The precise regulation of gene expression is fundamental to neurodevelopment, plasticity and cognitive function. Although several studies have profiled transcription in the developing human brain, there is a gap in understanding of accompanying translational regulation. In this study, we performed ribosome profiling on 73 human prenatal and adult cortex samples. We characterized the translational regulation of annotated open reading frames (ORFs) and identified thousands of previously unknown translation events, including small ORFs that give rise to human-specific and/or brain-specific microproteins, many of which we independently verified using proteomics. Ribosome profiling in stem-cell-derived human neuronal cultures corroborated these findings and revealed that several neuronal activity-induced non-coding RNAs encode previously undescribed microproteins. Physicochemical analysis of brain microproteins identified a class of proteins that contain arginine-glycine-glycine (RGG) repeats and, thus, may be regulators of RNA metabolism. This resource expands the known translational landscape of the human brain and illuminates previously unknown brain-specific protein products.

Epoxyeicosatrienoic acids (EETs), lipid mediators produced by cytochrome P450 epoxygenases, regulate inflammation, angiogenesis, and vascular tone. Despite pleiotropic effects on cells, the role of these epoxyeicosanoids in normal organ and tissue regeneration remains unknown. EETs are produced predominantly in the endothelium. Normal organ and tissue regeneration require an active paracrine role of the microvascular endothelium, which in turn depends on angiogenic growth factors. Thus, we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis.

Background In a recent multicenter study of perinatal outcome in fetuses with Ebstein anomaly or tricuspid valve dysplasia, we found that one third of live-born patients died before hospital discharge. We sought to further describe postnatal management strategies and to define risk factors for neonatal mortality and circulatory outcome at discharge. Methods and Results This 23-center, retrospective study from 2005 to 2011 included 243 fetuses with Ebstein anomaly or tricuspid valve dysplasia. Among live-born patients, clinical and echocardiographic factors were evaluated for association with neonatal mortality and palliated versus biventricular circulation at discharge. Of 176 live-born patients, 7 received comfort care, 11 died <24 hours after birth, and 4 had insufficient data. Among 154 remaining patients, 38 (25%) did not survive to discharge. Nearly half (46%) underwent intervention. Mortality differed by procedure; no deaths occurred in patients who underwent right ventricular exclusion. At discharge, 56% of the cohort had a biventricular circulation (13% following intervention) and 19% were palliated. Lower tricuspid regurgitation jet velocity (odds ratio [OR], 2.3 [1.1-5.0], 95% CI, per m/s; P=0.025) and lack of antegrade flow across the pulmonary valve (OR, 4.5 [1.3-14.2]; P=0.015) were associated with neonatal mortality by multivariable logistic regression. These variables, along with smaller pulmonary valve dimension, were also associated with a palliated outcome. Conclusions Among neonates with Ebstein anomaly or tricuspid valve dysplasia diagnosed in utero, a variety of management strategies were used across centers, with poor outcomes overall. High-risk patients with low tricuspid regurgitation jet velocity and no antegrade pulmonary blood flow should be considered for right ventricular exclusion to optimize their chance of survival.

Background

Ebstein anomaly and tricuspid valve dysplasia are rare congenital tricuspid valve malformations associated with high perinatal mortality. The literature consists of small, single-center case series spanning several decades. We performed a multicenter study to assess the outcomes and factors associated with mortality after fetal diagnosis in the current era.

Methods and results

Fetuses diagnosed with Ebstein anomaly and tricuspid valve dysplasia from 2005 to 2011 were included from 23 centers. The primary outcome was perinatal mortality, defined as fetal demise or death before neonatal discharge. Of 243 fetuses diagnosed at a mean gestational age of 27±6 weeks, there were 11 lost to follow-up (5%), 15 terminations (6%), and 41 demises (17%). In the live-born cohort of 176 live-born patients, 56 (32%) died before discharge, yielding an overall perinatal mortality of 45%. Independent predictors of mortality at the time of diagnosis were gestational age <32 weeks (odds ratio, 8.6; 95% confidence interval, 3.5-21.0; P<0.001), tricuspid valve annulus diameter z-score (odds ratio, 1.3; 95% confidence interval, 1.1-1.5; P<0.001), pulmonary regurgitation (odds ratio, 2.9; 95% confidence interval, 1.4-6.2; P<0.001), and a pericardial effusion (odds ratio, 2.5; 95% confidence interval, 1.1-6.0; P=0.04). Nonsurvivors were more likely to have pulmonary regurgitation at any gestational age (61% versus 34%; P<0.001), and lower gestational age and weight at birth (35 versus 37 weeks; 2.5 versus 3.0 kg; both P<0.001).

Conclusion

In this large, contemporary series of fetuses with Ebstein anomaly and tricuspid valve dysplasia, perinatal mortality remained high. Fetuses with pulmonary regurgitation, indicating circular shunt physiology, are a high-risk cohort and may benefit from more innovative therapeutic approaches to improve survival.