Approximate probabilistic verification of hybrid systems

Hybrid systems whose mode dynamics are governed by non-linear ordinary differential equations (ODEs) are often a natural model for biological processes. However such models are difficult to analyze. To address this, we develop a probabilistic analysis method by approximating the mode transitions as stochastic events. We assume that the probability of making a mode transition is proportional to the measure of the set of pairs of time points and value states at which the mode transition is enabled. To ensure a sound mathematical basis, we impose a natural continuity property on the non-linear ODEs. We also assume that the states of the system are observed at discrete time points but that the mode transitions may take place at any time between two successive discrete time points. This leads to a discrete time Markov chain as a probabilistic approximation of the hybrid system. We then show that for BLTL (bounded linear time temporal logic) specifications the hybrid system meets a specification iff its Markov chain approximation meets the same specification with probability $1$. Based on this, we formulate a sequential hypothesis testing procedure for verifying -approximately- that the Markov chain meets a BLTL specification with high probability. Our case studies on cardiac cell dynamics and the circadian rhythm indicate that our scheme can be applied in a number of realistic settings

Information-Theoretic Active Learning for Content-Based Image Retrieval

We propose Information-Theoretic Active Learning (ITAL), a novel batch-mode active learning method for binary classification, and apply it for acquiring meaningful user feedback in the context of content-based image retrieval. Instead of combining different heuristics such as uncertainty, diversity, or density, our method is based on maximizing the mutual information between the predicted relevance of the images and the expected user feedback regarding the selected batch. We propose suitable approximations to this computationally demanding problem and also integrate an explicit model of user behavior that accounts for possible incorrect labels and unnameable instances. Furthermore, our approach does not only take the structure of the data but also the expected model output change caused by the user feedback into account. In contrast to other methods, ITAL turns out to be highly flexible and provides state-of-the-art performance across various datasets, such as MIRFLICKR and ImageNet.Comment: GCPR 2018 paper (14 pages text + 2 pages references + 6 pages appendix

Potential conservation of circadian clock proteins in the phylum Nematoda as revealed by bioinformatic searches

Although several circadian rhythms have been described in C. elegans, its molecular clock remains elusive. In this work we employed a novel bioinformatic approach, applying probabilistic methodologies, to search for circadian clock proteins of several of the best studied circadian model organisms of different taxa (Mus musculus, Drosophila melanogaster, Neurospora crassa, Arabidopsis thaliana and Synechoccocus elongatus) in the proteomes of C. elegans and other members of the phylum Nematoda. With this approach we found that the Nematoda contain proteins most related to the core and accessory proteins of the insect and mammalian clocks, which provide new insights into the nematode clock and the evolution of the circadian system.Fil: Romanowski, Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; ArgentinaFil: Garavaglia, Matías Javier. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Ing.genética y Biolog.molecular y Celular. Area Virus de Insectos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Goya, María Eugenia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ghiringhelli, Pablo Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Ing.genética y Biolog.molecular y Celular. Area Virus de Insectos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Golombek, Diego Andres. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

THE EFFECTS OF CIRCADIAN RHYTHM ON INFLAMMATORY RESPONSE AND CYTOKINE LEVELS IN HEPATIC MACROPHAGES

In mammals, many aspects of daily behavior and physiology such as the sleep-wake cycle, body temperature, and liver metabolism are regulated by endogenous circadian mechanisms. Despite tissue-specific physiological differences, these circadian rhythms share a highly conserved negative feedback mechanism, consisting of transcriptional activators and repressors. This feedback loop system is critical for normal physiology and behavior, and its disruption can lead to sleep disorders, metabolic syndrome, cancer, and a whole host of other diseases, including immune related dysfunction. In this study, the loss of Bmal, a key transcriptional activator, and its ability to regulate a macrophage response was evaluated. To do this, a loxP-cre system was used to create mice with a macrophage-specific deletion of Bmal (lysZ-Bmal -/-). This was the first look at the role of macrophage-specific circadian gene expression in regulation of hepatic immune response and its influence on macrophage differentiation and inflammatory liver disease in vivo. Cre-negative littermate controls and lysZ-Bmal -/- mice were stimulated with the endotoxin lipopolysaccharide (LPS) to provoke a pro-inflammatory response. In lysZ-Bmal -/- mice, cells stimulated with LPS had an exacerbated pro-inflammatory response but a blunted anti-inflammatory response compared to cells from cre-negative littermates. LysZ-Bmal -/- mice also had larger liver to bodyweight ratios as well as increased relative mRNA levels of critical pro-inflammatory cytokines and serum ALT. In summary, this study suggests that circadian regulation in macrophages may be important for lipid control and that Bmal regulates a pro-inflammatory response in hepatic macrophages.  M.S

Asynchronous Rhythm of Steroidogenic Factor 1 and Period Homolog 2 mRNA Expression in Mouse Y1 Adrenocorticol Tumor Cells

The relationship between the expression of Steroidogenic factor 1 (Sf1) and the circadian-related gene, period homolog 2 (Per2), in the adrenal cortex is still unknown. We show here that in Y1 adrenocortical tumor cells, expression of steroidogenic-related genes such as P450scc mRNA and Sf1 mRNA were asynchronous with Per2 mRNA. SF1 promoter analyses showed that the E-box element functions in a rhythmic pattern. Rhythmic expression of Upstream factor 1 mRNA, correlated well with Sf1 mRNA expression. We propose that tumorigenesis of adrenocortical lesions cause disruption of synchronous expression of steroidogenic-related and circadian-related genes

EVOLUTION OF THE CIRCADIAN CLOCK IN EXTREME ENVIRONMENT: LESSONS FROM CAVEFISH.

Evolution has been strongly influenced by the daily cycles of temperature and light imposed by the rotation of the Earth. Fascinating demonstrations of this are seen in extreme environments such as caves where some animals have remained completely isolated from the day-night cycle for millions of years. Most of these species show convergent evolution, sharing a range of striking physical properties such as eye loss. One fundamental issue is whether “hypogean” species retain a functional circadian clock. This highly conserved, physiological timing mechanism allows organisms to anticipate daily environmental changes and is synchronized primarily by light. The Somalian cavefish, Phreatichthys andruzzii does possess a circadian clock that is entrained by a daily regular feeding time but strikingly, not by light. Under constant conditions the P. andruzzii clock oscillates with an extremely long period and also lacks normal temperature compensation. We document multiple mutations affecting a light-induced clock gene, Period2 as well as the genes encoding the extra-retinal photoreceptors Melanopsin (Opn4m2) and TMT-opsin. Remarkably, we show that ectopic expression of zebrafish homologs of these opsins rescues light induced clock gene expression in P. andruzzii cells. Thus, by studying this natural mutant we provide direct evidence for a peripheral light-sensing function of extra-retinal opsins in vertebrates. Furthermore, the properties of this cavefish illustrate that evolution in constant darkness leads not only to anatomical changes but also to loss of gene function linked with the detection and anticipation of the day-night cycle

Regulation of Peripheral Molecular Clocks in Mammalian Tissues and In Vitro Skeletal Muscle Activation of AMP-Activated Protein Kinase via AICAR

Most organisms possess a common molecular machinery that governs cellular and tissue circadian rhythmicity through a roughly 24-hour transcription-translation feedback loop. It is estimated that up to 15 percent of human genes are influenced by the core clock machinery. It is likely, however, that the metabolic networks affected by the molecular clock differ according to body tissue. Recent evidence suggests that peripheral molecular clocks are governed to a greater extent by energy availability than by light and dark cycles. AMP-activated protein kinase (AMPK) acts as a cellular fuel gauge within the cell and is activated in response to exercise and fasting. AMPK can also be pharmacologically activated by 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR). AMPK likely serves as an intermediary between metabolism and the molecular clock due to its activation of the rate-limiting enzyme in Nicotinamide adenine dinucleotide (NAD) biosynthesis, Nicotinamide phosphoribosyltransferase (NAMPT), and its role in PER and CRY degradation. The NAD-dependent histone deacetylase SIRT 1 inhibits the BMAL1-CLOCK complex in a NAMPT-dependent manner.The complex interplay between metabolism and peripheral clocks mediated by AMPK is beginning to be unraveled. AMPK’s tissue-specific influence on the molecular clock in skeletal muscles and other mammalian tissues requires further elucidation as it may provide insight into the etiology and treatment of metabolic disease. [excerpt

UPAL: Unbiased Pool Based Active Learning

In this paper we address the problem of pool based active learning, and provide an algorithm, called UPAL, that works by minimizing the unbiased estimator of the risk of a hypothesis in a given hypothesis space. For the space of linear classifiers and the squared loss we show that UPAL is equivalent to an exponentially weighted average forecaster. Exploiting some recent results regarding the spectra of random matrices allows us to establish consistency of UPAL when the true hypothesis is a linear hypothesis. Empirical comparison with an active learner implementation in Vowpal Wabbit, and a previously proposed pool based active learner implementation show good empirical performance and better scalability.Comment: 20 pages, 4 figures, 2 tables, a few minor typos were correcte