Star-topology decoupled state-space search in AI planning and model checking

State-space search is a widely employed concept in many areas of computer science. The well-known state explosion problem, however, imposes a severe limitation to the effective implementation of search in state spaces that are exponential in the size of a compact system description, which captures the state-transition semantics. Decoupled state-space search, decoupled search for short, is a novel approach to tackle the state explosion. It decomposes the system such that the dependencies between components take the form of a star topology with a center and several leaf components. Decoupled search exploits that the leaves in that topology are conditionally independent. Such independence naturally arises in many kinds of factored model representations, where the overall state space results from the product of several system components. In this work, we introduce decoupled search in the context of artificial intelligence planning and formal verification using model checking. Building on common formalisms, we develop the concept of the decoupled state space and prove its correctness with respect to capturing reachability of the underlying model exactly. This allows us to connect decoupled search to any search algorithm, and, important for planning, adapt any heuristic function to the decoupled state representation. Such heuristics then guide the search towards states that satisfy a desired goal condition. In model checking, we address the problems of verifying safety properties, which express system states that must never occur, and liveness properties, that must hold in any infinite system execution. Many approaches have been proposed in the past to tackle the state explosion problem. Most prominently partial-order reduction, symmetry breaking, Petri-net unfolding, and symbolic state representations. Like decoupled search, all of these are capable of exponentially reducing the search effort, either by pruning part of the state space (the former two), or by representing large state sets compactly (the latter two). For all these techniques, we prove that decoupled search can be exponentially more efficient, confirming that it is indeed a novel concept that exploits model properties in a unique way. Given such orthogonality, we combine decoupled search with several complementary methods. Empirically, we show that decoupled search favourably compares to state-of-the-art planners in common algorithmic planning problems using standard benchmarks. In model checking, decoupled search outperforms well-established tools, both in the context of the verification of safety and liveness properties.Die Zustandsraumsuche ist ein weit verbreitetes Konzept in vielen Bereichen der Informatik, deren effektive Anwendung jedoch durch das Problem der Zustandsexplosion deutlich erschwert wird. Die Zustandsexplosion ist dadurch charakterisiert dass kompakte Systemmodelle exponentiell große Zustandsräume beschreiben. Entkoppelte Zustandsraumsuche (entkoppelte Suche) beschreibt einen neuartigen Ansatz der Zustandsexplosion entgegenzuwirken indem die Struktur des Modells, insbesondere die bedingte Unabhängigkeit von Systemkomponenten in einer Sterntopologie, ausgenutzt wird. Diese Unabhängigkeit ergibt sich bei vielen faktorisierten Modellen deren Zustandsraum sich aus dem Produkt mehrerer Komponenten zusammensetzt. In dieser Arbeit wird die entkoppelte Suche in der Planung, als Teil der Künstlichen Intelligenz, und der Verifikation mittels Modellprüfung eingeführt. In etablierten Formalismen wird das Konzept des entkoppelten Zustandsraums entwickelt und dessen Korrektheit bezüglich der exakten Erfassung der Erreichbarkeit von Modellzuständen bewiesen. Dies ermöglicht die Kombination der entkoppelten Suche mit beliebigen Suchalgorithmen. Wichtig für die Planung ist zudem die Nutzung von Heuristiken, die die Suche zu Zuständen führen, die eine gewünschte Zielbedingung erfüllen, mit der entkoppelten Zustandsdarstellung. Im Teil zur Modellprüfung wird die Verifikation von Sicherheits- sowie Lebendigkeitseigenschaften betrachtet, die unerwünschte Zustände, bzw. Eigenschaften, die bei unendlicher Systemausführung gelten müssen, beschreiben. Es existieren diverse Ansätze um die Zustandsexplosion anzugehen. Am bekanntesten sind die Reduktion partieller Ordnung, Symmetriereduktion, Entfaltung von Petri-Netzen und symbolische Suche. Diese können, wie die entkoppelte Suche, den Suchaufwand exponentiell reduzieren. Dies geschieht durch Beschneidung eines Teils des Zustandsraums, oder durch die kompakte Darstellung großer Zustandsmengen. Für diese Verfahren wird bewiesen, dass die entkoppelte Suche exponentiell effizienter sein kann. Dies belegt dass es sich um ein neuartiges Konzept handelt, das sich auf eigene Art der Modelleigenschaften bedient. Auf Basis dieser Beobachtung werden, mit Ausnahme der Entfaltung, Kombinationen mit entkoppelter Suche entwickelt. Empirisch kann die entkoppelte Suche im Vergleich zu modernen Planern zu deutlichen Vorteilen führen. In der Modellprüfung werden, sowohl bei der Überprüfung von Sicherheit-, als auch Lebendigkeitseigenschaften, etablierte Programme übertroffen.Deutsche Forschungsgesellschaft; Star-Topology Decoupled State Space Searc

Additive Pattern Databases for Decoupled Search

Abstraction heuristics are the state of the art in optimal classical planning as heuristic search. Despite their success for explicit-state search, though, abstraction heuristics are not available for decoupled state-space search, an orthogonal reduction technique that can lead to exponential savings by decomposing planning tasks. In this paper, we show how to compute pattern database (PDB) heuristics for decoupled states. The main challenge lies in how to additively employ multiple patterns, which is crucial for strong search guidance of the heuristics. We show that in the general case, for arbitrary collections of PDBs, computing the heuristic for a decoupled state is exponential in the number of leaf components of decoupled search. We derive several variants of decoupled PDB heuristics that allow to additively combine PDBs avoiding this blow-up and evaluate them empirically

Efficient Evaluation of Large Abstractions for Decoupled Search: Merge-and-Shrink and Symbolic Pattern Databases

Abstraction heuristics are a state-of-the-art technique to solve classical planning problems optimally. A common approach is to precompute many small abstractions and combine them admissibly using cost partitioning. Recent work has shown that this approach does not work out well when using such heuristics for decoupled state space search, where search nodes represent potentially large sets of states. This is due to the fact that admissibly combining the estimates of several heuristics without sacrificing accuracy is NP-hard for decoupled states. In this work we propose to use a single large abstraction instead. We focus on merge-and-shrink and symbolic pattern database heuristics, which are designed to produce such abstractions. For these heuristics, we prove that the evaluation of decoupled states is NP-hard in general, but we also identify conditions under which it is polynomial. We introduce algorithms for both the general and the polynomial case. Our experimental evaluation shows that single large abstraction heuristics lead to strong performance when the heuristic evaluation is polynomial

Cellular Interrogation: Exploiting Cell-to-Cell Variability to Discriminate Regulatory Mechanisms in Oscillatory Signalling

The molecular complexity within a cell may be seen as an evolutionary response to the external complexity of the cell’s environment. This suggests that the external environment may be harnessed to interrogate the cell’s internal molecular architecture. Cells, however, are not only nonlinear and non-stationary, but also exhibit heterogeneous responses within a clonal, isogenic population. In effect, each cell undertakes its own experiment. Here, we develop a method of cellular interrogation using programmable microfluidic devices which exploits the additional information present in cell-to-cell variation, without requiring model parameters to be fitted to data. We focussed on Ca2+ signalling in response to hormone stimulation, which exhibits oscillatory spiking in many cell types and chose eight models of Ca2+ signalling networks which exhibit similar behaviour in simulation. We developed a nonlinear frequency analysis for non-stationary responses, which could classify models into groups under parameter variation, but found that this question alone was unable to distinguish critical feedback loops. We further developed a nonlinear amplitude analysis and found that the combination of both questions ruled out six of the models as inconsistent with the experimentally-observed dynamics and heterogeneity. The two models that survived the double interrogation were mathematically different but schematically identical and yielded the same unexpected predictions that we confirmed experimentally. Further analysis showed that subtle mathematical details can markedly influence non-stationary responses under parameter variation, emphasising the difficulty of finding a “correct” model. By developing questions for the pathway being studied, and designing more versatile microfluidics, cellular interrogation holds promise as a systematic strategy that can complement direct intervention by genetics or pharmacology

A phase I dose-escalation study of the immunocytokine EMD 521873 (Selectikine) in patients with advanced solid tumours

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31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Revisiting Dominance Pruning in Decoupled Search

In classical planning as search, duplicate state pruning is a standard method to avoid unnecessarily handling the same state multiple times. In decoupled search, similar to symbolic search approaches, search nodes, called decoupled states, do not correspond to individual states, but to sets of states. Therefore, duplicate state pruning is less effective in decoupled search, and dominance pruning is employed, taking into account the state sets. We observe that the time required for dominance checking dominates the overall runtime, and propose two ways to tackle this issue. Our main contribution is a stronger variant of dominance checking for optimal planning, where efficiency and pruning power are most crucial. The new variant greatly improves the latter, without incurring a computational overhead. Moreover, we develop three methods that make the dominance check more efficient: exact duplicate checking, which, albeit resulting in weaker pruning, can pay off due to the use of hashing; avoiding the dominance check in non-optimal planning if leaf state spaces are invertible; and exploiting the transitivity of the dominance relation to only check against the relevant subset of visited decoupled states. We show empirically that all our improvements are indeed beneficial in many standard benchmarks

Beating LM-Cut with h-max (Sometimes): Fork-Decoupled State Space Search

Factored planning decouples planning tasks into subsets (factors) of state variables. The traditional focus is on handling complex cross-factor interactions. Departing from this, we introduce a form of target-profile factoring, forcing the cross-factor interactions to take the form of a fork, with several leaf factors and one potentially very large root factor. We show that forward state space search gracefully extends to such structure, by augmenting regular search on the root factor with maintenance of the cheapest compliant paths within each leaf factor. We analyze how to guarantee optimality. Connecting to standard heuristics, the performance improvements relative to A* are substantial, and sometimes dramatic: In four IPC benchmark domains, fork-decoupled state space search outperforms standard state space search even when using h^max in the former vs. LM-cut in the latter