The PTW microSilicon diode: Performance in small 6 and 15 MV photon fields and utility of density compensation

PURPOSE: We have experimentally and computationally characterized the PTW microSilicon 60023-type diode's performance in 6 and 15 MV photon fields ≥5 × 5 mm2 projected to isocenter. We tested the detector on- and off-axis at 5 and 15 cm depths in water, and investigated whether its response could be improved by including within it a thin airgap. METHODS: Experimentally, detector readings were taken in fields generated by a Varian TrueBeam linac and compared with doses-to-water measured using Gafchromic film and ionization chambers. An unmodified 60023-type diode was tested along with detectors modified to include 0.6, 0.8, and 1.0 mm thick airgaps. Computationally, doses absorbed by water and detectors’ sensitive volumes were calculated using the EGSnrc/BEAMnrc Monte Carlo radiation transport code. Detector response was characterized using K^{fdin, 4cm}_{Qclin, 4cm}, a factor that corrects for differences in the ratio of dose-to-water to detector reading between small fields and the reference condition, in this study 5 cm deep on-axis in a 4 × 4 cm2 field. RESULTS: The greatest errors in measurements of small field doses made using uncorrected readings from the unmodified 60023-type detector were over-responses of 2.6% ± 0.5% and 5.3% ± 2.0% determined computationally and experimentally, relative to the reading-per-dose in the reference field. Corresponding largest errors for the earlier 60017-type detector were 11.9% ± 0.6% and 11.7% ± 1.4% over-responses. Adding even the thinnest, 0.6 mm, airgap to the 60023-type detector over-corrected it, leading to under-responses of up to 4.8% ± 0.6% and 5.0% ± 1.8% determined computationally and experimentally. Further, Monte Carlo calculations indicate that a detector with a 0.3 mm airgap would read correctly to within 1.3% on-axis. The ratio of doses at 15 and 5 cm depths in water in a 6 MV 4 × 4 cm2 field was measured more accurately using the unmodified 60023-type detector than using the 60017-type detector, and was within 0.3% of the ratio measured using an ion chamber. The 60023-type diode's sensitivity also varied negligibly as dose-rate was reduced from 13 to 4 Gy min–1 by decreasing the linac pulse repetition frequency, whereas the sensitivity of the 60017-type detector fell by 1.5%. CONCLUSIONS: The 60023-type detector performed well in small fields across a wide range of beam energies, field sizes, depths, and off-axis positions. Its response can potentially be further improved by adding a thin, 0.3 mm, airgap

Binary Population Synthesis: Methods, Normalization, and Surprises

In this paper we present a brief overview of population synthesis methods with a discussion of their main advantages and disadvantages. In the second part, we present some recent results from synthesis models of close binary compact objects with emphasis on the predicted rates, their uncertainties, and the model input parameters the rates are most sensitive to. We also report on a new evolutionary path leading to the formation of close double neutron stars (NS), with the unique characteristic that none of the two NS ever had the chance to be recycled by accretion. Their formation rates turn out to be comparable to or maybe even higher than those of recycled NS-NS binaries (like the ones observed), but their detection probability as binary pulsars is much smaller because of their short lifetimes. We discuss the implications of such a population for gravitational-wave detection of NS-NS inspiral events, and possibly for gamma-ray bursts and their host galaxies.Comment: 15 pages, 1 figure, to appear in the proceedings ``The influence of binaries on stellar population studies'', Brussels, August 2000 (Kluwer Academic Publishers), ed. D.Vanbevere

Partitioning the Proteome: Phase Separation for Targeted Analysis of Membrane Proteins in Human Post-Mortem Brain

Neuroproteomics is a powerful platform for targeted and hypothesis driven research, providing comprehensive insights into cellular and sub-cellular disease states, Gene × Environmental effects, and cellular response to medication effects in human, animal, and cell culture models. Analysis of sub-proteomes is becoming increasingly important in clinical proteomics, enriching for otherwise undetectable proteins that are possible markers for disease. Membrane proteins are one such sub-proteome class that merit in-depth targeted analysis, particularly in psychiatric disorders. As membrane proteins are notoriously difficult to analyse using traditional proteomics methods, we evaluate a paradigm to enrich for and study membrane proteins from human post-mortem brain tissue. This is the first study to extensively characterise the integral trans-membrane spanning proteins present in human brain. Using Triton X-114 phase separation and LC-MS/MS analysis, we enriched for and identified 494 membrane proteins, with 194 trans-membrane helices present, ranging from 1 to 21 helices per protein. Isolated proteins included glutamate receptors, G proteins, voltage gated and calcium channels, synaptic proteins, and myelin proteins, all of which warrant quantitative proteomic investigation in psychiatric and neurological disorders. Overall, our sub-proteome analysis reduced sample complexity and enriched for integral membrane proteins by 2.3 fold, thus allowing for more manageable, reproducible, and targeted proteomics in case vs. control biomarker studies. This study provides a valuable reference for future neuroproteomic investigations of membrane proteins, and validates the use Triton X-114 detergent phase extraction on human post mortem brain

The Gaia-ESO survey: Matching chemodynamical simulations to observations of the Milky Way

The typical methodology for comparing simulated galaxies with observational surveys is usually to apply a spatial selection to the simulation to mimic the region of interest covered by a comparable observational survey sample. In this work we compare this approach with a more sophisticated post-processing in which the observational uncertainties and selection effects (photometric, surface gravity and effective temperature) are taken into account. We compare a `solar neighbourhood analogue' region in a model Milky Way-like galaxy simulated with RAMSES-CH with fourth release Gaia-ESO survey data. We find that a simple spatial cut alone is insufficient and that observational uncertainties must be accounted for in the comparison. This is particularly true when the scale of uncertainty is large compared to the dynamic range of the data, e.g. in our comparison, the [Mg/Fe] distribution is affected much more than the more accurately determined [Fe/H] distribution. Despite clear differences in the underlying distributions of elemental abundances between simulation and observation, incorporating scatter to our simulation results to mimic observational uncertainty produces reasonable agreement. The quite complete nature of the Gaia-ESO survey means that the selection function has minimal impact on the distribution of observed age and metal abundances but this would become increasingly more important for surveys with narrower selection functions

Public health and economic impact of vaccination with 7-valent pneumococcal vaccine (PCV7) in the context of the annual influenza epidemic and a severe influenza pandemic

Background: Influenza pandemic outbreaks occurred in the US in 1918, 1957, and 1968. Historical evidence suggests that the majority of influenza-related deaths during the 1918 US pandemic were attributable to bacterial pneumococcal infections. The 2009 novel influenza A (H1N1) outbreak highlights the importance of interventions that may mitigate the impact of a pandemic. Methods: A decision-analytic model was constructed to evaluate the impact of 7-valent pneumococcal conjugate vaccine (PCV7) on pneumococcal disease incidence and mortality during a typical influenza season (13/100) and a severe influenza pandemic (30/100). Outcomes were compared for current PCV7 vaccination practices vs. no vaccination. The model was estimated using published sources and includes indirect (herd) protection of non-vaccinated persons. Results: The model predicts that PCV7 vaccination in the US is cost saving for a normal influenza season, reducing pneumococcal-related costs by $1.6 billion. In a severe influenza pandemic, vaccination would save$7.3 billion in costs and prevent 512,000 cases of IPD, 719,000 cases of pneumonia, 62,000 IPD deaths, and 47,000 pneumonia deaths; 84% of deaths are prevented due to indirect (herd) protection in the unvaccinated. Conclusions: PCV7 vaccination is highly effective and cost saving in both normal and severe pandemic influenza seasons. Current infant vaccination practices may prevent >1 million pneumococcal-related deaths in a severe influenza pandemic, primarily due to herd protection

Oligosaccharyltransferase Inhibition Induces Senescence in RTK-Driven Tumor Cells

Asparagine (N)-linked glycosylation is a protein modification critical for glycoprotein folding, stability, and cellular localization. To identify small molecules that inhibit new targets in this biosynthetic pathway, we initiated a cell-based high throughput screen and lead compound optimization campaign that delivered a cell permeable inhibitor (NGI-1). NGI-1 targets the oligosaccharyltransferase (OST), a hetero-oligomeric enzyme that exists in multiple isoforms and transfers oligosaccharides to recipient proteins. In non-small cell lung cancer cells NGI-1 blocks cell surface localization and signaling of the EGFR glycoprotein, but selectively arrests proliferation in only those cell lines that are dependent on EGFR (or FGFR) for survival. In these cell lines OST inhibition causes cell cycle arrest accompanied by induction of p21, autofluorescence, and changes in cell morphology; all hallmarks of senescence. These results identify OST inhibition as a potential therapeutic approach for treating receptor tyrosine kinase-dependent tumors and provides a chemical probe for reversibly regulating N-linked glycosylation in mammalian cells

Vinculin controls talin engagement with the actomyosin machinery

The link between extracellular-matrix-bound integrins and intracellular F-actin is essential for cell spreading and migration. Here, we demonstrate how the actin-binding proteins talin and vinculin cooperate to provide this link. By expressing structure-based talin mutants in talin null cells, we show that while the C-terminal actin-binding site (ABS3) in talin is required for adhesion complex assembly, the central ABS2 is essential for focal adhesion (FA) maturation. Thus, although ABS2 mutants support cell spreading, the cells lack FAs, fail to polarize and exert reduced force on the surrounding matrix. ABS2 is inhibited by the preceding mechanosensitive vinculin-binding R3 domain, and deletion of R2R3 or expression of constitutively active vinculin generates stable force-independent FAs, although cell polarity is compromised. Our data suggest a model whereby force acting on integrin-talin complexes via ABS3 promotes R3 unfolding and vinculin binding, activating ABS2 and locking talin into an actin-binding configuration that stabilizes FAs