Qualification Tests of 474 Photomultiplier Tubes for the Inner Detector of the Double Chooz Experiment

The hemispherical 10" photomultiplier tube (PMT) R7081 from Hamamatsu Photonics K.K. (HPK) is used in various experiments in particle and astroparticle physics. We describe the test and calibration of 474 PMTs for the reactor antineutrino experiment Double Chooz. The unique test setup at Max-Planck-Institut f\"ur Kernphysik Heidelberg (MPIK) allows one to calibrate 30 PMTs simultaneously and to characterize the single photo electron response, transit time spread, linear behaviour and saturation effects, photon detection efficiency and high voltage calibration

Qualification Tests of 474 Photomultiplier Tubes for the Inner Detector of the Double Chooz Experiment

The hemispherical 10" photomultiplier tube (PMT) R7081 from Hamamatsu Photonics K.K. (HPK) is used in various experiments in particle and astroparticle physics. We describe the test and calibration of 474 PMTs for the reactor antineutrino experiment Double Chooz. The unique test setup at Max-Planck-Institut f\"ur Kernphysik Heidelberg (MPIK) allows one to calibrate 30 PMTs simultaneously and to characterize the single photo electron response, transit time spread, linear behaviour and saturation effects, photon detection efficiency and high voltage calibration

Qualification Tests of 474 Photomultiplier Tubes for the Inner Detector of the Double Chooz Experiment

The hemispherical 10" photomultiplier tube (PMT) R7081 from Hamamatsu Photonics K.K. (HPK) is used in various experiments in particle and astroparticle physics. We describe the test and calibration of 474 PMTs for the reactor antineutrino experiment Double Chooz. The unique test setup at Max-Planck-Institut f\"ur Kernphysik Heidelberg (MPIK) allows one to calibrate 30 PMTs simultaneously and to characterize the single photo electron response, transit time spread, linear behaviour and saturation effects, photon detection efficiency and high voltage calibration

Synergistic effects of targeted PI3K signaling inhibition and chemotherapy in liposarcoma.

While liposarcoma is the second most common soft tissue malignant tumor, the molecular pathogenesis in this malignancy is poorly understood. Our goal was therefore to expand the understanding of molecular mechanisms that drive liposarcoma and identify therapeutically-susceptible genetic alterations. We studied a cohort of high-grade liposarcomas and benign lipomas across multiple disease sites, as well as two liposarcoma cell lines, using multiplexed mutational analysis. Nucleic acids extracted from diagnostic patient tissue were simultaneously interrogated for 150 common mutations across 15 essential cancer genes using a clinically-validated platform for cancer genotyping. Western blot analysis was implemented to detect activation of downstream pathways. Liposarcoma cell lines were used to determine the effects of PI3K targeted drug treatment with or without chemotherapy. We identified mutations in the PIK3CA gene in 4 of 18 human liposarcoma patients (22%). No PIK3CA mutations were identified in benign lipomas. Western blot analysis confirmed downstream activation of AKT in both PIK3CA mutant and non-mutant liposarcoma samples. PI-103, a dual PI3K/mTOR inhibitor, effectively inhibited the activation of the PI3K/AKT in liposarcoma cell lines and induced apoptosis. Importantly, combination with PI-103 treatment strongly synergized the growth-inhibitory effects of the chemotherapy drugs doxorubicin and cisplatin in liposarcoma cells. Taken together, these findings suggest that activation of the PI3K/AKT pathway is an important cancer mechanism in liposarcoma. Targeting the PI3K/AKT/pathway with small molecule inhibitors in combination with chemotherapy could be exploited as a novel strategy in the treatment of liposarcoma

Capturing sleep-wake cycles by using day-to-day smartphone touchscreen interactions

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How large is the gap between present and efficient transport prices in Europe?

In this paper we analyse the gap between present transport prices and efficient transport prices. Efficient transport prices are those prices that maximise economic welfare, including external costs (congestion, air pollution, accidents). The methodology is applied to six urban and interregional case studies using one common optimal pricing model. The case studies cover passenger as well as freight transport and cover all modes. We find that prices need to be raised most for peak urban passenger car transport and to a lesser extent for interregional road transport. Optimal pricing results for public transport are more mixed. We show that current external costs on congested roads are a bad guide for optimal taxes and tolls: the optimal toll that takes into account the reaction of demand is often less than one third of the present marginal external cost.transport pricing; external costs; social costs; congestion pricing

Retinoic Acid Resistance at Late Stages of Human Papillomavirus Type 16-Mediated Transformation of Human Keratinocytes Arises Despite Intact Retinoid Signaling and Is Due to a Loss of Sensitivity to Transforming Growth Factor-β

AbstractIn our in vitro model of human cell carcinogenesis, normal human foreskin keratinocytes (HKc) transfected with human papillomavirus type 16 DNA (HKc/HPV16) progress toward malignancy through several phenotypically defined and reproducible “steps” that include immortalization, growth factor independence (HKc/GFI), differentiation resistance (HKc/DR), and ultimately malignant conversion. While HKc/HPV16 are very sensitive to growth inhibition by all-trans-retinoic acid (RA) at early passages, they lose their sensitivity to RA during progression in culture. However, gel mobility shift assays using the retinoid response elements DR1 and DR5 showed no changes in binding activity of nuclear extracts obtained from HKc/HPV16 at different stages of in vitro progression. Similarly, Western blot analyses for retinoic acid receptor γ-1 and the retinoid X receptors failed to reveal any decreases in the levels of these retinoid receptors throughout progression. In addition, luciferase activity driven by the SV40 promoter with a DR5 enhancer element was activated following RA treatment of HKc/DR that were resistant to growth inhibition by RA. Since RA induces transforming growth factor-β2 (TGF-β2) in normal HKc and HKc/HPV16, we investigated whether this response changed during progression. Again, RA induced TGF-β2 mRNA in early and late passage HKc/HPV16, HKc/GFI, and HKc/DR approximately to the same extent, confirming that the RA signaling pathways remained intact during in vitro progression despite the fact that the cells become resistant to growth inhibition by RA. We then investigated the sensitivity of HKc/HPV16 to growth inhibition by TGF-β. While early passage HKc/HPV16 were as sensitive as normal HKc to growth inhibition by TGF-β1 and TGF-β2, the cells became increasingly resistant to both TGF-β isotypes during in vitro progression. In addition, while both RA and TGF-β produced a decrease in the levels of mRNA for the HPV16 oncogenes E6 and E7 in early passage HKc/HPV16, this effect was also lost at later stages of progression. Finally, blocking anti-TGF-β antibodies partially prevented RA inhibition of growth and E6/E7 expression in early passage HKc/HPV16. Taken together, these data strongly suggest that inhibition of growth and HPV16 early gene expression in HKc/HPV16 by RA is mediated by TGF-β and that a loss of RA sensitivity is linked to TGF-β resistance rather than alterations in RA signaling

Epigenetic regulation of CD133 and tumorigenicity of CD133 positive and negative endometrial cancer cells

<p>Abstract</p> <p>Background</p> <p>Recent data provide significant evidence to support the hypothesis that there are sub-populations of cells within solid tumors that have an increased tumor initiating potential relative to the total tumor population. CD133, a cell surface marker expressed on primitive cells of neural, hematopoietic, endothelial and epithelial lineages has been identified as a marker for tumor initiating cells in solid tumors of the brain, colon, pancreas, ovary and endometrium. Our objectives were to assess the relative level of CD133 expressing cells in primary human endometrial tumors, confirm their tumorigenic potential, and determine whether CD133 expression was epigenetically modified.</p> <p>Methods</p> <p>We assessed CD133 expression in primary human endometrial tumors by flow cytometry and analyzed the relative tumorigenicity of CD133+ and CD133- cells in an <it>in vivo </it>NOD/SCID mouse model. We assessed potential changes in CD133 expression over the course of serial transplantation by immunofluorescence and flow cytometry. We further examined CD133 promoter methylation and expression in normal endometrium and malignant tumors.</p> <p>Results</p> <p>As determined by flow cytometric analysis, the percentage of CD133+ cells in primary human endometrial cancer samples ranged from 5.7% to 27.4%. In addition, we confirmed the tumor initiating potential of CD133+ and CD133^-cell fractions in NOD/SCID mice. Interestingly, the percentage of CD133+ cells in human endometrial tumor xenografts, as evidenced by immunofluorescence, increased with serial transplantation although this trend was not consistently detected by flow cytometry. We also determined that the relative levels of CD133 increased in endometrial cancer cell lines following treatment with 5-aza-2'-deoxycytidine suggesting a role for methylation in the regulation of CD133. To support this finding, we demonstrated that regions of the CD133 promoter were hypomethylated in malignant endometrial tissue relative to benign control endometrial tissue. Lastly, we determined that methylation of the CD133 promoter decreases over serial transplantation of an endometrial tumor xenograft.</p> <p>Conclusions</p> <p>These findings support the hypotheses that CD133 expression in endometrial cancer may be epigenetically regulated and that cell fractions enriched for CD133+ cells may well contribute to endometrial cancer tumorigenicity, pathology and recurrence.</p

Making sense of ultrahigh-resolution movement data: A new algorithm for inferring sites of interest

Decomposing the life track of an animal into behavioral segments is a fundamental challenge for movement ecology. The proliferation of high‐resolution data, often collected many times per second, offers much opportunity for understanding animal movement. However, the sheer size of modern data sets means there is an increasing need for rapid, novel computational techniques to make sense of these data. Most existing methods were designed with smaller data sets in mind and can thus be prohibitively slow. Here, we introduce a method for segmenting high‐resolution movement trajectories into sites of interest and transitions between these sites. This builds on a previous algorithm of Benhamou and Riotte‐Lambert (2012). Adapting it for use with high‐resolution data. The data’s resolution removed the need to interpolate between successive locations, allowing us to increase the algorithm’s speed by approximately two orders of magnitude with essentially no drop in accuracy. Furthermore, we incorporate a color scheme for testing the level of confidence in the algorithm's inference (high = green, medium = amber, low = red). We demonstrate the speed and accuracy of our algorithm with application to both simulated and real data (Alpine cattle at 1 Hz resolution). On simulated data, our algorithm correctly identified the sites of interest for 99% of “high confidence” paths. For the cattle data, the algorithm identified the two known sites of interest: a watering hole and a milking station. It also identified several other sites which can be related to hypothesized environmental drivers (e.g., food). Our algorithm gives an efficient method for turning a long, high‐resolution movement path into a schematic representation of broadscale decisions, allowing a direct link to existing point‐to‐point analysis techniques such as optimal foraging theory. It is encoded into an R package called SitesInterest, so should serve as a valuable tool for making sense of these increasingly large data streams