Fission Yeast Sec3 and Exo70 Are Transported on Actin Cables and Localize the Exocyst Complex to Cell Poles

The exocyst complex is essential for many exocytic events, by tethering vesicles at the plasma membrane for fusion. In fission yeast, polarized exocytosis for growth relies on the combined action of the exocyst at cell poles and myosin-driven transport along actin cables. We report here the identification of fission yeast Schizosaccharomyces pombe Sec3 protein, which we identified through sequence homology of its PH-like domain. Like other exocyst subunits, sec3 is required for secretion and cell division. Cells deleted for sec3 are only conditionally lethal and can proliferate when osmotically stabilized. Sec3 is redundant with Exo70 for viability and for the localization of other exocyst subunits, suggesting these components act as exocyst tethers at the plasma membrane. Consistently, Sec3 localizes to zones of growth independently of other exocyst subunits but depends on PIP2 and functional Cdc42. FRAP analysis shows that Sec3, like all other exocyst subunits, localizes to cell poles largely independently of the actin cytoskeleton. However, we show that Sec3, Exo70 and Sec5 are transported by the myosin V Myo52 along actin cables. These data suggest that the exocyst holocomplex, including Sec3 and Exo70, is present on exocytic vesicles, which can reach cell poles by either myosin-driven transport or random walk

Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche

Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps

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. 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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). 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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. 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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. 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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. 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HIV-1 Tat and AIDS-associated cancer: targeting the cellular anti-cancer barrier?

The acquired immunodeficiency syndrome (AIDS) is accompanied by a significant increase in the incidence of neoplasms. Several causative agents have been proposed for this phenomenon. These include immunodeficiency and oncogenic DNA viruses and the HIV-1 protein Tat. Cancer in general is closely linked to genomic instability and DNA repair mechanisms. The latter maintains genomic stability and serves as a cellular anti-cancer barrier. Defects in DNA repair pathway are associated with carcinogenesis

Reviewing the use of resilience concepts in forest sciences

Purpose of the review Resilience is a key concept to deal with an uncertain future in forestry. In recent years, it has received increasing attention from both research and practice. However, a common understanding of what resilience means in a forestry context, and how to operationalise it is lacking. Here, we conducted a systematic review of the recent forest science literature on resilience in the forestry context, synthesising how resilience is defined and assessed. Recent findings Based on a detailed review of 255 studies, we analysed how the concepts of engineering resilience, ecological resilience, and social-ecological resilience are used in forest sciences. A clear majority of the studies applied the concept of engineering resilience, quantifying resilience as the recovery time after a disturbance. The two most used indicators for engineering resilience were basal area increment and vegetation cover, whereas ecological resilience studies frequently focus on vegetation cover and tree density. In contrast, important social-ecological resilience indicators used in the literature are socio-economic diversity and stock of natural resources. In the context of global change, we expected an increase in studies adopting the more holistic social-ecological resilience concept, but this was not the observed trend. Summary Our analysis points to the nestedness of these three resilience concepts, suggesting that they are complementary rather than contradictory. It also means that the variety of resilience approaches does not need to be an obstacle for operationalisation of the concept. We provide guidance for choosing the most suitable resilience concept and indicators based on the management, disturbance and application context

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified