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Exogenous ketone supplements are a potential augmentation strategy for cognitive resilience during acute hypoxic exposure due to their capacity to attenuate the decline in oxygen (O2) availability, and by providing an alternative substrate for cerebral metabolism. Utilizing a single‐blind randomized crossover design, 16 male military personnel (age, 25.3 ± 2.4 year, body mass, 86.2 ± 9.3 kg) performed tests of cognitive performance at rest in three environments: room air (baseline), normoxia (20 min; 0 m; 20.9% O2) and hypoxia (20 min; 6096 m, 9.7% O2) using a reduced O2 breathing device (ROBD). (R)‐3‐Hydroxybutyl (R)‐3‐hydroxybutyrate (R‐BD R‐βHB) ketone monoester (KME; 650 mg/kg, split dose given at 30 min prior to each exposure) or taste‐matched placebo (PLA) was ingested prior to normoxia and hypoxic exposure. Blood R‐βHB and glucose concentrations, cognitive performance and O2 saturation (SpO2${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$) were collected throughout. KME ingestion increased blood R‐βHB concentration, which was rapid and sustained (>4 mM 30 min post; P < 0.001) and accompanied by lower blood glucose concentration (∼20 mg/dL; P < 0.01) compared to PLA. Declines in cognitive performance during hypoxic exposure, assessed as cognitive efficiency during a Defense Automated Neurobehavioral Assessment (DANA) code substitution task, were attenuated with KME leading to 6.8 (95% CL: 1.0, 12.6) more correct responses per minute compared to PLA (P = 0.018). The decline in SpO2${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ during hypoxic exposure was attenuated (6.40% SpO2${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$; 95% CL: 0.04, 12.75; P = 0.049) in KME compared to PLA (KME, 76.8 ± 6.4% SpO2${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$; PLA, 70.4 ± 7.4% SpO2${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$). Acute ingestion of KME attenuated the decline in cognitive performance during acute severe hypoxic exposure, which coincided with attenuation of declines in O2 saturation. What is the central question of this study?Can exogenous ketosis act as a countermeasure to declines in blood oxygen saturation and cognitive performance during acute severe hypoxic exposure at rest?What is the main finding and its importance?Acute exogenous ketosis via ingestion of a drink containing the (R)‐3‐hydroxybutyl (R)‐3‐hydroxybutyrate ketone monoester prior to acute severe hypoxic exposure attenuated hypoxia‐induced declines in blood oxygen saturation and cognitive performance at rest. [ABSTRACT FROM AUTHOR]

Acute ingestion of exogenous ketone supplements in the form of a (R)‐3‐hydroxybutyl (R)‐3‐hydroxybutyrate (R‐BD R‐βHB) ketone monoester (KME) can attenuate declines in oxygen availability during hypoxic exposure and might impact cognitive performance at rest and in response to moderate‐intensity exercise. In a single‐blind randomized crossover design, 16 males performed assessments of cognitive performance before and during hypoxic exposure with moderate exercise [2 × 20 min weighted ruck (∼22 kg) at 3.2 km/h at 10% incline] in a normobaric altitude chamber (4572 m, 11.8% O2). The R‐BD R‐βHB KME (573 mg/kg) or a calorie‐ and taste‐matched placebo (∼50 g maltodextrin) were co‐ingested with 40 g of dextrose before exposure to hypoxia. The R‐βHB concentrations were rapidly elevated and sustained (>3 mM; P < 0.001) by KME. The decline in oxygen saturation during hypoxic exposure was attenuated in KME conditions by 2.4%–4.2% (P < 0.05) compared with placebo. Outcomes of cognitive performance tasks, in the form of the Defense Automated Neurobehavioral Assessment (DANA) code substitution task, the Stroop color and word task, and a shooting simulation, did not differ between trials before and during hypoxic exposure. These data suggest that the acute exogenous ketosis induced by KME ingestion can attenuate declining blood oxygen saturation during acute hypoxic exposure both at rest and during moderate‐intensity exercise, but this did not translate into differences in cognitive performance before or after exercise in the conditions investigated. What is the central question of this study?Can exogenous ketosis act as a countermeasure to declines in blood oxygen saturation and cognitive performance during acute hypoxic exposure while performing a weighted ruck exercise?What is the main finding and its importance?Acute exogenous ketosis via ingestion of a drink containing the (R)‐3‐hydroxybutyl (R)‐3‐hydroxybutyrate ketone monoester prior to acute hypoxic exposure attenuated hypoxia‐induced declines in blood oxygen saturation but had no effect on cognitive performance during exercise. [ABSTRACT FROM AUTHOR]

Myeloid/lymphoid or mixed-lineage leukemia (MLL)-iamHy genes encode histone lysine methyltransferases that play important roles in epigenetic regulation of gene transcription. MLL genes are frequently mutated in human cancers. Unlike MLL1, MLL2 (also known as ALR/MLL4) and its homolog MLL3 are not well-under-stood. Specifically, little is known regarding the extent of global MLL2 involvement in the regulation of gene expression and the mechanism underlying its alterations in driving tumorigenesis. Here we profile the global loci targeted by MLL2. A combinatorial analysis of the MLL2 binding profile and gene expression in MLL2 wild-type versus MLL2-null isogenic cell lines identified direct transcriptional target genes and revealed the connection of MLL2 to multiple cellular signaling pathways, including the p53 pathway, cAMP-mediated signaling, and cholestasis signaling. In particular, we demonstrate that MLL2 participates in retinoic acid receptor signaling by promoting retinoic acid-responsive gene transcription. Our results present a genome-wide integrative analysis of the MLL2 target loci and suggest potential mechanisms underlying tumorigenesis driven by MLL2 alterations. [ABSTRACT FROM AUTHOR]