increase their dislocation densities, not only by virtue of slip inside the twin, but also through dislocations that transmute from the parents as the twin volume fraction increases. A correspondence matrix rule is used to determine the type of converted dislocations while tracking and parameterizing their evolution. This hypothesis provides a modeling framework for capturing slip-twin interactions. The model is used to simulate the mechanical response of pure Mg and provides a more physically based approach for modeling stress-strain behavior.
RESUMEN
Loss of the growth-suppressive effects of bone morphogenetic protein (BMP) signaling has been demonstrated to promote pulmonary arterial endothelial cell dysfunction and induce pulmonary arterial smooth muscle cell (PASMC) proliferation, leading to the development of pulmonary arterial hypertension (PAH). MicroRNAs (miRs) mediate higher order regulation of cellular function through coordinated modulation of mRNA targets; however, miR expression is altered by disease development and drug therapy. Here, we examined treatment-naive patients and experimental models of PAH and identified a reduction in the levels of miR-140-5p. Inhibition of miR-140-5p promoted PASMC proliferation and migration in vitro. In rat models of PAH, nebulized delivery of miR-140-5p mimic prevented the development of PAH and attenuated the progression of established PAH. Network and pathway analysis identified SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) as a key miR-140-5p target and regulator of BMP signaling. Evaluation of human tissue revealed that SMURF1 is increased in patients with PAH. miR-140-5p mimic or SMURF1 knockdown in PASMCs altered BMP signaling, further supporting these factors as regulators of BMP signaling. Finally, Smurf1 deletion protected mice from PAH, demonstrating a critical role in disease development. Together, these studies identify both miR-140-5p and SMURF1 as key regulators of disease pathology and as potential therapeutic targets for the treatment of PAH.