Autophagy regulates stemness: Embryonic stem cells can propagate indefinitely and differentiate when called to do so. Xu et al. now analyze how cellular metabolism affects the balance between pluripotency and differentiation (see the Perspective by Borsa and Simon). For cells in the pluripotent state, the transcription factors Oct4 and Sox2 suppress chaperone-mediated autophagy (CMA). When CMA is released with differentiation, the isocitrate dehydrogenases IDH1 and IDH2 are degraded, resulting in less α-ketoglutarate, which is needed by the histone and DNA demethylases that sustain pluripotency. CMA thus links cellular metabolism to epigenetic regulation, tipping the balance between pluripotent renewal and differentiation. Science , this issue p. 397 ; see also p. 373

Placental dysfunction is implicated in the pathogenesis of spontaneous preterm birth (SPTB). We investigated race (self-identified maternal race) and fetal sex differences in the placental metabolome and transcriptome associated with early SPTB (<32 weeks). Long-chain polyunsaturated fatty acids, acylcarnitines, acylglycerols, plasmalogens, and lysophospholipids were remarkably different between SPTB and Term placentas. These alterations were much more profound in Black than in White SPTB placentas. Mode of delivery and body mass index (BMI) had no effect on these differences. The lipid metabolic pathways disrupted in early SPTB placentas also exhibited fetal sex differences, particularly between Black male and Black female placentas. The expression of genes involved in multiple lipid metabolism regulating pathways (e.g., PI3K/AKT signaling and phospholipase activity), especially eicosanoid synthesis and secretion, was significantly altered in early SPTB placentas. The race- and sex-specific changes in lipid metabolites and gene expression were consistent with inflammation in SPTB placentas, which was further supported by dysregulation of various inflammation and immune response pathways. These findings reveal race and fetal sex differences in lipid metabolism and inflammation in SPTB placentas and suggest greater dysfunction and inflammation in Black compared to White SPTB placentas, which may explain mechanisms underlying early SPTB and the risk of SPTB in different populations.

There is wide variation in how individuals perceive the chemosensory attributes of liquid formulations of ibuprofen, encompassing both adults and children. To understand personal variation in the taste and chemesthesis properties of this medicine, and how to measure it, our first scientific strategy centered on utilizing trained adult panelists, due to the complex and time-consuming psychophysical tasks needed at this initial stage. We conducted a double-blind cohort study in which panelists underwent whole-genome-wide genotyping and psychophysically evaluated an over-the-counter pediatric medicine containing ibuprofen. Associations between sensory phenotypes and genetic variation near/within irritant and taste receptor genes were determined. Panelists who experienced the urge to cough or throat sensations found the medicine less palatable and sweet, and more irritating. Perceptions varied with genetic ancestry; panelists of African genetic ancestry had fewer chemesthetic sensations, rating the medicine sweeter, less irritating, and more palatable than did those of European genetic ancestry. We discovered a novel association between TRPA1 rs11988795 and tingling sensations, independent of ancestry. We also determined for the first time that just tasting the medicine allowed predictions of perceptions after swallowing, simplifying future psychophysical studies on diverse populations of different age groups needed to understand genetic, cultural–dietary, and epigenetic factors that influence individual perceptions of palatability and, in turn, adherence and the risk of accidental ingestion.

Acesulfame potassium (Ace-K) is a low-calorie sweetener (LCS) widely used as an ingredient in foods and beverages and an excipient in pediatric medicines. While prior candidate gene studies have established that genetic variants in bitter taste receptor (TAS2R) genes are associated with variation in the taste of Ace-K, we sought to identify genetic contributions to its taste using a genome-wide association study (GWAS) of 141 adult panelists who rated the taste of an aqueous solution of Ace-K using the general labelled magnitude scale (gLMS) and its palatability using the hedonic gLMS. To determine whether GWAS-identified associations with Ace-K generalized to a more complex stimulus, panelists also rated the taste of a pediatric medicine that contains Ace-K as an excipient (Children’s Motrin™). We identified that a TAS2R-containing locus on chromosome 12 was associated with bitterness ratings of Ace-K (p-values < 5 × 10^− 8), and the lead SNP rs2708381 in this locus was associated with the sweetness intensity of Children’s Motrin™ (p-value = 0.001). SNP rs2708381 was also associated with perceived intensity ratings of another LCS, neohesperidine dihydrochalcone, in a replication GWAS of 1,757 panelists (p-value = 0.002). A locus within the gene ELMO1, which encodes engulfment and cell motility protein 1, was associated with hedonic ratings of Ace-K (p-values < 5 × 10^− 8), and no genome-wide significant signals were observed for sweetness ratings. These findings identify a novel genetic locus containing TAS2R genes that contributes to personal differences in the taste of Ace-K, which may impact the acceptance of medicines, food, and beverages containing Ace-K. Clinical trials registration: Sensory evaluation of the taste of pediatric medicines (MEDTASTE); clinical trials registry number NCT03627351, registered on 13 August 2018.