Specificity prediction of adenylation domains in nonribosomal peptide synthetases (NRPS) using transductive support vector machines (TSVMs)

We present a new support vector machine (SVM)-based approach to predict the substrate specificity of subtypes of a given protein sequence family. We demonstrate the usefulness of this method on the example of aryl acid-activating and amino acid-activating adenylation domains (A domains) of nonribosomal peptide synthetases (NRPS). The residues of gramicidin synthetase A that are 8 Å around the substrate amino acid and corresponding positions of other adenylation domain sequences with 397 known and unknown specificities were extracted and used to encode this physico-chemical fingerprint into normalized real-valued feature vectors based on the physico-chemical properties of the amino acids. The SVM software package SVM(light) was used for training and classification, with transductive SVMs to take advantage of the information inherent in unlabeled data. Specificities for very similar substrates that frequently show cross-specificities were pooled to the so-called composite specificities and predictive models were built for them. The reliability of the models was confirmed in cross-validations and in comparison with a currently used sequence-comparison-based method. When comparing the predictions for 1230 NRPS A domains that are currently detectable in UniProt, the new method was able to give a specificity prediction in an additional 18% of the cases compared with the old method. For 70% of the sequences both methods agreed, for <6% they did not, mainly on low-confidence predictions by the existing method. None of the predictive methods could infer any specificity for 2.4% of the sequences, suggesting completely new types of specificity

Faster Algorithms for Weighted Recursive State Machines

Pushdown systems (PDSs) and recursive state machines (RSMs), which are linearly equivalent, are standard models for interprocedural analysis. Yet RSMs are more convenient as they (a) explicitly model function calls and returns, and (b) specify many natural parameters for algorithmic analysis, e.g., the number of entries and exits. We consider a general framework where RSM transitions are labeled from a semiring and path properties are algebraic with semiring operations, which can model, e.g., interprocedural reachability and dataflow analysis problems. Our main contributions are new algorithms for several fundamental problems. As compared to a direct translation of RSMs to PDSs and the best-known existing bounds of PDSs, our analysis algorithm improves the complexity for finite-height semirings (that subsumes reachability and standard dataflow properties). We further consider the problem of extracting distance values from the representation structures computed by our algorithm, and give efficient algorithms that distinguish the complexity of a one-time preprocessing from the complexity of each individual query. Another advantage of our algorithm is that our improvements carry over to the concurrent setting, where we improve the best-known complexity for the context-bounded analysis of concurrent RSMs. Finally, we provide a prototype implementation that gives a significant speed-up on several benchmarks from the SLAM/SDV project

Enhancing POI Testing Approach through the Use of Additional Information

[EN] Recently, a new approach to perform regression testing has been defined: the point of interest (POI) testing. A POI, in this context, is any expression of a program. The approach receives as input a set of relations between POIs from a version of a program and POIs from another version, and also a sequence of entry points, i.e. test cases. Then, a program instrumentation, an input test case generation and different comparison functions are used to obtain the final report which indicates whether the alternative version of the program behaves as expected, e.g. it produces the same outputs or it uses less CPU/memory. In this paper, we present a method to improve POI testing by including additional context information for a certain type of POIs. Concretely, we use this method to obtain an enhanced tracing of calls. Additionally, it enables new comparison modes and a categorization of unexpected behaviours.This work has been partially supported by MINECO/AEI/FEDER (EU) under grant TIN2016-76843-C4-1-R, and by the Generalitat Valenciana under grant PROMETEOII/2015/013 (SmartLogic). Salvador Tamarit was partially supported by the Conselleria de Educación, Investigación, Cultura y Deporte de la Generalitat Valenciana under grant APOSTD/2016/036.Pérez-Rubio, S.; Tamarit Muñoz, S. (2019). Enhancing POI Testing Approach through the Use of Additional Information. Lecture Notes in Computer Science. 11285:74-90. https://doi.org/10.1007/978-3-030-16202-3_5S74901128

Automatic Abstraction for Congruences

One approach to verifying bit-twiddling algorithms is to derive invariants between the bits that constitute the variables of a program. Such invariants can often be described with systems of congruences where in each equation $\vec{c} \cdot \vec{x} = d \mod m$, (unknown variable m)$is a power of two,$\vec{c}$is a vector of integer coefficients, and$\vec{x}$ is a vector of propositional variables (bits). Because of the low-level nature of these invariants and the large number of bits that are involved, it is important that the transfer functions can be derived automatically. We address this problem, showing how an analysis for bit-level congruence relationships can be decoupled into two parts: (1) a SAT-based abstraction (compilation) step which can be automated, and (2) an interpretation step that requires no SAT-solving. We exploit triangular matrix forms to derive transfer functions efficiently, even in the presence of large numbers of bits. Finally we propose program transformations that improve the analysis results

Interprocedural shape analysis for effectively cutpoint-free programs

Abstract. We present a framework for local interprocedural shape analysis that computes procedure summaries as transformers of procedure-local heaps (the parts of the heap that the procedure may reach). A main challenge in procedurelocal shape analysis is the handling of cutpoints, objects that separate the input heap of an invoked procedure from the rest of the heap, which-from the viewpoint of that invocation-is non-accessible and immutable. In this paper, we limit our attention to effectively cutpoint-free programsprograms in which the only objects that separate the callee&apos;s heap from the rest of the heap, when considering live reference fields, are the ones pointed to by the actual parameters of the invocation. This limitation (and certain variations of it, which we also describe) simplifies the local-reasoning about procedure calls because the analysis needs not track cutpoints. Furthermore, our analysis (conservatively) verifies that a program is effectively cutpoint-free

Cell Migration in the Immune System: the Evolving Inter-Related Roles of Adhesion Molecules and Proteinases

Leukocyte extravasation into perivascular tissue during inflammation and lymphocyte homing to lymphoid organs involve transient adhesion to the vessel endothelium, followed by transmigration through the endothelial cell (EC) layer and establishment of residency at the tissue site for a period of time. In these processes, leukocytes undergo multiple attachments to, and detachments from, the vessel-lining endothelial cells, prior to transendothelial cell migration. Transmigrating leukocytes must traverse a subendothelial basement membrane en route to perivascular tissues and utilize enzymes known as matrix metalloproteinases to make selective clips in the extracellular matrix components of the basement membrane. This review will focus on the evidence for a link between adhesion of leukocytes to endothelial cells, the induction of matrix metalloproteinases mediated by engagement of adhesion receptors on leukocytes, and the ability to utilize these matrix metalloproteinases to facilitate leukocyte invasion of tissues. Leukocytes with invasive phenotypes express high levels of MMPs, and expression of MMPs enhances the migratory and invasive properties of these cells. Furthermore, MMPs may be used by lymphocytes to proteolytically cleave molecules such as adhesion receptors and membrane bound cytokines, increasing their efficiency in the immune response. Engagement of leukocyte adhesion receptors may modulate adhesive (modulation of integrin affinities and expression), synthetic (proteinase induction and activation), and surface organization (clustering of proteolyric complexes) behaviors of invasive leukocytes. Elucidation of these pathways will lead to better understanding of controlling mechanisms in order to develop rational therapeutic approaches in the areas of inflammation and autoimmunity

System dependence graphs in sequential Erlang

The system dependence graph (SDG) is a data structure used in the imperative paradigm for different static analysis, and particularly, for program slicing. Program slicing allows us to determine the part of a program (called slice) that influences a given variable of interest. Thanks to the SDG, we can produce precise slices for interprocedural programs. Unfortunately, the SDG cannot be used in the functional paradigm due to important features that are not considered in this formalism (e.g., pattern matching, higher-order, composite expressions, etc.). In this work we propose the first adaptation of the SDG to a functional language facing these problems. We take Erlang as the host language and we adapt the algorithms used to slice the SDG to produce precise slices of Erlang interprocedural programs. As a proof-of-concept, we have implemented a program slicer for Erlang based on our SDGs.This work has been partially supported by the Spanish Ministerio de Ciencia e Innovaci´on under grant TIN2008-06622-C03-02 and by the Generalitat Valenciana under grant PROMETEO/2011/052. Salvador Tamarit was partially supported by the Spanish MICINN under FPI grant BES-2009-015019Silva Galiana, JF.; Tamarit Muñoz, S.; Tomás Franco, C. (2012). System dependence graphs in sequential Erlang. En Fundamental Approaches to Software Engineering. Springer Verlag (Germany). 486-500. https://doi.org/10.1007/978-3-642-28872-2_33S486500Agrawal, H., Horgan, J.R.: Dynamic program slicing. In: Programming Language Design and Implementation (PLDI), pp. 246–256 (1990)Brown, C.: Tool Support for Refactoring Haskell Programs. PhD thesis, School of Computing, University of Kent, Canterbury, Kent, UK (2008)Cheda, D., Silva, J., Vidal, G.: Static slicing of rewrite systems. Electron. Notes Theor. Comput. Sci. 177, 123–136 (2007)Ferrante, J., Ottenstein, K.J., Warren, J.D.: The Program Dependence Graph and Its Use in Optimization. ACM Transactions on Programming Languages and Systems 9(3), 319–349 (1987)Field, J., Ramalingam, G., Tip, F.: Parametric program slicing. In: Proceedings of the 22nd ACM SIGPLAN-SIGACT Symposium on Principles of Programming Languages, POPL 1995, pp. 379–392. ACM, New York (1995)Horwitz, S., Reps, T., Binkley, D.: Interprocedural slicing using dependence graphs. ACM Transactions Programming Languages and Systems 12(1), 26–60 (1990)Korel, B., Laski, J.: Dynamic Program Slicing. Information Processing Letters 29(3), 155–163 (1988)Larsen, L., Harrold, M.J.: Slicing object-oriented software. In: Proceedings of the 18th International Conference on Software Engineering, ICSE 1996, pp. 495–505. IEEE Computer Society, Washington, DC (1996)Liang, D., Harrold, M.J.: Slicing objects using system dependence graphs. In: Proceedings of the International Conference on Software Maintenance, ICSM 1998, pp. 358–367. IEEE Computer Society, Washington, DC (1998)Lindahl, T., Sagonas, K.F.: Typer: a type annotator of erlang code. In: Sagonas, K.F., Armstrong, J. (eds.) Erlang Workshop, pp. 17–25. ACM (2005)Lindahl, T., Sagonas, K.F.: Practical type inference based on success typings. In: Bossi, A., Maher, M.J. (eds.) PPDP, pp. 167–178. ACM (2006)Ochoa, C., Silva, J., Vidal, G.: Dynamic slicing based on redex trails. In: Proceedings of the 2004 ACM SIGPLAN Symposium on Partial Evaluation and Semantics-Based Program Manipulation, PEPM 2004, pp. 123–134. ACM, New York (2004)Reps, T., Turnidge, T.: Program Specialization via Program Slicing. In: Danvy, O., Thiemann, P., Glück, R. (eds.) Dagstuhl Seminar 1996. LNCS, vol. 1110, pp. 409–429. Springer, Heidelberg (1996)Rodrigues, N.F., Barbosa, L.S.: Component identification through program slicing. In: Proc. of Formal Aspects of Component Software (FACS 2005). Elsevier ENTCS, pp. 291–304. Elsevier (2005)Tip, F.: A survey of program slicing techniques. Journal of Programming Languages 3(3), 121–189 (1995)Tóth, M., Bozó, I., Horváth, Z., Lövei, L., Tejfel, M., Kozsik, T.: Impact Analysis of Erlang Programs Using Behaviour Dependency Graphs. In: Horváth, Z., Plasmeijer, R., Zsók, V. (eds.) CEFP 2009. LNCS, vol. 6299, pp. 372–390. Springer, Heidelberg (2010)Walkinshaw, N., Roper, M., Wood, M., Roper, N.W.M.: The java system dependence graph. In: Third IEEE International Workshop on Source Code Analysis and Manipulation, p. 5 (2003)Weiser, M.: Program Slicing. In: Proceedings of the 5th International Conference on Software Engineering, pp. 439–449. IEEE Press (1981)Widera, M.: Flow graphs for testing sequential erlang programs. In: Proceedings of the 2004 ACM SIGPLAN Workshop on Erlang, ERLANG 2004, pp. 48–53. ACM, New York (2004)Widera, M., Informatik, F.: Concurrent erlang flow graphs. In: Proceedings of the Erlang/OTP User Conference (2005)Zhao, J.: Slicing aspect-oriented software. In: Proceedings of the 10th International Workshop on Program Comprehension, IWPC 2002, pp. 251–260. IEEE Computer Society, Washington, DC (2002

Software Model Checking with Explicit Scheduler and Symbolic Threads

In many practical application domains, the software is organized into a set of threads, whose activation is exclusive and controlled by a cooperative scheduling policy: threads execute, without any interruption, until they either terminate or yield the control explicitly to the scheduler. The formal verification of such software poses significant challenges. On the one side, each thread may have infinite state space, and might call for abstraction. On the other side, the scheduling policy is often important for correctness, and an approach based on abstracting the scheduler may result in loss of precision and false positives. Unfortunately, the translation of the problem into a purely sequential software model checking problem turns out to be highly inefficient for the available technologies. We propose a software model checking technique that exploits the intrinsic structure of these programs. Each thread is translated into a separate sequential program and explored symbolically with lazy abstraction, while the overall verification is orchestrated by the direct execution of the scheduler. The approach is optimized by filtering the exploration of the scheduler with the integration of partial-order reduction. The technique, called ESST (Explicit Scheduler, Symbolic Threads) has been implemented and experimentally evaluated on a significant set of benchmarks. The results demonstrate that ESST technique is way more effective than software model checking applied to the sequentialized programs, and that partial-order reduction can lead to further performance improvements.Comment: 40 pages, 10 figures, accepted for publication in journal of logical methods in computer scienc