Congenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized mice.

Unlike primary myelofibrosis (PMF) in adults, myelofibrosis in children is rare. Congenital (inherited) forms of myelofibrosis (cMF) have been described, but the underlying genetic mechanisms remain elusive. Here we describe 4 families with autosomal recessive inherited macrothrombocytopenia with focal myelofibrosis due to germ line loss-of-function mutations in the megakaryocyte-specific immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor G6b-B (G6b, C6orf25, or MPIG6B). Patients presented with a mild-to-moderate bleeding diathesis, macrothrombocytopenia, anemia, leukocytosis and atypical megakaryocytes associated with a distinctive, focal, perimegakaryocytic pattern of bone marrow fibrosis. In addition to identifying the responsible gene, the description of G6b-B as the mutated protein potentially implicates aberrant G6b-B megakaryocytic signaling and activation in the pathogenesis of myelofibrosis. Targeted insertion of human G6b in mice rescued the knockout phenotype and a copy number effect of human G6b-B expression was observed. Homozygous knockin mice expressed 25% of human G6b-B and exhibited a marginal reduction in platelet count and mild alterations in platelet function; these phenotypes were more severe in heterozygous mice that expressed only 12% of human G6b-B. This study establishes G6b-B as a critical regulator of platelet homeostasis in humans and mice. In addition, the humanized G6b mouse will provide an invaluable tool for further investigating the physiological functions of human G6b-B as well as testing the efficacy of drugs targeting this receptor

Improved spectral fitting of nitrogen dioxide from OMI in the 405–465 nm window

An improved nitrogen dioxide (NO2) slant column density retrieval for the Ozone Monitoring Instrument (OMI) in the 405–465 nm spectral region is presented. Since the launch of OMI on board NASA's EOS-Aura satellite in 2004, differential optical absorption spectroscopy (DOAS) retrievals of NO2 slant column densities have been the starting point for the KNMI DOMINO and NASA SP NO2 vertical column data as well as the OMI NO2 data of some other institutes. However, recent intercomparisons between NO2 retrievals from OMI and other UV/Vis and limb spectrometers, as well as ground-based measurements, suggest that OMI stratospheric NO2 is biased high. This study revises and, for the first time, fully documents the OMI NO2 retrieval in detail. The representation of the OMI slit function to convolve high-resolution reference spectra onto the relevant spectral grid is improved. The window used for the wavelength calibration is optimised, leading to much-reduced fitting errors. Ozone and water vapour spectra used in the fit are updated, reflecting the recently improved knowledge of their absorption cross section in the literature. The improved spectral fit also accounts for absorption by the O2–O2 collision complex and by liquid water over clear-water areas. The main changes in the improved spectral fitting result from the updates related to the wavelength calibration: the RMS error of the fit is reduced by 23% and the NO2 slant column by 0.85 × 1015 molec cm-2, independent of latitude, solar zenith angle and NO2 value. Including O2–O2 and liquid water absorption and updating the O3 and water vapour cross-section spectra further reduces NO2 slant columns on average by 0.35 × 1015 molec cm-2, accompanied by a further 9% reduction in the RMS error of the fit. The improved OMI NO2 slant columns are consistent with independent NO2 retrievals from other instruments to within a range that can be explained by photochemically driven diurnal increases in stratospheric NO2 and by small differences in fitting window and approach. The revisions indicate that current OMI NO2 slant columns suffered mostly from an additive positive offset, which is removed by the improved wavelength calibration and representation of the OMI slit function. It is therefore anticipated that the improved NO2 slant columns are most important to retrievals of spatially homogeneous stratospheric NO2 rather than to heterogeneous tropospheric NO2

Quantification of nitrogen oxides emissions from build-up of pollution over Paris with TROPOMI

Nitrogen dioxide (NO2) is a regulated air pollutant that is of particular concern in many cities, where concentrations are high. Emissions of nitrogen oxides to the atmosphere lead to the formation of ozone and particulate matter, with adverse impacts on human health and ecosystems. The effects of emissions are often assessed through modeling based on inventories relying on indirect information that is often outdated or incomplete. Here we show that NO2 measurements from the new, high-resolution TROPOMI satellite sensor can directly determine the strength and distribution of emissions from Paris. From the observed build-up of NO2 pollution, we find highest emissions on cold weekdays in February 2018, and lowest emissions on warm weekend days in spring 2018. The new measurements provide information on the spatio-temporal distribution of emissions within a large city, and suggest that Paris emissions in 2018 are only 5–15% below inventory estimates for 2011–2012, reflecting the difficulty of meeting NOx emission reduction targets.</p