A semiparametric approach for item response function estimation to detect item misfit

When scaling data using item response theory, valid statements based on the measurement model are only permissible if the model fits the data. Most item fit statistics used to assess the fit between observed item responses and the item responses predicted by the measurement model show significant weaknesses, such as the dependence of fit statistics on sample size and number of items. In order to assess the size of misfit and to thus use the fit statistic as an effect size, dependencies on properties of the data set are undesirable. The present study describes a new approach and empirically tests it for consistency. We developed an estimator of the distance between the predicted item response functions (IRFs) and the true IRFs by semiparametric adaptation of IRFs. For the semiparametric adaptation, the approach of extended basis functions due to Ramsay and Silverman (2005) is used. The IRF is defined as the sum of a linear term and a more flexible term constructed via basis function expansions. The group lasso method is applied as a regularization of the flexible term, and determines whether all parameters of the basis functions are fixed at zero or freely estimated. Thus, the method serves as a selection criterion for items that should be adjusted semiparametrically. The distance between the predicted and semiparametrically adjusted IRF of misfitting items can then be determined by describing the fitting items by the parametric form of the IRF and the misfitting items by the semiparametric approach. In a simulation study, we demonstrated that the proposed method delivers satisfactory results in large samples (i.e., N ≥ 1,000). (DIPF/Orig.

Consulting Project 2018/19: Manufacturing process of superconducting magnets: Analysis of manufacturing chain technologies for market-oriented industries. Report

An international consortium of more than 150 organisations worldwide is studying the feasibility of future particle collider scenarios to expand our understanding of the inner workings of the Universe. The core of this Future Circular Collider (FCC) study, hosted by CERN, an international organisation near Geneva (Switzerland), is a 100 km long circular particle collider infrastructure that extends CERN's current accelerator complex. As a first step, an intensity frontier electron-positron collider is assumed. The ultimate goal is to build a proton collider with an energy seven times larger than the Large Hadron Collider (LHC). Such a machine has to be built with novel superconductive magnet technology. Since it takes decades for such technology to reach industrial maturity levels, R&D has already started. The superconducting magnet system is considered the major cost driver for construction of such a proton collider. A good cost-benefit balance for industrial suppliers is considered an important factor for the funding of such a project. Aim The aim of this investigation was to identify the industrial impact potentials of the key processes needed for the manufacturing of novel high-field superconducting magnets and to find innovative additional applications for these technologies outside the particle-accelerator domain. Suppliers and manufacturing partners of CERN would benefit if the know-how could be used for other markets and to improve their internal efficiency and competitivity on the world-market. Eventually, being more cost-effective in the manufacturing and being able to leverage further markets on a long-time scale will also reduce the cost for each step in the manufacturing chain and ultimately lead to lower costs for the superconducting magnet system of a future high-energy particle collider. Method The project is carried out by means of the Technology Competence Leveraging method, which has been pioneered by the Vienna University of economics and business in Austria. It aims to find new application fields for the three most promising technologies required to manufacture novel high-field superconducting magnets. This is achieved by gathering information from user-communities, conducting interviews with experts in different industries and brainstorming for new out-of-the-box ideas. The most valuable application fields were evaluated according to their Benefit Relevance and Strategic Fit. During the process, 71 interviews with experts have been carried out, through which 38 new application fields were found with credible impacts beyond particle accelerator projects. They relate to manufacturing "superconducting Rutherford cables" (15), "thermal treatment" (10) and "vacuum impregnation with novel epoxy" (13). Superconducting magnet manufacturing technologies for market-oriented industries Report. Results: A short description of all application fields that were classified as "high potential" can be found here: Superconducting Rutherford cable * Aircraft charging: Commercial airplanes only spend around 45 minutes on the ground at a time to load and unload passengers. For future electric aircraft this time window would be to small to charge using conventional cables. The superconducting Rutherford cable could charge an electric plane fast and efficiently. * Electricity distribution in hybrid-electric aircraft: On a shorter time scale, hybrid-electric aircraft is an appealing ecological technology with economic advantages. In this case, electricity for the electric engines is produced by a generator. Cables with high current densities are needed inside the aircraft to distribute the energy. The superconducting Rutherford cable could be a candidate for this task. * Compact and efficient electricity generators: Using the superconducting Rutherford cable, small and light engines and generators can be constructed. One end-use example is for instance the generation of electricity using highly-efficient wind turbines. Thermal treatment: Heat treatment is needed during the production of superconducting magnet coils. In this processing step, the raw materials are reacted to form the superconductor. This processing step is used for certain lowtemperature superconductors as well as for certain high-temperature superconductors. * Scrap metal recycling: Using a large-scale oven with very accurate temperature stabilisation over long time periods, melting points of different metals can be selected. This leads to more efficient recycling of scrap metal. It also permits a higher degrees of process automation and quality management. * Thermal treatment of aluminium: Thermal treatment of aluminium comprises technologies like tempering and hardening. The goal of this technique is to change the characteristics of aluminium and alloys containing aluminium. End-use applications include for instance the automotive and aerospace industry, where such exact treatment is necessary. Vacuum impregnation * Waste treatmnent companies currently face challenges because new legislation require more leak-tight containers. Novel epoxy resin developed for superconducting magnets in particle colliders also needs to withstand high radiation levels. Therefore, this technology can be useful in the process of managing highly-activated radioactive waste

Environmental heterogeneity predicts global species richness patterns better than area

Aim It is widely accepted that biodiversity is influenced by both niche‐related and spatial processes from local to global scales. Their relative importance, however, is still disputed, and empirical tests are surprisingly scarce at the global scale. Here, we compare the importance of area (as a proxy for pure spatial processes) and environmental heterogeneity (as a proxy for niche‐related processes) for predicting native mammal species richness world‐wide and within biogeographical regions. Location Global. Time period We analyse a spatial snapshot of richness data collated by the International Union for Conservation of Nature. Major taxa studied All terrestrial mammal species, including possibly extinct species and species with uncertain presence. Methods We applied a spreading dye algorithm to analyse how native mammal species richness changes with area and environmental heterogeneity. As measures for environmental heterogeneity, we used elevation ranges and precipitation ranges, which are well‐known correlates of species richness. Results We found that environmental heterogeneity explained species richness relationships better than did area, suggesting that niche‐related processes are more prevalent than pure area effects at broad scales. Main conclusions Our results imply that niche‐related processes are essential to understand broad‐scale species–area relationships and that habitat diversity is more important than area alone for the protection of global biodiversity

Tyrosine 192 within the SH2 domain of the Src-protein tyrosine kinase p56Lck regulates T-cell activation independently of Lck/CD45 interactions.

Funder: DFGFunder: Projekt DEALBACKGROUND: Upon engagement of the T-cell receptor (TCR), the Src-family protein tyrosine kinase p56Lck phosphorylates components of the TCR (e.g. the TCRζ chains), thereby initiating T-cell activation. The enzymatic activity of Lck is primarily regulated via reversible and dynamic phosphorylation of two tyrosine residues, Y394 and Y505. Lck possesses an additional highly conserved tyrosine Y192, located within the SH2 domain, whose role in T-cell activation is not fully understood. METHODS: Knock-in mice expressing a phospho-mimetic (Y192E) form of Lck were generated. Cellular and biochemical characterization was performed to elucidate the function of Y192 in primary T cells. HEK 293T and Jurkat T cells were used for in vitro studies. RESULTS: Co-immunoprecipitation studies and biochemical analyses using T cells from LckY192E knock-in mice revealed a diminished binding of LckY192E to CD45 and a concomitant hyperphosphorylation of Y505, thus corroborating previous data obtained in Jurkat T cells. Surprisingly however, in vitro kinase assays showed that LckY192E possesses a normal enzymatic activity in human and murine T cells. FLIM/FRET measurements employing an LckY192E biosensor further indicated that the steady state conformation of the LckY192E mutant is similar to Lckwt. These data suggest that Y192 might regulate Lck functions also independently from the Lck/CD45-association. Indeed, when LckY192E was expressed in CD45-/-/Csk-/- non-T cells (HEK 293T cells), phosphorylation of Y505 was similar to Lckwt, but LckY192E still failed to optimally phosphorylate and activate the Lck downstream substrate ZAP70. Furthermore, LckY19E was recruited less to CD3 after TCR stimulation. CONCLUSIONS: Taken together, phosphorylation of Y192 regulates Lck functions in T cells at least twofold, by preventing Lck association to CD45 and by modulating ligand-induced recruitment of Lck to the TCR. MAJOR FINDINGS: Our data change the current view on the function of Y192 and suggest that Y192 also regulates Lck activity in a manner independent of Y505 phosphorylation. Video Abstract

Tyrosine 192 within the SH2 domain of the Src-protein tyrosine kinase p56 Lck regulates T-cell activation independently of Lck/CD45 interactions

Funder: DFGFunder: Projekt DEALAbstract: Background: Upon engagement of the T-cell receptor (TCR), the Src-family protein tyrosine kinase p56Lck phosphorylates components of the TCR (e.g. the TCRζ chains), thereby initiating T-cell activation. The enzymatic activity of Lck is primarily regulated via reversible and dynamic phosphorylation of two tyrosine residues, Y394 and Y505. Lck possesses an additional highly conserved tyrosine Y192, located within the SH2 domain, whose role in T-cell activation is not fully understood. Methods: Knock-in mice expressing a phospho-mimetic (Y192E) form of Lck were generated. Cellular and biochemical characterization was performed to elucidate the function of Y192 in primary T cells. HEK 293T and Jurkat T cells were used for in vitro studies. Results: Co-immunoprecipitation studies and biochemical analyses using T cells from LckY192E knock-in mice revealed a diminished binding of LckY192E to CD45 and a concomitant hyperphosphorylation of Y505, thus corroborating previous data obtained in Jurkat T cells. Surprisingly however, in vitro kinase assays showed that LckY192E possesses a normal enzymatic activity in human and murine T cells. FLIM/FRET measurements employing an LckY192E biosensor further indicated that the steady state conformation of the LckY192E mutant is similar to Lckwt. These data suggest that Y192 might regulate Lck functions also independently from the Lck/CD45-association. Indeed, when LckY192E was expressed in CD45−/−/Csk−/− non-T cells (HEK 293T cells), phosphorylation of Y505 was similar to Lckwt, but LckY192E still failed to optimally phosphorylate and activate the Lck downstream substrate ZAP70. Furthermore, LckY19E was recruited less to CD3 after TCR stimulation. Conclusions: Taken together, phosphorylation of Y192 regulates Lck functions in T cells at least twofold, by preventing Lck association to CD45 and by modulating ligand-induced recruitment of Lck to the TCR. Major findings: Our data change the current view on the function of Y192 and suggest that Y192 also regulates Lck activity in a manner independent of Y505 phosphorylation. FN7ZF7ULbDVsMsT6Sckwh1Video Abstrac

The PROFOUND Database for evaluating vegetation models and simulating climate impacts on European forests

Process-based vegetation models are widely used to predict local and global ecosystem dynamics and climate change impacts. Due to their complexity, they require careful parameterization and evaluation to ensure that projections are accurate and reliable. The PROFOUND Database (PROFOUND DB) provides a wide range of empirical data on European forests to calibrate and evaluate vegetation models that simulate climate impacts at the forest stand scale. A particular advantage of this database is its wide coverage of multiple data sources at different hierarchical and temporal scales, together with environmental driving data as well as the latest climate scenarios. Specifically, the PROFOUND DB provides general site descriptions, soil, climate, CO2, nitrogen deposition, tree and forest stand level, and remote sensing data for nine contrasting forest stands distributed across Europe. Moreover, for a subset of five sites, time series of carbon fluxes, atmospheric heat conduction and soil water are also available. The climate and nitrogen deposition data contain several datasets for the historic period and a wide range of future climate change scenarios following the Representative Concentration Pathways (RCP2.6, RCP4.5, RCP6.0, RCP8.5). We also provide pre-industrial climate simulations that allow for model runs aimed at disentangling the contribution of climate change to observed forest productivity changes. The PROFOUND DB is available freely as a "SQLite" relational database or "ASCII" flat file version (at https://doi.org/10.5880/PIK.2020.006/; Reyer et al., 2020). The data policies of the individual contributing datasets are provided in the metadata of each data file. The PROFOUND DB can also be accessed via the ProfoundData R package (https://CRAN.R- project.org/package=ProfoundData; Silveyra Gonzalez et al., 2020), which provides basic functions to explore, plot and extract the data for model set-up, calibration and evaluation.Peer reviewe

Signaling Signatures and Functional Properties of Anti-Human CD28 Superagonistic Antibodies

Superagonistic CD28 antibodies (CD28SAs) activate T lymphocytes without concomitant perturbation of the TCR/CD3-complex. In rodents these reagents induce the preferential expansion of regulatory T cells and can be used for the treatment of autoimmune diseases. Unexpectedly, the humanized CD28 superagonist TGN1412 caused severe and life threatening adverse effects during a recently conducted phase I clinical trail. The underlying molecular mechanisms are as yet unclear. We show that TGN1412 as well as the commercially available CD28 superagonist ANC28.1 induce a delayed but extremely sustained calcium response in human naïve and memory CD4+ T cells but not in cynomolgus T lymphocytes. The sustained Ca++-signal was associated with the activation of multiple intracellular signaling pathways and together these events culminated in the rapid de novo synthesis of high amounts of pro-inflammatory cytokines, most notably IFN-γ and TNF-α. Importantly, sustained transmembranous calcium flux, activation of Src-kinases as well as activation of PI3K were found to be absolutely required for CD28SA-mediated production of IFN-γ and IL-2. Collectively, our data suggest a molecular basis for the severe side effects caused by TGN1412 and impinge upon the relevance of non-human primates as preclinical models for reagents that are supposed to modify the function of human T cells

Coulomb dissociation of O-16 into He-4 and C-12

We measured the Coulomb dissociation of O-16 into He-4 and C-12 within the FAIR Phase-0 program at GSI Helmholtzzentrum fur Schwerionenforschung Darmstadt, Germany. From this we will extract the photon dissociation cross section O-16(alpha,gamma)C-12, which is the time reversed reaction to C-12(alpha,gamma)O-16. With this indirect method, we aim to improve on the accuracy of the experimental data at lower energies than measured so far. The expected low cross section for the Coulomb dissociation reaction and close magnetic rigidity of beam and fragments demand a high precision measurement. Hence, new detector systems were built and radical changes to the (RB)-B-3 setup were necessary to cope with the high-intensity O-16 beam. All tracking detectors were designed to let the unreacted O-16 ions pass, while detecting the C-12 and He-4