Airborne, in situ measurements from PEM-Tropics-A (September/October 1996) are analyzed to show the presence of distinct pollution plumes in the middle-tropical troposphere of the remote South Pacific (10-30°S). These elevated plumes cause a relative maximum at about 5-7km altitude in the vertical distribution of primary and secondary species characteristic of fuel combustion and biomass burning (CO, C2H2, C2H6, CH3Cl, PAN, O3). Similar plumes were also observed at mid-latitudes in the middle troposphere during three flights east of New Zealand (40-45°S). In all, pollution plumes with CO larger than 100 ppb were observed 24 times on seven separate flight days south of the equator. The observed plumes were frequently embedded in very dry air. Ten-day back trajectory analysis supports the view that these originated from the biomass burning regions of South Africa (and South America) and were transported to the South Pacific along long-distance subsiding trajectories. The chemical composition of the southern Pacific troposphere analyzed from the PEM-Tropics-A data is compared with data from the tropical regions of the northern Pacific (PEM-West-A) and southern Atlantic (TRACE-A) during the same Sept/Oct time period. Sizable perturbations in the abundance of ozone and its key precursors, resulting from the transport of pollution originating from biomass burning sources, are observed in much of the Southern Hemispheric troposphere. Copyright (C) 2000 Elsevier Science B.V.

Background and purpose

Following inflammatory stimuli, neutrophils are recruited to sites of inflammation and exert effector functions that often have deleterious effects on tissue integrity, which can lead to organ failure. Bruton's tyrosine kinase (Btk) is expressed in neutrophils and constitutes a promising pharmacological target for neutrophil-mediated tissue damage. Here, we evaluate a selective reversible inhibitor of Btk, PRN473, for its ability to dampen neutrophil influx via inhibition of adhesion receptor signalling pathways.

Experimental approach

In vitro assays were used to assess fMLP receptor 1 (Fpr-1)-mediated binding of ligands to the adhesion receptors macrophage antigen-1 (Mac-1) and lymphocyte function antigen-1. Intravital microscopy of the murine cremaster was used to evaluate post-adhesion strengthening and endoluminal crawling. Finally, neutrophil influx was visualized in a clinically relevant model of sterile liver injury in vivo. Btk knockout animals were used as points of reference for Btk functions.

Key results

Pharmacological inhibition of Btk by PRN473 reduced fMLP-induced phosphorylation of Btk and Mac-1 activation. Biochemical experiments demonstrated the specificity of the inhibitor. PRN473 (20 mg·kg^-1 ) significantly reduced intravascular crawling and neutrophil recruitment into inflamed tissue in a model of sterile liver injury, down to levels seen in Btk-deficient animals. A higher dose did not provide additional reduction of intravascular crawling and neutrophil recruitment.

Conclusions and implications

PRN473, a highly selective inhibitor of Btk, potently attenuates sterile liver injury by inhibiting the activation of the β₂ -integrin Mac-1 and subsequently neutrophil recruitment into inflamed tissue.

Hydrogen peroxide and methylhydroperoxide were measured in the troposphere over the western North Pacific as part of the airborne portion of NASA's Global Tropospheric Experiment/Pacific Exploratory Mission-West A field mission. The flights circled the North Pacific, focusing on the western Pacific, and extended from 300 to 13,000 m altitude. The hydroperoxides were uniquely separated and quantified using a high-pressure liquid chromatography system in conjunction with a continuous enzyme fluorometric instrument. Results show a latitudinal gradient in both peroxides at all altitudes; for example, between 3 and 5 km, H2O2 median values decrease from 1700 to 500 parts per trillion by volume (pptv) in going from 0°-15°N to 45°-60°N, and the corresponding decrease in CH3OOH was 1100 to 200 pptv. Concentration maxima are observed in both species at altitudes of 2 to 3 km with H2O2 concentrations below 1 km lower by 30%, 10% for CH3OOH, and even lower, by a factor of 10, for both above 9 km. The H2O2 to CH3OOH ratio increased with altitude and latitude with ratios <1 in the tropical surface layer and >2 at midlatitude high altitude. Highest peroxide concentrations were encountered over the Celebes Sea in air which was impacted by aged biomass fire and urban pollutants. CH3OOH was below the level of detection in stratospheric air. H2O2 exceeded SO2 95% of the time, with the exceptions generally above 9 km. Above 3 km, O3 increases with decreasing H2O2 and CH3OOH. Below 3 km the O3-CH3OOH trend is the same but O3 increases with increasing H2O2. The measurements are compared with predictions based upon a photochemical steady state zero-dimensional model and a three-dimensional mesoscale time-dependent model. These models capture observed trends in H2O2 and CH3OOH, with the possible exception of H2O2 below 2 km where surface removal is important. A surface removal lifetime of 3.5 days brings the observed and zero-dimensional model-estimated H2O2 into agreement. The steady state model suggests a strong correlation between the ratios of NO/CO or HO2/HO and the ratio of H2O2/CH3OOH. The observed hydroperoxide ratios bracket the modeled relationship with occasionally much lower H2O2 than expected. Copyright 1996 by the American Geophysical Union.

Reversible covalency, achieved with, for instance, highly electron-deficient olefins, offers a compelling strategy to design chemical probes and drugs that benefit from the sustained target engagement afforded by irreversible compounds, while avoiding permanent protein modification. Reversible covalency has mainly been evaluated for cysteine residues in individual kinases and the broader potential for this strategy to engage cysteines across the proteome remains unexplored. Herein, we describe a mass-spectrometry-based platform that integrates gel filtration with activity-based protein profiling to assess cysteine residues across the human proteome for both irreversible and reversible interactions with small-molecule electrophiles. Using this method, we identify numerous cysteine residues from diverse protein classes that are reversibly engaged by cyanoacrylamide fragment electrophiles, revealing the broad potential for reversible covalency as a strategy for chemical-probe discovery.

Extensive observations of tropospheric trace species during the second NASA Global Tropospheric Experiment Western Pacific Exploratory Mission (PEM-West B) in February-March 1994 showed significant seasonal variability in comparison with the first mission (PEM-West A), conducted in September-October 1991. In this study we adopt a previously established analytical method, i.e., the ratio C2H2/CO as a measure of the relative degree of atmospheric processing, to elucidate the key similarities and variations between the two missions. In addition, the C2H2/CO ratio scheme is combined with the back-trajectory-based and the LIDAR-based air mass classification schemes, respectively, to make in-depth analysis of the seasonal variation between PEM-West A and PEM-West B (hereinafter referred to as PEM-WA and PEM-WB). A large number of compounds, including long-lived NMHCs, CH4, and CO2, are, as expected, well correlated with the ratio C2H2/CO. In comparison with PEM-WA, a significantly larger range of observed C2H2/CO values at the high end for the PEM-WB period indicates that the western Pacific was more impacted by "fresher" source emissions, i.e., faster or more efficient continental outflow. As in the case of PEM-WA, the C2H2/CO scheme complements the back-trajectory air mass classification scheme very well. By combining the two schemes, we found that the atmospheric processing in the region is dominated by atmospheric mixing for the trace species analyzed. This PEM-WB wintertime result is similar to that found in PEM-WA for the autumn. In both cases, photochemical reactions are found to play a significant role in determining the background mixing ratios of trace gases, and in this way the two processes are directly related and dependent upon each other. This analysis also indicates that many of the upper tropospheric air masses encountered over the western Pacific during PEM-WB may have had little impact from eastern Asia's continental surface sources. NOx mixing ratios were significantly enhanced during PEM-WB when compared with PEM-WA, in the upper troposphere's more atmospherically processed air masses. These high levels of NOx resulted in a substantial amount of photochemical production of O3. A lack of corresponding enhancements in surface emission tracers strongly implies that in situ atmospheric sources such as lightning are responsible for the enhanced upper tropospheric NOx. The similarity in NOx values between the northern (higher air traffic) and southern continental air masses together with the indications of a large seasonal shift suggests that aircraft emissions are not the dominant source. However, photochemical recycling cannot be ruled out as this in situ source of NOx. Copyright 1999 by the American Geophysical Union.

This study examines the influence of photochemical processes on tropospheric ozone distributions over the extratropical western North Pacific. The analysis presented ere is based on data collected during the Pacific Exploratory Mission-West Phase B (PEM-West B) field study conducted in February-March 1994. Sampling in the study region involved altitudes of 0-12 km and latitudes of 10°S to 50°N. The extratropical component of the data set (i.e., 20-50°N) was defined by markedly different photochemical environments north and south of 30°N. This separation was clearly defined by an abrupt decrease in the tropopause height near 30°N and a concomitant increase in total O3 column density. This shift in overhead O3 led to highly reduced rates of O3 formation and destruction for the 30-50°N latitude regime. Both latitude ranges, however, stili exhibited net O3 production at all altitudes. Of special significance was the finding that net O3 production prevailed even at boundary layer and lower free tropospheric altitudes (e.g., < 4 km), a condition uncommon to Pacific marine environments. These results reflect the strong impact of continental outflow of O3 precursors (e.g., NO and NMHCs) into the northwestern Pacific Basin. Comparisons with PEM-West A, which sampled the same region in a different season (September-October), revealed major differences at altitudes below 4 km, the altitude range most influenced by continental outflow. The resulting net rate of increase in the tropospheric O3 column for PEM-West B was 1-3% per day, while for PEM-West A it was approximately zero. Unique to the PEM-West B study is the finding that even under wintertime conditions substantial column production of tropospheric O3 can occur at subtropical and mid-latitudes. While such impacts may not be totally unexpected at near coast locations, the present study suggests that the impact from continental outflow on the marine BL could extend out to distances of more than 2000 km from the Asian Pacific Rim.

During September/October 1991, NASA's Global Tropospheric Experiment (GTE) conducted an airborne field measurement program (PEM-West A) in the troposphere over the western Pacific Ocean. In this paper we describe and use the relative abundance of the combustion products C2H2 and CO to classify air masses encountered during PEM-West A based on the degree that these tracers were processed by the combined effects of photochemical reactions and dynamical mixing (termed the degree of atmospheric processing). A large number of trace compounds (e.g., C2H6, C3H8, C6H6, NOy, and O3) are found to be well correlated with the degree of atmospheric processing that is reflected by changes in the ratio of C2H2/CO over the range of values from ∼0.3 to 2.0 (parts per trillion volume) C2H2/ (parts per billion volume) CO. This C2H2/CO-based classification scheme is compared to model simulations and to two independent classification schemes based on air mass back-trajectory analyses and lidar profiles of O3 and aerosols. In general, these schemes agree well, and in combination they suggest that the functional dependence that other observed species exhibit with respect to the C2H2/CO atmospheric processing scale can be used to study the origin, sources, and sinks of trace species and to derive several important findings. First, the degree of atmospheric processing is found to be dominated by dilution associated with atmospheric mixing, which is found to primarily occur through the vertical mixing of relatively recent emissions of surface layer trace species. Photochemical reactions play their major role by influencing the background concentrations of trace species that are entrained during the mixing (i.e., dilution) process. Second, a significant noncontinental source(s) of NO (and NOx) in the free troposphere is evident. In particular, the enhanced NO mixing ratios that were observed in convected air masses are attributed to either emissions from lightning or the rapid recycling of NOy compounds. Third, nonsoluble trace species emitted in the continental boundary layer, such as CO and hydrocarbons, are vertically transported to the upper troposphere as efficiently as they are to the midtroposphere. In addition, the mixing ratios of CO and hydrocarbons in the upper troposphere over the western Pacific may reflect a significant contribution from northern hemisphere land areas other than Asia. Finally, we believe that these results can be valuable for the quantitative evaluation of the vertical transport processes that are usually parameterized in models. Copyright 1996 by the American Geophysical Union.

Bruton tyrosine kinase (BTK) is expressed in B cells and innate immune cells, acting as an essential signaling element in multiple immune cell pathways. Selective BTK inhibition has the potential to target multiple immune-mediated disease pathways. Rilzabrutinib is an oral, reversible, covalent BTK inhibitor designed for immune-mediated diseases. We examined the pharmacodynamic profile of rilzabrutinib and its preclinical mechanisms of action. In addition to potent and selective BTK enzyme and cellular activity, rilzabrutinib inhibited activation and inflammatory activities of B cells and innate cells such as macrophages, basophils, mast cells, and neutrophils, without cell death (in human and rodent assay systems). Rilzabrutinib demonstrated dose-dependent improvement of clinical scores and joint pathology in a rat model of collagen-induced arthritis and demonstrated reductions in autoantibody-mediated FcγR signaling in vitro and in vivo, with blockade of rat Arthus reaction, kidney protection in mouse Ab-induced nephritis, and reduction in platelet loss in mouse immune thrombocytopenia. Additionally, rilzabrutinib inhibited IgE-mediated, FcεR-dependent immune mechanisms in human basophils and mast cell-dependent mouse models. In canines with naturally occurring pemphigus, rilzabrutinib treatment resulted in rapid clinical improvement demonstrated by anti-inflammatory effects visible within 2 wk and all animals proceeding to complete or substantial disease control. Rilzabrutinib is characterized by reversible covalent BTK binding, long BTK residence time with low systemic exposure, and multiple mechanistic and biological effects on immune cells. Rilzabrutinib's unique characteristics and promising efficacy and safety profile support clinical development of rilzabrutinib for a broad array of immune-mediated diseases.