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2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene
(2003)
3D Printers as Sociable Technologies: Taking Appropriation Infrastructures to the Internet of Things
(2017)
The aim of design science research (DSR) in information systems is the user-centred creation of IT-artifacts with regard to specific social environments. For culture research in the field, which is necessary for a proper localization of IT-artifacts, models and research approaches from social sciences usually are adopted. Descriptive dimension-based culture models most commonly are applied for this purpose, which assume culture being a national phenomenon and tend to reduce it to basic values. Such models are useful for investigations in behavioural culture research because it aims to isolate, describe and explain culture-specific attitudes and characteristics within a selected society. In contrast, with the necessity to deduce concrete decisions for artifact-design, research results from DSR need to go beyond this aim. As hypothesis, this contribution generally questions the applicability of such generic culture dimensions’ models for DSR and focuses on their theoretical foundation, which goes back to Hofstede’s conceptual Onion Model of Culture. The herein applied literature-based analysis confirms the hypothesis. Consequently, an alternative conceptual culture model is being introduced and discussed as theoretical foundation for culture research in DSR.
A framework of decision‐support systems in advanced manufacturing enterprises ‐ a systems view
(1997)
Striated muscle contraction is regulated by the translocation of troponin-tropomyosin strands over the thin filament surface. Relaxation relies partly on highly-favorable, conformation-dependent electrostatic contacts between actin and tropomyosin, which position tropomyosin such that it impedes actomyosin associations. Impaired relaxation and hypercontractile properties are hallmarks of various muscle disorders. The α-cardiac actin M305L hypertrophic cardiomyopathy-causing mutation lies near residues that help confine tropomyosin to an inhibitory position along thin filaments. Here, we investigate M305L actin in vivo, in vitro, and in silico to resolve emergent pathological properties and disease mechanisms. Our data suggest the mutation reduces actin flexibility and distorts the actin-tropomyosin electrostatic energy landscape that, in muscle, result in aberrant contractile inhibition and excessive force. Thus, actin flexibility may be required to establish and maintain interfacial contacts with tropomyosin as well as facilitate its movement over distinct actin surface features and is, therefore, likely necessary for proper regulation of contraction.
Today’s computer systems face a vast array of severe threats that are posed by automated attacks performed by malicious software as well as manual attacks by individual humans. These attacks not only differ in their technical implementation but may also be location-dependent. Consequentially, it is necessary to join the information from heterogeneous and distributed attack sensors in order to acquire comprehensive information on current ongoing cyber attacks.
Currently, there are a lot of research activities dealing with gamma titanium aluminide (γ-TiAl) alloys as new materials for low pressure turbine (LPT) blades. Even though the scatter in mechanical properties of such intermetallic alloys is more distinctive as in conventional metallic alloys, stochastic investigations on γ -TiAl alloys are very rare. For this reason, we analyzed the scatter in static and dynamic mechanical properties of the cast alloy Ti-48Al-2Cr-2Nb. It was found that this alloy shows a size effect in strength which is less pronounced than the size effect of brittle materials. A weakest-link approach is enhanced for describing a scalable size effect under multiaxial stress states and implemented in a post processing tool for reliability analysis of real components. The presented approach is a first applicable reliability model for semi-brittle materials. The developed reliability tool was integrated into a multidisciplinary optimization of the geometry of a LPT blade. Some processes of the optimization were distributed in a wide area network, so that specialized tools for each discipline could be employed. The optimization results show that it is possible to increase the aerodynamic efficiency and the structural mechanics reliability at the same time, while ensuring the blade can be manufactured in an investment casting process.
A structural mapping of mutations causing succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency
(2013)
Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is a rare inherited metabolic disorder of ketone metabolism, characterized by ketoacidotic episodes and often permanent ketosis. To date there are ~20 disease-associated alleles on the OXCT1 gene that encodes the mitochondrial enzyme SCOT. SCOT catalyzes the first, rate-limiting step of ketone body utilization in peripheral tissues, by transferring a CoA moiety from succinyl-CoA to form acetoacetyl-CoA, for entry into the tricarboxylic acid cycle for energy production. We have determined the crystal structure of human SCOT, providing a molecular understanding of the reported mutations based on their potential structural effects. An interactive version of this manuscript (which may contain additional mutations appended after acceptance of this manuscript) may be found on the web address:
http://www.thesgc.org/jimd/SCOT
The article explores SME (Small and Medium Sized Enterprises) brand strategies as a means to position and successfully engage in competitive markets. A derived typology of brand strategy types deals with social profiling and sheds light on brand strategy internalization of two current managerial paradigms—sustainability and co-creation. N = 895 German SME wineries were examined, leaning on a netnographic analysis of predominantly websites and social media interactions. A two-step clustering method thereby identified eight winery SME brand strategy types. The importance of sustainability across the identified eight brand strategy types is significant. Co-creation turned out to be a key profiling trait characterizing one brand strategy type. The typology illustrates strategic richness, with brand strategies leaning predominantly on traditional values, on sustainability, on external reputation, or on more innovative customer centric concepts such as co-creation. Hereby, the typology and the identified brand levers invite to strategically design brand management, governance, and sustainability. Wineries which focus on traditional positioning and legitimacy were found to be cautious in deploying co-creation through social media. Winery brands that are characterized by engagement in digital co-creation apparently either tend to expand their scope or partially combine it with traditional values, making them the most diverse type identified. Sustainability obviously needs to be addressed by all brand strategies. Despite industry and country focus, the analyses illustrate the relevance of socially-oriented profiling and highlights that sustainability has reached a status of a fundamental business approach still allowing to differentiate thereon. Furthermore, the business models of the SMEs need to deliver communicated values.
AAV-encoded expression of TRAIL in experimental human colorectal cancer leads to tumor regression
(2004)
Hydrogen sulfide (H2S) is well known as a highly toxic environmental chemical threat. Prolonged exposure to H2S can lead to the formation of pulmonary edema. However, the mechanisms of how H2S facilitates edema formation are poorly understood. Since edema formation can be enhanced by an impaired clearance of electrolytes and, consequently, fluid across the alveolar epithelium, it was questioned whether H2S may interfere with transepithelial electrolyte absorption. Electrolyte absorption was electrophysiologically measured across native distal lung preparations (Xenopus laevis) in Ussing chambers. The exposure of lung epithelia to H2S decreased net transepithelial electrolyte absorption. This was due to an impairment of amiloride-sensitive sodium transport. H2S inhibited the activity of the Na+/K+-ATPase as well as lidocaine-sensitive potassium channels located in the basolateral membrane of the epithelium. Inhibition of these transport molecules diminishes the electrochemical gradient which is necessary for transepithelial sodium absorption. Since sodium absorption osmotically facilitates alveolar fluid clearance, interference of H2S with the epithelial transport machinery provides a mechanism which enhances edema formation in H2S-exposed lungs.
Adaptability as a Special Demand on Open Educational Resources: The Cultural Context of e-Learning
(2011)
Producing and providing Open Educational Resources (OERs) is driven by the concepts of openness and sharing. Although there already are a lot of free high-quality resources available, practitioners often rather rewrite learning resources than creatively embed (and thus, reuse) existing OERs. In this paper, we analyse the reasons for this in two different educational contexts. As a result of this analysis, we found that the uncertainty on possible adaptation needs is one of the major barriers. In order to overcome this barrier and make different learning contexts comparable, we analysed the context of learners and in particular, in the research project ‘Learning Culture’, we investigated the field of culturally motivated expectations and attitudes of learners. This paper shows the results of this research project and discusses which cultural issues should be taken into consideration when OERs are to be adapted from one to another cultural context.
Adaptation of e-Learning Environments: Determining National Differences through Context Metadata
(2008)
The paper shows how existing e-learning modules can be internationalized using structured information on the context and specifically culture. Reusing e-Learning contents is a promising concept for the internationalization or cross-cultural purposes. However, most adaptation efforts are often limited to pure language translation.
As the only alternative is rewriting, reusability allows a massive cost reduction by implementing and adapting already established courses, for example into developing countries on a low-cost level. Our approach provides a basis for international and cross-cultural adaptation. In the approach, we identify, collect and store as many parameters about the source and target context and culture as available. After comparing contexts, we determine changing needs by analyzing the impacting differences.
To implement this approach on a large-scale, we plan a public database containing the necessary information for the comparison process. In our research, we have identified a set of around 170 parameters describing national and, more specifically, cultural attributes related to various situations. Utilizing those in an adequate way will lead to an easier and efficient adaptation process.
One of the main aims of current social robotic research is to improve the robots’ abilities to interact with humans. In order to achieve an interaction similar to that among humans, robots should be able to communicate in an intuitive and natural way and appropriately interpret human affects during social interactions. Similarly to how humans are able to recognize emotions in other humans, machines are capable of extracting information from the various ways humans convey emotions-including facial expression, speech, gesture or text-and using this information for improved human computer interaction. This can be described as Affective Computing, an interdisciplinary field that expands into otherwise unrelated fields like psychology and cognitive science and involves the research and development of systems that can recognize and interpret human affects. To leverage these emotional capabilities by embedding them in humanoid robots is the foundation of the concept Affective Robots, which has the objective of making robots capable of sensing the user’s current mood and personality traits and adapt their behavior in the most appropriate manner based on that. In this paper, the emotion recognition capabilities of the humanoid robot Pepper are experimentally explored, based on the facial expressions for the so-called basic emotions, as well as how it performs in contrast to other state-of-the-art approaches with both expression databases compiled in academic environments and real subjects showing posed expressions as well as spontaneous emotional reactions. The experiments’ results show that the detection accuracy amongst the evaluated approaches differs substantially. The introduced experiments offer a general structure and approach for conducting such experimental evaluations. The paper further suggests that the most meaningful results are obtained by conducting experiments with real subjects expressing the emotions as spontaneous reactions.
The development of pulmonary edema can be considered as a combination of alveolar flooding via increased fluid filtration, impaired alveolar-capillary barrier integrity, and disturbed resolution due to decreased alveolar fluid clearance. An important mechanism regulating alveolar fluid clearance is sodium transport across the alveolar epithelium. Transepithelial sodium transport is largely dependent on the activity of sodium channels in alveolar epithelial cells. This paper describes how sodium channels contribute to alveolar fluid clearance under physiological conditions and how deregulation of sodium channel activity might contribute to the pathogenesis of lung diseases associated with pulmonary edema. Furthermore, sodium channels as putative molecular targets for the treatment of pulmonary edema are discussed.
Gene expression and cell growth rely on the intracellular concentration of amino acids, which in metazoans depends on extracellular amino acid availability and transmembrane transport. To investigate the impact of extracellular amino acid concentrations on the expression of a concentrative amino acid transporter, we overexpressed the main kidney proximal tubule luminal neutral amino acid transporter B0AT1-collectrin (SLC6A19-TMEM27) in MDCK cell epithelia. Exogenously expressed proteins co-localized at the luminal membrane and mediated neutral amino acid uptake. However, the transgenes were lost over few cell culture passages. In contrast, the expression of a control transgene remained stable. To test whether this loss was due to inappropriately high amino acid uptake, freshly transduced MDCK cell lines were cultivated either with physiological amounts of amino acids or with the high concentration found in standard cell culture media. Expression of exogenous transporters was unaffected by physiological amino acid concentration in the media. Interestingly, mycoplasma infection resulted in a significant increase in transgene expression and correlated with the rapid metabolism of L-arginine. However, L-arginine metabolites were shown to play no role in transgene expression. In contrast, activation of the GCN2 pathway revealed by an increase in eIF2α phosphorylation may trigger transgene derepression. Taken together, high extracellular amino acid concentration provided by cell culture media appears to inhibit the constitutive expression of concentrative amino acid transporters whereas L-arginine depletion by mycoplasma induces the expression of transgenes possibly via stimulation of the GCN2 pathway.
An exploratory study: Analysis of Serbian tourism market and identification of major market segments
(2016)
The limited sodium availability of freshwater and terrestrial environments was a major physiological challenge during vertebrate evolution. The epithelial sodium channel (ENaC) is present in the apical membrane of sodium-absorbing vertebrate epithelia and evolved as part of a machinery for efficient sodium conservation. ENaC belongs to the degenerin/ENaC protein family and is the only member that opens without an external stimulus. We hypothesized that ENaC evolved from a proton-activated sodium channel present in ionocytes of freshwater vertebrates and therefore investigated whether such ancestral traits are present in ENaC isoforms of the aquatic pipid frog Xenopus laevis. Using whole-cell and single-channel electrophysiology of Xenopus oocytes expressing ENaC isoforms assembled from alpha beta gamma- or delta beta gamma-subunit combinations, we demonstrate that Xenopus delta beta gamma-ENaC is profoundly activated by extracellular acidification within biologically relevant ranges (pH 8.0-6.0). This effect was not observed in Xenopus alpha beta gamma-ENaC or human ENaC orthologs. We show that protons interfere with allosteric ENaC inhibition by extracellular sodium ions, thereby increasing the probability of channel opening. Using homology modeling of ENaC structure and site-directed mutagenesis, we identified a cleft region within the extracellular loop of the delta-subunit that contains several acidic amino acid residues that confer proton-sensitivity and enable allosteric inhibition by extracellular sodium ions. We propose that Xenopus delta beta gamma-ENaC can serve as a model for investigating ENaC transformation from a proton-activated toward a constitutively-active ion channel. Such transformation might have occurred during the evolution of tetrapod vertebrates to enable bulk sodium absorption during the water-to-land transition.
Dihydropyrimidine dehydrogenase (DPD) deficiency is an infrequently described autosomal recessive disorder of the pyrimidine degradation pathway and can lead to mental and motor retardation and convulsions. DPD deficiency is also known to cause a potentially lethal toxicity following administration of the antineoplastic agent 5-fluorouracil. In an ongoing study of 72 DPD deficient patients, we analysed the molecular background of 5 patients in more detail in whom initial sequence analysis did not reveal pathogenic mutations. In three patients, a 13.8 kb deletion of exon 12 was found and in one patient a 122 kb deletion of exon 14–16 of DPYD. In the fifth patient, a c.299_302delTCAT mutation in exon 4 was found and also loss of heterozygosity of the entire DPD gene. Further analysis demonstrated a de novo deletion of approximately 14 Mb of chromosome 1p13.3–1p21.3, which includes DPYD. Haploinsufficiency of NTNG1, LPPR4, GPSM2, COL11A1 and VAV3 might have contributed to the severe psychomotor retardation and unusual craniofacial features in this patient. Our study showed for the first time the presence of genomic deletions affecting DPYD in 7% (5/72) of all DPD deficient patients. Therefore, screening of DPD deficient patients for genomic deletions should be considered.
BACKGROUND
Neuronal migration is a crucial process that allows neurons to reach their correct target location to allow the nervous system to function properly. AP-2alpha is a transcription factor essential for neural crest cell migration and its mutation results in apoptosis within this cell population, as demonstrated by genetic models.
RESULTS
We down-modulated AP-2alpha expression in GN-11 neurons by RNA interference and observe reduced neuron migration following the activation of a specific genetic programme including the Adhesion Related Kinase (Axl) gene. We prove that Axl is able to coordinate migration per se and by ChIP and promoter analysis we observe that its transcription is directly driven by AP-2alpha via the binding to one or more functional AP-2alpha binding sites present in its regulatory region. Analysis of migration in AP-2alpha null mouse embryo fibroblasts also reveals an essential role for AP-2alpha in cell movement via the activation of a distinct genetic programme.
CONCLUSION
We show that AP-2alpha plays an essential role in cell movement via the activation of cell-specific genetic programmes. Moreover, we demonstrate that the AP-2alpha regulated gene Axl is an essential player in GN-11 neuron migration.
Apoptosis in the terminal endbud of the murine mammary gland: a mechanism of ductal morphogenesis
(1996)
Autoantikörper und das Komplementsystem - Bedeutung für die Pathogenese der Rheumatoiden Arthritis?
(2002)
Automated force field optimisation of small molecules using a gradient-based workflow package
(2010)
In this study, the recently developed gradient-based optimisation workflow for the automated development of molecular models is for the first time applied to the parameterisation of force fields for molecular dynamics simulations. As a proof-of-concept, two small molecules (benzene and phosgene) are considered. In order to optimise the underlying intermolecular force field (described by the (12,6)-Lennard-Jones and the Coulomb potential), the energetic and diameter parameters ε and σ are fitted to experimental physical properties by gradient-based numerical optimisation techniques. Thereby, a quadratic loss function between experimental and simulated target properties is minimised with respect to the force field parameters. In this proof-of-concept, the considered physical target properties are chosen to be diverse: density, enthalpy of vapourisation and self-diffusion coefficient are optimised simultaneously at different temperatures. We found that in both cases, the optimisation could be successfully concluded by fulfillment of a pre-defined stopping criterion. Since a fairly small number of iterations were needed to do so, this study will serve as a good starting point for more complex systems and further improvements of the parametrisation task.
Introduction. The experience of pain is regularly accompanied by facial expressions. The gold standard for analyzing these facial expressions is the Facial Action Coding System (FACS), which provides so-called action units (AUs) as parametrical indicators of facial muscular activity. Particular combinations of AUs have appeared to be pain-indicative. The manual coding of AUs is, however, too time- and labor-intensive in clinical practice. New developments in automatic facial expression analysis have promised to enable automatic detection of AUs, which might be used for pain detection. Objective. Our aim is to compare manual with automatic AU coding of facial expressions of pain. Methods. FaceReader7 was used for automatic AU detection. We compared the performance of FaceReader7 using videos of 40 participants (20 younger with a mean age of 25.7 years and 20 older with a mean age of 52.1 years) undergoing experimentally induced heat pain to manually coded AUs as gold standard labeling. Percentages of correctly and falsely classified AUs were calculated, and we computed as indicators of congruency, "sensitivity/recall," "precision," and "overall agreement (F1)." Results. The automatic coding of AUs only showed poor to moderate outcomes regarding sensitivity/recall, precision, and F1. The congruency was better for younger compared to older faces and was better for pain-indicative AUs compared to other AUs. Conclusion. At the moment, automatic analyses of genuine facial expressions of pain may qualify at best as semiautomatic systems, which require further validation by human observers before they can be used to validly assess facial expressions of pain.
Yams of the most widely differing nature are produced in textile mills. The production stages necessary for this are carried out with the aid of textile machines. Between these individual textile machines - from cards to spinning machines - sliver cans serve as a rule as transport containers, in which the sensitive sliver material is temporarily stored, and presented to the next production stage.
Der vorliegende Beitrag befaßt sich mit Automatisierungsmöglichkeiten in Textilbetrieben für konventionelle als auch für nichtkonventionelle Spinnverfahren. Aus der Vielzahl derzeit existenter Produktionsschritte werden die standardisierbaren Automatisierungskombinationen zwischen den eingesetzten Textilmaschinen von Karden bis zu Spinnautomaten herausgearbeitet. Hierfür werden die heute in der Praxis befindlichen Transportmittel aufgezeigt und, vom Materialfluß ausgehend, die Zuordnungsmöglichkeiten der Maschinen in den Produktionsschritten und deren Automatisierungsbausteine definiert. Durch eine ganzheitliche Betrachtungsweise werden je nach Automatisierungsziel die verschiedenen Lösungsansätze diskutiert und als Bausteine gegenübergestellt. Hierdurch werden neue mechatronische Automatisierungslösungen vorgestellt, die eine Integration von Produktionsschritten oder die Automatisierung zwischen den einzelnen Produktionsschritten ermöglicht.
In an explorative study, we investigated on German schoolteachers how they use, reuse, produce and manage Open Educational Resources. The main questions in this research have been, what their motivators and barriers are in their use of Open Educational Resources, what others can learn from their Open Educational Practices, and what we can do to raise the dissemination level of OER in schools.
Bcl-2 is known to have dual antiproliferative and antiapoptotic roles. Overexpression of Bcl-2 in the mammary gland using a whey acidic protein (WAP) promoter-driven Bcl-2 transgene inhibits apoptosis in the mammary gland during pregnancy, lactation, and involution, and also counteracts apoptosis induced by overexpression of a mutant p53 transgene (WAP-p53 172 R-L). WAP-Bcl-2 mice and nontransgenic controls were treated with the carcinogen dimethylbenz(a)anthracene (DMBA). Surprisingly, the nontransgenic mice developed mammary tumors with decreased latency. Tumors arising in WAP-Bcl-2 mice displayed substantially reduced levels of proliferation relative to those seen in nontransgenic mice (P < 0.015), perhaps resulting in the observed increase in tumor latency following carcinogen treatment. This WAP-Bcl-2 mouse tumor model reflects the situation seen in some human breast cancers overexpressing Bcl-2, where expression of Bcl-2 has been shown to correlate with a lower proliferative index in tumors.