[1] Cloud and aerosol data acquired by the National Research Council of Canada (NRC) Convair-580 aircraft in, above, and below single-layer arctic stratocumulus cloud during the Indirect and Semi-Direct Aerosol Campaign (ISDAC) in April 2008 were used to test three aerosol indirect effects hypothesized to act in mixed-phase clouds: the riming indirect effect, the glaciation indirect effect, and the thermodynamic indirect effect. The data showed a correlation of R = 0.78 between liquid drop number concentration, N liq inside cloud and ambient aerosol number concentration N PCASP below cloud. This, combined with increasing liquid water content LWC with height above cloud base and the nearly constant vertical profile of N liq , suggested that liquid drops nucleated from aerosol at cloud base. No evidence of a riming indirect effect was observed, but a strong correlation of R = 0.69 between ice crystal number concentration N i and N PCASP above cloud was noted. Increases in ice nuclei (IN) concentration with N PCASP above cloud for 2 flight dates combined with the subadiabatic LWC profiles suggest possible mixing of IN from cloud top consistent with the glaciation indirect effect. The lower N ice and lower effective radius r el for the more polluted ISDAC cases compared to data collected in cleaner single-layer stratocumulus conditions during the Mixed-Phase Arctic Cloud Experiment is consistent with the operation of the thermodynamic indirect effect. However, more data in a wider variety of meteorological and surface conditions, with greater variations in aerosol forcing, are required to identify the dominant aerosol forcing mechanisms in mixed-phase arctic clouds.
[1] A modeling study of a low-lying mixed-phase cloud layer observed on 8 April 2008 during the Indirect and Semi-Direct Aerosol Campaign is presented. Large-eddy simulations with size-resolved microphysics were used to test the hypothesis that heterogeneous ice nucleus (IN) concentrations measured above cloud top can account for observed ice concentrations, while also matching ice size distributions, radar reflectivities, and mean Doppler velocities. The conditions for the case are favorable for the hypothesis: springtime IN concentrations are high in the Arctic, the predominant ice habit falls slowly, and overlying IN concentrations were greater than ice particle number concentrations. Based on particle imagery, we considered two dendrite types, broad armed (high density) and stellar (low density), in addition to high and low density aggregates. Two simulations with low-density aggregates reproduced observations best overall: one in which IN concentrations aloft were increased fourfold (as could have been present above water saturation) and another in which initial IN concentrations were vertically uniform. A key aspect of the latter was an IN reservoir under the well-mixed cloud layer: as the simulations progressed, the reservoir IN slowly mixed upward, helping to maintain ice concentrations close to those observed. Given the uncertainties of the measurements and parameterizations of the microphysical processes embedded in the model, we found agreement between simulated and measured ice number concentrations in most of the simulations, in contrast with previous modeling studies of Arctic mixed-phase clouds, which typically show a large discrepancy when IN are treated prognostically and constrained by measurements.
Targeted therapies have yet to have significant impact on the survival of patients with bladder cancer. In this study, we focused on the urea cycle enzyme argininosuccinate synthetase 1 (ASS1) as a therapeutic target in bladder cancer, based on our discovery of the prognostic and functional import of ASS1 in this setting. ASS1 expression status in bladder tumors from 183 Caucasian and 295 Asian patients was analyzed, along with its hypothesized prognostic impact and association with clinicopathologic features, including tumor size and invasion. Furthermore, the genetics, biology, and therapeutic implications of ASS1 loss were investigated in urothelial cancer cells. We detected ASS1 negativity in 40% of bladder cancers, in which multivariate analysis indicated worse disease-specific and metastasis-free survival. ASS1 loss secondary to epigenetic silencing was accompanied by increased tumor cell proliferation and invasion, consistent with a tumor-suppressor role for ASS1. In developing a treatment approach, we identified a novel targeted antimetabolite strategy to exploit arginine deprivation with pegylated arginine deiminase (ADI-PEG20) as a therapeutic. ADI-PEG20 was synthetically lethal in ASS1-methylated bladder cells and its exposure was associated with a marked reduction in intracellular levels of thymidine, due to suppression of both uptake and de novo synthesis. We found that thymidine uptake correlated with thymidine kinase-1 protein levels and that thymidine levels were imageable with [ 18 F]-fluoro-L-thymidine (FLT)-positron emission tomography (PET). In contrast, inhibition of de novo synthesis was linked to decreased expression of thymidylate synthase and dihydrofolate reductase. Notably, inhibition of de novo synthesis was associated with potentiation of ADI-PEG20 activity by the antifolate drug pemetrexed. Taken together, our findings argue that arginine deprivation combined with antifolates warrants clinical investigation in ASS1-negative urothelial and related cancers, using FLT-PET as an early surrogate marker of response. Cancer Res; 74(3); 896-907. Ó2013 AACR.
The Open University's repository of research publications and other research outputs Discovery and characterization of 2-Anilino-4-(Thiazol-5-yl)Pyrimidine transcriptional CDK inhibitors as anticancer agents
The protease(s) responsible for removing the amino-terminal extension of nascent presecretory proteins (signal peptidase) has been extracted from rough microsomes of dog pancreas with the detergent sodium deoxycholate. Preprolactin and pre-growth-hormone, prepared by in vitro translation of bovine pituitary RNA in the wheat germ system, were used to assay signal peptidase in the extract. When added to the wheat germ system during translation, the extract reduced the size of preprolactin and pre-growth-hormone to that of prolactin and growth hormone, respectively. Post-translational addition of the extract also reduced the size of preprolactin and pre-growth-hormone to that of the authentic hormones. The prolactin produced by post-translational cleavage of radiolabeled preprolactin has been shown, by partial amino-terminal sequence analysis, to have the correct amino terminus. This post-translational assay has permitted the investigation of the subcellular localization of the enzyme. Sodium deoxycholate extracts of rough microsomes were active, whereas extracts of smooth microsomes were inactive. However, without detergent treatment, neither rough nor smooth microsomes were capable of cleaving preprolactin in the post-translational assay. From this we conclude that the signa peptidase activity is confined to the rough endoplasmic reticulum and is latent. Finally, we have detected two small peptides which we believe could be the signal peptides generated by the endoproteolytic cleavage of preprolactin and pre-rowth-hormone by signal peptidase.Numerous secretory proteins have been shown to be synthesized as presecretory proteins containing an amino-terminal extension of 15-30 amino acid residues (signal peptide) when their mRNAs are translated in a cell-free system in the absence of microsomal membranes (1-9). In the signal hypothesis (10), it has been proposed that the signal peptide of a nascent presecretory protein nucleates the formation of a functional ribosome-membrane junction which, in turn, provides the topological condition for a cotranslational transfer of the nascent secretory protein across the rough endoplasmic reticulum (RER) membrane into the intracisternal space of the RER. It has been shown for the light chain of immunoglobulin (10, 11) that removal of the signal peptide from the nascent presecretory protein is a cotranslational event-i.e., the signal peptide is removed before the entire secretory protein has been synthesized. Although it has been demonstrated that correct cleavage of nascent presecretory polypeptides can be obtained in vitro by adding microsomal membranes cotranslationally to the cell-free system (1, 2, 12), the complexity of the cell-free system has impeded study of the protease (signal peptidase) responsible for removing the signal peptide.A post-translation assay that is not dependent upon concurrent in vitro translation would greatly facilitate the identifi-The costs of publication of this article were defrayed in part by the payment of page charges. This article must...
This article responds to Andrew Wright's critique of my views on the representation of religions. Using various literary devicesassociating my work closely with that of others whose views are in some ways different from my own, referring very selectively to published texts and exaggerating, and sometimes misrepresenting, what I actually say-Wright presents my work as dualistic, nominalist and as not genuinely hermeneutical. Wright contrasts what he sees as my extreme idea of religions as 'constructions' with his own view of them as 'social facts'. My reply illustrates and responds to Wright's account of my work, clarifies my own position, and raises questions about Wright's views, especially in relation to those of Gavin Flood, whom he cites with favour. My conclusion includes the suggestion that, although our epistemological positions are different in some ways, they spawn pedagogies utilizing some common principles and values.
The variability of cirrus ice microphysical properties is investigated using observations obtained during the Small Particles in Cirrus (SPARTICUS) campaign. An existing approach that represents a size distribution (SD) as a single gamma function using an ellipsoid of equally realizable solutions in (N0, λ, μ) phase space is modified to automatically identify multiple modes in SDs and characterize each mode by such an ellipsoid. The modified approach is applied to ice crystals with maximum dimension D > 15 µm collected by the 2‐D stereo and 2‐D precipitation probes on the Stratton Park Engineering Company Learjet. The dependencies of N0, μ, and λ from each mode, total number concentration, bulk extinction, ice water content (IWC), and mass median maximum dimension Dmm as a function of temperature T and cirrus type are then analyzed. The changes in the observed codependencies between N0, μ, and λ, bulk extinction, IWC, and Dmm with environmental conditions indicate that particles were larger at higher T during SPARTICUS. At most two modes were observed in any SD during SPARTICUS, with the average boundary between them at 115 µm, similar to past studies not using probes with shatter mitigating tips and artifact removal algorithms. The bimodality of the SDs increased with T. This and the differences in N0, μ, and λ between the modes suggest that particles with smaller D nucleated more recently than particles with larger D, which grew via vapor deposition and aggregation. Because smaller crystals, whose concentrations are uncertain, make marginal contributions to higher order moments, the use of higher moments for evaluating model fields is suggested.
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