Regulation of ceramide biosynthesis by TOR complex 2.

Ceramides and sphingoid long-chain bases (LCBs) are precursors to more complex sphingolipids and play distinct signaling roles crucial for cell growth and survival. Conserved reactions within the sphingolipid biosynthetic pathway are responsible for the formation of these intermediates. Components of target of rapamycin complex 2 (TORC2) have been implicated in the biosynthesis of sphingolipids in S. cerevisiae; however, the precise step regulated by this complex remains unknown. Here we demonstrate that yeast cells deficient in TORC2 activity are impaired for de novo ceramide biosynthesis both in vivo and in vitro. We find that TORC2 regulates this step in part by activating the AGC kinase Ypk2 and that this step is antagonized by the Ca2+/calmodulin-dependent phosphatase calcineurin. Because Ypk2 is activated independently by LCBs, the direct precursors to ceramides, our data suggest a model wherein TORC2 signaling is coupled with LCB levels to control Ypk2 activity and, ultimately, regulate ceramide formation.

Study Looking at End Expiratory Pressure for Altitude Illness Decrease (SLEEP-AID).

Lipman, Grant S., Nicholas C. Kanaan, Caleb Phillips, Dave Pomeranz, Patrick Cain, Kristin Fontes, Becky Higbee, Carolyn Meyer, Michael Shaheen, Sean Wentworth, and Diane Walsh. Study Looking at End Expiratory Pressure for Altitude Illness Decrease (SLEEP-AID). High Alt Med Biol 16:154-161, 2015.--Acute mountain sickness (AMS) affects 25%-70% of the tens of millions of high altitude travelers annually, with hypoxia and nocturnal desaturations as major contributing factors. This is the first double blind randomized placebo controlled trial to assess expiratory positive airway pressure (EPAP) for AMS prevention and nocturnal hypoxic events. Healthy adult participants trekking in the Khumbu region of the Himalayas were randomized to a single-use EPAP nasal strip, or a visually identical sham device (placebo) prior to first night sleeping between 4371-4530 m (14,340-14,800 ft). The primary outcome was AMS incidence, measured by Lake Louise Questionnaire (LLQ), with secondary outcomes of AMS severity (by LLQ) and physiologic sleep indices measured by continuous sleep monitor. Intent-to-treat analysis included 219 participants with comparable demographic characteristics, of which 115 received EPAP and 104 placebo. There was no decrease in AMS with EPAP intervention (14% EPAP vs. 17% placebo; p=0.65; risk difference (-)3.15%, 95% CI (-)12.85%-6.56%). While overall AMS severity was not different between groups, EPAP reported decreased incidence of headache (64% vs. 76%; p<0.05, OR 0.51, 95% CI 0.27-0.95) and dizziness (81% vs. 98%; p<0.03, OR 0.29, 95% CI 0.09-0.78). During sleep, EPAP resulted in significant improvements in average peripheral oxygenation (Spo(2)) (80% versus 78%; p<0.01, mean difference=2, 95% CI 0.58-3.63) and a reduced percentage of time below 80% Spo(2) (31% vs. 46%; p<0.03, median difference=16, 95% CI 2.22-28.18). This lightweight and inexpensive EPAP device did not prevent acute mountain sickness, but did reduce the subgroup incidence of headache and dizziness while improving average nighttime peripheral oxygenation.