Affinity-optimizing enhancer variants disrupt development.

Enhancers control the location and timing of gene expression and contain the majority of variants associated with disease. The ZRS is arguably the most well-studied vertebrate enhancer and mediates the expression of Shh in the developing limb. Thirty-one human single-nucleotide variants (SNVs) within the ZRS are associated with polydactyly.

A physiologic and biochemical profile of clinically rejected lungs on a normothermic ex vivo lung perfusion platform.

Background: Although ex vivo lung perfusion (EVLP) is increasingly being used to evaluate and manipulate potential donor lungs before lung transplantation (LTx), data on the biochemistry of lungs during EVLP are limited. In this study, we examined the physiology and biochemistry of human lungs on an EVLP circuit.

Methods: We recovered unallocated double lungs in standard fashion and split them into single lungs.

Inhaled hydrogen sulfide improves graft function in an experimental model of lung transplantation.

Objectives: Ischemia/reperfusion injury (IRI) is a common complication of lung transplantation (LTx). Hydrogen sulfide (H(2)S) is a novel agent previously shown to slow metabolism and scavenge reactive oxygen species, potentially mitigating IRI. We hypothesized that pretreatment with inhaled H(2)S would improve graft function in an ex vivo model of LTx.

Hydrogen sulfide decreases reactive oxygen in a model of lung transplantation.

Background: Ischemia-reperfusion injury is a common complication after lung transplantation. Ischemia-reperfusion injury is thought to be mediated by reactive oxygen species (ROS). Hydrogen sulfide (H(2)S) is a novel agent that has been previously shown to scavenge ROS and slow metabolism.

Nitric oxide regulates tissue transglutaminase localization and function in the vasculature.

The multifunctional enzyme tissue transglutaminase (TG2) contributes to the development and progression of several cardiovascular diseases. Extracellular rather than intracellular TG2 is enzymatically active, however, the mechanism by which it is exported out of the cell remains unknown. Nitric oxide (NO) is shown to constrain TG2 externalization in endothelial and fibroblast cells.

S-nitrosation of arginase 1 requires direct interaction with inducible nitric oxide synthase.

Arginase constrains endothelial nitric oxide synthase activity by competing for the common substrate, L -Arginine. We have recently shown that inducible nitric oxide synthase (NOS2) S-nitrosates and activates arginase 1 (Arg1) leading to age-associated vascular dysfunction. Here, we demonstrate that a direct interaction of Arg1 with NOS2 is necessary for its S-nitrosation.