Large-scale Multi-item Auctions : Evidence from Multimedia-supported Experiments

This book presents two experimental studies that deal with the comparison of multi-item auction designs for two specific applications: the sale of 2.6 GHz radio spectrum rights in Europe, and the sale of emissions permits in Australia. In order to tackle the complexity of these experiments, a cognitively based toolkit is proposed, including modularized video instructions, comprehension tests, a learning platform, a graphical one-screen user interface, and comprehension-based group matching

Paid Peering and Content Delivery

Recent conflicts between big content and service providers (CSPs) like Netflix, transit providers (TPs), and Internet service providers (ISPs) have generated considerate media attention and ignited a debate on interconnection agreements, market power of last-mile ISPs and net neutrality. We propose an experimental design to analyze a stylized interconnection market that captures key aspects of actual interconnection markets with a focus on the entry of big CSPs. Participants are invited to assume the roles of ISPs, TPs and CSPs in a computer-aided laboratory experiment. The experiment serves to evaluate potential regulatory tools like transparency and interconnection obligation with respect to the efficiency of the overall interconnection market. Furthermore, we present results of a pre-test of the experimental design and the software implementation. Our preliminary results indicate that operators underinvest into network infrastructure and do not realize the full potential of mutual peering agreements when a CSP participates in the market

Dark-adapted versus bleached state in fluorescence lifetime imaging ophthalmoscopy

Purpose: The (early) detection of diseases based on metabolic changes in the retina is the goal of the novel autofluorescence lifetime ophthalmoscopy (FLIO) technique. These metabolic changes can be detected as alterations in the fundus autofluorescence (FAF) lifetimes. The influences of the photopigment bleaching and photobleaching on the FAF lifetimes are unknown. Thus, we performed a volunteer study to investigate these influences. Methods: In 21 healthy volunteers (23.6±3.8 years) time-resolved FAF was measured with a FLIO device (30° of fundus, excitation at 473nm, detection in two spectral channels: 500-560nm (ch1) and 560-720nm (ch2), time-correlated single photon counting method). All subjects had a crystalline lens. The pupil was dilated with 0.5% Tropicamid. After volunteers adapted to the dark using a custom-made lightproof eyewear over a period of 30 min, the first FLIO measurement was recorded (dark-adapted state). Subsequently, one eye was bleached for 1 min using a luminance of 3200cd/m2, followed by a FLIO measurement (bleached state). The fluorescence lifetimes were estimated from the FAF decays, based on three exponential functions, using the software FLIMX (www.flimx.de). Average values from the central region, and the inner and outer rings of the ETDRS grid were utilized to compare both bleaching states using analysis of variance, Friedman, and post hoc tests. Results : Only ch2 yielded significant changes (p<0.05) for the fluorescence lifetime τ2 from all ETDRS regions (+19-28ps), for the fluorescence lifetime τ1 (+6ps) and the mean fluorescence lifetime (+6ps) in the central area that were less than 10% in magnitude. Additionally, the acquisition time in the bleached state was significantly reduced by approximately 20% on average, compared to the dark-adapted state. The fluorescence lifetime differences caused by bleaching were much smaller than pathological states known from literature. Conclusions: We conclude that bleaching is not relevant for current clinical FLIO applications because of the small magnitude of the elicited fluorescence lifetime changes. Thus, it is advisable to instruct patients to wait in a bright room before FLIO measurements. If the expected changes in the fluorescence lifetime in a specific experimental paradigm are small, FLIO users should follow a strict acquisition protocol in terms of the photopigment bleaching state of the patients to obtain the most reliable results

APP dimer formation is initiated in the endoplasmic reticulum and differs between APP isoforms

The amyloid precursor protein (APP) is part of a larger gene family, which has been found to form homo- or heterotypic complexes with its homologues, whereby the exact molecular mechanism and origin of dimer formation remains elusive. In order to assess the cellular location of dimerization, we have generated a cell culture model system in CHO-K1 cells, stably expressing human APP, harboring dilysine-based organelle sorting motifs [KKAA-endoplasmic reticulum (ER); KKFF-Golgi], accomplishing retention within early secretory compartments. We show that APP exists as disulfide-bonded dimers upon ER retention after it was isolated from cells, and analyzed by SDS-polyacrylamide gel electrophoresis under non-reducing conditions. In contrast, strong denaturing and reducing conditions, or deletion of the E1 domain, resulted in the disappearance of those dimers. Thus we provide first evidence that a fraction of APP can associate via intermolecular disulfide bonds, likely generated between cysteines located in the extracellular E1 domain. We particularly visualize APP dimerization itself and identified the ER as subcellular compartment of its origin using biochemical or split GFP approaches. Interestingly, we also found that minor amounts of SDS-resistant APP dimers were located to the cell surface, revealing that once generated in the oxidative environment of the ER, dimers remained stably associated during transport. In addition, we show that APP isoforms encompassing the Kunitz-type protease inhibitor (KPI) domain exhibit a strongly reduced ability to form cis-directed dimers in the ER, whereas trans-mediated cell aggregation of Drosophila Schneider S2-cells was isoform independent. Thus, suggesting that steric properties of KPI-APP might be the cause for weaker cis-interaction in the ER, compared to APP695. Finally, we provide evidence that APP/APLP1 heterointeractions are likewise initiated in the ER

Bleaching effects and fluorescence lifetime imaging ophthalmoscopy

This study investigates the influence of photopigment bleaching on autofluorescence lifetimes in the fundus in 21 young healthy volunteers. Three measurements of 30° retinal fields in two spectral channels (SSC: 498–560 nm, LSC: 560–720 nm) were obtained for each volunteer using fluorescence lifetime imaging ophthalmoscopy (FLIO). After dark-adaptation by wearing a custom-made lightproof mask for 30 minutes, the first FLIO-measurement was recorded (dark-adapted state). Subsequently, the eye was bleached for 1 minute (luminance: 3200 cd/m2), followed by a second FLIO-measurement (bleached state). Following an additional 10 minute dark adaptation using the mask, a final FLIO-measurement was recorded (recovered state). Average values of the fluorescence lifetimes were calculated from within different areas of a standardized early treatment diabetic retinopathy study (ETDRS) grid (central area, inner and outer rings). The acquisition time in the bleached state was significantly shortened by approximately 20%. The SSC did not show any significant changes in fluorescence lifetimes with photopigment bleaching, only the LSC showed small but significant bleaching-related changes in the fluorescence lifetimes τ1 and τ2 from all regions, as well as the mean fluorescence lifetime in the central area. The fluorescence lifetime differences caused by bleaching were by far less significant than pathological changes caused by eye diseases. The magnitudes of fluorescence lifetime changes are <10% and do not interfere with healthy or disease related FLIO patterns. Thus, we conclude that bleaching is not a relevant confounder in current clinical applications of FLIO

Clathrin- and Dynamin-Independent Endocytosis of FGFR3 – Implications for Signalling

Endocytosis of tyrosine kinase receptors can influence both the duration and the specificity of the signal emitted. We have investigated the mechanisms of internalization of fibroblast growth factor receptor 3 (FGFR3) and compared it to that of FGFR1 which is internalized predominantly through clathrin-mediated endocytosis. Interestingly, we observed that FGFR3 was internalized at a slower rate than FGFR1 indicating that it may use a different endocytic mechanism than FGFR1. Indeed, after depletion of cells for clathrin, internalization of FGFR3 was only partly inhibited while endocytosis of FGFR1 was almost completely abolished. Similarly, expression of dominant negative mutants of dynamin resulted in partial inhibition of the endocytosis of FGFR3 whereas internalization of FGFR1 was blocked. Interfering with proposed regulators of clathrin-independent endocytosis such as Arf6, flotillin 1 and 2 and Cdc42 did not affect the endocytosis of FGFR1 or FGFR3. Furthermore, depletion of clathrin decreased the degradation of FGFR1 resulting in sustained signalling. In the case of FGFR3, both the degradation and the signalling were only slightly affected by clathrin depletion. The data indicate that clathrin-mediated endocytosis is required for efficient internalization and downregulation of FGFR1 while FGFR3, however, is internalized by both clathrin-dependent and clathrin-independent mechanisms

The Combined Dexamethasone/CRH Test (DEX/CRH Test) and Prediction of Acute Treatment Response in Major Depression

In this study the predictive value of the combined dexamethasone/CRH test (DEX/CRH test) for acute antidepressant response was investigated. In 114 depressed inpatients suffering from unipolar or bipolar depression (sample 1) the DEX/CRH test was performed at admission and shortly before discharge. During their stay in the hospital patients received different antidepressant treatment regimens. At admission, the rate of nonsuppression (basal cortisol levels >75.3 nmol/l) was 24.6% and was not related to the later therapeutic response. Moreover, 45 out of 114 (39.5%) patients showed an enhancement of HPA axis function at discharge in spite of clinical improvement. In a second sample, 40 depressed patients were treated either with reboxetine or mirtazapine for 5 weeks. The DEX/CRH test was performed before, after 1 week, and after 5 weeks of pharmacotherapy. Attenuation of HPA axis activity after 1 week was associated with a more pronounced alleviation of depressive symptoms after 5-week mirtazapine treatment, whereas downregulation of HPA system activity after 5 weeks was related to clinical response to reboxetine. However, early improvement of HPA axis dysregulation was not necessarily followed by a beneficial treatment outcome. Taken together, performance of a single DEX/CRH test does not predict the therapeutic response. The best predictor for response seems to be an early attenuation of HPA axis activity within 1 or 2 weeks. However, early improvement of HPA system dysfunction is not a sufficient condition for a favourable response. Since a substantial part of depressive patients display a persistence of HPA axis hyperactivity at discharge, downregulation of HPA system function is not a necessary condition for acute clinical improvement either. Our data underline the importance of HPA axis dysregulation for treatment outcome in major depression, although restoration of HPA system dysfunction seems to be neither a necessary nor a sufficient determinant for acute treatment response

Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future

Purpose Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. Design Meta-analysis of prevalence data. Participants A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe. Methods AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). Main Outcome Measures Prevalence of early and late AMD, BCVA, and number of AMD cases. Results Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%–5.0%) in those aged 55–59 years to 17.6% (95%