Hillel Kugler

Bar Ilan University | BIU · Faculty of Engineering

The inference of gene regulatory networks (GRNs) from single-cell RNAseq data allows for mechanistic characterization of the different cell states and their dynamics in complex biological processes. While numerous algorithms have been proposed to infer GRNs from single-cell transcriptomic data, multiple network solutions may explain the same datase...

Deep Neural Networks (DNNs) are ubiquitous in real-world applications, yet they remain vulnerable to errors and adversarial attacks. This work tackles the challenge of applying formal verification to ensure the safety of computer vision models, extending verification beyond image classification to object detection. We propose a general formulation...

We present a framework called the Reasoning Engine, which implements Satisfiability Modulo Theories (SMT)-based methods within a unified computational environment to address diverse biological analysis problems. The Reasoning Engine was used to reproduce results from key scientific studies, as well as supporting new research in stem cell biology. T...

During embryonic development, naive pluripotent epiblast cells transit to a formative state. The formative epiblast cells form a polarized epithelium, exhibit distinct transcriptional and epigenetic profiles and acquire competence to differentiate into all somatic and germline lineages. However, we have limited understanding of how the transition t...

We present a framework called the Reasoning Engine, which implements Satisfiability Modulo Theories (SMT) based methods within a unified computational environment to address diverse biological analysis problems. The reasoning engine was used to reproduce results from key scientific studies, as well as supporting new research in stem cell biology. T...

Reinforcement-Learning-based solutions have achieved many successes in numerous complex tasks. However, their training process may be unstable, and achieving convergence can be difficult, expensive, and in some instances impossible. We propose herein an approach that enables the integration of strong formal verification methods in order to improve...

The 3‐satisfiability Problem (3‐SAT) is a demanding combinatorial problem that is of central importance among the nondeterministic polynomial (NP) complete problems, with applications in circuit design, artificial intelligence, and logistics. Even with optimized algorithms, the solution space that needs to be explored grows exponentially with the i...

Network-based biocomputation (NBC) is an alternative, parallel computation approach that potentially can solve technologically important, combinatorial problems with much lower energy consumption than electronic processors. In NBC, a combinatorial problem is encoded into a physical, nanofabricated network. The problem is solved by biological agents...

Information processing by traditional, serial electronic processors consumes an ever-increasing part of the global electricity supply. An alternative, highly energy efficient, parallel computing paradigm is network-based biocomputation (NBC). In NBC a given combinatorial problem is encoded into a nanofabricated, modular network. Parallel exploratio...

Computational methods and tools are a powerful complementary approach to experimental work for studying regulatory interactions in living cells and systems. We demonstrate the use of formal reasoning methods as applied to the Caenorhabditis elegans germ line, which is an accessible system for stem cell research. The dynamics of the underlying genet...

The 3-Satisfiability Problem (3-SAT) is a demanding combinatorial problem, of central importance among the non-deterministic polynomial (NP) complete problems, with applications in circuit design, artificial intelligence and logistics. Even with optimized algorithms, the solution space that needs to be explored grows exponentially with increasing s...

The high energy consumption of electronic data processors, together with physical challenges limiting their further improvement, has triggered intensive interest in alternative computation paradigms. Here we focus on network-based biocomputation (NBC), a massively parallel approach where computational problems are encoded in planar networks impleme...

Computational methods and tools are a powerful complementary approach to experimental work for studying regulatory interactions in living cells and systems. We demonstrate the use of formal reasoning methods as applied to the Caenorhabditis elegans germ line, which is an accessible model system for stem cell research. The dynamics of the underlying...

Exact cover is a non-deterministic polynomial time (NP)-complete problem that is central to optimization challenges such as airline fleet planning and allocation of cloud computing resources. Solving exact cover requires the exploration of a solution space that increases exponentially with cardinality. Hence, it is time- and energy consuming to sol...

The high energy consumption of electronic data processors, together with physical challenges limiting their further improvement, has triggered intensive interest in alternative computation paradigms. Here we focus on network-based biocomputation (NBC), a massively parallel approach that benefits from the energy efficiency of biological agents, such...

Network-Based Biocomputation Circuits (NBCs) offer a new paradigm for solving complex computational problems by utilizing biological agents that operate in parallel to explore manufactured planar devices. The approach can also have future applications in diagnostics and medicine by combining NBCs computational power with the ability to interface wi...

Mouse embryonic stem (ES) cells are derived from the epiblast of the preimplantation embryo and retain the capacity to give rise to all embryo lineages. ES cells can be released into differentiation from a near-homogeneous maintenance condition. Exit from the ES cell state can be accurately monitored using the Rex1-GFPd2 transgenic reporter, provid...

Computational modelling of metabolic processes has proven to be a useful approach to formulate our knowledge and improve our understanding of core biochemical systems that are crucial to maintaining cellular functions. Towards understanding the broader role of metabolism on cellular decision-making in health and disease conditions, it is important...

A recurring set of small sub-networks have been identified as the building blocks of biological networks across diverse organisms. These network motifs are associated with certain dynamical behaviors and define key modules that are important for understanding complex biological programs. Besides studying the properties of motifs in isolation, curre...

We present the BRE:IN tool, a Backend for Reasoning about Interaction Networks. Our tool supports the framework and methodology originally introduced by the RE:IN tool, where an Abstract Boolean Network (ABN) specifies partial information about the network topology, and experimental observations are used to constrain the ABN, allowing to synthesize...

Synthesis methods based on formal reasoning are a powerful way to automate the process of constructing computational models of gene regulatory networks (GRNs) and increase predictive power by considering a set of consistent models that are guaranteed to satisfy known experimental data. Previously, a formal reasoning based approach enabling the synt...

Semantics of temporal logic over truncated paths (i.e. finite paths that correspond to prefixes of computations of the system at hand) have been found useful in incomplete verification methods (such as bounded model checking and dynamic verification), in modeling hardware resets, and clock shifts and in online and offline monitoring of cyber-physic...

A recurring set of small sub-networks have been identified as the building blocks of biological networks across diverse organisms. These network motifs have been associated with certain dynamical behaviors and define key modules that are important for understanding complex biological programs. Besides studying the properties of motifs in isolation,...

Despite significant research progress made and methodological experience gained over the past few decades, a tight integration between programming and modelling, guided and supported by intuitive yet rigorous formal reasoning and verification methods that ensure high reliability and quality of the developed system remains challenging and is still f...

Computational models are an invaluable tool in modern biology. They provide a framework within which to summarize existing knowledge, enable competing hypotheses to be compared qualitatively and quantitatively, and to facilitate the interpretation of complex data. Moreover, models allow questions to be investigated that are difficult to approach ex...

Predictive biology is elusive because rigorous, data-constrained, mechanistic models of complex biological systems are difficult to derive and validate. Current approaches tend to construct and examine static interaction network models, which are descriptively rich, but often lack explanatory and predictive power, or dynamic models that can be simu...

Studying the gene regulatory networks (GRNs) that govern how cells change into specific cell types with unique roles throughout development is an active area of experimental research. The fate specification process can be viewed as a program prescribing the system dynamics, governed by a network of genetic interactions. To investigate the possibili...

The C. elegans germ line is an outstanding model system to study the control of cell division and differentiation. While many of the molecules that regulate germ cell proliferation and fate decisions have been identified, how these signals interact with cellular dynamics and physical forces within the gonad remains poorly understood. We therefore d...

A fundamental question in biology is how cells change into specific cell types with unique roles throughout development. This process can be viewed as a program prescribing the system dynamics, governed by a network of genetic interactions. Recent experimental evidence suggests that these networks are not fixed but rather change their topology as c...

We present a novel technique to analyze the bounded reachability probability problem for large Markov chains. The essential idea is to incrementally search for sets of paths that lead to the goal region and to choose the sets in a way that allows us to easily determine the probability mass they represent. To effectively analyze the system dynamics...

Deciphering the developmental program of an embryo is a fundamental question in biology. Landmark papers [9,10] have recently shown how computational models of gene regulatory networks provide system-level causal understanding of the developmental processes of the sea urchin, and enable powerful predictive capabilities. A crucial aspect of the work...

Understanding how biological systems develop and function remains one of the main open scientific challenges of our times. An improved quantitative understanding of biological systems, assisted by computational models is also important for future bioengineering and biomedical applications. We present a computational approach aimed towards unifying...

Advanced computational models are transforming the way research is done in biology, by providing quantitative means to assess the validity of theories and hypotheses and allowing predictive capabilities, raising an urgent need to be able to systematically and efficiently analyze runtime properties of models. In this tutorial I describe key biologic...

We present a method for the analysis of functional properties of large-scale DNA strand displacement (DSD) circuits based on Satisfiability Modulo Theories that enables us to prove the functional correctness of DNA circuit designs for arbitrary inputs, and provides significantly improved scalability and expressivity over existing methods. We implem...

Synthetic biology focuses on the re-engineering of living organisms for useful purposes while DNA computing targets the construction of therapeutics and computational circuits directly from DNA strands. The complexity of biological systems is a major engineering challenge and their modeling relies on a number of diverse formalisms. Moreover, many a...

The proper renewal and maintenance of tissues by stem cell populations is simultaneously influenced by anatomical constraints, cell proliferation dynamics and cell fate specification. However, their relative influence is difficult to examine in vivo. To address this difficulty we built, as a test case, a cell-centered state-based computational mode...

Studies of biological systems are often facilitated by diagram “models” that summarize the current understanding of underlying mechanisms. The increasing complexity of our understanding of biology necessitates computational models that can extend these representations to include their dynamic behavior. We present here a new tool we call Synthesizin...

A main idea underlying bounded model checking is to limit the length of the potential counter-examples, and then prove properties for the bounded version of the problem. In software model checking, that means that only program traces up to a given length are considered. Additionally, the program’s input space must be made finite by defining bounds...

Smart play-out is a method for executing declarative scenario-based specifications, which utilizes powerful computation methods to compute safe supersteps, thus helping to avoid violations that may be caused by naïve execution. Major challenges for smart play-out are performance and scalability. In this work we show how to accelerate smart play-out...

This paper combines three topics to which Amir Pnueli contributed significantly: the semantics of languages for concurrency, the semantics of statecharts, and reactive and hybrid systems. It is also no accident that the main motivation of our paper comes from biological systems: in recent years Amir became interested in these too. In [KLH10] we int...

We address one of the central issues in devising languages, methods and tools for the modelling and analysis of complex biological systems, that of linking high-level (e.g. intercellular) information with lower-level (e.g. intracellular) information. Adequate ways of dealing with this issue are crucial for understanding biological networks and path...

Synthesis is the process of automatically generating a correct running system from its specification. In this paper, we suggest a translation of a Live Sequence Chart specification into a two-player game for the purpose of synthesis. We use this representation for synthesizing a reactive system, and introduce a novel algorithm for composing two suc...

Live Sequence Charts (LSCs) is a visual requirements language for specifying reactive system behavior. When modeling and designing open reac- tive systems, it is often essential to have a guarantee that the requirements can be satisfied under all possible circumstances. We apply results in the area of con- troller synthesis to a subset of the LSC l...

This paper presents a game-model of a gym training system, where the behavior of the system is specied using languages developed originally for reactive system design, which drive a game engine. The approach makes it possible to describe behaviors of dierent parts of the system using dierent re- active system design languages and tools. It thus pro...

Studies of developmental biology are often facilitated by diagram "models" that summarize the current understanding of underlying mechanisms. The increasing complexity of our understanding of development necessitates computational models that can extend these representations to include their dynamic behavior. Here we present a prototype model of Ca...

We apply the scenario-based approach to mode- ling, via the language of live sequence charts (LSCs) and the Play-Engine tool to a real-world complex telecommunica- tion service, Depannage. It allows a user to call for help from a doctor, the fire brigade, a car maintenance service, etc. These kinds of services are built on top of an embedded platfo...

We describe an approach to support UML-based development of embedded systems by formal techniques. A subset of UML is extended with timing annotations and given a formal semantics. UML models are translated, via XMI, to the input format of formal tools, to allow timed and non-timed model checking and interactive theorem proving. Moreover, the Play-...

Live Sequence Charts (LSCs) is a scenario-based language for modeling object-based reactive systems with liveness properties. A tool called the Play-Engine allows users to create LSC requirements using a point-and-click interface and generate executable traces using features called play-out and smart play-out. Finite executable trace fragments call...

Analysis of biological data often requires an understanding of components of pathways and/or networks and their mutual dependency relationships. Such systems are often analyzed and understood from datasets made up of the states of the relevant components and a set of dis- crete outcomes or results. The analysis of these systems can be assisted by m...

The play-in/play-out approach suggests a new paradigm for system development using scenario-based requirements. It allows the user to develop a high level scenario-based model of the system and directly execute system behavior. The supporting tool, the Play-Engine has been used successfully in several projects and case-studies. As systems devel- op...

We provide semantics for the powerful scenario-based lan- guage of live sequence charts (LSCs). We show how the semantics of live sequence charts can be captured using temporal logic. This is done by studying various subsets of the LSC language and providing an explicit translation into temporal logic. We show how a kernel subset of the LSC languag...

The Object Constraint Language (OCL) is the established language for the specification of properties of objects and object structures in UML models. One reason that it is not yet widely adopted in industry is the lack of proper and integrated tool support for OCL. Therefore, we present a prototype tool, which analyzes the syntax and semantics of OC...

Constructing a program from a specification is a long-known general and fundamental problem. Besides its theoretical interest, this question also has practical implications, since finding good synthesis algorithms could bring about a major improvement in the reliable development of complex systems. In this paper we describe a methodology for synthe...

4 OMEGA UML PROFILE FOR REAL-TIME AND EMBEDDED SYSTEMS AND ITS SEMANTICS........................................................................................................................................... 13 4.1 UML PROFILE...........................................................................................................................

In recent years, UML has been applied to the development of reactive safety-critical systems, in which the quality of the developed software is a key factor. In this paper we present an approach for the deductive verification of such systems using the PVS interactive theorem prover. Using a PVS specification of a UML kernel language semantics, we g...

Smart play-out is a powerful technique for executing live sequence charts (LSCs). It uses verification techniques to help run a program, rather than to prove properties thereof. We extend smart play-out to cover a larger set of the LSC language features and to deal more efficiently with larger models. The extensions cover two key features of the ri...

We describe the semantics of statecharts as implemented in the current version of the Rhapsody tool. In its original 1996 version this was among the first executable semantics for object-oriented statecharts, and many of its fundamentals have been adopted in the Unified Modeling Language (UML). Due to the special challenges of object-oriented behav...

We describe the semantics of statecharts as implemented in the current version of the Rhapsody tool. In its original 1996 version this was among the first executable semantics for object-oriented statecharts, and many of its fundamentals have been adopted in the Unified Modeling Language (UML). Due to the special challenges of object-oriented behav...

The Object Constraint Language (OCL) is the established language for the specification of properties of objects and object structures in UML models. One reason that it is not yet widely adopted in industry is the lack of proper and integrated tool support for OCL. Therefore, we present a prototype tool, which analyzes the syntax and semantics of OC...

We describe "smart play-out", a new method for executing and analyzing scenario based behavior, which is part of the Play-In/Play-Out methodology and the Play-Engine tool. Behavior is "played in" directly from the system's GUI, and as this is being done the Play-Engine continuously constructs Live Sequence Charts (LSCs), a powerful extension of seq...

We describe the semantics of statecharts as implemented in the current version of the Rhapsody tool. In its original 1996 version this was among the first executable semantics for object-oriented statecharts, and many of its fundamentals have been adopted in the Unified Modeling Language (UML). Due to the special challenges of object-oriented behav...

We demonstrate the use of the language of Live Sequence Charts (LSCs) for specifying part of the air traffic control system CTAS (Center TRACON Automation System). We use a recent extension of LSCs to handle symbolic instances, allowing an instance to be associated with a class rather than with an object. This allows us to specify scenario-based re...

We present preliminary results of a new approach to the formal modeling of biological phenomena. The approach stems from the conceptual compatibility of the methods and logic of data collection and analysis in the field of developmental genetics with the languages, methods and tools of scenario-based reactive system design. In particular, we use th...

The play-in/play-out approach is a method for specifying and developing complex reactive systems. It is built upon a scenario- based philosophy, and uses the language of live sequence charts (LSCs) and a support tool called the Play-Engine. We present some conclusions from the initial experience we have had using the approach on several projects, a...

We describe a methodology for executing scenario-based requirements of reactive systems, focusing on "playing-out" the behavior using formal verification techniques for driving the execution. The methodology is implemented in full in our playengine tool . The approach appears to be useful in many stages in the development of reactive systems, and m...

Live sequence charts (LSCs) have been defined recently as an extension of message sequence charts (MSCs; or their UML variant, sequence diagrams) for rich inter-object specification. One of the main additions is the notion of universal charts and hot, mandatory behavior, which, among other things, enables one to specify forbidden scenarios.

A powerful methodology for specifying scenario-based requirements of reactive systems is described, in which behavioral requirements are "played in" directly from the system's GUI or some abstract version thereof, and full behavior can then be "played out" freely, just as if a conventional system model were present. The approach is supported and il...

We extend live sequence charts (LSCs), a highly expressive variant of sequence diagrams, and provide the extension with an executable semantics. The extension involves support for instances that can bind to multiple objects and symbolic variables that can bind to arbitrary values. The result is a powerful executable language for expressing behavior...