CD73 is a cell surface enzyme of the purine catabolic pathway that catalyzes the breakdown of AMP to adenosine. Because of the strong immunosuppressive and antiinflammatory properties of adenosine, ...we predicted that cd73⁻/⁻ mice would develop severe experimental autoimmune encephalomyelitis (EAE), an animal model for the central nervous system (CNS) inflammatory disease, multiple sclerosis. Surprisingly, cd73⁻/⁻ mice were resistant to EAE. However, CD4 T cells from cd73⁻/⁻ mice secreted more proinflammatory cytokines than wild-type (WT) mice and were able to induce EAE when transferred into naïve cd73⁺/⁺ T cell-deficient recipients. Therefore, the protection from EAE observed in cd73⁻/⁻ mice was not caused by a deficiency in T cell responsiveness. Immunohistochemistry showed that cd73⁻/⁻ mice had fewer infiltrating lymphocytes in their CNS compared with WT mice. Importantly, susceptibility to EAE could be induced in cd73⁻/⁻ mice after the transfer of WT CD73⁺CD4⁺ T cells, suggesting that CD73 must be expressed either on T cells or in the CNS for disease induction. In the search for the source of CD73 in the CNS that might facilitate lymphocyte migration, immunohistochemistry revealed a lack of CD73 expression on brain endothelial cells and high expression in the choroid plexus epithelium which regulates lymphocyte immunosurveillance between the blood and cerebrospinal fluid. Because blockade of adenosine receptor signaling with the A₂a adenosine receptor-specific antagonist SCH58261 protected WT mice from EAE induction, we conclude that CD73 expression and adenosine receptor signaling are required for the efficient entry of lymphocytes into the CNS during EAE development.
Neuropilin-1 (Nrp1) is a cell surface molecule originally identified for its role in neuronal development. Recently, Nrp1 has been implicated in several aspects of immune function including ...maintenance of the immune synapse and development of regulatory T (Treg) cells. In this study, we provide evidence for a central role of Nrp1 in the regulation of CD4 T-cell immune responses in experimental autoimmune encephalitis (EAE). EAE serves as an animal model for the central nervous system (CNS) inflammatory disorder multiple sclerosis (MS). EAE is mediated primarily by CD4⁺ T cells that migrate to the CNS and mount an inflammatory attack against myelin components, resulting in CNS pathology. Using a tissue-specific deletion system, we observed that the lack of Nrp1 on CD4⁺ T cells results in increased EAE severity. These conditional knockout mice exhibit preferential TH-17 lineage commitment and decreased Treg-cell functionality. Conversely, CD4⁺ T cells expressing Nrp1 suppress effector T-cell proliferation and cytokine production both in vivo and in vitro independent of Treg cells. Nrp1-mediated suppression can be inhibited by TGF-β blockade but not by IL-10 blockade. These results suggest that Nrp1 is essential for proper maintenance of peripheral tolerance and its absence can result in unchecked autoreactive responses, leading to diseases like EAE and potentially MS.
Allergic asthma patients manifest airway inflammation and some show increases in eosinophils, T(H)2 cells, and cytokines, increased mucous production in the lung, and elevated serum IgE. This ...T(H)2-type response suggests a prominent role for T(H)2 cells and their cytokines in the pathology of this disease. The Tec family nonreceptor tyrosine kinase inducible T cell kinase (ITK) has been shown to play a role in the differentiation and/or function of T(H)2-type cells, suggesting that ITK may represent a good target for the control of asthma. Using a murine model of allergic asthma, we show here that ITK is involved in the development of immunological symptoms seen in this model. We show that mice lacking ITK have drastically reduced lung inflammation, eosinophil infiltration, and mucous production following induction of allergic asthma. Notably, T cell influx into the lung was reduced in mice lacking ITK. T cells from ITK(-/-) mice also exhibited reduced proliferation and cytokine secretion, in particular IL-5 and IL-13, in response to challenge with the allergen OVA, despite elevated levels of total IgE and increased OVA-specific IgE responses. Our results suggest that the tyrosine kinase ITK preferentially regulates the secretion of the T(H)2 cytokines IL-5 and IL-13 and may be an attractive target for antiasthmatic drugs.
Abstract Background According to prescribing information for rheumatoid arthritis (RA) treatments in the United States, infliximab should be administered at weeks 1, 2, 6, and then every 8 weeks ...starting at a 3-mg/kg dose, with flexible dosing up to 10 mg/kg and/or every 4 weeks based on clinical response. Objective This study evaluated dosing and intervals of the first 12 infliximab infusions in patients with RA across multiple large administrative databases. Methods Data were obtained from 4 databases: HealthCore Integrated Research Database (HIRD), IMS LifeLink Health Plan Claims Database (IMS Lifelink), Premier Perspective Database (PPD), and Wolters Kluwer Pharma Solutions (WKPS). Patients were aged ≥18 years, diagnosed with RA, and naive to biologic therapy. Patients with other select inflammatory conditions were excluded. The induction period included infusions 1 through 3; the maintenance period included infusions 4 through 12. Results Observed dosing patterns from the HIRD, IMS LifeLink, PPD, and WKPS databases demonstrated minimal dose increases from the first infusion (93.5, 103.3, 58.8, and 73.2 mg, respectively) and from the first maintenance infusion (69.1, 64.3, 45.7, and 45.7 mg, respectively) to the highest dose during the first 12 infusions. The mean number of days between infusions in the maintenance period ranged from 53.3 to 63.5 in HIRD, 53.7 to 60.3 in IMS LifeLink, 53.4 to 59.4 in PPD, and 52.3 to 55.0 in the WKPS database. Conclusion Data from multiple databases of patients with RA suggest that, in clinical practice, infliximab dosing and intervals are consistent with FDA prescribing information and remain relatively stable during the first 12 infusions.
Flash flooding represents a significant hazard to human safety and a threat to property. Simulation and prediction of floods in complex urban settings requires high-resolution precipitation estimates ...and distributed hydrologic modeling. The need for reliable flash flood forecasting has increased in recent years, especially in urban communities, because of the high costs associated with flood occurrences. Several storm nowcast systems use radar to provide quantitative precipitation forecasts that can potentially afford great benefits to flood warning and short-term forecasting in urban settings. In this paper, the potential benefits of high-resolution weather radar data, physically based distributed hydrologic modeling, and quantitative precipitation nowcasting for urban hydrology and flash flood prediction were demonstrated by forcing a physically based distributed hydrologic model with precipitation forecasts made by a convective storm nowcast system to predict flash floods in a small, highly urbanized catchment in Denver, Colorado. Two rainfall events on 5 and 8 July 2001 in the Harvard Gulch watershed are presented that correspond to times during which the storm nowcast system was operated. Results clearly indicate that high-resolution radar-rainfall estimates and advanced nowcasting can potentially lead to improvements in flood warning and forecasting in urban watersheds, even for short-lived events on small catchments. At lead times of 70 min before the occurrence of peak discharge, forecast accuracies of approximately 17% in peak discharge and 10 min in peak timing were achieved for a 10 km² highly urbanized catchment.
Nowcasting Thunderstorms Wilson, James W.; Crook, N. Andrew; Mueller, Cynthia K. ...
Bulletin of the American Meteorological Society,
10/1998, Letnik:
79, Številka:
10
Journal Article
Recenzirano
Odprti dostop
This paper reviews the status of forecasting convective precipitation for time periods less than a few hours (nowcasting). Techniques for nowcasting thunderstorm location were developed in the 1960s ...and 1970s by extrapolating radar echoes. The accuracy of these forecasts generally decreases very rapidly during the first 30 min because of the very short lifetime of individual convective cells. Fortunately more organized features like squall lines and supercells can be successfully extrapolated for longer time periods. Physical processes that dictate the initiation and dissipation of convective storms are not necessarily observable in the past history of a particular echo development; rather, they are often controlled by boundary layer convergence features, environmental vertical wind shear, and buoyancy. Thus, successful forecasts of storm initiation depend on accurate specification of the initial thermodynamic and kinematic fields with particular attention to convergence lines. For these reasons the ability to improve on simple extrapolation techniques had stagnated until the present national observational network modernization program. The ability to observe small-scale boundary layer convergence lines is now possible with operational Doppler radars and satellite imagery. In addition, it has been demonstrated that high-resolution wind retrievals can be obtained from single Doppler radar. Two methods are presently under development for using these modern datasets to forecast thunderstorm evolution: knowledge-based expert systems and numerical forecasting models that are initialized with radar data. Both these methods are very promising and progressing rapidly. Operational tests of expert systems are presently taking place in the United Kingdom and in the United States.
The immune mechanism leading to the generation of protective antibody responses following influenza trivalent inactivated vaccine (TIV) vaccinations remains largely uncharacterized. We recently ...reported that TIV vaccination induced a transient increase of circulating ICOS(+)PD-1(+)CXCR3(+) T follicular helper (cTfh) cells in blood, which positively correlated with the induction of protective antibody responses measured at day 28. However, whether and how these T cells directly contribute to antibody response remains unclear. In this study, we analyzed the changes after TIV vaccination in the amount and the avidity of the polyclonal antibodies specific for the HA1 subunit of the pandemic H1N1 virus, and analyzed the correlation with the increase of ICOS(+)PD-1(+)CXCR3(+) cTfh cells. We found that both the amount and the avidity of specific antibodies rapidly increased during the first 7 days after TIV. Importantly, the increase of ICOS(+)PD-1(+)CXCR3(+) cTfh cells strongly correlated with the increase in the avidity of antibodies, particularly in subjects who did not have high affinity antibodies at baseline. We propose that ICOS(+)PD-1(+)CXCR3(+) Tfh cells directly contribute to the generation of high-avidity antibodies after TIV vaccinations by selectively interacting with high affinity B cells at extrafollicular sites.
During the summer months at the U.S. Army Test and Evaluation Command’s (ATEC) White Sands Missile Range (WSMR), forecasting thunderstorm activity is one of the primary duties of the range ...forecasters. The safety of personnel working on the range and the protection of expensive test equipment depend critically on the quality of forecasts of thunderstorms and associated hazards, including cloud-to-ground lightning, hail, strong winds, heavy rainfall, flash flooding, and tornadoes. The National Center for Atmospheric Research (NCAR) Auto-Nowcast (ANC) system is one of the key forecast tools in the ATEC Four-Dimensional Weather System (4DWX) at WSMR, where its purpose is to aid WSMR meteorologists in their mission of very short term thunderstorm forecasting. Besides monitoring the weather activity throughout the region and warning personnel of potentially hazardous thunderstorms, forecasters play a key role in assisting with the day-to-day planning of test operations on the range by providing guidance with regard to weather conditions favorable to testing. Moreover, based on climatological information about the local weather conditions, forecasters advise their range customers about scheduling tests at WSMR months in advance. This paper reviews the NCAR ANC system, provides examples of the ANC system’s use in thunderstorm forecasting, and describes climatological analyses of WSMR summertime thunderstorm activity relevant for long-range planning of tests. The climatological analysis illustrates that radar-detected convective cells with reflectivity of ≥35 dBZ at WSMR are 1) short lived, with 76% having lifetimes of less than 30 min; 2) small, with 67% occupying areas of less than 25 km²; 3) slow moving, with 79% exhibiting speeds of less than 4 m s−1; 4) moderately intense, with 80% showing reflectivities in excess of 40 dBZ; and 5) deep, with 80% of the storms reaching far enough above the freezing level to be capable of generating lightning.
The stated goals of the Sydney 2000 Forecast Demonstration Project (FDP) were to demonstrate the capability of modern forecast systems and to quantify the associated benefits in the delivery of a ...real-time nowcast service. Wilson et al describe the capability of the assembled systems, which represented the state of the art in operational nowcasting technology, to forecast convective weather in the 0-1-h range. Proposed future directions concerning the specificity of nowcast products, experimental test beds, and additional observations and research required are also discussed.
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