How metabolism is reprogrammed during neuronal differentiation is unknown. We found that the loss of hexokinase (HK2) and lactate dehydrogenase (LDHA) expression, together with a switch in pyruvate kinase gene splicing from PKM2 to PKM1, marks the transition from aerobic glycolysis in neural progenitor cells (NPC) to neuronal oxidative phosphorylation. The protein levels of c-MYC and N-MYC, transcriptional activators of the HK2 and LDHA genes, decrease dramatically. Constitutive expression of HK2 and LDHA during differentiation leads to neuronal cell death, indicating that the shut-off aerobic glycolysis is essential for neuronal survival. The metabolic regulators PGC-1α and ERRγ increase significantly upon neuronal differentiation to sustain the transcription of metabolic and mitochondrial genes, whose levels are unchanged compared to NPCs, revealing distinct transcriptional regulation of metabolic genes in the proliferation and post-mitotic differentiation states. Mitochondrial mass increases proportionally with neuronal mass growth, indicating an unknown mechanism linking mitochondrial biogenesis to cell size.DOI: http://dx.doi.org/10.7554/eLife.13374.001

Long-term treatment with aerosolized iloprost is safe and has sustained effects on exercise capacity and pulmonary hemodynamics in patients with primary pulmonary hypertension.

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To support food security for current and future generations, there is a need to understand the relation between sustainable diets and the health of a population. In recent years, a number of studies have investigated and compared different dietary patterns to better understand which foods and eating patterns have less of an environmental impact while meeting nutritional needs and promoting health. This systematic review (SR) of population-level dietary patterns and food sustainability extends and updates the SR that was conducted by the 2015 US Dietary Guidelines Advisory Committee, an expert committee commissioned by the federal government to inform dietary guidance as it relates to the committee's original conclusions. In the original SR, 15 studies met the criteria for inclusion; since then, an additional 8 studies have been identified and included. The relations between dietary intake patterns and both health and environmental outcomes were compared across studies, with methodologies that included modeling, life cycle assessment, and land use analysis. Across studies, consistent evidence indicated that a dietary pattern higher in plant-based foods (e.g., vegetables, fruits, legumes, seeds, nuts, whole grains) and lower in animal-based foods (especially red meat), as well as lower in total energy, is both healthier and associated with a lesser impact on the environment. This dietary pattern differs from current average consumption patterns in the United States. Our updated SR confirms and strengthens the conclusions of the original US Dietary Guidelines Advisory Committee SR, which found that adherence to several well-characterized dietary patterns, including vegetarian (with variations) diets, dietary guidelines-related diets, Mediterranean-style diets, the Dietary Approaches to Stop Hypertension (DASH) diet, and other sustainable diet scenarios, promotes greater health and has a less negative impact on the environment than current average dietary intakes.

Assessment of cardiac output is an important part of the management of patients with pulmonary hypertension. The accuracy of the thermodilution technique in patients with low cardiac output or severe tricuspid regurgitation has been questioned. To address this issue, we simultaneously compared 105 cardiac output measurements by the Fick method and thermodilution in 35 patients with pulmonary hypertension. Moreover, we evaluated the acetylene rebreathing technique, a noninvasive method of determining cardiac output. The mean difference +/- 95% limit of agreement between thermodilution and the Fick method was +0.01 +/- 1.1 L/min. The mean difference +/- 95% limit of agreement between acetylene rebreathing and the Fick method was -0.23 +/- 1.14 L/min. Neither the mean agreement nor the 95% limits of agreement of both thermodilution and acetylene rebreathing with the Fick method were affected by the presence of low cardiac output or severe tricuspid regurgitation. We conclude that thermodilution and acetylene rebreathing are useful tools for assessing cardiac output in patients with pulmonary hypertension, even in the presence of low cardiac output or severe tricuspid regurgitation.

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The brain's serotonergic system centrally regulates several physiological processes and its dysfunction has been implicated in the pathophysiology of several neuropsychiatric disorders. While in the past our understanding of serotonergic neurotransmission has come mainly from mouse models, the development of pluripotent stem cell and induced fibroblast-to-neuron (iN) transdifferentiation technologies has revolutionized our ability to generate human neurons in vitro. Utilizing these techniques and a novel lentiviral reporter for serotonergic neurons, we identified and overexpressed key transcription factors to successfully generate human serotonergic neurons. We found that overexpressing the transcription factors NKX2.2, FEV, GATA2 and LMX1B in combination with ASCL1 and NGN2 directly and efficiently generated serotonergic neurons from human fibroblasts. Induced serotonergic neurons (iSNs) showed increased expression of specific serotonergic genes that are known to be expressed in raphe nuclei. iSNs displayed spontaneous action potentials, released serotonin in vitro and functionally responded to selective serotonin reuptake inhibitors (SSRIs). Here, we demonstrate the efficient generation of functional human serotonergic neurons from human fibroblasts as a novel tool for studying human serotonergic neurotransmission in health and disease.

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