Haplotype-based association analysis of the MAPT locus in Late Onset Alzheimer's disease

BACKGROUND: Late onset Alzheimer's disease (LOAD) is a common sporadic form of the illness, affecting individuals above the age of 65 yrs. A prominent hypothesis for the aetiopathology of Alzheimer's disease is that in the presence of a β-amyloid load, individuals expressing a pathogenic form of tau protein (MAPT) are at increased risk for developing the disease. Genetic studies in this pursuit have, however, yielded conflicting results. A recent study showed a significant haplotype association (H1c) with AD. The current study is an attempt to replicate this association in an independently ascertained cohort. RESULTS: In this report we present the findings of a haplotype analysis at the MAPT locus. We failed to detect evidence of association of the H1c haplotype at the MAPT locus with LOAD. None of the six SNPs forming the H1c haplotype showed evidence of association with disease. In addition, nested clade analysis suggested the presence of independent mutations at multiple points in the haplotype network or homoplasy at the MAPT locus. Such homoplasy can confound single SNP tests for association. We do not detect evidence that the set of SNPs forming the H1c haplotype in general or rs242557 in particular are pathogenic for LOAD. CONCLUSION: In conclusion, we employed two contemporary haplotype analysis tools to perform haplotype association analysis at the MAPT locus. Our data suggest that the tagged SNPs forming the H1c haplotype do not have a causal role in the pathogenesis of LOAD

The 1979 outburst of U Scorpii

Optical and ultraviolet observations are presented of the 1979 outburst of the recurrent nova U Sco. For the first time the evolution through outburst is documented photometrically and spectroscopically. Lines of the following ions are identified: H I, He II, C IV, N III, N IV, N V, O IV, O VI and Si IV. No forbidden lines were observed. Mg I was seen in absorption at a late stage in the decline. The Balmer lines have broad and narrow components which change with time. There is evidence that nitrogen is overabundant with respect to carbon and the helium to hydrogen number ratio is about 2

Apolipoprotein E levels in cerebrospinal fluid and the effects of ABCA1 polymorphisms

BACKGROUND: Animal studies suggest that brain apolipoprotein E (apoE) levels influence amyloid-β (Aβ) deposition and thus risk for Alzheimer's disease (AD). We have previously demonstrated that deletion of the ATP-binding cassette A1 transporter (ABCA1) in mice causes dramatic reductions in brain and cerebrospinal fluid (CSF) apoE levels and lipidation. To examine whether polymorphisms in ABCA1 affect CSF apoE levels in humans, we measured apoE in CSF taken from 168 subjects who were 43 to 91 years old and were either cognitively normal or who had mild AD. We then genotyped the subjects for ten previously identified ABCA1 single nucleotide polymorphisms (SNPs). RESULTS: In all subjects, the mean CSF apoE level was 9.09 μg/ml with a standard deviation of 2.70 μg/ml. Levels of apoE in CSF samples taken from the same individual two weeks apart were strongly correlated (r(2 )= 0.93, p < 0.01). In contrast, CSF apoE levels in different individuals varied widely (coefficient of variation = 46%). CSF apoE levels did not vary according to AD status, APOE genotype, gender or race. Average apoE levels increased with age by ~0.5 μg/ml per 10 years (r(2 )= 0.05, p = 0.003). We found no significant associations between CSF apoE levels and the ten ABCA1 SNPs we genotyped. Moreover, in a separate sample of 1225 AD cases and 1431 controls, we found no association between the ABCA1 SNP rs2230806 and AD as has been previously reported. CONCLUSION: We found that CSF apoE levels vary widely between individuals, but are stable within individuals over a two-week interval. AD status, APOE genotype, gender and race do not affect CSF apoE levels, but average CSF apoE levels increase with age. Given the lack of association between CSF apoE levels and genotypes for the ABCA1 SNPs we examined, either these SNPs do not affect ABCA1 function or if they do, they do not have strong effects in the CNS. Finally, we find no evidence for an association between the ABCA1 SNP rs2230806 and AD in a large sample set

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio

Considerations about quality in model-driven engineering

The final publication is available at Springer via http://dx.doi.org/10.1007/s11219-016-9350-6The virtue of quality is not itself a subject; it depends on a subject. In the software engineering field, quality means good software products that meet customer expectations, constraints, and requirements. Despite the numerous approaches, methods, descriptive models, and tools, that have been developed, a level of consensus has been reached by software practitioners. However, in the model-driven engineering (MDE) field, which has emerged from software engineering paradigms, quality continues to be a great challenge since the subject is not fully defined. The use of models alone is not enough to manage all of the quality issues at the modeling language level. In this work, we present the current state and some relevant considerations regarding quality in MDE, by identifying current categories in quality conception and by highlighting quality issues in real applications of the model-driven initiatives. We identified 16 categories in the definition of quality in MDE. From this identification, by applying an adaptive sampling approach, we discovered the five most influential authors for the works that propose definitions of quality. These include (in order): the OMG standards (e.g., MDA, UML, MOF, OCL, SysML), the ISO standards for software quality models (e.g., 9126 and 25,000), Krogstie, Lindland, and Moody. We also discovered families of works about quality, i.e., works that belong to the same author or topic. Seventy-three works were found with evidence of the mismatch between the academic/research field of quality evaluation of modeling languages and actual MDE practice in industry. We demonstrate that this field does not currently solve quality issues reported in industrial scenarios. The evidence of the mismatch was grouped in eight categories, four for academic/research evidence and four for industrial reports. These categories were detected based on the scope proposed in each one of the academic/research works and from the questions and issues raised by real practitioners. We then proposed a scenario to illustrate quality issues in a real information system project in which multiple modeling languages were used. For the evaluation of the quality of this MDE scenario, we chose one of the most cited and influential quality frameworks; it was detected from the information obtained in the identification of the categories about quality definition for MDE. We demonstrated that the selected framework falls short in addressing the quality issues. Finally, based on the findings, we derive eight challenges for quality evaluation in MDE projects that current quality initiatives do not address sufficiently.F.G, would like to thank COLCIENCIAS (Colombia) for funding this work through the Colciencias Grant call 512-2010. This work has been supported by the Gene-ralitat Valenciana Project IDEO (PROMETEOII/2014/039), the European Commission FP7 Project CaaS (611351), and ERDF structural funds.Giraldo-Velásquez, FD.; España Cubillo, S.; Pastor López, O.; Giraldo, WJ. (2016). Considerations about quality in model-driven engineering. Software Quality Journal. 1-66. https://doi.org/10.1007/s11219-016-9350-6S166(1985). Iso information processing—documentation symbols and conventions for data, program and system flowcharts, program network charts and system resources charts. ISO 5807:1985(E) (pp. 1–25).(2011). Iso/iec/ieee systems and software engineering – architecture description. ISO/IEC/IEEE 42010:2011(E) (Revision of ISO/IEC 42010:2007 and IEEE Std 1471-2000) (pp. 1–46).Abran, A., Moore, J.W., Bourque, P., Dupuis, R., & Tripp, L.L. (2013). Guide to the Software Engineering Body of Knowledge (SWEBOK) version 3 public review. IEEE. ISO Technical Report ISO/IEC TR 19759.Agner, L.T.W., Soares, I.W., Stadzisz, P.C., & Simão, J.M. (2013). A brazilian survey on {UML} and model-driven practices for embedded software development. Journal of Systems and Software, 86(4), 997–1005. {SI} : Software Engineering in Brazil: Retrospective and Prospective Views.Amstel, M.F.V. (2010). The right tool for the right job: assessing model transformation quality. pages 69–74. Affiliation: Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, Netherlands. Cited By (since 1996):1.Aranda, J., Damian, D., & Borici, A. (2012). Transition to model-driven engineering: what is revolutionary, what remains the same?. In Proceedings of the 15th international conference on model driven engineering languages and systems, MODELS’12 (pp. 692–708). Berlin, Heidelberg: Springer.Arendt, T., & Taentzer, G. (2013). A tool environment for quality assurance based on the eclipse modeling framework. Automated Software Engineering, 20(2), 141–184.Atkinson, C., Bunse, C., & Wüst, J. (2003). Driving component-based software development through quality modelling, volume 2693. Cited By (since 1996):3.Baker, P., Loh, S., & Weil, F. (2005). Model-driven engineering in a large industrial context—motorola case study. In Briand, L., & Williams, C. (Eds.) Model Driven Engineering Languages and Systems, volume 3713 of Lecture Notes in Computer Science (pp. 476–491). Berlin, Heidelberg: Springer.Barišić, A., Amaral, V., Goulão, M., & Barroca, B. (2011). Quality in use of domain-specific languages: a case study. In Proceedings of the 3rd ACM SIGPLAN workshop on evaluation and usability of programming languages and tools, PLATEAU ’11 (pp. 65–72). New York: ACM.Becker, J., Bergener, P., Breuker, D., & Rackers, M. (2010). Evaluating the expressiveness of domain specific modeling languages using the bunge-wand-weber ontology. In 2010 43rd Hawaii international conference on system sciences (HICSS) (pp. 1–10).Bertrand Portier, L.A. (2009). Model driven development misperceptions and challenges.Bézivin, J., & Kurtev, I. (2005). Model-based technology integration with the technical space concept. In Proceedings of the Metainformatics Symposium: Springer.Brambilla, M. (2016). How mature is of model-driven engineering as an engineering discipline @ONLINE.Brambilla, M., & Fraternali, P. (2014). Large-scale model-driven engineering of web user interaction: The webml and webratio experience. Science of Computer Programming, 89 Part B(0), 71 – 87. Special issue on Success Stories in Model Driven Engineering.Brown, A. (2009). Simple and practical model driven architecture (mda) @ONLINE.Bruel, J.-M., Combemale, B., Ober, I., & Raynal, H. (2015). Mde in practice for computational science. Procedia Computer Science, 51, 660–669.Budgen, D., Burn, A.J., Brereton, O.P., Kitchenham, B.A., & Pretorius, R. (2011). Empirical evidence about the uml: a systematic literature review. Software: Practice and Experience, 41(4), 363–392.Burden, H., Heldal, R., & Whittle, J. (2014). Comparing and contrasting model-driven engineering at three large companies. In Proceedings of the 8th ACM/IEEE International Symposium on Empirical Software Engineering and Measurement, ESEM ’14 (pp. 14:1–14:10). New York: ACM.Cabot, J. Has mda been abandoned (by the omg)?Cabot, J. (2009). Modeling will be commonplace in three years time @ONLINE.Cachero, C., Poels, G., Calero, C., & Marhuenda, Y. (2007). Towards a Quality-Aware Engineering Process for the Development of Web Applications. Working Papers of Faculty of Economics and Business Administration, Ghent University, Belgium 07/462, Ghent University, Faculty of Economics and Business Administration.Challenger, M., Kardas, G., & Tekinerdogan, B. (2015). A systematic approach to evaluating domain-specific modeling language environments for multi-agent systems. Software Quality Journal, 1–41.Chaudron, M.V., Heijstek, W., & Nugroho, A. (2012). How effective is uml modeling? Software & Systems Modeling, 11(4), 571–580. J2: Softw Syst Model.Chenouard, R., Granvilliers, L., & Soto, R. (2008). Model-driven constraint programming. pages 236–246. Affiliation: CNRS, LINA, Universit de Nantes, France; Affiliation: Pontificia Universidad Catlica de, Valparaiso, Chile. Cited By (since 1996):8.Clark, T., & Muller, P.-A. (2012). Exploiting model driven technology: a tale of two startups. Software and Systems Modeling, 11(4), 481–493.Corneliussen, L. (2008). What do you think of model-driven software development?Costal, D., Gómez, C., & Guizzardi, G. (2011). Formal semantics and ontological analysis for understanding subsetting, specialization and redefinition of associations in uml. In Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics), 6998 LNCS:189–203. cited By (since 1996)3.Cruz-Lemus, J.A., Maes, A., Género, M., Poels, G., & Piattini, M. (2010). The impact of structural complexity on the understandability of uml statechart diagrams. Information Sciences, 180(11), 2209–2220. Cited By (since 1996):14.Cuadrado, J.S., Izquierdo, J.L.C., & Molina, J.G. (2014). Applying model-driven engineering in small software enterprises. Science of Computer Programming, 89 Part B(0), 176 – 198. Special issue on Success Stories in Model Driven Engineering.Da Silva, A.R. (2015). Model-driven engineering: a survey supported by the unified conceptual model. Computer Languages Systems and Structures, 43, 139–155.Da Silva Teixeira, D.G.M., Quirino, G.K., Gailly, F., De Almeida Falbo, R., Guizzardi, G., & Perini Barcellos, M. (2016). PoN-S: a Systematic Approach for Applying the Physics of Notation (PoN), (pp. 432–447). Cham: Springer International Publishing.Davies, I., Green, P., Rosemann, M., Indulska, M., & Gallo, S. (2006). How do practitioners use conceptual modeling in practice? Data and Knowledge Engineering, 58(3), 358 – 380. Including the special issue : {ER} 2004ER 2004.Davies, J., Milward, D., Wang, C.-W., & Welch, J. (2015). Formal model-driven engineering of critical information systems. Science of Computer Programming, 103(0), 88 – 113. Selected papers from the First International Workshop on Formal Techniques for Safety-Critical Systems (FTSCS 2012).De Oca, I.M.-M., Snoeck, M., Reijers, H.A., & Rodríguez-Morffi, A. (2015). A systematic literature review of studies on business process modeling quality. Information and Software Technology, 58, 187–205.DenHaan, J. (2009). 8 reasons why model driven development is dangerous @ONLINE.DenHaan, J. (2010). Model driven engineering vs the commando pattern @ONLINE.DenHaan, J. (2011a). Why aren’t we all doing model driven development yet @ONLINE.DenHaan, J. (2011b). Why there is no future model driven development @ONLINE.Di Ruscio, D., Iovino, L., & Pierantonio, A. (2013). Managing the coupled evolution of metamodels and textual concrete syntax specifications. cited By (since 1996)0.Dijkman, R.M., Dumas, M., & Ouyang, C. (2008). Semantics and analysis of business process models in {BPMN}. Information and Software Technology, 50(12), 1281–1294.Domínguez-Mayo, F.J., Escalona, M.J., Mejías, M., Ramos, I., & Fernández, L. (2011). A framework for the quality evaluation of mdwe methodologies and information technology infrastructures. International Journal of Human Capital and Information Technology Professionals, 2(4), 11–22.Domínguez-Mayo, F.J., Escalona, M.J., Mejías, M., & Torres, A.H. (2010). A quality model in a quality evaluation framework for mdwe methodologies. pages 495–506. Affiliation: Departamento de Lenguajes y Sistemas Informíticos, University of Seville, Seville, Spain., Cited By (since 1996):1.Dubray, J.-J. (2011). Why did mde miss the boat?.Escalona, M.J., Gutiérrez, J.J., Pérez-Pérez, M., Molina, A., Domínguez-Mayo, E., & Domínguez-Mayo, F.J. (2011). Measuring the Quality of Model-Driven Projects with NDT-Quality, (pp. 307–317). New York: Springer.Espinilla, M., Domínguez-Mayo, F.J., Escalona, M.J., Mejías, M., Ross, M., & Staples, G. (2011). A Method Based on AHP to Define the Quality Model of QuEF (Vol. 123, pp. 685–694). Berlin, Heidelberg: Springer.Fabra, J., Castro, V.D., Álvarez, P., & Marcos, E. (2012). Automatic execution of business process models: exploiting the benefits of model-driven engineering approaches. Journal of Systems and Software, 85(3), 607–625. Novel approaches in the design and implementation of systems/software architecture.Falkenberg, E.D., Hesse, W., Lindgreen, P., Nilsson, B.E., Oei, J.L.H., Rolland, C., Stamper, R.K., Assche, F.J.M.V., Verrijn-Stuart, A.A., & Voss, K. (1996). Frisco: a framework of information system concepts. Technical report, The IFIP WG 8. 1 Task Group FRISCO.Fettke, P., Houy, C., Vella, A.-L., & Loos, P. (2012). Towards the Reconstruction and Evaluation of Conceptual Model Quality Discourses – Methodical Framework and Application in the Context of Model Understandability, volume 113 of Lecture Notes in Business Information Processing, chapter 28, pages 406–421, Springer, Berlin, Heidelberg.Finnie, S. (2015). Modeling community: Are we missing something?Fournier, C. (2008). Is uml [email protected], R., & Rumpe, B. (2007). Model-driven development of complex software: a research roadmap. In Future of Software Engineering, 2007, FOSE ’07 (pp. 37–54).Gallego, M., Giraldo, F.D., & Hitpass, B. (2015). Adapting the pbec-otss software selection approach for bpm suites: an application case. In 2015 34th International Conference of the Chilean Computer Science Society (SCCC) (pp. 1–10).Galvão, I., & Goknil, A. (2007). Survey of traceability approaches in model-driven engineering. cited By (since 1996)22.Giraldo, F., España, S., Giraldo, W., & Pastor, O. (2015). Modelling language quality evaluation in model-driven information systems engineering: a roadmap. In 2015 IEEE 9th International Conference on Research Challenges in Information Science (RCIS) (pp. 64–69).Giraldo, F., España, S., & Pastor, O. (2014). Analysing the concept of quality in model-driven engineering literature: a systematic review. In 2014 IEEE Eighth International Conference on Research Challenges in Information Science (RCIS) (pp. 1–12).Giraldo, F.D., España, S., & Pastor, O. (2016). Evidences of the mismatch between industry and academy on modelling language quality evaluation. arXiv: 1606.02025 .González, C., & Cabot, J. (2014). Formal verification of static software models in mde: a systematic review. Information and Software Technology, 56(8), 821–838. cited By (since 1996)0.González, C.A., Büttner, F., Clarisó, R., & Cabot, J. (2012). Emftocsp: a tool for the lightweight verification of emf models. pages 44–50. Affiliation: cole des Mines de Nantes, INRIA, LINA, Nantes, France; Affiliation: Universitat Oberta de Catalunya, Barcelona, Spain. Cited By (since 1996):1.Gorschek, T., Tempero, E., & Angelis, L. (2014). On the use of software design models in software development practice: an empirical investigation. Journal of Systems and Software, 95(0), 176– 193.Goulão, M., Amaral, V., & Mernik, M. (2016). Quality in model-driven engineering: a tertiary study. Software Quality Journal, 1–33.Grobshtein, Y., & Dori, D. (2011). Generating sysml views from an opm model: design and evaluation. Systems Engineering, 14(3), 327–340.Haan, J.d. (2008). 8 reasons why model-driven approaches (will) fail.Harel, D., & Rumpe, B. (2000). Modeling languages: Syntax, semantics and all that stuff, part i: The basic stuff, Israel. Technical report Jerusalem Israel.Harel, D., & Rumpe, B. (2004). Meaningful modeling: what’s the semantics of semantics? Computer, 37(10), 64–72.Hebig, R., & Bendraou, R. (2014). On the need to study the impact of model driven engineering on software processes. In Proceedings of the 2014 International Conference on Software and System Process, ICSSP 2014 (pp. 164–168). New York: ACM.Heidari, F., & Loucopoulos, P. (2014). Quality evaluation framework (qef): modeling and evaluating quality of business processes. International Journal of Accounting Information Systems, 15(3), 193–223. Business Process Modeling.Heymans, P., Schobbens, P.Y., Trigaux, J.C., Bontemps, Y., Matulevicius, R., & Classen, A. (2008). Evaluating formal properties of feature diagram languages. Software, IET, 2(3), 281–302. ID 2.Hindawi, M., Morel, L., Aubry, R., & Sourrouille, J.-L. (2009). Description and Implementation of a UML Style Guide (Vol. 5421, pp. 291–302). Berlin: Springer.Hoang, D. (2012). Current limitations of mdd and its implications @ONLINE.Hodges, W. (2013). Model theory Zalta, E.N. (Ed.) The Stanford Encyclopedia of Philosophy. Fall 2013 edition.Hutchinson, J., Rouncefield, M., & Whittle, J. (2011a). Model-driven engineering practices in industry. In Proceedings of the 33rd International Conference on Software Engineering, ICSE’11 (pp. 633–642). New York: ACM.Hutchinson, J., Whittle, J., & Rouncefield, M. (2014). Model-driven engineering practices in industry: social, organizational and managerial factors that lead to success or failure. Science of Computer Programming, 89 Part B(0), 144–161. Special issue on Success Stories in Model Driven Engineering.Hutchinson, J., Whittle, J., Rouncefield, M., & Kristoffersen, S. (2011b). Empirical assessment of mde in industry. In Proceedings of the 33rd International Conference on Software Engineering, ICSE’11 (pp. 471–480). New York: ACM.Igarza, I.M.H., Boada, D.H.G., & Valdés, A.P. (2012). Una introducción al desarrollo de software dirigido por modelos. Serie Científica, 5(3).ISO/IEC (2001). ISO/IEC 9126. Software engineering—Product quality. ISO/IEC.Izurieta, C., Rojas, G., & Griffith, I. (2015). Preemptive management of model driven technical debt for improving software quality. In Proceedings of the 11th International ACM SIGSOFT Conference on Quality of Software Architectures, QoSA’15 (pp. 31–36). New York: ACM.Jalali, S., & Wohlin, C. (2012). Systematic literature studies: Database searches vs. backward snowballing. In Proceedings of the ACM-IEEE International Symposium on Empirical Software Engineering and Measurement, ESEM’12 (pp. 29–38). New York: ACM.Kahraman, G., & Bilgen, S. (2013). A framework for qualitative assessment of domain-specific languages. Software & Systems Modeling, 1–22.Kessentini, M., Langer, P., & Wimmer, M. (2013). Searching models, modeling search: On the synergies of sbse and mde (pp. 51–54).Kitchenham, B., & Charters, S. (2007). Guidelines for performing Systematic Literature Reviews in Software Engineering. Technical Report EBSE 2007-001, Keele University and Durham University Joint Report.Kitchenham, B., Pfleeger, S., Pickard, L., Jones, P., Hoaglin, D., El Emam, K., & Rosenberg, J. (2002). Preliminary guidelines for empirical research in software engineering. IEEE Transactions on Software Engineering, 28(8), 721–734.Klinke, M. (2008). Do you use mda/mdd/mdsd, any kind of model-driven approach? Will it be the future?Köhnlein, J. (2013). Eclipse diagram editors from a user’s perspective.Kolovos, D.S., Paige, R.F., & Polack, F.A. (2008). The grand challenge of scalability for model driven engineering. In Models in Software Engineering (pp. 48–53): Springer.Kolovos, D.S., Rose, L.M., Matragkas, N., Paige, R.F., Guerra, E., Cuadrado, J.S., De Lara, J., Ráth, I., Varró, D., Tisi, M., & Cabot, J. (2013). A research roadmap towards achieving scalability in model driven engineering. In Proceedings of the Workshop on Scalability in Model Driven Engineering, BigMDE’13 (pp. 2:1–2:10). New York: ACM.Krill, P. (2016). Uml to be ejected from microsoft visual studio (infoworld).Krogstie, J. (2012a). Model-based development and evolution of information systems: a quality approach, Springer Publishing Company, Incorporated.Krogstie, J. (2012b). Quality of modelling languages, (pp. 249–280). London: Springer.Krogstie, J. (2012c). Quality of models, (pp. 205–247). London: Springer.Krogstie, J. (2012d). Specialisations of SEQUAL, (pp. 281–326). London: Springer.Krogstie, J., Lindland, O.I., & Sindre, G. (1995). Defining quality aspects for conceptual models. In Proceedings of the IFIP International Working Conference on Information System Concepts: Towards a Consolidation of Views (pp. 216–231). London: Chapman & Hall, Ltd.Kruchten, P. (2000). The rational unified process: an introduction, 2nd edn. Boston: Addison-Wesley Longman Publishing Co., Inc.Kruchten, P., Nord, R., & Ozkaya, I. (2012). Technical debt: from metaphor to theory and practice. Software, IEEE, 29(6), 18–21.Kulkarni, V., Reddy, S., & Rajbhoj, A. (2010). Scaling up model driven engineering – experience and lessons learnt. In Petriu, D., Rouquette, N., & Haugen, y. (Eds.) Model Driven Engineering Languages and Systems, volume 6395 of Lecture Notes in Computer Science (pp. 331–345). Berlin, Heidelberg: Springer.Laguna, M.A., & Marqués, J.M. (2010). Uml support for designing software product lines: the package merge mechanism, 16(17), 2313–2332.Lange, C. (2007a). Model size matters. Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics), 4364 LNCS:211–216. cited By (since 1996)1.Lange, C., & Chaudron, M. (2005). Managing Model Quality in UML-Based Software Development. In 13th IEEE International Workshop on Technology and Engineering Practice, 2005 (pp. 7–16).Lange, C., Chaudron, M.R.V., Muskens, J., Somers, L.J., & Dortmans, H.M. (2003). An empirical investigation in quantifying inconsistency and incompleteness of uml designs. In Incompleteness of UML Designs, Proceedings Workshop on Consistency Problems in UML-based Software Development, 6th International Conference on Unified Modeling Language, UML, 2003.Lange, C., DuBois, B., Chaudron, M., & Demeyer, S. (2006). An experimental investigation of uml modeling conventions. In Nierstrasz, O., Whittle, J., Harel, D., & Reggio, G. (Eds.) Model Driven Engineering Languages and Systems, volume 4199 of Lecture Notes in Computer Science (pp. 27–41). Berlin, Heidelberg: Springer.Lange, C.F.J., & Chaudron, M.R.V. (2006). Effe

Cell Lineage Analysis of the Mammalian Female Germline

Fundamental aspects of embryonic and post-natal development, including maintenance of the mammalian female germline, are largely unknown. Here we employ a retrospective, phylogenetic-based method for reconstructing cell lineage trees utilizing somatic mutations accumulated in microsatellites, to study female germline dynamics in mice. Reconstructed cell lineage trees can be used to estimate lineage relationships between different cell types, as well as cell depth (number of cell divisions since the zygote). We show that, in the reconstructed mouse cell lineage trees, oocytes form clusters that are separate from hematopoietic and mesenchymal stem cells, both in young and old mice, indicating that these populations belong to distinct lineages. Furthermore, while cumulus cells sampled from different ovarian follicles are distinctly clustered on the reconstructed trees, oocytes from the left and right ovaries are not, suggesting a mixing of their progenitor pools. We also observed an increase in oocyte depth with mouse age, which can be explained either by depth-guided selection of oocytes for ovulation or by post-natal renewal. Overall, our study sheds light on substantial novel aspects of female germline preservation and development

Rehabilitation needs for older adults with stroke living at home: perceptions of four populations

<p>Abstract</p> <p>Background</p> <p>Many people who have suffered a stroke require rehabilitation to help them resume their previous activities and roles in their own environment, but only some of them receive inpatient or even outpatient rehabilitation services. Partial and unmet rehabilitation needs may ultimately lead to a loss of functional autonomy, which increases utilization of health services, number of hospitalizations and early institutionalization, leading to a significant psychological and financial burden on the patients, their families and the health care system. The aim of this study was to explore partially met and unmet rehabilitation needs of older adults who had suffered a stroke and who live in the community. The emphasis was put on needs that act as obstacles to social participation in terms of personal factors, environmental factors and life habits, from the point of view of four target populations.</p> <p>Methods</p> <p>Using the focus group technique, we met four types of experts living in three geographic areas of the province of Québec (Canada): older people with stroke, caregivers, health professionals and health care managers, for a total of 12 groups and 72 participants. The audio recordings of the meetings were transcribed and NVivo software was used to manage the data. The process of reducing, categorizing and analyzing the data was conducted using themes from the Disability Creation Process model.</p> <p>Results</p> <p>Rehabilitation needs persist for nine capabilities (e.g. related to behaviour or motor activities), nine factors related to the environment (e.g. type of teaching, adaptation and rehabilitation) and 11 life habits (e.g. nutrition, interpersonal relationships). The caregivers and health professionals identified more unmet needs and insisted on an individualized rehabilitation. Older people with stroke and the health care managers had a more global view of rehabilitation needs and emphasized the availability of resources.</p> <p>Conclusion</p> <p>Better knowledge of partially met or unmet rehabilitation needs expressed by the different types of people involved should lead to increased attention being paid to education for caregivers, orientation of caregivers towards resources in the community, and follow-up of patients' needs in terms of adjustment and rehabilitation, whether for improving their skills or for carrying out their activities of daily living.</p

The p53 Inhibitor MDM2 Facilitates Sonic Hedgehog-Mediated Tumorigenesis and Influences Cerebellar Foliation

Disruption of cerebellar granular neuronal precursor (GNP) maturation can result in defects in motor coordination and learning, or in medulloblastoma, the most common childhood brain tumor. The Sonic Hedgehog (Shh) pathway is important for GNP proliferation; however, the factors regulating the extent and timing of GNP proliferation, as well as GNP differentiation and migration are poorly understood. The p53 tumor suppressor has been shown to negatively regulate the activity of the Shh effector, Gli1, in neural stem cells; however, the contribution of p53 to the regulation of Shh signaling in GNPs during cerebellar development has not been determined. Here, we exploited a hypomorphic allele of Mdm2 (Mdm2puro), which encodes a critical negative regulator of p53, to alter the level of wild-type MDM2 and p53 in vivo. We report that mice with reduced levels of MDM2 and increased levels of p53 have small cerebella with shortened folia, reminiscent of deficient Shh signaling. Indeed, Shh signaling in Mdm2-deficient GNPs is attenuated, concomitant with decreased expression of the Shh transducers, Gli1 and Gli2. We also find that Shh stimulation of GNPs promotes MDM2 accumulation and enhances phosphorylation at serine 166, a modification known to increase MDM2-p53 binding. Significantly, loss of MDM2 in Ptch1+/− mice, a model for Shh-mediated human medulloblastoma, impedes cerebellar tumorigenesis. Together, these results place MDM2 at a major nexus between the p53 and Shh signaling pathways in GNPs, with key roles in cerebellar development, GNP survival, cerebellar foliation, and MB tumorigenesis