Effect of General Anesthesia on Cardiac Magnetic Resonance-Derived Cardiac Function in Repaired Tetralogy of Fallot.

Cardiac magnetic resonance imaging (CMR)-derived ejection fraction (EF) predicts adverse outcomes in repaired tetralogy of Fallot (rTOF) and drives timing of pulmonary valve replacement. Certain patient populations require sedation for successful CMR image acquisition. General anesthesia (GA) has been shown to depress EF and heart rate (HR) in animal models, however, its effect on congenital heart disease is unknown. A retrospective review was conducted of all CMR patients referred with rTOF between January 2011 and May 2019. The cohort was separated into GA and non-GA groups. Propensity score matching (PSM) adjusted for selection bias. A kernel matching algorithm was used to match subjects and the differences in mean treatment effect on the treated were computed for left ventricular (LV) and right ventricular (RV) EF, HR, and cardiac index (CI). 143 patients met criteria, 37 patients under GA (mean age 15 years, range 2-45, 59% male), and 106 patients without GA (mean age 21 years, range 10-53, 50% male). Unmatched analysis showed significant depression of LV EF (50 vs. 57%, p < 0.001) and RV EF (42 vs. 48%, p < 0.001) in the GA group compared to the non-GA group. There was no significant difference in HR or CI. After matching and PSM adjustment, the GA group had a significant decrease in LV EF (49 vs. 56%, p < 0.001), RV EF (41 vs. 48%, p < 0.001), CI (2728 vs. 3701 ml/min/m2, p < 0.001), and HR (72 vs. 79 bpm, p = 0.04). General anesthesia with sevoflurane results in depressed CMR-derived EF.

Arabidopsis Glutaredoxin S17 Contributes to Vegetative Growth, Mineral Accumulation, and Redox Balance during Iron Deficiency.

Iron (Fe) is an essential mineral nutrient and a metal cofactor required for many proteins and enzymes involved in the processes of DNA synthesis, respiration, and photosynthesis. Iron limitation can have detrimental effects on plant growth and development. Such effects are mediated, at least in part, through the generation of reactive oxygen species (ROS). Thus, plants have evolved a complex regulatory network to respond to conditions of iron limitations. However, the mechanisms that couple iron deficiency and oxidative stress responses are not fully understood. Here, we report the discovery that an Arabidopsis thaliana monothiol glutaredoxin S17 (AtGRXS17) plays a critical role in the plants ability to respond to iron deficiency stress and maintain redox homeostasis. In a yeast expression assay, AtGRXS17 was able to suppress the iron accumulation in yeast ScGrx3/ScGrx4 mutant cells. Genetic analysis indicated that plants with reduced AtGRXS17 expression were hypersensitive to iron deficiency and showed increased iron concentrations in mature seeds. Disruption of AtGRXS17 caused plant sensitivity to exogenous oxidants and increased ROS production under iron deficiency. Addition of reduced glutathione rescued the growth and alleviates the sensitivity of atgrxs17 mutants to iron deficiency. These findings suggest AtGRXS17 helps integrate redox homeostasis and iron deficiency responses.

Identification and characterization of a supraclavicular brown adipose tissue in mice.

A fundamental challenge to our understanding of brown adipose tissue (BAT) is the lack of an animal model that faithfully represents human BAT. Such a model is essential for direct assessment of the function and therapeutic potential of BAT depots in humans. In human adults, most of the thermoactive BAT depots are located in the supraclavicular region of the neck, while mouse studies focus on depots located in the interscapular region of the torso. We recently discovered BAT depots that are located in a region analogous to that of human supraclavicular BAT (scBAT). Here, we report that the mouse scBAT depot has morphological characteristics of classical BAT, possesses the potential for high thermogenic activity, and expresses a gene signature that is similar to that of human scBAT. Taken together, our studies reveal a mouse BAT depot that represents human BAT and provides a unique tool for developing new translatable approaches for utilizing human scBAT.

Postnatal epigenetic regulation of intestinal stem cells requires DNA methylation and is guided by the microbiome.

BACKGROUND: DNA methylation is an epigenetic mechanism central to development and maintenance of complex mammalian tissues, but our understanding of its role in intestinal development is limited. RESULTS: We use whole genome bisulfite sequencing, and find that differentiation of mouse colonic intestinal stem cells to intestinal epithelium is not associated with major changes in DNA methylation. However, we detect extensive dynamic epigenetic changes in intestinal stem cells and their progeny during the suckling period, suggesting postnatal epigenetic development in this stem cell population. We find that postnatal DNA methylation increases at 3' CpG islands (CGIs) correlate with transcriptional activation of glycosylation genes responsible for intestinal maturation. To directly test whether 3' CGI methylation regulates transcription, we conditionally disrupted two major DNA methyltransferases, Dnmt1 or Dnmt3a, in fetal and adult intestine. Deficiency of Dnmt1 causes severe intestinal abnormalities in neonates and disrupts crypt homeostasis in adults, whereas Dnmt3a loss was compatible with intestinal development. These studies reveal that 3' CGI methylation is functionally involved in the regulation of transcriptional activation in vivo, and that Dnmt1 is a critical regulator of postnatal epigenetic changes in intestinal stem cells. Finally, we show that postnatal 3' CGI methylation and associated gene activation in intestinal epithelial cells are significantly altered by germ-free conditions. CONCLUSIONS: Our results demonstrate that the suckling period is critical for epigenetic development of intestinal stem cells, with potential important implications for lifelong gut health, and that the gut microbiome guides and/or facilitates these postnatal epigenetic processes.