Search

The Zurich region frequently ranks among the top innovative and competitive regions in the world. This chapter explores the drivers of Zurich’s unique interplay of high competitiveness and innovativeness, distilling the important components of this far-reaching innovation ecosystem. The analysis not only evaluates the relative strengths of resources for economic activities, but also includes the institutional, political, and social characteristics of the Zurich region ecosystem.

System dynamics (SD) is an established discipline to model and simulate complex dynamic systems. The primary goal of SD is to evaluate and design new policies that can impact the system under study in a desired way. Policy design, that is, identifying effective model levers, however, is a challenge and in many cases trial-and-error driven. In this article, we introduce a new and coherent framework for model analysis, called structural analysis methods (SAM), to facilitate the policy design process in complex SD models. SAM provides a resource-efficient and effective means for the detection of candidate policy parameters. It enables to identify intended and unintended effects of activating these policy parameters, and to discover candidate structural changes such as introducing new variables and links in SD models. The main innovation of SAM is that it translates the structure of SD models into weighted digraphs allowing algorithmic tools from the realms of graph theory and network science to be applied to SD. SAM is validated on the basis of two well-known simulation models of increasing complexity: the third-order Phosphorus Loops in Soil and Sediment (PLUM) model and the fifth-order World2 model. The validation shows that SAM seems to be most valuable for the analysis of more complex simulation models (World2) and is less suited for the analysis of low complexity models (PLUM)., Simulation Modelling Practice and Theory, 110, ISSN:1569-190X

Leleu, A., et al., Determining the architecture of multi-planetary systems is one of the cornerstones of understanding planet formation and evolution. Resonant systems are especially important as the fragility of their orbital configuration ensures that no significant scattering or collisional event has taken place since the earliest formation phase when the parent protoplanetary disc was still present. In this context, TOI-178 has been the subject of particular attention since the first TESS observations hinted at the possible presence of a near 2:3:3 resonant chain. Here we report the results of observations from CHEOPS, ESPRESSO, NGTS, and SPECULOOS with the aim of deciphering the peculiar orbital architecture of the system. We show that TOI-178 harbours at least six planets in the super-Earth to mini-Neptune regimes, with radii ranging from 1.152to 2.87Earth radii and periods of 1.91, 3.24, 6.56, 9.96, 15.23, and 20.71 days. All planets but the innermost one form a 2:4:6:9:12 chain of Laplace resonances, and the planetary densities show important variations from planet to planet, jumping from 1.02to 0.177times the Earth's density between planets c and d. Using Bayesian interior structure retrieval models, we show that the amount of gas in the planets does not vary in a monotonous way, contrary to what one would expect from simple formation and evolution models and unlike other known systems in a chain of Laplace resonances. The brightness of TOI-178 (H = 8.76 mag, J = 9.37 mag, V = 11.95 mag) allows for a precise characterisation of its orbital architecture as well as of the physical nature of the six presently known transiting planets it harbours. The peculiar orbital configuration and the diversity in average density among the planets in the system will enable the study of interior planetary structures and atmospheric evolution, providing important clues on the formation of super-Earths and mini-Neptunes., The authors acknowledge support from the Swiss NCCR PlanetS and the Swiss National Science Foundation. Y.A. and M.J.H. acknowledge the support of the Swiss National Fund under grant 200020_172746. A.C.C. and T.W. acknowledge support from STFC consolidated grant number ST/M001296/1. This work was granted access to the HPC resources of MesoPSL financed by the Region Ile de France and the project Equip@Meso (reference ANR-10-EQPX-29-01) of the programme Investissements d’Avenir supervised by the Agence Nationale pour la Recherche. SH acknowledges CNES funding through the grant 837319. Based on data collected under the NGTS project at the ESO La Silla Paranal Observatory. The NGTS facility is operated by the consortium institutes with support from the UK Science and Technology Facilities Council (STFC) project ST/M001962/1. The Belgian participation to CHEOPS has been supported by the Belgian Federal Science Policy Office (BELSPO) in the framework of the PRODEX Program, and by the University of Liège through an ARC grant for Concerted Research Actions financed by the Wallonia-Brussels Federation. V.A. acknowledges the support from FCT through Investigador FCT contract nr. IF/00650/2015/CP1273/CT0001. We acknowledge support from the Spanish Ministry of Science and Innovation and the European Regional Development Fund through grants ESP2016-80435-C2-1-R, ESP2016-80435-C2-2-R, PGC2018-098153-B-C33, PGC2018-098153-B-C31, ESP2017-87676-C5-1-R, MDM-2017-0737 Unidad de Excelencia “María de Maeztu”- Centro de Astrobiología (INTA-CSIC), as well as the support of the Generalitat de Catalunya/CERCA programme. The MOC activities have been supported by the ESA contract No. 4000124370. S.C.C.B. acknowledges support from FCT through FCT contracts nr. IF/01312/2014/CP1215/CT0004. X.B., S.C., D.G., M.F. and J.L. acknowledge their role as ESA-appointed CHEOPS science team members. ABr was supported by the SNSA. A.C. acknowledges support by CFisUC projects (UIDB/04564/2020 and UIDP/04564/2020), GRAVITY (PTDC/FIS-AST/7002/2020), ENGAGE SKA (POCI-01-0145-FEDER-022217), and PHOBOS (POCI-01-0145-FEDER-029932), funded by COMPETE 2020 and FCT, Portugal. This work was supported by FCT - Fundaçãopara a Ciência e a Tecnologia through national funds and by FEDER through COMPETE2020 - Programa OperacionalCompetitividade e Internacionalização by these grants: UID/FIS/04434/2019; UIDB/04434/2020; UIDP/04434/2020; PTDC/FIS-AST/32113/2017 and POCI-01-0145-FEDER- 032113; PTDC/FIS-AST/28953/2017 and POCI-01-0145-FEDER-028953; PTDC/FIS-AST/28987/2017 and POCI-01-0145-FEDER-028987. O.D.S.D. is supported in the form of work contract (DL 57/2016/CP1364/CT0004) funded by national funds through FCT. B.-O.D. acknowledges support from the Swiss National Science Foundation (PP00P2-190080). M.F. and C.M.P. gratefully acknowledgethe support of the Swedish National Space Agency (DNR 65/19, 174/18). D.G. gratefully acknowledges financial support from the CRT foundation under Grant No. 2018.2323 “Gaseousor rocky? Unveiling the nature of small worlds”. E.G. gratefully acknowledges support from the David and Claudia Harding Foundation in the form of a WintonExoplanet Fellowship. M.G. is an F.R.S.-FNRS Senior Research Associate. J.I.G.H. acknowledges financial support from Spanish Ministry of Science and Innovation (MICINN) under the 2013 Ramón y Cajal programme RYC-2013-14875. J.I.G.H., A.S.M., R.R., and C.A.P. acknowledge financial support from the Spanish MICINN AYA2017-86389-P. A.S.M. acknowledges financial support from the Spanish Ministry of Science and Innovation (MICINN) under the 2019 Juan de la Cierva Programme. MNG ackowledges support from the MIT Kavli Institute as a Juan Carlos Torres Fellow. J.H. acknowledges the support of the Swiss National Fund under grant 200020_172746. KGI is the ESA CHEOPS Project Scientist and is responsible for the ESA CHEOPS Guest Observers Programme.She does not participate in, or contribute to, the definition of the Guaranteed Time Programme of the CHEOPS mission through which observations described in this paper have been taken, nor to any aspect of target selection forthe programme. J.S.J. acknowledges support by FONDECYT grant 1201371, and partial support from CONICYT project Basal AFB-170002. A.J. acknowledges support from ANID - Millennium Science Initiative - ICN12_009 and from FONDECYT project 1171208. P.M. acknowledges support from STFC research grant number ST/M001040/1. N.J.N is supported by the contract and exploratory project IF/00852/2015, and projects UID/FIS/04434/2019, PTDC/FIS-OUT/29048/2017, COMPETE2020: POCI-01-0145-FEDER-028987 & FCT: PTDC/FIS-AST/28987/2017. N.J.N is supported by the contract and exploratory project IF/00852/2015, and project PTDC/FIS-OUT/29048/2017. This work was also partially supported by a grant from the Simons Foundation (PI Queloz, grant number 327127). Acknowledges support from the Spanish Ministry of Science and Innovation and the European Regional Development Fund through grant PGC2018-098153-B- C33, as well as the support of the Generalitat de Catalunya/CERCA programme. S.G.S. acknowledges support from FCT through FCT contract nr. CEECIND/00826/2018 and POPH/FSE (EC). This work has made use of data from the European Space Agency (ESA) mission Gaia (https://www.cosmos.esa.int/gaia), processed by the Gaia Data Processing and Analysis Consortium (DPAC, https://www.cosmos.esa.int/web/gaia/dpac/consortium). Funding for the DPAC has been provided by national institutions, in particular the institutions participating in the Gaia Multilateral Agreement. This project has been supported by the Hungarian National Research, Development and Innovation Office (NKFIH) grants GINOP-2.3.2-15-2016-00003, K-119517, K-125015, and the City of Szombathely under Agreement No. 67.177-21/2016. This research received funding from the MERAC foundation, from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement no 803193/ BEBOP, and from the Science and Technology Facilites Council (STFC, grant no ST/S00193X/1). V.V.G. is an F.R.S-FNRS Research Associate. J.I.V. acknowledges support of CONICYT-PFCHA/Doctorado Nacional-21191829. M. R. Z. O. acknowledges financial support from projects AYA2016-79425-C3-2-P and PID2019-109522GB-C51 from the Spanish Ministry of Science, Innovation and Universities.

M. J. Hooton et al., [Context] The light curves of tidally locked hot Jupiters transiting fast-rotating, early-type stars are a rich source of information about both the planet and star, with full-phase coverage enabling a detailed atmospheric characterisation of the planet. Although it is possible to determine the true spin–orbit angle Ψ – a notoriously difficult parameter to measure – from any transit asymmetry resulting from gravity darkening induced by the stellar rotation, the correlations that exist between the transit parameters have led to large disagreements in published values of Ψ for some systems., [Aims] We aimed to study these phenomena in the light curves of the ultra-hot Jupiter MASCARA-1 b, which is characteristically similar to well-studied contemporaries such as KELT-9 b and WASP-33 b., [Methods] We obtained optical CHaracterising ExOPlanet Satellite (CHEOPS) transit and occultation light curves of MASCARA-1 b, and analysed them jointly with a Spitzer/IRAC 4.5 μm full-phase curve to model the asymmetric transits, occultations, and phase-dependent flux modulation. For the latter, we employed a novel physics-driven approach to jointly fit the phase modulation by generating a single 2D temperature map and integrating it over the two bandpasses as a function of phase to account for the differing planet–star flux contrasts. The reflected light component was modelled using the general ab initio solution for a semi-infinite atmosphere., [Results] When fitting the CHEOPS and Spitzer transits together, the degeneracies are greatly diminished and return results consistent with previously published Doppler tomography. Placing priors informed by the tomography achieves even better precision, allowing a determination of Ψ = 72.1−2.4+2.5 deg. From the occultations and phase variations, we derived dayside and nightside temperatures of 3062−68+66 K and 1720 ± 330 K, respectively.Our retrieval suggests that the dayside emission spectrum closely follows that of a blackbody. As the CHEOPS occultation is too deep to be attributed to blackbody flux alone, we could separately derive geometric albedo Ag = 0.171−0.068+0.066 and spherical albedo As = 0.266−0.100+0.097 from the CHEOPS data, and Bond albedoAB = 0.057−0.101+0.083 from the Spitzer phase curve.Although small, the Ag and As indicate that MASCARA-1 b is more reflective than most other ultra-hot Jupiters, where H− absorption is expected to dominate., [Conclusions] Where possible, priors informed by Doppler tomography should be used when fitting transits of fast-rotating stars, though multi-colour photometry may also unlock an accurate measurement of Ψ. Our approach to modelling the phase variations at different wavelengths provides a template for how to separate thermal emission from reflected light in spectrally resolved James Webb Space Telescope phase curve data., Y.A. acknowledge the support of the Swiss National Fund under grant 200020_172746. S.H. gratefully acknowledges CNES funding through the grant 837319. D.K. acknowledges partial financial support from the Center for Space and Habitability (CSH), the PlanetS National Center of Competence in Research (NCCR), and the Swiss National Science Foundation and the Swiss-based MERAC Foundation. A.C.C. and T.G.W. acknowledge support from STFC consolidated grant number ST/M001296/1. P.M. acknowledges support from STFC research grant number ST/M001040/1. This work was also partially supported by a grant from the Simons Foundation (PI Queloz, grant number 327127). B.-O.D. acknowledges support from the Swiss National Science Foundation (PP00P2-190080). S.S. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 833925, project STAREX). A.Br. was supported by the SNSA. This work was supported by FCT – Fundação para a Ciência e a Tecnologia through national funds and by FEDER through COMPETE2020 – Programa Operacional Competitividade e Internacionalizacão by these grants: UID/FIS/04434/2019, UIDB/04434/2020, UIDP/04434/2020, PTDC/FIS-AST/32113/2017 and POCI-01-0145-FEDER- 032113, PTDC/FIS-AST/28953/2017 and POCI-01-0145-FEDER-028953, PTDC/FIS-AST/28987/2017 and POCI-01-0145-FEDER-028987, O.D.S.D. is supported in the form of work contract (DL 57/2016/CP1364/CT0004) funded by national funds through FCT. We acknowledge support from the Spanish Ministry of Science and Innovation and the European Regional Development Fund through grants ESP2016-80435-C2-1-R, ESP2016-80435-C2-2-R, PGC2018-098153-B-C33, PGC2018-098153-B-C31, ESP2017-87676-C5-1-R, MDM-2017-0737 Unidad de Excelencia Maria de Maeztu-Centro de Astrobiologí a (INTA-CSIC), as well as the support of the Generalitat de Catalunya/CERCA programme. The MOC activities have been supported by the ESA contract No. 4000124370. S.C.C.B. acknowledges support from FCT through FCT contracts nr. IF/01312/2014/CP1215/CT0004. X.B., S.C., D.G., M.F., and J.L. acknowledge their roles as ESA-appointed CHEOPS science team members. This project was supported by the CNES. The Belgian participation to CHEOPS has been supported by the Belgian Federal Science Policy Office (BELSPO) in the framework of the PRODEX Program, and by the University of Liège through an ARC grant for Concerted Research Actions financed by the Wallonia-Brussels Federation. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (project FOUR ACES. grant agreement no. 724427). D.E. acknowledges financial support from the Swiss National Science Foundation for project 200021_200726. C.M.P. and M.F. gratefully acknowledge the support of the Swedish National Space Agency (DNR 65/19, 174/18). D.G. gratefully acknowledges financial support from the CRT foundation under Grant No. 2018.2323 ‘Gaseousor rocky? Unveiling the nature of small worlds’. M.G. is an F.R.S.-FNRS Senior Research Associate. KGI is the ESA CHEOPS Project Scientist and is responsible for the ESA CHEOPS Guest Observers Programme. She does not participate in, or contribute to, the definition of the Guaranteed Time Programme of the CHEOPS mission through which observations described in this paper have been taken, nor to any aspect of target selection for the programme. This work was granted access to the HPC resources of MesoPSL financed by the Region Ile de France and the project Equip@Meso (reference ANR-10-EQPX-29-01) of the programme Investissements d’Avenir supervised by the Agence Nationale pour la Recherche. Acknowledges support from the Spanish Ministry of Science and Innovation and the European Regional Development Fund through grant PGC2018-098153-B-C33, as well as the support of the Generalitat de Catalunya/CERCA programme. S.G.S. acknowledges support from FCT through FCT contract nr. CEECIND/00826/2018 and POPH/FSE (EC). This project has been supported by the Hungarian National Research, Development and Innovation Office (NKFIH) grants GINOP-2.3.2-15-2016-00003, K-119517, K-125015, and the City of Szombathely under Agreement No. 67.177-21/2016., , , ,

International audience; Background: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD.Methods and findings: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial.Conclusion: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

There is a common perception that Social Media, a form of digital social networks [Boyd and Ellison, 2007] have substantial innovation potential as they can create novel combinations of resources, knowledge, and ideas in the Schumpeterian perspective of innovation. [Schumpeter, 1942]. Furthermore, the innovation created through these “knowledge flows across organizational boundaries” [Chesbrough & Bogers, 2014] can be defined as “Open Innovation” since the interactive nature of Social Media specifically enables these “inflows and outflows of knowledge” [Chesbrough, 2003; Enkel et al., 2009] across firms and ecosystems at a speed and exponential nature never witnessed before. Consequently, Social Media appear to be an ideal tool for Open Innovation [Mount and Martinez, 2014]. The perspective of this work is centred around the inbound and outbound open innovation process designed to save costs and augment innovation possibilities [Bogers and West, 2012; Enkel, Gassmann & Chesbrough, 2009; Dahlander & Gann, 2010]. This research not only analyses social media usage as a tool for open innovation creation, which is a new field, it also addresses an area that is truly under-researched in this relation: SMEs.

Inductive heating of electrically insulating materials like fiberglass reinforced thermoplastics (FRTP) without susceptors is not possible. However, due to their low thermal conductivity a volumetric heat generation method is advisable to reach short heating times to melt this material for reshaping. This can be done with magnetic nanoparticles as susceptors within the thermoplastic of the FRTP using Neel relaxation. During the heating process the particle's magnetic moment rotates with the field while the particle itself is fixed within the thermoplastic. Therefore the heat dissipation of each particle depends on its orientation within the field. To achieve the maximum heat generation of the particles we pre-oriented the particles within a plastic at the best angle to the applied AC field for induction. To do this, five mass percent nanoparticles were dispersed in an epoxy resin, which was then hardened at room temperature in a static three Tesla magnetic field. After its solidification the heating behavior of the sample was compared to a reference sample, which was hardened without a field. The oriented particles showed an increased heating rate when oriented parallel to the applied AC field. The absorption rate was 3.3 times as high as the undirected reference sample. When the alternating electromagnetic field was perpendicular to the oriented particles, the specific absorption rate was similar to that of the reference sample. We compare this result with theory and with calculations from literature, and conduct a numerical simulation.

The boundaries of the firm shape the development of capabilities and the accumulation of knowledge within the firm. Changes in the firm’s boundaries therefore entail changes in how the firm creates...

Direct metal laser sintering (DMLS) is a selective laser melting (SLM) manufacturing process that can produce near net shape parts from metallic powders. A range of materials are suitable for SLM; they include various metals such as titanium, steel, aluminium, and cobalt-chrome alloys. This paper forms part of a research drive that aims to evaluate the material performance of the SLM-manufactured metals. It presents DMLS-produced Ti-6Al-4V, a titanium alloy often used in biomedical and aerospace applications. This paper also studies the effect of several heat treatments on the microstructure and mechanical properties of Ti-6Al-4V processed by SLM. It reports the achievable mechanical properties of the alloy, including quasi-static, crack growth behaviour, density and porosity distribution, and post-processing using various heat-treatment conditions.

Das Kleben mittels elektromagnetischer Induktion ermoglicht schnelle Prozesse und eine Aushartung auch dicker oder schwer zuganglicher Klebspalte. Fur die Formulierung induktiv hartender Klebstoffe sind Epoxidharze gut geeignet. Zur Verfugung stehen 1K- und 2K-Systeme, mit denen sowohl metallische Werkstoffe als auch Kunststoffe geklebt bzw. vergossen werden konnen.

Digital social networks should enhance innovation potential as they create novel combinations of resources, knowledge and ideas in the Schumpeteriansense of innovation. Evaluating the innovation potential of these social networks during this digital revolution is the research question this study seeks to answer. There is no doubt that social networks are a disruptive form of innovation, however do they foster innovation in return and if so, how? To answer this question, both quantitative and qualitative surveys methods have been combined. It appears that the interactive nature of social networksshould foster innovation by enabling diversity and information exchange between a wide variety of groups. Surprisingly, the empirical results from our surveys, both the personal interviews as well as online surveys provided somewhat negative results in regards to the “perceived” innovation impact of social networks. We refer to this as the “Digital Paradox”, an expression coined to illustrate that the diversity enabled by digital is not being leveraged to its full potential. Although a diverse group member is only a click away, thanks to digital, this does not necessarily create heterogeneity. On the contrary, it seems that digital is sometimes counterproductive by promoting heavy clustering between homogenous groups. Respondents acknowledged the benefits of social networks only at the very last stages of innovation, which also seems surprising. Furthermore we understand that the innovation potential of social networks is not fully realized at present within many enterprises due to organizational boundaries.

The KATRIN experiment aims to determine the neutrino mass scale with a sensitivity of 200 meV/c^2 (90% C.L.) by a precision measurement of the shape of the tritium $\beta$-spectrum in the endpoint region. The energy analysis of the decay electrons is achieved by a MAC-E filter spectrometer. To determine the transmission properties of the KATRIN main spectrometer, a mono-energetic and angular-selective electron source has been developed. In preparation for the second commissioning phase of the main spectrometer, a measurement phase was carried out at the KATRIN monitor spectrometer where the device was operated in a MAC-E filter setup for testing. The results of these measurements are compared with simulations using the particle-tracking software "Kassiopeia", which was developed in the KATRIN collaboration over recent years., Comment: 19 pages, 16 figures, submitted to European Physical Journal C

Hintergrund: Da aus Deutschland kaum Daten zur Heiminfusionstherapie bei chronisch Kranken vorliegen, wurde eine Studie zur Verlagerung der Infusionstherapie vom Krankenhaus/Arzt in das hausliche Umfeld des Patienten am Beispiel des Morbus Fabry durchgefuhrt. Methoden: In die offene, nicht kontrollierte, multizentrische, nicht-interventionelle Beobachtungsstudie wurden 69 Patienten mit M. Fabry aufgenommen. Die Betroffenen erhielten in 14-tagigen Abstanden eine intravenose Therapie mit dem Enzymersatzpraparat Agalsidase alfa. Nach einer Einstellungsphase in einem Spezialzentrum wurden die Folge-Infusionen durch eine geschulte Pflegekraft in der Wohnung des Patienten verabreicht. Primares Zielkriterium war die Veranderung der Patientenzufriedenheit auf einer 11-stufigen Likert-Skala. Ergebnisse: Die Beobachtungsdauer unter Heimtherapie betrug zwischen 96 und 401 Tagen (Median: 180 Tage; IQR: 166–184 Tage). Die Patientenzufriedenheit nahm unter der Heimtherapie signifikant zu (p = 0,001), bei gleichzeitig guter Vertraglichkeit und Sicherheit der Heiminfusionen. Die Lebensqualitat (SF-36) zeigte signifikante Verbesserungen bei der korperlichen Rollenfunktion (p = 0,003), den korperlichen Schmerzen (p = 0,032), der Vitalitat (p Schlussfolgerung: Chronisch kranke Patienten, die regelmasig Infusionen benotigen, konnen von einer Heimtherapie profitieren. Das Beispiel der Enzymersatztherapie bei Patienten mit M. Fabry zeigt, dass dies eine geeignete Option ist, wenn die bisherigen Infusionen in der Klinik/beim Arzt gut vertragen wurden.

This study focuses on how firms form and sequentially adapt their inter-organizational knowledge sourcing structures within research and development (R&D) alliances and how this process impacts their innovation performance. In contrast to the previous literature that mainly ignores the dynamic aspects of how firms adapt their search strategies, our approach accounts for sequential adaptation. Our proposed framework explores the role of simultaneous diversification and sequential adaptation of collaboration partners within R&D alliances according to specific innovation outcomes. The results emphasize that firms should not remain within the same search activities indefinitely, as non-adapting inter-organizational knowledge transfer structures lead to inferior performance. Notably, this study highlights important partner-type selectivity and identifies appropriate simultaneous diversification and sequential adaptation strategies in relation to specific innovation outcomes and firm sizes.

Invariant natural killer T (iNKT) cells are a specialised subset of T cells that are restricted to the MHC class I like molecule, CD1d. The ligands for iNKT cells are lipids, with the canonical superagonist being α-galactosylceramide, a non-mammalian glycosphingolipid. Trafficking of CD1d through the lysosome is required for the development of murine iNKT cells. Niemann-Pick type C (NPC) disease is a lysosomal storage disorder caused by dysfunction in either of two lysosomal proteins, NPC1 or NPC2, resulting in the storage of multiple lipids, including glycosphingolipids. In the NPC1 mouse model, iNKT cells are virtually undetectable, which is likely due to the inability of CD1d to be loaded with the selecting ligand due to defective lysosomal function and/or CD1d trafficking. However, in this study we have found that in NPC1 patients iNKT cells are present at normal frequencies, with no phenotypic or functional differences. In addi-tion, antigen-presenting cells derived from NPC1 patients are functionally competent to present several different CD1d/iNKT-cell ligands. This further supports the hypothesis that there are different trafficking requirements for the development of murine and human iNKT cells, and a functional lysosomal/late-endosomal compartment is not required for human iNKT-cell development.

M. Niemann-Pick Typ C (NPC) ist eine seltene, neuroviszerale lysosomale Speicherkrankheit. Auf der Basis einer Defizienz des NPC1- oder NPC2-Proteins kommt es zu einer Storung der Digestion von Plasmamembranlipiden mit konsekutiver lysosomaler Speicherung. Viszerale Befunde konnen der neurologischen Manifestation um Jahre vorausgehen. Der Verlaufstyp wird durch den Zeitpunkt und die Progression der Neurodegeneration bestimmt. Zur Behandlung der neurologischen Symptomatik steht eine Substratreduktionstherapie mit Miglustat zur Verfugung, die in einer klinischen Studie bei 72% der Patienten zu einer Stabilisierung bzw. Verlangsamung der Progredienz des Krankheitsbildes fuhrte und heute in Europa die einzige zugelassene Therapieoption fur diese Patienten ist. Der Krankheitsverlauf und der Nutzen einer Therapie mit Miglustat sollten regelmasig standardisiert dokumentiert werden. Weitere Forschungsbemuhungen zum molekularen Verstandnis und zur Klinik des NPC sind notwendig, um betroffenen Patienten so fruh wie moglich einer zielorientierten und wirksamen Behandlung zum Eindammen der normalerweise progredienten Erkrankung zuzufuhren.

Aim: To evaluate the safety and explore the efficacy of enzyme replacement therapy (ERT) for Fabry disease with agalsidase alfa in young children enrolled in the Fabry Outcome Survey (FOS). Methods: This retrospective chart review identified eight children (mean age = 5.0 ± 1.6 [mean ± SD]) in FOS who began treatment with agalsidase alfa (0.2 mg/kg, i.v., every other week) when

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked, recessive, lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase. It has multisystemic involvement, with manifestations in the brain, upper respiratory tract, heart, abdomen, joints and bones. Bone involvement leads to decreased growth velocity and short stature in nearly all patients. A therapeutic option for patients with MPS II is enzyme replacement therapy (ERT) with idursulfase (Elaprase®). We compared annual growth rates before and during ERT in 18 patients from Mainz, Germany, and Manchester, UK. Group 1 included nine patients who started ERT before 10 years of age; group 2 contained nine patients aged more than 10 years at the start of ERT. All patients had received weekly or biweekly ERT or placebo for 1 year, followed by ERT for more than 3 years. For patients in group 1, the mean (± SD) height increase was 14.6 ± 5.5 cm during 3 years of ERT. Only one patient in this group (who was below the 3rd percentile when starting ERT) deviated from the normal growth curve over this time. Patients in group 2 had a mean height increase of 8.1 ± 1.7 cm after 3 years of ERT compared with an increase of 1 cm in the year before ERT. ERT seems to have a positive influence on growth in patients with MPS II. Most benefit is seen in patients beginning ERT before the age of 10 years. This supports the recommendation that ERT should be started as early as possible in patients with MPS II.

Background: Fabry disease is a rare X-linked lysosomal storage disorder characterised by severe multisystemic involvement that leads to major organ failure and premature death in affected men and women. Over the past 7 years, the Fabry Outcome Survey (FOS) has collected data on the natural history of Fabry disease, and the long-term efficacy and safety of enzyme-replacement therapy. This paper provides an update on the first analysis of FOS data. Design: Baseline data on clinical manifestations and causes of death in a cohort of 1453 patients (699 male, 754 female) from 19 countries worldwide were analysed. Causes of death of affected relatives were analysed separately. Results: The most frequently reported signs and symptoms of Fabry disease were neurological. Cardiac, ocular, gastrointestinal, dermatological, auditory and renal manifestations were also common. The principal causes of death among 181 affected relatives of patients in FOS (most of whom had died before 2001) were renal failure in males (42%) and cerebrovascular disease in females (25%). In contrast, of the 42 patients enrolled in FOS whose deaths were reported between 2001 and 2007, cardiac disease was the main cause of death in both male (34%) and female (57%) patients. Conclusion: These data suggest that the importance of renal disease as a cause of death in patients with Fabry disease is decreasing while the importance of cardiac disease is increasing. This pattern probably reflects improvements in the management of renal disease in patients with Fabry disease.

Growth factors are often used in tissue regeneration to stimulate vascularisation of polymeric scaffolds, with vascular endothelial growth factor (VEGF) having been extensively studied for short-term vessel ingrowth. We have therefore evaluated the effect of different concentrations of VEGF on the vascularisation of a porous scaffold in the short-, intermediate- and long-term, by delivering 15, 150 and 1500ng VEGF/day to polyurethane scaffolds by osmotic pumps for up to 6 weeks. An increased vascularisation months after termination of VEGF delivery was only achieved with 150ng/day (46%, p

Mukopolysaccharidosen sind seltene Erkrankungen, die den katabolen, lysosomalen Stoffwechsel betreffen. Diese heriditaren Erkrankungen bewirken eine progrediente Schadigung von Zellen, Geweben und Organen mit einem grosen Spektrum an Phanotypen. Um irreversible Schaden zu vermeiden, ist eine fruhzeitige Diagnosestellung anhand von typischen Leitsymptomen und Symptomkomplexen anzustreben. Fruhe radiologische Zeichen sind der Gibbus am thorakolumbalen Ubergang, verkurzte und verplumpte Metakarpalia, azetabulare Dysplasie, ruderblattformige Rippen und multiforme Wirbelkorper. Es findet sich eine typische Beckenkonfiguration, die meist im Kindesalter zur Ausbildung einer Huftluxation fuhrt. Haufig tritt ein beidseitiges Karpaltunnelsyndrom auf. Als systemische Therapie steht die Stammzelltransplantation und Enzymersatztherapie zur Verfugung. Orthopadische Behandlungen stellen meist Individualentscheidungen dar.

Background and objective Fabry's disease is a rare, X-chromosome linked recessive lysosomal storage disorder. In its course multiple organ damage occurs, e.g. in skin, nerves, kidneys and heart. The disease not only markedly impairs the quality of life but also shortens life expectancy if untreated. As it is a rare and not widely known disease with considerable variability of its symptoms it is often not or only belatedly diagnosed. Since 2001, enzyme replacement has become available as an option in the causal treatment. It was the aim of this study to analyse the demography and clinical expression of the disease. Patients and methods Data were obtained from the Fabry Outcome Survey (FOS), a Europe-wide data bank for the documentation of the disease's clinical course, on 262 patients (130 males, 132 females; mean age 37.5 and 34 years, respectively on entry in the FOS) in Germany, Switzerland and Austria. Results Typical symptoms - acroparesthesias, joint pain, hypohidrosis, fever and angiokeratoma - have their onset in childhood (mean age nine years). Symptoms start significantly earlier in males than females. The interval between onset of the first symptoms and establishment of the diagnosis is about 15 years. The severity of the clinical picture, as measured in the POS Mainz severity score index (MSSI), correlates significantly with the person's age (p = 0.0001). Main causes of morbidity and death in Fabry's disease are involvement of the kidneys or heart, the one or other occurring in 75% of patients. 171 patients (38 [65.3%]: 92 males, 79 females) are at present being continually treated with enzyme-replacement (ERT), agalsidase-a, i.e. 70.8% of all male and 59.8 of all female patients in the FOS. Conclusions It is of great importance for the prognosis and quality that Fabry's disease is diagnosed as early as possible and treated adequately before the onset of organ damage. If the listed symptoms by themselves remain unexplained, Fabry's disease should be considered in the differential diagnosis. National and international observational studies, such as the FOS, significantly contribute to gaining important clinical data on this heterogeneous disease.

Introduction: The most common subtype of Gaucher disease is the non-neuronopathic form with only visceral symptoms. At the opposite end of the spectrum is chronic neuronopathic Gaucher disease with severe neurological symptoms and typically a decreased life span. Methods: We report 15 patients (median age at manifestation, 1.2 years) with chronic neuronopathic Gaucher disease and 20 patients with non-neuronopathic Gaucher disease (median age at manifestation, 3.0 years). Results: In most patients with chronic neuronopathic Gaucher disease (12 out of 15), the 1448T-C mutation was found, whereas in 18 out of 20 patients with non-neuronopathic Gaucher disease the mutation identified was N370S. At initial presentation, patients with chronic neuronopathic Gaucher disease had significantly higher chitotriosidase levels (median, 21 307 versus 5611 nmol/ml/hour). Thirteen of these patients had a strabismus, all patients suffered from saccade initiation failure, and eight of the nine patients assessed showed abnormal brainstem auditory evoked response (BAER) (none of these were found in patients with non-neuronopathic disease). Three of the patients with neuronopathic disease had multifocal myoclonic epilepsy. Additionally, in ten of these patients pulmonary manifestation was seen (versus three of the patients with non-neuronopathic Gaucher disease). After treatment with enzyme replacement therapy (60–120 IU/kg) for between 18 months and 8 years, three of the children with chronic neuronopathic Gaucher disease experienced an improvement in BAER. Eight out of the nine patients with bone pain before enzyme replacement therapy had no pain. The patients with non-neuronopathic Gaucher disease received 60 IU/kg or less to maintain their therapy response and were observed for 3–13 years. Conclusion: Neurological manifestations are often associated with chitotriosidase activities greater than 20 000. In patients with chronic neuronopathic Gaucher disease, a higher dose between 60 and 120 IU/kg bodyweight may be required to reduce the visceral manifestations of disease.

This study investigates the efficacy of public R&D support. Compared to most existing studies, we do not stop at substitution effects or general innovation outcome measures, but we are interested in knowing where the policy effect is highest: on innovation close to the market (i.e. incremental innovation) or on innovation that is still far from the market and hence more risky and radical. Using firm level data from the period 1999 to 2011, we find that the policy hits where the market failure is highest, that is, for radical innovation. Taking into account that the Swiss funding agency encourages collaboration, we find no evidence that the impact of the policy is positively effected by various R&D collaboration patterns.

In order to estimate the cumulative incidence rates of the mucopolysaccharidoses (MPS) in Germany, a retrospective epidemiological survey covering the period between 1980 and 1995 was implemented. Multiple ascertainment sources were used to identify affected patients. A prevalence of approximately 0.69 cases per 100,000 births was obtained for MPS I (Hurler phenotype). Within the study period, 4 patients with Hurler/Scheie phenotype and 7 cases with Scheie disease were detected. The cumulative incidence for MPS II (Hunter syndrome) was estimated as 0.64 cases per 100,000 births (1.3 cases per 100,000 male live births); that for MPS III (Sanfilippo syndrome types A, B and C) as 1.57 cases in 100,000 births; that for MPS IV A (Morquio syndrome) as 0.38 cases in 100,000; and that for MPS VI (Maroteaux-Lamy syndrome) as 0.23 cases per 100,000 births. Two cases of MPS IVB (beta-galactosidase deficiency) have been identified, but no patients with MPS VII or MPS IX. A relatively high number of patients with MPS IIIB, MPS IVA and MPS VI were of Turkish origin. The crude rate for all types of mucopolysaccharidoses is approximately 3.53 cases in 100,000 live births. The cumulative incidence pattern of MPS in Germany was compared with the corresponding rates among other industrial nations obtained from recent literature: the crude cumulative rates for all types of mucopolysaccharidoses (3.4-4.5 in 100,000 live births) were similar among all published populations; however, different frequencies of the various forms of MPS were observed.

Background Fabry disease is a rare X-linked disorder caused by deficient activity of the lysosomal enzyme α-galactosidase A. Progressive accumulation of the substrate globotriaosylceramide in cells throughout the body leads to major organ failure and premature death. The Fabry Outcome Survey (FOS) is a European outcomes database which was established to collect data on the natural history of this little-known disease and to monitor the long-term efficacy and safety of enzyme replacement therapy (ERT) with agalsidase alfa. This paper presents the first analysis of the FOS database on the effects of ERT on renal function, heart size, pain and quality of life. Design The effects of 1 and 2 years of ERT with agalsidase alfa on renal function (assessed by estimated glomerular filtration rate), heart size (assessed by echocardiography), pain (assessed by the Brief Pain Inventory) and quality of life (assessed by the European Quality of Life Questionnaire EQ-5D) were analyzed in a cohort of 545 patients, 314 of whom were receiving treatment (188 for at least 12 months and 92 for at least 24 months; mean duration of treatment, 17 months; maximum duration, 56 months). Results Treatment with agalsidase alfa stabilized renal function in patients with a mild or moderate deterioration in renal function at baseline, reduced left ventricular size in patients who had an enlarged heart at baseline, and improved pain scores and quality of life. These improvements were similar in hemizygous men and heterozygous women with Fabry disease. Conclusions Enzyme replacement therapy with agalsidase alfa leads to significant clinical benefits in patients with Fabry disease, and treatment is likely to alter the natural history of this disorder.

Eine 26-jahrige Patientin wurde unter der Diagnose "Fieber unbekannter Ursache" und Nierenversagen aufgenommen. Mittels Nierenbiopsie, einschlieslich histologischer, immunhistochemischer und elektronenmikroskopischer Verfahren wurden neben einem Morbus Fabry, eine extrakapillar-proliferative Glomerulonephritis (mit Halbmondbildung) und granulomatose interstitielle Nephritis diagnostiziert. Der Bruder der Patientin hatte vor Jahren eine Nierenbiopsie mit der Diagnose einer metabolischen Storung. Die Nachbeurteilung dieser Nierenbiopsie zeigte auch hier Nierenveranderungen im Rahmen eines Morbus Fabry, wobei assoziiert eine tubulointerstitielle Nephritis vorlag. Nach unserer Kenntnis ist dies die erste Familie, bei der ein Morbus Fabry kombiniert mit weiteren Nierenveranderungen bei 2 Familienmitgliedern vorlag.

Summary: Extensive clinical heterogeneity is seen in lysosomal storage disorders, regarding the age of onset and severity of symptoms, the organs involved, and effects on the central nervous system. A broad phenotypic spectrum is seen, for example, in mucopolysaccharidosis type I (Hurler/Scheie disease), Gaucher disease, the severalforms of GM2-gangliosidosis and the different manifestations of β-galactosidasedeficiency (GM1-gangliosidosis and Morquio disease type B). Variable clinical expression of the same enzyme defect is not well understood. The presence of different mutations is only part of the explanation, as intrafamilial variability is observed in many cases. Other mechanisms, for example the effect of specific activators, may also have an influence on phenotype.

UNLABELLED It is well known that patients with atopic disease have anomalies of fatty acid composition in their blood. The aim of the present study was to evaluate whether infants from atopic families also have abnormal cord blood levels of long-chain polyunsaturated fatty acids (LC-PUFA) in plasma and red blood cells. The levels of LC-PUFA in umbilical cord blood of 50 healthy, full-term infants with a hereditary risk of atopic disease were analysed and compared with a control group of 50 infants from families without a history of atopic disease. The atopy group was comprised of children from families suffering from atopic dermatitis, allergic rhinitis, asthma bronchiale and food allergy. Within this group, a group (n = 11) was formed in which the risk was determined only by paternal atopy. Fatty acids of plasma and red blood cell phospholipids, triglycerides and sterol esters were separated by high-resolution gas-liquid chromatography. In particular, the levels of arachidonic acid (C20:4n-6) and docosatetraenoic acid (C22:4n-6) were significantly lower in infants at risk of atopic disease than in infants not at risk. Interestingly, there were more significant differences shown between the control group and the paternal atopy group than between the control group and the entire atopy group. CONCLUSION The results of this study could be due to a genetic influence of fatty acid metabolism or could reflect the different dietary behaviours of the mothers during pregnancy.

2×2 parallel fed and 3×3 serial fed patch antenna arrays on a benzocyclobutene (BCB) polymer layer are integrated with a 70 μm wide, dry etched, double metal waveguide quantum cascade laser, operating at about 1.9 THz. The BCB surrounds the quantum cascade laser ridge and is planarized to fit precisely its height. The patch antenna arrays emit a linearly polarized, highly symmetric beam perpendicular to the antenna plane. The beams have a FWHM angle of 49° (2×2) and 35° (3×3). Both measurements and simulations indicate coupling factors to a Gaussian beam of over 90%. The antenna design is strongly governed by the high thickness (h=13.6 μm) and the low dielectric constant (ϵsubr/sub=2.45) of the BCB substrate. Because the patch array has a very low input reflectivity of -13 to -20 dB over the 1.7-2.1 THz operation band, the laser needs a partially transmitting reflector to maintain the Q-factor of the active medium resonator to assure lasing in the antennas operation band. By changing the dimensions of the reflector, the facet transparency can be designed in a wide range from fully transmissive to highly reflective.

Terrorism is a complex problem and therefore simple solutions focusing just on one aspect are destined to fail. We have to capture terrorism in its entirety and system dynamics offers various tools to support us. We developed a semi-quantitative system dynamics approach aiming to characterize relationships between different variables and their impact on the system as a whole. The authors established a network to model terrorism consisting of 16 variables and performed different analysis to gain a better understanding of the mechanisms behind terrorism. We showed how to determine which variables are suited for intervention and described in detail their effects on the influence of the terrorist organization. The paper gives also an insight how to elicit elements that destabilize and ultimately break down the terror network. Because we clarify our approach using fictitious numbers, the relevance of this work is not so much in specific policy recommendations that it proposes as in the framework for reasoning that it provides.

The increasing complexity of the modern world creates both higher risks and new interdependencies in the socioeconomic environment. To cope with these challenges powerful new tools must be applied to find sustainable solutions. System dynamics is a field that offers potential assistance in dealing with complex issues. However, managers and politicians often lack the knowledge and necessary skills to apply quantitative methods in their decision-making process. In contrast, qualitative approaches are easily understood and handled but have limited capacities for analysis. To address this gap, we have developed a bundle of tools tailored for managers and politicians facing complex problems. These tools enable executives to recognize effective levers and assess potential consequences of specific interventions in a highly interconnected system. The approach detailed here equips decision makers with a powerful method to develop, test, and communicate strategies to find long-term sustainable solutions for complex issues in business and society.

The increasing complexity of the modern world creates both higher risks and new interdependencies in the socioeconomic environment. To cope with these challenges powerful new tools must be applied to find sustainable solutions. System dynamics is a field that offers potential assistance in dealing with complex issues. However, managers and politicians often lack the knowledge and necessary skills to apply quantitative methods in their decision-making process. In contrast, qualitative approaches are easily understood and handled but have limited capacities for analysis. To address this gap, we have developed a bundle of tools tailored for managers and politicians facing complex problems. These tools enable executives to recognize effective levers and assess potential consequences of specific interventions in a highly interconnected system. The approach detailed here equips decision makers with a powerful method to develop, test, and communicate strategies to find long-term sustainable solutions for complex issues in business and society.

The KATRIN experiment aims at the direct model-independent determination of the average electron neutrino mass via the measurement of the endpoint region of the tritium beta decay spectrum. The electron spectrometer of the MAC-E filter type is used, requiring very high stability of the electric filtering potential. This work proves the feasibility of implanted 83Rb/83mKr calibration electron sources which will be utilised in the additional monitor spectrometer sharing the high voltage with the main spectrometer of KATRIN. The source employs conversion electrons of 83mKr which is continuously generated by 83Rb. The K-32 conversion line (kinetic energy of 17.8 keV, natural line width of 2.7 eV) is shown to fulfill the KATRIN requirement of the relative energy stability of +/-1.6 ppm/month. The sources will serve as a standard tool for continuous monitoring of KATRIN's energy scale stability with sub-ppm precision. They may also be used in other applications where the precise conversion lines can be separated from the low energy spectrum caused by the electron inelastic scattering in the substrate., Comment: 30 pages, 10 figures, 1 table, minor revision of the preprint, accepted by JINST on 5.2.2013