Atmospheric blockages as trigger of environmental contingencies in Mexico City.

Atmospheric pollution in cities is due to several human factors, for instance the number of cars in circulation, fuel efficiency and industrial waste, as well as orographic and meteorological conditions that determine air circulation. Ozone contingencies cause health disorders on the population, making it important to understand the factors that trigger such contingencies. Here, we analyze meteorological (wind, temperature, relative humidity) and atmospheric composition (ozone, and NOx) data of five atmospheric monitoring stations on Mexico City, from March 2004 to May 2018, comparing normal days with the extreme days in the 90th percentile of ozone. Moreover, we present the synoptic patterns of the seasonal differences of geopotential height at 500 hPa between extreme and control days. We found that, in the dry-hot season (from March to May) an atmospheric blockage with meteorological conditions of almost no wind, low relative humidity, and small temperature fluctuations occurs. Because the air in the city permanently contains large amounts of ozone precursors like NOx, this meteorological scenario raises ozone levels to those of an environmental contingency. Thus, during the dry-hot season on Mexico City, ozone contingencies are triggered by atmospheric blocking. This scenario will be present in cities surrounded by mountains with high levels of Ozone precursors.

Human induced pluripotent stem cell-derived extracellular vesicles reduce hepatic stellate cell activation and liver fibrosis.

Progression of fibrosis and the development of cirrhosis are responsible for the liver related morbidity and mortality associated with chronic liver diseases. There is currently a great unmet need for effective anti-fibrotic strategies. Stem cells play a central role in wound healing responses to restore liver homeostasis following injury. Here we tested the hypothesis that extracellular vesicles (EVs) isolated from induced pluripotent stem cells (iPSC) modulate hepatic stellate cell (HSCs) activation and may have anti-fibrotic effects. Human iPSCs were generated by reprogramming primary skin fibroblasts. EVs were isolated by differential centrifugation, quantified by flow cytometry (FACS) and characterized by dynamic light scattering (DLS) and electron microscopy (TEM). Primary human HSCs were activated with TGFß (10 ng/mL) and exposed to iPSC-EVs. Efficacy of iPSC-EVs was tested on HSC in vitro and in two murine models of liver injury (CCl4 and bile duct ligation). Characterization of iPSC-derived EVs by flow cytometry identified a large population of EVs released by iPSC, primarily with a diameter of 300 nm and that could be visualized by TEM as round, cup-shaped objects. Fluorescent tracing assays detected iPSC-EVs in HSC cytosol after a short incubation and EV uptake by HSCs resulted in both decrease of pro-fibrogenic markers αSMA, CollagenIα1, Fibronectin and TIMP-1 and HSC pro-fibrogenic responses such as chemotaxis and proliferation. Genomics analyses of iPSC-EV miRNA cargo revealed 22 highly expressed miRNAs, among which miR-92a-3p resulted the most abundant. Transcriptome analysis identified 60 genes down-modulated and 235 up-regulated in TGF-ß-primed HSC in presence or absence of iPSC-EVs. Intravenous injection of iPSC-EVs in CCl4 and bile duct ligation-induced liver fibrosis resulted in anti-fibrotic effects at protein and gene levels. Results of this study identify iPSC-EVs as a novel anti-fibrotic approach that may reduce or reverse liver fibrosis in patients with chronic liver disease.

Rapid whole-genome sequencing identifies a novel homozygous NPC1 variant associated with Niemann-Pick type C1 disease in a 7-week-old male with cholestasis.

Niemann-Pick type C disease (NPC; OMIM #257220) is an inborn error of intracellular cholesterol trafficking. It is an autosomal recessive disorder caused predominantly by mutations in NPC1 Although characterized as a progressive neurological disorder, it can also cause cholestasis and liver dysfunction because of intrahepatocyte lipid accumulation. We report a 7-wk-old infant who was admitted with neonatal cholestasis, and who was diagnosed with a novel homozygous stop-gain variant in NPC1 by rapid whole-genome sequencing (WGS). WGS results were obtained 16 d before return of the standard clinical genetic test results and prompted initiation of targeted therapy.