541 research outputs found
Structural basis of severe acute respiratory syndrome coronavirus ADP-ribose-1''-phosphate dephosphorylation by a conserved domain of nsP3.
The crystal structure of a conserved domain of nonstructural protein 3 (nsP3) from severe acute respiratory syndrome coronavirus (SARS-CoV) has been solved by single-wavelength anomalous dispersion to 1.4 A resolution. The structure of this "X" domain, seen in many single-stranded RNA viruses, reveals a three-layered alpha/beta/alpha core with a macro-H2A-like fold. The putative active site is a solvent-exposed cleft that is conserved in its three structural homologs, yeast Ymx7, Archeoglobus fulgidus AF1521, and Er58 from E. coli. Its sequence is similar to yeast YBR022W (also known as Poa1P), a known phosphatase that acts on ADP-ribose-1''-phosphate (Appr-1''-p). The SARS nsP3 domain readily removes the 1'' phosphate group from Appr-1''-p in in vitro assays, confirming its phosphatase activity. Sequence and structure comparison of all known macro-H2A domains combined with available functional data suggests that proteins of this superfamily form an emerging group of nucleotide phosphatases that dephosphorylate Appr-1''-p
Differences in BVOC oxidation and SOA formation above and below the forest canopy
Gas-phase biogenic volatile organic compounds (BVOCs) are oxidized in the troposphere to produce secondary pollutants such as ozone (O3), organic nitrates (RONO2), and secondary organic aerosol (SOA). Two coupled zero-dimensional models have been used to investigate differences in oxidation and SOA production from isoprene and α-pinene, especially with respect to the nitrate radical (NO3), above and below a forest canopy in rural Michigan. In both modeled environments (above and below the canopy), NO3 mixing ratios are relatively small (<âŻ0.5âŻpptv); however, daytime (08:00â20:00âŻLT) mixing ratios below the canopy are 2 to 3 times larger than those above. As a result of this difference, NO3 contributes 12âŻ% of total daytime α-pinene oxidation below the canopy while only contributing 4âŻ% above. Increasing background pollutant levels to simulate a more polluted suburban or peri-urban forest environment increases the average contribution of NO3 to daytime below-canopy α-pinene oxidation to 32âŻ%. Gas-phase RONO2 produced through NO3 oxidation undergoes net transport upward from the below-canopy environment during the day, and this transport contributes up to 30âŻ% of total NO3-derived RONO2 production above the canopy in the morning (âŒâ07:00). Modeled SOA mass loadings above and below the canopy ultimately differ by less than 0.5âŻÂ”gâŻmâ3, and extremely low-volatility organic compounds dominate SOA composition. Lower temperatures below the canopy cause increased partitioning of semi-volatile gas-phase products to the particle phase and up to 35âŻ% larger SOA mass loadings of these products relative to above the canopy in the model. Including transport between above- and below-canopy environments increases above-canopy NO3-derived α-pinene RONO2 SOA mass by as much as 45âŻ%, suggesting that below-canopy chemical processes substantially influence above-canopy SOA mass loadings, especially with regard to monoterpene-derived RONO2
Allergic asthma is distinguished by sensitivity of allergen-specific CD4+ T cells and airway structural cells to type 2 inflammation
Despite systemic sensitization, not all allergic individuals develop asthma symptoms upon airborne allergen exposure. Determination of the factors that lead to the asthma phenotype in allergic individuals could guide treatment and identify novel therapeutic targets. In this study, we utilized segmental allergen challenge (SAC) of allergic asthmatics (AA) and allergic non-asthmatic controls (AC) to determine if there are differences in the airway immune response or airway structural cells that could drive the development of asthma. Both groups developed prominent allergic airway inflammation in response to allergen. However, asthmatic subjects had markedly higher levels of innate type 2 receptors on allergen-specific CD4+ T cells recruited into the airway. There were also increased levels of type 2 cytokines, increased total mucin and increased MUC5AC in response to allergen in the airways of AA subjects. Furthermore, type 2 cytokine levels correlated with the mucin response in AA but not AC subjects, suggesting differences in the airway epithelial response to inflammation. Finally, AA subjects had increased airway smooth muscle mass at baseline measured in vivo using novel orientation-registered optical coherence tomography (OR-OCT). Our data demonstrate that the development of allergic asthma is dependent on the responsiveness of allergen-specific CD4+ T cells to innate type 2 mediators as well as increased sensitivity of airway epithelial cells and smooth muscle to type 2 inflammation
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Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.
Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management
Synergetic use of IASI and TROPOMI space borne sensors for generating a tropospheric methane profile product
The thermal infrared nadir spectra of IASI (Infrared Atmospheric Sounding Interferometer) are successfully used for retrievals of different atmospheric trace gas profiles. However, these retrievals offer generally reduced information about the lowermost tropospheric layer due to the lack of thermal contrast close to the surface. Spectra of scattered solar radiation observed in the near and/or short wave infrared, for instance by TROPOMI (TROPOspheric Monitoring Instrument) offer higher sensitivity near ground and are used for the retrieval of total column averaged mixing ratios of a variety of atmospheric trace gases. Here we present a method for the synergetic use of IASI profile and TROPOMI total column data. Our method uses the output of the individual retrievals and consists of linear algebra a posteriori calculations (i.e. calculation after the individual retrievals). We show that this approach is largely equivalent to applying the spectra of the different sensors together in a single retrieval procedure, but with the substantial advantage of being applicable to data generated with different individual retrieval processors, of being very time efficient, and of directly benefiting from the high quality and most recent improvements of the individual retrieval processors.This research has largely benefit from funds of the Deutsche Forschungsgemeinschaft (provided for the two projects MOTIV and TEDDY with IDs/GeschĂ€ftszeichen 290612604/GZ:SCHN1126/2-1 and 416767181/GZ:SCHN1126/5-1, respectively) and from support by the European Space Agency in the context the "Sentinel-5p+Innovation (S5p+I) - Water Vapour Isotopologues (H2O-ISO)" activities. Furthermore, we acknowledge funds from the Ministerio de EconomĂa y Competividad from Spain for the project INMENSE (CGL2016-80688-P)
Respiration driven CO2 pulses dominate Australia's flux variability
The Australian continent contributes substantially to the year-to-year
variability of the global terrestrial carbon dioxide (CO2) sink. However, the
scarcity of in-situ observations in remote areas prevents deciphering the
processes that force the CO2 flux variability. Here, examining atmospheric CO2
measurements from satellites in the period 2009-2018, we find recurrent
end-of-dry-season CO2 pulses over the Australian continent. These pulses
largely control the year-to-year variability of Australia's CO2 balance, due to
2-3 times higher seasonal variations compared to previous top-down inversions
and bottom-up estimates. The CO2 pulses occur shortly after the onset of
rainfall and are driven by enhanced soil respiration preceding photosynthetic
uptake in Australia's semi-arid regions. The suggested continental-scale
relevance of soil rewetting processes has large implications for our
understanding and modelling of global climate-carbon cycle feedbacks.Comment: 28 pages (including supplementary materials), 3 main figures, 7
supplementary figure
Differential limit on the extremely-high-energy cosmic neutrino flux in the presence of astrophysical background from nine years of IceCube data
We report a quasi-differential upper limit on the extremely-high-energy (EHE)
neutrino flux above GeV based on an analysis of nine years of
IceCube data. The astrophysical neutrino flux measured by IceCube extends to
PeV energies, and it is a background flux when searching for an independent
signal flux at higher energies, such as the cosmogenic neutrino signal. We have
developed a new method to place robust limits on the EHE neutrino flux in the
presence of an astrophysical background, whose spectrum has yet to be
understood with high precision at PeV energies. A distinct event with a
deposited energy above GeV was found in the new two-year sample, in
addition to the one event previously found in the seven-year EHE neutrino
search. These two events represent a neutrino flux that is incompatible with
predictions for a cosmogenic neutrino flux and are considered to be an
astrophysical background in the current study. The obtained limit is the most
stringent to date in the energy range between and GeV. This result constrains neutrino models predicting a three-flavor
neutrino flux of $E_\nu^2\phi_{\nu_e+\nu_\mu+\nu_\tau}\simeq2\times 10^{-8}\
{\rm GeV}/{\rm cm}^2\ \sec\ {\rm sr}10^9\ {\rm GeV}$. A significant part
of the parameter-space for EHE neutrino production scenarios assuming a
proton-dominated composition of ultra-high-energy cosmic rays is excluded.Comment: The version accepted for publication in Physical Review
Synergetic use of IASI profile and TROPOMI total-column level 2 methane retrieval products
The thermal infrared nadir spectra of IASI (Infrared Atmospheric Sounding Interferometer) are successfully used for retrievals of different atmospheric trace gas profiles. However, these retrievals offer generally reduced information about the lowermost tropospheric layer due to the lack of thermal contrast close to the surface. Spectra of scattered solar radiation observed in the near-infrared and/or shortwave infrared, for instance by TROPOMI (TROPOspheric Monitoring Instrument), offer higher sensitivity near the ground and are used for the retrieval of total-column-averaged mixing ratios of a variety of atmospheric trace gases. Here we present a method for the synergetic use of IASI profile and TROPOMI total-column level 2 retrieval products. Our method uses the output of the individual retrievals and consists of linear algebra a posteriori calculations (i.e. calculation after the individual retrievals). We show that this approach has strong theoretical similarities to applying the spectra of the different sensors together in a single retrieval procedure but with the substantial advantage of being applicable to data generated with different individual retrieval processors, of being very time efficient, and of directly benefiting from the high quality and most recent improvements of the individual retrieval processors.
We demonstrate the method exemplarily for atmospheric methane (CH). We perform a theoretical evaluation and show that the a posteriori combination method yields a total-column-averaged CH product (XCH) that conserves the good sensitivity of the corresponding TROPOMI product while merging it with the high-quality upper troposphereâlower stratosphere (UTLS) CH partial-column information of the corresponding IASI product. As a consequence, the combined product offers additional sensitivity for the tropospheric CH partial column, which is not provided by the individual TROPOMI nor the individual IASI product. The theoretically predicted synergetic effect is verified by comparisons to CH reference data obtained from collocated XCH measurements at 14 globally distributed TCCON (Total Carbon Column Observing Network) stations, CH profile measurements made by 36 individual AirCore soundings, and tropospheric CH data derived from continuous ground-based in situ observations made at two nearby Global Atmospheric Watch (GAW) mountain stations. The comparisons clearly demonstrate that the combined product can reliably detect the actual variations of atmospheric XCH, CH in the UTLS, and CH in the troposphere. A similar good reliability for the latter is not achievable by the individual TROPOMI and IASI products
Mutation discovery in mice by whole exome sequencing
We report the development and optimization of reagents for in-solution, hybridization-based capture of the mouse exome. By validating this approach in a multiple inbred strains and in novel mutant strains, we show that whole exome sequencing is a robust approach for discovery of putative mutations, irrespective of strain background. We found strong candidate mutations for the majority of mutant exomes sequenced, including new models of orofacial clefting, urogenital dysmorphology, kyphosis and autoimmune hepatitis
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