Lumpability Abstractions of Rule-based Systems

The induction of a signaling pathway is characterized by transient complex formation and mutual posttranslational modification of proteins. To faithfully capture this combinatorial process in a mathematical model is an important challenge in systems biology. Exploiting the limited context on which most binding and modification events are conditioned, attempts have been made to reduce the combinatorial complexity by quotienting the reachable set of molecular species, into species aggregates while preserving the deterministic semantics of the thermodynamic limit. Recently we proposed a quotienting that also preserves the stochastic semantics and that is complete in the sense that the semantics of individual species can be recovered from the aggregate semantics. In this paper we prove that this quotienting yields a sufficient condition for weak lumpability and that it gives rise to a backward Markov bisimulation between the original and aggregated transition system. We illustrate the framework on a case study of the EGF/insulin receptor crosstalk.Comment: In Proceedings MeCBIC 2010, arXiv:1011.005

Secrecy capacity of a class of orthogonal relay eavesdropper channels

The secrecy capacity of relay channels with orthogonal components is studied in the presence of an additional passive eavesdropper node. The relay and destination receive signals from the source on two orthogonal channels such that the destination also receives transmissions from the relay on its channel. The eavesdropper can overhear either one or both of the orthogonal channels. Inner and outer bounds on the secrecy capacity are developed for both the discrete memoryless and the Gaussian channel models. For the discrete memoryless case, the secrecy capacity is shown to be achieved by a partial decode-and-forward (PDF) scheme when the eavesdropper can overhear only one of the two orthogonal channels. Two new outer bounds are presented for the Gaussian model using recent capacity results for a Gaussian multi-antenna point-to-point channel with a multi-antenna eavesdropper. The outer bounds are shown to be tight for two sub-classes of channels. The first sub-class is one in which the source and relay are clustered and the and the eavesdropper receives signals only on the channel from the source and the relay to the destination, for which the PDF strategy is optimal. The second is a sub-class in which the source does not transmit to the relay, for which a noise-forwarding strategy is optimal.Comment: Submitted to Eurasip Journal on Wireless Communications and Networking special issue on Wireless physical layer security, Dec. 2008, Revised Jun. 200

Automatic Verification of Finite Precision Implementations of Linear Controllers

We consider the problem of verifying finite precision implementation of linear time-invariant controllers against mathematical specifications. A specification may have multiple correct implementations which are different from each other in controller state representation, but equivalent from a perspective of input-output behavior (e.g., due to optimization in a code generator). The implementations may use finite precision computations (e.g. floating-point arithmetic) which cause quantization (i.e., roundoff) errors. To address these challenges, we first extract a controller\u27s mathematical model from the implementation via symbolic execution and floating-point error analysis, and then check approximate input-output equivalence between the extracted model and the specification by similarity checking. We show how to automatically verify the correctness of floating-point controller implementation in C language using the combination of techniques such as symbolic execution and convex optimization problem solving. We demonstrate the scalability of our approach through evaluation with randomly generated controller specifications of realistic size

Ketamine's antidepressant effect is mediated by energy metabolism and antioxidant defense system.

Fewer than 50% of all patients with major depressive disorder (MDD) treated with currently available antidepressants (ADs) show full remission. Moreover, about one third of the patients suffering from MDD does not respond to conventional ADs and develop treatment-resistant depression (TRD). Ketamine, a non-competitive, voltage-dependent N-Methyl-D-aspartate receptor (NMDAR) antagonist, has been shown to have a rapid antidepressant effect, especially in patients suffering from TRD. Hippocampi of ketamine-treated mice were analysed by metabolome and proteome profiling to delineate ketamine treatment-affected molecular pathways and biosignatures. Our data implicate mitochondrial energy metabolism and the antioxidant defense system as downstream effectors of the ketamine response. Specifically, ketamine tended to downregulate the adenosine triphosphate (ATP)/adenosine diphosphate (ADP) metabolite ratio which strongly correlated with forced swim test (FST) floating time. Furthermore, we found increased levels of enzymes that are part of the 'oxidative phosphorylation' (OXPHOS) pathway. Our study also suggests that ketamine causes less protein damage by rapidly decreasing reactive oxygen species (ROS) production and lend further support to the hypothesis that mitochondria have a critical role for mediating antidepressant action including the rapid ketamine response

Polarization angle accuracy for future CMB experiments. The COSMOCal project and its prototype in the 1mm band

The Cosmic Microwave Background (CMB) radiation offers a unique window into the early Universe, facilitating precise examinations of fundamental cosmological theories. However, the quest for detecting B-modes in the CMB, predicted by theoretical models of inflation, faces substantial challenges in terms of calibration and foreground modeling. The COSMOCal (COsmic Survey of Millimeter wavelengths Objects for CMB experiments Calibration) project aims at enhancing the accuracy of the absolute calibration of the polarization angle $\psi$ of current and future CMB experiments. The concept includes the build of a very well known artificial source emitting in the frequency range [20-350] GHz that would act as an absolute calibrator for several polarization facilities on Earth. A feasibility study to place the artificial source in geostationary orbit, in the far field for all the telescopes on Earth, is ongoing. In the meanwhile ongoing hardware work is dedicated to build a prototype to test the technology, the precision and the stability of the polarization recovering in the 1 mm band (220-300 GHz). High-resolution experiments as the NIKA2 camera at the IRAM 30m telescope will be deployed for such use. Once carefully calibrated ($\Delta\psi$ < 0.1 degrees) it will be used to observe astrophysical sources such as the Crab nebula, which is the best candidate in the sky for the absolute calibration of CMB experiments.Comment: to appear in Proc. of the mm Universe 2023 conference, Grenoble (France), June 2023, published by F. Mayet et al. (Eds), EPJ Web of conferences, EDP Science

Sharing Ghost Variables in a Collection of Abstract Domains

International audienceWe propose a framework in which we share ghost variables across a collection of abstract domains allowing precise proofs of complex properties. In abstract interpretation, it is often necessary to be able to express complex properties while doing a precise analysis. A way to achieve that is to combine a collection of domains, each handling some kind of properties, using a reduced product. Separating domains allows an easier and more modular implementation, and eases soundness and termination proofs. This way, we can add a domain for any kind of property that is interesting. The reduced product, or an approximation of it, is in charge of refining abstract states, making the analysis precise. In program verification, ghost variables can be used to ease proofs of properties by storing intermediate values that do not appear directly in the execution. We propose a reduced product of abstract domains that allows domains to use ghost variables to ease the representation of their internal state. Domains must be totally agnostic with respect to other existing domains. In particular the handling of ghost variables must be entirely decentralized while still ensuring soundness and termination of the analysis

Genetic counselling for psychiatric disorders: accounts of psychiatric health professionals in the United Kingdom

Genetic counselling is not routinely offered for psychiatric disorders in the United Kingdom through NHS regional clinical genetics departments. However, recent genomic advances, confirming a genetic contribution to mental illness, are anticipated to increase demand for psychiatric genetic counselling. This is the first study of its kind to employ qualitative methods of research to explore accounts of psychiatric health professionals regarding the prospects for genetic counselling services within clinical psychiatry in the UK. Data were collected from 32 questionnaire participants, and 9 subsequent interviewees. Data analysis revealed that although participants had not encountered patients explicitly demanding psychiatric genetic counselling, psychiatric health professionals believe that such a service would be useful and desirable. Genomic advances may have significant implications for genetic counselling in clinical psychiatry even if these discoveries do not lead to genetic testing. Psychiatric health professionals describe clinical genetics as a skilled profession capable of combining complex risk communication with much needed psychosocial support. However, participants noted barriers to the implementation of psychiatric genetic counselling services including, but not limited to, the complexities of uncertainty in psychiatric diagnoses, patient engagement and ethical concerns regarding limited capacity

Exact Hybrid Particle/Population Simulation of Rule-Based Models of Biochemical Systems

Detailed modeling and simulation of biochemical systems is complicated by the problem of combinatorial complexity, an explosion in the number of species and reactions due to myriad protein-protein interactions and post-translational modifications. Rule-based modeling overcomes this problem by representing molecules as structured objects and encoding their interactions as pattern-based rules. This greatly simplifies the process of model specification, avoiding the tedious and error prone task of manually enumerating all species and reactions that can potentially exist in a system. From a simulation perspective, rule-based models can be expanded algorithmically into fully-enumerated reaction networks and simulated using a variety of network-based simulation methods, such as ordinary differential equations or Gillespie's algorithm, provided that the network is not exceedingly large. Alternatively, rule-based models can be simulated directly using particle-based kinetic Monte Carlo methods. This "network-free" approach produces exact stochastic trajectories with a computational cost that is independent of network size. However, memory and run time costs increase with the number of particles, limiting the size of system that can be feasibly simulated. Here, we present a hybrid particle/population simulation method that combines the best attributes of both the network-based and network-free approaches. The method takes as input a rule-based model and a user-specified subset of species to treat as population variables rather than as particles. The model is then transformed by a process of "partial network expansion" into a dynamically equivalent form that can be simulated using a population-adapted network-free simulator. The transformation method has been implemented within the open-source rule-based modeling platform BioNetGen, and resulting hybrid models can be simulated using the particle-based simulator NFsim. Performance tests show that significant memory savings can be achieved using the new approach and a monetary cost analysis provides a practical measure of its utility. © 2014 Hogg et al