Snow model verification using ensemble prediction and operational benchmarks

Hydrologic model evaluations have traditionally focused on measuring how closely the model can simulate various characteristics of historical observations. Although advancing hydrologic forecasting is an often-stated goal of numerous modeling studies, testing in a forecasting mode is seldom undertaken, limiting information derived from these analyses. One can overcome this limitation through generation, and subsequent analysis, of ensemble hindcasts. In this study, long-range ensemble hindcasts are generated for the available period of record for a basin in southwestern Idaho for the purpose of evaluating the Snow-Atmosphere-Soil Transfer (SAST) model against the current operational benchmark, the National Weather Service's (NWS) snow accumulation and ablation model SNOW17. Both snow models were coupled with the NWS operational rainfall runoff model and ensembles of seasonal discharge and weekly snow water equivalent (SWE) were evaluated. Ensemble predictions from both the SAST and SNOW17 models were better than climatology forecasts, for the period studied. In most cases, the accuracy of the SAST-generated predictions was similar to the SNOW17-generated predictions, except during periods of significant melting. Differences in model performance are partially attributed to initial condition errors. After updating the SWE state in the snow models with the observed SWE, the forecasts were improved during the first 2-4 weeks of the forecast window and the skills were essentially equal in both forecasting systems for the study watershed. Climate dominated the forecast uncertainty in the latter part of the forecast window while initial conditions controlled the forecast skill in the first 3-4 weeks of the forecast. The use of hindcasting in the snow model analysis revealed that, given the dominance of the initial conditions on forecast skill, streamflow predictions will be most improved through the use of state updating. © 2008 American Meteorological Society

Operational snow modeling: Addressing the challenges of an energy balance model for National Weather Service forecasts

Prediction of snowmelt has become a critical issue in much of the western United States given the increasing demand for water supply, changing snow cover patterns, and the subsequent requirement of optimal reservoir operation. The increasing importance of hydrologic predictions necessitates that traditional forecasting systems be re-evaluated periodically to assure continued evolution of the operational systems given scientific advancements in hydrology. The National Weather Service (NWS) SNOW17, a conceptually based model used for operational prediction of snowmelt, has been relatively unchanged for decades. In this study, the Snow-Atmosphere-Soil Transfer (SAST) model, which employs the energy balance method, is evaluated against the SNOW17 for the simulation of seasonal snowpack (both accumulation and melt) and basin discharge. We investigate model performance over a 13-year period using data from two basins within the Reynolds Creek Experimental Watershed located in southwestern Idaho. Both models are coupled to the NWS runoff model [SACramento Soil Moisture Accounting model (SACSMA)] to simulate basin streamflow. Results indicate that while in many years simulated snowpack and streamflow are similar between the two modeling systems, the SAST more often overestimates SWE during the spring due to a lack of mid-winter melt in the model. The SAST also had more rapid spring melt rates than the SNOW17, leading to larger errors in the timing and amount of discharge on average. In general, the simpler SNOW17 performed consistently well, and in several years, better than, the SAST model. Input requirements and related uncertainties, and to a lesser extent calibration, are likely to be primary factors affecting the implementation of an energy balance model in operational streamflow prediction. © 2008 Elsevier B.V. All rights reserved

Surface Wave Modes on Spherical Cavities Excited by Incident Ultrasound

It has been shown both experimentally and theoretically1 that ultrasonic waves propagate circumferentially around the surface of cavities in an elastic medium, besides being reflected from its “flash points”. Surface wave returns were seen to decisively influence the time structure of the echo return from incident ultrasonic pulses. Nagase2 has solved a characteristic equation applicable to the spherical cavity problem, from which it could be shown3 that the surface of a spherical cavity supports a Rayleigh-type and two (P and S) Franz-type surface waves, of known speeds and dispersions. On the other hand, the complex eigenfrequencies of cavities were recently obtained numerically4. We have used these numerical results in order to satisfy Nagase’s solutions, presented in the form of propagation constants of the surface waves as series of fractional powers of the frequency, and have obtained in this way a mode number assignment for all the complex eigenfrequencies. Using this, we calculate dispersion curves for the Rayleigh, P and S- type surface wave phase velocities; their knowledge will permit an accurate interpretation of ultrasonic scattering experiments1, which previously could be analyzed in a qualitative way only

Copper signaling axis as a target for prostate cancer therapeutics.

Previously published reports indicate that serum copper levels are elevated in patients with prostate cancer and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for prostate cancer cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting prostate cancer cell proclivity for copper uptake, we developed a "conditional lethal" screen to identify compounds whose cytotoxic actions were manifested in a copper-dependent manner. Emerging from this screen was a series of dithiocarbamates, which, when complexed with copper, induced reactive oxygen species-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, disulfiram (DSF), is an FDA-approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies, DSF alone had a minimal effect on the growth of prostate cancer tumors when propagated as xenografts. However, when DSF was coadministered with copper, a very dramatic inhibition of tumor growth in models of hormone-sensitive and of castrate-resistant disease was observed. Furthermore, we determined that prostate cancer cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of androgen receptor (AR)-positive prostate cancer cell lines with androgens. Not surprisingly, robust CTR1-dependent uptake of copper into prostate cancer cells was observed, an activity that was accentuated by activation of AR. Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of patients with prostate cancer whose disease is resistant to classical androgen ablation therapies

Regional differences in APD restitution can initiate wavebreak and re-entry in cardiac tissue: A computational study

Background Regional differences in action potential duration (APD) restitution in the heart favour arrhythmias, but the mechanism is not well understood. Methods We simulated a 150 × 150 mm 2D sheet of cardiac ventricular tissue using a simplified computational model. We investigated wavebreak and re-entry initiated by an S1S2S3 stimulus protocol in tissue sheets with two regions, each with different APD restitution. The two regions had a different APD at short diastolic interval (DI), but similar APD at long DI. Simulations were performed twice; once with both regions having steep (slope > 1), and once with both regions having flat (slope < 1) APD restitution. Results Wavebreak and re-entry were readily initiated using the S1S2S3 protocol in tissue sheets with two regions having different APD restitution properties. Initiation occurred irrespective of whether the APD restitution slopes were steep or flat. With steep APD restitution, the range of S2S3 intervals resulting in wavebreak increased from 1 ms with S1S2 of 250 ms, to 75 ms (S1S2 180 ms). With flat APD restitution, the range of S2S3 intervals resulting in wavebreak increased from 1 ms (S1S2 250 ms), to 21 ms (S1S2 340 ms) and then 11 ms (S1S2 400 ms). Conclusion Regional differences in APD restitution are an arrhythmogenic substrate that can be concealed at normal heart rates. A premature stimulus produces regional differences in repolarisation, and a further premature stimulus can then result in wavebreak and initiate re-entry. This mechanism for initiating re-entry is independent of the steepness of the APD restitution curve

Demographics of paediatric renal replacement therapy in Europe: 2007 annual report of the ESPN/ERA-EDTA registry

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Targeting of highly conserved Dengue virus sequences with anti-Dengue virus trans-splicing group I introns

<p>Abstract</p> <p>Background</p> <p>Dengue viruses (DENV) are one of the most important viral diseases in the world with approximately 100 million infections and 200,000 deaths each year. The current lack of an approved tetravalent vaccine and ineffective insecticide control measures warrant a search for alternatives to effectively combat DENV. The <it>trans</it>-splicing variant of the <it>Tetrahymena thermophila </it>group I intron catalytic RNA, or ribozyme, is a powerful tool for post-transcriptional RNA modification. The nature of the ribozyme and the predictability with which it can be directed makes it a powerful tool for modifying RNA in nearly any cell type without the need for genome-altering gene therapy techniques or dependence on native cofactors.</p> <p>Results</p> <p>Several anti-DENV Group I <it>trans</it>-splicing introns (αDENV-GrpIs) were designed and tested for their ability to target DENV-2 NGC genomes <it>in situ</it>. We have successfully targeted two different uracil bases on the positive sense genomic strand within the highly conserved 5'-3' cyclization sequence (CS) region common to all serotypes of DENV with our αDENV-GrpIs. Our ribozymes have demonstrated ability to specifically <it>trans</it>-splice a new RNA sequence downstream of the targeted site <it>in vitro </it>and in transfected insect cells as analyzed by firefly luciferase and RT-PCR assays. The effectiveness of these αDENV-GrpIs to target infecting DENV genomes is also validated in transfected or transformed Aedes mosquito cell lines upon infection with unattenuated DENV-2 NGC.</p> <p>Conclusions</p> <p>Analysis shows that our αDENV-GrpIs have the ability to effectively <it>trans</it>-splice the DENV genome <it>in situ</it>. Notably, these results show that the αDENV-GrpI 9v1, designed to be active against all forms of Dengue virus, effectively targeted the DENV-2 NGC genome in a sequence specific manner. These novel αDENV-GrpI introns provide a striking alternative to other RNA based approaches for the transgenic suppression of DENV in transformed mosquito cells and tissues.</p

[(18)F]Fluoroethyltyrosine- positron emission tomography-guided radiotherapy for high-grade glioma

BACKGROUND: To compare morphological gross tumor volumes (GTVs), defined as pre- and postoperative gadolinium enhancement on T1-weighted magnetic resonance imaging to biological tumor volumes (BTVs), defined by the uptake of (18)F fluoroethyltyrosine (FET) for the radiotherapy planning of high-grade glioma, using a dedicated positron emission tomography (PET)-CT scanner equipped with three triangulation lasers for patient positioning. METHODS: Nineteen patients with malignant glioma were included into a prospective protocol using FET PET-CT for radiotherapy planning. To be eligible, patients had to present with residual disease after surgery. Planning was performed using the clinical target volume (CTV = GTV union or logical sum BTV) and planning target volume (PTV = CTV + 20 mm). First, the interrater reliability for BTV delineation was assessed among three observers. Second, the BTV and GTV were quantified and compared. Finally, the geometrical relationships between GTV and BTV were assessed. RESULTS: Interrater agreement for BTV delineation was excellent (intraclass correlation coefficient 0.9). Although, BTVs and GTVs were not significantly different (p = 0.9), CTVs (mean 57.8 +/- 30.4 cm(3)) were significantly larger than BTVs (mean 42.1 +/- 24.4 cm(3); p &lt; 0.01) or GTVs (mean 38.7 +/- 25.7 cm(3); p &lt; 0.01). In 13 (68%) and 6 (32%) of 19 patients, FET uptake extended &gt;or= 10 and 20 mm from the margin of the gadolinium enhancement. CONCLUSION: Using FET, the interrater reliability had excellent agreement for BTV delineation. With FET PET-CT planning, the size and geometrical location of GTVs and BTVs differed in a majority of patients

Atrial arrhythmogenesis in wild-type and Scn5a+/Δ murine hearts modelling LQT3 syndrome

Long QT(3) (LQT3) syndrome is associated with abnormal repolarisation kinetics, prolonged action potential durations (APD) and QT intervals and may lead to life-threatening ventricular arrhythmias. However, there have been few physiological studies of its effects on atrial electrophysiology. Programmed electrical stimulation and burst pacing induced atrial arrhythmic episodes in 16 out of 16 (16/16) wild-type (WT) and 7/16 genetically modified Scn5a+/Δ (KPQ) Langendorff-perfused murine hearts modelling LQT3 (P < 0.001 for both), and in 14/16 WT and 1/16 KPQ hearts (P < 0.001 for both; Fisher’s exact test), respectively. The arrhythmogenic WT hearts had significantly larger positive critical intervals (CI), given by the difference between atrial effective refractory periods (AERPs) and action potential durations at 90% recovery (APD90), compared to KPQ hearts (8.1 and 3.2 ms, respectively, P < 0.001). Flecainide prevented atrial arrhythmias in all arrhythmogenic WT (P < 0.001) and KPQ hearts (P < 0.05). It prolonged the AERP to a larger extent than it did the APD90 in both WT and KPQ groups, giving negative CIs. Quinidine similarly exerted anti-arrhythmic effects, prolonged AERP over corresponding APD90 in both WT and KPQ groups. These findings, thus, demonstrate, for the first time, inhibitory effects of the KPQ mutation on atrial arrhythmogenesis and its modification by flecainide and quinidine. They attribute these findings to differences in the CI between WT and mutant hearts, in the presence or absence of these drugs. Thus, prolongation of APD90 over AERP gave positive CI values and increased atrial arrhythmogenicity whereas lengthening of AERP over APD90 reduced such CI values and produced the opposite effect