Copyright © 2020 by the American Academy of Pediatrics.Randomized controlled trials in the 1990s confirmed the safety and efficacy of inhaled nitric oxide (iNO) in near-term and term newborns with hypoxemic respiratory failure and pulmonary hypertension, demonstrating improved oxygenation and reduced need for extracorporeal membrane oxygenation (ECMO) therapy. However, in about 30% to 40% of sick newborns, these improvements in oxygenation and hemodynamics are not sustained and affected infants often require rapid transfer to an ECMO center despite the initiation of iNO. Abrupt discontinuation of iNO therapy before transport in patients who have had little apparent clinical benefit can be harmful because of acute deterioration with severe hypoxemia. Thus, continued use of iNO therapy during hospital transfer of infants with pulmonary hypertension is important. In this review, we describe 1) the history of iNO use during transport; 2) a practical approach to iNO during transport; and 3) guidelines for the initiation of iNO before or during transport. Copyright © 2020 by the American Academy of Pediatrics.Andragogy, the art and science of helping adults learn, is a learner-centric conceptual framework that considers adult learner characteristics and their motivations for learning. These motivations range from internal will, readiness to learn, and relevance to one’s own life. The flipped classroom, an increasingly popular educational method for both learners and educators, aligns with an andragogical approach as it uses classroom time for application of knowledge and critical thinking rather than for a passive didactic lecture. The growing body of educational research demonstrating increased performance and knowledge retention using this method has led to its incorporation into graduate medical education materials, including the National Neonatology Curriculum. In this article, the authors review how the flipped classroom, an active educational method that embraces the tenets of adult learning theory, may be more effective in graduate medical education compared with traditional lecture. Copyright © 2020 by the American Academy of Pediatrics.T helper (Th) cells are CD4+ effector T cells that play a critical role in immunity by shaping the inflammatory cytokine environment in a variety of physiological and pathological situations. Using a combined chemico-genetic approach, we identify histone H3K27 demethylases KDM6A and KDM6B as central regulators of human Th subsets. The prototypic KDM6 inhibitor GSK-J4 increases genome-wide levels of the repressive H3K27me3 chromatin mark and leads to suppression of the key transcription factor RORγt during Th17 differentiation. In mature Th17 cells, GSK-J4 induces an altered transcriptional program with a profound metabolic reprogramming and concomitant suppression of IL-17 cytokine levels and reduced proliferation. Single-cell analysis reveals a specific shift from highly inflammatory cell subsets toward a resting state upon demethylase inhibition. The root cause of the observed antiinflammatory phenotype in stimulated Th17 cells is reduced expression of key metabolic transcription factors, such as PPRC1. Overall, this leads to reduced mitochondrial biogenesis, resulting in a metabolic switch with concomitant antiinflammatory effects. These data are consistent with an effect of GSK-J4 on Th17 T cell differentiation pathways directly related to proliferation and include regulation of effector cytokine profiles. This suggests that inhibiting KDM6 demethylases may be an effective, even in the short term, therapeutic target for autoimmune diseases, including ankylosing spondylitis. Copyright © 2020 the Author(s). B02 supplier Published by PNAS.Understanding the molecular basis of adaptation to the environment is a central question in evolutionary biology, yet linking detected signatures of positive selection to molecular mechanisms remains challenging. Here we demonstrate that combining sequence-based phylogenetic methods with structural information assists in making such mechanistic interpretations on a genomic scale. Our integrative analysis shows that positively selected sites tend to colocalize on protein structures and that positively selected clusters are found in functionally important regions of proteins, indicating that positive selection can contravene the well-known principle of evolutionary conservation of functionally important regions. This unexpected finding, along with our discovery that positive selection acts on structural clusters, opens previously unexplored strategies for the development of better models of protein evolution. Remarkably, proteins where we detect the strongest evidence of clustering belong to just two functional groups Components of immune response and metabolic enzymes. This gives a coherent picture of pathogens and xenobiotics as important drivers of adaptive evolution of mammals.Neurofibromatosis 1 (NF1) is caused by mutations in the NF1 gene, which encodes the protein, neurofibromin, an inhibitor of Ras activity. Cortical GABAergic interneurons (CINs) are implicated in NF1 pathology, but the cellular and molecular changes to CINs are unknown. We deleted mouse Nf1 from the medial ganglionic eminence, which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin. Nf1 loss led to a persistence of immature oligodendrocytes that prevented later-generated oligodendrocytes from occupying the cortex. Moreover, molecular and cellular properties of parvalbumin (PV)-positive CINs were altered by the loss of Nf1, without changes in somatostatin (SST)-positive CINs. We discovered that loss of Nf1 results in a dose-dependent decrease in Lhx6 expression, the transcription factor necessary to establish SST+ and PV+ CINs, which was rescued by the MEK inhibitor SL327, revealing a mechanism whereby a neurofibromin/Ras/MEK pathway regulates a critical CIN developmental milestone.The 300-kDa ClpP1P2 protease from Mycobacterium tuberculosis collaborates with the AAA+ (ATPases associated with a variety of cellular activities) unfoldases, ClpC1 and ClpX, to degrade substrate proteins. Unlike in other bacteria, all of the components of the Clp system are essential for growth and virulence of mycobacteria, and their inhibitors show promise as antibiotics. MtClpP1P2 is unique in that it contains a pair of distinct ClpP1 and ClpP2 rings and also requires the presence of activator peptides, such as benzoyl-leucyl-leucine (Bz-LL), for function. Understanding the structural basis for this requirement has been elusive but is critical for the rational design and improvement of antituberculosis (anti-TB) therapeutics that target the Clp system. Here, we present a combined biophysical and biochemical study to explore the structure-dynamics-function relationship in MtClpP1P2. Electron cryomicroscopy (cryo-EM) structures of apo and acyldepsipeptide-bound MtClpP1P2 explain their lack of activity by showing loss of a key β-sheet in a sequence known as the handle region that is critical for the proper formation of the catalytic triad.