ALBERT

Description: Cell biology: Calcium contradictions in cilia Nature 531, 7596 (2016). doi:10.1038/nature17313 Authors: Dominic P. Norris & Peter K. Jackson Organelles called primary cilia that protrude from cells have been thought to sense the surrounding environment through calcium-channel proteins that respond to force. Two scientists discuss the implications for developmental biology and kidney disease of a study that challenges this hypothesis. See Letter p.656

Description: Integrin αIIbβ3 plays key roles in thrombosis and hemostasis primarily through mediating platelet adhesion and aggregation. We recently reported that the active site of thiol-isomerase enzymes, CXXC motif, is expressed twice within the plexin-semaphorin-integrin (PSI) domain across all integrins and species, and the PSI domain of β3 integrin possesses endogenous thiol-isomerase activity, which may be a novel target for anti-thrombotic therapy (Blood, 2017). We developed four mouse anti-mouse β3 integrin PSI domain monoclonal antibodies (mAbs). These mAbs cross-react with β3 PSI domains of human, mouse, pig, rat, and rabbit tested but not other regions of β3 integrin, other integrins or other thiol-isomerase enzymes. They inhibit the thiol-isomerase activity of β3 PSI domain, decrease platelet adhesion/aggregation and thrombosis without increasing bleeding. Interestingly, the inhibitory effect of these mAbs on thrombosis in vivo (no anti-coagulant) was 10-20 times greater than their inhibitory effect on platelet aggregation in anti-coagulated platelet-rich plasma in vitro. This motivated us to explore whether this PSI domain contributes to blood coagulation. To asses blood clot formation and retraction, blood was incubated in non-stick tubes for two hours at 37°C in clot retraction assays. These assays showed less clot retraction and significantly lower dry clot weight in human and mouse whole blood treated with these anti-PSI mAbs compared to controls (p

Description: Autoantibody-opsonized platelets in immune thrombocytopenia (ITP) are thought to be destroyed primarily by macrophage Fc gamma receptor (FcγR)-mediated phagocytosis in the spleen. Blockade of splenic macrophage FcγRs has been proposed as a therapeutic mechanism for ITP intervention. Unfortunately, the contribution of specific FcγRs to disease in ITP remains unknown. Our objective was to determine which FcγRs are responsible for the phagocytosis of ITP autoantibody-opsonized platelets by splenic macrophages. Splenic macrophages were purified by CD14 positive selection from spleens of splenectomized ITP patients, and were treated with blocking antibodies to FcγRI, FcγRIIa, FcγRIIa/b/c, and FcγRIII. Blocking antibodies were deglycosylated to prevent non-specific blocking effects by their Fc region. Two separate ITP sera confirmed positive for anti-GPIIb/IIIa autoantibodies by the monoclonal antibody immobilization of platelet antigens (MAIPA) assay were used to opsonize healthy donor human platelets. Phagocytosis was determined by confocal microscopy and non-phagocytosed (external) platelets were differentiated by an anti-platelet antibody stain following macrophage fixation. Human ITP splenic macrophages were found to express FcγRI, FcγRIIa, FcγRIIa/b/c, and FcγRIII, and expression was not significantly different compared to healthy (trauma) controls (n=5). The two anti-GPIIb/IIIa-positive ITP sera induced a mean 3.7- and 4.2-fold increase of platelet uptake by ITP splenic macrophages relative to normal human serum controls (n=3 each, p

Description: Immune thrombocytopenia (ITP) results from autoimmunization against platelet antigens. Autoantibodies (aabs) are considered to represent a major mechanism of thrombocytopenia in ITP by inducing platelet clearance from the circulation. Several lines of evidence demonstrate that aabs against glycoproteins (GP) IIb/IIIa and Ib/IX are predominant in ITP patients. Both disease severity and treatment response rates to specific therapeutics have been associated with aabs patterns. GP V is a well characterized immune target in Varicella-associated and drug-induced thrombocytopenia, but has never been studied systematically in ITP. In this study, patients with a suspected diagnosis of primary ITP were included once they met pre-defined clinical inclusion criteria. The presence of GP IIb/IIIa-, GP Ib/IX, and GP V-specific aabs was investigated by monoclonal antibody immobilization of platelet antigens (MAIPA) assay, both on patients' autologous platelets (direct MAIPA) and in serum (indirect MAIPA). In addition, serum IgG fractions were prepared from all patients with a positive direct MAIPA. IgG fractions were tested by surface plasmon resonance (SPR) technology for the presence of anti-GP V aabs. Complete data sets were obtained from 1,140 qualified patients. Platelet-bound aabs were detected in 343/1,140 patients (30.1%). Of these, 222 (64.7%) had platelet-bound anti-GP V aabs, either alone (10/222), or together with other specificities (211/222). Free anti-GP V aabs were detected in 30/222 patients by indirect MAIPA, but in 88/222 by SPR. The avidity of aabs detected by both methods (n=29; R700/R350=0.73±0.14) was significantly higher than the avidity for aabs detected by SPR only (n=59; R700/R350=0.32±0.13, p 〈 0.001). In order to study the potential biological relevance of anti-GP V, a phagocytosis assay using CD14+ positively-selected macrophages from spleen specimens from splenectomized ITP patients was performed. Anti-GPV aabs induced a modest amount of platelet uptake above the normal human serum-incubated control. No difference was observed between high avidity and low avidity anti-GP V. The effect of anti-GPV on platelet clearance was further studied in a NOD/SCID mouse model. Freshly isolated human platelets were injected into the lateral mouse tail vein; after 30 min, IgG fractions isolated from human sera containing anti-GPV antibodies or control sera from healthy donors were injected into the other lateral tail vein, and the survival of human platelets in the mouse circulation was analyzed by taking murine blood 60, 120, 300 min and 24h after baseline. High avidity and low avidity anti-GP V aabs (n=3 per group) eliminated human platelets with no detectable difference between the groups (mean platelet survival at t=300 min: 40% [range 27-55] versus 35% [range, 16-46]). A comparable, dose-dependent platelet clearance was also obtained with monoclonal antibody SW16 against GP V. In summary, we have demonstrated that anti-GP V autoantibodies are regularly detectable in ITP patients; and that they are able to induce phagocytosis and platelet clearance. Our findings have implications for both, further development of laboratory testing, and guidance for clinical decision making. First, comparison between MAIPA and SPR reveals that free aabs may be more frequent than reported, since aabs appear to escape detection by standard laboratory methods because of low avidity. Better test methods are required. Second, predicting disease severity and/or tailoring ITP therapy can possibly not be restricted to the postulated difference between anti-GP IIb/IIIa and anti-GP Ib/IX. Prospective studies are required to understand the impact of different GP-specific platelet aabs on the clinical course of ITP including, anti-GP V. Disclosures Rummel: Celgene: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbio: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Honoraria. Bakchoul:Aspen Germany gGmbH, CLS Behring, Stago gGmbH: Honoraria; German Research Society (DFG): Research Funding; Robert Bosch gGmbH: Research Funding.

Description: The Multi-sensor Cloud Retrieval Simulator (MCRS) produces a “simulated radiance” product from any high-resolution general circulation model with interactive aerosol as if a specific sensor such as the Moderate Resolution Imaging Spectroradiometer (MODIS) were viewing a combination of the atmospheric column and land–ocean surface at a specific location. Previously the MCRS code only included contributions from atmosphere and clouds in its radiance calculations and did not incorporate properties of aerosols. In this paper we added a new aerosol properties module to the MCRS code that allows users to insert a mixture of up to 15 different aerosol species in any of 36 vertical layers.This new MCRS code is now known as MCARS (Multi-sensor Cloud and Aerosol Retrieval Simulator). Inclusion of an aerosol module into MCARS not only allows for extensive, tightly controlled testing of various aspects of satellite operational cloud and aerosol properties retrieval algorithms, but also provides a platform for comparing cloud and aerosol models against satellite measurements. This kind of two-way platform can improve the efficacy of model parameterizations of measured satellite radiances, allowing the assessment of model skill consistently with the retrieval algorithm. The MCARS code provides dynamic controls for appearance of cloud and aerosol layers. Thereby detailed quantitative studies of the impacts of various atmospheric components can be controlled.In this paper we illustrate the operation of MCARS by deriving simulated radiances from various data field output by the Goddard Earth Observing System version 5 (GEOS-5) model. The model aerosol fields are prepared for translation to simulated radiance using the same model subgrid variability parameterizations as are used for cloud and atmospheric properties profiles, namely the ICA technique. After MCARS computes modeled sensor radiances equivalent to their observed counterparts, these radiances are presented as input to operational remote-sensing algorithms.Specifically, the MCARS-computed radiances are input into the processing chain used to produce the MODIS Data Collection 6 aerosol product (M{O/Y}D04). The M{O/Y}D04 product is of course normally produced from M{O/Y}D021KM MODIS Level-1B radiance product directly acquired by the MODIS instrument. MCARS matches the format and metadata of a M{O/Y}D021KM product. The resulting MCARS output can be directly provided to MODAPS (MODIS Adaptive Processing System) as input to various operational atmospheric retrieval algorithms. Thus the operational algorithms can be tested directly without needing to make any software changes to accommodate an alternative input source.We show direct application of this synthetic product in analysis of the performance of the MOD04 operational algorithm. We use biomass-burning case studies over Amazonia employed in a recent Working Group on Numerical Experimentation (WGNE)-sponsored study of aerosol impacts on numerical weather prediction (Freitas et al., 2015). We demonstrate that a known low bias in retrieved MODIS aerosol optical depth appears to be due to a disconnect between actual column relative humidity and the value assumed by the MODIS aerosol product.

Description: This report documents an evaluation by the Global Modeling and Assimilation Office (GMAO) of a two-year 7-km-resolution non-hydrostatic global mesoscale simulation produced with the Goddard Earth Observing System (GEOS-5) atmospheric general circulation model. The simulation was produced as a Nature Run for conducting observing system simulation experiments (OSSEs). Generation of the GEOS-5 Nature Run (G5NR) was motivated in part by the desire of the OSSE community for an improved high-resolution sequel to an existing Nature Run produced by the European Centre for Medium-Range Weather Forecasts (ECMWF), which has served the community for several years. The intended use of the G5NR in this context is for generating simulated observations to test proposed observing system designs regarding new instruments and their deployments. Because NASA's interest in OSSEs extends beyond traditional weather forecasting applications, the G5NR includes, in addition to standard meteorological components, a suite of aerosol types and several trace gas concentrations, with emissions downscaled to 10 km using ancillary information such as power plant location, population density and night-light information. The evaluation exercise described here involved more than twenty-five GMAO scientists investigating various aspects of the G5NR performance, including time mean temperature and wind fields, energy spectra, precipitation and the hydrological cycle, the representation of waves, tropical cyclones and midlatitude storms, land and ocean surface characteristics, the representation and forcing effects of clouds and radiation, dynamics of the stratosphere and mesosphere, and the representation of aerosols and trace gases. Comparisons are made with observational data sets when possible, as well as with reanalyses and other long model simulations. The evaluation is broad in scope, as it is meant to assess the overall realism of basic aspects of the G5NR deemed relevant to the conduct of OSSEs. However, because of the relatively short record and other practical considerations, these comparisons cannot provide a definitive, statistically sound assessment of all model deficiencies, or guarantee the G5NR's suitability for all OSSE applications. Differences between the observed and simulated behavior also must be judged in the context of basic internal atmospheric variability which can introduce variations that are not necessarily controlled by the prescribed sea surface temperatures used in generating the G5NR. The results show that the G5NR performs well as measured by the majority of metrics applied in this evaluation. Particular benefits derived from the 7-km resolution of G5NR include realistic representations of extreme weather events in both the tropics and extratropics including tropical cyclones, Nor'easters and mesoscale convective complexes; improved representation of the diurnal cycle of precipitation over land; well-resolved surface-atmosphere interactions such as katabatic wind flows over Antarctica and Greenland; and resolution of orographically generated gravity waves that propagate into the upper atmosphere and influence the large scale circulation. Obvious deficiencies in the G5NR include a "splitting" of the inter-tropical convergence zone, which leads to a weaker-than-observed Hadley circulation and related deficiencies in the depiction of stationary wave patterns. Also, while the G5NR captures global cloud features and radiative effects well in general, close comparison with observations reveals higher-than-observed cloud brightness, likely due to an overabundance of cloud condensate; less distinct cloud minima in subtropical subsidence zones, consistent with a weak Hadley circualtion; and too few near-coastal marine stratocumulus clouds.

Description: The Multi-sensor Cloud Retrieval Simulator (MCRS) produces a simulated radiance product from any high-resolution general circulation model with interactive aerosol as if a specific sensor such as the Moderate Resolution Imaging Spectroradiometer (MODIS) were viewing a combination of the atmospheric column and land ocean surface at a specific location. Previously the MCRS code only included contributions from atmosphere and clouds in its radiance calculations and did not incorporate properties of aerosols. In this paper we added a new aerosol properties module to the MCRS code that allows users to insert a mixture of up to 15 different aerosol species in any of 36 vertical layers. This new MCRS code is now known as MCARS (Multi-sensor Cloud and Aerosol Retrieval Simulator). Inclusion of an aerosol module into MCARS not only allows for extensive, tightly controlled testing of various aspects of satellite operational cloud and aerosol properties retrieval algorithms, but also provides a platform for comparing cloud and aerosol models against satellite measurements. This kind of two-way platform can improve the efficacy of model parameterizations of measured satellite radiances, allowing the assessment of model skill consistently with the retrieval algorithm. The MCARS code provides dynamic controls for appearance of cloud and aerosol layers. Thereby detailed quantitative studies of the impacts of various atmospheric components can be controlled. In this paper we illustrate the operation of MCARS by deriving simulated radiances from various data field output by the Goddard Earth Observing System version 5 (GEOS-5) model. The model aerosol fields are prepared for translation to simulated radiance using the same model sub grid variability parameterizations as are used for cloud and atmospheric properties profiles, namely the ICA technique. After MCARS computes modeled sensor radiances equivalent to their observed counterparts, these radiances are presented as input to operational remote-sensing algorithms. Specifically, the MCARS-computed radiances are input into the processing chain used to produce the MODIS Data Collection 6 aerosol product (MOYD04). TheMOYD04 product is of course normally produced from MOYD021KM MODIS Level-1B radiance product directly acquired by the MODIS instrument. MCARS matches the format and metadata of a MOYD021KM product. The resulting MCARS output can be directly provided to MODAPS (MODIS Adaptive Processing System) as input to various operational atmospheric retrieval algorithms. Thus the operational algorithms can be tested directly without needing to make any software changes to accommodate an alternative input source. We show direct application of this synthetic product in analysis of the performance of the MOD04 operational algorithm. We use biomass-burning case studies over Amazonia employed in a recent Working Group on Numerical Experimentation (WGNE)-sponsored study of aerosol impacts on numerical weather prediction (Freitas et al., 2015). We demonstrate that a known low bias in retrieved MODIS aerosol optical depth appears to be due to a disconnect between actual column relative humidity and the value assumed by the MODIS aerosol product.

Description: Part 1 of this series presented a Monte Carlo Bayesian method for constraining a complex statistical model of global circulation model (GCM) sub-gridcolumn moisture variability using high-resolution Moderate Resolution Imaging Spectroradiometer (MODIS) cloud data, thereby permitting parameter estimation and cloud data assimilation for large-scale models. This article performs some basic testing of this new approach, verifying that it does indeed reduce mean and standard deviation biases significantly with respect to the assimilated MODIS cloud optical depth, brightness temperature and cloud-top pressure and that it also improves the simulated rotational-Raman scattering cloud optical centroid pressure (OCP) against independent (non-assimilated) retrievals from the Ozone Monitoring Instrument (OMI). Of particular interest, the Monte Carlo method does show skill in the especially difficult case where the background state is clear but cloudy observations exist. In traditional linearized data assimilation methods, a subsaturated background cannot produce clouds via any infinitesimal equilibrium perturbation, but the Monte Carlo approach allows non-gradient-based jumps into regions of non-zero cloud probability. In the example provided, the method is able to restore marine stratocumulus near the Californian coast, where the background state has a clear swath. This article also examines a number of algorithmic and physical sensitivities of the new method and provides guidance for its cost-effective implementation. One obvious difficulty for the method, and other cloud data assimilation methods as well, is the lack of information content in passive-radiometer-retrieved cloud observables on cloud vertical structure, beyond cloud-top pressure and optical thickness, thus necessitating strong dependence on the background vertical moisture structure. It is found that a simple flow-dependent correlation modification from Riishojgaard provides some help in this respect, by better honouring inversion structures in the background state.