@article{3990, abstract = {The writhing number measures the global geometry of a closed space curve or knot. We show that this measure is related to the average winding number of its Gauss map. Using this relationship, we give an algorithm for computing the writhing number for a polygonal knot with n edges in time roughly proportional to n(1.6). We also implement a different, simple algorithm and provide experimental evidence for its practical efficiency.}, author = {Agarwal, Pankaj K and Herbert Edelsbrunner and Wang, Yusu}, journal = {Discrete & Computational Geometry}, number = {1}, pages = {37 -- 53}, publisher = {Springer}, title = {{Computing the writhing number of a polygonal knot}}, doi = {10.1007/s00454-004-2864-x}, volume = {32}, year = {2004}, } @article{4172, abstract = {During vertebrate gastrulation, a relatively limited number of blastodermal cells undergoes a stereotypical set of cellular movements that leads to formation of the three germ layers: ectoderm, mesoderm and endoderm. Gastrulation, therefore, provides a unique developmental system in which to study cell movements in vivo in a fairly simple cellular context. Recent advances have been made in elucidating the cellular and molecular mechanisms that underlie cell movements during zebrafish gastrulation. These findings can be compared with observations made in other model systems to identify potential general mechanisms of cell migration during development.}, author = {Montero, Juan and Heisenberg, Carl-Philipp J}, journal = {Trends in Cell Biology}, number = {11}, pages = {620 -- 627}, publisher = {Cell Press}, title = {{Gastrulation dynamics: cells move into focus}}, doi = {10.1016/j.tcb.2004.09.008}, volume = {14}, year = {2004}, } @article{4224, abstract = {Developing cells acquire positional information by reading the graded distribution of morphogens. In Drosophila, the Dpp morphogen forms a long-range concentration gradient by spreading from a restricted source in the developing wing. It has been assumed that Dpp spreads by extracellular diffusion. Under this assumption, the main role of endocytosis in gradient formation is to downregulate receptors at the cell surface. These surface receptors bind to the ligand and thereby interfere with its long-range movement. Recent experiments indicate that Dpp spreading is mediated by Dynamin-dependent endocytosis in the target tissue, suggesting that extracellular diffusion alone cannot account for Dpp dispersal. Here, we perform a theoretical study of a model for morphogen spreading based on extracellular diffusion, which takes into account receptor binding and trafficking. We compare profiles of ligand and surface receptors obtained in this model with experimental data. To this end, we monitored directly the pool of surface receptors and extracellular Dpp with specific antibodies. We conclude that current models considering pure extracellular diffusion cannot explain the observed role of endocytosis during Dpp long-range movement.}, author = {Kruse, Karsten and Pantazis, Periklis and Bollenbach, Mark Tobias and Julicher, Frank and Gonzalez Gaitan, Marcos}, journal = {Development}, number = {19}, pages = {4843 -- 4856}, publisher = {Company of Biologists}, title = {{Dpp gradient formation by dynamin-dependent endocytosis: receptor trafficking and the diffusion model}}, doi = {10.1242/dev.01335}, volume = {131}, year = {2004}, } @inbook{4230, author = {Harold Vladar and Cipriani, Roberto and Scharifker, Benjamin and Bubis, Jose}, booktitle = {Life in the Universe From the Miller Experiment to the Search for Life on Other Worlds}, editor = {Hanslmeier,A. and Kempe,S. and Seckbach,J.}, pages = {83 -- 87}, publisher = {Springer}, title = {{A mechanism for the prebiotic emergence of proteins}}, year = {2004}, } @phdthesis{4236, author = {de Vladar, Harold}, publisher = {Centro de estudios avazados, IVIC}, title = {{Métodos no lineales y sus aplicaciones en dinámicas aleatorias de poblaciones celulares}}, doi = {3810}, year = {2004}, } @article{4238, abstract = {The dynamical basis of tumoral growth has been controversial. Many models have been proposed to explain cancer development. The descriptions employ exponential, potential, logistic or Gompertzian growth laws. Some of these models are concerned with the interaction between cancer and the immunological, system. Among other properties, these models are concerned with the microscopic behavior of tumors and the emergence of cancer. We propose a modification of a previous model by Stepanova, which describes the specific immunological response against cancer. The modification consists of the substitution of a Gompertian law for the exponential rate used for tumoral growth. This modification is motivated by the numerous works confirming that Gompertz's equation correctly describes solid tumor growth. The modified model predicts that near zero, tumors always tend to grow. Immunological contraposition never suffices to induce a complete regression of the tumor. Instead, a stable microscopic equilibrium between cancer and immunological activity can be attained. In other words, our model predicts that the theory of immune surveillance is plausible. A macroscopic equilibrium in which the system develops cancer is also possible. In this case, immunological activity is depleted. This is consistent with the phenomena of cancer tolerance. Both equilibrium points can coexist or can exist without the other. In all cases the fixed point at zero tumor size is unstable. Since immunity cannot induce a complete tumor regression, a therapy is required. We include constant-dose therapies and show that they are insufficient. Final levels of immunocompetent cells and tumoral cells are finite, thus post-treatment regrowth of the tumor is certain. We also evaluate late-intensification therapies which are successful. They induce an asymptotic regression to zero tumor size. Immune response is also suppressed by the therapy, and thus plays a negligible role in the remission. We conclude that treatment evaluation should be successful without taking into account immunological effects. (C) 2003 Elsevier Ltd. All rights reserved.}, author = {de Vladar, Harold and González, J.}, journal = {Journal of Theoretical Biology}, number = {3}, pages = {335 -- 348}, publisher = {Elsevier}, title = {{Dynamic response of cancer under the influence of immunological activity and therapy}}, doi = {3801}, volume = {227}, year = {2004}, } @inbook{4239, author = {Harold Vladar and Cipriani, Roberto and Scharifker, Benjamin and Bubis, Jose}, booktitle = {Life in the Universe From the Miller Experiment to the Search for Life on Other Worlds}, editor = {Seckbach,J. and Chela-Flores,J. and Owen,T. and Raulin,F.}, pages = {83 -- 87}, publisher = {Springer}, title = {{A Mechanism for the Prebiotic Emergence of Proteins}}, doi = {3807}, volume = {7}, year = {2004}, } @article{4253, abstract = {We consider a single genetic locus which carries two alleles, labelled P and Q. This locus experiences selection and mutation. It is linked to a second neutral locus with recombination rate r. If r = 0, this reduces to the study of a single selected locus. Assuming a Moran model for the population dynamics, we pass to a diffusion approximation and, assuming that the allele frequencies at the selected locus have reached stationarity, establish the joint generating function for the genealogy of a sample from the population and the frequency of the P allele. In essence this is the joint generating function for a coalescent and the random background in which it evolves. We use this to characterize, for the diffusion approximation, the probability of identity in state at the neutral locus of a sample of two individuals (whose type at the selected locus is known) as solutions to a system of ordinary differential equations. The only subtlety is to find the boundary conditions for this system. Finally, numerical examples are presented that illustrate the accuracy and predictions of the diffusion approximation. In particular, a comparison is made between this approach and one in which the frequencies at the selected locus are estimated by their value in the absence of fluctuations and a classical structured coalescent model is used.}, author = {Nicholas Barton and Etheridge, Alison M and Sturm, Anja K}, journal = {Annals of Applied Probability}, number = {2}, pages = {754 -- 785}, publisher = {Institute of Mathematical Statistics}, title = {{Coalescence in a Random Background}}, volume = {14}, year = {2004}, } @inproceedings{4372, author = {Maler, Oded and Dejan Nickovic}, pages = {152 -- 166}, publisher = {Springer}, title = {{Monitoring Temporal Properties of Continuous Signals}}, doi = {1572}, year = {2004}, } @phdthesis{4424, abstract = {The enormous cost and ubiquity of software errors necessitates the need for techniques and tools that can precisely analyze large systems and prove that they meet given specifications, or if they don't, return counterexample behaviors showing how the system fails. Recent advances in model checking, decision procedures, program analysis and type systems, and a shift of focus to partial specifications common to several systems (e.g., memory safety and race freedom) have resulted in several practical verification methods. However, these methods are either precise or they are scalable, depending on whether they track the values of variables or only a fixed small set of dataflow facts (e.g., types), and are usually insufficient for precisely verifying large programs. We describe a new technique called Lazy Abstraction (LA) which achieves both precision and scalability by localizing the use of precise information. LA automatically builds, explores and refines a single abstract model of the program in a way that different parts of the model exhibit different degrees of precision, namely just enough to verify the desired property. The algorithm automatically mines the information required by partitioning mechanical proofs of unsatisfiability of spurious counterexamples into Craig Interpolants. For multithreaded systems, we give a new technique based on analyzing the behavior of a single thread executing in a context which is an abstraction of the other (arbitrarily many) threads. We define novel context models and show how to automatically infer them and analyze the full system (thread + context) using LA. LA is implemented in BLAST. We have run BLAST on Windows and Linux Device Drivers to verify API conformance properties, and have used it to find (or guarantee the absence of) data races in multithreaded Networked Embedded Systems (NESC) applications. BLAST is able to prove the absence of races in several cases where earlier methods, which depend on lock-based synchronization, fail.}, author = {Jhala, Ranjit}, pages = {1 -- 165}, publisher = {University of California, Berkeley}, title = {{Program verification by lazy abstraction}}, year = {2004}, } @inproceedings{4445, abstract = {We present a type system for E code, which is an assembly language that manages the release, interaction, and termination of real-time tasks. E code specifies a deadline for each task, and the type system ensures that the deadlines are path-insensitive. We show that typed E programs allow, for given worst-case execution times of tasks, a simple schedulability analysis. Moreover, the real-time programming language Giotto can be compiled into typed E~code. This shows that typed E~code identifies an easily schedulable yet expressive class of real-time programs. We have extended the Giotto compiler to generate typed E code, and enabled the run-time system for E code to perform a type and schedulability check before executing the code.}, author = {Thomas Henzinger and Kirsch, Christoph M}, pages = {104 -- 113}, publisher = {ACM}, title = {{A typed assembly language for real-time programs}}, doi = {10.1145/1017753.1017774}, year = {2004}, } @inproceedings{4458, abstract = {The success of model checking for large programs depends crucially on the ability to efficiently construct parsimonious abstractions. A predicate abstraction is parsimonious if at each control location, it specifies only relationships between current values of variables, and only those which are required for proving correctness. Previous methods for automatically refining predicate abstractions until sufficient precision is obtained do not systematically construct parsimonious abstractions: predicates usually contain symbolic variables, and are added heuristically and often uniformly to many or all control locations at once. We use Craig interpolation to efficiently construct, from a given abstract error trace which cannot be concretized, a parsominous abstraction that removes the trace. At each location of the trace, we infer the relevant predicates as an interpolant between the two formulas that define the past and the future segment of the trace. Each interpolant is a relationship between current values of program variables, and is relevant only at that particular program location. It can be found by a linear scan of the proof of infeasibility of the trace.We develop our method for programs with arithmetic and pointer expressions, and call-by-value function calls. For function calls, Craig interpolation offers a systematic way of generating relevant predicates that contain only the local variables of the function and the values of the formal parameters when the function was called. We have extended our model checker Blast with predicate discovery by Craig interpolation, and applied it successfully to C programs with more than 130,000 lines of code, which was not possible with approaches that build less parsimonious abstractions.}, author = {Thomas Henzinger and Jhala, Ranjit and Majumdar, Ritankar S and McMillan, Kenneth L}, pages = {232 -- 244}, publisher = {ACM}, title = {{Abstractions from proofs}}, doi = {10.1145/964001.964021}, year = {2004}, } @inproceedings{4459, abstract = {Software model checking has been successful for sequential programs, where predicate abstraction offers suitable models, and counterexample-guided abstraction refinement permits the automatic inference of models. When checking concurrent programs, we need to abstract threads as well as the contexts in which they execute. Stateless context models, such as predicates on global variables, prove insufficient for showing the absence of race conditions in many examples. We therefore use richer context models, which combine (1) predicates for abstracting data state, (2) control flow quotients for abstracting control state, and (3) counters for abstracting an unbounded number of threads. We infer suitable context models automatically by a combination of counterexample-guided abstraction refinement, bisimulation minimization, circular assume-guarantee reasoning, and parametric reasoning about an unbounded number of threads. This algorithm, called CIRC, has been implemented in BLAST and succeeds in checking many examples of NESC code for data races. In particular, BLAST proves the absence of races in several cases where previous race checkers give false positives.}, author = {Thomas Henzinger and Jhala, Ranjit and Majumdar, Ritankar S}, pages = {1 -- 13}, publisher = {ACM}, title = {{Race checking by context inference}}, doi = {10.1145/996841.996844}, year = {2004}, } @inbook{4461, abstract = {One of the central axioms of extreme programming is the disciplined use of regression testing during stepwise software development. Due to recent progress in software model checking, it has become possible to supplement this process with automatic checks for behavioral safety properties of programs, such as conformance with locking idioms and other programming protocols and patterns. For efficiency reasons, all checks must be incremental, i.e., they must reuse partial results from previous checks in order to avoid all unnecessary repetition of expensive verification tasks. We show that the lazy-abstraction algorithm, and its implementation in Blast, can be extended to support the fully automatic and incremental checking of temporal safety properties during software development.}, author = {Thomas Henzinger and Jhala, Ranjit and Majumdar, Ritankar S and Sanvido, Marco A}, booktitle = {Verification: Theory and Practice}, pages = {332 -- 358}, publisher = {Springer}, title = {{Extreme model checking}}, doi = {10.1007/978-3-540-39910-0_16}, volume = {2772}, year = {2004}, } @inproceedings{4525, abstract = {We present a new high-level programming language, called xGiotto, for programming applications with hard real-time constraints. Like its predecessor, xGiotto is based on the LET (logical execution time) assumption: the programmer specifies when the outputs of a task become available, and the compiler checks if the specification can be implemented on a given platform. However, while the predecessor language xGiotto was purely time-triggered, xGiotto accommodates also asynchronous events. Indeed, through a mechanism called event scoping, events are the main structuring principle of the new language. The xGiotto compiler and run-time system implement event scoping through a tree-based event filter. The compiler also checks programs for determinism (absence of race conditions).}, author = {Ghosal, Arkadeb and Thomas Henzinger and Kirsch, Christoph M and Sanvido, Marco A}, pages = {167 -- 170}, publisher = {Springer}, title = {{Event-driven programming with logical execution times}}, doi = {10.1007/978-3-540-24743-2_24}, volume = {2993}, year = {2004}, } @inproceedings{4555, abstract = {Strategies in repeated games can be classified as to whether or not they use memory and/or randomization. We consider Markov decision processes and 2-player graph games, both of the deterministic and probabilistic varieties. We characterize when memory and/or randomization are required for winning with respect to various classes of w-regular objectives, noting particularly when the use of memory can be traded for the use of randomization. In particular, we show that Markov decision processes allow randomized memoryless optimal strategies for all M?ller objectives. Furthermore, we show that 2-player probabilistic graph games allow randomized memoryless strategies for winning with probability 1 those M?ller objectives which are upward-closed. Upward-closure means that if a set α of infinitely repeating vertices is winning, then all supersets of α are also winning.}, author = {Krishnendu Chatterjee and de Alfaro, Luca and Thomas Henzinger}, pages = {206 -- 217}, publisher = {IEEE}, title = {{Trading memory for randomness}}, doi = {10.1109/QEST.2004.10051}, year = {2004}, } @article{4556, abstract = {We study the problem of determining stack boundedness and the exact maximum stack size for three classes of interrupt-driven programs. Interrupt-driven programs are used in many real-time applications that require responsive interrupt handling. In order to ensure responsiveness, programmers often enable interrupt processing in the body of lower-priority interrupt handlers. In such programs a programming error can allow interrupt handlers to be interrupted in a cyclic fashion to lead to an unbounded stack, causing the system to crash. For a restricted class of interrupt-driven programs, we show that there is a polynomial-time procedure to check stack boundedness, while determining the exact maximum stack size is PSPACE-complete. For a larger class of programs, the two problems are both PSPACE-complete, and for the largest class of programs we consider, the two problems are PSPACE-hard and can be solved in exponential time. While the complexities are high, our algorithms are exponential only in the number of handlers, and polynomial in the size of the program.}, author = {Krishnendu Chatterjee and Ma, Di and Majumdar, Ritankar S and Zhao, Tian and Thomas Henzinger and Palsberg, Jens}, journal = {Information and Computation}, number = {2}, pages = {144 -- 174}, publisher = {Elsevier}, title = {{Stack size analysis for interrupt-driven programs}}, doi = {10.1016/j.ic.2004.06.001}, volume = {194}, year = {2004}, } @inproceedings{4558, abstract = {We study perfect-information stochastic parity games. These are two-player nonterminating games which are played on a graph with turn-based probabilistic transitions. A play results in an infinite path and the conflicting goals of the two players are ω-regular path properties, formalized as parity winning conditions. The qualitative solution of such a game amounts to computing the set of vertices from which a player has a strategy to win with probability 1 (or with positive probability). The quantitative solution amounts to computing the value of the game in every vertex, i.e., the highest probability with which a player can guarantee satisfaction of his own objective in a play that starts from the vertex.For the important special case of one-player stochastic parity games (parity Markov decision processes) we give polynomial-time algorithms both for the qualitative and the quantitative solution. The running time of the qualitative solution is O(d · m3/2) for graphs with m edges and d priorities. The quantitative solution is based on a linear-programming formulation.For the two-player case, we establish the existence of optimal pure memoryless strategies. This has several important ramifications. First, it implies that the values of the games are rational. This is in contrast to the concurrent stochastic parity games of de Alfaro et al.; there, values are in general algebraic numbers, optimal strategies do not exist, and ε-optimal strategies have to be mixed and with infinite memory. Second, the existence of optimal pure memoryless strategies together with the polynomial-time solution forone-player case implies that the quantitative two-player stochastic parity game problem is in NP ∩ co-NP. This generalizes a result of Condon for stochastic games with reachability objectives. It also constitutes an exponential improvement over the best previous algorithm, which is based on a doubly exponential procedure of de Alfaro and Majumdar for concurrent stochastic parity games and provides only ε-approximations of the values.}, author = {Krishnendu Chatterjee and Jurdziński, Marcin and Thomas Henzinger}, pages = {121 -- 130}, publisher = {SIAM}, title = {{Quantitative stochastic parity games}}, year = {2004}, } @article{2623, abstract = {Patients with Hodgkin's disease can develop paraneoplastic cerebellar ataxia because of the generation of autoantibodies against mGluR1 (mGluR1-Abs). Yet, the pathophysiological mechanisms underlying their motor coordination deficits remain to be elucidated. Here, we show that application of IgG purified from the patients' serum to cerebellar slices of mice acutely reduces the basal activity of Purkinje cells, whereas application to the flocculus of mice in vivo evokes acute disturbances in the performance of their compensatory eye movements. In addition, the mGluR1-Abs block induction of long-term depression in cultured mouse Purkinje cells, whereas the cerebellar motor learning behavior of the patients is affected in that they show impaired adaptation of their saccadic eye movements. Finally, postmortem analysis of the cerebellum of a paraneoplastic cerebellar ataxia patient showed that the number of Purkinje cells was significantly reduced by approximately two thirds compared with three controls. We conclude that autoantibodies against mGluR1 can cause cerebellar motor coordination deficits caused by a combination of rapid effects on both acute and plastic responses of Purkinje cells and chronic degenerative effects.}, author = {Coesmans, Michiel P and Sillevis-Smitt, Peter A and Linden, David J and Ryuichi Shigemoto and Hirano, Tomoo and Yamakawa, Yoshinori and Van Alphen, Adriaan M and Luo, Chongde and Van Der Geest, Jos N and Kros, Johan M and Gaillard, Carlo A and Frens, Maarten A and De Zeeuw, Chris I}, journal = {Annals of Neurology}, number = {3}, pages = {325 -- 336}, publisher = {Wiley-Blackwell}, title = {{Mechanisms underlying cerebellar motor deficits due to mGluR1-autoantibodies}}, doi = {10.1002/ana.10451}, volume = {53}, year = {2003}, } @article{2625, abstract = {Metabotropic glutamate receptor 1 (mGluR1) plays a crucial role in synaptic plasticity and motor learning in the cerebellum. We have studied activity-dependent changes in mGluR1 function in mouse cultured Purkinje neurons. Depolarizing stimulation potentiated Ca2+ and current responses to an mGluR1 agonist for several hours in the cultured Purkinje neurons. It also blocked internalization of mGluR1 and increased the number of mGluR1s on the cell membrane. We found that depolarization simultaneously increased transcription of Homer1a in Purkinje neurons. Homer1a inhibited internalization and increased cell-surface expression of mGluR1 when coexpressed in human embryonic kidney (HEK)-293 cells. Depolarization-induced Homer1a expression in Purkinje neurons was blocked by a mitogen-activated protein kinase (MAPK) inhibitor. Changes in internalization and mGluR1-mediated Ca2+ response were also blocked by inhibition of MAPK activity, suggesting that localization and activity of mGluR1 were regulated in the same signalling pathway as Homer1a expression. It is thus suggested that depolarization of the Purkinje neuron leads to the increment in mGluR1 responsiveness through MAPK activity and induction of Homer1a expression, which increases active mGluR1 on the cell surface by blocking internalization of mGluR1.}, author = {Minami, Itsunari and Kengaku, Mineko and Smitt, Sillevis P and Ryuichi Shigemoto and Hirano, Tomoo}, journal = {European Journal of Neuroscience}, number = {5}, pages = {1023 -- 1032}, publisher = {Wiley-Blackwell}, title = {{Long-term potentiation of mGluR1 activity by depolarization-induced Homer1a in mouse cerebellar Purkinje neurons}}, doi = {10.1046/j.1460-9568.2003.02499.x}, volume = {17}, year = {2003}, }