TY - JOUR
AB - The basic idea of evolutionary game theory is that payoff determines reproductive rate. Successful individuals have a higher payoff and produce more offspring. But in evolutionary and ecological situations there is not only reproductive rate but also carrying capacity. Individuals may differ in their exposure to density limiting effects. Here we explore an alternative approach to evolutionary game theory by assuming that the payoff from the game determines the carrying capacity of individual phenotypes. Successful strategies are less affected by density limitation (crowding) and reach higher equilibrium abundance. We demonstrate similarities and differences between our framework and the standard replicator equation. Our equation is defined on the positive orthant, instead of the simplex, but has the same equilibrium points as the replicator equation. Linear stability analysis produces the classical conditions for asymptotic stability of pure strategies, but the stability properties of internal equilibria can differ in the two frameworks. For example, in a two-strategy game with an internal equilibrium that is always stable under the replicator equation, the corresponding equilibrium can be unstable in the new framework resulting in a limit cycle.
AU - Novak, Sebastian
AU - Chatterjee, Krishnendu
AU - Nowak, Martin
ID - 2817
JF - Journal of Theoretical Biology
TI - Density games
VL - 334
ER -
TY - JOUR
AB - Models of neural responses to stimuli with complex spatiotemporal correlation structure often assume that neurons are selective for only a small number of linear projections of a potentially high-dimensional input. In this review, we explore recent modeling approaches where the neural response depends on the quadratic form of the input rather than on its linear projection, that is, the neuron is sensitive to the local covariance structure of the signal preceding the spike. To infer this quadratic dependence in the presence of arbitrary (e.g., naturalistic) stimulus distribution, we review several inference methods, focusing in particular on two information theory–based approaches (maximization of stimulus energy and of noise entropy) and two likelihood-based approaches (Bayesian spike-triggered covariance and extensions of generalized linear models). We analyze the formal relationship between the likelihood-based and information-based approaches to demonstrate how they lead to consistent inference. We demonstrate the practical feasibility of these procedures by using model neurons responding to a flickering variance stimulus.
AU - Rajan, Kanaka
AU - Marre, Olivier
AU - Tkacik, Gasper
ID - 2818
IS - 7
JF - Neural Computation
TI - Learning quadratic receptive fields from neural responses to natural stimuli
VL - 25
ER -
TY - CONF
AB - We introduce quantatitive timed refinement metrics and quantitative timed simulation functions, incorporating zenoness checks, for timed systems. These functions assign positive real numbers between zero and infinity which quantify the timing mismatches between two timed systems, amongst non-zeno runs. We quantify timing mismatches in three ways: (1) the maximum timing mismatch that can arise, (2) the "steady-state" maximum timing mismatches, where initial transient timing mismatches are ignored; and (3) the (long-run) average timing mismatches amongst two systems. These three kinds of mismatches constitute three important types of timing differences. Our event times are the global times, measured from the start of the system execution, not just the time durations of individual steps. We present algorithms over timed automata for computing the three quantitative simulation functions to within any desired degree of accuracy. In order to compute the values of the quantitative simulation functions, we use a game theoretic formulation. We introduce two new kinds of objectives for two player games on finite state game graphs: (1) eventual debit-sum level objectives, and (2) average debit-sum level objectives. We present algorithms for computing the optimal values for these objectives for player 1, and then use these algorithms to compute the values of the quantitative timed simulation functions.
AU - Chatterjee, Krishnendu
AU - Prabhu, Vinayak
ID - 2819
T2 - Proceedings of the 16th International Conference on Hybrid Systems: Computation and Control
TI - Quantitative timed simulation functions and refinement metrics for real-time systems
VL - 1
ER -
TY - CONF
AB - Depth-Bounded Systems form an expressive class of well-structured transition systems. They can model a wide range of concurrent infinite-state systems including those with dynamic thread creation, dynamically changing communication topology, and complex shared heap structures. We present the first method to automatically prove fair termination of depth-bounded systems. Our method uses a numerical abstraction of the system, which we obtain by systematically augmenting an over-approximation of the system’s reachable states with a finite set of counters. This numerical abstraction can be analyzed with existing termination provers. What makes our approach unique is the way in which it exploits the well-structuredness of the analyzed system. We have implemented our work in a prototype tool and used it to automatically prove liveness properties of complex concurrent systems, including nonblocking algorithms such as Treiber’s stack and several distributed processes. Many of these examples are beyond the scope of termination analyses that are based on traditional counter abstractions.
AU - Bansal, Kshitij
AU - Koskinen, Eric
AU - Wies, Thomas
AU - Zufferey, Damien
ED - Piterman, Nir
ED - Smolka, Scott
ID - 2847
TI - Structural Counter Abstraction
VL - 7795
ER -
TY - CONF
AB - Mathematical objects can be measured unambiguously, but not so objects from our physical world. Even the total length of tubelike shapes has its difficulties. We introduce a combination of geometric, probabilistic, and topological methods to design a stable length estimate for tube-like shapes; that is: one that is insensitive to small shape changes.
AU - Edelsbrunner, Herbert
AU - Pausinger, Florian
ID - 2843
T2 - 17th IAPR International Conference on Discrete Geometry for Computer Imagery
TI - Stable length estimates of tube-like shapes
VL - 7749
ER -
TY - JOUR
AB - As soon as a seed germinates, plant growth relates to gravity to ensure that the root penetrates the soil and the shoot expands aerially. Whereas mechanisms of positive and negative orthogravitropism of primary roots and shoots are relatively well understood [1-3], lateral organs often show more complex growth behavior [4]. Lateral roots (LRs) seemingly suppress positive gravitropic growth and show a defined gravitropic set-point angle (GSA) that allows radial expansion of the root system (plagiotropism) [3, 4]. Despite its eminent importance for root architecture, it so far remains completely unknown how lateral organs partially suppress positive orthogravitropism. Here we show that the phytohormone auxin steers GSA formation and limits positive orthogravitropism in LR. Low and high auxin levels/signaling lead to radial or axial root systems, respectively. At a cellular level, it is the auxin transport-dependent regulation of asymmetric growth in the elongation zone that determines GSA. Our data suggest that strong repression of PIN4/PIN7 and transient PIN3 expression limit auxin redistribution in young LR columella cells. We conclude that PIN activity, by temporally limiting the asymmetric auxin fluxes in the tip of LRs, induces transient, differential growth responses in the elongation zone and, consequently, controls root architecture.
AU - Rosquete, Michel
AU - Von Wangenheim, Daniel
AU - Marhavy, Peter
AU - Barbez, Elke
AU - Stelzer, Ernst
AU - Benková, Eva
AU - Maizel, Alexis
AU - Kleine Vehn, Jürgen
ID - 2844
IS - 9
JF - Current Biology
TI - An auxin transport mechanism restricts positive orthogravitropism in lateral roots
VL - 23
ER -
TY - JOUR
AB - At synapses formed between dissociated neurons, about half of all synaptic vesicles are refractory to evoked release, forming the so-called "resting pool." Here, we use optical measurements of vesicular pH to study developmental changes in pool partitioning and vesicle cycling in cultured hippocampal slices. Two-photon imaging of a genetically encoded two-color release sensor (ratio-sypHy) allowed us to perform calibrated measurements at individual Schaffer collateral boutons. Mature boutons released a large fraction of their vesicles during simulated place field activity, and vesicle retrieval rates were 7-fold higher compared to immature boutons. Saturating stimulation mobilized essentially all vesicles at mature synapses. Resting pool formation and a concomitant reduction in evoked release was induced by chronic depolarization but not by acute inhibition of the protein phosphatase calcineurin. We conclude that synapses in CA1 undergo a prominent refinement of vesicle use during early postnatal development that is not recapitulated in dissociated neuronal culture.
AU - Rose, Tobias
AU - Schönenberger, Philipp
AU - Jezek, Karel
AU - Oertner, Thomas
ID - 2845
IS - 6
JF - Neuron
TI - Developmental refinement of vesicle cycling at Schaffer collateral synapses
VL - 77
ER -
TY - JOUR
AB - The Red Queen hypothesis proposes that coevolving parasites select for outcrossing in the host. Outcrossing relies on males, which often show lower immune investment due to, for example, sexual selection. Here, we demonstrate that such sex differences in immunity interfere with parasite-mediated selection for outcrossing. Two independent coevolution experiments with Caenorhabditis elegans and its microparasite Bacillus thuringiensis produced decreased yet stable frequencies of outcrossing male hosts. A subsequent systematic analysis verified that male C. elegans suffered from a direct selective disadvantage under parasite pressure (i.e. lower resistance, decreased sexual activity, increased escape behaviour), which can reduce outcrossing and thus male frequencies. At the same time, males offered an indirect selective benefit, because male-mediated outcrossing increased offspring resistance, thus favouring male persistence in the evolving populations. As sex differences in immunity are widespread, such interference of opposing selective constraints is likely of central importance during host adaptation to a coevolving parasite.
AU - El Masri, Leila
AU - Schulte, Rebecca
AU - Timmermeyer, Nadine
AU - Thanisch, Stefanie
AU - Crummenerl, Lena
AU - Jansen, Gunther
AU - Michiels, Nico
AU - Schulenburg, Hinrich
ID - 2846
IS - 4
JF - Ecology Letters
TI - Sex differences in host defence interfere with parasite-mediated selection for outcrossing during host-parasite coevolution
VL - 16
ER -
TY - JOUR
AB - In the hippocampus, cell assemblies forming mnemonic representations of space are thought to arise as a result of changes in functional connections of pyramidal cells. We have found that CA1 interneuron circuits are also reconfigured during goal-oriented spatial learning through modification of inputs from pyramidal cells. As learning progressed, new pyramidal assemblies expressed in theta cycles alternated with previously established ones, and eventually overtook them. The firing patterns of interneurons developed a relationship to new, learning-related assemblies: some interneurons associated their activity with new pyramidal assemblies while some others dissociated from them. These firing associations were explained by changes in the weight of monosynaptic inputs received by interneurons from new pyramidal assemblies, as these predicted the associational changes. Spatial learning thus engages circuit modifications in the hippocampus that incorporate a redistribution of inhibitory activity that might assist in the segregation of competing pyramidal cell assembly patterns in space and time.
AU - Dupret, David
AU - O'Neill, Joseph
AU - Csicsvari, Jozsef L
ID - 2860
IS - 1
JF - Neuron
TI - Dynamic reconfiguration of hippocampal interneuron circuits during spatial learning
VL - 78
ER -
TY - JOUR
AB - We consider a two-parameter family of piecewise linear maps in which the moduli of the two slopes take different values. We provide numerical evidence of the existence of some parameter regions in which the Lyapunov exponent and the topological entropy remain constant. Analytical proof of this phenomenon is also given for certain cases. Surprisingly however, the systems with that property are not conjugate as we prove by using kneading theory.
AU - Botella Soler, Vicente
AU - Oteo, José
AU - Ros, Javier
AU - Glendinning, Paul
ID - 2861
IS - 12
JF - Journal of Physics A: Mathematical and Theoretical
TI - Lyapunov exponent and topological entropy plateaus in piecewise linear maps
VL - 46
ER -
TY - JOUR
AB - Motile cilia perform crucial functions during embryonic development and throughout adult life. Development of organs containing motile cilia involves regulation of cilia formation (ciliogenesis) and formation of a luminal space (lumenogenesis) in which cilia generate fluid flows. Control of ciliogenesis and lumenogenesis is not yet fully understood, and it remains unclear whether these processes are coupled. In the zebrafish embryo, lethal giant larvae 2 (lgl2) is expressed prominently in ciliated organs. Lgl proteins are involved in establishing cell polarity and have been implicated in vesicle trafficking. Here, we identified a role for Lgl2 in development of ciliated epithelia in Kupffer's vesicle, which directs left-right asymmetry of the embryo; the otic vesicles, which give rise to the inner ear; and the pronephric ducts of the kidney. Using Kupffer's vesicle as a model ciliated organ, we found that depletion of Lgl2 disrupted lumen formation and reduced cilia number and length. Immunofluorescence and time-lapse imaging of Kupffer's vesicle morphogenesis in Lgl2-deficient embryos suggested cell adhesion defects and revealed loss of the adherens junction component E-cadherin at lateral membranes. Genetic interaction experiments indicate that Lgl2 interacts with Rab11a to regulate E-cadherin and mediate lumen formation that is uncoupled from cilia formation. These results uncover new roles and interactions for Lgl2 that are crucial for both lumenogenesis and ciliogenesis and indicate that these processes are genetically separable in zebrafish.
AU - Tay, Hwee
AU - Schulze, Sabrina
AU - Compagnon, Julien
AU - Foley, Fiona
AU - Heisenberg, Carl-Philipp J
AU - Yost, H Joseph
AU - Abdelilah Seyfried, Salim
AU - Amack, Jeffrey
ID - 2862
IS - 7
JF - Development
TI - Lethal giant larvae 2 regulates development of the ciliated organ Kupffer’s vesicle
VL - 140
ER -
TY - JOUR
AB - Neural populations encode information about their stimulus in a collective fashion, by joint activity patterns of spiking and silence. A full account of this mapping from stimulus to neural activity is given by the conditional probability distribution over neural codewords given the sensory input. For large populations, direct sampling of these distributions is impossible, and so we must rely on constructing appropriate models. We show here that in a population of 100 retinal ganglion cells in the salamander retina responding to temporal white-noise stimuli, dependencies between cells play an important encoding role. We introduce the stimulus-dependent maximum entropy (SDME) model—a minimal extension of the canonical linear-nonlinear model of a single neuron, to a pairwise-coupled neural population. We find that the SDME model gives a more accurate account of single cell responses and in particular significantly outperforms uncoupled models in reproducing the distributions of population codewords emitted in response to a stimulus. We show how the SDME model, in conjunction with static maximum entropy models of population vocabulary, can be used to estimate information-theoretic quantities like average surprise and information transmission in a neural population.
AU - Granot Atedgi, Einat
AU - Tkacik, Gasper
AU - Segev, Ronen
AU - Schneidman, Elad
ID - 2863
IS - 3
JF - PLoS Computational Biology
TI - Stimulus-dependent maximum entropy models of neural population codes
VL - 9
ER -
TY - JOUR
AB - Lateral root (LR) formation is initiated when pericycle cells accumulate auxin, thereby acquiring founder cell (FC) status and triggering asymmetric cell divisions, giving rise to a new primordium. How this auxin maximum in pericycle cells builds up and remains focused is not understood. We report that the endodermis plays an active role in the regulation of auxin accumulation and is instructive for FCs to progress during the LR initiation (LRI) phase. We describe the functional importance of a PIN3 (PIN-formed) auxin efflux carrier-dependent hormone reflux pathway between overlaying endodermal and pericycle FCs. Disrupting this reflux pathway causes dramatic defects in the progress of FCs towards the next initiation phase. Our data identify an unexpected regulatory function for the endodermis in LRI as part of the fine-tuning mechanism that appears to act as a check point in LR organogenesis after FCs are specified.
AU - Marhavy, Peter
AU - Vanstraelen, Marleen
AU - De Rybel, Bert
AU - Zhaojun, Ding
AU - Bennett, Malcolm
AU - Beeckman, Tom
AU - Benková, Eva
ID - 2880
IS - 1
JF - EMBO Journal
TI - Auxin reflux between the endodermis and pericycle promotes lateral root initiation
VL - 32
ER -
TY - JOUR
AB - Gravitropic bending of plant organs is mediated by an asymmetric signaling of the plant hormone auxin between the upper and lower side of the respective organ. Here, we show that also another plant hormone, gibberellic acid (GA), shows asymmetric action during gravitropic responses. Immunodetection using an antibody against GA and monitoring GA signaling output by downstream degradation of DELLA proteins revealed an asymmetric GA distribution and response with the maximum at the lower side of gravistimulated roots. Genetic or pharmacological manipulation of GA levels or response affects gravity-mediated auxin redistribution and root bending response. The higher GA levels at the lower side of the root correlate with increased amounts of PIN-FORMED2 (PIN2) auxin transporter at the plasma membrane. The observed increase in PIN2 stability is caused by a specific GA effect on trafficking of PIN proteins to lytic vacuoles that presumably occurs downstream of brefeldin A-sensitive endosomes. Our results suggest that asymmetric auxin distribution instructive for gravity-induced differential growth is consolidated by the asymmetric action of GA that stabilizes the PIN-dependent auxin stream along the lower side of gravistimulated roots.
AU - Löfke, Christian
AU - Zwiewka, Marta
AU - Heilmann, Ingo
AU - Van Montagu, Marc
AU - Teichmann, Thomas
AU - Friml, Jirí
ID - 2882
IS - 9
JF - PNAS
TI - Asymmetric gibberellin signaling regulates vacuolar trafficking of PIN auxin transporters during root gravitropism
VL - 110
ER -
TY - JOUR
AB - Plant architecture is influenced by the polar, cell-to-cell transport of auxin that is primarily provided and regulated by plasma membrane efflux catalysts of the PIN-FORMED and B family of ABC transporter (ABCB) classes. The latter were shown to require the functionality of the FK506 binding protein42 TWISTED DWARF1 (TWD1), although underlying mechanisms are unclear. By genetic manipulation of TWD1 expression, we show here that TWD1 affects shootward root auxin reflux and, thus, downstream developmental traits, such as epidermal twisting and gravitropism of the root. Using immunological assays, we demonstrate a predominant lateral, mainly outward-facing, plasma membrane location for TWD1 in the root epidermis characterized by the lateral marker ABC transporter G36/PLEIOTROPIC DRUG-RESISTANCE8/PENETRATION3. At these epidermal plasma membrane domains, TWD1 colocalizes with nonpolar ABCB1. In planta bioluminescence resonance energy transfer analysis was used to verify specific ABC transporter B1 (ABCB1)-TWD1 interaction. Our data support a model in which TWD1 promotes lateral ABCB-mediated auxin efflux via protein-protein interaction at the plasma membrane, minimizing reflux from the root apoplast into the cytoplasm.
AU - Wang, Bangjun
AU - Bailly, Aurélien
AU - Zwiewk, Marta
AU - Henrichs, Sina
AU - Azzarello, Elisa
AU - Mancuso, Stefano
AU - Maeshima, Masayoshi
AU - Friml, Jirí
AU - Schulz, Alexander
AU - Geisler, Markus
ID - 2883
IS - 1
JF - Plant Cell
TI - Arabidopsis TWISTED DWARF1 functionally interacts with auxin exporter ABCB1 on the root plasma membrane
VL - 25
ER -
TY - JOUR
AU - Maître, Jean-Léon
AU - Berthoumieux, Hélène
AU - Krens, Gabriel
AU - Salbreux, Guillaume
AU - Julicher, Frank
AU - Paluch, Ewa
AU - Heisenberg, Carl-Philipp J
ID - 2884
IS - 2
JF - Medecine Sciences
TI - Cell adhesion mechanics of zebrafish gastrulation
VL - 29
ER -
TY - GEN
AB - This volume contains the post-proceedings of the 8th Doctoral Workshop on Mathematical and Engineering Methods in Computer Science, MEMICS 2012, held in Znojmo, Czech Republic, in October, 2012. The 13 thoroughly revised papers were carefully selected out of 31 submissions and are presented together with 6 invited papers. The topics covered by the papers include: computer-aided analysis and verification, applications of game theory in computer science, networks and security, modern trends of graph theory in computer science, electronic systems design and testing, and quantum information processing.
ED - Kucera, Antonin
ED - Henzinger, Thomas A
ED - Nesetril, Jaroslav
ED - Vojnar, Tomas
ED - Antos, David
ID - 2885
TI - Mathematical and Engineering Methods in Computer Science
VL - 7721
ER -
TY - CONF
AB - We focus on the realizability problem of Message Sequence Graphs (MSG), i.e. the problem whether a given MSG specification is correctly distributable among parallel components communicating via messages. This fundamental problem of MSG is known to be undecidable. We introduce a well motivated restricted class of MSG, so called controllable-choice MSG, and show that all its models are realizable and moreover it is decidable whether a given MSG model is a member of this class. In more detail, this class of MSG specifications admits a deadlock-free realization by overloading existing messages with additional bounded control data. We also show that the presented class is the largest known subclass of MSG that allows for deadlock-free realization.
AU - Chmelik, Martin
AU - Řehák, Vojtěch
ID - 2886
TI - Controllable-choice message sequence graphs
VL - 7721
ER -
TY - JOUR
AB - Root system growth and development is highly plastic and is influenced by the surrounding environment. Roots frequently grow in heterogeneous environments that include interactions from neighboring plants and physical impediments in the rhizosphere. To investigate how planting density and physical objects affect root system growth, we grew rice in a transparent gel system in close proximity with another plant or a physical object. Root systems were imaged and reconstructed in three dimensions. Root-root interaction strength was calculated using quantitative metrics that characterize the extent towhich the reconstructed root systems overlap each other. Surprisingly, we found the overlap of root systems of the same genotype was significantly higher than that of root systems of different genotypes. Root systems of the same genotype tended to grow toward each other but those of different genotypes appeared to avoid each other. Shoot separation experiments excluded the possibility of aerial interactions, suggesting root communication. Staggered plantings indicated that interactions likely occur at root tips in close proximity. Recognition of obstacles also occurred through root tips, but through physical contact in a size-dependent manner. These results indicate that root systems use two different forms of communication to recognize objects and alter root architecture: root-root recognition, possibly mediated through root exudates, and root-object recognition mediated by physical contact at the root tips. This finding suggests that root tips act as local sensors that integrate rhizosphere information into global root architectural changes.
AU - Fang, Suqin
AU - Clark, Randy
AU - Zheng, Ying
AU - Iyer Pascuzzi, Anjali
AU - Weitz, Joshua
AU - Kochian, Leon
AU - Edelsbrunner, Herbert
AU - Liao, Hong
AU - Benfey, Philip
ID - 2887
IS - 7
JF - PNAS
TI - Genotypic recognition and spatial responses by rice roots
VL - 110
ER -
TY - CONF
AB - We introduce the M-modes problem for graphical models: predicting the M label configurations of highest probability that are at the same time local maxima of the probability landscape. M-modes have multiple possible applications: because they are intrinsically diverse, they provide a principled alternative to non-maximum suppression techniques for structured prediction, they can act as codebook vectors for quantizing the configuration space, or they can form component centers for mixture model approximation. We present two algorithms for solving the M-modes problem. The first algorithm solves the problem in polynomial time when the underlying graphical model is a simple chain. The second algorithm solves the problem for junction chains. In synthetic and real dataset, we demonstrate how M-modes can improve the performance of prediction. We also use the generated modes as a tool to understand the topography of the probability distribution of configurations, for example with relation to the training set size and amount of noise in the data.
AU - Chen, Chao
AU - Kolmogorov, Vladimir
AU - Yan, Zhu
AU - Metaxas, Dimitris
AU - Lampert, Christoph
ID - 2901
TI - Computing the M most probable modes of a graphical model
VL - 31
ER -
TY - CONF
AB - Motivated by an application in cell biology, we describe an extension of the kinetic data structures framework from Delaunay triangulations to fixed-radius alpha complexes. Our algorithm is implemented
using CGAL, following the exact geometric computation paradigm. We report on several
techniques to accelerate the computation that turn our implementation applicable to the underlying biological
problem.
AU - Kerber, Michael
AU - Edelsbrunner, Herbert
ID - 2906
T2 - 2013 Proceedings of the 15th Workshop on Algorithm Engineering and Experiments
TI - 3D kinetic alpha complexes and their implementation
ER -
TY - CHAP
AB - Sex and recombination are among the most striking features of the living world, and they play a crucial role in allowing the evolution of complex adaptation. The sharing of genomes through the sexual union of different individuals requires elaborate behavioral and physiological adaptations. At the molecular level, the alignment of two DNA double helices, followed by their precise cutting and rejoining, is an extraordinary feat. Sex and recombination have diverse—and often surprising—evolutionary consequences: distinct sexes, elaborate mating displays, selfish genetic elements, and so on.
AU - Barton, Nicholas H
ID - 2907
SN - 9780691149776
T2 - The Princeton Guide to Evolution
TI - Recombination and sex
ER -
TY - JOUR
AB - Hybridization is an almost inevitable component of speciation, and its study can tell us much about that process. However, hybridization itself may have a negligible influence on the origin of species: on the one hand, universally favoured alleles spread readily across hybrid zones, whilst on the other, spatially heterogeneous selection causes divergence despite gene flow. Thus, narrow hybrid zones or occasional hybridisation may hardly affect the process of divergence.
AU - Barton, Nicholas H
ID - 2908
IS - 2
JF - Journal of Evolutionary Biology
TI - Does hybridisation influence speciation?
VL - 26
ER -
TY - JOUR
AB - We survey a class of models for spatially structured populations
which we have called spatial Λ-Fleming–Viot processes. They arise from a flexible
framework for modelling in which the key innovation is that random genetic drift
is driven by a Poisson point process of spatial ‘events’. We demonstrate how this
overcomes some of the obstructions to modelling populations which evolve in two-
(and higher-) dimensional spatial continua, how its predictions match phenomena
observed in data and how it fits with classical models. Finally we outline some
directions for future research.
AU - Barton, Nicholas H
AU - Etheridge, Alison
AU - Véber, Amandine
ID - 2909
IS - 1
JF - Journal of Statistical Mechanics Theory and Experiment
TI - Modelling evolution in a spatial continuum
VL - 2013
ER -
TY - JOUR
AB - Coalescent simulation has become an indispensable tool in population genetics and many complex evolutionary scenarios have been incorporated into the basic algorithm. Despite many years of intense interest in spatial structure, however, there are no available methods to simulate the ancestry of a sample of genes that occupy a spatial continuum. This is mainly due to the severe technical problems encountered by the classical model of isolation
by distance. A recently introduced model solves these technical problems and provides a solid theoretical basis for the study of populations evolving in continuous space. We present a detailed algorithm to simulate the coalescent process in this model, and provide an efficient implementation of a generalised version of this algorithm as a freely available Python module.
AU - Kelleher, Jerome
AU - Barton, Nicholas H
AU - Etheridge, Alison
ID - 2910
IS - 7
JF - Bioinformatics
TI - Coalescent simulation in continuous space
VL - 29
ER -
TY - JOUR
AB - The ability of an organism to distinguish between various stimuli is limited by the structure and noise in the population code of its sensory neurons. Here we infer a distance measure on the stimulus space directly from the recorded activity of 100 neurons in the salamander retina. In contrast to previously used measures of stimulus similarity, this "neural metric" tells us how distinguishable a pair of stimulus clips is to the retina, based on the similarity between the induced distributions of population responses. We show that the retinal distance strongly deviates from Euclidean, or any static metric, yet has a simple structure: we identify the stimulus features that the neural population is jointly sensitive to, and show the support-vector-machine- like kernel function relating the stimulus and neural response spaces. We show that the non-Euclidean nature of the retinal distance has important consequences for neural decoding.
AU - Tkacik, Gasper
AU - Granot Atedgi, Einat
AU - Segev, Ronen
AU - Schneidman, Elad
ID - 2913
IS - 5
JF - Physical Review Letters
TI - Retinal metric: a stimulus distance measure derived from population neural responses
VL - 110
ER -
TY - JOUR
AB - The scale invariance of natural images suggests an analogy to the statistical mechanics of physical systems at a critical point. Here we examine the distribution of pixels in small image patches and show how to construct the corresponding thermodynamics. We find evidence for criticality in a diverging specific heat, which corresponds to large fluctuations in how "surprising" we find individual images, and in the quantitative form of the entropy vs energy. We identify special image configurations as local energy minima and show that average patches within each basin are interpretable as lines and edges in all orientations.
AU - Stephens, Greg
AU - Mora, Thierry
AU - Tkacik, Gasper
AU - Bialek, William
ID - 2914
IS - 1
JF - Physical Review Letters
TI - Statistical thermodynamics of natural images
VL - 110
ER -
TY - JOUR
AB - High relatedness among interacting individuals has generally been considered a precondition for the evolution of altruism. However, kin-selection theory also predicts the evolution of altruism when relatedness is low, as long as the cost of the altruistic act is minor compared with its benefit. Here, we demonstrate evidence for a low-cost altruistic act in bacteria. We investigated Escherichia coli responding to the attack of an obligately lytic phage by committing suicide in order to prevent parasite transmission to nearby relatives. We found that bacterial suicide provides large benefits to survivors at marginal costs to committers. The cost of suicide was low, because infected cells are moribund, rapidly dying upon phage infection, such that no more opportunity for reproduction remains. As a consequence of its marginal cost, host suicide was selectively favoured even when relatedness between committers and survivors approached zero. Altogether, our findings demonstrate that low-cost suicide can evolve with ease, represents an effective host-defence strategy, and seems to be widespread among microbes. Moreover, low-cost suicide might also occur in higher organisms as exemplified by infected social insect workers leaving the colony to die in isolation.
AU - Refardt, Dominik
AU - Bergmiller, Tobias
AU - Kümmerli, Rolf
ID - 2853
IS - 1759
JF - Proceedings of the Royal Society of London Series B Biological Sciences
TI - Altruism can evolve when relatedness is low: Evidence from bacteria committing suicide upon phage infection
VL - 280
ER -
TY - JOUR
AB - We consider concurrent games played on graphs. At every round of a game, each player simultaneously and independently selects a move; the moves jointly determine the transition to a successor state. Two basic objectives are the safety objective to stay forever in a given set of states, and its dual, the reachability objective to reach a given set of states. First, we present a simple proof of the fact that in concurrent reachability games, for all ε>0, memoryless ε-optimal strategies exist. A memoryless strategy is independent of the history of plays, and an ε-optimal strategy achieves the objective with probability within ε of the value of the game. In contrast to previous proofs of this fact, our proof is more elementary and more combinatorial. Second, we present a strategy-improvement (a.k.a. policy-iteration) algorithm for concurrent games with reachability objectives. Finally, we present a strategy-improvement algorithm for turn-based stochastic games (where each player selects moves in turns) with safety objectives. Our algorithms yield sequences of player-1 strategies which ensure probabilities of winning that converge monotonically (from below) to the value of the game. © 2012 Elsevier Inc.
AU - Chatterjee, Krishnendu
AU - De Alfaro, Luca
AU - Henzinger, Thomas A
ID - 2854
IS - 5
JF - Journal of Computer and System Sciences
TI - Strategy improvement for concurrent reachability and turn based stochastic safety games
VL - 79
ER -
TY - JOUR
AB - Genomic imprinting leads to preferred expression of either the maternal or paternal alleles of a subset of genes. Imprinting is essential for mammalian development, and its deregulation causes many diseases. However, the functional relevance of imprinting at the cellular level is poorly understood for most imprinted genes. We used mosaic analysis with double markers (MADM) in mice to create uniparental disomies (UPDs) and to visualize imprinting effects with single-cell resolution. Although chromosome 12 UPD did not produce detectable phenotypes, chromosome 7 UPD caused highly significant paternal growth dominance in the liver and lung, but not in the brain or heart. A single gene on chromosome 7, encoding the secreted insulin-like growth factor 2 (IGF2), accounts for most of the paternal dominance effect. Mosaic analyses implied additional imprinted loci on chromosome 7 acting cell autonomously to transmit the IGF2 signal. Our study reveals chromosome- and cell-type specificity of genomic imprinting effects.
AU - Hippenmeyer, Simon
AU - Johnson, Randy
AU - Luo, Liqun
ID - 2855
IS - 3
JF - Cell Reports
TI - Mosaic analysis with double markers reveals cell type specific paternal growth dominance
VL - 3
ER -
TY - JOUR
AB - G protein–coupled receptors (GPCRs), the largest family of membrane signaling proteins, respond to neurotransmitters, hormones and small environmental molecules. The neuronal function of many GPCRs has been difficult to resolve because of an inability to gate them with subtype specificity, spatial precision, speed and reversibility. To address this, we developed an approach for opto-chemical engineering of native GPCRs. We applied this to the metabotropic glutamate receptors (mGluRs) to generate light-agonized and light-antagonized mGluRs (LimGluRs). The light-agonized LimGluR2, on which we focused, was fast, bistable and supported multiple rounds of on/off switching. Light gated two of the primary neuronal functions of mGluR2: suppression of excitability and inhibition of neurotransmitter release. We found that the light-antagonized tool LimGluR2-block was able to manipulate negative feedback of synaptically released glutamate on transmitter release. We generalized the optical control to two additional family members: mGluR3 and mGluR6. This system worked in rodent brain slices and in zebrafish in vivo, where we found that mGluR2 modulated the threshold for escape behavior. These light-gated mGluRs pave the way for determining the roles of mGluRs in synaptic plasticity, memory and disease.
AU - Levitz, Joshua
AU - Pantoja, Carlos
AU - Gaub, Benjamin
AU - Janovjak, Harald L
AU - Reiner, Andreas
AU - Hoagland, Adam
AU - Schoppik, David
AU - Kane, Brian
AU - Stawski, Philipp
AU - Schier, Alexander
AU - Trauner, Dirk
AU - Isacoff, Ehud
ID - 2856
JF - Nature Neuroscience
TI - Optical control of metabotropic glutamate receptors
VL - 16
ER -
TY - JOUR
AB - In the vibrant field of optogenetics, optics and genetic targeting are combined to commandeer cellular functions, such as the neuronal action potential, by optically stimulating light-sensitive ion channels expressed in the cell membrane. One broadly applicable manifestation of this approach are covalently attached photochromic tethered ligands (PTLs) that allow activating ligand-gated ion channels with outstanding spatial and temporal resolution. Here, we describe all steps towards the successful development and application of PTL-gated ion channels in cell lines and primary cells. The basis for these experiments forms a combination of molecular modeling, genetic engineering, cell culture, and electrophysiology. The light-gated glutamate receptor (LiGluR), which consists of the PTL-functionalized GluK2 receptor, serves as a model.
AU - Szobota, Stephanie
AU - Mckenzie, Catherine
AU - Janovjak, Harald L
ID - 2857
JF - Methods in Molecular Biology
TI - Optical control of ligand-gated ion channels
VL - 998
ER -
TY - JOUR
AB - Recent work emphasizes that the maximum entropy principle provides a bridge between statistical mechanics models for collective behavior in neural networks and experiments on networks of real neurons. Most of this work has focused on capturing the measured correlations among pairs of neurons. Here we suggest an alternative, constructing models that are consistent with the distribution of global network activity, i.e. the probability that K out of N cells in the network generate action potentials in the same small time bin. The inverse problem that we need to solve in constructing the model is analytically tractable, and provides a natural 'thermodynamics' for the network in the limit of large N. We analyze the responses of neurons in a small patch of the retina to naturalistic stimuli, and find that the implied thermodynamics is very close to an unusual critical point, in which the entropy (in proper units) is exactly equal to the energy. © 2013 IOP Publishing Ltd and SISSA Medialab srl.
AU - Tkacik, Gasper
AU - Marre, Olivier
AU - Mora, Thierry
AU - Amodei, Dario
AU - Berry, Michael
AU - Bialek, William
ID - 2850
IS - 3
JF - Journal of Statistical Mechanics Theory and Experiment
TI - The simplest maximum entropy model for collective behavior in a neural network
VL - 2013
ER -
TY - JOUR
AB - The number of possible activity patterns in a population of neurons grows exponentially with the size of the population. Typical experiments explore only a tiny fraction of the large space of possible activity patterns in the case of populations with more than 10 or 20 neurons. It is thus impossible, in this undersampled regime, to estimate the probabilities with which most of the activity patterns occur. As a result, the corresponding entropy - which is a measure of the computational power of the neural population - cannot be estimated directly. We propose a simple scheme for estimating the entropy in the undersampled regime, which bounds its value from both below and above. The lower bound is the usual 'naive' entropy of the experimental frequencies. The upper bound results from a hybrid approximation of the entropy which makes use of the naive estimate, a maximum entropy fit, and a coverage adjustment. We apply our simple scheme to artificial data, in order to check their accuracy; we also compare its performance to those of several previously defined entropy estimators. We then apply it to actual measurements of neural activity in populations with up to 100 cells. Finally, we discuss the similarities and differences between the proposed simple estimation scheme and various earlier methods. © 2013 IOP Publishing Ltd and SISSA Medialab srl.
AU - Berry, Michael
AU - Tkacik, Gasper
AU - Dubuis, Julien
AU - Marre, Olivier
AU - Da Silveira, Ravá
ID - 2851
IS - 3
JF - Journal of Statistical Mechanics Theory and Experiment
TI - A simple method for estimating the entropy of neural activity
VL - 2013
ER -
TY - JOUR
AB - Tumor growth is caused by the acquisition of driver mutations, which enhance the net reproductive rate of cells. Driver mutations may increase cell division, reduce cell death, or allow cells to overcome density-limiting effects. We study the dynamics of tumor growth as one additional driver mutation is acquired. Our models are based on two-type branching processes that terminate in either tumor disappearance or tumor detection. In our first model, both cell types grow exponentially, with a faster rate for cells carrying the additional driver. We find that the additional driver mutation does not affect the survival probability of the lesion, but can substantially reduce the time to reach the detectable size if the lesion is slow growing. In our second model, cells lacking the additional driver cannot exceed a fixed carrying capacity, due to density limitations. In this case, the time to detection depends strongly on this carrying capacity. Our model provides a quantitative framework for studying tumor dynamics during different stages of progression. We observe that early, small lesions need additional drivers, while late stage metastases are only marginally affected by them. These results help to explain why additional driver mutations are typically not detected in fast-growing metastases.
AU - Reiter, Johannes
AU - Božić, Ivana
AU - Allen, Benjamin
AU - Chatterjee, Krishnendu
AU - Nowak, Martin
ID - 2858
IS - 1
JF - Evolutionary Applications
TI - The effect of one additional driver mutation on tumor progression
VL - 6
ER -
TY - JOUR
AB - Given a continuous function f:X-R on a topological space, we consider the preimages of intervals and their homology groups and show how to read the ranks of these groups from the extended persistence diagram of f. In addition, we quantify the robustness of the homology classes under perturbations of f using well groups, and we show how to read the ranks of these groups from the same extended persistence diagram. The special case X=R3 has ramifications in the fields of medical imaging and scientific visualization.
AU - Bendich, Paul
AU - Edelsbrunner, Herbert
AU - Morozov, Dmitriy
AU - Patel, Amit
ID - 2859
IS - 1
JF - Homology, Homotopy and Applications
TI - Homology and robustness of level and interlevel sets
VL - 15
ER -
TY - JOUR
AB - Cell polarisation in development is a common and fundamental process underlying embryo patterning and morphogenesis, and has been extensively studied over the past years. Our current knowledge of cell polarisation in development is predominantly based on studies that have analysed polarisation of single cells, such as eggs, or cellular aggregates with a stable polarising interface, such as cultured epithelial cells (St Johnston and Ahringer, 2010). However, in embryonic development, particularly of vertebrates, cell polarisation processes often encompass large numbers of cells that are placed within moving and proliferating tissues, and undergo mesenchymal-to-epithelial transitions with a highly complex spatiotemporal choreography. How such intricate cell polarisation processes in embryonic development are achieved has only started to be analysed. By using live imaging of neurulation in the transparent zebrafish embryo, Buckley et al (2012) now describe a novel polarisation strategy by which cells assemble an apical domain in the part of their cell body that intersects with the midline of the forming neural rod. This mechanism, along with the previously described mirror-symmetric divisions (Tawk et al, 2007), is thought to trigger formation of both neural rod midline and lumen.
AU - Compagnon, Julien
AU - Heisenberg, Carl-Philipp J
ID - 2920
IS - 1
JF - EMBO Journal
TI - Neurulation coordinating cell polarisation and lumen formation
VL - 32
ER -
TY - JOUR
AB - Oriented mitosis is essential during tissue morphogenesis. The Wnt/planar cell polarity (Wnt/PCP) pathway orients mitosis in a number of developmental systems, including dorsal epiblast cell divisions along the animal-vegetal (A-V) axis during zebrafish gastrulation. How Wnt signalling orients the mitotic plane is, however, unknown. Here we show that, in dorsal epiblast cells, anthrax toxin receptor 2a (Antxr2a) accumulates in a polarized cortical cap, which is aligned with the embryonic A-V axis and forecasts the division plane. Filamentous actin (F-actin) also forms an A-V polarized cap, which depends on Wnt/PCP and its effectors RhoA and Rock2. Antxr2a is recruited to the cap by interacting with actin. Antxr2a also interacts with RhoA and together they activate the diaphanous-related formin zDia2. Mechanistically, Antxr2a functions as a Wnt-dependent polarized determinant, which, through the action of RhoA and zDia2, exerts torque on the spindle to align it with the A-V axis.
AU - Castanon, Irinka
AU - Abrami, Laurence
AU - Holtzer, Laurent
AU - Heisenberg, Carl-Philipp J
AU - Van Der Goot, Françoise
AU - González Gaitán, Marcos
ID - 2918
IS - 1
JF - Nature Cell Biology
TI - Anthrax toxin receptor 2a controls mitotic spindle positioning
VL - 15
ER -
TY - JOUR
AB - The distribution of the phytohormone auxin regulates many aspects of plant development including growth response to gravity. Gravitropic root curvature involves coordinated and asymmetric cell elongation between the lower and upper side of the root, mediated by differential cellular auxin levels. The asymmetry in the auxin distribution is established and maintained by a spatio-temporal regulation of the PIN-FORMED (PIN) auxin transporter activity. We provide novel insights into the complex regulation of PIN abundance and activity during root gravitropism. We show that PIN2 turnover is differentially regulated on the upper and lower side of gravistimulated roots by distinct but partially overlapping auxin feedback mechanisms. In addition to regulating transcription and clathrin-mediated internalization, auxin also controls PIN abundance at the plasma membrane by promoting their vacuolar targeting and degradation. This effect of elevated auxin levels requires the activity of SKP-Cullin-F-box TIR1/AFB (SCF TIR1/AFB)-dependent pathway. Importantly, also suboptimal auxin levels mediate PIN degradation utilizing the same signalling pathway. These feedback mechanisms are functionally important during gravitropic response and ensure fine-tuning of auxin fluxes for maintaining as well as terminating asymmetric growth.
AU - Baster, Pawel
AU - Robert, Stéphanie
AU - Kleine Vehn, Jürgen
AU - Vanneste, Steffen
AU - Kania, Urszula
AU - Grunewald, Wim
AU - De Rybel, Bert
AU - Beeckman, Tom
AU - Friml, Jirí
ID - 2919
IS - 2
JF - EMBO Journal
TI - SCF^TIR1 AFB-auxin signalling regulates PIN vacuolar trafficking and auxin fluxes during root gravitropism
VL - 32
ER -
TY - CONF
AB - A chain rule for an entropy notion H(.) states that the entropy H(X) of a variable X decreases by at most l if conditioned on an l-bit string A, i.e., H(X|A)>= H(X)-l. More generally, it satisfies a chain rule for conditional entropy if H(X|Y,A)>= H(X|Y)-l.
All natural information theoretic entropy notions we are aware of (like Shannon or min-entropy) satisfy some kind of chain rule for conditional entropy. Moreover, many computational entropy notions (like Yao entropy, unpredictability entropy and several variants of HILL entropy) satisfy the chain rule for conditional entropy, though here not only the quantity decreases by l, but also the quality of the entropy decreases exponentially in l. However, for
the standard notion of conditional HILL entropy (the computational equivalent of min-entropy) the existence of such a rule was unknown so far.
In this paper, we prove that for conditional HILL entropy no meaningful chain rule exists, assuming the existence of one-way permutations: there exist distributions X,Y,A, where A is a distribution over a single bit, but $H(X|Y)>>H(X|Y,A)$, even if we simultaneously allow for a massive degradation in the quality of the entropy.
The idea underlying our construction is based on a surprising connection between the chain rule for HILL entropy and deniable encryption.
AU - Krenn, Stephan
AU - Pietrzak, Krzysztof Z
AU - Wadia, Akshay
ED - Sahai, Amit
ID - 2940
TI - A counterexample to the chain rule for conditional HILL entropy, and what deniable encryption has to do with it
VL - 7785
ER -
TY - JOUR
AB - We propose a two-step procedure for estimating multiple migration rates in an approximate Bayesian computation (ABC) framework, accounting for global nuisance parameters. The approach is not limited to migration, but generally of interest for inference problems with multiple parameters and a modular structure (e.g. independent sets of demes or loci). We condition on a known, but complex demographic model of a spatially subdivided population, motivated by the reintroduction of Alpine ibex (Capra ibex) into Switzerland. In the first step, the global parameters ancestral mutation rate and male mating skew have been estimated for the whole population in Aeschbacher et al. (Genetics 2012; 192: 1027). In the second step, we estimate in this study the migration rates independently for clusters of demes putatively connected by migration. For large clusters (many migration rates), ABC faces the problem of too many summary statistics. We therefore assess by simulation if estimation per pair of demes is a valid alternative. We find that the trade-off between reduced dimensionality for the pairwise estimation on the one hand and lower accuracy due to the assumption of pairwise independence on the other depends on the number of migration rates to be inferred: the accuracy of the pairwise approach increases with the number of parameters, relative to the joint estimation approach. To distinguish between low and zero migration, we perform ABC-type model comparison between a model with migration and one without. Applying the approach to microsatellite data from Alpine ibex, we find no evidence for substantial gene flow via migration, except for one pair of demes in one direction.
AU - Aeschbacher, Simon
AU - Futschik, Andreas
AU - Beaumont, Mark
ID - 2944
IS - 4
JF - Molecular Ecology
TI - Approximate Bayesian computation for modular inference problems with many parameters: the example of migration rates.
VL - 22
ER -
TY - CONF
AB - Many visual datasets are traditionally used to analyze the performance of different learning techniques. The evaluation is usually done within each dataset, therefore it is questionable if such results are a reliable indicator of true generalization ability. We propose here an algorithm to exploit the existing data resources when learning on a new multiclass problem. Our main idea is to identify an image representation that decomposes orthogonally into two subspaces: a part specific to each dataset, and a part generic to, and therefore shared between, all the considered source sets. This allows us to use the generic representation as un-biased reference knowledge for a novel classification task. By casting the method in the multi-view setting, we also make it possible to use different features for different databases. We call the algorithm MUST, Multitask Unaligned Shared knowledge Transfer. Through extensive experiments on five public datasets, we show that MUST consistently improves the cross-datasets generalization performance.
AU - Tommasi, Tatiana
AU - Quadrianto, Novi
AU - Caputo, Barbara
AU - Lampert, Christoph
ID - 2948
TI - Beyond dataset bias: Multi-task unaligned shared knowledge transfer
VL - 7724
ER -
TY - JOUR
AB - Multithreaded programs coordinate their interaction through synchronization primitives like mutexes and semaphores, which are managed by an OS-provided resource manager. We propose algorithms for the automatic construction of code-aware resource managers for multithreaded embedded applications. Such managers use knowledge about the structure and resource usage (mutex and semaphore usage) of the threads to guarantee deadlock freedom and progress while managing resources in an efficient way. Our algorithms compute managers as winning strategies in certain infinite games, and produce a compact code description of these strategies. We have implemented the algorithms in the tool Cynthesis. Given a multithreaded program in C, the tool produces C code implementing a code-aware resource manager. We show in experiments that Cynthesis produces compact resource managers within a few minutes on a set of embedded benchmarks with up to 6 threads. © 2012 Springer Science+Business Media, LLC.
AU - Chatterjee, Krishnendu
AU - De Alfaro, Luca
AU - Faella, Marco
AU - Majumdar, Ritankar
AU - Raman, Vishwanath
ID - 3116
IS - 2
JF - Formal Methods in System Design
TI - Code aware resource management
VL - 42
ER -
TY - JOUR
AB - The fact that a sum of isotropic Gaussian kernels can have more modes than kernels is surprising. Extra (ghost) modes do not exist in ℝ1 and are generally not well studied in higher dimensions. We study a configuration of n+1 Gaussian kernels for which there are exactly n+2 modes. We show that all modes lie on a finite set of lines, which we call axes, and study the restriction of the Gaussian mixture to these axes in order to discover that there are an exponential number of critical points in this configuration. Although the existence of ghost modes remained unknown due to the difficulty of finding examples in ℝ2, we show that the resilience of ghost modes grows like the square root of the dimension. In addition, we exhibit finite configurations of isotropic Gaussian kernels with superlinearly many modes.
AU - Edelsbrunner, Herbert
AU - Fasy, Brittany Terese
AU - Rote, Günter
ID - 2815
IS - 4
JF - Discrete & Computational Geometry
TI - Add isotropic Gaussian kernels at own risk: More and more resilient modes in higher dimensions
VL - 49
ER -
TY - JOUR
AB - Cells in a developing embryo have no direct way of "measuring" their physical position. Through a variety of processes, however, the expression levels of multiple genes come to be correlated with position, and these expression levels thus form a code for "positional information." We show how to measure this information, in bits, using the gap genes in the Drosophila embryo as an example. Individual genes carry nearly two bits of information, twice as much as expected if the expression patterns consisted only of on/off domains separated by sharp boundaries. Taken together, four gap genes carry enough information to define a cell's location with an error bar of ~1% along the anterior-posterior axis of the embryo. This precision is nearly enough for each cell to have a unique identity, which is the maximum information the system can use, and is nearly constant along the length of the embryo. We argue that this constancy is a signature of optimality in the transmission of information from primary morphogen inputs to the output of the gap gene network.
AU - Dubuis, Julien
AU - Tkacik, Gasper
AU - Wieschaus, Eric
AU - Gregor, Thomas
AU - Bialek, William
ID - 3261
IS - 41
JF - PNAS
TI - Positional information, in bits
VL - 110
ER -
TY - GEN
AU - Quadrianto, Novi
AU - Lampert, Christoph
ED - Dubitzky, Werner
ED - Wolkenhauer, Olaf
ED - Cho, Kwang
ED - Yokota, Hiroki
ID - 3321
T2 - Encyclopedia of Systems Biology
TI - Kernel based learning
VL - 3
ER -
TY - JOUR
AB - We consider Markov decision processes (MDPs) with Büchi (liveness) objectives. We consider the problem of computing the set of almost-sure winning states from where the objective can be ensured with probability 1. Our contributions are as follows: First, we present the first subquadratic symbolic algorithm to compute the almost-sure winning set for MDPs with Büchi objectives; our algorithm takes O(n · √ m) symbolic steps as compared to the previous known algorithm that takes O(n 2) symbolic steps, where n is the number of states and m is the number of edges of the MDP. In practice MDPs have constant out-degree, and then our symbolic algorithm takes O(n · √ n) symbolic steps, as compared to the previous known O(n 2) symbolic steps algorithm. Second, we present a new algorithm, namely win-lose algorithm, with the following two properties: (a) the algorithm iteratively computes subsets of the almost-sure winning set and its complement, as compared to all previous algorithms that discover the almost-sure winning set upon termination; and (b) requires O(n · √ K) symbolic steps, where K is the maximal number of edges of strongly connected components (scc's) of the MDP. The win-lose algorithm requires symbolic computation of scc's. Third, we improve the algorithm for symbolic scc computation; the previous known algorithm takes linear symbolic steps, and our new algorithm improves the constants associated with the linear number of steps. In the worst case the previous known algorithm takes 5×n symbolic steps, whereas our new algorithm takes 4×n symbolic steps.
AU - Chatterjee, Krishnendu
AU - Henzinger, Monika
AU - Joglekar, Manas
AU - Shah, Nisarg
ID - 2831
IS - 3
JF - Formal Methods in System Design
TI - Symbolic algorithms for qualitative analysis of Markov decision processes with Büchi objectives
VL - 42
ER -
TY - JOUR
AB - In this paper, we present the first output-sensitive algorithm to compute the persistence diagram of a filtered simplicial complex. For any Γ > 0, it returns only those homology classes with persistence at least Γ. Instead of the classical reduction via column operations, our algorithm performs rank computations on submatrices of the boundary matrix. For an arbitrary constant δ ∈ (0, 1), the running time is O (C (1 - δ) Γ R d (n) log n), where C (1 - δ) Γ is the number of homology classes with persistence at least (1 - δ) Γ, n is the total number of simplices in the complex, d its dimension, and R d (n) is the complexity of computing the rank of an n × n matrix with O (d n) nonzero entries. Depending on the choice of the rank algorithm, this yields a deterministic O (C (1 - δ) Γ n 2.376) algorithm, an O (C (1 - δ) Γ n 2.28) Las-Vegas algorithm, or an O (C (1 - δ) Γ n 2 + ε{lunate}) Monte-Carlo algorithm for an arbitrary ε{lunate} > 0. The space complexity of the Monte-Carlo version is bounded by O (d n) = O (n log n).
AU - Chen, Chao
AU - Kerber, Michael
ID - 2939
IS - 4
JF - Computational Geometry: Theory and Applications
TI - An output sensitive algorithm for persistent homology
VL - 46
ER -
TY - THES
AB - Motivated by the analysis of highly dynamic message-passing systems, i.e. unbounded thread creation, mobility, etc. we present a framework for the analysis of depth-bounded systems. Depth-bounded systems are one of the most expressive known fragment of the π-calculus for which interesting verification problems are still decidable. Even though they are infinite state systems depth-bounded systems are well-structured, thus can be analyzed algorithmically. We give an interpretation of depth-bounded systems as graph-rewriting systems. This gives more flexibility and ease of use to apply depth-bounded systems to other type of systems like shared memory concurrency.
First, we develop an adequate domain of limits for depth-bounded systems, a prerequisite for the effective representation of downward-closed sets. Downward-closed sets are needed by forward saturation-based algorithms to represent potentially infinite sets of states. Then, we present an abstract interpretation framework to compute the covering set of well-structured transition systems. Because, in general, the covering set is not computable, our abstraction over-approximates the actual covering set. Our abstraction captures the essence of acceleration based-algorithms while giving up enough precision to ensure convergence. We have implemented the analysis in the PICASSO tool and show that it is accurate in practice. Finally, we build some further analyses like termination using the covering set as starting point.
AU - Zufferey, Damien
ID - 1405
TI - Analysis of dynamic message passing programs
ER -
TY - JOUR
AB - Understanding the relative importance of heterosis and outbreeding depression over multiple generations is a key question in evolutionary biology and is essential for identifying appropriate genetic sources for population and ecosystem restoration. Here we use 2455 experimental crosses between 12 population pairs of the rare perennial plant Rutidosis leptorrhynchoides (Asteraceae) to investigate the multi-generational (F1, F2, F3) fitness outcomes of inter-population hybridization. We detected no evidence of outbreeding depression, with inter-population hybrids and backcrosses showing either similar fitness or significant heterosis for fitness components across the three generations. Variation in heterosis among population pairs was best explained by characteristics of the foreign source or home population, and was greatest when the source population was large, with high genetic diversity and low inbreeding, and the home population was small and inbred. Our results indicate that the primary consideration for maximizing progeny fitness following population augmentation or restoration is the use of seed from large, genetically diverse populations.
AU - Pickup, Melinda
AU - Field, David
AU - Rowell, David
AU - Young, Andrew
ID - 450
IS - 1750
JF - Proceedings of the Royal Society of London Series B Biological Sciences
TI - Source population characteristics affect heterosis following genetic rescue of fragmented plant populations
VL - 280
ER -
TY - JOUR
AB - Maternal exposure to infection occurring mid-gestation produces a three-fold increase in the risk of schizophrenia in the offspring. The critical initiating factor appears to be the maternal immune activation (MIA) that follows infection. This process can be induced in rodents by exposure of pregnant dams to the viral mimic Poly I:C, which triggers an immune response that results in structural, functional, behavioral, and electrophysiological phenotypes in the adult offspring that model those seen in schizophrenia. We used this model to explore the role of synchronization in brain neural networks, a process thought to be dysfunctional in schizophrenia and previously associated with positive, negative, and cognitive symptoms of schizophrenia. Exposure of pregnant dams to Poly I:C on GD15 produced an impairment in long-range neural synchrony in adult offspring between two regions implicated in schizophrenia pathology; the hippocampus and the medial prefrontal cortex (mPFC). This reduction in synchrony was ameliorated by acute doses of the antipsychotic clozapine. MIA animals have previously been shown to have impaired pre-pulse inhibition (PPI), a gold-standard measure of schizophrenia-like deficits in animal models. Our data showed that deficits in synchrony were positively correlated with the impairments in PPI. Subsequent analysis of LFP activity during the PPI response also showed that reduced coupling between the mPFC and the hippocampus following processing of the pre-pulse was associated with reduced PPI. The ability of the MIA intervention to model neurodevelopmental aspects of schizophrenia pathology provides a useful platform from which to investigate the ontogeny of aberrant synchronous processes. Further, the way in which the model expresses translatable deficits such as aberrant synchrony and reduced PPI will allow researchers to explore novel intervention strategies targeted to these changes.
AU - Dickerson, Desiree
AU - Bilkey, David
ID - 476
IS - DEC
JF - Frontiers in Behavioral Neuroscience
TI - Aberrant neural synchrony in the maternal immune activation model: Using translatable measures to explore targeted interventions
VL - 7
ER -
TY - JOUR
AB - Background: Reassortment between the RNA segments encoding haemagglutinin (HA) and neuraminidase (NA), the major antigenic influenza proteins, produces viruses with novel HA and NA subtype combinations and has preceded the emergence of pandemic strains. It has been suggested that productive viral infection requires a balance in the level of functional activity of HA and NA, arising from their closely interacting roles in the viral life cycle, and that this functional balance could be mediated by genetic changes in the HA and NA. Here, we investigate how the selective pressure varies for H7 avian influenza HA on different NA subtype backgrounds. Results: By extending Bayesian stochastic mutational mapping methods to calculate the ratio of the rate of non-synonymous change to the rate of synonymous change (d N/d S), we found the average d N/d S across the avian influenza H7 HA1 region to be significantly greater on an N2 NA subtype background than on an N1, N3 or N7 background. Observed differences in evolutionary rates of H7 HA on different NA subtype backgrounds could not be attributed to underlying differences between avian host species or virus pathogenicity. Examination of d N/d S values for each subtype on a site-by-site basis indicated that the elevated d N/d S on the N2 NA background was a result of increased selection, rather than a relaxation of selective constraint. Conclusions: Our results are consistent with the hypothesis that reassortment exposes influenza HA to significant changes in selective pressure through genetic interactions with NA. Such epistatic effects might be explicitly accounted for in future models of influenza evolution.
AU - Ward, Melissa
AU - Lycett, Samantha
AU - Avila, Dorita
AU - Bollback, Jonathan P
AU - Leigh Brown, Andrew
ID - 500
IS - 1
JF - BMC Evolutionary Biology
TI - Evolutionary interactions between haemagglutinin and neuraminidase in avian influenza
VL - 13
ER -
TY - JOUR
AB - All known species of extant tapirs are allopatric: 1 in southeastern Asia and 3 in Central and South America. The fossil record for tapirs, however, is much wider in geographical range, including Europe, Asia, and North and South America, going back to the late Oligocene, making the present distribution a relict of the original one. We here describe a new species of living Tapirus from the Amazon rain forest, the 1st since T. bairdii Gill, 1865, and the 1st new Perissodactyla in more than 100 years, from both morphological and molecular characters. It is shorter in stature than T. terrestris (Linnaeus, 1758) and has distinctive skull morphology, and it is basal to the clade formed by T. terrestris and T. pinchaque (Roulin, 1829). This highlights the unrecognized biodiversity in western Amazonia, where the biota faces increasing threats. Local peoples have long recognized our new species, suggesting a key role for traditional knowledge in understanding the biodiversity of the region.
AU - Cozzuol, Mario
AU - Clozato, Camila
AU - Holanda, Elizete
AU - Rodrigues, Flávio
AU - Nienow, Samuel
AU - De Thoisy, Benoit
AU - Fernandes Redondo, Rodrigo A
AU - Santos, Fabrício
ID - 501
IS - 6
JF - Journal of Mammalogy
TI - A new species of tapir from the Amazon
VL - 94
ER -
TY - JOUR
AB - Blind signatures allow users to obtain signatures on messages hidden from the signer; moreover, the signer cannot link the resulting message/signature pair to the signing session. This paper presents blind signature schemes, in which the number of interactions between the user and the signer is minimal and whose blind signatures are short. Our schemes are defined over bilinear groups and are proved secure in the common-reference-string model without random oracles and under standard assumptions: CDH and the decision-linear assumption. (We also give variants over asymmetric groups based on similar assumptions.) The blind signatures are Waters signatures, which consist of 2 group elements. Moreover, we instantiate partially blind signatures, where the message consists of a part hidden from the signer and a commonly known public part, and schemes achieving perfect blindness. We propose new variants of blind signatures, such as signer-friendly partially blind signatures, where the public part can be chosen by the signer without prior agreement, 3-party blind signatures, as well as blind signatures on multiple aggregated messages provided by independent sources. We also extend Waters signatures to non-binary alphabets by proving a new result on the underlying hash function.
AU - Blazy, Olivier
AU - Fuchsbauer, Georg
AU - Pointcheval, David
AU - Vergnaud, Damien
ID - 502
IS - 5
JF - Journal of Computer Security
TI - Short blind signatures
VL - 21
ER -
TY - JOUR
AB - Alkyd resins are polyesters containing unsaturated fatty acids that are used as binding agents in paints and coatings. Chemical drying of these polyesters is based on heavy metal catalyzed cross-linking of the unsaturated fatty acid moieties. Among the heavy-metal catalysts, cobalt complexes are the most effective, yet they have been proven to be carcinogenic. Therefore, strategies to replace the cobalt-based catalyst by environmentally friendlier and less toxic alternatives are under development. Here, we demonstrate for the first time that a laccase-mediator system can effectively replace the heavy-metal catalyst and cross-link alkyd resins. Interestingly, the biocatalytic reaction does not only work in aqueous media, but also in a solid film, where enzyme diffusion is limited. Within the catalytic cycle, the mediator oxidizes the alkyd resin and is regenerated by the laccase, which is uniformly distributed within the drying film as evidenced by confocal laser scanning microscopy. During gradual build-up of molecular weight, there is a concomitant decrease of the oxygen content in the film. A new optical sensor to follow oxygen consumption during the cross-linking reaction was developed and validated with state of the art techniques. A remarkable feature is the low sample amount required, which allows faster screening of new catalysts.
AU - Greimel, Katrin
AU - Perz, Veronika
AU - Koren, Klaus
AU - Feola, Roland
AU - Temel, Armin
AU - Sohar, Christian
AU - Herrero Acero, Enrique
AU - Klimant, Ingo
AU - Guebitz, Georg
ID - 505
IS - 2
JF - Green Chemistry
TI - Banning toxic heavy-metal catalysts from paints: Enzymatic cross-linking of alkyd resins
VL - 15
ER -
TY - JOUR
AB - Fertilization in flowering plants requires the temporal and spatial coordination of many developmental processes, including pollen production, anther dehiscence, ovule production, and pollen tube elongation. However, it remains elusive as to how this coordination occurs during reproduction. Here, we present evidence that endocytosis, involving heterotetrameric adaptor protein complex 2 (AP-2), plays a crucial role in fertilization. An Arabidopsis thaliana mutant ap2m displays multiple defects in pollen production and viability, as well as elongation of staminal filaments and pollen tubes, all of which are pivotal processes needed for fertilization. Of these abnormalities, the defects in elongation of staminal filaments and pollen tubes were partially rescued by exogenous auxin. Moreover, DR5rev:GFP (for green fluorescent protein) expression was greatly reduced in filaments and anthers in ap2m mutant plants. At the cellular level, ap2m mutants displayed defects in both endocytosis of N-(3-triethylammonium-propyl)-4- (4-diethylaminophenylhexatrienyl) pyridinium dibromide, a lypophilic dye used as an endocytosis marker, and polar localization of auxin-efflux carrier PIN FORMED2 (PIN2) in the stamen filaments. Moreover, these defects were phenocopied by treatment with Tyrphostin A23, an inhibitor of endocytosis. Based on these results, we propose that AP-2-dependent endocytosis plays a crucial role in coordinating the multiple developmental aspects of male reproductive organs by modulating cellular auxin level through the regulation of the amount and polarity of PINs.
AU - Kim, Soo
AU - Xu, Zheng
AU - Song, Kyungyoung
AU - Kim, Dae
AU - Kang, Hyangju
AU - Reichardt, Ilka
AU - Sohn, Eun
AU - Friml, Jirí
AU - Juergens, Gerd
AU - Hwang, Inhwan
ID - 507
IS - 8
JF - Plant Cell
TI - Adaptor protein complex 2-mediated endocytosis is crucial for male reproductive organ development in arabidopsis
VL - 25
ER -
TY - JOUR
AB - The phagocyte NADPH oxidase catalyzes the reduction of O2 to reactive oxygen species with microbicidal activity. It is composed of two membrane-spanning subunits, gp91-phox and p22-phox (encoded by CYBB and CYBA, respectively), and three cytoplasmic subunits, p40-phox, p47-phox, and p67-phox (encoded by NCF4, NCF1, and NCF2, respectively). Mutations in any of these genes can result in chronic granulomatous disease, a primary immunodeficiency characterized by recurrent infections. Using evolutionary mapping, we determined that episodes of adaptive natural selection have shaped the extracellular portion of gp91-phox during the evolution of mammals, which suggests that this region may have a function in host-pathogen interactions. On the basis of a resequencing analysis of approximately 35 kb of CYBB, CYBA, NCF2, and NCF4 in 102 ethnically diverse individuals (24 of African ancestry, 31 of European ancestry, 24 of Asian/Oceanians, and 23 US Hispanics), we show that the pattern of CYBA diversity is compatible with balancing natural selection, perhaps mediated by catalase-positive pathogens. NCF2 in Asian populations shows a pattern of diversity characterized by a differentiated haplotype structure. Our study provides insight into the role of pathogen-driven natural selection in an innate immune pathway and sheds light on the role of CYBA in endothelial, nonphagocytic NADPH oxidases, which are relevant in the pathogenesis of cardiovascular and other complex diseases.
AU - Tarazona Santos, Eduardo
AU - Machado, Moara
AU - Magalhães, Wagner
AU - Chen, Renee
AU - Lyon, Fernanda
AU - Burdett, Laurie
AU - Crenshaw, Andrew
AU - Fabbri, Cristina
AU - Pereira, Latife
AU - Pinto, Laelia
AU - Fernandes Redondo, Rodrigo A
AU - Sestanovich, Ben
AU - Yeager, Meredith
AU - Chanock, Stephen
ID - 508
IS - 9
JF - Molecular Biology and Evolution
TI - Evolutionary dynamics of the human NADPH oxidase genes CYBB, CYBA, NCF2, and NCF4: Functional implications
VL - 30
ER -
TY - JOUR
AB - Clathrin-mediated endocytosis (CME) regulates many aspects of plant development, including hormone signaling and responses to environmental stresses. Despite the importance of this process, the machinery that regulates CME in plants is largely unknown. In mammals, the heterotetrameric ADAPTOR PROTEIN COMPLEX-2 (AP-2) is required for the formation of clathrin-coated vesicles at the plasma membrane (PM). Although the existence of AP-2 has been predicted in Arabidopsis thaliana, the biochemistry and functionality of the complex is still uncharacterized. Here, we identified all the subunits of the Arabidopsis AP-2 by tandem affinity purification and found that one of the large AP-2 subunits, AP2A1, localized at the PM and interacted with clathrin. Furthermore, endocytosis of the leucine-rich repeat receptor kinase, BRASSINOSTEROID INSENSITIVE1 (BRI1), was shown to depend on AP-2. Knockdown of the two Arabidopsis AP2A genes or overexpression of a dominant-negative version of the medium AP-2 subunit, AP2M, impaired BRI1 endocytosis and enhanced the brassinosteroid signaling. Our data reveal that the CME machinery in Arabidopsis is evolutionarily conserved and that AP-2 functions in receptormediated endocytosis.
AU - Di Rubbo, Simone
AU - Irani, Niloufer
AU - Kim, Soo
AU - Xu, Zheng
AU - Gadeyne, Astrid
AU - Dejonghe, Wim
AU - Vanhoutte, Isabelle
AU - Persiau, Geert
AU - Eeckhout, Dominique
AU - Simon, Sibu
AU - Song, Kyungyoung
AU - Kleine Vehn, Jürgen
AU - Friml, Jirí
AU - De Jaeger, Geert
AU - Van Damme, Daniël
AU - Hwang, Inhwan
AU - Russinova, Eugenia
ID - 509
IS - 8
JF - Plant Cell
TI - The clathrin adaptor complex AP-2 mediates endocytosis of brassinosteroid INSENSITIVE1 in arabidopsis
VL - 25
ER -
TY - JOUR
AB - In plants, changes in local auxin concentrations can trigger a range of developmental processes as distinct tissues respond differently to the same auxin stimulus. However, little is known about how auxin is interpreted by individual cell types. We performed a transcriptomic analysis of responses to auxin within four distinct tissues of the Arabidopsis thaliana root and demonstrate that different cell types show competence for discrete responses. The majority of auxin‐responsive genes displayed a spatial bias in their induction or repression. The novel data set was used to examine how auxin influences tissue‐specific transcriptional regulation of cell‐identity markers. Additionally, the data were used in combination with spatial expression maps of the root to plot a transcriptomic auxin‐response gradient across the apical and basal meristem. The readout revealed a strong correlation for thousands of genes between the relative response to auxin and expression along the longitudinal axis of the root. This data set and comparative analysis provide a transcriptome‐level spatial breakdown of the response to auxin within an organ where this hormone mediates many aspects of development.
AU - Bargmann, Bastiaan
AU - Vanneste, Steffen
AU - Krouk, Gabriel
AU - Nawy, Tal
AU - Efroni, Idan
AU - Shani, Eilon
AU - Choe, Goh
AU - Friml, Jirí
AU - Bergmann, Dominique
AU - Estelle, Mark
AU - Birnbaum, Kenneth
ID - 516
IS - 1
JF - Molecular Systems Biology
TI - A map of cell type‐specific auxin responses
VL - 9
ER -
TY - JOUR
AB - Exposure of an isogenic bacterial population to a cidal antibiotic typically fails to eliminate a small fraction of refractory cells. Historically, fractional killing has been attributed to infrequently dividing or nondividing "persisters." Using microfluidic cultures and time-lapse microscopy, we found that Mycobacterium smegmatis persists by dividing in the presence of the drug isoniazid (INH). Although persistence in these studies was characterized by stable numbers of cells, this apparent stability was actually a dynamic state of balanced division and death. Single cells expressed catalase-peroxidase (KatG), which activates INH, in stochastic pulses that were negatively correlated with cell survival. These behaviors may reflect epigenetic effects, because KatG pulsing and death were correlated between sibling cells. Selection of lineages characterized by infrequent KatG pulsing could allow nonresponsive adaptation during prolonged drug exposure.
AU - Wakamoto, Yurichi
AU - Dhar, Neraaj
AU - Chait, Remy P
AU - Schneider, Katrin
AU - Signorino Gelo, François
AU - Leibler, Stanislas
AU - Mckinney, John
ID - 499
IS - 6115
JF - Science
TI - Dynamic persistence of antibiotic-stressed mycobacteria
VL - 339
ER -
TY - JOUR
AB - The native auxin, indole-3-acetic acid (IAA), is a major regulator of plant growth and development. Its nonuniform distribution between cells and tissues underlies the spatiotemporal coordination of many developmental events and responses to environmental stimuli. The regulation of auxin gradients and the formation of auxin maxima/minima most likely involve the regulation of both metabolic and transport processes. In this article, we have demonstrated that 2-oxindole-3-acetic acid (oxIAA) is a major primary IAA catabolite formed in Arabidopsis thaliana root tissues. OxIAA had little biological activity and was formed rapidly and irreversibly in response to increases in auxin levels. We further showed that there is cell type-specific regulation of oxIAA levels in the Arabidopsis root apex. We propose that oxIAA is an important element in the regulation of output from auxin gradients and, therefore, in the regulation of auxin homeostasis and response mechanisms.
AU - Pěnčík, Aleš
AU - Simonovik, Biljana
AU - Petersson, Sara
AU - Henyková, Eva
AU - Simon, Sibu
AU - Greenham, Kathleen
AU - Zhang, Yi
AU - Kowalczyk, Mariusz
AU - Estelle, Mark
AU - Zažímalová, Eva
AU - Novák, Ondřej
AU - Sandberg, Göran
AU - Ljung, Karin
ID - 511
IS - 10
JF - Plant Cell
TI - Regulation of auxin homeostasis and gradients in Arabidopsis roots through the formation of the indole-3-acetic acid catabolite 2-oxindole-3-acetic acid
VL - 25
ER -
TY - JOUR
AB - The apical-basal axis of the early plant embryo determines the body plan of the adult organism. To establish a polarized embryonic axis, plants evolved a unique mechanism that involves directional, cell-to-cell transport of the growth regulator auxin. Auxin transport relies on PIN auxin transporters [1], whose polar subcellular localization determines the flow directionality. PIN-mediated auxin transport mediates the spatial and temporal activity of the auxin response machinery [2-7] that contributes to embryo patterning processes, including establishment of the apical (shoot) and basal (root) embryo poles [8]. However, little is known of upstream mechanisms guiding the (re)polarization of auxin fluxes during embryogenesis [9]. Here, we developed a model of plant embryogenesis that correctly generates emergent cell polarities and auxin-mediated sequential initiation of apical-basal axis of plant embryo. The model relies on two precisely localized auxin sources and a feedback between auxin and the polar, subcellular PIN transporter localization. Simulations reproduced PIN polarity and auxin distribution, as well as previously unknown polarization events during early embryogenesis. The spectrum of validated model predictions suggests that our model corresponds to a minimal mechanistic framework for initiation and orientation of the apical-basal axis to guide both embryonic and postembryonic plant development.
AU - Wabnik, Krzysztof T
AU - Robert, Hélène
AU - Smith, Richard
AU - Friml, Jirí
ID - 527
IS - 24
JF - Current Biology
TI - Modeling framework for the establishment of the apical-basal embryonic axis in plants
VL - 23
ER -
TY - JOUR
AB - Establishment of the embryonic axis foreshadows the main body axis of adults both in plants and in animals, but underlying mechanisms are considered distinct. Plants utilize directional, cell-to-cell transport of the growth hormone auxin [1, 2] to generate an asymmetric auxin response that specifies the embryonic apical-basal axis [3-6]. The auxin flow directionality depends on the polarized subcellular localization of PIN-FORMED (PIN) auxin transporters [7, 8]. It remains unknown which mechanisms and spatial cues guide cell polarization and axis orientation in early embryos. Herein, we provide conceptually novel insights into the formation of embryonic axis in Arabidopsis by identifying a crucial role of localized tryptophan-dependent auxin biosynthesis [9-12]. Local auxin production at the base of young embryos and the accompanying PIN7-mediated auxin flow toward the proembryo are required for the apical auxin response maximum and the specification of apical embryonic structures. Later in embryogenesis, the precisely timed onset of localized apical auxin biosynthesis mediates PIN1 polarization, basal auxin response maximum, and specification of the root pole. Thus, the tight spatiotemporal control of distinct local auxin sources provides a necessary, non-cell-autonomous trigger for the coordinated cell polarization and subsequent apical-basal axis orientation during embryogenesis and, presumably, also for other polarization events during postembryonic plant life [13, 14].
AU - Robert, Hélène
AU - Grones, Peter
AU - Stepanova, Anna
AU - Robles, Linda
AU - Lokerse, Annemarie
AU - Alonso, Jose
AU - Weijers, Dolf
AU - Friml, Jirí
ID - 528
IS - 24
JF - Current Biology
TI - Local auxin sources orient the apical basal axis in arabidopsis embryos
VL - 23
ER -
TY - JOUR
AB - Podoplanin, a mucin-like plasma membrane protein, is expressed by lymphatic endothelial cells and responsible for separation of blood and lymphatic circulation through activation of platelets. Here we show that podoplanin is also expressed by thymic fibroblastic reticular cells (tFRC), a novel thymic medulla stroma cell type associated with thymic conduits, and involved in development of natural regulatory T cells (nTreg). Young mice deficient in podoplanin lack nTreg owing to retardation of CD4+CD25+ thymocytes in the cortex and missing differentiation of Foxp3+ thymocytes in the medulla. This might be due to CCL21 that delocalizes upon deletion of the CCL21-binding podoplanin from medullar tFRC to cortex areas. The animals do not remain devoid of nTreg but generate them delayed within the first month resulting in Th2-biased hypergammaglobulinemia but not in the death-causing autoimmune phenotype of Foxp3-deficient Scurfy mice.
AU - Fuertbauer, Elke
AU - Zaujec, Jan
AU - Uhrin, Pavel
AU - Raab, Ingrid
AU - Weber, Michele
AU - Schachner, Helga
AU - Bauer, Miroslav
AU - Schütz, Gerhard
AU - Binder, Bernd
AU - Sixt, Michael K
AU - Kerjaschki, Dontscho
AU - Stockinger, Hannes
ID - 522
IS - 1-2
JF - Immunology Letters
TI - Thymic medullar conduits-associated podoplanin promotes natural regulatory T cells
VL - 154
ER -
TY - CONF
AB - We consider two-player games played on weighted directed graphs with mean-payoff and total-payoff objectives, two classical quantitative objectives. While for single-dimensional games the complexity and memory bounds for both objectives coincide, we show that in contrast to multi-dimensional mean-payoff games that are known to be coNP-complete, multi-dimensional total-payoff games are undecidable. We introduce conservative approximations of these objectives, where the payoff is considered over a local finite window sliding along a play, instead of the whole play. For single dimension, we show that (i) if the window size is polynomial, deciding the winner takes polynomial time, and (ii) the existence of a bounded window can be decided in NP ∩ coNP, and is at least as hard as solving mean-payoff games. For multiple dimensions, we show that (i) the problem with fixed window size is EXPTIME-complete, and (ii) there is no primitive-recursive algorithm to decide the existence of a bounded window.
AU - Chatterjee, Krishnendu
AU - Doyen, Laurent
AU - Randour, Mickael
AU - Raskin, Jean
ID - 2279
TI - Looking at mean-payoff and total-payoff through windows
VL - 8172
ER -
TY - CONF
AB - In this work we present a flexible tool for tumor progression, which simulates the evolutionary dynamics of cancer. Tumor progression implements a multi-type branching process where the key parameters are the fitness landscape, the mutation rate, and the average time of cell division. The fitness of a cancer cell depends on the mutations it has accumulated. The input to our tool could be any fitness landscape, mutation rate, and cell division time, and the tool produces the growth dynamics and all relevant statistics.
AU - Reiter, Johannes
AU - Božić, Ivana
AU - Chatterjee, Krishnendu
AU - Nowak, Martin
ID - 2000
T2 - Proceedings of 25th Int. Conf. on Computer Aided Verification
TI - TTP: Tool for tumor progression
VL - 8044
ER -
TY - GEN
AB - In this work we present a flexible tool for tumor progression, which simulates the evolutionary dynamics of cancer. Tumor progression implements a multi-type branching process where the key parameters are the fitness landscape, the mutation rate, and the average time of cell division. The fitness of a cancer cell depends on the mutations it has accumulated. The input to our tool could be any fitness landscape, mutation rate, and cell division time, and the tool produces the growth dynamics and all relevant statistics.
AU - Reiter, Johannes
AU - Bozic, Ivana
AU - Chatterjee, Krishnendu
AU - Nowak, Martin
ID - 5399
SN - 2664-1690
TI - TTP: Tool for Tumor Progression
ER -
TY - GEN
AB - We consider partially observable Markov decision processes (POMDPs) with ω-regular conditions specified as parity objectives. The class of ω-regular languages extends regular languages to infinite strings and provides a robust specification language to express all properties used in verification, and parity objectives are canonical forms to express ω-regular conditions. The qualitative analysis problem given a POMDP and a parity objective asks whether there is a strategy to ensure that the objective is satis- fied with probability 1 (resp. positive probability). While the qualitative analysis problems are known to be undecidable even for very special cases of parity objectives, we establish decidability (with optimal complexity) of the qualitative analysis problems for POMDPs with all parity objectives under finite- memory strategies. We establish asymptotically optimal (exponential) memory bounds and EXPTIME- completeness of the qualitative analysis problems under finite-memory strategies for POMDPs with parity objectives.
AU - Chatterjee, Krishnendu
AU - Chmelik, Martin
AU - Tracol, Mathieu
ID - 5400
SN - 2664-1690
TI - What is decidable about partially observable Markov decision processes with ω-regular objectives
ER -
TY - GEN
AB - This document is created as a part of the project “Repository for Research Data at IST Austria”. It summarises the actual initiatives, projects and standards related to the project. It supports the preparation of standards and specifications for the project, which should be considered and followed to ensure interoperability and visibility of the uploaded data.
AU - Porsche, Jana
ID - 5401
TI - Initiatives and projects related to RD
ER -
TY - GEN
AB - Linearizability requires that the outcome of calls by competing threads to a concurrent data structure is the same as some sequential execution where each thread has exclusive access to the data structure. In an ordered data structure, such as a queue or a stack, linearizability is ensured by requiring threads commit in the order dictated by the sequential semantics of the data structure; e.g., in a concurrent queue implementation a dequeue can only remove the oldest element.
In this paper, we investigate the impact of this strict ordering, by comparing what linearizability allows to what existing implementations do. We first give an operational definition for linearizability which allows us to build the most general linearizable implementation as a transition system for any given sequential specification. We then use this operational definition to categorize linearizable implementations based on whether they are bound or free. In a bound implementation, whenever all threads observe the same logical state, the updates to the logical state and the temporal order of commits coincide. All existing queue implementations we know of are bound. We then proceed to present, to the best of our knowledge, the first ever free queue implementation. Our experiments show that free implementations have the potential for better performance by suffering less from contention.
AU - Henzinger, Thomas A
AU - Sezgin, Ali
ID - 5402
SN - 2664-1690
TI - How free is your linearizable concurrent data structure?
ER -
TY - CONF
AB - We consider partially observable Markov decision processes (POMDPs) with ω-regular conditions specified as parity objectives. The qualitative analysis problem given a POMDP and a parity objective asks whether there is a strategy to ensure that the objective is satisfied with probability 1 (resp. positive probability). While the qualitative analysis problems are known to be undecidable even for very special cases of parity objectives, we establish decidability (with optimal EXPTIME-complete complexity) of the qualitative analysis problems for POMDPs with all parity objectives under finite-memory strategies. We also establish asymptotically optimal (exponential) memory bounds.
AU - Chatterjee, Krishnendu
AU - Chmelik, Martin
AU - Tracol, Mathieu
ID - 2295
TI - What is decidable about partially observable Markov decision processes with omega-regular objectives
VL - 23
ER -
TY - GEN
AB - We consider concurrent games played by two-players on a finite state graph, where in every round the players simultaneously choose a move, and the current state along with the joint moves determine the successor state. We study the most fundamental objective for concurrent games, namely, mean-payoff or limit-average objective, where a reward is associated to every transition, and the goal of player 1 is to maximize the long-run average of the rewards, and the objective of player 2 is strictly the opposite (i.e., the games are zero-sum). The path constraint for player 1 could be qualitative, i.e., the mean-payoff is the maximal reward, or arbitrarily close to it; or quantitative, i.e., a given threshold between the minimal and maximal reward. We consider the computation of the almost-sure (resp. positive) winning sets, where player 1 can ensure that the path constraint is satisfied with probability 1 (resp. positive probability). Almost-sure winning with qualitative constraint exactly corresponds to the question whether there exists a strategy to ensure that the payoff is the maximal reward of the game. Our main results for qualitative path constraints are as follows: (1) we establish qualitative determinacy results that show for every state either player 1 has a strategy to ensure almost-sure (resp. positive) winning against all player-2 strategies or player 2 has a spoiling strategy to falsify almost-sure (resp. positive) winning against all player-1 strategies; (2) we present optimal strategy complexity results that precisely characterize the classes of strategies required for almost-sure and positive winning for both players; and (3) we present quadratic time algorithms to compute the almost-sure and the positive winning sets, matching the best known bound of the algorithms for much simpler problems (such as reachability objectives). For quantitative constraints we show that a polynomial time solution for the almost-sure or the positive winning set would imply a solution to a long-standing open problem (of solving the value problem of mean-payoff games) that is not known to be in polynomial time.
AU - Chatterjee, Krishnendu
AU - Ibsen-Jensen, Rasmus
ID - 5403
SN - 2664-1690
TI - Qualitative analysis of concurrent mean-payoff games
ER -
TY - GEN
AB - We study finite-state two-player (zero-sum) concurrent mean-payoff games played on a graph. We focus on the important sub-class of ergodic games where all states are visited infinitely often with probability 1. The algorithmic study of ergodic games was initiated in a seminal work of Hoffman and Karp in 1966, but all basic complexity questions have remained unresolved. Our main results for ergodic games are as follows: We establish (1) an optimal exponential bound on the patience of stationary strategies (where patience of a distribution is the inverse of the smallest positive probability and represents a complexity measure of a stationary strategy); (2) the approximation problem lie in FNP; (3) the approximation problem is at least as hard as the decision problem for simple stochastic games (for which NP and coNP is the long-standing best known bound). We show that the exact value can be expressed in the existential theory of the reals, and also establish square-root sum hardness for a related class of games.
AU - Chatterjee, Krishnendu
AU - Ibsen-Jensen, Rasmus
ID - 5404
SN - 2664-1690
TI - The complexity of ergodic games
ER -
TY - GEN
AB - Board games, like Tic-Tac-Toe and CONNECT-4, play an important role not only in development of mathematical and logical skills, but also in emotional and social development. In this paper, we address the problem of generating targeted starting positions for such games. This can facilitate new approaches for bringing novice players to mastery, and also leads to discovery of interesting game variants.
Our approach generates starting states of varying hardness levels for player 1 in a two-player board game, given rules of the board game, the desired number of steps required for player 1 to win, and the expertise levels of the two players. Our approach leverages symbolic methods and iterative simulation to efficiently search the extremely large state space. We present experimental results that include discovery of states of varying hardness levels for several simple grid-based board games. Also, the presence of such states for standard game variants like Tic-Tac-Toe on board size 4x4 opens up new games to be played that have not been played for ages since the default start state is heavily biased.
AU - Ahmed, Umair
AU - Chatterjee, Krishnendu
AU - Gulwani, Sumit
ID - 5410
SN - 2664-1690
TI - Automatic generation of alternative starting positions for traditional board games
ER -
TY - GEN
AB - The edit distance between two (untimed) traces is the minimum cost of a sequence of edit operations (insertion, deletion, or substitution) needed to transform one trace to the other. Edit distances have been extensively studied in the untimed setting, and form the basis for approximate matching of sequences in different domains such as coding theory, parsing, and speech recognition.
In this paper, we lift the study of edit distances from untimed languages to the timed setting. We define an edit distance between timed words which incorporates both the edit distance between the untimed words and the absolute difference in timestamps. Our edit distance between two timed words is computable in polynomial time. Further, we show that the edit distance between a timed word and a timed language generated by a timed automaton, defined as the edit distance between the word and the closest word in the language, is PSPACE-complete. While computing the edit distance between two timed automata is undecidable, we show that the approximate version, where we decide if the edit distance between two timed automata is either less than a given parameter or more than delta away from the parameter, for delta>0, can be solved in exponential space and is EXPSPACE-hard. Our definitions and techniques can be generalized to the setting of hybrid systems, and we show analogous decidability results for rectangular automata.
AU - Chatterjee, Krishnendu
AU - Ibsen-Jensen, Rasmus
AU - Majumdar, Rupak
ID - 5409
SN - 2664-1690
TI - Edit distance for timed automata
ER -
TY - GEN
AB - We consider the distributed synthesis problem fortemporal logic specifications. Traditionally, the problem has been studied for LTL, and the previous results show that the problem is decidable iff there is no information fork in the architecture. We consider the problem for fragments of LTLand our main results are as follows: (1) We show that the problem is undecidable for architectures with information forks even for the fragment of LTL with temporal operators restricted to next and eventually. (2) For specifications restricted to globally along with non-nested next operators, we establish decidability (in EXPSPACE) for star architectures where the processes receive disjoint inputs, whereas we establish undecidability for architectures containing an information fork-meet structure. (3)Finally, we consider LTL without the next operator, and establish decidability (NEXPTIME-complete) for all architectures for a fragment that consists of a set of safety assumptions, and a set of guarantees where each guarantee is a safety, reachability, or liveness condition.
AU - Chatterjee, Krishnendu
AU - Henzinger, Thomas A
AU - Otop, Jan
AU - Pavlogiannis, Andreas
ID - 5406
SN - 2664-1690
TI - Distributed synthesis for LTL Fragments
ER -
TY - GEN
AB - This document is created as a part of the project “Repository for Research Data at IST Austria”. It summarises the mandatory features, which need to be fulfilled to provide an institutional repository as a platform and also a service to the scientists at the institute. It also includes optional features, which would be of strong benefit for the scientists and would increase the usage of the repository, and hence the visibility of research at IST Austria.
AU - Porsche, Jana
ID - 5407
TI - Technical requirements and features
ER -
TY - CONF
AB - We consider the distributed synthesis problem for temporal logic specifications. Traditionally, the problem has been studied for LTL, and the previous results show that the problem is decidable iff there is no information fork in the architecture. We consider the problem for fragments of LTL and our main results are as follows: (1) We show that the problem is undecidable for architectures with information forks even for the fragment of LTL with temporal operators restricted to next and eventually. (2) For specifications restricted to globally along with non-nested next operators, we establish decidability (in EXPSPACE) for star architectures where the processes receive disjoint inputs, whereas we establish undecidability for architectures containing an information fork-meet structure. (3) Finally, we consider LTL without the next operator, and establish decidability (NEXPTIME-complete) for all architectures for a fragment that consists of a set of safety assumptions, and a set of guarantees where each guarantee is a safety, reachability, or liveness condition.
AU - Chatterjee, Krishnendu
AU - Henzinger, Thomas A
AU - Otop, Jan
AU - Pavlogiannis, Andreas
ID - 1376
T2 - 13th International Conference on Formal Methods in Computer-Aided Design
TI - Distributed synthesis for LTL fragments
ER -
TY - GEN
AB - The theory of graph games is the foundation for modeling and synthesizing reactive processes. In the synthesis of stochastic processes, we use 2-1/2-player games where some transitions of the game graph are controlled by two adversarial players, the System and the Environment, and the other transitions are determined probabilistically. We consider 2-1/2-player games where the objective of the System is the conjunction of a qualitative objective (specified as a parity condition) and a quantitative objective (specified as a mean-payoff condition). We establish that the problem of deciding whether the System can ensure that the probability to satisfy the mean-payoff parity objective is at least a given threshold is in NP ∩ coNP, matching the best known bound in the special case of 2-player games (where all transitions are deterministic) with only parity objectives, or with only mean-payoff objectives. We present an algorithm running
in time O(d · n^{2d}·MeanGame) to compute the set of almost-sure winning states from which the objective
can be ensured with probability 1, where n is the number of states of the game, d the number of priorities
of the parity objective, and MeanGame is the complexity to compute the set of almost-sure winning states
in 2-1/2-player mean-payoff games. Our results are useful in the synthesis of stochastic reactive systems
with both functional requirement (given as a qualitative objective) and performance requirement (given
as a quantitative objective).
AU - Chatterjee, Krishnendu
AU - Doyen, Laurent
AU - Gimbert, Hugo
AU - Oualhadj, Youssouf
ID - 5405
SN - 2664-1690
TI - Perfect-information stochastic mean-payoff parity games
ER -
TY - GEN
AB - We consider two-player partial-observation stochastic games where player 1 has partial observation and player 2 has perfect observation. The winning condition we study are omega-regular conditions specified as parity objectives. The qualitative analysis problem given a partial-observation stochastic game and a parity objective asks whether there is a strategy to ensure that the objective is satisfied with probability 1 (resp. positive probability). While the qualitative analysis problems are known to be undecidable even for very special cases of parity objectives, they were shown to be decidable in 2EXPTIME under finite-memory strategies. We improve the complexity and show that the qualitative analysis problems for partial-observation stochastic parity games under finite-memory strategies are
EXPTIME-complete; and also establish optimal (exponential) memory bounds for finite-memory strategies required for qualitative analysis.
AU - Chatterjee, Krishnendu
AU - Doyen, Laurent
AU - Nain, Sumit
AU - Vardi, Moshe
ID - 5408
SN - 2664-1690
TI - The complexity of partial-observation stochastic parity games with finite-memory strategies
ER -
TY - CONF
AB - We define the model-measuring problem: given a model M and specification φ, what is the maximal distance ρ such that all models M′ within distance ρ from M satisfy (or violate) φ. The model measuring problem presupposes a distance function on models. We concentrate on automatic distance functions, which are defined by weighted automata. The model-measuring problem subsumes several generalizations of the classical model-checking problem, in particular, quantitative model-checking problems that measure the degree of satisfaction of a specification, and robustness problems that measure how much a model can be perturbed without violating the specification. We show that for automatic distance functions, and ω-regular linear-time and branching-time specifications, the model-measuring problem can be solved. We use automata-theoretic model-checking methods for model measuring, replacing the emptiness question for standard word and tree automata by the optimal-weight question for the weighted versions of these automata. We consider weighted automata that accumulate weights by maximizing, summing, discounting, and limit averaging. We give several examples of using the model-measuring problem to compute various notions of robustness and quantitative satisfaction for temporal specifications.
AU - Henzinger, Thomas A
AU - Otop, Jan
ID - 2327
TI - From model checking to model measuring
VL - 8052
ER -
TY - CHAP
AU - Dragoi, Cezara
AU - Gupta, Ashutosh
AU - Henzinger, Thomas A
ID - 5747
SN - 0302-9743
T2 - Computer Aided Verification
TI - Automatic Linearizability Proofs of Concurrent Objects with Cooperating Updates
VL - 8044
ER -
TY - GEN
AB - In order to guarantee that each method of a data structure updates the logical state exactly once, al-most all non-blocking implementations employ Compare-And-Swap (CAS) based synchronization. For FIFO queue implementations this translates into concurrent enqueue or dequeue methods competing among themselves to update the same variable, the tail or the head, respectively, leading to high contention and poor scalability. Recent non-blocking queue implementations try to alleviate high contentionby increasing the number of contention points, all the while using CAS-based synchronization. Furthermore, obtaining a wait-free implementation with competition is achieved by additional synchronization which leads to further degradation of performance.In this paper we formalize the notion of competitiveness of a synchronizing statement which can beused as a measure for the scalability of concurrent implementations. We present a new queue implementation, the Speculative Pairing (SP) queue, which, as we show, decreases competitiveness by using Fetch-And-Increment (FAI) instead of CAS. We prove that the SP queue is linearizable and lock-free.We also show that replacing CAS with FAI leads to wait-freedom for dequeue methods without an adverse effect on performance. In fact, our experiments suggest that the SP queue can perform and scale better than the state-of-the-art queue implementations.
AU - Henzinger, Thomas A
AU - Payer, Hannes
AU - Sezgin, Ali
ID - 6440
SN - 2664-1690
TI - Replacing competition with cooperation to achieve scalable lock-free FIFO queues
ER -
TY - CONF
AB - Two-player games on graphs are central in many problems in formal verification and program analysis such as synthesis and verification of open systems. In this work, we consider both finite-state game graphs, and recursive game graphs (or pushdown game graphs) that model the control flow of sequential programs with recursion. The objectives we study are multidimensional mean-payoff objectives, where the goal of player 1 is to ensure that the mean-payoff is non-negative in all dimensions. In pushdown games two types of strategies are relevant: (1) global strategies, that depend on the entire global history; and (2) modular strategies, that have only local memory and thus do not depend on the context of invocation. Our main contributions are as follows: (1) We show that finite-state multidimensional mean-payoff games can be solved in polynomial time if the number of dimensions and the maximal absolute value of the weights are fixed; whereas if the number of dimensions is arbitrary, then the problem is known to be coNP-complete. (2) We show that pushdown graphs with multidimensional mean-payoff objectives can be solved in polynomial time. For both (1) and (2) our algorithms are based on hyperplane separation technique. (3) For pushdown games under global strategies both one and multidimensional mean-payoff objectives problems are known to be undecidable, and we show that under modular strategies the multidimensional problem is also undecidable; under modular strategies the one-dimensional problem is NP-complete. We show that if the number of modules, the number of exits, and the maximal absolute value of the weights are fixed, then pushdown games under modular strategies with one-dimensional mean-payoff objectives can be solved in polynomial time, and if either the number of exits or the number of modules is unbounded, then the problem is NP-hard. (4) Finally we show that a fixed parameter tractable algorithm for finite-state multidimensional mean-payoff games or pushdown games under modular strategies with one-dimensional mean-payoff objectives would imply the fixed parameter tractability of parity games.
AU - Chatterjee, Krishnendu
AU - Velner, Yaron
ID - 2329
TI - Hyperplane separation technique for multidimensional mean-payoff games
VL - 8052
ER -
TY - JOUR
AB - Background: Monoclonal antibodies (mAb), such as trastuzumab are a valuable addition to breast cancer therapy.
Data obtained from neoadjuvant settings revealed that antibody-dependent cell-mediated cytotoxicity (ADCC) is a
major mechanism of action for the mAb trastuzumab. Conflicting results still call into question whether disease
progression, prolonged treatment or concomitant chemotherapy influences ADCC and related immunological
phenomena.
Methods: We analyzed the activity of ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) of
peripheral blood mononuclear cells (PBMCs) from human epidermal growth factor receptor 2 (HER2/neu) positive
breast cancer patients receiving trastuzumab therapy either in an adjuvant (n = 13) or metastatic (n = 15) setting as
well as from trastuzumab treatment-naive (t-naive) HER2/neu negative patients (n = 15). PBMCs from healthy volunteers
(n = 24) were used as controls. ADCC and ADCP activity was correlated with the expression of antibody binding
Fc-gamma receptor (FcγR)I (CD64), FcγRII (CD32) and FcγRIII (CD16) on CD14+ (monocytes) and CD56+ (NK) cells, as well as the expression of CD107a+ (LAMP-1) on CD56+ cells and the total amount of CD4+CD25+FOXP3+ (Treg) cells. In metastatic patients, markers were correlated with progression-free survival (PFS).
Results: ADCC activity was significantly down regulated in metastatic, adjuvant and t-naive patient cohorts as compared to healthy controls. Reduced ADCC activity was inversely correlated with the expression of CD107a on CD56+
cells in adjuvant patients. ADCC and ADCP activity of the patient cohorts were similar, regardless of treatment duration
or additional chemotherapy. PFS in metastatic patients inversely correlated with the number of peripheral Treg cells.
Conclusion: The reduction of ADCC in patients as compared to healthy controls calls for adjuvant strategies, such as
immune-enhancing agents, to improve the activity of trastuzumab. However, efficacy of trastuzumab-specific ADCC
and ADCP appears not to be affected by treatment duration, disease progression or concomitant chemotherapy. This
finding supports the application of trastuzumab at any stage of the disease.
AU - Petricevic, Branka
AU - Laengle, Johannes
AU - Singer, Josef
AU - Sachet, Monika
AU - Fazekas, Judit
AU - Steger, Guenther
AU - Bartsch, Rupert
AU - Jensen-Jarolim, Erika
AU - Bergmann, Michael
ID - 8245
JF - Journal of Translational Medicine
SN - 1479-5876
TI - Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2/neu breast cancer patients
VL - 11
ER -
TY - JOUR
AB - The transition of proteins from their soluble functional state to amyloid fibrils and aggregates is associated with the onset of several human diseases. Protein aggregation often requires some structural reshaping and the subsequent formation of intermolecular contacts. Therefore, the study of the conformation of excited protein states and their ability to form oligomers is of primary importance for understanding the molecular basis of amyloid fibril formation. Here, we investigated the oligomerization processes that occur along the folding of the amyloidogenic human protein β2-microglobulin. The combination of real-time two-dimensional NMR data with real-time small-angle X-ray scattering measurements allowed us to derive thermodynamic and kinetic information on protein oligomerization of different conformational states populated along the folding pathways. In particular, we could demonstrate that a long-lived folding intermediate (I-state) has a higher propensity to oligomerize compared to the native state. Our data agree well with a simple five-state kinetic model that involves only monomeric and dimeric species. The dimers have an elongated shape with the dimerization interface located at the apical side of β2-microglobulin close to Pro32, the residue that has a trans conformation in the I-state and a cis conformation in the native (N) state. Our experimental data suggest that partial unfolding in the apical half of the protein close to Pro32 leads to an excited state conformation with enhanced propensity for oligomerization. This excited state becomes more populated in the transient I-state due to the destabilization of the native conformation by the trans-Pro32 configuration.
AU - Rennella, E.
AU - Cutuil, T.
AU - Schanda, Paul
AU - Ayala, I.
AU - Gabel, F.
AU - Forge, V.
AU - Corazza, A.
AU - Esposito, G.
AU - Brutscher, B.
ID - 8462
IS - 15
JF - Journal of Molecular Biology
KW - Molecular Biology
SN - 0022-2836
TI - Oligomeric states along the folding pathways of β2-microglobulin: Kinetics, thermodynamics, and structure
VL - 425
ER -
TY - JOUR
AB - To fight infectious diseases, host immune defenses are employed at multiple levels. Sanitary behavior, such as pathogen avoidance and removal, acts as a first line of defense to prevent infection [1] before activation of the physiological immune system. Insect societies have evolved a wide range of collective hygiene measures and intensive health care toward pathogen-exposed group members [2]. One of the most common behaviors is allogrooming, in which nestmates remove infectious particles from the body surfaces of exposed individuals [3]. Here we show that, in invasive garden ants, grooming of fungus-exposed brood is effective beyond the sheer mechanical removal of fungal conidiospores; it also includes chemical disinfection through the application of poison produced by the ants themselves. Formic acid is the main active component of the poison. It inhibits fungal growth of conidiospores remaining on the brood surface after grooming and also those collected in the mouth of the grooming ant. This dual function is achieved by uptake of the poison droplet into the mouth through acidopore self-grooming and subsequent application onto the infectious brood via brood grooming. This extraordinary behavior extends the current understanding of grooming and the establishment of social immunity in insect societies.
AU - Tragust, Simon
AU - Mitteregger, Barbara
AU - Barone, Vanessa
AU - Konrad, Matthias
AU - Ugelvig, Line V
AU - Cremer, Sylvia
ID - 2926
IS - 1
JF - Current Biology
TI - Ants disinfect fungus-exposed brood by oral uptake and spread of their poison
VL - 23
ER -
TY - CONF
AB - In this paper, we introduce the powerful framework of graph games for the analysis of real-time scheduling with firm deadlines. We introduce a novel instance of a partial-observation game that is suitable for this purpose, and prove decidability of all the involved decision problems. We derive a graph game that allows the automated computation of the competitive ratio (along with an optimal witness algorithm for the competitive ratio) and establish an NP-completeness proof for the graph game problem. For a given on-line algorithm, we present polynomial time solution for computing (i) the worst-case utility; (ii) the worst-case utility ratio w.r.t. a clairvoyant off-line algorithm; and (iii) the competitive ratio. A major strength of the proposed approach lies in its flexibility w.r.t. incorporating additional constraints on the adversary and/or the algorithm, including limited maximum or average load, finiteness of periods of overload, etc., which are easily added by means of additional instances of standard objective functions for graph games.
AU - Chatterjee, Krishnendu
AU - Kößler, Alexander
AU - Schmid, Ulrich
ID - 2820
SN - 978-1-4503-1567-8
T2 - Proceedings of the 16th International conference on Hybrid systems: Computation and control
TI - Automated analysis of real-time scheduling using graph games
ER -
TY - JOUR
AB - As sessile organisms, plants have to be able to adapt to a continuously changing environment. Plants that perceive some of these changes as stress signals activate signaling pathways to modulate their development and to enable them to survive. The complex responses to environmental cues are to a large extent mediated by plant hormones that together orchestrate the final plant response. The phytohormone cytokinin is involved in many plant developmental processes. Recently, it has been established that cytokinin plays an important role in stress responses, but does not act alone. Indeed, the hormonal control of plant development and stress adaptation is the outcome of a complex network of multiple synergistic and antagonistic interactions between various hormones. Here, we review the recent findings on the cytokinin function as part of this hormonal network. We focus on the importance of the crosstalk between cytokinin and other hormones, such as abscisic acid, jasmonate, salicylic acid, ethylene, and auxin in the modulation of plant development and stress adaptation. Finally, the impact of the current research in the biotechnological industry will be discussed.
AU - O'Brien, José
AU - Benková, Eva
ID - 827
JF - Frontiers in Plant Science
TI - Cytokinin cross talking during biotic and abiotic stress responses
VL - 4
ER -
TY - JOUR
AB - The plant root system is essential for providing anchorage to the soil, supplying minerals and water, and synthesizing metabolites. It is a dynamic organ modulated by external cues such as environmental signals, water and nutrients availability, salinity and others. Lateral roots (LRs) are initiated from the primary root post-embryonically, after which they progress through discrete developmental stages which can be independently controlled, providing a high level of plasticity during root system formation. Within this review, main contributions are presented, from the classical forward genetic screens to the more recent high-throughput approaches, combined with computer model predictions, dissecting how LRs and thereby root system architecture is established and developed.
AU - Cuesta, Candela
AU - Wabnik, Krzysztof T
AU - Benková, Eva
ID - 828
JF - Frontiers in Plant Science
TI - Systems approaches to study root architecture dynamics
VL - 4
ER -
TY - CONF
AB - Software model checking, as an undecidable problem, has three possible outcomes: (1) the program satisfies the specification, (2) the program does not satisfy the specification, and (3) the model checker fails. The third outcome usually manifests itself in a space-out, time-out, or one component of the verification tool giving up; in all of these failing cases, significant computation is performed by the verification tool before the failure, but no result is reported. We propose to reformulate the model-checking problem as follows, in order to have the verification tool report a summary of the performed work even in case of failure: given a program and a specification, the model checker returns a condition Ψ - usually a state predicate - such that the program satisfies the specification under the condition Ψ - that is, as long as the program does not leave the states in which Ψ is satisfied. In our experiments, we investigated as one major application of conditional model checking the sequential combination of model checkers with information passing. We give the condition that one model checker produces, as input to a second conditional model checker, such that the verification problem for the second is restricted to the part of the state space that is not covered by the condition, i.e., the second model checker works on the problems that the first model checker could not solve. Our experiments demonstrate that repeated application of conditional model checkers, passing information from one model checker to the next, can significantly improve the verification results and performance, i.e., we can now verify programs that we could not verify before.
AU - Beyer, Dirk
AU - Henzinger, Thomas A
AU - Keremoglu, Mehmet
AU - Wendler, Philipp
ID - 1384
T2 - Proceedings of the ACM SIGSOFT 20th International Symposium on the Foundations of Software Engineering
TI - Conditional model checking: A technique to pass information between verifiers
ER -
TY - CONF
AB - Leakage resilient cryptography attempts to incorporate side-channel leakage into the black-box security model and designs cryptographic schemes that are provably secure within it. Informally, a scheme is leakage-resilient if it remains secure even if an adversary learns a bounded amount of arbitrary information about the schemes internal state. Unfortunately, most leakage resilient schemes are unnecessarily complicated in order to achieve strong provable security guarantees. As advocated by Yu et al. [CCS’10], this mostly is an artefact of the security proof and in practice much simpler construction may already suffice to protect against realistic side-channel attacks. In this paper, we show that indeed for simpler constructions leakage-resilience can be obtained when we aim for relaxed security notions where the leakage-functions and/or the inputs to the primitive are chosen non-adaptively. For example, we show that a three round Feistel network instantiated with a leakage resilient PRF yields a leakage resilient PRP if the inputs are chosen non-adaptively (This complements the result of Dodis and Pietrzak [CRYPTO’10] who show that if a adaptive queries are allowed, a superlogarithmic number of rounds is necessary.) We also show that a minor variation of the classical GGM construction gives a leakage resilient PRF if both, the leakage-function and the inputs, are chosen non-adaptively.
AU - Faust, Sebastian
AU - Pietrzak, Krzysztof Z
AU - Schipper, Joachim
ID - 2048
T2 - Conference proceedings CHES 2012
TI - Practical leakage-resilient symmetric cryptography
VL - 7428
ER -
TY - CONF
AB - We propose a new authentication protocol that is provably secure based on a ring variant of the learning parity with noise (LPN) problem. The protocol follows the design principle of the LPN-based protocol from Eurocrypt’11 (Kiltz et al.), and like it, is a two round protocol secure against active attacks. Moreover, our protocol has small communication complexity and a very small footprint which makes it applicable in scenarios that involve low-cost, resource-constrained devices.
Performance-wise, our protocol is more efficient than previous LPN-based schemes, such as the many variants of the Hopper-Blum (HB) protocol and the aforementioned protocol from Eurocrypt’11. Our implementation results show that it is even comparable to the standard challenge-and-response protocols based on the AES block-cipher. Our basic protocol is roughly 20 times slower than AES, but with the advantage of having 10 times smaller code size. Furthermore, if a few hundred bytes of non-volatile memory are available to allow the storage of some off-line pre-computations, then the online phase of our protocols is only twice as slow as AES.
AU - Heyse, Stefan
AU - Kiltz, Eike
AU - Lyubashevsky, Vadim
AU - Paar, Christof
AU - Pietrzak, Krzysztof Z
ID - 2049
T2 - Conference proceedings FSE 2012
TI - Lapin: An efficient authentication protocol based on ring-LPN
VL - 7549
ER -
TY - JOUR
AB - Nestin-cre transgenic mice have been widely used to direct recombination to neural stem cells (NSCs) and intermediate neural progenitor cells (NPCs). Here we report that a readily utilized, and the only commercially available, Nestin-cre line is insufficient for directing recombination in early embryonic NSCs and NPCs. Analysis of recombination efficiency in multiple cre-dependent reporters and a genetic mosaic line revealed consistent temporal and spatial patterns of recombination in NSCs and NPCs. For comparison we utilized a knock-in Emx1cre line and found robust recombination in NSCs and NPCs in ventricular and subventricular zones of the cerebral cortices as early as embryonic day 12.5. In addition we found that the rate of Nestin-cre driven recombination only reaches sufficiently high levels in NSCs and NPCs during late embryonic and early postnatal periods. These findings are important when commercially available cre lines are considered for directing recombination to embryonic NSCs and NPCs.
AU - Liang, Huixuan
AU - Hippenmeyer, Simon
AU - Ghashghaei, H.
ID - 2263
IS - 12
JF - Biology open
TI - A Nestin-cre transgenic mouse is insufficient for recombination in early embryonic neural progenitors
VL - 1
ER -
TY - JOUR
AB - We introduce propagation models (PMs), a formalism able to express several kinds of equations that describe the behavior of biochemical reaction networks. Furthermore, we introduce the propagation abstract data type (PADT), which separates concerns regarding different numerical algorithms for the transient analysis of biochemical reaction networks from concerns regarding their implementation, thus allowing for portable and efficient solutions. The state of a propagation abstract data type is given by a vector that assigns mass values to a set of nodes, and its (next) operator propagates mass values through this set of nodes. We propose an approximate implementation of the (next) operator, based on threshold abstraction, which propagates only "significant" mass values and thus achieves a compromise between efficiency and accuracy. Finally, we give three use cases for propagation models: the chemical master equation (CME), the reaction rate equation (RRE), and a hybrid method that combines these two equations. These three applications use propagation models in order to propagate probabilities and/or expected values and variances of the model's variables.
AU - Henzinger, Thomas A
AU - Mateescu, Maria
ID - 2302
IS - 2
JF - IEEE ACM Transactions on Computational Biology and Bioinformatics
TI - The propagation approach for computing biochemical reaction networks
VL - 10
ER -
TY - JOUR
AB - The kingdom of fungi provides model organisms for biotechnology, cell biology, genetics, and life sciences in general. Only when their phylogenetic relationships are stably resolved, can individual results from fungal research be integrated into a holistic picture of biology. However, and despite recent progress, many deep relationships within the fungi remain unclear. Here, we present the first phylogenomic study of an entire eukaryotic kingdom that uses a consistency criterion to strengthen phylogenetic conclusions. We reason that branches (splits) recovered with independent data and different tree reconstruction methods are likely to reflect true evolutionary relationships. Two complementary phylogenomic data sets based on 99 fungal genomes and 109 fungal expressed sequence tag (EST) sets analyzed with four different tree reconstruction methods shed light from different angles on the fungal tree of life. Eleven additional data sets address specifically the phylogenetic position of Blastocladiomycota, Ustilaginomycotina, and Dothideomycetes, respectively. The combined evidence from the resulting trees supports the deep-level stability of the fungal groups toward a comprehensive natural system of the fungi. In addition, our analysis reveals methodologically interesting aspects. Enrichment for EST encoded data-a common practice in phylogenomic analyses-introduces a strong bias toward slowly evolving and functionally correlated genes. Consequently, the generalization of phylogenomic data sets as collections of randomly selected genes cannot be taken for granted. A thorough characterization of the data to assess possible influences on the tree reconstruction should therefore become a standard in phylogenomic analyses.
AU - Ebersberger, Ingo
AU - De Matos Simoes, Ricardo
AU - Kupczok, Anne
AU - Gube, Matthias
AU - Kothe, Erika
AU - Voigt, Kerstin
AU - Von Haeseler, Arndt
ID - 2411
IS - 5
JF - Molecular Biology and Evolution
TI - A consistent phylogenetic backbone for the fungi
VL - 29
ER -
TY - JOUR
AB - We show that bosons interacting via pair potentials with negative scattering length form bound states for a suitable number of particles. In other words, the absence of many-particle bound states of any kind implies the non-negativity of the scattering length of the interaction potential.
AU - Seiringer, Robert
ID - 2318
IS - 3
JF - Journal of Spectral Theory
TI - Absence of bound states implies non-negativity of the scattering length
VL - 2
ER -
TY - CONF
AB - We consider Markov decision processes (MDPs) with specifications given as Büchi (liveness) objectives. We consider the problem of computing the set of almost-sure winning vertices from where the objective can be ensured with probability 1. We study for the first time the average case complexity of the classical algorithm for computing the set of almost-sure winning vertices for MDPs with Büchi objectives. Our contributions are as follows: First, we show that for MDPs with constant out-degree the expected number of iterations is at most logarithmic and the average case running time is linear (as compared to the worst case linear number of iterations and quadratic time complexity). Second, for the average case analysis over all MDPs we show that the expected number of iterations is constant and the average case running time is linear (again as compared to the worst case linear number of iterations and quadratic time complexity). Finally we also show that given that all MDPs are equally likely, the probability that the classical algorithm requires more than constant number of iterations is exponentially small.
AU - Chatterjee, Krishnendu
AU - Joglekar, Manas
AU - Shah, Nisarg
ID - 2715
TI - Average case analysis of the classical algorithm for Markov decision processes with Büchi objectives
VL - 18
ER -
TY - CONF
AB - We study the problem of maximum marginal prediction (MMP) in probabilistic graphical models, a task that occurs, for example, as the Bayes optimal decision rule under a Hamming loss. MMP is typically performed as a two-stage procedure: one estimates each variable's marginal probability and then forms a prediction from the states of maximal probability. In this work we propose a simple yet effective technique for accelerating MMP when inference is sampling-based: instead of the above two-stage procedure we directly estimate the posterior probability of each decision variable. This allows us to identify the point of time when we are sufficiently certain about any individual decision. Whenever this is the case, we dynamically prune the variables we are confident about from the underlying factor graph. Consequently, at any time only samples of variables whose decision is still uncertain need to be created. Experiments in two prototypical scenarios, multi-label classification and image inpainting, show that adaptive sampling can drastically accelerate MMP without sacrificing prediction accuracy.
AU - Lampert, Christoph
ID - 2825
TI - Dynamic pruning of factor graphs for maximum marginal prediction
VL - 1
ER -
TY - JOUR
AB - We study evolutionary game theory in a setting where individuals learn from each other. We extend the traditional approach by assuming that a population contains individuals with different learning abilities. In particular, we explore the situation where individuals have different search spaces, when attempting to learn the strategies of others. The search space of an individual specifies the set of strategies learnable by that individual. The search space is genetically given and does not change under social evolutionary dynamics. We introduce a general framework and study a specific example in the context of direct reciprocity. For this example, we obtain the counter intuitive result that cooperation can only evolve for intermediate benefit-to-cost ratios, while small and large benefit-to-cost ratios favor defection. Our paper is a step toward making a connection between computational learning theory and evolutionary game dynamics.
AU - Chatterjee, Krishnendu
AU - Zufferey, Damien
AU - Nowak, Martin
ID - 2848
JF - Journal of Theoretical Biology
TI - Evolutionary game dynamics in populations with different learners
VL - 301
ER -