Steroids regulate cell proliferation, tissue development, and cell signaling via two pathways: a nuclear receptor mechanism and genome-independent signaling. Sperm activation, egg maturation, and steroid-induced anesthesia are executed via the latter pathway, the key components of which remain unknown. Here, we present characterization of the human sperm progesterone receptor that is conveyed by the orphan enzyme α/β hydrolase domain–containing protein 2 (ABHD2). We show that ABHD2 is highly expressed in spermatozoa, binds progesterone, and acts as a progesterone-dependent lipid hydrolase by depleting the endocannabinoid 2-arachidonoylglycerol (2AG) from plasma membrane. The 2AG inhibits the sperm calcium channel (CatSper), and its removal leads to calcium influx via CatSper and ensures sperm activation. This study reveals that progesterone-activated endocannabinoid depletion by ABHD2 is a general mechanism by which progesterone exerts its genome-independent action and primes sperm for fertilization.

Determining the layers of gene regulation within the innate immune response is critical to our understanding of the cellular responses to infection and dysregulation in disease. We identified a conserved mechanism of gene regulation in human and mouse via changes in alternative first exon (AFE) usage following inflammation, resulting in changes to isoform usage. Of these AFE events, we identified 50 unannotated transcription start sites (TSS) in mice using Oxford Nanopore native RNA sequencing, one of which is the cytosolic receptor for dsDNA and known inflammatory inducible gene, Aim2. We show that this unannotated AFE isoform of Aim2 is the predominant isoform transcribed during inflammation and contains an iron-responsive element in its 5′UTR enabling mRNA translation to be regulated by iron levels. This work highlights the importance of examining alternative isoform changes and translational regulation in the innate immune response and uncovers novel regulatory mechanisms of Aim2.

AbstractDetermining the layers of gene regulation within the innate immune response is critical to our understanding of the cellular responses to infection and dysregulation in disease. We identified a conserved mechanism of gene regulation in human and mouse via changes in alternative first exon (AFE) usage following inflammation, resulting in changes to isoform usage. Of these AFE events, we identified 50 unannotated transcription start sites (TSS) in mice using Oxford Nanopore native RNA sequencing, one of which is the cytosolic receptor for dsDNA and known inflammatory inducible gene, Aim2. We show that this unannotated AFE isoform of Aim2 is the predominant isoform transcribed during inflammation and contains an iron-responsive element in its 5′UTR enabling mRNA translation to be regulated by iron levels. This work highlights the importance of examining alternative isoform changes and translational regulation in the innate immune response and uncovers novel regulatory mechanisms of Aim2.Summary SentenceAlternative first exon usage was the major splicing event observed in macrophages during inflammation, which resulted in the elucidation of a novel isoform and iron mediated regulatory mechanism of the protein coding gene, Aim2.

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ObjectiveThis retrospective study aimed to evaluate the impact of anti-obesity medication (AOM) initiation, usage and duration on weight loss in a 72-week precision obesity programme. The type of AOM, diet and exercise plan was chosen based upon an individual's biological and psychosocial needs. The 72-week study duration allowed for a fair investigation of the downstream impact of delayed versus early AOM initiation. MethodsParticipants, aged ≥18 years with body mass index ≥30 kg m À2 , enrolled from 1 March 2015 to 1 April 2017, were included. Subgroups were assigned by AOM usage (users versus non-users, early [before 8 weeks] versus delayed [after 8 weeks] AOM initiation and short [<6 months] versus long [≥6 months] AOM duration). Primary endpoints included change in baseline weight at 72 weeks and proportions achieving ≥5%, ≥10% and ≥15% weight loss. Outcomes were compared between subgroups. ResultsMean age and body mass index (N = 129) were 45.0 ± 14.0 years and 37.0 ± 6.0 kg m À2 , respectively; 67% were female. At week 72, AOM users (N = 71) achieved significantly greater mean percentage reduction in baseline weight than non-users (N = 58). On average, baseline weight decreased by 14.04 ± 6.2% in users versus 10.9 ± 6.8% in nonusers (P = 0.008); 84% and 94% of non-user and AOM users lost >5% weight loss (P = 0.006). A higher proportion of users lost ≥15% of weight (45.1% vs. 19.0%; P < 0.001). Mean percentage reduction in weight was greater for early versus delayed starters (À17.60 ± 5.3% vs. À13.95 ± 5.5%; P = 0.024), and longer AOM usage trended towards increased weight loss. ConclusionEarly initiation of AOM may enhance weight loss.