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Einfluss der Elektromobilität auf die Gussproduktion in der deutschen Gießereiindustrie (Teil 2)
(2019)
The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson's disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson's disease.
Taar1 is a G protein-coupled receptor (GPCR) confined to primary cilia of rodent thyroid epithelial cells. Taar1-deficient mouse thyroid follicles feature luminal accumulation of thyroglobulin suggesting that Taar1 acts as a regulator of extra- and pericellular thyroglobulin processing, which is mediated by cysteine cathepsin proteases present at the apical plasma membrane of rodent thyrocytes. Here, by immunostaining and confocal laser scanning microscopy, we demonstrated co-localization of cathepsin L, but only little cathepsin B, with Taar1 at primary cilia of rat thyrocytes, the FRT cells. Because proteases were shown to affect half-lives of certain receptors, we determined the effect of cathepsin activity inhibition on sub-cellular localization of Taar1 in FRT cells, whereupon Taar1 localization altered such that it was retained in compartments of the secretory pathway. Since the same effect on Taar1 localization was observed in both cathepsin B and L inhibitor-treated cells, the interaction of cathepsin activities and sub-cellular localization of Taar1 was thought to be indirect. Indeed, we observed that cathepsin inhibition resulted in a lack of primary cilia from FRT cells. Next, we proved that primary cilia are a necessity for Taar1 trafficking to reach the plasma membrane of FRT cells, since the disruption of primary cilia by treatment with β-cyclodextrin resulted in Taar1 retention in compartments of the secretory pathway. Furthermore, in less well-polarized rat thyrocytes, namely in FRTL-5 cells lacking primary cilia, Taar1 was mainly confined to the compartments of the secretory pathway. We conclude that Taar1 localization in polarized thyroid epithelial cells requires the presence of primary cilia, which is dependent on the proteolytic activity of cysteine cathepsins B and L.
Wideband-tympanometry (WBT) could give more informative data about the tympanic condition than the conventional tympanometry. In the actual literature, the clinical profit of wideband-tympanometry in pediatric audiological settings is not well evaluated. The aim of this study was to analyze the additional clinical benefit.
Application of a robotic THz imaging system for sub-surface analysis of ancient human remains
(2019)
We used a robotic-based THz imaging system to investigate the sub-surface structure of an artificially mummified ancient Egyptian human left hand. The results obtained are compared to the results of a conventional CT and a micro-CT scan. Using such a robotic THz system promises new insights into the sub-surface structure of human remains. The depth resolution of the THz images exceeds the resolution of a conventional CT scan and is comparable with a micro-CT scan. The advantage of THz measurements over micro-CT scans is the fact that even comparatively large samples, like complete bodies, can be scanned. These would not fit into a conventional micro-CT scanner.
Capillary electrophoresis (CE) offers fast and high-resolution separation of charged analytes from small injection volumes. Coupled to mass spectrometry (MS), it represents a powerful analytical technique providing (exact) mass information and enables molecular characterization based on fragmentation. Although hyphenation of CE and MS is not straightforward, much emphasis has been placed on enabling efficient ionization and user-friendly coupling. Though several interfaces are now commercially available, research on more efficient and robust interfacing with nano-electrospray ionization (ESI), matrix-assisted laser desorption/ionization (MALDI) and inductively coupled plasma mass spectrometry (ICP) continues with considerable results. At the same time, CE-MS has been used in many fields, predominantly for the analysis of proteins, peptides and metabolites. This review belongs to a series of regularly published articles, summarizing 248 articles covering the time between June 2016 and May 2018. Latest developments on hyphenation of CE with MS as well as instrumental developments such as two-dimensional separation systems with MS detection are mentioned. Furthermore, applications of various CE-modes including capillary zone electrophoresis (CZE), nonaqueous capillary electrophoresis (NACE), capillary gel electrophoresis (CGE) and capillary isoelectric focusing (CIEF) coupled to MS in biological, pharmaceutical and environmental research are summarized.
It has been recently shown, that certain strains/isolates of Bacillus subtilis can be used as a probiotic for humans. The production of the macrocyclic sactibiotic subtilosin in B. subtilis ATCC 6633 is highly regulated. To improve the subtilosin productivity of B. subtilis, different growth conditions were compared for maximal expression of the sbo promoter that regulates the expression of the subtilosin biosynthetic gene cluster. Oxygen-limiting conditions led to a strong increase of sbo promoter activities compared to aerobic conditions, and accordingly, the subtilosin amount determined by reversed phase HPLC (7.8 mg/L) was 15-fold superior to the amount of aerobic grown cultures (0.5 mg/L). A further promising enhancement of the subtilosin yield was achieved using a deletion mutant that is avoiding the general transition state regulator protein AbrB. The subtilosin titer of 42 mg/L produced by ΔabrB cells grown under oxygen-limiting conditions corresponds to an 84-fold increase compared to the subtilosin titer obtained from B. subtilis wild type cells propagated in aerobic conditions. Furthermore, evidence is provided that oxygen-limiting conditions led to a strong decrease in the productivity of the lantipeptide subtilin suggesting contrary regulatory mechanisms for the B. subtilis antimicrobials subtilin and subtilosin.
Drugs containing amine groups react with CO2 to form crystalline ammonium carbamates or carbamic acids. In this approach, both the cation and anion of the salt, or the neutral CO2 adduct, are derived from the parent drug, generating new crystalline versions in a 'masked' or prodrug form. It is proposed that this approach may serve as a valuable new tool in engineering the physical properties of drugs for formulation purposes.
Virtuous cycles
(2019)
Pharmaceutical agents or drugs often have a pronounced impact on protein-protein interactions in cells, and in particular, cell membranes. Changes of molecular conformations as well as of intermolecular interactions may affect dipole-dipole interaction between chromophoric groups, which can be proven by measuring the Förster resonance energy transfer (FRET). If these chromophores are located within or in close proximity to the plasma membrane, they are excited preferentially by an evanescent electromagnetic wave upon total internal reflection (TIR) of an incident laser beam. For the TIR-FRET screening of larger cell collectives, we performed three separate steps: (1) setting up of a membrane associated test system for probing the interaction between the epidermal growth factor receptor (EGFR) and the growth factor receptor-bound protein 2; (2) use of the Epac-SH188 sensor for quantitative evaluation under the microscope; and (3) application of a TIR fluorescence reader to probe the interaction of GFP with Nile Red. In the first two steps, we measured FRET from cyan (CFP) to yellow fluorescent protein (YFP) by spectral analysis and fluorescence lifetime imaging (FLIM) upon illumination of whole cells (epi-illumination) as well as selective illumination of their plasma membranes by TIR. In particular, TIR excitation permitted FRET measurements with high sensitivity and low background. The Epac sensor showed a more rapid response to pharmaceutical agents, e.g., Forskolin or the A2B adenosine receptor agonist NECA, in close proximity to the plasma membrane compared to the cytosol. Finally, FRET from a membrane associated GFP to Nile Red was used to test a multi-well TIR fluorescence reader with simultaneous detection of a larger number of samples.
The present manuscript gives a short overview on Förster Resonance Energy Transfer (FRET) of molecular interactions in the nanometre range. First, its principle is described and a short historical overview is given. Subsequently some principal methods and applications of FRET sensing and imaging are described (with some emphasis on fluorescence lifetime imaging, FLIM), and finally two innovative FRET techniques are presented in more detail. Applications are focused on measurements of living cells.
Online mass spectrometry of CE (SDS)-separated proteins by two-dimensional capillary electrophoresis
(2019)
Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) is the fundamental technique for protein separation by size. Applying this technology in capillary format, gaining high separation efficiency in a more automated way, is a key technology for size separation of proteins in the biopharmaceutical industry. However, unequivocal identification by online mass spectrometry (MS) is impossible so far, due to strong interference in the electrospray process by SDS and other components of the SDS-MW separation gel buffer. Here, a heart-cut two-dimensional electrophoretic separation system applying an electrically isolated valve with an internal loop of 20 nL is presented. The peak of interest in the CE (SDS) separation is transferred to the CZE-MS, where electrospray-interfering substances of the SDS-MW gel are separated prior to online electrospray ionization mass spectrometry. An online SDS removal strategy for decomplexing the protein-SDS complex is implemented in the second dimension, consisting of the co-injection of organic solvent and cationic surfactant. This online CE (SDS)-CZE-MS system allows MS characterization of proteoforms separated in generic CE (SDS), gaining additional separation in the CZE and detailed MS information. In general, the system can be applied to all kinds of proteins separated by CE (SDS). Here, we present results of the CE (SDS)-CZE-MS system on the analysis of several biopharmaceutically relevant antibody impurities and fragments. Additionally, the versatile application spectrum of the system is demonstrated by the analysis of extracted proteins from soybean flour. The online hyphenation of CE (SDS) resolving power and MS identification capabilities will be a powerful tool for protein and mAb characterization. Graphical abstract Two-dimensional capillary electrophoresis system hyphenated with mass spectrometry for the characterization of CE (SDS)-separated proteins. As first dimension, a generic and high MS-interfering CE (SDS) separation is performed for size separation. After heart-cut transfer of the unknown CE (SDS) protein peak, via a four-port nanoliter valve to a volatile electrolyte system as second dimension, interference-free mass spectrometric data of separated mAb fragments and soybean proteins are obtained.
Brennpunkt Digitalisierung
(2019)
Strategic IT management
(2019)
Dementia is one of the most frequent diseases of people aged 65 and older. As a result of the upcoming demographic transition, a significant increase is expected to the current number of around 1.7 million dementia patients. A precise estimate of this increase is especially important for decision-makers and payers to the health-care system. This study examined the effects of different assumptions on the future frequency of disease using a time-discrete Markov model with population-related and disease-specific components. Based on health insurers' administrative data from AOK Baden-Württemberg, we determined age- and gender-specific prevalence rates, incidence rates, and mortality differences of dementia patients and combined them with demographic components from German population statistics. As a result, our Markov model showed a 20 to 25% higher number of dementia patients in 2030, compared to the results of the status quo projection applied in most previous studies, with the assumption of constant prevalence rates over time. Hence, our results indicate that even in the medium term payers will have to face significant increases in dementia-related health expenditures. By 2060, the number of dementia patients in Germany would rise to 3.3 million assuming a further increase to life expectancy and constant incidence rates over time. The assumption of a compression of the morbidity would reduce this number to 2.6 million.
Data logging (DL) is used to compare the patients’ testimonials about how often they used their hearing aids. In addition, the hearing aid acoustician can compare how long and in which acoustic environments the patients wore their hearing aids. The hearing aid users’ statements often deviate from the information gained from DL. This raises the question of whether and when complications can occur in the recording of wearing behavior. The present study examined the reliability of DL and the factors that can affect it. In addition to the duration of the logging, the situation detection for three different manufacturers was also investigated. Different acoustic situations were designed using eight loudspeakers while the duration of measurement was three and eight hours. The results show that de documentation of the overall wearing time is very reliable, while reliability for detecting the hearing environment depends on the situation a manufacturer. Das Data Logging (DL) kommt in der Praxis häufig zum Einsatz, um die Aussagen der Kunden hinsichtlich der Tragedauer von Hörgeräten abzugleichen. Ebenfalls ist es dem Hörakustiker möglich nachzuvollziehen, wie lange und in welcher Situation der Kunde das Hörsystem getragen hat. Oftmals kommt es jedoch zu dem Fall, dass die Aufzeichnungen der Geräte von den Aussagen der Kunden abweichen. Somit stellt sich die Frage ob und wann es zu Komplikationen in der Aufzeichnung des Trageverhaltens kommen kann. In der hier vorgestellten Studie wurden die Zuverlässigkeit des Data Loggings und die Faktoren, wie z.B. der binauralen Synchronisation, die dieses beeinträchtigen können, untersucht. Dazu wurde neben der Aufzeichnungsdauer auch die Situationserkennung für drei verschiedene Hersteller überprüft. Unter Laborbedingungen wurden zum einen akustisch definierte „Standardsituationen“ (Sprache in Ruhe, Sprache im Störgeräusch) sowie eine komplexe Situation (Sprache im Störgeräusch zusammen mit Musik) über einen Lautsprecherkreis konstruiert und anhand von 3- und 8-Stunden-Messungen ausgewertet. Die Ergebnisse zeigen, dass die Tragedauer insgesamt sehr zuverlässig aufgezeichnet wird, die Hörumgebung hingegen je nach Situation und Hersteller besser und schlechter erfasst wird.
Das Terminservice- und Versorgungsgesetz – TSVG aus vertragsarztrechtlicher Perspektive (Teil 1)
(2019)
Das Terminservice- und Versorgungsgesetz – TSVG aus vertragsarztrechtlicher Perspektive (Teil 2)
(2019)
Mobile Arbeit
(2019)
Multidimensional separation techniques play an increasingly important role in separation science, especially for the analysis of complex samples such as proteins. The combination of reversed-phase liquid chromatography in the nanoscale and CZE is especially beneficial due to their nearly orthogonal separation mechanism and well-suited geometries/dimensions. Here, a heart-cut nano-LC-CZE-MS setup was developed utilizing for the first time a mechanical 4-port valve as LC-CE interface. A model protein mixture containing four different protein species was first separated by nano LC followed by a heart-cut transfer of individual LC peaks and subsequent CZE-MS analysis. In the CZE dimension, various glycoforms of one protein species were separated. Improved separation capabilities were achieved compared to the 1D methods, which was exemplarily shown for ribonuclease B and its different glycosylated forms. LODs in the lower μg/mL range were determined, which are considerably lower compared to traditional CZE-MS. In addition, this study represents the first application of an LC-CE-MS system for intact protein analysis. The nano-LC-CZE-MS system is expected to be applicable to various other analytical challenges.
A ferromagnetic barrier thinner than the coherence length in high-temperature superconductors is realized in the multilayers of YBa2Cu3O7-δ and La0.67Ca0.33MnO3. We used epitaxial growth of YBCO on ⟨110⟩ SrTiO3 substrates by pulsed laser deposition to prepare thin superconducting films with copper oxide planes oriented at an angle to the substrate surface. Subsequent deposition of LCMO and finally a second YBCO layer produces a superconductor/ferromagnet/superconductor trilayer containing an ultrathin ferromagnetic barrier with sophisticated geometry at which the long axis of coherence length ovoid of YBCO is pointing across the LCMO ferromagnetic layer. A detailed characterization of this structure is achieved using high-resolution electron microscopy.
Effect of drilling-induced damage on the open hole flexural fatigue of carbon/epoxy composites
(2019)
Zuhörer fesseln
(2019)
Vom Sammler zum Jäger
(2019)
As the size of software program code bases in software development projects increases, insight into and comprehension of their underlying dependency structures presents a challenge for programmers. The increasing availability of virtual reality (VR) systems brings VR-based visualization of program code structures into practical reach for software developers and could support program comprehension and insight. However, the complete visual immersion with VR presents a cognitive burden and potential distractions. Applying gamification to such a VR visualization capability has hitherto been insufficiently investigated as to its potential motivation and program comprehension factors. This paper describes and evaluates a VR digital gamification approach for program code called VR Gamified Immersion in Software structures (VR-GaImS), which applies digital gamification to a multi-metaphor VR visualization of software program structures. The results of a preliminary empirical investigation utilizing our prototype indicate its potential to increase enjoyment and motivation, focus attention, and encourage the exploration of software structures.
Enterprise Architecture (EA) Frameworks (EAFs) have attempted to support comprehensive and cohesive modeling and documentation of the enterprise. However, these EAFs were not conceived for today’s rapidly digitalized enterprises and the associated IT complexity. A digitally-centric EAF is needed, freed from the past restrictive EAF paradigms and embracing the new potential in a data-centric world. This paper proposes an alternative EAF that is digital, holistic, and digitally sustainable - the Digital Diamond Framework. D2F is designed for responsive and agile enterprises, for aligning business plans and initiatives with the actual enterprise state, and addressing the needs of EA for digitized structure, order, modeling, and documentation. The feasibility of D2F is demonstrated with a prototype implementation of an EA tool that applies its principles, showing how the framework can be practically realized, while a case study based on ArchiSurance example and an initial performance and scalability characterization provide additional insights as to its viability.
Databases are becoming an ubiquitous and integral part of most software as the data era and the Internet of Everything unfolds. Alternative database types such as NoSQL grow in popularity and allow data to be stored and accessed more simply or in new ways. Thus, software developers, not just database specialists, are more likely to encounter and need to deal with databases. Virtual Reality (VR) technology has grown in popularity, yet its integration in the software development tool chain has been limited. One potential application area for VR technology that has not been sufficiently explored is database-model visualization. This paper describes Virtual Reality Immersion in Data Models (VRiDaM), a generic database-model approach for visualizing, navigating, and conveying database-model information interactively. It describes and explores both native VR and WebVR solution concepts, with prototypes showing the viability of the approach.