Cytoscape is an open source software project for integrating biomolecular interaction networks with high-throughput expression data and other molecular states into a unified conceptual framework. Although applicable to any system of molecular components and interactions, Cytoscape is most powerful when used in conjunction with large databases of protein-protein, protein-DNA, and genetic interactions that are increasingly available for humans and model organisms. Cytoscape's software Core provides basic functionality to layout and query the network; to visually integrate the network with expression profiles, phenotypes, and other molecular states; and to link the network to databases of functional annotations. The Core is extensible through a straightforward plug-in architecture, allowing rapid development of additional computational analyses and features. Several case studies of Cytoscape plug-ins are surveyed, including a search for interaction pathways correlating with changes in gene expression, a study of protein complexes involved in cellular recovery to DNA damage, inference of a combined physical/functional interaction network for Halobacterium, and an interface to detailed stochastic/kinetic gene regulatory models.[The Cytoscape v1.1 Core runs on all major operating systems and is freely available for download from http://www.cytoscape.org/ as an open source Java application.] Such models promise to transform biological research by providing a framework to (1) systematically interrogate and experimentally verify knowledge of a pathway; (2) manage the immense complexity of hundreds or potentially thousands of cellular components and interactions; and (3) reveal emergent properties and unanticipated consequences of different pathway configurations.Typically, models are directed toward a cellular process or disease pathway of interest (Gilman and Arkin 2002) and are built by formulating existing literature as a system of differential and/or stochastic equations. However, pathway-specific models are now being supplemented with global data gathered for an entire cell or organism, by use of two complementary approaches. First, recent technological developments have made it feasible to measure pathway structure systematically, using highthroughput screens for protein-protein (Ito et al. 2001;von Mering et al. 2002), protein-DNA (Lee et al. 2002, and genetic interactions (Tong et al. 2001). To complement these data, a second set of high-throughput methods are available to characterize the molecular and cellular states induced by pathway interactions under different experimental conditions. For instance, global changes in gene expression are measured with DNA microarrays (DeRisi et al. 1997), whereas changes in protein abundance (Gygi et al. 1999), protein phosphorylation state (Zhou et al. 2001), and metabolite concentrations (Griffin et al. 2001) may be quantified with mass spectrometry, NMR, and other advanced techniques. High-throughput data pertaining to molecular interactions and states are well matched, in...

Abstract. Focusing on path-dependent types, the paper develops foundations for Scala from first principles. Starting from a simple calculus D<: of dependent functions, it adds records, intersections and recursion to arrive at DOT, a calculus for dependent object types. The paper shows an encoding of System F with subtyping in D<: and demonstrates the expressiveness of DOT by modeling a range of Scala constructs in it.

A scalable programming language is one in which the same concepts can describe small as well as large parts. Towards this goal, Scala unifies concepts from object and module systems. An essential ingredient of this unification is the concept of objects with type members, which can be referenced through path-dependent types. Unfortunately, pathdependent types are not well-understood, and have been a roadblock in grounding the Scala type system on firm theory.We study several calculi for path-dependent types. We present µDOT which captures the essence -DOT stands for Dependent Object Types. We explore the design space bottom-up, teasing apart inherent from accidental complexities, while fully mechanizing our models at each step. Even in this simple setting, many interesting patterns arise from the interaction of structural and nominal features.Whereas our simple calculus enjoys many desirable and intuitive properties, we demonstrate that the theory gets much more complicated once we add another Scala feature, type refinement, or extend the subtyping relation to a lattice. We discuss possible remedies and trade-offs in modeling type systems for Scala-like languages.

Scala's type system unifies aspects of ML modules, objectoriented, and functional programming. The Dependent Object Types (DOT) family of calculi has been proposed as a new theoretic foundation for Scala and similar expressive languages. Unfortunately, type soundness has only been established for restricted subsets of DOT. In fact, it has been shown that important Scala features such as type refinement or a subtyping relation with lattice structure break at least one key metatheoretic property such as environment narrowing or invertible subtyping transitivity, which are usually required for a type soundness proof.The main contribution of this paper is to demonstrate how, perhaps surprisingly, even though these properties are lost in their full generality, a rich DOT calculus that includes recursive type refinement and a subtyping lattice with intersection types can still be proved sound. The key insight is that subtyping transitivity only needs to be invertible in code paths executed at runtime, with contexts consisting entirely of valid runtime objects, whereas inconsistent subtyping contexts can be permitted for code that is never executed.

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