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In this study, we report the isomerization of an aspartic acid residue in the complementarity-determining region (CDR) of crizanlizumab as a major degradation pathway. The succinimide intermediate and iso-aspartic acid degradation products were successfully isolated by ion exchange chromatography for characterization. The isomerization site was identified at a DG motif in the CDR by peptide mapping. The biological characterization of the isolated variants showed that the succinimide variant exhibited a loss in target binding and biological activity compared to the aspartic acid and iso-aspartic acid variants of the molecule. The influence of pH on this isomerization reaction was investigated using capillary zone electrophoresis. Below pH 6.3, the succinimide formation was predominant, whereas at pH values above 6.3, iso-aspartic acid was formed and the initial amounts of succinimide dropped to levels even lower than those observed in the starting material. Importantly, while the succinimide accumulated at long-term storage conditions of 2 to 8°C at pH values below 6.3, a complete hydrolysis of succinimide was observed at physiological conditions (pH 7.4, 37°C), resulting in full recovery of the biological activity. In this study, we demonstrate that the critical quality attribute succinimide with reduced potency has little or no impact on the efficacy of crizanlizumab due to the full recovery of the biological activity within a few hours under physiological conditions.

Although Augmented Reality (AR) encourages self-managed learning and enhances the learner’s reflection only few companies and schools use AR glasses in vocational training. In our research project we aim to support the dissemination of AR and speed up the augmentation of existing learning processes. But we did not come across methodologies for transferring a conventional learning processes into learning processes for AR Glasses. Therefore, we developed a methodology to enhance conventional learning processes with AR glasses by supporting the creation of AR enrichments for the individual process steps. We describe a use case of an electro engineering lesson that is enriched with AR elements using our methodology.

The interparticle Coulombic decay is a synchronized decay and ionization phenomenon occurring on two separated and only Coulomb interaction coupled electron binding sites. This publication explores how drastically small environmental changes in between the two sites, basically impurities, can alter the ionization properties and process rate, although the involved electronic transitions remain unaltered. A comparison among the present electron dynamics calculations for the example of different types of quantum dots, accommodating a one- or a two-dimensional continuum for the outgoing electron, and the well-investigated atomic and molecular cases with three-dimensional continuum, reveals that the impurity effect is most pronounced the stronger that electron is confined. This necessarily leads to challenges and opportunities in a quantum dot experiment to prove the interparticle Coulombic decay.

With a focus on elderly people this article puts forward a concept of media generation as athickeningof one or more age groups of people who in their media appropriation share a specific experience space of mediatization and subsequently, based on their personal media biographies, develop a shared self-image as a media generation. Such a conceptualisation grasps media generation as a process. It operates with the central aspects of media relatedness, media-generational specifics of appropriation, and self-positioning. This offers an understanding of elderly people after retirement as members of a mass-media media generation. As the qualitative empirical analysis presented in this article demonstrates, members of this mass-media media generation define themselves in contrast to younger media generations.

We have conducted a comprehensive investigation of the optical and vibrational properties of the binary semiconductor SnSe as a function of temperature and pressure by means of experimental and ab initio probes. Our high-temperature investigations at ambient pressure have successfully reproduced the progressive enhancement of the free carrier concentration upon approaching the Pnma → Bbmm transition, whereas the pressure-induced Pnma → Bbmm transformation at ambient temperature, accompanied by an electronic semiconductor → semi-metal transition, has been identified for bulk SnSe close to 10 GPa. Modeling of the Raman-active vibrations revealed that three-phonon anharmonic processes dominate the temperature-induced mode frequency evolution. In addition, SnSe was found to exhibit a pressure-induced enhancement of the Born effective charge. Such behavior is quite unique and cannot be rationalized within the proposed effective charge trends of binary materials under pressure.

We investigate electronic quantum fluxes during large amplitude nuclear vibrations of hydrocarbon (HnCCHn), hydrosilicon (HnSiSiHn) and organosilicon (HnSiCHn) compounds with n = 1, 2, 3. The total electronic fluxes are analysed in terms of contributions from localised molecular orbital densities. Furthermore, the vibrationally induced charge transfer in the polar compounds is investigated in terms of the underlying fluxes.

The interparticle Coulombic decay process in paired quantum dots is studied by electron dynamics calculations. We consider a pair of Coulomb-coupled one-electron charged gallium arsenide quantum dots embedded in a nanowire. The two-electron decay process is approximately described by a single active electron model. Within this model, we employ the time-dependent wavepacket approach to the Fermi golden rule (introduced in the context of vibrational predissociation) to calculate autoionization rates, which are compared to exact rates obtained from fully correlated two-electron dynamics calculations. We found that the approximate decay rates agree well with the exact results in the limit of sufficiently separated quantum dots. Finally, we explore whether the short-range behavior of the new model can be further enhanced by the inclusion of local exchange effects by means of regularization of the Coulomb-potential based on a Jastrow-Slater wavefunction. The proposed method may open a route to study the interparticle Coulombic decay in more intricate systems, e.g., paired metal-nanoparticle—quantum dot systems.The interparticle Coulombic decay process in paired quantum dots is studied by electron dynamics calculations. We consider a pair of Coulomb-coupled one-electron charged gallium arsenide quantum dots embedded in a nanowire. The two-electron decay process is approximately described by a single active electron model. Within this model, we employ the time-dependent wavepacket approach to the Fermi golden rule (introduced in the context of vibrational predissociation) to calculate autoionization rates, which are compared to exact rates obtained from fully correlated two-electron dynamics calculations. We found that the approximate decay rates agree well with the exact results in the limit of sufficiently separated quantum dots. Finally, we explore whether the short-range behavior of the new model can be further enhanced by the inclusion of local exchange effects by means of regularization of the Coulomb-potential based on a Jastrow-Slater wavefunction. The proposed method may open a route to study the interpa...

Very recently an ultralow thermal conductivity and a surpassing high thermoelectric figure of merit were reported in SnSe which makes this material very attractive for electrical energy harvesting. In this paper we follow the evolution of the low-energy phonons with doping, temperature and pressure and compare the experimental results with ab initio calculations to help understanding better the low thermal conductivity in SnSe and may help developing highly efficient thermoelectric materials.

Maritime Situational Awareness is of global importance and satellite remote sensing technologies are well suited to derive maritime value added products. Processing systems to derive information about oil spill, ship or iceberg detection from spaceborne Synthetic Aperture Radar (SAR) image data are being developed and integrated at the Ground Station Neustrelitz, part of the German Remote Sensing Data Center (DFD). Shortly, products of meteo-marine parameters like wind and wave will complement the product portfolio. Research and development aim at the implementation of highly automated services for operational use. At this time SAR images are widely used because of the possibility to provide maritime products with high spatial resolution over wide swaths and under all weather conditions. In combination with other information sources like Automatic Identification System (AIS) data fusion products are available to support the Maritime Situational Awareness.

Patent expiration of first-generation biologics and the high cost of innovative biologics are 2 drivers for the development of biosimilar products. There are, however, technical challenges to the production of exact copies of such large molecules. In this study, we performed a head-to-head comparison between the originator anti-VEGF-A Fab product LUCENTIS® (ranibizumab) and an intended copy product using an integrated analytical approach. While no differences could be observed using size-exclusion chromatography, capillary electrophoresis-sodium dodecyl sulfate and potency assays, different acidic peaks were identified with cation ion exchange chromatography and capillary zone electrophoresis. Further investigation of the intact Fab, subunits and primary sequence with mass spectrometry demonstrated the presence of a modified light chain variant in the intended copy product batches. This variant was characterized with a mass increase of 27.01 Da compared to the originator sequence and its abundance was estimated in the range of 6–9% of the intended copy product light chain. MS/MS spectra interrogation confirmed that this modification relates to a serine to asparagine sequence variant found in the intended copy product light chain. We demonstrated that the integration of high-resolution and sensitive orthogonal technologies was beneficial to assess the similarity of an originator and an intended copy product.

Characterization of charge-based variants by mass spectrometry (MS) is required for the analytical development of a new biologic entity and its marketing approval by health authorities. However, standard peak-based data analysis approaches are time-consuming and biased toward the detection, identification, and quantification of main variants only. The aim of this study was to characterize in-depth acidic and basic species of a stressed IgG1 monoclonal antibody using comprehensive and unbiased MS data evaluation tools. Fractions collected from cation ion exchange (CEX) chromatography were analyzed as intact, after reduction of disulfide bridges, and after proteolytic cleavage using Lys-C. Data of both intact and reduced samples were evaluated consistently using a time-resolved deconvolution algorithm. Peptide mapping data were processed simultaneously, quantified and compared in a systematic manner for all MS signals and fractions. Differences observed between the fractions were then further characterized and assigned. Time-resolved deconvolution enhanced pattern visualization and data interpretation of main and minor modifications in 3-dimensional maps across CEX fractions. Relative quantification of all MS signals across CEX fractions before peptide assignment enabled the detection of fraction-specific chemical modifications at abundances below 1%. Acidic fractions were shown to be heterogeneous, containing antibody fragments, glycated as well as deamidated forms of the heavy and light chains. In contrast, the basic fractions contained mainly modifications of the C-terminus and pyroglutamate formation at the N-terminus of the heavy chain. Systematic data evaluation was performed to investigate multiple data sets and comprehensively extract main and minor differences between each CEX fraction in an unbiased manner.

Heutige Medienkulturen zeichnen sich durch eine umfassende Mediatisierung aus, auch was deren Vergemeinschaftungen betrifft. Gerade jungen Menschen wird diesbezüglich eine nachhaltige Veränderung unterstellt. Bisherige Forschung setzt hierbei allerdings primär bei der Entität von Vergemeinschaftungen als solchen an oder aber bei der Betrachtung von Einzelmedien wie beispielsweise dem Social Web. In diesem Beitrag wird ein anderer Blick entwickelt, der die subjektiven mediatisierten Vergemeinschaftungshorizonte einzelner junger Menschen und deren gesamte kommunikative Vernetzung in den Fokus rückt. Grundmuster solcher mediatisierter Vergemeinschaftungshorizonte lassen sich in einem Spannungsverhältnis von mono- vs. multithematischer Ausrichtung, mediatisierten Vergemeinschaftungen vs. Mediatisierungsvergemeinschaftungen und lokaler vs. translokaler kommunikativer Vernetzung beschreiben. Während der Beitrag ein solches Raster anhand der Gegenüberstellung von zwei Extremfällen vorstellt, verweist er insgesamt auf eine medienethnografische Erforschung von 60 Fällen junger Menschen zwischen 16 und 30 Jahren mittels qualitativer Interviews und einer qualitativen Netzwerkforschung auf der Basis von Netzwerkkarten und Medientagebüchern.

Anabaena sp. PCC 7120 is a filamentous cyanobacterium that serves as a model to analyze prokaryotic cell differentiation, evolutionary development of plastids, and the regulation of nitrogen fixation. The cell wall is the cellular structure in contact with the surrounding medium. To understand the dynamics of the cell wall proteome during cell differentiation, the cell wall from Anabaena heterocysts was enriched and analyzed. In line with the recently proposed continuity of the outer membrane along the Anabaena filament, most of the proteins identified in the heterocyst cell-wall fraction are also present in the cell wall of vegetative cells, even though the lipid content of both membranes is different.

In the context of the project OpSSERVE - Optical Satellite Services for EMSA (European Maritime Safety Agency) – the European Space Imaging (EUSI) and the German Aerospace Center (DLR) established for the first time a fully operational and near real-time service to detect vessels and maritime activities with optical satellite imagery . The service was implemented in 2013 and contribute to maritime situation awareness, e.g. in order to reduce the risk of maritime accidents, marine pollution and the loss of human life at sea. Since its activation in 2007, EMSA’s CleanSeaNet (CSN) system provides pollution detection services in support of maritime surveillance and decision making for all participating European member states based on SAR satellite data. The main advantage of SAR data is their independence of weather conditions (cloud coverage), but the identification of small vessels is rather difficult. The use of very high resolution (VHR) optical data provides valuable information to identify small vessels. From the VHR optical imagery, actionable information products are created in an automatic processing chain including image pre-processing, data transcription, automatic vessel detection, GUI based interactive vessel and activity detection and finally the delivery of standardized products to EMSA. The service provides access to globally collected satellite imagery and receives data and derived products in near real-time (1 or 3 hours). In OpSSERVE, five satellite missions are available: WorldView-1, WorldView-2, GeoEye-1, IKONOS and EROS-B. The poster will present the experiences of the operational service and give an overview on future aspects and possible applications.

Michael Sommer Bildungsarbeit katholischer Verbände -Institutionen der Katholischen Erwachsenenbildung (5) Matthias Berg Das Interesse kirchlicher Erwachsenenbildung Kontroverse Diskussionen, interessante Gesprächspartner und ein Thema mit Potenzial

The C-terminal fragment of merozoite surface protein-1 (MSP-1) of the mouse malaria parasite Plasmodium chabaudi chabaudi (AS) stimulates a weak CD4 T cell response when compared to the response to a more structurally simple region of the molecule. The tertiary structure of the C-terminal region of MSP-1 is maintained by five disulfide bonds. A peptide from this region could only be processed and loaded onto newly synthesized MHC class II molecules, whereas a peptide from the structurally simple region was available for loading onto recycling MHC class II. CD4(+) T cell hybridomas took longer to recognize an epitope derived from the disulfide-bonded region whether native parasite or recombinant MSP-1 antigen was used. Reduction of disulfide bonds in the C-terminal region subsequently allowed peptides to be loaded onto recycling MHC class II and greatly enhanced the rapidity of the T cell response. These data demonstrate that differential processing occurs intramolecularly in MSP-1, which may be responsible for the observed weak CD4 T cell responses against this region. The consequences of this in vivo may be that limited T cell help is available for protective antibody production which has important implications for designing vaccines based on MSP-1.

Die öffentliche Auftragsvergabe kann sich auch an innovativen Aspekten der Produkte und Dienst leistungen orientieren. Dadurch können innovative Unternehmen gefördert, nachhaltige Lösungen ausgewählt und die Verwaltung modernisiert werden.

Cryptographic hash functions provide a basic data authentication mechanism and are used pervasively as building blocks to realize many cryptographic functionalities, including block ciphers, message authentication codes, key exchange protocols, and encryption and digital signature schemes. Since weaknesses in hash functions may imply vulnerabilities in the constructions that build upon them, ensuring their security is essential. Unfortunately, many widely used hash functions, including SHA-1 and MD5, are subject to practical attacks. The search for a secure replacement is one of the most active topics in the field of cryptography. In this paper we report on the first machine-checked and independently-verifiable proofs of collision-resistance and in differentiability of Merkle-Damgaard, a construction that underlies many existing hash functions. Our proofs are built and verified using an extension of the Easy Crypt framework, which relies on state-of-the-art verification tools such as automated theorem provers, SMT solvers, and interactive proof assistants.

Quantitative information-flow analysis (QIF) determines the amount of information that a program leaks about its secret inputs. For this, QIF requires an assumption about the distribution of the secret inputs. Existing techniques either consider the worst-case over a (sub-)set of all input distributions and thereby over-approximate the amount of leaked information; or they are tailored to reasoning about uniformly distributed inputs and are hence not directly applicable to non-uniform use-cases; or they deal with explicitly represented distributions, for which suitable abstraction techniques are only now emerging. In this paper we propose a novel approach for a precise QIF with respect to non-uniform input distributions: We present a reduction technique that transforms the problem of QIF w.r.t. non-uniform distributions into the problem of QIF for the uniform case. This reduction enables us to directly apply existing techniques for uniform QIF to the non-uniform case. We furthermore show that quantitative information flow is robust with respect to variations of the input distribution. This result allows us to perform QIF based on approximate input distributions, which can significantly simplify the analysis. Finally, we perform a case study where we illustrate our techniques by using them to analyze an integrity check on non-uniformly distributed PINs, as they are used for banking.

Granule-associated perforin and granzymes (gzms) are key effector molecules of cytotoxic T lymphocytes (Tc cells) and natural killer cells and play a critical role in the control of intracellular pathogens and cancer. Based on the notion that many gzms, including A, B, C, K, H, and M exhibit cytotoxic activity in vitro, all gzms are believed to serve a similar function in vivo. However, more recent evidence supports the concept that gzms are not unidimensional but, rather, possess non-cytotoxic potential, including stimulation of pro-inflammatory cytokines and anti-viral activities. The present study shows that isolated mouse gzmB cleaves the actin-severing mouse protein, cytoplasmic gelsolin (c-gelsolin) in vitro. However, when delivered to intact target cells by ex vivo immune Tc cells, gzmB mediates c-gelsolin proteolysis via activation of caspases 3/7. The NH(2)-terminal c-gelsolin fragment generated by either gzmB or caspase 3 in vitro constitutively severs actin filaments without destroying the target cells. The observation that gzmB secreted by Tc cells initiates a caspase cascade that disintegrates the actin cytoskeleton in target cells suggests that this intracellular process may contribute to anti-viral host defense.

Summary Chronic neurodegenerative diseases are characterized by the accumulation of aggregated protein species, and functional impairment of the ubiquitin proteasome system has been hypothesized to contribute to neuronal cell loss. Decreased proteolytic activity of the 20S proteasome has been shown postmortem in crude brain lysates from Alzheimer’s disease (AD) patients. In the present study, we demonstrate, however, that catalytic activity of the 20S proteasome increases during chromatographic purification from AD brains as compared with age-matched controls. By two-dimensional difference gel electrophoresis we detected pI shifts in several proteasome subunits in AD samples pointing to differential post-translational modifications. Moreover, we identified N-terminal acetylation and dephosphorylation of subunit α7 in AD by tandem mass spectrometry. Thus, reduced peptidase activity in AD brain extracts is not an intrinsic property of the 20S proteasome, but may be resulting from the presence of endogenous inhibitory proteins or substrates. Post-translational modifications of non-catalytic subunits in situ may contribute to the trend towards enhanced hydrolytic activity of the isolated 20S proteasome after removal of the endogenous inhibitors.

Traditional analysis of liquid chromatography-mass spectrometry (LC-MS) data, typically performed by reviewing chromatograms and the corresponding mass spectra, is both time-consuming and difficult. Detailed data analysis is therefore often omitted in proteomics applications. When analysing multiple proteomics samples, it is usually only the final list of identified proteins that is reviewed. This may lead to unnecessarily complex or even contradictory results because the content of the list of identified proteins depends heavily on the conditions for triggering the collection of tandem mass spectra. Small changes in the signal intensity of a peptide in different LC-MS experiments can lead to the collection of a tandem mass spectrum in one experiment but not in another. Also, the quality of the tandem mass spectrometry experiments can vary, leading to successful identification in some cases but not in others. Using a novel image analysis approach, it is possible to achieve repeat analysis with a very high reproducibility by matching peptides across different LC-MS experiments using the retention time and parent mass over charge (m/z). It is also easy to confirm the final result visually. This approach has been investigated by using tryptic digests of integral membrane proteins from organelle-enriched fractions from Arabidopsis thaliana and it has been demonstrated that very highly reproducible, consistent, and reliable LC-MS data interpretation can be made.

The present work is concerned with the weak interactions between hydrogen and halogen molecules, i.e., the interactions of pairs H2–X2 with X = F, Cl, Br, which are dominated by dispersion and quadrupole-quadrupole forces. The global minimum of the four-dimensional (4D) coupled cluster with singles and doubles and perturbative triples (CCSD(T)) pair potentials is always a T shaped structure where H2 acts as the hat of the T, with well depths (D e ) of 1.3, 2.4, and 3.1 kJ/mol for F2, Cl2, and Br2, respectively. MP2/AVQZ results, in reasonable agreement with CCSD(T) results extrapolated to the basis set limit, are used for detailed scans of the potentials. Due to the large difference in the rotational constants of the monomers, in the adiabatic approximation, one can solve the rotational Schrodinger equation for H2 in the potential of the X2 molecule. This yields effective two-dimensional rotationally adiabatic potential energy surfaces where pH2 and oH2 are point-like particles. These potentials for the H2–X2 complexes have global and local minima for effective linear and T-shaped complexes, respectively, which are separated by 0.4-1.0 kJ/mol, where oH2 binds stronger than pH2 to X2, due to higher alignment to minima structures of the 4D-pair potential. Further, we provide fits of an analytical function to the rotationally adiabatic potentials.