MONITORED GEOLOGIC REPOSITORY LIFE CYCLE COST ESTIMATE ASSUMPTIONS DOCUMENT

The purpose of this assumptions document is to provide general scope, strategy, technical basis, schedule and cost assumptions for the Monitored Geologic Repository (MGR) life cycle cost (LCC) estimate and schedule update incorporating information from the Viability Assessment (VA) , License Application Design Selection (LADS), 1999 Update to the Total System Life Cycle Cost (TSLCC) estimate and from other related and updated information. This document is intended to generally follow the assumptions outlined in the previous MGR cost estimates and as further prescribed by DOE guidance

Structural neural networks subserving oculomotor function in first-episode schizophrenia

BACKGROUND: Smooth pursuit and antisaccade abnormalities are well documented in schizophrenia, but their neuropathological correlates remain unclear. METHODS: In this study, we used statistical parametric mapping to investigate the relationship between oculomotor abnormalities and brain structure in a sample of first-episode schizophrenia patients (n = 27). In addition to conventional volumetric magnetic resonance imaging, we also used magnetization transfer ratio, a technique that allows more precise tissue characterization. RESULTS: We found that smooth pursuit abnormalities were associated with reduced magnetization transfer ratio in several regions, predominantly in the right prefrontal cortex. Antisaccade errors correlated with gray matter volume in the right medial superior frontal cortex as measured by conventional magnetic resonance imaging but not with magnetization transfer ratio. CONCLUSIONS: These preliminary results demonstrate that specific structural abnormalities are associated with abnormal eye movements in schizophrenia

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Characteristics of the nuclear (18S, 5.8S, 28S and 5S) and mitochondrial (12S and 16S) rRNA genes of Apis mellifera (Insecta: Hymenoptera): structure, organization, and retrotransposable elements

As an accompanying manuscript to the release of the honey bee genome, we report the entire sequence of the nuclear (18S, 5.8S, 28S and 5S) and mitochondrial (12S and 16S) ribosomal RNA (rRNA)-encoding gene sequences (rDNA) and related internally and externally transcribed spacer regions of Apis mellifera (Insecta: Hymenoptera: Apocrita). Additionally, we predict secondary structures for the mature rRNA molecules based on comparative sequence analyses with other arthropod taxa and reference to recently published crystal structures of the ribosome. In general, the structures of honey bee rRNAs are in agreement with previously predicted rRNA models from other arthropods in core regions of the rRNA, with little additional expansion in non-conserved regions. Our multiple sequence alignments are made available on several public databases and provide a preliminary establishment of a global structural model of all rRNAs from the insects. Additionally, we provide conserved stretches of sequences flanking the rDNA cistrons that comprise the externally transcribed spacer regions (ETS) and part of the intergenic spacer region (IGS), including several repetitive motifs. Finally, we report the occurrence of retrotransposition in the nuclear large subunit rDNA, as R2 elements are present in the usual insertion points found in other arthropods. Interestingly, functional R1 elements usually present in the genomes of insects were not detected in the honey bee rRNA genes. The reverse transcriptase products of the R2 elements are deduced from their putative open reading frames and structurally aligned with those from another hymenopteran insect, the jewel wasp Nasonia (Pteromalidae). Stretches of conserved amino acids shared between Apis and Nasonia are illustrated and serve as potential sites for primer design, as target amplicons within these R2 elements may serve as novel phylogenetic markers for Hymenoptera. Given the impending completion of the sequencing of the Nasonia genome, we expect our report eventually to shed light on the evolution of the hymenopteran genome within higher insects, particularly regarding the relative maintenance of conserved rDNA genes, related variable spacer regions and retrotransposable elements

Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial

Background STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL). Methods and findings Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire. Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p < 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p < 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively. Conclusions Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC. Trial registration ClinicalTrials.gov NCT00268476, ISRCTN.com ISRCTN78818544

A physiologically based pharmacokinetic (PB/PK) model for multiple exposure routes for soman in multiple species

A physiologically based pharmacokinetic (PB/PK) model has been developed in advanced computer simulation language (ACSL) to describe blood and tissue concentration-time profiles of the C(±)P(-) stereoisomers of soman after inhalation, subcutaneous and intravenous exposures at low (0.8-1.0 × LD50), medium (2-3 × LD50) and high (6 × LD50) levels of soman challenge in three species (rat, guinea pig, marmoset). Allometric formulae were used to compute the compartment volumes, blood flow rates, tidal volume and respiratory rate based upon total animal weight. Blood/tissue partition coefficients for soman, initial carboxylesterase and acetylcholinesterase levels and the rate constants for interactions between soman and these enzymes were species-dependent and were obtained from in vitro measurements reported in the literature. The model incorporated arterial and venous blood, lung, kidney, liver, richly perfused, poorly perfused and fat tissue compartments as well as subcutaneous and nasal exposure site compartments. First-order absorption from linearly filled soman deposits into metabolizing exposure site compartments was employed to model subcutaneous and inhalation exposures. The model was validated by comparing the predicted and observed values for C(±)P(-)-soman in arterial blood at various times following exposure and by regression analysis. Sensitivity analysis was used to determine the effects of perturbations in the model parameters on the time-course of arterial C(-)P(-)-soman concentrations for different exposure routes. In our evaluation of 28 datasets, predicted values were generally within 95% confidence limits of the observed values, and regression coefficients comparing predicted and observed data were greater than 0.85 for 95% of the intravenous and subcutaneous datasets and 25% of the inhalation datasets. We conclude that the model predicts the soman toxicokinetics for doses ≥1 × LD50 for intravenous and subcutaneous exposures and inhalation exposures of 8 min or less sufficiently well to allow its use in the modeling of bioscavenger protection. © 2006 Springer-Verlag

A physiologically based model for the toxicokinetics of C(±)P(±)-soman in the atropinized guinea pig and marmoset - Effect of scavengers and hydrolytic enzymes promoting elimination

Previously, we developed a physiologically based model describing the toxicokinetics of the summed C(±)P(-)-isomers and of the individual C(±)P(+)-isomers in anesthetized, atropinized and mechanically ventilated guinea pigs after intoxication with i.v. doses of 0.8 – 6 LD50 of C(±)P(±)-soman. Some improved parameters have been introduced into this model, which leads to a better prediction of the C(±)P(-)-soman concentrations in blood. Furthermore, the model was extended to the toxicokinetics in anesthetized, atropinized and mechanically ventilated marmosets after intoxication with i.v. doses of 2 – 6 LD50 of C(±)P(±)-soman. The model was used to predict the efficacy of i.v.-administered prophylactic agents that promote elimination processes of C(±)P(±)-soman. On a molar basis, sufficient protection against intoxication with 2 – 5 LD50 of C(±)P(±)-soman is offered by an i.v. dose of human butyrylcholinesterase corresponding with 0.5 - 0.7 times the C(±)P(±)-soman dose in both species. These predictions correspond with results obtained in protection experiments performed in mice, rats and rhesus monkeys (Ashani et al., 1993). Furthermore, modeling predicts that enzymes capable of hydrolyzing C(±)P(-)- soman should be approximately as effective as the endogenous enzymes for hydrolysis of C(-)P(+)-soman in order to achieve sufficient protection against an i.v. dose of 2 LD50 of C(±)P(±)-soman

Evaluation of industry strategies to supply dietary chelated trace minerals (Zn, Mn, and Cu) and their impact on broiler breeder hen reproductive performance, egg quality, and early offspring performance

SUMMARY: Dietary trace minerals have profound functions in broiler breeder reproduction. Organic hydroxy analog of methionine (HMTBa) trace minerals have been included at lower levels in poultry feeds compared to inorganic sources without affecting performance and in some cases improving it. We compared 3 breeder hen trace mineral blends of economic interest to a large U.S. integrator. Treatment diets (fed wk 26–65) provided Zn, Mn, and Cu (mg/kg), respectively: CTL = control, predominantly inorganic trace minerals (143–180–123); ORG = reduced levels using solely HMTBa trace minerals (50–60–15); and MIX = a blend of inorganic/HMTBa trace minerals (75/25–90/30–22.5/7.5). On average, ORG-fed hens were 1.3 and 1.1% heavier compared to CTL and MIX hens, respectively (P = 0.002). Overall (wk 25–65), hens fed the MIX diet had higher egg production (P < 0.001) and laid heavier eggs (P = 0.038) compared to hens fed the CTL or ORG diet. During the second half of lay, MIX-fed hens showed improved eggshell quality (P ≤ 0.037) and cuticle deposition (P = 0.019). Fertility and hatchability were unaffected by diet (P ≥ 0.205). Broilers hatched from young ORG hens (29 wk) had higher bone mineral density (P = 0.004) and after a 7-day grow-out (P = 0.047) when obtained from ORG hens of 41 wk of age. In conclusion, the industry levels provided by combining inorganic and HMTBa trace minerals in breeder hen diets were advantageous for sustaining high-quality settable egg production