Obesity increases risk for liver toxicity by the anti-leukemic agent asparaginase, but the mechanism is unknown. Asparaginase activates the integrated stress response (ISR) via sensing amino acid depletion by the eukaryotic initiation factor 2 (eIF2) kinase GCN2. The goal of this work was to discern the impact of obesity, alone alongside genetic disruption of the ISR, on mechanisms of liver protection during chronic asparaginase exposure in mice. Following diet-induced obesity, biochemical analysis of livers revealed that asparaginase provoked hepatic steatosis that coincided with activation of another eIF2 kinase PKR-like endoplasmic reticulum kinase (PERK), a major ISR transducer to ER stress. Genetic loss of intensified hepatic PERK activation to asparaginase, yet surprisingly, mRNA levels of key ISR gene targets such as and failed to increase. Instead, mechanistic target of rapamycin complex 1 (mTORC1) signal transduction was unleashed, and this coincided with liver dysfunction reflected by a failure to maintain hydrogen sulfide production or apolipoprotein B100 (ApoB100) expression. In contrast, obese mice lacking hepatic activating transcription factor 4 () showed an exaggerated ISR and greater loss of endogenous hydrogen sulfide but normal inhibition of mTORC1 and maintenance of ApoB100 during asparaginase exposure. In both genetic mouse models, expression and phosphorylation of Sestrin2, an ATF4 gene target, was increased by asparaginase, suggesting mTORC1 inhibition during asparaginase exposure is not driven via eIF2-ATF4-Sestrin2. In conclusion, obesity promotes a maladaptive ISR during asparaginase exposure. GCN2 functions to repress mTORC1 activity and maintain ApoB100 protein levels independently of expression, whereas hydrogen sulfide production is promoted via GCN2-ATF4 pathway.

Phytoecdysteroids such as 20-hydroxyecdysone (20HE) are nutritional supplements marketed as enhancers of lean body mass. In this study the impact of 20HE ingestion on protein kinase B/Akt-mechanistic target of rapamycin complex 1 signaling in the skeletal muscle and liver of male rats was found to be limited. Bioavailability of 20HE, whether consumed alone or with leucine, also remained low at all doses ingested. Additional work is necessary to clarify 20HE mechanism of action in vivo.

No abstract

Background: This study sought to explore the relationship between semantic competence (or dyscompetence) displayed during “think-alouds” performed by resident and attending physicians and clinical reasoning performance. Methods: Internal medicine resident physicians and practicing internists participated in think-alouds performed after watching videos of typical presentations of common diseases in internal medicine. The think-alouds were evaluated for the presence of semantic competence and dyscompetence and these results were correlated with clinical reasoning performance.  Results: We found that the length of think-aloud was negatively correlated with clinical reasoning performance. Beyond this finding, however, we did not find any other significant correlations between semantic competence or dyscompetence and clinical reasoning performance. Conclusions: While this study did not produce the previously hypothesized findings of correlation between semantic competence and clinical reasoning performance, we discuss the possible implications and areas of future study regarding the relationship between semantic competency and clinical reasoning performance.