Search results for: Ludwig Wolfgang

Authors: Bright Chukwunwike Uzuegbunam, Wojciech Paslawski, Hans Agren, Christer Halldin, Wolfgang Weber, Markus Luster, Thomas Arzberger, Behrooz Hooshyar Yousefi

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There is a need to develop a PET tracer that will enable to diagnosis and track the progression of Alpha-synucleinopathies (Parkinson’s disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA]) in living subjects over time. Alpha-synuclein aggregates (a-syn), which are present in all the stages of disease progression, for instance, in PD, are a suitable target for in vivo PET imaging. For this reason, we have developed some promising a-syn tracers based on a disarylbisthiazole (DABTA) scaffold. The precursors are synthesized via a modified Hantzsch thiazole synthesis. The precursors were then radiolabeled via one- or two-step radiofluorination methods. The ligands were initially screened using a combination of molecular dynamics and quantum/molecular mechanics approaches in order to calculate the binding affinity to a-syn (in silico binding experiments). Experimental in vitro binding assays were also performed. The ligands were further screened in other experiments such as log D, in vitro plasma protein binding & plasma stability, biodistribution & brain metabolite analyses in healthy mice. Radiochemical yields were up to 30% - 72% in some cases. Molecular docking revealed possible binding sites in a-syn and also the free energy of binding to those sites (-28.9 - -66.9 kcal/mol), which correlated to the high binding affinity of the DABTAs to a-syn (Ki as low as 0.5 nM) and selectivity (> 100-fold) over Aβ and tau, which usually co-exist with a-synin some pathologies. The log D values range from 2.88 - 2.34, which correlated with free-protein fraction of 0.28% - 0.5%. Biodistribution experiments revealed that the tracers are taken up (5.6 %ID/g - 7.3 %ID/g) in the brain at 5 min (post-injection) p.i., and cleared out (values as low as 0.39 %ID/g were obtained at 120 min p.i. Analyses of the mice brain 20 min p.i. Revealed almost no radiometabolites in the brain in most cases. It can be concluded that in silico study presents a new venue for the rational development of radioligands with suitable features. The results obtained so far are promising and encourage us to further validate the DABTAs in autoradiography, immunohistochemistry, and in vivo imaging in non-human primates and humans.

Keywords: alpha-synuclein aggregates, alpha-synucleinopathies, PET imaging, tracer development

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Authors: Agnieszka H. Ludwig-Slomczynska, Michal T. Seweryn, Przemyslaw Kapusta, Ewelina Pitera, Katarzyna Cyganek, Urszula Mantaj, Lucja Dobrucka, Ewa Wender-Ozegowska, Maciej T. Malecki, Pawel Wolkow

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Obesity results from an imbalance between energy intake and its expenditure. Genome-Wide Association Study (GWAS) analyses have led to discovery of only about 100 variants influencing body mass index (BMI), which explain only a small portion of genetic variability. Analysis of gene epistasis gives a chance to discover another part. Since it was shown that interaction and communication between nuclear and mitochondrial genome are indispensable for normal cell function, we have looked for epistatic interactions between the two genomes to find their correlation with BMI. Methods: The analysis was performed on 366 T1DM patients using Illumina Infinium OmniExpressExome-8 chip and followed by imputation on Michigan Imputation Server. Only genes which influence mitochondrial functioning (listed in Human MitoCarta 2.0) were included in the analysis – variants of nuclear origin (MAF > 5%) in 1140 genes and 42 mitochondrial variants (MAF > 1%). Gene expression analysis was performed on GTex data. Association analysis between genetic variants and BMI was performed with the use of Linear Mixed Models as implemented in the package 'GENESIS' in R. Analysis of association between mRNA expression and BMI was performed with the use of linear models and standard significance tests in R. Results: Among variants involved in epistasis between mitochondria and nucleus we have identified one in mitochondrial transcription factor, TFB2M (rs6701836). It interacted with mitochondrial variants localized to MT-RNR1 (p=0.0004, MAF=15%), MT-ND2 (p=0.07, MAF=5%) and MT-ND4 (p=0.01, MAF=1.1%). Analysis of the interaction between nuclear variant rs6701836 (nuc) and rs3021088 localized to MT-ND2 mitochondrial gene (mito) has shown that the combination of the two led to BMI decrease (p=0.024). Each of the variants on its own does not correlate with higher BMI [p(nuc)=0.856, p(mito)=0.116)]. Although rs6701836 is intronic, it influences gene expression in the thyroid (p=0.000037). rs3021088 is a missense variant that leads to alanine to threonine substitution in the MT-ND2 gene which belongs to complex I of the electron transport chain. The analysis of the influence of genetic variants on gene expression has confirmed the trend explained above – the interaction of the two genes leads to BMI decrease (p=0.0308). Each of the mRNAs on its own is associated with higher BMI (p(mito)=0.0244 and p(nuc)=0.0269). Conclusıons: Our results show that nuclear-mitochondrial epistasis can influence BMI in T1DM patients. The correlation between transcription factor expression and mitochondrial genetic variants will be subject to further analysis.

Keywords: body mass index, epistasis, mitochondria, type 1 diabetes

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Authors: Torsten Hermanns, Thoufik Al Khawli, Wolfgang Schulz

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In laser cutting as well as in long pulsed laser drilling of metals, it can be demonstrated that the ablation shape (the shape of cut faces respectively the hole shape) that is formed approaches a so-called asymptotic shape such that it changes only slightly or not at all with further irradiation. These findings are already known from the ultrashort pulse (USP) ablation of dielectric and semiconducting materials. The explanation for the occurrence of an asymptotic shape in laser cutting and long pulse drilling of metals is identified, its underlying mechanism numerically implemented, tested and clearly confirmed by comparison with experimental data. In detail, there now is a model that allows the simulation of the temporal (pulse-resolved) evolution of the hole shape in laser drilling as well as the final (asymptotic) shape of the cut faces in laser cutting. This simulation especially requires much less in the way of resources, such that it can even run on common desktop PCs or laptops. Individual parameters can be adjusted using sliders – the simulation result appears in an adjacent window and changes in real time. This is made possible by an application-specific reduction of the underlying ablation model. Because this reduction dramatically decreases the complexity of calculation, it produces a result much more quickly. This means that the simulation can be carried out directly at the laser machine. Time-intensive experiments can be reduced and set-up processes can be completed much faster. The high speed of simulation also opens up a range of entirely different options, such as metamodeling. Suitable for complex applications with many parameters, metamodeling involves generating high-dimensional data sets with the parameters and several evaluation criteria for process and product quality. These sets can then be used to create individual process maps that show the dependency of individual parameter pairs. This advanced simulation makes it possible to find global and local extreme values through mathematical manipulation. Such simultaneous optimization of multiple parameters is scarcely possible by experimental means. This means that new methods in manufacturing such as self-optimization can be executed much faster. However, the software’s potential does not stop there; time-intensive calculations exist in many areas of industry. In laser welding or laser additive manufacturing, for example, the simulation of thermal induced residual stresses still uses up considerable computing capacity or is even not possible. Transferring the principle of reduced models promises substantial savings there, too.

Keywords: asymptotic ablation shape, interactive process simulation, laser drilling, laser cutting, metamodeling, reduced modeling

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Authors: Shivani Dhande, Sanjiv Choudhary, Adarshlata Singh

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Introduction: Early age of onset of baldness has marked psychological impact on personality. Combination therapies have better efficacy than monotherapy in androgenetic alopecia. Although medical, surgical treatment and cosmetic aids are available for treatment of pattern baldness, medical is first preferred the line of treatment. Although only 5% topical minoxidil is USFDA approved, 10% is available in India since 2007. Efficacy of tablet finasteride is well established in male pattern baldness. 5% topical minoxidil is effective and safe in female pattern baldness. There is a role of saw palmetto in regrowth of scalp hair. With this background research was undertaken to study efficacy and safety of topical minoxidil 10% + tab. Finesteride (1mg) + dermaroller in male pattern baldness and topical minoxidil 5% + cap. Saw palmetto (320 mg) + dermaroller in female pattern baldness. Methods and Materials: It was a randomized uncontrolled evaluator blind study consisting of total 21 patients, 15 of male pattern baldness and 6 of female pattern baldness within 20-35 yrs of age were enrolled. Male patients had Hamilton grade 2-4 MPB and females had Ludwig grade 2 FPB. Male patients were treated with Tab Finesteride 1mg once daily + 10% topical Minoxidil 1ml twice daily for 6 months. Female patients were treated with Cap. Saw palmetto 320 mg once daily + 5% topical Minoxidil twice daily for 6 months. In both male & female patients dermaroller therapy was used once in 10 days for 4 sittings followed by once in 15 days for next 5 months. Blood pressure and possible side effects were monitored in every follow up visits. Pre and post treatment photographs were taken. Assessment of hair growth was done at baseline and at the end of 6 months. Patients satisfactory grading scale and Physician assessment of hair growth scale were used to assessing the results. Trichoscan was done for assessment of hair-shaft diameter and density. Pre and post treatment photographs and Trichoscan hair growth analysis (by diameter and density) was done by physician (dermatologist) not directly involved in this study (evaluator blind). Result: This combination therapy showed moderate response in female pattern alopecia and good to excellent results in male pattern alopecia at the end of 6 months. During therapy none of the patients showed side effects like hypotension, headache and loss of libido, hirsuitism. Mild irritation due to crystal deposition was noted by 3 patients. Conclusion: Effective and early treatment using combination therapy with higher percent of Minoxidil for rapid hair growth is necessary in initial period since it will boost up the self-confidence in patients leading to better treatment compliance. Subsequent maintenance of hair growth can be done with lower concentration. No significant side effects with treatment are observed in both group of patients.

Keywords: androgenetic alopecia, dermaroller, finasteride, minoxidil, saw palmetto

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Authors: Alireza Fallahfard, Ludwig Vinches, Stephane Halle

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In the workplace, the exposure level of airborne contaminants should be evaluated due to health and safety issues. It can be done by numerical models or experimental measurements, but the numerical approach can be useful when it is challenging to perform experiments. One of the simplest models is the well-mixed room (WMR) model, which has shown its usefulness to predict inhalation exposure in many situations. However, since the WMR is limited to gases and vapors, it cannot be used to predict exposure to aerosols. The main objective is to modify the WMR model to expand its application to exposure scenarios involving aerosols. To reach this objective, the standard WMR model has been modified to consider the deposition of particles by gravitational settling and Brownian and turbulent deposition. Three deposition models were implemented in the model. The time-dependent concentrations of airborne particles predicted by the model were compared to experimental results conducted in a 0.512 m3 chamber. Polystyrene particles of 1, 2, and 3 µm in aerodynamic diameter were generated with a nebulizer under two air changes per hour (ACH). The well-mixed condition and chamber ACH were determined by the tracer gas decay method. The mean friction velocity on the chamber surfaces as one of the input variables for the deposition models was determined by computational fluid dynamics (CFD) simulation. For the experimental procedure, the particles were generated until reaching the steady-state condition (emission period). Then generation stopped, and concentration measurements continued until reaching the background concentration (decay period). The results of the tracer gas decay tests revealed that the ACHs of the chamber were: 1.4 and 3.0, and the well-mixed condition was achieved. The CFD results showed the average mean friction velocity and their standard deviations for the lowest and highest ACH were (8.87 ± 0.36) ×10-2 m/s and (8.88 ± 0.38) ×10-2 m/s, respectively. The numerical results indicated the difference between the predicted deposition rates by the three deposition models was less than 2%. The experimental and numerical aerosol concentrations were compared in the emission period and decay period. In both periods, the prediction accuracy of the modified model improved in comparison with the classic WMR model. However, there is still a difference between the actual value and the predicted value. In the emission period, the modified WMR results closely follow the experimental data. However, the model significantly overestimates the experimental results during the decay period. This finding is mainly due to an underestimation of the deposition rate in the model and uncertainty related to measurement devices and particle size distribution. Comparing the experimental and numerical deposition rates revealed that the actual particle deposition rate is significant, but the deposition mechanisms considered in the model were ten times lower than the experimental value. Thus, particle deposition was significant and will affect the airborne concentration in occupational settings, and it should be considered in the airborne exposure prediction model. The role of other removal mechanisms should be investigated.

Keywords: aerosol, CFD, exposure assessment, occupational settings, well-mixed room model, zonal model

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Authors: Michael Huber, Maximilian J. Poller, Jens Tochtermann, Wolfgang Korth, Andreas Jess, Jakob Albert

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Aside from the desulfurisation, the denitrogenation of fuels is of great importance to minimize the environmental impact of transport emissions. The oxidative reaction pathway of organic nitrogen in the catalytic oxidative denitrogenation could be successfully elucidated. This is the first time such a pathway could be traced in detail in non-microbial systems. It was found that the organic nitrogen is first oxidized to nitrate, which is subsequently reduced to molecular nitrogen via nitrous oxide. Hereby, the organic substrate serves as a reducing agent. The discovery of this pathway is an important milestone for the further development of fuel denitrogenation technologies. The United Nations aims to counteract global warming with Net Zero Emissions (NZE) commitments; however, it is not yet foreseeable when crude oil-based fuels will become obsolete. In 2021, more than 50 million barrels per day (mb/d) were consumed for the transport sector alone. Above all, heteroatoms such as sulfur or nitrogen produce SO₂ and NOx during combustion in the engines, which is not only harmful to the climate but also to health. Therefore, in refineries, these heteroatoms are removed by hy-drotreating to produce clean fuels. However, this catalytic reaction is inhibited by the basic, nitrogenous reactants (e.g., quinoline) as well as by NH3. The ion pair of the nitrogen atom forms strong pi-bonds to the active sites of the hydrotreating catalyst, which dimin-ishes its activity. To maximize the desulfurization and denitrogenation effectiveness in comparison to just extraction and adsorption, selective oxidation is typically combined with either extraction or selective adsorption. The selective oxidation produces more polar compounds that can be removed from the non-polar oil in a separate step. The extraction step can also be carried out in parallel to the oxidation reaction, as a result of in situ separation of the oxidation products (ECODS; extractive catalytic oxidative desulfurization). In this process, H8PV5Mo7O40 (HPA-5) is employed as a homogeneous polyoxometalate (POM) catalyst in an aqueous phase, whereas the sulfur containing fuel components are oxidized after diffusion from the organic fuel phase into the aqueous catalyst phase, to form highly polar products such as H₂SO₄ and carboxylic acids, which are thereby extracted from the organic fuel phase and accumulate in the aqueous phase. In contrast to the inhibiting properties of the basic nitrogen compounds in hydrotreating, the oxidative desulfurization improves with simultaneous denitrification in this system (ECODN; extractive catalytic oxidative denitrogenation). The reaction pathway of ECODS has already been well studied. In contrast, the oxidation of nitrogen compounds in ECODN is not yet well understood and requires more detailed investigations.

Keywords: oxidative reaction pathway, denitrogenation of fuels, molecular catalysis, polyoxometalate

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Authors: Torsten Hermanns, You Wang, Stefan Janssen, Markus Niessen, Christoph Schoeler, Ulrich Thombansen, Wolfgang Schulz

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In long pulse laser drilling of metals, it can be demonstrated that the ablation shape approaches a so-called asymptotic shape such that it changes only slightly or not at all with further irradiation. These findings are already known from ultra short pulse (USP) ablation of dielectric and semiconducting materials. The explanation for the occurrence of an asymptotic shape in long pulse drilling of metals is identified, a model for the description of the asymptotic hole shape numerically implemented, tested and clearly confirmed by comparison with experimental data. The model assumes a robust process in that way that the characteristics of the melt flow inside the arising melt film does not change qualitatively by changing the laser or processing parameters. Only robust processes are technically controllable and thus of industrial interest. The condition for a robust process is identified by a threshold for the mass flow density of the assist gas at the hole entrance which has to be exceeded. Within a robust process regime the melt flow characteristics can be captured by only one model parameter, namely the intensity threshold. In analogy to USP ablation (where it is already known for a long time that the resulting hole shape results from a threshold for the absorbed laser fluency) it is demonstrated that in the case of robust long pulse ablation the asymptotic shape forms in that way that along the whole contour the absorbed heat flux density is equal to the intensity threshold. The intensity threshold depends on the special material and radiation properties and has to be calibrated be one reference experiment. The model is implemented in a numerical simulation which is called AsymptoticDrill and requires such a few amount of resources that it can run on common desktop PCs, laptops or even smart devices. Resulting hole shapes can be calculated within seconds what depicts a clear advantage over other simulations presented in literature in the context of industrial every day usage. Against this background the software additionally is equipped with a user-friendly GUI which allows an intuitive usage. Individual parameters can be adjusted using sliders while the simulation result appears immediately in an adjacent window. A platform independent development allow a flexible usage: the operator can use the tool to adjust the process in a very convenient manner on a tablet during the developer can execute the tool in his office in order to design new processes. Furthermore, at the best knowledge of the authors AsymptoticDrill is the first simulation which allows the import of measured real beam distributions and thus calculates the asymptotic hole shape on the basis of the real state of the specific manufacturing system. In this paper the emphasis is placed on the investigation of the effect of multiple reflections on the asymptotic hole shape which gain in importance when drilling holes with large aspect ratios.

Keywords: asymptotic hole shape, intensity threshold, long pulse laser drilling, robust process

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Authors: Ben Otange, Wolfgang Parak, Florian Schulz, Michael Alexander Rubhausen

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The feasibility of extending the usage of molecular imprinting technique in complex biomolecules is demonstrated in this research. This technique is promising in diverse applications in areas such as drug delivery, diagnosis of diseases, catalysts, and impurities detection as well as treatment of various complications. While molecularly imprinted polymers MIP remain robust in the synthesis of molecules with remarkable binding sites that have high affinities to specific molecules of interest, extending the usage to complex biomolecules remains futile. This work reports on the successful synthesis of MIP from complex proteins: BSA, Transferrin, and MUC1. We show in this research that despite the heterogeneous binding sites and higher conformational flexibility of the chosen proteins, relying on their respective epitopes and motifs rather than the whole template produces highly sensitive and selective MIPs for specific molecular binding. Introduction: Proteins are vital in most biological processes, ranging from cell structure and structural integrity to complex functions such as transport and immunity in biological systems. Unlike other imprinting templates, proteins have heterogeneous binding sites in their complex long-chain structure, which makes their imprinting to be marred by challenges. In addressing this challenge, our attention is inclined toward the targeted delivery, which will use molecular imprinting on the particle surface so that these particles may recognize overexpressed proteins on the target cells. Our goal is thus to make surfaces of nanoparticles that specifically bind to the target cells. Results and Discussions: Using epitopes of BSA and MUC1 proteins and motifs with conserved receptors of transferrin as the respective templates for MIPs, significant improvement in the MIP sensitivity to the binding of complex protein templates was noted. Through the Fluorescence Correlation Spectroscopy FCS measurements on the size of protein corona after incubation of the synthesized nanoparticles with proteins, we noted a high affinity of MIPs to the binding of their respective complex proteins. In addition, quantitative analysis of hard corona using SDS-PAGE showed that only a specific protein was strongly bound on the respective MIPs when incubated with similar concentrations of the protein mixture. Conclusion: Our findings have shown that the merits of MIPs can be extended to complex molecules of higher biomolecular mass. As such, the unique merits of the technique, including high sensitivity and selectivity, relative ease of synthesis, production of materials with higher physical robustness, and higher stability, can be extended to more templates that were previously not suitable candidates despite their abundance and usage within the body.

Keywords: molecularly imprinted polymers, specific binding, drug delivery, high biomolecular mass-templates

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Authors: Gerhard Gritsch, Ana Skupch, Manfred Hartmann, Wolfgang Frühwirt, Hannes Perko, Dieter Grossegger, Tilmann Kluge

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Rehabilitation of stroke patients is dominated by classical physiotherapy. Nowadays, a field of research is the application of neurofeedback techniques in order to help stroke patients to get rid of their motor impairments. Especially, if a certain limb is completely paralyzed, neurofeedback is often the last option to cure the patient. Certain exercises, like the imagination of the impaired motor function, have to be performed to stimulate the neuroplasticity of the brain, such that in the neighboring parts of the injured cortex the corresponding activity takes place. During the exercises, it is very important to keep the motivation of the patient at a high level. For this reason, the missing natural feedback due to a movement of the effected limb may be replaced by a synthetic feedback based on the motor-related brain function. To generate such a synthetic feedback a system is needed which measures, detects, localizes and visualizes the motor related µ-rhythm. Fast therapeutic success can only be achieved if the feedback features high specificity, comes in real-time and without large delay. We describe such an approach that offers a 3D visualization of µ-rhythms in real time with a delay of 500ms. This is accomplished by combining smart EEG preprocessing in the frequency domain with source localization techniques. The algorithm first selects the EEG channel featuring the most prominent rhythm in the alpha frequency band from a so-called motor channel set (C4, CZ, C3; CP6, CP4, CP2, CP1, CP3, CP5). If the amplitude in the alpha frequency band of this certain electrode exceeds a threshold, a µ-rhythm is detected. To prevent detection of a mixture of posterior alpha activity and µ-activity, the amplitudes in the alpha band outside the motor channel set are not allowed to be in the same range as the main channel. The EEG signal of the main channel is used as template for calculating the spatial distribution of the µ - rhythm over all electrodes. This spatial distribution is the input for a inverse method which provides the 3D distribution of the µ - activity within the brain which is visualized in 3D as color coded activity map. This approach mitigates the influence of lid artifacts on the localization performance. The first results of several healthy subjects show that the system is capable of detecting and localizing the rarely appearing µ-rhythm. In most cases the results match with findings from visual EEG analysis. Frequent eye-lid artifacts have no influence on the system performance. Furthermore, the system will be able to run in real-time. Due to the design of the frequency transformation the processing delay is 500ms. First results are promising and we plan to extend the test data set to further evaluate the performance of the system. The relevance of the system with respect to the therapy of stroke patients has to be shown in studies with real patients after CE certification of the system. This work was performed within the project ‘LiveSolo’ funded by the Austrian Research Promotion Agency (FFG) (project number: 853263).

Keywords: real-time EEG neuroimaging, neurofeedback, stroke, EEG–signal processing, rehabilitation

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Authors: Korbinian Schmidtner, Rudolf Sailer, Perry Bartelt, Wolfgang Fellin, Jan-Thomas Fischer, Matthias Granig

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This study focuses on the evaluation of snow avalanche simulations, based on a survey that has been carried out among avalanche experts. In the last decades, the application of avalanche simulation tools has gained recognition within the realm of hazard management. Traditionally, avalanche runout models were used to predict extreme avalanche runout and prepare avalanche maps. This has changed rather dramatically with the application of numerical models. For safety regulations such as road safety simulation tools are now being coupled with real-time meteorological measurements to predict frequent avalanche hazard. That places new demands on model accuracy and requires the simulation of physical processes that previously could be ignored. These simulation tools are based on a deterministic description of the avalanche movement allowing to predict certain quantities (e.g. pressure, velocities, flow heights, runout lengths etc.) of the avalanche flow. Because of the highly variable regimes of the flowing snow, no uniform rheological law describing the motion of an avalanche is known. Therefore, analogies to fluid dynamical laws of other materials are stated. To transfer these constitutional laws to snow flows, certain assumptions and adjustments have to be imposed. Besides these limitations, there exist high uncertainties regarding the initial and boundary conditions. Further challenges arise when implementing the underlying flow model equations into an algorithm executable by a computer. This implementation is constrained by the choice of adequate numerical methods and their computational feasibility. Hence, the model development is compelled to introduce further simplifications and the related uncertainties. In the light of these issues many questions arise on avalanche simulations, on their assets and drawbacks, on potentials for improvements as well as their application in practice. To address these questions a survey among experts in the field of avalanche science (e.g. researchers, practitioners, engineers) from various countries has been conducted. In the questionnaire, special attention is drawn on the expert’s opinion regarding the influence of certain variables on the simulation result, their uncertainty and the reliability of the results. Furthermore, it was tested to which degree a simulation result influences the decision making for a hazard assessment. A discrepancy could be found between a large uncertainty of the simulation input parameters as compared to a relatively high reliability of the results. This contradiction can be explained taking into account how the experts employ the simulations. The credibility of the simulations is the result of a rather thoroughly simulation study, where different assumptions are tested, comparing the results of different flow models along with the use of supplemental data such as chronicles, field observation, silent witnesses i.a. which are regarded as essential for the hazard assessment and for sanctioning simulation results. As the importance of avalanche simulations grows within the hazard management along with their further development studies focusing on the modeling fashion could contribute to a better understanding how knowledge of the avalanche process can be gained by running simulations.

Keywords: expert interview, hazard management, modeling, simulation, snow avalanche

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Authors: Marcel Verwey, Anna M. Joubert, Elsie M. Nolte, Wolfgang Dohle, Barry V. L. Potter, Anne E. Theron

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A tetrahydroisoquinolinone (THIQ) core can be used to mimic the A,B-ring of colchicine site-binding microtubule disruptors such as 2-methoxyestradiol in the design of anti-cancer agents. Steroidomimeric microtubule disruptors were synthesized by introducing C'2 and C'3 of the steroidal A-ring to C'6 and C'7 of the THIQ core and by introducing a decorated hydrogen bond acceptor motif projecting from the steroidal D-ring to N'2. For this in vitro study, four non-steroidal THIQ-based analogues were investigated and comparative studies were done between the non-sulphamoylated compound STX 3450 and the sulphamoylated compounds STX 2895, STX 3329 and STX 3451. The objective of this study was to investigate the modes of cell death induced by these four THIQ-based analogues in A549 lung carcinoma epithelial cells and metastatic breast adenocarcinoma MDA-MB-231 cells. Cytotoxicity studies to determine the half maximal growth inhibitory concentrations were done using spectrophotometric quantification via crystal violet staining and lactate dehydrogenase (LDH) assays. Microtubule integrity and morphologic changes of exposed cells were investigated using polarization-optical transmitted light differential interference contrast microscopy, transmission electron microscopy and confocal microscopy. Flow cytometric quantification was used to determine apoptosis induction and the effect that THIQ-based analogues have on cell cycle progression. Signal transduction pathways were elucidated by quantification of the mitochondrial membrane integrity, cytochrome c release and caspase 3, -6 and -8 activation. Induction of autophagic cell death by the THIQ-based analogues was investigated by morphological assessment of fluorescent monodansylcadaverine (MDC) staining of acidic vacuoles and by quantifying aggresome formation via flow cytometry. Results revealed that these non-steroidal microtubule disrupting analogues inhibited 50% of cell growth at nanomolar concentrations. Immunofluorescence microscopy indicated microtubule depolarization and the resultant mitotic arrest was further confirmed through cell cycle analysis. Apoptosis induction via the intrinsic pathway was observed due to depolarization of the mitochondrial membrane, induction of cytochrome c release as well as, caspase 3 activation. Potential involvement of programmed cell death type II was observed due to the presence of acidic vacuoles and aggresome formation. Necrotic cell death did not contribute significantly, indicated by stable LDH levels. This in vitro study revealed the induction of the intrinsic apoptotic pathway as well as possible involvement of autophagy after exposure to these THIQ-based analogues in both MDA-MB-231- and A549 cells. Further investigation of this series of anticancer drugs still needs to be conducted to elucidate the temporal, mechanistic and functional crosstalk mechanisms between the two observed programmed cell deaths pathways.

Keywords: apoptosis, autophagy, cancer, microtubule disruptor

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Authors: Sascha Kraus, Wolfgang Hora, Philipp Stieg, Thomas Niemand, Ferdinand Thies, Matthias Filser

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In most countries, small and medium-sized enterprises (SME) are the backbone of the economy due to their impact on job creation, innovation and wealth creation. Moreover, the ongoing globalization makes it inevitable – even for SME that traditionally focused on their domestic markets – to internationalize their business activities to realize further growth and survive in international markets. Thus, internationalization has become one of the most common growth strategies for SME and has received increasing scholarly attention over the last two decades. One the downside internationalization can be also regarded as the most complex strategy that a firm can undertake. Particularly for family firms, that are often characterized by limited financial capital, a risk-averse nature and limited growth aspirations, it could be argued that family firms are more likely to face greater challenges when taking the pathway to internationalization. Especially the triangulation of family, ownership, and management (so-called ‘familiness’) manifests in a unique behavior and decision-making process which is often characterized by the importance given to noneconomic goals and distinguishes a family firm from other businesses. Taking this into account, the concept of socio-emotional wealth (SEW) has been evolved to describe the behavior of family firms. In order to investigate how different internal and external firm characteristics shape internationalization success of family firms, we drew on a sample consisting of 297 small and medium-sized family firms from Germany, Austria, Switzerland, and Liechtenstein. Thus, we include SEW as essential family firm characteristic and added the two major intra-organizational characteristics, entrepreneurial orientation (EO), absorptive capacity (AC) as well as collaboration intensity (CI) and relational knowledge (RK) as two major external network characteristics. Based on previous research we assume that these characteristics are important to explain internationalization success of family firm SME. Regarding the data analysis, we applied a Fuzzy Set Qualitative Comparative Analysis (fsQCA), an approach that allows identifying configurations of firm characteristics, specifically used to study complex causal relationships where traditional regression techniques reach their limits. Results indicate that several combinations of these family firm characteristics can lead to international success, with no permanently required key characteristic. Instead, there are many roads to walk down for family firms to achieve internationalization success. Consequently, our data states that family owned SME are heterogeneous and internationalization is a complex and dynamic process. Results further show that network related characteristics occur in all sets, thus represent an essential element in the internationalization process of family owned SME. The contribution of our study is twofold, as we investigate different forms of international expansion for family firms and how to improve them. First, we are able to broaden the understanding of the intersection between family firm and SME internationalization with respect to major intra-organizational and network-related variables. Second, from a practical perspective, we offer family firm owners a basis for setting up internal capabilities to achieve international success.

Keywords: entrepreneurial orientation, family firm, fsQCA, internationalization, socio-emotional wealth

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Authors: Alaa Fezai, Anuj Sharma, Wolfgang Mueller-Hirsch, André Zimmermann

Abstract:

Viscoelastic materials have been widely used in the automotive industry over the last few decades with different functionalities. Besides their main application as a simple and efficient surface damping treatment, they may ensure optimal operating conditions for on-board electronics as thermal interface or sealing layers. The dynamic behavior of viscoelastic materials is generally dependent on many environmental factors, the most important being temperature and strain rate or frequency. Prior to the reliability analysis of systems including viscoelastic layers, it is, therefore, crucial to accurately predict the dynamic and lifetime behavior of these materials. This includes the identification of the dynamic material parameters under critical temperature and frequency conditions along with a precise damage localization and identification methodology. The goal of this work is twofold. The first part aims at applying an inverse viscoelastic material-characterization approach for a wide frequency range and under different temperature conditions. For this sake, dynamic measurements are carried on a single lap joint specimen using an electrodynamic shaker and an environmental chamber. The specimen consists of aluminum beams assembled to adapter plates through a viscoelastic adhesive layer. The experimental setup is reproduced in finite element (FE) simulations, and frequency response functions (FRF) are calculated. The parameters of both the generalized Maxwell model and the fractional derivatives model are identified through an optimization algorithm minimizing the difference between the simulated and the measured FRFs. The second goal of the current work is to guarantee an on-line detection of the damage, i.e., delamination in the viscoelastic bonding of the described specimen during frequency monitored end-of-life testing. For this purpose, an inverse technique, which determines the damage location and size based on the modal frequency shift and on the change of the mode shapes, is presented. This includes a preliminary FE model-based study correlating the delamination location and size to the change in the modal parameters and a subsequent experimental validation achieved through dynamic measurements of specimen with different, pre-generated crack scenarios and comparing it to the virgin specimen. The main advantage of the inverse characterization approach presented in the first part resides in the ability of adequately identifying the material damping and stiffness behavior of soft viscoelastic materials over a wide frequency range and under critical temperature conditions. Classic forward characterization techniques such as dynamic mechanical analysis are usually linked to limitations under critical temperature and frequency conditions due to the material behavior of soft viscoelastic materials. Furthermore, the inverse damage detection described in the second part guarantees an accurate prediction of not only the damage size but also its location using a simple test setup and outlines; therefore, the significance of inverse numerical-experimental approaches in predicting the dynamic behavior of soft bonding layers applied in automotive electronics.

Keywords: damage detection, dynamic characterization, inverse approaches, vibration testing, viscoelastic layers

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Authors: Christiane Paulus

Abstract:

Post-Islamism assumes that the Quran should not be viewed in terms of what Lyotard identifies as a ‘meta-narrative'. However, its socio-ethical content can be viewed as critical of power discourse (Foucault). Practicing religion seems to be limited to rites and individual spirituality, taqwa. Alternatively, can we build on Muhammad Abduh's classic-modern reform and develop it through a postmodernist frame? This is the main question of this study. Through his general and vague remarks on the context of the Quran, Abduh was the first to refer to the historical and cultural distance of the text as an obstacle for interpretation. His application, however, corresponded to the modern absolute idea of authentic sharia. He was followed by Amin al-Khuli, who hermeneutically linked the content of the Quran to the theory of evolution. Fazlur Rahman and Nasr Hamid abu Zeid remain reluctant to go beyond the general level in terms of context. The hermeneutic circle, therefore, persists in challenging, how to get out to overcome one’s own assumptions. The insight into and the acceptance of the lasting ambivalence of understanding can be grasped as a postmodern approach; it is documented in Derrida's discovery of the shift in text meanings, difference, also in Lyotard's theory of différend. The resulting mixture of meanings (Wolfgang Welsch) can be read together with the classic ambiguity of the premodern interpreters of the Quran (Thomas Bauer). Confronting hermeneutic difficulties in general, Niklas Luhmann proves every description an attribution, tautology, i.e., remaining in the circle. ‘De-tautologization’ is possible, namely by analyzing the distinctions in the sense of objective, temporal and social information that every text contains. This could be expanded with the Kantian aesthetic dimension of reason (critique of pure judgment) corresponding to the iʽgaz of the Coran. Luhmann asks, ‘What distinction does the observer/author make?’ Quran as a speech from God to the first listeners could be seen as a discourse responding to the problems of everyday life of that time, which can be viewed as the general goal of the entire Qoran. Through reconstructing koranic Lifeworlds (Alfred Schütz) in detail, the social structure crystallizes the socio-economic differences, the enormous poverty. The koranic instruction to provide the basic needs for the neglected groups, which often intersect (old, poor, slaves, women, children), can be seen immediately in the text. First, the references to lifeworlds/social problems and discourses in longer koranic passages should be hypothesized. Subsequently, information from the classic commentaries could be extracted, the classical Tafseer, in particular, contains rich narrative material for reconstructing. By selecting and assigning suitable, specific context information, the meaning of the description becomes condensed (Clifford Geertz). In this manner, the text gets necessarily an alienation and is newly accessible. The socio-ethical implications can thus be grasped from the difference of the original problem and the revealed/improved order/procedure; this small step can be materialized as such, not as an absolute solution but as offering plausible patterns for today’s challenges as the Agenda 2030.

Keywords: postmodern hermeneutics, condensed description, sociological approach, small steps of reform

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