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In the developed world, extreme prematurity is the leading cause of neonatal mortality and morbidity due to a combination of organ immaturity and iatrogenic injury. Until now, efforts to extend gestation using extracorporeal systems have achieved limited success. Here we report the development of a system that incorporates a pumpless oxygenator circuit connected to the fetus of a lamb via an umbilical cord interface that is maintained within a closed ‘amniotic fluid’ circuit that closely reproduces the environment of the womb. We show that fetal lambs that are developmentally equivalent to the extreme premature human infant can be physiologically supported in this extra-uterine device for up to 4 weeks. Lambs on support maintain stable haemodynamics, have normal blood gas and oxygenation parameters and maintain patency of the fetal circulation. With appropriate nutritional support, lambs on the system demonstrate normal somatic growth, lung maturation and brain growth and myelination. The ability to support the development of a premature fetus in the form of an extracorporeal system has had limited success. Here, the authors show that an extra-uterine device that mimics the intra-uterine environment can provide physiologic support for the extreme premature lamb fetus for four weeks.

The Golgi enzyme β1,6 N-acetylglucosaminyltransferase V (Mgat5) is upregulated in carcinomas and promotes the substitution of N-glycan with poly N-acetyllactosamine, the preferred ligand for galectin-3 (Gal-3). Here, we report that expression of Mgat5 sensitized mouse cells to multiple cytokines. Gal-3 cross-linked Mgat5-modified N-glycans on epidermal growth factor and transforming growth factor-β receptors at the cell surface and delayed their removal by constitutive endocytosis. Mgat5 expression in mammary carcinoma was rate limiting for cytokine signaling and consequently for epithelial-mesenchymal transition, cell motility, and tumor metastasis. Mgat5 also promoted cytokine-mediated leukocyte signaling, phagocytosis, and extravasation in vivo. Thus, conditional regulation of N-glycan processing drives synchronous modification of cytokine receptors, which balances their surface retention against loss via endocytosis.

This corrects the article DOI: 10.1038/ncomms15112.

Purpose of Review Complications of prematurity consistently rank as the leading cause of death in children under the age of 5 and as the leading cause of death in infants in North America according to Liu et al. Lancet ( 2016 ); 388: 3027–35 and Callaghan et al. Pediatrics ( 2006 );118: 1566–73. Despite advances in prenatal care, prematurity remains a persistent clinical problem, with 1 in 8 births occurring prematurely (prior to 37 weeks of gestation) in the USA as discussed by Frey and Klebanoff Semin Fetal Neonatal Med ( 2016 );21: 68–73, . Advances in neonatology including gentle ventilation strategies, permissive hypercapnia, and the use of corticosteroids have led to substantial improvements in survival; however, long-term survivors of preterm birth face considerable morbidities affecting every major organ system. Chronic lung disease represents one of the most common and significant long-term complications of preterm birth and is attributable largely to iatrogenic injury due to the underdeveloped nature of the alveoli and lack of compliance of the immature lung as stated by Behrman and Butler ( 2007 ). Conventional gas-based ventilation of the premature lung leads to barotrauma, inflammation, respiratory distress syndrome (RDS), and bronchopulmonary dysplasia (BPD) as discussed by Sinha and Donn Semin Fetal Neonatal Med ( 2006 );11: 166–73. Recent Findings Since the discovery of perfluorocarbons (PFCs) over 70 years ago, liquid ventilation has been examined as a viable alternative to conventional gas-based mechanical ventilation in a variety of disease models, including that of extreme prematurity. PFCs are biologically inert organofluorine compounds with remarkably high gas dissolving properties due to weak intermolecular attractive forces, allowing dissolution of up to twenty times the amount of oxygen and three times the amount of carbon dioxide than water as discussed by Wesseler, Iltis, and Clark J Fluor Chem. Elsevier Sequoia S.A ( 1977 );9: 137–46. These compounds have low surface tension, have low viscosity, are relatively dense, and have low vapor pressure (11–85 torr), permitting rapid evaporation from the lungs. One perfluorocarbon liquid of particular clinical interest is perflubron, a PFC with a bromine substituted for a primary fluorine. This compound has been used as a contrast medium and is radiographically opaque, allowing clinicians to examine lung filling in real time according to the study of Kazerooni et al. Radiology ( 1962 );198: 137–42 . Initial studies of liquid ventilation have shown increased gas exchange and alveoli recruitment, in addition to the return to fluid-filled physiology similar to that experienced during gestation, as discussed by Kylstram et al. Trans Am SOC Artif Intern Organs ( 1962 ;8: 378–83, Clark and Gollan ( 1966 ), and Schoenfisch Anid and Kylstra J Appl Physiol ( 1973 );35: 117–21, leading to the identification of liquid ventilation as a promising intervention to support critically preterm infants. Summary This review will summarize the history of clinical and translational research studies of liquid ventilation, with a focus on studies targeting prematurity, and will explore the areas requiring further study prior to widespread clinical implementation.

Nature Communications 8: Article number: 15112 (2017); Published 25 April 2017; Updated 23 May 2017 A patent based on the work reported in this Article was inadvertently omitted from the Competing interests section of this article. The Competing interests statement should read: E.M., A.F. and M.D. are co-authors on a patent entitled ‘Extracorporeal life support system and methods of use thereof’ (Patent no.

Purpose of Review Prematurity is a global health problem representing one of the most significant causes of morbidity and mortality in children. The concept of an artificial womb has been explored as an innovation which could substantially improve clinical outcomes in preterm patients by offering the ability to support growth and development of the neonate in a manner consistent with fetal physiology. This review will address the contemporary literature exploring the development of the artificial womb, with a focus on promising new breakthroughs in the field. Recent Findings Our laboratory has reported the development of an artificial womb incorporating the critical components of intrauterine physiology, namely sterile fluidic incubation of the isolated fetus as well as perfusion and gas exchange using a pumpless extracorporeal circuit. We have demonstrated support of fetal lambs for up to 4 weeks with stable hemodynamics and normal growth and development. Summary The artificial womb represents unprecedented potential for improvement in clinical outcomes in critically preterm infants. Recent studies have demonstrated promising results in preclinical animal models, supporting the translation of this technology to human clinical trials.

Oncogenic upregulation of N-acetylglucosaminyltransferase V (Mgat5) is a common feature of epithelial malignancies. Elevated Mgat5 activity results in the increased substitution of N-glycans with poly N-acetyllactosamine, the preferred ligand for the galectins. Mgat5-/- mice display delayed tumor growth and reduced metastasis when crossed with MMTV-PyMT-transgenic mice. Cell lines were generated from Mgat5+/+ (2.6) and Mgat5 -/- (22.9) mammary carcinomas, and we demonstrate that Mgat5 expression lowers thresholds for RTK and TGF-β signaling. Galectin-3 cross-links Mgat5-modified N-glycans on growth factor receptors, delaying their removal by endocytosis and thereby increasing receptor levels at the cell surface. We demonstrate that Mgat5 expression is required for epithelial-mesenchymal transition (EMT), cell motility and tumor metastasis. Mgat5 also promotes cytokine mediated leukocyte signaling, phagocytosis, and extravasation in vivo. Mutations and epigenetic changes in tumor cells that enhance cytokine receptor signaling can contribute to tumor progression. Caveolin-1 is a tumor suppressor, and exhibits broad activity as an antagonist of growth factor receptor signaling. Levels of caveolin-1 are inversely related to tumor growth in PyMT Mgat5-/- mice, while no such correlation is observable in Mgat5+/- tumors. Mgat5-/- tumor cells deficient in caveolin-1 (22.10) show robust cytokine responsiveness, and over-expression of caveolin-1 suppressed EGF signaling to levels observed in the Mgat5 -/- (22.9) cells. These results suggest that caveolin-1 negatively regulates tumor growth by down-regulating oncogenic signaling, while Mgat5 sustains cytokine signaling and promotes the malignant phenotype. Glucose flux through the hexosamine pathway supplies UDP-GlcNAc to N-glycan biosynthesis. Glucose supplies positive feedback to PI3K/Akt and Erk signaling, though the molecular mechanism underlying these observations remains unknown. Here we present evidence that nutrient supply to the hexosamine pathway regulates cellular sensitivity to cytokines by supplying UDP-GlcNAc to N-glycan processing and the galectin-glycoprotein lattice. Supplementing the hexosamine pathway in Mgat5-/- (22.9) cells resulted in increased galectin binding to cytokine receptors, restored surface receptor levels, sensitized RTK and TGF-β signaling, and the induction of EMT in response to enhanced autocrine growth factor signaling. Our data reveals a molecular mechanism for synchronous regulation of cytokine receptors dependent on metabolic supply to the hexosamine pathway and N-glycan processing, which balances receptor retention against loss to endocytosis.