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ZusammenfassungDas therapeutische Angebot der Klinik Zugersee beinhaltet Behandlungen für sämtliche Formen psychischer Erkrankungen (z. B. Depressionen, Ängste, Psychosen, Abhängigkeitserkrankungen und verschiedene Demenzformen) sowie psychosomatischer Erkrankungen (z. B. Schlafstörungen und Schmerzstörungen).

The transcription factor PAX8 is critical for the development of the thyroid and urogenital system. Comprehensive genomic screens furthermore indicate an additional oncogenic role for PAX8 in renal and ovarian cancers. While a plethora of PAX8-regulated genes in different contexts have been proposed, we still lack a mechanistic understanding of how PAX8 engages molecular complexes to drive disease-relevant oncogenic transcriptional programs. Here we show that protein isoforms originating from the MECOM locus form a complex with PAX8. These include MDS1-EVI1 (also called PRDM3) for which we map its interaction with PAX8 in vitro and in vivo. We show that PAX8 binds a large number of genomic sites and forms transcriptional hubs. At a subset of these, PAX8 together with PRDM3 regulates a specific gene expression module involved in adhesion and extracellular matrix. This gene module correlates with PAX8 and MECOM expression in large scale profiling of cell lines, patient-derived xenografts (PDXs) and clinical cases and stratifies gynecological cancer cases with worse prognosis. PRDM3 is amplified in ovarian cancers and we show that the MECOM locus and PAX8 sustain in vivo tumor growth, further supporting that the identified function of the MECOM locus underlies PAX8-driven oncogenic functions in ovarian cancer., Lineage-restricted transcription factor PAX8 is oncogenic in ovarian cancer cells. Here the authors show that PAX8 interacts and recruits a splice variant of the MECOM locus PRDM3 to control the gene expression module involved in adhesion and extracellular matrix, and consequently promotes ovarian tumorigenesis.

Die Digitalisierung der Produktdokumentation eroffnet mittels Augmented Reality neue Moglichkeiten im Produktlebenszyklus, im Engineering, in der Produktion und der Produktnutzungsphase.

Pseudoenzymes have burst into the limelight recently as they provide another dimension to regulation of cellular protein activity. In the eudicot plant lineage, the pseudoenzyme PDX1.2 and its cognate enzyme PDX1.3 interact to regulate vitamin B6 biosynthesis. This partnership is important for plant fitness during environmental stress, in particular heat stress. PDX1.2 increases the catalytic activity of PDX1.3, with an overall increase in vitamin B6 biosynthesis. However, the mechanism by which this is achieved is not known. In this study, the Arabidopsis thaliana PDX1.2–PDX1.3 complex was crystallized in the absence and presence of ligands, and attempts were made to solve the X-ray structures. Three PDX1.2–PDX1.3 complex structures are presented: the PDX1.2–PDX1.3 complex as isolated, PDX1.2–PDX1.3-intermediate (in the presence of substrates) and a catalytically inactive complex, PDX1.2–PDX1.3-K97A. Data were also collected from a crystal of a selenomethionine-substituted complex, PDX1.2–PDX1.3-SeMet. In all cases the protein complexes assemble as dodecamers, similar to the recently reported individual PDX1.3 homomer. Intriguingly, the crystals of the protein complex are statistically disordered owing to the high degree of structural similarity of the individual PDX1 proteins, such that the resulting configuration is a composite of both proteins. Despite the differential methionine content, selenomethionine substitution of the PDX1.2–PDX1.3 complex did not resolve the problem. Furthermore, a comparison of the catalytically competent complex with a noncatalytic complex did not facilitate the resolution of the individual proteins. Interestingly, another catalytic lysine in PDX1.3 (Lys165) that pivots between the two active sites in PDX1 (P1 and P2), and the corresponding glutamine (Gln169) in PDX1.2, point towards P1, which is distinctive to the initial priming for catalytic action. This state was previously only observed upon trapping PDX1.3 in a catalytically operational state, as Lys165 points towards P2 in the resting state. Overall, the study shows that the integration of PDX1.2 into a heteromeric dodecamer assembly with PDX1.3 does not cause a major structural deviation from the overall architecture of the homomeric complex. Nonetheless, the structure of the PDX1.2–PDX1.3 complex highlights enhanced flexibility in key catalytic regions for the initial steps of vitamin B6 biosynthesis. This report highlights what may be an intrinsic limitation of X-ray crystallography in the structural investigation of pseudoenzymes.

To study the behavior of MDM2-p53 inhibitors in a disease-relevant cellular model, we have developed and validated a set of bioorthogonal probes that can be fluorescently labeled in cells and used in high-content screening assays. By using automated image analysis with single-cell resolution, we could visualize the intracellular target binding of compounds by co-localization and quantify target upregulation upon MDM2-p53 inhibition in an osteosarcoma model. Additionally, we developed a high-throughput assay to quantify target occupancy of non-tagged MDM2-p53 inhibitors by competition and to identify novel chemical matter. This approach could be expanded to other targets for lead discovery applications.

CLK2 inhibition has been proposed as a potential mechanism to improve autism and neuronal functions in Phelan-McDermid syndrome (PMDS). Herein, the discovery of a very potent indazole CLK inhibitor series and the CLK2 X-ray structure of the most potent analogue are reported. This new indazole series was identified through a biochemical CLK2 Caliper assay screen with 30k compounds selected by an in silico approach. Novel high-resolution X-ray structures of all CLKs, including the first CLK4 X-ray structure, bound to known CLK2 inhibitor tool compounds (e.g., TG003, CX-4945), are also shown and yield insight into inhibitor selectivity in the CLK family. The efficacy of the new CLK2 inhibitors from the indazole series was demonstrated in the mouse brain slice assay, and potential safety concerns were investigated. Genotoxicity findings in the human lymphocyte micronucleus test (MNT) assay are shown by using two structurally different CLK inhibitors to reveal a major concern for pan-CLK inhibition in PMDS.

Two cis-12,13-cyclopropyl-epothilone B variants have been synthesized, differing only in the configuration of the stereocenters at C12 and C13. The syntheses were based on a common allylic alcohol intermediate that was converted into the corresponding diastereomeric hydroxymethyl-cyclopropanes by means of stereoselective Charette cyclopropanations. Macrocyclizations were accomplished through ring-closing metathesis (RCM). Substantial differences between the two compounds were found with regard to microtubule binding affinity, antiproliferative activity and their effects on the cellular microtubule network. While the analogue with the cyclopropane moiety oriented in a corresponding way to the epoxide configuration in natural epothilones was almost equipotent with epothilone A, the other was significantly less active. Based on these findings, natural epothilone-like activity of cis-fused 12,13-cyclopropyl-epothilone analogues is tightly linked to the natural orientation of the cyclopropane moiety., K.H.A. and F.Z.G. are indebted to the Swiss National Science Foundation (SNF) (project 205320-117594) and ETH Zürich for generous financial support. J.F.D. acknowledges financial support by the Ministerio de Economia of Spain and from the Comunidad de Madrid (projects BIO2013-42984-R and S2010/BMD-2457 BIPPED, respectively).

Vitamin B6 is indispensible for all organisms, notably as the coenzyme form pyridoxal 5'-phosphate. Plants make the compound de novo using a relatively simple pathway comprising pyridoxine synthase (PDX1) and pyridoxine glutaminase (PDX2). PDX1 is remarkable given its multifaceted synthetic ability to carry out isomerization, imine formation, ammonia addition, aldol-type condensation, cyclization, and aromatization, all in the absence of coenzymes or recruitment of specialized domains. Two active sites (P1 and P2) facilitate the plethora of reactions, but it is not known how the two are coordinated and, moreover, if intermediates are tunneled between active sites. Here we present X-ray structures of PDX1.3 from Arabidopsis thaliana, the overall architecture of which is a dodecamer of (β/α)8 barrels, similar to the majority of its homologs. An apoenzyme structure revealed that features around the P1 active site in PDX1.3 have adopted inward conformations consistent with a catalytically primed state and delineated a substrate accessible cavity above this active site, not noted in other reported structures. Comparison with the structure of PDX1.3 with an intermediate along the catalytic trajectory demonstrated that a lysine residue swings from the distinct P2 site to the P1 site at this stage of catalysis and is held in place by a molecular catch and pin, positioning it for transfer of serviced substrate back to P2. The study shows that a simple lysine swinging arm coordinates use of chemically disparate sites, dispensing with the need for additional factors, and provides an elegant example of solving complex chemistry to generate an essential metabolite.

Fiber-reinforced polymer composites with integrated intelligence, such as sensors, actuators, and communication capabilities, are desirable as infrastructures for the next generation of "internet of things." However, the shape mismatch between the 3D composites and a planar electronic circuit causes difficulties in integrating electronic circuit-based intelligences. Here, an easily scalable approach, by incorporating a large-area stretchable circuit with thermoforming technology, to fabricate 3D multifunctional composites is reported. The stretchable circuit is first fabricated on a rigid and planar carrier board, then transferred and sandwiched between thermoplastic composites through lamination processes. A thermoforming step shapes the sandwiched and planar structure by heating up the encapsulating polymers beyond their glass transition temperature and pushing them and the circuit against a mold. Using the proposed process, large-sized composites with integrated matrices of light-emitting diodes (LEDs) and capacitive sensors are successfully fabricated. A giant (with a size of 0.5 m x 1 m) seven-segment display is assembled using the fabricated composites with integrated LEDs and capacitive sensors to display 128 symbols. The results demonstrate the potential of the proposed approach as a facile, reproducible, and scalable process for creating 3D multifunctional composites.

Die präoperative Evaluation dient der Risikobeurteilung des Patienten mit dem Ziel einer Risikominimierung für den anschließenden operativen Eingriff. In Abhängigkeit von Systemanamnese, Befunden und geplantem Eingriff werden bei Bedarf weitergehende Abklärungen durchgeführt. Der klinische Zustand des Patienten wird, falls nötig, optimiert und das perioperative Vorgehen geplant. Der Patient wird über Anästhesie und perioperative Periode aufgeklärt. Das Einverständnis zum vereinbarten Anästhesieverfahren wird eingeholt. Leistungsfähige Patienten ohne Risikofaktoren können dank neuer Technologien einfacher und effizienter evaluiert werden.

SummaryIn the study of protein complexes, is there a computational method for inferring which combinations of proteins in an organism are likely to form a crystallizable complex? Here we attempt to answer this question, using the Protein Data Bank (PDB) to assess the usefulness of inferred functional protein linkages from the Prolinks database. We find that of the 242 nonredundant prokaryotic protein complexes shared between the current PDB and Prolinks, 44% (107/242) contain proteins linked at high confidence by one or more methods of computed functional linkages. Similarly, high-confidence linkages detect 47% of known Escherichia coli protein complexes, with 45% accuracy. Together these findings suggest that functional linkages will be useful in defining protein complexes for structural studies, including for structural genomics. We offer a database of inferred linkages corresponding to likely protein complexes for some 629,952 pairs of proteins in 154 prokaryotes and archaea.

Fragile X syndrome (FXS) is the most common form of inherited mental retardation, and it is caused in most of cases by epigenetic silencing of the Fmr1 gene. Today, no specific therapy exists for FXS, and current treatments are only directed to improve behavioral symptoms. Neuronal progenitors derived from FXS patient induced pluripotent stem cells (iPSCs) represent a unique model to study the disease and develop assays for large-scale drug discovery screens since they conserve the Fmr1 gene silenced within the disease context. We have established a high-content imaging assay to run a large-scale phenotypic screen aimed to identify compounds that reactivate the silenced Fmr1 gene. A set of 50,000 compounds was tested, including modulators of several epigenetic targets. We describe an integrated drug discovery model comprising iPSC generation, culture scale-up, and quality control and screening with a very sensitive high-content imaging assay assisted by single-cell image analysis and multiparametric data analysis based on machine learning algorithms. The screening identified several compounds that induced a weak expression of fragile X mental retardation protein (FMRP) and thus sets the basis for further large-scale screens to find candidate drugs or targets tackling the underlying mechanism of FXS with potential for therapeutic intervention.

The measurement of the internal deformations occurring in real-life composite components is a very challenging task, especially for those components that are rather difficult to access. Optical fiber sensors can overcome such a problem, since they can be embedded in the composite materials and serve as in situ sensors. In this article, embedded optical fiber Bragg grating (FBG) sensors are used to analyze the vibration characteristics of two real-life composite components. The first component is a carbon fiber-reinforced polymer automotive control arm, the second is a glass fiber-reinforced polymer aeronautic hinge arm. The modal parameters of both components were estimated by processing the FBG signals with two interrogation techniques: the maximum detection and fast phase correlation algorithms were employed for the demodulation of the FBG signals, the Peak-Picking and PolyMax techniques were instead used for the parameter estimation. To validate the FBG outcomes, reference measurements were performed by means of a laser Doppler vibrometer. The analysis of the results showed that the FBG sensing capabilities were enhanced when the recently-introduced fast phase correlation algorithm was combined with the state-of-the-art PolyMax estimator curve fitting method. In this case, the FBGs provided the most accurate results, i.e., it was possible to fully characterize the vibration behavior of both composite components. When using more traditional interrogation algorithms (maximum detection) and modal parameter estimation techniques (Peak-Picking), some of the modes were not successfully identified.

Fibre Reinforced Polymer (FRP) is becoming a valid alternative to many traditional heavy metal industries because of its high specific stiffness over the more classical construction metals. Recent trend of more complex geometry of composites is causing increasing difficulty in composite manufacturing. A method to optimize the manufacturing process is thus imposed to ensure and improve the quality of manufactured parts. Because of the irregular 3D shapes of the composites, traditional flat sensor system is becoming unfavorable and nonpractical for monitoring purpose. In this work, the current development status of a deformable microsystem for in situ cure degree monitoring of a glass fibre reinforced plastic is presented. To accommodate the non-flat shape of the composites, the proposal is to interconnect non-deformable functional island, which contains the capacitive sensor for cure degree monitoring, with meander-shaped deformable interconnections. The developed sensor system is able to withstand the manufacturing process where change of pressure and internal strain, thus force exerted on the sensor system, is involved.

The crystal structure of the tetrameric form of D-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) isolated from rabbit muscle was solved at 2.4 A resolution after careful dynamic light-scattering experiments to find a suitable buffer for crystallization trials. The refined model has a crystallographic R factor of 20.3%. Here, the first detailed model of a mammalian GAPDH is presented. The cofactor NAD(+) (nicotinamide adenine dinucleotide) is bound to two subunits of the tetrameric enzyme, which is consistent with the negative cooperativity of NAD(+) binding to this enzyme. The structure of rabbit-muscle GAPDH is of interest because it shares 91% sequence identity with the human enzyme; human GAPDH is a potential target for the development of anti-apoptotic drugs. In addition, differences in the cofactor-binding pocket compared with the homology-model structure of GAPDH from the malaria parasite Plasmodium falciparum could be exploited in order to develop novel selective and potential antimalaria drugs.

Death effector domains (DEDs) are protein–protein interaction domains found in the death inducing signaling complex (DISC). Performing a structure-based alignment of all DED sequences we identified a region of high diversity in α-helix 3 and propose a classification of DEDs into class I DEDs typically containing a stretch of basic residues in the α-helix 3 region whereas DEDs of class II do not. Functional assays using mutants of Fas-associated death domain revealed that this basic region influences binding and recruitment of caspase-8 and cellular FLICE inhibitor protein to the DISC.

The crystal structure of a mutant form of the single-chain fragment (scFv), derived from the monoclonal anti-His tag antibody 3D5, in complex with a hexahistidine peptide has been determined at 2.7 A resolution. The peptide binds to a deep pocket formed at the interface of the variable domains of the light and the heavy chain, mainly through hydrophobic interaction to aromatic residues and hydrogen bonds to acidic residues. The antibody recognizes the C-terminal carboxylate group of the peptide as well as the main chain of the last four residues and the last three imidazole side-chains. The crystals have a solvent content of 77% (v/v) and form 70 A-wide channels that would allow the diffusion of peptides or even small proteins. The anti-His scFv crystals could thus act as a framework for the crystallization of His-tagged target proteins. Designed mutations in framework regions of the scFv lead to high-level expression of soluble protein in the periplasm of Escherichia coli. The recombinant anti-His scFv is a convenient detection tool when fused to alkaline phosphatase. When immobilized on a matrix, the antibody can be used for affinity purification of recombinant proteins carrying a very short tag of just three histidine residues, suitable for crystallization. The experimental structure is now the basis for the design of antibodies with even higher stability and affinity.

Unwanted enzyme side reactions and spontaneous decomposition of metabolites can lead to a build-up of compounds that compete with natural enzyme substrates and must be dealt with for efficient metabolism. It has recently been realized that there are enzymes that process such compounds, formulating the concept of metabolite repair. NADH and NADPH are vital cellular redox cofactors but can form non-functional hydrates (named NAD(P)HX) spontaneously or enzymatically that compete with enzymes dependent on NAD(P)H, impairing normal enzyme function. Here we report on the functional characterization of components of a potential NAD(P)H repair pathway in plants comprising a stereospecific dehydratase (NNRD) and an epimerase (NNRE), the latter being fused to a vitamin B6 salvage enzyme. Through the use of the recombinant proteins, we show that the ATP-dependent NNRD and NNRE act concomitantly to restore NAD(P)HX to NAD(P)H. NNRD behaves as a tetramer and NNRE as a dimer, but the proteins do not physically interact. In vivo fluorescence analysis demonstrates that the proteins are localized to mitochondria and/or plastids, implicating these as the key organelles where this repair is required. Expression analysis indicates that whereas NNRE is present ubiquitously, NNRD is restricted to seeds but appears to be dispensable during the normal Arabidopsis life cycle.

Vitamin B6 is an indispensable compound for survival, well known as a cofactor for numerous central metabolic enzymes and more recently for playing a role in several stress responses, particularly in association with oxidative stress. Regulatory aspects for the use of the vitamin in these roles are not known. Here we show that certain plants carry a pseudoenzyme (PDX1.2), which is involved in regulating vitamin B6 biosynthesis de novo under stress conditions. Specifically, we demonstrate that Arabidopsis PDX1.2 enhances the activity of its catalytic paralogs by forming a heterododecameric complex. PDX1.2 is strongly induced by heat as well as singlet oxygen stress, concomitant with an enhancement of vitamin B6 production. Analysis of pdx1.2 knockdown lines demonstrates that boosting vitamin B6 content is dependent on PDX1.2, revealing that this pseudoenzyme acts as a positive regulator of vitamin B6 biosynthesis during such stress conditions in plants., Journal of Biological Chemistry, 289 (12), ISSN:0021-9258, ISSN:1083-351X

Fuhrungskrafte in der Lebensmittelsicherheit mussen analytisch-methodisch fit sein und sich im internationalen Warenverkehr, bei der Ernahrungspolitik und der Toxikologie gut auskennen. Zudem sollten sie Kompetenzen in Betriebsfuhrung und Offentlichkeitsarbeit mitbringen. In der Schweiz tragt ein neues Ausbildungskonzept fur Lebensmittelchemiker diesen Anspruchen Rechnung.

A case study for the cost optimization of aircraft structures based on the operating cost as an objective function is presented. The proposed optimization framework contains modules for estimation of the weight, manufacturing cost, nondestructive inspection cost, and structural performance; the latter is enhanced by a kinematic draping model that allows the fiber angles to be simulated more realistically. The case study includes five material systems: aircraft-grade aluminum, two types of resin-transfer molded noncrimp fabric reinforcements, and two types of M21/T800 prepreg. The results are compared in relation to each other, and it is shown that (depending on the estimated fuel burn share of the component) a different material system is favorable when optimizing for low-operating cost. QC 20110907

Mycobacterium tuberculosis encodes five gene clusters (ESX-1 to ESX-5) for Type VII protein secretion systems that are implicated in mycobacterial pathogenicity. Substrates for the secretion apparatus are encoded within the gene clusters and in additional loci that lack the components of the secretion apparatus. The best characterized substrates are the ESX complexes, 1:1 heterodimers of ESAT-6 and CFP-10, the prototypical member that has been shown to be essential for Mycobacterium tuberculosis pathogenesis. We have determined the structure of EsxRS, a homolog of EsxGH of the ESX-3 gene cluster, at 1.91 Å resolution. The EsxRS structure is composed of two four-helix bundles resulting from the 3D domain swapping of the C-terminal domain of EsxS, the CFP-10 homolog. The four-helix bundles at the extremities of the complex have a similar architecture to the structure of ESAT-6·CFP-10 (EsxAB) of ESX-1, but in EsxRS a hinge loop linking the α-helical domains of EsxS undergoes a loop-to-helix transition that creates the domain swapped EsxRS tetramer. Based on the atomic structure of EsxRS and existing biochemical data on ESX complexes, we propose that higher order ESX oligomers may increase avidity of ESX binding to host receptor molecules or, alternatively, the conformational change that creates the domain swapped structure may be the basis of ESX complex dissociation that would free ESAT-6 to exert a cytotoxic effect.

The application of hand-laid carbon fiber prepreg is very expensive from a labor perspective. Therefore the manufacturing cost should be included in the design process. In this work, we propose a novel optimization framework which contains a draping simulation in combination with a detailed cost estimation package and the calculation of the structural performance based on FE. We suggest applying the methodology in two steps. First, a draping knowledge database is generated in which combinations of seed points and reference angles are evaluated in terms of fiber angle deviation, scrap, ultrasonic cuts and material shear. Second, a cost/weight optimization framework picks the best sets of plies during the subsequent optimization. The methodology is tested by means of a curved C-spar which is designed using plain weave and unidirectional prepreg. Different objectives in the generation of the draping database lead to different design solutions. Uppdaterad från submitted till published: 20100723 QC 20100723 European Framework Program 6, project ALCAS, AIP4-CT-2003-516092 Nationella flygtekniska forskningsprogrammet (NFFP) 4, project kostnadseffektiv kompositstruktur (KEKS)

A methodology for a combined cost/weight optimization of aircraft components is proposed. The objective function is formed by a simplified form of direct operating cost, i.e. by a weighted sum of the manufacturing costs and the component weight. Hence, the structural engineer can perform the evaluation of a design solution based on economical values rather than pure cost or weight targets.The parameter that governs the balance between manufacturing cost and weight is called weight penalty and incorporates the effect of fuel burn, environmental impact or contractual penalties due to overweight. Unlike previous work, the analytical cost model and structural models are replaced by commercially available software packages that allow a more realistic model of the manufacturing costs; further, arbitrary constraints for the structural analysis can be implemented. By means of parametric studies it is shown that the design solution strongly depends on the magnitude of the weight penalty. Parts of this paper have been presented as: Kaufmann M, Zenkert D, Wennhage W. "Integrated cost/weight optimization of composite skin/stringer elements", Proceedings of ICCM-16, Kyoto (2007). QC 20100723. European Framework Program 6, project ALCAS, AIP4-CT-2003-516092 Nationella flygtekniska forskningsprogrammet (NFFP) 4, project kostnadseffektiv kompositstruktur (KEKS)

Perioperative risk analysis and risk reduction is the main goal of every preoperative evaluation. Exercise tolerance is a key determinant of patient risk. Preoperative tests should only be ordered based on defined indications and relevant findings. Empathy towards the patient as well as good information is crucial. "Remote premedication" is a new method for low risk patient groups with phone and internet access. Based on modern information technology, this new method can be more efficient while preserving information flow and patient satisfaction.

BACKGROUND AND OBJECTIVES Alpha-2 agonists offer useful effects that make these drugs an interesting alternative for pharmacological premedication. METHODS In a randomized, double-blind study, effects of clonidine (150 microg orally), midazolam (7.5 mg orally) and placebo administered 60-90 min prior to estimated anaesthesia induction time were investigated in 60 healthy ASA I or II patients. All patients received dipotassiumchlorazepate the evening before surgery. At predefined time points, effects of premedication on bispectral index, sedation score and visual analogue scales for anxiety and pain, cognitive function and stress hormones were determined. RESULTS Administration of low-dose clonidine was associated with slightly lower bispectral index scores than a standard dose of midazolam or placebo. There were no significant differences in sedation score, visual analogue scale for anxiety and pain and cognitive function between treatment regimens. Clonidine, but not midazolam, reduced anaesthetic requirements for induction of anaesthesia and prevented an increase in heart rate as well as an increase in adrenocorticotropic hormone plasma levels during the preoperative period (P < 0.05 vs. placebo). Clonidine administration did not delay postoperative recovery. CONCLUSION Clonidine augmented haemodynamic stability and partially blunted stress responses as determined by adrenocorticotropic hormone plasma levels. In addition, clonidine did not delay postoperative recovery. Therefore, surrogate parameters indicate that preanaesthetic medication with clonidine may be superior to midazolam in healthy individuals. Further studies have to confirm these results with regard to outcome parameters.

Even though it is known that dental injuries may occur in connection with tracheal intubation, the topic has hardly been evaluated in literature so far. Thus, this retrospective study was conducted including the data of 115-151 patients. All patients involved had been exposed to general anesthesia between 1995 and 2005. The resulting tooth injuries were assessed according to the following parameters: age, kind of hospital conducting treatment, intubation difficulties, pre-existing tooth damage, type and localization of tooth, type of tooth damage, and the number of teeth injured. At least 170 teeth were injured in 130 patients, while patients 50 years of age and older were especially affected. In contrast to older patients where in the majority of cases the periodontium (lateral dislocation) was injured, in younger patients dental hard tissue (crown fracture) was more likely to be affected. It was calculated that patients from the cardiothoracic surgery clinic were showing the highest risk of tooth damage. In more than three-fourth of all cases the anterior teeth of the maxilla, especially the maxillary central incisors, were affected. Pre-existing dental pathology like caries, marginal periodontitis and tooth restorations were often distinguishable prior to operation. Mouthguards in connection with tracheal intubation are not generally recommended as preventive device, due to the already limited amount of space available. Instead, pre-existing risk factors should be thoroughly explored before the induction of intubation narcosis.

A methodology is developed that enables cost-efficient design of composite aircraft structures. In earlier work, a cost/weight optimisation framework was presented. This framework is here enhanced by a module that minimises the manufacturing cost in each iteration by adaptation of manufacturing parameters. The proposed framework is modular and applicable to a variety of parts and geometries. Commercially available software is used in all steps of theoptimisation. The framework extension is added to an existing cost/weight optimisation implementation and tested on an airliner centre wing box rear spar. Three optimisation runs are performed, and a low cost, an intermediate and a low weight design solution are found. The difference between the two extreme solutions is 4.4% in manufacturing cost and 9.7% in weight. Based on these optimisation trials, the effect of the introduced parameter adaptation module is analysed. QC 20100723 European Framework Program 6, project ALCAS, AIP4-CT-2003-516092 Nationella flygtekniska forskningsprogrammet (NFFP) 4, project kostnadseffektiv kompositstruktur (KEKS)

Composite structures can lower the weight of an airliner significantly. The increased production cost, however, requires the application of cost-effective design strategies in which cost, weight and the desired laminate quality are taken into account. This paper proposes an optimization framework for composite aircraft structures that minimizes the direct operating cost on a part level. In addition to previous models, a non-destructive testing model is implemented that calculates design allowables of a laminate based on ultrasonic scan parameters. In a case study, the effect of the laminate quality on the direct operating cost is discussed. It is investigated how the permissible flaw size and therefore the scan pitch of a composite laminate can influence the optimal solution in terms of cost and weight; thus, the manufacturing cost, the non-destructive testing cost and the weight of a component can be balanced by optimizing the laminate quality in an early design phase. QC 20100723 European Framework Program 6, project ALCAS, AIP4-CT-2003-516092 Nationella flygtekniska forskningsprogrammet (NFFP) 4, project kostnadseffektiv kompositstruktur (KEKS)

Oculocutaneous albinism (OCA) in man may be caused by mutations within the tyrosinase gene (TYR) resulting in OCA1. Analysing patients with recessively inherited albinism we found DNA variations in 82 unrelated individuals. 53 out of 78 mutations and polymorphisms revealed by this study are not published previously. The changes include 68 nucleotide substitutions resulting in amino acid changes, stop mutations and polymorphisms as well as four nucleotide insertions and six deletions. Furthermore, we found an accumulation of three to five mutations in 17 patients with OCA1.

The IICB(Glc) subunit of the glucose transporter acts by a mechanism which couples vectorial translocation with phosphorylation of the substrate. It contains 8 transmembrane segments connected by 4 periplasmic, 2 short, 1 long (80 residues), cytoplasmic loops and an independently folding cytoplasmic domain at the C-terminus. Random DNase I cleavage, EcoRI linker insertion, and screening for transport-active mutants afforded 12 variants with between 46% and 116% of wild-type sugar phosphorylation activity. They carried inserts of up to 29 residues and short deletions in periplasmic loops 1, 2, and 3, in the long cytoplasmic loop 3, and in the linker region between the membrane spanning IIC(Glc) and the cytoplasmic IIB(Glc) domains. Disruption of the gene at the sites of linker insertion decreased the expression level and diminished phosphotransferase activity to between 7% and 32%. IICB(Glc) with a discontinuity in the cytoplasmic loop was purified to homogeneity as a stable complex. It was active only if encoded by a dicistronic operon but not if encoded by two genes on two different replicons, suggesting that spatial proximity of the nascent polypeptide chains is important for folding and membrane assembly.

Oculocutaneous albinism (OCA) in man may be caused by mutations within the tyrosinase gene (TYR) resulting in OCA1. Analysing patients with recessively inherited albinism we found DNA variations in 82 unrelated individuals. 53 out of 78 mutations and polymorphisms revealed by this study are not published previously. The changes include 68 nucleotide substitutions resulting in amino acid changes, stop mutations and polymorphisms as well as four nucleotide insertions and six deletions. Furthermore, we found an accumulation of three to five mutations in 17 patients with OCA1. © 2004 Wiley-Liss, Inc.

The continuous growth of the composites industry accompanied by the use of emerging new materials and even more complex shapes and structures cause increasing difficulties in design, production and maintenance of composite products. One issue is the insufficient knowledge about the cure kinetics of the composites during the production phase, which directly results in some imperfectly cured composite parts. Another issue is the insufficient knowledge about the structural health of the composites, for instance the ageing, during the operation phase. In this paper, current progress in the development of a dielectric sensor system for the on-line cure monitoring of composites is presented. The dielectric sensor was fabricated by Printed Circuit Board (PCB) technology on a flexible substrate into a final interdigital structure. The dielectric properties of the resin, which were monitored by the interdigital sensor, changed during the curing. By analysing the dielectric data (relative permittivity, and loss factor), the degree of the cure can be understood. The data obtained in the experiments clearly showed the different stages of the cure, which can be used with confidence as a tool for the monitoring of the composite cure.

In this study, a capacitive sensing based non-destructive evaluation technique is applied to a vacuum assisted resin infusion process for the fabrication of glass fibre reinforced composites, as such different steps of the fabrication process (the injection of resin, the curing and the post curing) can be better understood to increase the quality of the fabricated part and reduce the fabrication costs. An interdigital coplanar capacitive sensor was designed, fabricated, and embedded in the glass fibre reinforced composites. Experimental data clearly shows different stages of the resin infusion process: wetting of the glass fibres marked by rapid increase of capacitance; domination of ionic conduction at the early stage of the cure when the resin is still in a liquid state; the vitrification point, indicating a transition of the resin from a gelly state to a glassy state, marked by the relatively big decrease in capacitance; further polymerization during post-curing, marked by a peak in capacitance at the beginning of post-curing cycle, and finally the completion of the cure marked by the saturation of capacitance to a final value. The different phenomena observed during the experiment can be used as a tool for in situ on-line monitoring of composites cure.