TY - CONF AB - In classical machine learning, regression is treated as a black box process of identifying a suitable function from a hypothesis set without attempting to gain insight into the mechanism connecting inputs and outputs. In the natural sciences, however, finding an interpretable function for a phenomenon is the prime goal as it allows to understand and generalize results. This paper proposes a novel type of function learning network, called equation learner (EQL), that can learn analytical expressions and is able to extrapolate to unseen domains. It is implemented as an end-to-end differentiable feed-forward network and allows for efficient gradient based training. Due to sparsity regularization concise interpretable expressions can be obtained. Often the true underlying source expression is identified. AU - Martius, Georg S AU - Lampert, Christoph ID - 6841 T2 - 5th International Conference on Learning Representations, ICLR 2017 - Workshop Track Proceedings TI - Extrapolation and learning equations ER - TY - JOUR AB - We generalize winning conditions in two-player games by adding a structural acceptance condition called obligations. Obligations are orthogonal to the linear winning conditions that define whether a play is winning. Obligations are a declaration that player 0 can achieve a certain value from a configuration. If the obligation is met, the value of that configuration for player 0 is 1. We define the value in such games and show that obligation games are determined. For Markov chains with Borel objectives and obligations, and finite turn-based stochastic parity games with obligations we give an alternative and simpler characterization of the value function. Based on this simpler definition we show that the decision problem of winning finite turn-based stochastic parity games with obligations is in NP∩co-NP. We also show that obligation games provide a game framework for reasoning about p-automata. © 2017 The Association for Symbolic Logic. AU - Chatterjee, Krishnendu AU - Piterman, Nir ID - 684 IS - 2 JF - Journal of Symbolic Logic SN - 0022-4812 TI - Obligation blackwell games and p-automata VL - 82 ER - TY - JOUR AB - By applying methods and principles from the physical sciences to biological problems, D'Arcy Thompson's On Growth and Form demonstrated how mathematical reasoning reveals elegant, simple explanations for seemingly complex processes. This has had a profound influence on subsequent generations of developmental biologists. We discuss how this influence can be traced through twentieth century morphologists, embryologists and theoreticians to current research that explores the molecular and cellular mechanisms of tissue growth and patterning, including our own studies of the vertebrate neural tube. AU - Briscoe, James AU - Kicheva, Anna ID - 685 JF - Mechanisms of Development SN - 09254773 TI - The physics of development 100 years after D'Arcy Thompson's “on growth and form” VL - 145 ER - TY - CONF AB - We show that the framework of topological data analysis can be extended from metrics to general Bregman divergences, widening the scope of possible applications. Examples are the Kullback - Leibler divergence, which is commonly used for comparing text and images, and the Itakura - Saito divergence, popular for speech and sound. In particular, we prove that appropriately generalized čech and Delaunay (alpha) complexes capture the correct homotopy type, namely that of the corresponding union of Bregman balls. Consequently, their filtrations give the correct persistence diagram, namely the one generated by the uniformly growing Bregman balls. Moreover, we show that unlike the metric setting, the filtration of Vietoris-Rips complexes may fail to approximate the persistence diagram. We propose algorithms to compute the thus generalized čech, Vietoris-Rips and Delaunay complexes and experimentally test their efficiency. Lastly, we explain their surprisingly good performance by making a connection with discrete Morse theory. AU - Edelsbrunner, Herbert AU - Wagner, Hubert ID - 688 SN - 18688969 TI - Topological data analysis with Bregman divergences VL - 77 ER - TY - JOUR AB - Pursuing the similarity between the Kontsevich-Soibelman construction of the cohomological Hall algebra (CoHA) of BPS states and Lusztig's construction of canonical bases for quantum enveloping algebras, and the similarity between the integrality conjecture for motivic Donaldson-Thomas invariants and the PBW theorem for quantum enveloping algebras, we build a coproduct on the CoHA associated to a quiver with potential. We also prove a cohomological dimensional reduction theorem, further linking a special class of CoHAs with Yangians, and explaining how to connect the study of character varieties with the study of CoHAs. AU - Davison, Ben ID - 687 IS - 2 JF - Quarterly Journal of Mathematics SN - 00335606 TI - The critical CoHA of a quiver with potential VL - 68 ER - TY - JOUR AB - Tissues are thought to behave like fluids with a given surface tension. Differences in tissue surface tension (TST) have been proposed to trigger cell sorting and tissue envelopment. D'Arcy Thompson in his seminal book ‘On Growth and Form’ has introduced this concept of differential TST as a key physical mechanism dictating tissue formation and organization within the developing organism. Over the past century, many studies have picked up the concept of differential TST and analyzed the role and cell biological basis of TST in development, underlining the importance and influence of this concept in developmental biology. AU - Heisenberg, Carl-Philipp J ID - 686 JF - Mechanisms of Development SN - 09254773 TI - D'Arcy Thompson's ‘on growth and form’: From soap bubbles to tissue self organization VL - 145 ER - TY - JOUR AB - Rett syndrome modeling in monkey mirrors the human disorder. AU - Novarino, Gaia ID - 689 IS - 393 JF - Science Translational Medicine SN - 19466234 TI - Rett syndrome modeling goes simian VL - 9 ER - TY - JOUR AB - Many central synapses contain a single presynaptic active zone and a single postsynaptic density. Vesicular release statistics at such “simple synapses” indicate that they contain a small complement of docking sites where vesicles repetitively dock and fuse. In this work, we investigate functional and morphological aspects of docking sites at simple synapses made between cerebellar parallel fibers and molecular layer interneurons. Using immunogold labeling of SDS-treated freeze-fracture replicas, we find that Cav2.1 channels form several clusters per active zone with about nine channels per cluster. The mean value and range of intersynaptic variation are similar for Cav2.1 cluster numbers and for functional estimates of docking-site numbers obtained from the maximum numbers of released vesicles per action potential. Both numbers grow in relation with synaptic size and decrease by a similar extent with age between 2 wk and 4 wk postnatal. Thus, the mean docking-site numbers were 3.15 at 2 wk (range: 1–10) and 2.03 at 4 wk (range: 1–4), whereas the mean numbers of Cav2.1 clusters were 2.84 at 2 wk (range: 1–8) and 2.37 at 4 wk (range: 1–5). These changes were accompanied by decreases of miniature current amplitude (from 93 pA to 56 pA), active-zone surface area (from 0.0427 μm2 to 0.0234 μm2), and initial success rate (from 0.609 to 0.353), indicating a tightening of synaptic transmission with development. Altogether, these results suggest a close correspondence between the number of functionally defined vesicular docking sites and that of clusters of voltage-gated calcium channels. AU - Miki, Takafumi AU - Kaufmann, Walter AU - Malagon, Gerardo AU - Gomez, Laura AU - Tabuchi, Katsuhiko AU - Watanabe, Masahiko AU - Shigemoto, Ryuichi AU - Marty, Alain ID - 693 IS - 26 JF - PNAS SN - 00278424 TI - Numbers of presynaptic Ca2+ channel clusters match those of functionally defined vesicular docking sites in single central synapses VL - 114 ER - TY - JOUR AB - A change regarding the extent of adhesion - hereafter referred to as adhesion plasticity - between adhesive and less-adhesive states of mammalian cells is important for their behavior. To investigate adhesion plasticity, we have selected a stable isogenic subpopulation of human MDA-MB-468 breast carcinoma cells growing in suspension. These suspension cells are unable to re-adhere to various matrices or to contract three-dimensional collagen lattices. By using transcriptome analysis, we identified the focal adhesion protein tensin3 (Tns3) as a determinant of adhesion plasticity. Tns3 is strongly reduced at mRNA and protein levels in suspension cells. Furthermore, by transiently challenging breast cancer cells to grow under non-adherent conditions markedly reduces Tns3 protein expression, which is regained upon re-adhesion. Stable knockdown of Tns3 in parental MDA-MB-468 cells results in defective adhesion, spreading and migration. Tns3-knockdown cells display impaired structure and dynamics of focal adhesion complexes as determined by immunostaining. Restoration of Tns3 protein expression in suspension cells partially rescues adhesion and focal contact composition. Our work identifies Tns3 as a crucial focal adhesion component regulated by, and functionally contributing to, the switch between adhesive and non-adhesive states in MDA-MB-468 cancer cells. AU - Veß, Astrid AU - Blache, Ulrich AU - Leitner, Laura AU - Kurz, Angela AU - Ehrenpfordt, Anja AU - Sixt, Michael K AU - Posern, Guido ID - 694 IS - 13 JF - Journal of Cell Science SN - 00219533 TI - A dual phenotype of MDA MB 468 cancer cells reveals mutual regulation of tensin3 and adhesion plasticity VL - 130 ER - TY - CONF AB - De, Trevisan and Tulsiani [CRYPTO 2010] show that every distribution over n-bit strings which has constant statistical distance to uniform (e.g., the output of a pseudorandom generator mapping n-1 to n bit strings), can be distinguished from the uniform distribution with advantage epsilon by a circuit of size O( 2^n epsilon^2). We generalize this result, showing that a distribution which has less than k bits of min-entropy, can be distinguished from any distribution with k bits of delta-smooth min-entropy with advantage epsilon by a circuit of size O(2^k epsilon^2/delta^2). As a special case, this implies that any distribution with support at most 2^k (e.g., the output of a pseudoentropy generator mapping k to n bit strings) can be distinguished from any given distribution with min-entropy k+1 with advantage epsilon by a circuit of size O(2^k epsilon^2). Our result thus shows that pseudoentropy distributions face basically the same non-uniform attacks as pseudorandom distributions. AU - Pietrzak, Krzysztof Z AU - Skórski, Maciej ID - 697 SN - 18688969 TI - Non uniform attacks against pseudoentropy VL - 80 ER - TY - JOUR AB - Extracellular matrix signals from the microenvironment regulate gene expression patterns and cell behavior. Using a combination of experiments and geometric models, we demonstrate correlations between cell geometry, three-dimensional (3D) organization of chromosome territories, and gene expression. Fluorescence in situ hybridization experiments showed that micropatterned fibroblasts cultured on anisotropic versus isotropic substrates resulted in repositioning of specific chromosomes, which contained genes that were differentially regulated by cell geometries. Experiments combined with ellipsoid packing models revealed that the mechanosensitivity of chromosomes was correlated with their orientation in the nucleus. Transcription inhibition experiments suggested that the intermingling degree was more sensitive to global changes in transcription than to chromosome radial positioning and its orientations. These results suggested that cell geometry modulated 3D chromosome arrangement, and their neighborhoods correlated with gene expression patterns in a predictable manner. This is central to understanding geometric control of genetic programs involved in cellular homeostasis and the associated diseases. AU - Wang, Yejun AU - Nagarajan, Mallika AU - Uhler, Caroline AU - Shivashankar, Gv ID - 698 IS - 14 JF - Molecular Biology of the Cell SN - 10591524 TI - Orientation and repositioning of chromosomes correlate with cell geometry dependent gene expression VL - 28 ER - TY - JOUR AB - In antagonistic symbioses, such as host–parasite interactions, one population’s success is the other’s loss. In mutualistic symbioses, such as division of labor, both parties can gain, but they might have different preferences over the possible mutualistic arrangements. The rates of evolution of the two populations in a symbiosis are important determinants of which population will be more successful: Faster evolution is thought to be favored in antagonistic symbioses (the “Red Queen effect”), but disfavored in certain mutualistic symbioses (the “Red King effect”). However, it remains unclear which biological parameters drive these effects. Here, we analyze the effects of the various determinants of evolutionary rate: generation time, mutation rate, population size, and the intensity of natural selection. Our main results hold for the case where mutation is infrequent. Slower evolution causes a long-term advantage in an important class of mutualistic interactions. Surprisingly, less intense selection is the strongest driver of this Red King effect, whereas relative mutation rates and generation times have little effect. In antagonistic interactions, faster evolution by any means is beneficial. Our results provide insight into the demographic evolution of symbionts. AU - Veller, Carl AU - Hayward, Laura AU - Nowak, Martin AU - Hilbe, Christian ID - 699 IS - 27 JF - PNAS SN - 00278424 TI - The red queen and king in finite populations VL - 114 ER - TY - JOUR AB - Microtubules provide the mechanical force required for chromosome separation during mitosis. However, little is known about the dynamic (high-frequency) mechanical properties of microtubules. Here, we theoretically propose to control the vibrations of a doubly clamped microtubule by tip electrodes and to detect its motion via the optomechanical coupling between the vibrational modes of the microtubule and an optical cavity. In the presence of a red-detuned strong pump laser, this coupling leads to optomechanical-induced transparency of an optical probe field, which can be detected with state-of-the art technology. The center frequency and line width of the transparency peak give the resonance frequency and damping rate of the microtubule, respectively, while the height of the peak reveals information about the microtubule-cavity field coupling. Our method opens the new possibilities to gain information about the physical properties of microtubules, which will enhance our capability to design physical cancer treatment protocols as alternatives to chemotherapeutic drugs. AU - Barzanjeh, Shabir AU - Salari, Vahid AU - Tuszynski, Jack AU - Cifra, Michal AU - Simon, Christoph ID - 700 IS - 1 JF - Physical Review E Statistical Nonlinear and Soft Matter Physics SN - 24700045 TI - Optomechanical proposal for monitoring microtubule mechanical vibrations VL - 96 ER - TY - JOUR AB - A d-dimensional simplex S is called a k-reptile (or a k-reptile simplex) if it can be tiled by k simplices with disjoint interiors that are all mutually congruent and similar to S. For d = 2, triangular k-reptiles exist for all k of the form a^2, 3a^2 or a^2+b^2 and they have been completely characterized by Snover, Waiveris, and Williams. On the other hand, the only k-reptile simplices that are known for d ≥ 3, have k = m^d, where m is a positive integer. We substantially simplify the proof by Matoušek and the second author that for d = 3, k-reptile tetrahedra can exist only for k = m^3. We then prove a weaker analogue of this result for d = 4 by showing that four-dimensional k-reptile simplices can exist only for k = m^2. AU - Kynčl, Jan AU - Patakova, Zuzana ID - 701 IS - 3 JF - The Electronic Journal of Combinatorics SN - 10778926 TI - On the nonexistence of k reptile simplices in ℝ^3 and ℝ^4 VL - 24 ER - TY - JOUR AB - Leading autism-associated mutation in mouse partially mimics human disorder. AU - Novarino, Gaia ID - 702 IS - 399 JF - Science Translational Medicine SN - 19466234 TI - The riddle of CHD8 haploinsufficiency in autism spectrum disorder VL - 9 ER - TY - JOUR AB - A hippocampal mossy fiber synapse has a complex structure and is implicated in learning and memory. In this synapse, the mossy fiber boutons attach to the dendritic shaft by puncta adherentia junctions and wrap around a multiply-branched spine, forming synaptic junctions. We have recently shown using transmission electron microscopy, immunoelectron microscopy and serial block face-scanning electron microscopy that atypical puncta adherentia junctions are formed in the afadin-deficient mossy fiber synapse and that the complexity of postsynaptic spines and mossy fiber boutons, the number of spine heads, the area of postsynaptic densities and the density of synaptic vesicles docked to active zones are decreased in the afadin-deficient synapse. We investigated here the roles of afadin in the functional differentiations of the mossy fiber synapse using the afadin-deficient mice. The electrophysiological studies showed that both the release probability of glutamate and the postsynaptic responsiveness to glutamate were markedly reduced, but not completely lost, in the afadin-deficient mossy fiber synapse, whereas neither long-term potentiation nor long-term depression was affected. These results indicate that afadin plays roles in the functional differentiations of the presynapse and the postsynapse of the hippocampal mossy fiber synapse. AU - Geng, Xiaoqi AU - Maruo, Tomohiko AU - Mandai, Kenji AU - Supriyanto, Irwan AU - Miyata, Muneaki AU - Sakakibara, Shotaro AU - Mizoguchi, Akira AU - Takai, Yoshimi AU - Mori, Masahiro ID - 706 IS - 8 JF - Genes to Cells SN - 13569597 TI - Roles of afadin in functional differentiations of hippocampal mossy fiber synapse VL - 22 ER - TY - JOUR AB - We answer a question of M. Gromov on the waist of the unit ball. AU - Akopyan, Arseniy AU - Karasev, Roman ID - 707 IS - 4 JF - Bulletin of the London Mathematical Society SN - 00246093 TI - A tight estimate for the waist of the ball VL - 49 ER - TY - JOUR AB - In the developing and adult brain, oligodendrocyte precursor cells (OPCs) are influenced by neuronal activity: they are involved in synaptic signaling with neurons, and their proliferation and differentiation into myelinating glia can be altered by transient changes in neuronal firing. An important question that has been unanswered is whether OPCs can discriminate different patterns of neuronal activity and respond to them in a distinct way. Here, we demonstrate in brain slices that the pattern of neuronal activity determines the functional changes triggered at synapses between axons and OPCs. Furthermore, we show that stimulation of the corpus callosum at different frequencies in vivo affects proliferation and differentiation of OPCs in a dissimilar way. Our findings suggest that neurons do not influence OPCs in “all-or-none” fashion but use their firing pattern to tune the response and behavior of these nonneuronal cells. AU - Nagy, Balint AU - Hovhannisyan, Anahit AU - Barzan, Ruxandra AU - Chen, Ting AU - Kukley, Maria ID - 708 IS - 8 JF - PLoS Biology SN - 15449173 TI - Different patterns of neuronal activity trigger distinct responses of oligodendrocyte precursor cells in the corpus callosum VL - 15 ER - TY - JOUR AB - Adipose tissues play key roles in energy homeostasis. Brown adipocytes and beige adipocytes in white adipose tissue (WAT) share the similar characters of thermogenesis, both of them could be potential targets for obesity management. Several thermo-sensitive transient receptor potential channels (thermoTRPs) are shown to be involved in adipocyte biology. However, the expression pattern of thermoTRPs in adipose tissues from obese mice is still unknown. The mRNA expression of thermoTRPs in subcutaneous WAT (sWAT) and interscapular brown adipose tissue (iBAT) from lean and obese mice were measured using reverse transcriptase-quantitative PCRs (RT-qPCR). The results demonstrated that all 10 thermoTRPs are expressed in both iBAT and sWAT, and without significant difference in the mRNA expression level of thermoTRPs between these two tissues. Moreover, Trpv1 and Trpv3 mRNA expression levels in both iBAT and sWAT were significantly decreased in high fat diet (HFD)-induced obese mice and db/db (leptin receptor deficient) mice. Trpm2 mRNA expression level was significantly decreased only in sWAT from HFD-induced obese mice and db/db mice. On the other hand, Trpv2 and Trpv4 mRNA expression levels in iBAT and sWAT were significantly increased in HFD-induced obese mice and db/db mice. Taken together, we conclude that all 10 thermoTRPs are expressed in iBAT and sWAT. And several thermoTRPs differentially expressed in adipose tissues from HFD-induced obese mice and db/db mice, suggesting a potential involvement in anti-obesity regulations. AU - Sun, Wuping AU - Li, Chen AU - Zhang, Yonghong AU - Jiang, Changyu AU - Zhai, Ming-Zhu AU - Zhou, Qian AU - Xiao, Lizu AU - Deng, Qiwen ID - 709 IS - 8 JF - Cell Biology International SN - 10656995 TI - Gene expression changes of thermo sensitive transient receptor potential channels in obese mice VL - 41 ER - TY - CONF AB - We revisit the problem of estimating entropy of discrete distributions from independent samples, studied recently by Acharya, Orlitsky, Suresh and Tyagi (SODA 2015), improving their upper and lower bounds on the necessary sample size n. For estimating Renyi entropy of order alpha, up to constant accuracy and error probability, we show the following * Upper bounds n = O(1) 2^{(1-1/alpha)H_alpha} for integer alpha>1, as the worst case over distributions with Renyi entropy equal to H_alpha. * Lower bounds n = Omega(1) K^{1-1/alpha} for any real alpha>1, with the constant being an inverse polynomial of the accuracy, as the worst case over all distributions on K elements. Our upper bounds essentially replace the alphabet size by a factor exponential in the entropy, which offers improvements especially in low or medium entropy regimes (interesting for example in anomaly detection). As for the lower bounds, our proof explicitly shows how the complexity depends on both alphabet and accuracy, partially solving the open problem posted in previous works. The argument for upper bounds derives a clean identity for the variance of falling-power sum of a multinomial distribution. Our approach for lower bounds utilizes convex optimization to find a distribution with possibly worse estimation performance, and may be of independent interest as a tool to work with Le Cam’s two point method. AU - Obremski, Maciej AU - Skórski, Maciej ID - 710 SN - 18688969 TI - Renyi entropy estimation revisited VL - 81 ER - TY - JOUR AB - To determine the dynamics of allelic-specific expression during mouse development, we analyzed RNA-seq data from 23 F1 tissues from different developmental stages, including 19 female tissues allowing X chromosome inactivation (XCI) escapers to also be detected. We demonstrate that allelic expression arising from genetic or epigenetic differences is highly tissue-specific. We find that tissue-specific strain-biased gene expression may be regulated by tissue-specific enhancers or by post-transcriptional differences in stability between the alleles. We also find that escape from X-inactivation is tissue-specific, with leg muscle showing an unexpectedly high rate of XCI escapers. By surveying a range of tissues during development, and performing extensive validation, we are able to provide a high confidence list of mouse imprinted genes including 18 novel genes. This shows that cluster size varies dynamically during development and can be substantially larger than previously thought, with the Igf2r cluster extending over 10 Mb in placenta. AU - Andergassen, Daniel AU - Dotter, Christoph AU - Wenzel, Dyniel AU - Sigl, Verena AU - Bammer, Philipp AU - Muckenhuber, Markus AU - Mayer, Daniela AU - Kulinski, Tomasz AU - Theussl, Hans AU - Penninger, Josef AU - Bock, Christoph AU - Barlow, Denise AU - Pauler, Florian AU - Hudson, Quanah ID - 713 JF - eLife SN - 2050084X TI - Mapping the mouse Allelome reveals tissue specific regulation of allelic expression VL - 6 ER - TY - CONF AB - Nested weighted automata (NWA) present a robust and convenient automata-theoretic formalism for quantitative specifications. Previous works have considered NWA that processed input words only in the forward direction. It is natural to allow the automata to process input words backwards as well, for example, to measure the maximal or average time between a response and the preceding request. We therefore introduce and study bidirectional NWA that can process input words in both directions. First, we show that bidirectional NWA can express interesting quantitative properties that are not expressible by forward-only NWA. Second, for the fundamental decision problems of emptiness and universality, we establish decidability and complexity results for the new framework which match the best-known results for the special case of forward-only NWA. Thus, for NWA, the increased expressiveness of bidirectionality is achieved at no additional computational complexity. This is in stark contrast to the unweighted case, where bidirectional finite automata are no more expressive but exponentially more succinct than their forward-only counterparts. AU - Chatterjee, Krishnendu AU - Henzinger, Thomas A AU - Otop, Jan ID - 711 SN - 18688969 TI - Bidirectional nested weighted automata VL - 85 ER - TY - JOUR AB - We establish a weak–strong uniqueness principle for solutions to entropy-dissipating reaction–diffusion equations: As long as a strong solution to the reaction–diffusion equation exists, any weak solution and even any renormalized solution must coincide with this strong solution. Our assumptions on the reaction rates are just the entropy condition and local Lipschitz continuity; in particular, we do not impose any growth restrictions on the reaction rates. Therefore, our result applies to any single reversible reaction with mass-action kinetics as well as to systems of reversible reactions with mass-action kinetics satisfying the detailed balance condition. Renormalized solutions are known to exist globally in time for reaction–diffusion equations with entropy-dissipating reaction rates; in contrast, the global-in-time existence of weak solutions is in general still an open problem–even for smooth data–, thereby motivating the study of renormalized solutions. The key ingredient of our result is a careful adjustment of the usual relative entropy functional, whose evolution cannot be controlled properly for weak solutions or renormalized solutions. AU - Fischer, Julian L ID - 712 JF - Nonlinear Analysis: Theory, Methods and Applications SN - 0362546X TI - Weak–strong uniqueness of solutions to entropy dissipating reaction–diffusion equations VL - 159 ER - TY - JOUR AB - Background HIV-1 infection and drug abuse are frequently co-morbid and their association greatly increases the severity of HIV-1-induced neuropathology. While nucleus accumbens (NAcc) function is severely perturbed by drugs of abuse, little is known about how HIV-1 infection affects NAcc. Methods We used calcium and voltage imaging to investigate the effect of HIV-1 trans-activator of transcription (Tat) on rat NAcc. Based on previous neuronal studies, we hypothesized that Tat modulates intracellular Ca2+ homeostasis of NAcc neurons. Results We provide evidence that Tat triggers a Ca2+ signaling cascade in NAcc medium spiny neurons (MSN) expressing D1-like dopamine receptors leading to neuronal depolarization. Firstly, Tat induced inositol 1,4,5-trisphsophate (IP3) receptor-mediated Ca2+ release from endoplasmic reticulum, followed by Ca2+ and Na+ influx via transient receptor potential canonical channels. The influx of cations depolarizes the membrane promoting additional Ca2+ entry through voltage-gated P/Q-type Ca2+ channels and opening of tetrodotoxin-sensitive Na+ channels. By activating this mechanism, Tat elicits a feed-forward depolarization increasing the excitability of D1-phosphatidylinositol-linked NAcc MSN. We previously found that cocaine targets NAcc neurons directly (independent of the inhibition of dopamine transporter) only when IP3-generating mechanisms are concomitantly initiated. When tested here, cocaine produced a dose-dependent potentiation of the effect of Tat on cytosolic Ca2+. Conclusion We describe for the first time a HIV-1 Tat-triggered Ca2+ signaling in MSN of NAcc involving TRPC and depolarization and a potentiation of the effect of Tat by cocaine, which may be relevant for the reward axis in cocaine-abusing HIV-1-positive patients. AU - Brailoiu, Gabriela AU - Deliu, Elena AU - Barr, Jeffrey AU - Console Bram, Linda AU - Ciuciu, Alexandra AU - Abood, Mary AU - Unterwald, Ellen AU - Brǎiloiu, Eugen ID - 714 JF - Drug and Alcohol Dependence SN - 03768716 TI - HIV Tat excites D1 receptor-like expressing neurons from rat nucleus accumbens VL - 178 ER - TY - JOUR AB - D-cycloserine ameliorates breathing abnormalities and survival rate in a mouse model of Rett syndrome. AU - Novarino, Gaia ID - 715 IS - 405 JF - Science Translational Medicine SN - 19466234 TI - More excitation for Rett syndrome VL - 9 ER - TY - JOUR 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 solving recursive game graphs (or pushdown game graphs) that model the control flow of sequential programs with recursion.While pushdown games have been studied before with qualitative objectives-such as reachability and ?-regular objectives- in this work, we study for the first time such games with the most well-studied quantitative objective, the mean-payoff objective. In pushdown games, two types of strategies are relevant: (1) global strategies, which depend on the entire global history; and (2) modular strategies, which have only local memory and thus do not depend on the context of invocation but rather only on the history of the current invocation of the module. Our main results are as follows: (1) One-player pushdown games with mean-payoff objectives under global strategies are decidable in polynomial time. (2) Two-player pushdown games with mean-payoff objectives under global strategies are undecidable. (3) One-player pushdown games with mean-payoff objectives under modular strategies are NP-hard. (4) Two-player pushdown games with mean-payoff objectives under modular strategies can be solved in NP (i.e., both one-player and two-player pushdown games with mean-payoff objectives under modular strategies are NP-complete). We also establish the optimal strategy complexity by showing that global strategies for mean-payoff objectives require infinite memory even in one-player pushdown games and memoryless modular strategies are sufficient in two-player pushdown games. Finally, we also show that all the problems have the same complexity if the stack boundedness condition is added, where along with the mean-payoff objective the player must also ensure that the stack height is bounded. AU - Chatterjee, Krishnendu AU - Velner, Yaron ID - 716 IS - 5 JF - Journal of the ACM SN - 00045411 TI - The complexity of mean-payoff pushdown games VL - 64 ER - TY - JOUR AB - We consider finite-state and recursive game graphs with multidimensional mean-payoff objectives. In recursive games two types of strategies are relevant: global strategies and modular strategies. Our contributions are: (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 weights are fixed; whereas for arbitrary dimensions the problem is coNP-complete. (2) We show that one-player recursive games with multidimensional mean-payoff objectives can be solved in polynomial time. Both above algorithms are based on hyperplane separation technique. (3) For recursive games we show that under modular strategies the multidimensional problem is undecidable. We show that if the number of modules, exits, and the maximal absolute value of the weights are fixed, then one-dimensional recursive mean-payoff games under modular strategies can be solved in polynomial time, whereas for unbounded number of exits or modules the problem is NP-hard. AU - Chatterjee, Krishnendu AU - Velner, Yaron ID - 717 JF - Journal of Computer and System Sciences TI - Hyperplane separation technique for multidimensional mean-payoff games VL - 88 ER - TY - JOUR AB - The ubiquity of computation in modern machines and devices imposes a need to assert the correctness of their behavior. Especially in the case of safety-critical systems, their designers need to take measures that enforce their safe operation. Formal methods has emerged as a research field that addresses this challenge: by rigorously proving that all system executions adhere to their specifications, the correctness of an implementation under concern can be assured. To achieve this goal, a plethora of techniques are nowadays available, all of which are optimized for different system types and application domains. AU - Chatterjee, Krishnendu AU - Ehlers, Rüdiger ID - 719 IS - 6 JF - Acta Informatica SN - 00015903 TI - Special issue: Synthesis and SYNT 2014 VL - 54 ER - TY - JOUR AB - Advances in multi-unit recordings pave the way for statistical modeling of activity patterns in large neural populations. Recent studies have shown that the summed activity of all neurons strongly shapes the population response. A separate recent finding has been that neural populations also exhibit criticality, an anomalously large dynamic range for the probabilities of different population activity patterns. Motivated by these two observations, we introduce a class of probabilistic models which takes into account the prior knowledge that the neural population could be globally coupled and close to critical. These models consist of an energy function which parametrizes interactions between small groups of neurons, and an arbitrary positive, strictly increasing, and twice differentiable function which maps the energy of a population pattern to its probability. We show that: 1) augmenting a pairwise Ising model with a nonlinearity yields an accurate description of the activity of retinal ganglion cells which outperforms previous models based on the summed activity of neurons; 2) prior knowledge that the population is critical translates to prior expectations about the shape of the nonlinearity; 3) the nonlinearity admits an interpretation in terms of a continuous latent variable globally coupling the system whose distribution we can infer from data. Our method is independent of the underlying system’s state space; hence, it can be applied to other systems such as natural scenes or amino acid sequences of proteins which are also known to exhibit criticality. AU - Humplik, Jan AU - Tkacik, Gasper ID - 720 IS - 9 JF - PLoS Computational Biology SN - 1553734X TI - Probabilistic models for neural populations that naturally capture global coupling and criticality VL - 13 ER - TY - JOUR AB - Let S be a positivity-preserving symmetric linear operator acting on bounded functions. The nonlinear equation -1/m=z+Sm with a parameter z in the complex upper half-plane ℍ has a unique solution m with values in ℍ. We show that the z-dependence of this solution can be represented as the Stieltjes transforms of a family of probability measures v on ℝ. Under suitable conditions on S, we show that v has a real analytic density apart from finitely many algebraic singularities of degree at most 3. Our motivation comes from large random matrices. The solution m determines the density of eigenvalues of two prominent matrix ensembles: (i) matrices with centered independent entries whose variances are given by S and (ii) matrices with correlated entries with a translation-invariant correlation structure. Our analysis shows that the limiting eigenvalue density has only square root singularities or cubic root cusps; no other singularities occur. AU - Ajanki, Oskari H AU - Krüger, Torben H AU - Erdös, László ID - 721 IS - 9 JF - Communications on Pure and Applied Mathematics SN - 00103640 TI - Singularities of solutions to quadratic vector equations on the complex upper half plane VL - 70 ER - TY - JOUR AB - Plants are sessile organisms rooted in one place. The soil resources that plants require are often distributed in a highly heterogeneous pattern. To aid foraging, plants have evolved roots whose growth and development are highly responsive to soil signals. As a result, 3D root architecture is shaped by myriad environmental signals to ensure resource capture is optimised and unfavourable environments are avoided. The first signals sensed by newly germinating seeds — gravity and light — direct root growth into the soil to aid seedling establishment. Heterogeneous soil resources, such as water, nitrogen and phosphate, also act as signals that shape 3D root growth to optimise uptake. Root architecture is also modified through biotic interactions that include soil fungi and neighbouring plants. This developmental plasticity results in a ‘custom-made’ 3D root system that is best adapted to forage for resources in each soil environment that a plant colonises. AU - Morris, Emily AU - Griffiths, Marcus AU - Golebiowska, Agata AU - Mairhofer, Stefan AU - Burr Hersey, Jasmine AU - Goh, Tatsuaki AU - Von Wangenheim, Daniel AU - Atkinson, Brian AU - Sturrock, Craig AU - Lynch, Jonathan AU - Vissenberg, Kris AU - Ritz, Karl AU - Wells, Darren AU - Mooney, Sacha AU - Bennett, Malcolm ID - 722 IS - 17 JF - Current Biology SN - 09609822 TI - Shaping 3D root system architecture VL - 27 ER - TY - JOUR AB - Individual computations and social interactions underlying collective behavior in groups of animals are of great ethological, behavioral, and theoretical interest. While complex individual behaviors have successfully been parsed into small dictionaries of stereotyped behavioral modes, studies of collective behavior largely ignored these findings; instead, their focus was on inferring single, mode-independent social interaction rules that reproduced macroscopic and often qualitative features of group behavior. Here, we bring these two approaches together to predict individual swimming patterns of adult zebrafish in a group. We show that fish alternate between an “active” mode, in which they are sensitive to the swimming patterns of conspecifics, and a “passive” mode, where they ignore them. Using a model that accounts for these two modes explicitly, we predict behaviors of individual fish with high accuracy, outperforming previous approaches that assumed a single continuous computation by individuals and simple metric or topological weighing of neighbors’ behavior. At the group level, switching between active and passive modes is uncorrelated among fish, but correlated directional swimming behavior still emerges. Our quantitative approach for studying complex, multi-modal individual behavior jointly with emergent group behavior is readily extensible to additional behavioral modes and their neural correlates as well as to other species. AU - Harpaz, Roy AU - Tkacik, Gasper AU - Schneidman, Elad ID - 725 IS - 38 JF - PNAS SN - 00278424 TI - Discrete modes of social information processing predict individual behavior of fish in a group VL - 114 ER - TY - JOUR AB - We investigate the stationary and dynamical behavior of an Anderson localized chain coupled to a single central bound state. Although this coupling partially dilutes the Anderson localized peaks towards nearly resonant sites, the most weight of the original peaks remains unchanged. This leads to multifractal wave functions with a frozen spectrum of fractal dimensions, which is characteristic for localized phases in models with power-law hopping. Using a perturbative approach we identify two different dynamical regimes. At weak couplings to the central site, the transport of particles and information is logarithmic in time, a feature usually attributed to many-body localization. We connect such transport to the persistence of the Poisson statistics of level spacings in parts of the spectrum. In contrast, at stronger couplings the level repulsion is established in the entire spectrum, the problem can be mapped to the Fano resonance, and the transport is ballistic. AU - Hetterich, Daniel AU - Serbyn, Maksym AU - Domínguez, Fernando AU - Pollmann, Frank AU - Trauzettel, Björn ID - 724 IS - 10 JF - Physical Review B SN - 24699950 TI - Noninteracting central site model localization and logarithmic entanglement growth VL - 96 ER - TY - JOUR AB - Genetic variations in the oxytocin receptor gene affect patients with ASD and ADHD differently. AU - Novarino, Gaia ID - 731 IS - 411 JF - Science Translational Medicine SN - 19466234 TI - The science of love in ASD and ADHD VL - 9 ER - TY - JOUR AB - Inflammation, which is a highly regulated host response against danger signals, may be harmful if it is excessive and deregulated. Ideally, anti-inflammatory therapy should autonomously commence as soon as possible after the onset of inflammation, should be controllable by a physician, and should not systemically block beneficial immune response in the long term. We describe a genetically encoded anti-inflammatory mammalian cell device based on a modular engineered genetic circuit comprising a sensor, an amplifier, a “thresholder” to restrict activation of a positive-feedback loop, a combination of advanced clinically used biopharmaceutical proteins, and orthogonal regulatory elements that linked modules into the functional device. This genetic circuit was autonomously activated by inflammatory signals, including endogenous cecal ligation and puncture (CLP)-induced inflammation in mice and serum from a systemic juvenile idiopathic arthritis (sIJA) patient, and could be reset externally by a chemical signal. The microencapsulated anti-inflammatory device significantly reduced the pathology in dextran sodium sulfate (DSS)-induced acute murine colitis, demonstrating a synthetic immunological approach for autonomous anti-inflammatory therapy. AU - Smole, Anže AU - Lainšček, Duško AU - Bezeljak, Urban AU - Horvat, Simon AU - Jerala, Roman ID - 7360 IS - 1 JF - Molecular Therapy SN - 1525-0016 TI - A synthetic mammalian therapeutic gene circuit for sensing and suppressing inflammation VL - 25 ER - TY - CONF AB - Modern communication technologies allow first responders to contact thousands of potential volunteers simultaneously for support during a crisis or disaster event. However, such volunteer efforts must be well coordinated and monitored, in order to offer an effective relief to the professionals. In this paper we extend earlier work on optimally assigning volunteers to selected landmark locations. In particular, we emphasize the aspect that obtaining good assignments requires not only advanced computational tools, but also a realistic measure of distance between volunteers and landmarks. Specifically, we propose the use of the Open Street Map (OSM) driving distance instead of he previously used flight distance. We find the OSM driving distance to be better aligned with the interests of volunteers and first responders. Furthermore, we show that relying on the flying distance leads to a substantial underestimation of the number of required volunteers, causing negative side effects in case of an actual crisis situation. AU - Pielorz, Jasmin AU - Prandtstetter, Matthias AU - Straub, Markus AU - Lampert, Christoph ID - 750 SN - 978-153862714-3 T2 - 2017 IEEE International Conference on Big Data TI - Optimal geospatial volunteer allocation needs realistic distances ER - TY - JOUR AB - We introduce a common generalization of the strong Hanani–Tutte theorem and the weak Hanani–Tutte theorem: if a graph G has a drawing D in the plane where every pair of independent edges crosses an even number of times, then G has a planar drawing preserving the rotation of each vertex whose incident edges cross each other evenly in D. The theorem is implicit in the proof of the strong Hanani–Tutte theorem by Pelsmajer, Schaefer and Štefankovič. We give a new, somewhat simpler proof. AU - Fulek, Radoslav AU - Kynčl, Jan AU - Pálvölgyi, Dömötör ID - 795 IS - 3 JF - Electronic Journal of Combinatorics SN - 10778926 TI - Unified Hanani Tutte theorem VL - 24 ER - TY - JOUR AB - Phasenübergänge helfen beim Verständnis von Vielteilchensystemen in der Festkörperphysik und Fluiddynamik bis hin zur Teilchenphysik. Unserer internationalen Kollaboration ist es gelungen, einen neuartigen Phasenübergang in einem Quantensystem zu beobachten [1]. In einem Mikrowellenresonator konnte erstmals die spontane Zustandsänderung von undurchsichtig zu transparent nachgewiesen werden. AU - Fink, Johannes M ID - 797 IS - 3 JF - Physik in unserer Zeit TI - Photonenblockade aufgelöst VL - 48 ER - TY - JOUR AB - On January the 1st, 2016 a new agreement between 32 Austrian scientific libraries and the publisher Springer took its effect: this deal covers accessing the licensed content on the one hand, and publishing open access on the other hand. More than 1000 papers by Austrian authors were published open access at Springer in the first year alone. The working group "Springer Compact Evaluierung" made the data for these articles available via the platform OpenAPC and would like to use this opportunity to give a short account of what this publishing agreement actually entails and the working group intends to do. AU - Andrae, Magdalena AU - Villányi, Márton ID - 807 IS - 2 JF - Mitteilungen der Vereinigung Österreichischer Bibliothekarinnen und Bibliothekare SN - 10222588 TI - Der Springer Compact-Deal – Ein erster Einblick in die Evaluierung einer Offsetting-Vereinbarung VL - 70 ER - TY - JOUR AB - What data is needed about data? Describing the process to answer this question for the institutional data repository IST DataRep. AU - Petritsch, Barbara ID - 825 IS - 2 JF - Mitteilungen der Vereinigung Österreichischer Bibliothekarinnen & Bibliothekare SN - 10222588 TI - Metadata for research data in practice VL - 70 ER - TY - JOUR AB - Cytosine methylation regulates essential genome functions across eukaryotes, but the fundamental question of whether nucleosomal or naked DNA is the preferred substrate of plant and animal methyltransferases remains unresolved. Here, we show that genetic inactivation of a single DDM1/Lsh family nucleosome remodeler biases methylation toward inter-nucleosomal linker DNA in Arabidopsis thaliana and mouse. We find that DDM1 enables methylation of DNA bound to the nucleosome, suggesting that nucleosome-free DNA is the preferred substrate of eukaryotic methyltransferases in vivo. Furthermore, we show that simultaneous mutation of DDM1 and linker histone H1 in Arabidopsis reproduces the strong linker-specific methylation patterns of species that diverged from flowering plants and animals over a billion years ago. Our results indicate that in the absence of remodeling, nucleosomes are strong barriers to DNA methyltransferases. Linker-specific methylation can evolve simply by breaking the connection between nucleosome remodeling and DNA methylation. AU - Lyons, David B AU - Zilberman, Daniel ID - 9445 JF - eLife TI - DDM1 and Lsh remodelers allow methylation of DNA wrapped in nucleosomes VL - 6 ER - TY - CHAP AB - Small molecule biosensors based on Forster resonance energy transfer (FRET) enable small molecule signaling to be monitored with high spatial and temporal resolution in complex cellular environments. FRET sensors can be constructed by fusing a pair of fluorescent proteins to a suitable recognition domain, such as a member of the solute-binding protein (SBP) superfamily. However, naturally occurring SBPs may be unsuitable for incorporation into FRET sensors due to their low thermostability, which may preclude imaging under physiological conditions, or because the positions of their N- and C-termini may be suboptimal for fusion of fluorescent proteins, which may limit the dynamic range of the resulting sensors. Here, we show how these problems can be overcome using ancestral protein reconstruction and circular permutation. Ancestral protein reconstruction, used as a protein engineering strategy, leverages phylogenetic information to improve the thermostability of proteins, while circular permutation enables the termini of an SBP to be repositioned to maximize the dynamic range of the resulting FRET sensor. We also provide a protocol for cloning the engineered SBPs into FRET sensor constructs using Golden Gate assembly and discuss considerations for in situ characterization of the FRET sensors. AU - Clifton, Ben AU - Whitfield, Jason AU - Sanchez Romero, Inmaculada AU - Herde, Michel AU - Henneberger, Christian AU - Janovjak, Harald L AU - Jackson, Colin ED - Stein, Viktor ID - 957 SN - 10643745 T2 - Synthetic Protein Switches TI - Ancestral protein reconstruction and circular permutation for improving the stability and dynamic range of FRET sensors VL - 1596 ER - TY - CONF AB - Network games are widely used as a model for selfish resource-allocation problems. In the classical model, each player selects a path connecting her source and target vertex. The cost of traversing an edge depends on the number of players that traverse it. Thus, it abstracts the fact that different users may use a resource at different times and for different durations, which plays an important role in defining the costs of the users in reality. For example, when transmitting packets in a communication network, routing traffic in a road network, or processing a task in a production system, the traversal of the network involves an inherent delay, and so sharing and congestion of resources crucially depends on time. We study timed network games , which add a time component to network games. Each vertex v in the network is associated with a cost function, mapping the load on v to the price that a player pays for staying in v for one time unit with this load. In addition, each edge has a guard, describing time intervals in which the edge can be traversed, forcing the players to spend time on vertices. Unlike earlier work that add a time component to network games, the time in our model is continuous and cannot be discretized. In particular, players have uncountably many strategies, and a game may have uncountably many pure Nash equilibria. We study properties of timed network games with cost-sharing or congestion cost functions: their stability, equilibrium inefficiency, and complexity. In particular, we show that the answer to the question whether we can restrict attention to boundary strategies, namely ones in which edges are traversed only at the boundaries of guards, is mixed. AU - Avni, Guy AU - Guha, Shibashis AU - Kupferman, Orna ID - 963 SN - 18688969 TI - Timed network games with clocks VL - 83 ER - TY - GEN AB - Across the nervous system, certain population spiking patterns are observed far more frequently than others. A hypothesis about this structure is that these collective activity patterns function as population codewords–collective modes–carrying information distinct from that of any single cell. We investigate this phenomenon in recordings of ∼150 retinal ganglion cells, the retina’s output. We develop a novel statistical model that decomposes the population response into modes; it predicts the distribution of spiking activity in the ganglion cell population with high accuracy. We found that the modes represent localized features of the visual stimulus that are distinct from the features represented by single neurons. Modes form clusters of activity states that are readily discriminated from one another. When we repeated the same visual stimulus, we found that the same mode was robustly elicited. These results suggest that retinal ganglion cells’ collective signaling is endowed with a form of error-correcting code–a principle that may hold in brain areas beyond retina. AU - Prentice, Jason AU - Marre, Olivier AU - Ioffe, Mark AU - Loback, Adrianna AU - Tkačik, Gašper AU - Berry, Michael ID - 9709 TI - Data from: Error-robust modes of the retinal population code ER - TY - JOUR AB - While we have good understanding of bacterial metabolism at the population level, we know little about the metabolic behavior of individual cells: do single cells in clonal populations sometimes specialize on different metabolic pathways? Such metabolic specialization could be driven by stochastic gene expression and could provide individual cells with growth benefits of specialization. We measured the degree of phenotypic specialization in two parallel metabolic pathways, the assimilation of glucose and arabinose. We grew Escherichia coli in chemostats, and used isotope-labeled sugars in combination with nanometer-scale secondary ion mass spectrometry and mathematical modeling to quantify sugar assimilation at the single-cell level. We found large variation in metabolic activities between single cells, both in absolute assimilation and in the degree to which individual cells specialize in the assimilation of different sugars. Analysis of transcriptional reporters indicated that this variation was at least partially based on cell-to-cell variation in gene expression. Metabolic differences between cells in clonal populations could potentially reduce metabolic incompatibilities between different pathways, and increase the rate at which parallel reactions can be performed. AU - Nikolic, Nela AU - Schreiber, Frank AU - Dal Co, Alma AU - Kiviet, Daniel AU - Bergmiller, Tobias AU - Littmann, Sten AU - Kuypers, Marcel AU - Ackermann, Martin ID - 541 IS - 12 JF - PLoS Genetics SN - 15537390 TI - Cell-to-cell variation and specialization in sugar metabolism in clonal bacterial populations VL - 13 ER - TY - GEN AB - information on culture conditions, phage mutagenesis, verification and lysate preparation; Raw data AU - Pleska, Maros AU - Guet, Calin C ID - 9847 TI - Supplementary materials and methods; Full data set from effects of mutations in phage restriction sites during escape from restriction–modification ER - TY - GEN AB - Estimates of 13 C-arabinose and 2 H-glucose uptake from the fractions of heavy isotopes measured in single cells AU - Nikolic, Nela AU - Schreiber, Frank AU - Dal Co, Alma AU - Kiviet, Daniel AU - Bergmiller, Tobias AU - Littmann, Sten AU - Kuypers, Marcel AU - Ackermann, Martin ID - 9845 TI - Mathematical model ER - TY - GEN AB - This text provides additional information about the model, a derivation of the analytic results in Eq (4), and details about simulations of an additional parameter set. AU - Lukacisinova, Marta AU - Novak, Sebastian AU - Paixao, Tiago ID - 9849 TI - Modelling and simulation details ER - TY - GEN AB - In this text, we discuss how a cost of resistance and the possibility of lethal mutations impact our model. AU - Lukacisinova, Marta AU - Novak, Sebastian AU - Paixao, Tiago ID - 9850 TI - Extensions of the model ER - TY - GEN AU - Nikolic, Nela AU - Schreiber, Frank AU - Dal Co, Alma AU - Kiviet, Daniel AU - Bergmiller, Tobias AU - Littmann, Sten AU - Kuypers, Marcel AU - Ackermann, Martin ID - 9846 TI - Supplementary methods ER - TY - JOUR AB - In order to respond reliably to specific features of their environment, sensory neurons need to integrate multiple incoming noisy signals. Crucially, they also need to compete for the interpretation of those signals with other neurons representing similar features. The form that this competition should take depends critically on the noise corrupting these signals. In this study we show that for the type of noise commonly observed in sensory systems, whose variance scales with the mean signal, sensory neurons should selectively divide their input signals by their predictions, suppressing ambiguous cues while amplifying others. Any change in the stimulus context alters which inputs are suppressed, leading to a deep dynamic reshaping of neural receptive fields going far beyond simple surround suppression. Paradoxically, these highly variable receptive fields go alongside and are in fact required for an invariant representation of external sensory features. In addition to offering a normative account of context-dependent changes in sensory responses, perceptual inference in the presence of signal-dependent noise accounts for ubiquitous features of sensory neurons such as divisive normalization, gain control and contrast dependent temporal dynamics. AU - Chalk, Matthew J AU - Masset, Paul AU - Gutkin, Boris AU - Denève, Sophie ID - 680 IS - 6 JF - PLoS Computational Biology SN - 1553734X TI - Sensory noise predicts divisive reshaping of receptive fields VL - 13 ER - TY - GEN AB - Based on the intuitive derivation of the dynamics of SIM allele frequency pM in the main text, we present a heuristic prediction for the long-term SIM allele frequencies with χ > 1 stresses and compare it to numerical simulations. AU - Lukacisinova, Marta AU - Novak, Sebastian AU - Paixao, Tiago ID - 9851 TI - Heuristic prediction for multiple stresses ER - TY - GEN AB - We show how different combination strategies affect the fraction of individuals that are multi-resistant. AU - Lukacisinova, Marta AU - Novak, Sebastian AU - Paixao, Tiago ID - 9852 TI - Resistance frequencies for different combination strategies ER - TY - GEN AB - Includes derivation of optimal estimation algorithm, generalisation to non-poisson noise statistics, correlated input noise, and implementation of in a multi-layer neural network. AU - Chalk, Matthew J AU - Masset, Paul AU - Gutkin, Boris AU - Denève, Sophie ID - 9855 TI - Supplementary appendix ER - TY - CONF AB - Recently there has been a proliferation of automated program repair (APR) techniques, targeting various programming languages. Such techniques can be generally classified into two families: syntactic- and semantics-based. Semantics-based APR, on which we focus, typically uses symbolic execution to infer semantic constraints and then program synthesis to construct repairs conforming to them. While syntactic-based APR techniques have been shown successful on bugs in real-world programs written in both C and Java, semantics-based APR techniques mostly target C programs. This leaves empirical comparisons of the APR families not fully explored, and developers without a Java-based semantics APR technique. We present JFix, a semantics-based APR framework that targets Java, and an associated Eclipse plugin. JFix is implemented atop Symbolic PathFinder, a well-known symbolic execution engine for Java programs. It extends one particular APR technique (Angelix), and is designed to be sufficiently generic to support a variety of such techniques. We demonstrate that semantics-based APR can indeed efficiently and effectively repair a variety of classes of bugs in large real-world Java programs. This supports our claim that the framework can both support developers seeking semantics-based repair of bugs in Java programs, as well as enable larger scale empirical studies comparing syntactic- and semantics-based APR targeting Java. The demonstration of our tool is available via the project website at: https://xuanbachle.github.io/semanticsrepair/ AU - Le, Xuan AU - Chu, Duc Hiep AU - Lo, David AU - Le Goues, Claire AU - Visser, Willem ID - 941 T2 - Proceedings of the 26th ACM SIGSOFT International Symposium on Software Testing and Analysis TI - JFIX: Semantics-based repair of Java programs via symbolic PathFinder ER - TY - JOUR AB - Methylation in the bodies of active genes is common in animals and vascular plants. Evolutionary patterns indicate homeostatic functions for this type of methylation. AU - Zilberman, Daniel ID - 9506 IS - 1 JF - Genome Biology SN - 1474-760X TI - An evolutionary case for functional gene body methylation in plants and animals VL - 18 ER - TY - CHAP AB - Biosensors that exploit Forster resonance energy transfer (FRET) can be used to visualize biological and physiological processes and are capable of providing detailed information in both spatial and temporal dimensions. In a FRET-based biosensor, substrate binding is associated with a change in the relative positions of two fluorophores, leading to a change in FRET efficiency that may be observed in the fluorescence spectrum. As a result, their design requires a ligand-binding protein that exhibits a conformational change upon binding. However, not all ligand-binding proteins produce responsive sensors upon conjugation to fluorescent proteins or dyes, and identifying the optimum locations for the fluorophores often involves labor-intensive iterative design or high-throughput screening. Combining the genetic fusion of a fluorescent protein to the ligand-binding protein with site-specific covalent attachment of a fluorescent dye can allow fine control over the positions of the two fluorophores, allowing the construction of very sensitive sensors. This relies upon the accurate prediction of the locations of the two fluorophores in bound and unbound states. In this chapter, we describe a method for computational identification of dye-attachment sites that allows the use of cysteine modification to attach synthetic dyes that can be paired with a fluorescent protein for the purposes of creating FRET sensors. AU - Mitchell, Joshua AU - Zhang, William AU - Herde, Michel AU - Henneberger, Christian AU - Janovjak, Harald L AU - O'Mara, Megan AU - Jackson, Colin ED - Stein, Viktor ID - 958 SN - 10643745 T2 - Synthetic Protein Switches TI - Method for developing optical sensors using a synthetic dye fluorescent protein FRET pair and computational modeling and assessment VL - 1596 ER - TY - GEN AB - Branching morphogenesis of the epithelial ureteric bud forms the renal collecting duct system and is critical for normal nephron number, while low nephron number is implicated in hypertension and renal disease. Ureteric bud growth and branching requires GDNF signaling from the surrounding mesenchyme to cells at the ureteric bud tips, via the Ret receptor tyrosine kinase and coreceptor Gfrα1; Ret signaling up-regulates transcription factors Etv4 and Etv5, which are also critical for branching. Despite extensive knowledge of the genetic control of these events, it is not understood, at the cellular level, how renal branching morphogenesis is achieved or how Ret signaling influences epithelial cell behaviors to promote this process. Analysis of chimeric embryos previously suggested a role for Ret signaling in promoting cell rearrangements in the nephric duct, but this method was unsuited to study individual cell behaviors during ureteric bud branching. Here, we use Mosaic Analysis with Double Markers (MADM), combined with organ culture and time-lapse imaging, to trace the movements and divisions of individual ureteric bud tip cells. We first examine wild-type clones and then Ret or Etv4 mutant/wild-type clones in which the mutant and wild-type sister cells are differentially and heritably marked by green and red fluorescent proteins. We find that, in normal kidneys, most individual tip cells behave as self-renewing progenitors, some of whose progeny remain at the tips while others populate the growing UB trunks. In Ret or Etv4 MADM clones, the wild-type cells generated at a UB tip are much more likely to remain at, or move to, the new tips during branching and elongation, while their Ret−/− or Etv4−/− sister cells tend to lag behind and contribute only to the trunks. By tracking successive mitoses in a cell lineage, we find that Ret signaling has little effect on proliferation, in contrast to its effects on cell movement. Our results show that Ret/Etv4 signaling promotes directed cell movements in the ureteric bud tips, and suggest a model in which these cell movements mediate branching morphogenesis. AU - Riccio, Paul AU - Cebrián, Christina AU - Zong, Hui AU - Hippenmeyer, Simon AU - Costantini, Frank ID - 9707 TI - Data from: Ret and Etv4 promote directed movements of progenitor cells during renal branching morphogenesis ER - TY - GEN AU - Nikolic, Nela AU - Schreiber, Frank AU - Dal Co, Alma AU - Kiviet, Daniel AU - Bergmiller, Tobias AU - Littmann, Sten AU - Kuypers, Marcel AU - Ackermann, Martin ID - 9844 TI - Source data for figures and tables ER - TY - GEN AU - Schlögl, Alois AU - Kiss, Janos ID - 12905 T2 - AHPC17 – Austrian HPC Meeting 2017 TI - Scientific Computing at IST Austria ER - TY - CONF AB - Transforming deterministic ω -automata into deterministic parity automata is traditionally done using variants of appearance records. We present a more efficient variant of this approach, tailored to Rabin automata, and several optimizations applicable to all appearance records. We compare the methods experimentally and find out that our method produces smaller automata than previous approaches. Moreover, the experiments demonstrate the potential of our method for LTL synthesis, using LTL-to-Rabin translators. It leads to significantly smaller parity automata when compared to state-of-the-art approaches on complex formulae. AU - Kretinsky, Jan AU - Meggendorfer, Tobias AU - Waldmann, Clara AU - Weininger, Maximilian ID - 13160 SN - 0302-9743 T2 - Tools and Algorithms for the Construction and Analysis of Systems TI - Index appearance record for transforming Rabin automata into parity automata VL - 10205 ER - TY - CONF AB - Two-player games on graphs are widely studied in formal methods as they model the interaction between a system and its environment. The game is played by moving a token throughout a graph to produce an infinite path. There are several common modes to determine how the players move the token through the graph; e.g., in turn-based games the players alternate turns in moving the token. We study the bidding mode of moving the token, which, to the best of our knowledge, has never been studied in infinite-duration games. Both players have separate budgets, which sum up to $1$. In each turn, a bidding takes place. Both players submit bids simultaneously, and a bid is legal if it does not exceed the available budget. The winner of the bidding pays his bid to the other player and moves the token. For reachability objectives, repeated bidding games have been studied and are called Richman games. There, a central question is the existence and computation of threshold budgets; namely, a value t\in [0,1] such that if\PO's budget exceeds $t$, he can win the game, and if\PT's budget exceeds 1-t, he can win the game. We focus on parity games and mean-payoff games. We show the existence of threshold budgets in these games, and reduce the problem of finding them to Richman games. We also determine the strategy-complexity of an optimal strategy. Our most interesting result shows that memoryless strategies suffice for mean-payoff bidding games. AU - Avni, Guy AU - Henzinger, Thomas A AU - Chonev, Ventsislav K ID - 950 SN - 1868-8969 TI - Infinite-duration bidding games VL - 85 ER - TY - CONF AB - Given a triangulation of a point set in the plane, a flip deletes an edge e whose removal leaves a convex quadrilateral, and replaces e by the opposite diagonal of the quadrilateral. It is well known that any triangulation of a point set can be reconfigured to any other triangulation by some sequence of flips. We explore this question in the setting where each edge of a triangulation has a label, and a flip transfers the label of the removed edge to the new edge. It is not true that every labelled triangulation of a point set can be reconfigured to every other labelled triangulation via a sequence of flips, but we characterize when this is possible. There is an obvious necessary condition: for each label l, if edge e has label l in the first triangulation and edge f has label l in the second triangulation, then there must be some sequence of flips that moves label l from e to f, ignoring all other labels. Bose, Lubiw, Pathak and Verdonschot formulated the Orbit Conjecture, which states that this necessary condition is also sufficient, i.e. that all labels can be simultaneously mapped to their destination if and only if each label individually can be mapped to its destination. We prove this conjecture. Furthermore, we give a polynomial-time algorithm to find a sequence of flips to reconfigure one labelled triangulation to another, if such a sequence exists, and we prove an upper bound of O(n7) on the length of the flip sequence. Our proof uses the topological result that the sets of pairwise non-crossing edges on a planar point set form a simplicial complex that is homeomorphic to a high-dimensional ball (this follows from a result of Orden and Santos; we give a different proof based on a shelling argument). The dual cell complex of this simplicial ball, called the flip complex, has the usual flip graph as its 1-skeleton. We use properties of the 2-skeleton of the flip complex to prove the Orbit Conjecture. AU - Lubiw, Anna AU - Masárová, Zuzana AU - Wagner, Uli ID - 683 TI - A proof of the orbit conjecture for flipping edge labelled triangulations VL - 77 ER - TY - THES AB - This dissertation concerns the automatic verification of probabilistic systems and programs with arrays by statistical and logical methods. Although statistical and logical methods are different in nature, we show that they can be successfully combined for system analysis. In the first part of the dissertation we present a new statistical algorithm for the verification of probabilistic systems with respect to unbounded properties, including linear temporal logic. Our algorithm often performs faster than the previous approaches, and at the same time requires less information about the system. In addition, our method can be generalized to unbounded quantitative properties such as mean-payoff bounds. In the second part, we introduce two techniques for comparing probabilistic systems. Probabilistic systems are typically compared using the notion of equivalence, which requires the systems to have the equal probability of all behaviors. However, this notion is often too strict, since probabilities are typically only empirically estimated, and any imprecision may break the relation between processes. On the one hand, we propose to replace the Boolean notion of equivalence by a quantitative distance of similarity. For this purpose, we introduce a statistical framework for estimating distances between Markov chains based on their simulation runs, and we investigate which distances can be approximated in our framework. On the other hand, we propose to compare systems with respect to a new qualitative logic, which expresses that behaviors occur with probability one or a positive probability. This qualitative analysis is robust with respect to modeling errors and applicable to many domains. In the last part, we present a new quantifier-free logic for integer arrays, which allows us to express counting. Counting properties are prevalent in array-manipulating programs, however they cannot be expressed in the quantified fragments of the theory of arrays. We present a decision procedure for our logic, and provide several complexity results. AU - Daca, Przemyslaw ID - 1155 SN - 2663-337X TI - Statistical and logical methods for property checking ER - TY - THES AB - Bacteria and their pathogens – phages – are the most abundant living entities on Earth. Throughout their coevolution, bacteria have evolved multiple immune systems to overcome the ubiquitous threat from the phages. Although the molecu- lar details of these immune systems’ functions are relatively well understood, their epidemiological consequences for the phage-bacterial communities have been largely neglected. In this thesis we employed both experimental and theoretical methods to explore whether herd and social immunity may arise in bacterial popu- lations. Using our experimental system consisting of Escherichia coli strains with a CRISPR based immunity to the T7 phage we show that herd immunity arises in phage-bacterial communities and that it is accentuated when the populations are spatially structured. By fitting a mathematical model, we inferred expressions for the herd immunity threshold and the velocity of spread of a phage epidemic in partially resistant bacterial populations, which both depend on the bacterial growth rate, phage burst size and phage latent period. We also investigated the poten- tial for social immunity in Streptococcus thermophilus and its phage 2972 using a bioinformatic analysis of potentially coding short open reading frames with a signalling signature, encoded within the CRISPR associated genes. Subsequently, we tested one identified potentially signalling peptide and found that its addition to a phage-challenged culture increases probability of survival of bacteria two fold, although the results were only marginally significant. Together, these results demonstrate that the ubiquitous arms races between bacteria and phages have further consequences at the level of the population. AU - Payne, Pavel ID - 6291 SN - 2663-337X TI - Bacterial herd and social immunity to phages ER - TY - JOUR AB - Restriction–modification systems are widespread genetic elements that protect bacteria from bacteriophage infections by recognizing and cleaving heterologous DNA at short, well-defined sequences called restriction sites. Bioinformatic evidence shows that restriction sites are significantly underrepresented in bacteriophage genomes, presumably because bacteriophages with fewer restriction sites are more likely to escape cleavage by restriction–modification systems. However, how mutations in restriction sites affect the likelihood of bacteriophage escape is unknown. Using the bacteriophage l and the restriction–modification system EcoRI, we show that while mutation effects at different restriction sites are unequal, they are independent. As a result, the probability of bacteriophage escape increases with each mutated restriction site. Our results experimentally support the role of restriction site avoidance as a response to selection imposed by restriction–modification systems and offer an insight into the events underlying the process of bacteriophage escape. AU - Pleska, Maros AU - Guet, Calin C ID - 561 IS - 12 JF - Biology Letters SN - 1744-9561 TI - Effects of mutations in phage restriction sites during escape from restriction–modification VL - 13 ER - TY - THES AB - Antibiotics have diverse effects on bacteria, including massive changes in bacterial gene expression. Whereas the gene expression changes under many antibiotics have been measured, the temporal organization of these responses and their dependence on the bacterial growth rate are unclear. As described in Chapter 1, we quantified the temporal gene expression changes in the bacterium Escherichia coli in response to the sudden exposure to antibiotics using a fluorescent reporter library and a robotic system. Our data show temporally structured gene expression responses, with response times for individual genes ranging from tens of minutes to several hours. We observed that many stress response genes were activated in response to antibiotics. As certain stress responses cross-protect bacteria from other stressors, we then asked whether cellular responses to antibiotics have a similar protective role in Chapter 2. Indeed, we found that the trimethoprim-induced acid stress response protects bacteria from subsequent acid stress. We combined microfluidics with time-lapse imaging to monitor survival, intracellular pH, and acid stress response in single cells. This approach revealed that the variable expression of the acid resistance operon gadBC strongly correlates with single-cell survival time. Cells with higher gadBC expression following trimethoprim maintain higher intracellular pH and survive the acid stress longer. Overall, we provide a way to identify single-cell cross-protection between antibiotics and environmental stressors from temporal gene expression data, and show how antibiotics can increase bacterial fitness in changing environments. While gene expression changes to antibiotics show a clear temporal structure at the population-level, it is unclear whether this clear temporal order is followed by every single cell. Using dual-reporter strains described in Chapter 3, we measured gene expression dynamics of promoter pairs in the same cells using microfluidics and microscopy. Chapter 4 shows that the oxidative stress response and the DNA stress response showed little timing variability and a clear temporal order under the antibiotic nitrofurantoin. In contrast, the acid stress response under trimethoprim ran independently from all other activated response programs including the DNA stress response, which showed particularly high timing variability in this stress condition. In summary, this approach provides insight into the temporal organization of gene expression programs at the single-cell level and suggests dependencies between response programs and the underlying variability-introducing mechanisms. Altogether, this work advances our understanding of the diverse effects that antibiotics have on bacteria. These results were obtained by taking into account gene expression dynamics, which allowed us to identify general principles, molecular mechanisms, and dependencies between genes. Our findings may have implications for infectious disease treatments, and microbial communities in the human body and in nature. AU - Mitosch, Karin ID - 818 SN - 2663-337X TI - Timing, variability and cross-protection in bacteria – insights from dynamic gene expression responses to antibiotics ER - TY - JOUR AB - Antibiotics elicit drastic changes in microbial gene expression, including the induction of stress response genes. While certain stress responses are known to “cross-protect” bacteria from other stressors, it is unclear whether cellular responses to antibiotics have a similar protective role. By measuring the genome-wide transcriptional response dynamics of Escherichia coli to four antibiotics, we found that trimethoprim induces a rapid acid stress response that protects bacteria from subsequent exposure to acid. Combining microfluidics with time-lapse imaging to monitor survival and acid stress response in single cells revealed that the noisy expression of the acid resistance operon gadBC correlates with single-cell survival. Cells with higher gadBC expression following trimethoprim maintain higher intracellular pH and survive the acid stress longer. The seemingly random single-cell survival under acid stress can therefore be predicted from gadBC expression and rationalized in terms of GadB/C molecular function. Overall, we provide a roadmap for identifying the molecular mechanisms of single-cell cross-protection between antibiotics and other stressors. AU - Mitosch, Karin AU - Rieckh, Georg AU - Bollenbach, Tobias ID - 666 IS - 4 JF - Cell Systems SN - 24054712 TI - Noisy response to antibiotic stress predicts subsequent single cell survival in an acidic environment VL - 4 ER - TY - THES AB - This dissertation focuses on algorithmic aspects of program verification, and presents modeling and complexity advances on several problems related to the static analysis of programs, the stateless model checking of concurrent programs, and the competitive analysis of real-time scheduling algorithms. Our contributions can be broadly grouped into five categories. Our first contribution is a set of new algorithms and data structures for the quantitative and data-flow analysis of programs, based on the graph-theoretic notion of treewidth. It has been observed that the control-flow graphs of typical programs have special structure, and are characterized as graphs of small treewidth. We utilize this structural property to provide faster algorithms for the quantitative and data-flow analysis of recursive and concurrent programs. In most cases we make an algebraic treatment of the considered problem, where several interesting analyses, such as the reachability, shortest path, and certain kind of data-flow analysis problems follow as special cases. We exploit the constant-treewidth property to obtain algorithmic improvements for on-demand versions of the problems, and provide data structures with various tradeoffs between the resources spent in the preprocessing and querying phase. We also improve on the algorithmic complexity of quantitative problems outside the algebraic path framework, namely of the minimum mean-payoff, minimum ratio, and minimum initial credit for energy problems. Our second contribution is a set of algorithms for Dyck reachability with applications to data-dependence analysis and alias analysis. In particular, we develop an optimal algorithm for Dyck reachability on bidirected graphs, which are ubiquitous in context-insensitive, field-sensitive points-to analysis. Additionally, we develop an efficient algorithm for context-sensitive data-dependence analysis via Dyck reachability, where the task is to obtain analysis summaries of library code in the presence of callbacks. Our algorithm preprocesses libraries in almost linear time, after which the contribution of the library in the complexity of the client analysis is (i)~linear in the number of call sites and (ii)~only logarithmic in the size of the whole library, as opposed to linear in the size of the whole library. Finally, we prove that Dyck reachability is Boolean Matrix Multiplication-hard in general, and the hardness also holds for graphs of constant treewidth. This hardness result strongly indicates that there exist no combinatorial algorithms for Dyck reachability with truly subcubic complexity. Our third contribution is the formalization and algorithmic treatment of the Quantitative Interprocedural Analysis framework. In this framework, the transitions of a recursive program are annotated as good, bad or neutral, and receive a weight which measures the magnitude of their respective effect. The Quantitative Interprocedural Analysis problem asks to determine whether there exists an infinite run of the program where the long-run ratio of the bad weights over the good weights is above a given threshold. We illustrate how several quantitative problems related to static analysis of recursive programs can be instantiated in this framework, and present some case studies to this direction. Our fourth contribution is a new dynamic partial-order reduction for the stateless model checking of concurrent programs. Traditional approaches rely on the standard Mazurkiewicz equivalence between traces, by means of partitioning the trace space into equivalence classes, and attempting to explore a few representatives from each class. We present a new dynamic partial-order reduction method called the Data-centric Partial Order Reduction (DC-DPOR). Our algorithm is based on a new equivalence between traces, called the observation equivalence. DC-DPOR explores a coarser partitioning of the trace space than any exploration method based on the standard Mazurkiewicz equivalence. Depending on the program, the new partitioning can be even exponentially coarser. Additionally, DC-DPOR spends only polynomial time in each explored class. Our fifth contribution is the use of automata and game-theoretic verification techniques in the competitive analysis and synthesis of real-time scheduling algorithms for firm-deadline tasks. On the analysis side, we leverage automata on infinite words to compute the competitive ratio of real-time schedulers subject to various environmental constraints. On the synthesis side, we introduce a new instance of two-player mean-payoff partial-information games, and show how the synthesis of an optimal real-time scheduler can be reduced to computing winning strategies in this new type of games. AU - Pavlogiannis, Andreas ID - 821 SN - 2663-337X TI - Algorithmic advances in program analysis and their applications ER - TY - THES AB - The lac operon is a classic model system for bacterial gene regulation, and has been studied extensively in E. coli, a classic model organism. However, not much is known about E. coli’s ecology and life outside the laboratory, in particular in soil and water environments. The natural diversity of the lac operon outside the laboratory, its role in the ecology of E. coli and the selection pressures it is exposed to, are similarly unknown. In Chapter Two of this thesis, I explore the genetic diversity, phylogenetic history and signatures of selection of the lac operon across 20 natural isolates of E. coli and divergent clades of Escherichia. I found that complete lac operons were present in all isolates examined, which in all but one case were functional. The lac operon phylogeny conformed to the whole-genome phylogeny of the divergent Escherichia clades, which excludes horizontal gene transfer as an explanation for the presence of functional lac operons in these clades. All lac operon genes showed a signature of purifying selection; this signature was strongest for the lacY gene. Lac operon genes of human and environmental isolates showed similar signatures of selection, except the lacZ gene, which showed a stronger signature of selection in environmental isolates. In Chapter Three, I try to identify the natural genetic variation relevant for phenotype and fitness in the lac operon, comparing growth rate on lactose and LacZ activity of the lac operons of these wild isolates in a common genetic background. Sequence variation in the lac promoter region, upstream of the -10 and -35 RNA polymerase binding motif, predicted variation in LacZ activity at full induction, using a thermodynamic model of polymerase binding (Tugrul, 2016). However, neither variation in LacZ activity, nor RNA polymerase binding predicted by the model correlated with variation in growth rate. Lac operons of human and environmental isolates did not differ systematically in either growth rate on lactose or LacZ protein activity, suggesting that these lac operons have been exposed to similar selection pressures. We thus have no evidence that the phenotypic variation we measured is relevant for fitness. To start assessing the effect of genomic background on the growth phenotype conferred by the lac operon, I compared growth on minimal medium with lactose between lac operon constructs and the corresponding original isolates, I found that maximal growth rate was determined by genomic background, with almost all backgrounds conferring higher growth rates than lab strain K12 MG1655. However, I found no evidence that the lactose concentration at which growth was half maximal depended on genomic background. AU - Jesse, Fabienne ID - 820 SN - 2663-337X TI - The lac operon in the wild ER - TY - THES AB - In this thesis we discuss the exact security of message authentications codes HMAC , NMAC , and PMAC . NMAC is a mode of operation which turns a fixed input-length keyed hash function f into a variable input-length function. A practical single-key variant of NMAC called HMAC is a very popular and widely deployed message authentication code (MAC). PMAC is a block-cipher based mode of operation, which also happens to be the most famous fully parallel MAC. NMAC was introduced by Bellare, Canetti and Krawczyk Crypto’96, who proved it to be a secure pseudorandom function (PRF), and thus also a MAC, under two assumptions. Unfortunately, for many instantiations of HMAC one of them has been found to be wrong. To restore the provable guarantees for NMAC , Bellare [Crypto’06] showed its security without this assumption. PMAC was introduced by Black and Rogaway at Eurocrypt 2002. If instantiated with a pseudorandom permutation over n -bit strings, PMAC constitutes a provably secure variable input-length PRF. For adversaries making q queries, each of length at most ` (in n -bit blocks), and of total length σ ≤ q` , the original paper proves an upper bound on the distinguishing advantage of O ( σ 2 / 2 n ), while the currently best bound is O ( qσ/ 2 n ). In this work we show that this bound is tight by giving an attack with advantage Ω( q 2 `/ 2 n ). In the PMAC construction one initially XORs a mask to every message block, where the mask for the i th block is computed as τ i := γ i · L , where L is a (secret) random value, and γ i is the i -th codeword of the Gray code. Our attack applies more generally to any sequence of γ i ’s which contains a large coset of a subgroup of GF (2 n ). As for NMAC , our first contribution is a simpler and uniform proof: If f is an ε -secure PRF (against q queries) and a δ - non-adaptively secure PRF (against q queries), then NMAC f is an ( ε + `qδ )-secure PRF against q queries of length at most ` blocks each. We also show that this ε + `qδ bound is basically tight by constructing an f for which an attack with advantage `qδ exists. Moreover, we analyze the PRF-security of a modification of NMAC called NI by An and Bellare that avoids the constant rekeying on multi-block messages in NMAC and allows for an information-theoretic analysis. We carry out such an analysis, obtaining a tight `q 2 / 2 c bound for this step, improving over the trivial bound of ` 2 q 2 / 2 c . Finally, we investigate, if the security of PMAC can be further improved by using τ i ’s that are k -wise independent, for k > 1 (the original has k = 1). We observe that the security of PMAC will not increase in general if k = 2, and then prove that the security increases to O ( q 2 / 2 n ), if the k = 4. Due to simple extension attacks, this is the best bound one can hope for, using any distribution on the masks. Whether k = 3 is already sufficient to get this level of security is left as an open problem. Keywords: Message authentication codes, Pseudorandom functions, HMAC, PMAC. AU - Rybar, Michal ID - 838 SN - 2663-337X TI - (The exact security of) Message authentication codes ER - TY - JOUR AB - PMAC is a simple and parallel block-cipher mode of operation, which was introduced by Black and Rogaway at Eurocrypt 2002. If instantiated with a (pseudo)random permutation over n-bit strings, PMAC constitutes a provably secure variable input-length (pseudo)random function. For adversaries making q queries, each of length at most l (in n-bit blocks), and of total length σ ≤ ql, the original paper proves an upper bound on the distinguishing advantage of Ο(σ2/2n), while the currently best bound is Ο (qσ/2n).In this work we show that this bound is tight by giving an attack with advantage Ω (q2l/2n). In the PMAC construction one initially XORs a mask to every message block, where the mask for the ith block is computed as τi := γi·L, where L is a (secret) random value, and γi is the i-th codeword of the Gray code. Our attack applies more generally to any sequence of γi’s which contains a large coset of a subgroup of GF(2n). We then investigate if the security of PMAC can be further improved by using τi’s that are k-wise independent, for k > 1 (the original distribution is only 1-wise independent). We observe that the security of PMAC will not increase in general, even if the masks are chosen from a 2-wise independent distribution, and then prove that the security increases to O(q<2/2n), if the τi are 4-wise independent. Due to simple extension attacks, this is the best bound one can hope for, using any distribution on the masks. Whether 3-wise independence is already sufficient to get this level of security is left as an open problem. AU - Gazi, Peter AU - Pietrzak, Krzysztof Z AU - Rybar, Michal ID - 6196 IS - 2 JF - IACR Transactions on Symmetric Cryptology TI - The exact security of PMAC VL - 2016 ER - TY - THES AB - The hippocampus is a key brain region for memory and notably for spatial memory, and is needed for both spatial working and reference memories. Hippocampal place cells selectively discharge in specific locations of the environment to form mnemonic represen tations of space. Several behavioral protocols have been designed to test spatial memory which requires the experimental subject to utilize working memory and reference memory. However, less is known about how these memory traces are presented in the hippo campus, especially considering tasks that require both spatial working and long -term reference memory demand. The aim of my thesis was to elucidate how spatial working memory, reference memory, and the combination of both are represented in the hippocampus. In this thesis, using a radial eight -arm maze, I examined how the combined demand on these memories influenced place cell assemblies while reference memories were partially updated by changing some of the reward- arms. This was contrasted with task varian ts requiring working or reference memories only. Reference memory update led to gradual place field shifts towards the rewards on the switched arms. Cells developed enhanced firing in passes between newly -rewarded arms as compared to those containing an unchanged reward. The working memory task did not show such gradual changes. Place assemblies on occasions replayed trajectories of the maze; at decision points the next arm choice was preferentially replayed in tasks needing reference memory while in the pure working memory task the previously visited arm was replayed. Hence trajectory replay only reflected the decision of the animal in tasks needing reference memory update. At the reward locations, in all three tasks outbound trajectories of the current arm were preferentially replayed, showing the animals’ next path to the center. At reward locations trajectories were replayed preferentially in reverse temporal order. Moreover, in the center reverse replay was seen in the working memory task but in the other tasks forward replay was seen. Hence, the direction of reactivation was determined by the goal locations so that part of the trajectory which was closer to the goal was reactivated later in an HSE while places further away from the goal were reactivated earlier. Altogether my work demonstrated that reference memory update triggers several levels of reorganization of the hippocampal cognitive map which are not seen in simpler working memory demand s. Moreover, hippocampus is likely to be involved in spatial decisions through reactivating planned trajectories when reference memory recall is required for such a decision. AU - Xu, Haibing ID - 837 SN - 2663-337X TI - Reactivation of the hippocampal cognitive map in goal-directed spatial tasks ER - TY - THES AB - The thesis encompasses several topics of plant cell biology which were studied in the model plant Arabidopsis thaliana. Chapter 1 concerns the plant hormone auxin and its polar transport through cells and tissues. The highly controlled, directional transport of auxin is facilitated by plasma membrane-localized transporters. Transporters from the PIN family direct auxin transport due to their polarized localizations at cell membranes. Substantial effort has been put into research on cellular trafficking of PIN proteins, which is thought to underlie their polar distribution. I participated in a forward genetic screen aimed at identifying novel regulators of PIN polarity. The screen yielded several genes which may be involved in PIN polarity regulation or participate in polar auxin transport by other means. Chapter 2 focuses on the endomembrane system, with particular attention to clathrin-mediated endocytosis. The project started with identification of several proteins that interact with clathrin light chains. Among them, I focused on two putative homologues of auxilin, which in non-plant systems is an endocytotic factor known for uncoating clathrin-coated vesicles in the final step of endocytosis. The body of my work consisted of an in-depth characterization of transgenic A. thaliana lines overexpressing these putative auxilins in an inducible manner. Overexpression of these proteins leads to an inhibition of endocytosis, as documented by imaging of cargoes and clathrin-related endocytic machinery. An extension of this work is an investigation into a concept of homeostatic regulation acting between distinct transport processes in the endomembrane system. With auxilin overexpressing lines, where endocytosis is blocked specifically, I made observations on the mutual relationship between two opposite trafficking processes of secretion and endocytosis. In Chapter 3, I analyze cortical microtubule arrays and their relationship to auxin signaling and polarized growth in elongating cells. In plants, microtubules are organized into arrays just below the plasma membrane, and it is thought that their function is to guide membrane-docked cellulose synthase complexes. These, in turn, influence cell wall structure and cell shape by directed deposition of cellulose fibres. In elongating cells, cortical microtubule arrays are able to reorient in relation to long cell axis, and these reorientations have been linked to cell growth and to signaling of growth-regulating factors such as auxin or light. In this chapter, I am addressing the causal relationship between microtubule array reorientation, growth, and auxin signaling. I arrive at a model where array reorientation is not guided by auxin directly, but instead is only controlled by growth, which, in turn, is regulated by auxin. AU - Adamowski, Maciek ID - 938 SN - 2663-337X TI - Investigations into cell polarity and trafficking in the plant model Arabidopsis thaliana ER - TY - THES AB - An instance of the Constraint Satisfaction Problem (CSP) is given by a finite set of variables, a finite domain of labels, and a set of constraints, each constraint acting on a subset of the variables. The goal is to find an assignment of labels to its variables that satisfies all constraints (or decide whether one exists). If we allow more general “soft” constraints, which come with (possibly infinite) costs of particular assignments, we obtain instances from a richer class called Valued Constraint Satisfaction Problem (VCSP). There the goal is to find an assignment with minimum total cost. In this thesis, we focus (assuming that P 6 = NP) on classifying computational com- plexity of CSPs and VCSPs under certain restricting conditions. Two results are the core content of the work. In one of them, we consider VCSPs parametrized by a constraint language, that is the set of “soft” constraints allowed to form the instances, and finish the complexity classification modulo (missing pieces of) complexity classification for analogously parametrized CSP. The other result is a generalization of Edmonds’ perfect matching algorithm. This generalization contributes to complexity classfications in two ways. First, it gives a new (largest known) polynomial-time solvable class of Boolean CSPs in which every variable may appear in at most two constraints and second, it settles full classification of Boolean CSPs with planar drawing (again parametrized by a constraint language). AU - Rolinek, Michal ID - 992 SN - 2663-337X TI - Complexity of constraint satisfaction ER - TY - JOUR AB - Mapping every simplex in the Delaunay mosaic of a discrete point set to the radius of the smallest empty circumsphere gives a generalized discrete Morse function. Choosing the points from a Poisson point process in ℝ n , we study the expected number of simplices in the Delaunay mosaic as well as the expected number of critical simplices and nonsingular intervals in the corresponding generalized discrete gradient. Observing connections with other probabilistic models, we obtain precise expressions for the expected numbers in low dimensions. In particular, we obtain the expected numbers of simplices in the Poisson–Delaunay mosaic in dimensions n ≤ 4. AU - Edelsbrunner, Herbert AU - Nikitenko, Anton AU - Reitzner, Matthias ID - 718 IS - 3 JF - Advances in Applied Probability SN - 00018678 TI - Expected sizes of poisson Delaunay mosaics and their discrete Morse functions VL - 49 ER - TY - CONF AB - Proofs of space (PoS) were suggested as more ecological and economical alternative to proofs of work, which are currently used in blockchain designs like Bitcoin. The existing PoS are based on rather sophisticated graph pebbling lower bounds. Much simpler and in several aspects more efficient schemes based on inverting random functions have been suggested, but they don’t give meaningful security guarantees due to existing time-memory trade-offs. In particular, Hellman showed that any permutation over a domain of size N can be inverted in time T by an algorithm that is given S bits of auxiliary information whenever (Formula presented). For functions Hellman gives a weaker attack with S2· T≈ N2 (e.g., S= T≈ N2/3). To prove lower bounds, one considers an adversary who has access to an oracle f: [ N] → [N] and can make T oracle queries. The best known lower bound is S· T∈ Ω(N) and holds for random functions and permutations. We construct functions that provably require more time and/or space to invert. Specifically, for any constant k we construct a function [N] → [N] that cannot be inverted unless Sk· T∈ Ω(Nk) (in particular, S= T≈ (Formula presented). Our construction does not contradict Hellman’s time-memory trade-off, because it cannot be efficiently evaluated in forward direction. However, its entire function table can be computed in time quasilinear in N, which is sufficient for the PoS application. Our simplest construction is built from a random function oracle g: [N] × [N] → [ N] and a random permutation oracle f: [N] → N] and is defined as h(x) = g(x, x′) where f(x) = π(f(x′)) with π being any involution without a fixed point, e.g. flipping all the bits. For this function we prove that any adversary who gets S bits of auxiliary information, makes at most T oracle queries, and inverts h on an ϵ fraction of outputs must satisfy S2· T∈ Ω(ϵ2N2). AU - Abusalah, Hamza M AU - Alwen, Joel F AU - Cohen, Bram AU - Khilko, Danylo AU - Pietrzak, Krzysztof Z AU - Reyzin, Leonid ID - 559 SN - 978-331970696-2 TI - Beyond Hellman’s time-memory trade-offs with applications to proofs of space VL - 10625 ER - TY - JOUR AB - For large random matrices X with independent, centered entries but not necessarily identical variances, the eigenvalue density of XX* is well-approximated by a deterministic measure on ℝ. We show that the density of this measure has only square and cubic-root singularities away from zero. We also extend the bulk local law in [5] to the vicinity of these singularities. AU - Alt, Johannes ID - 550 JF - Electronic Communications in Probability SN - 1083589X TI - Singularities of the density of states of random Gram matrices VL - 22 ER - TY - CONF AB - Despite researchers’ efforts in the last couple of decades, reachability analysis is still a challenging problem even for linear hybrid systems. Among the existing approaches, the most practical ones are mainly based on bounded-time reachable set over-approximations. For the purpose of unbounded-time analysis, one important strategy is to abstract the original system and find an invariant for the abstraction. In this paper, we propose an approach to constructing a new kind of abstraction called conic abstraction for affine hybrid systems, and to computing reachable sets based on this abstraction. The essential feature of a conic abstraction is that it partitions the state space of a system into a set of convex polyhedral cones which is derived from a uniform conic partition of the derivative space. Such a set of polyhedral cones is able to cut all trajectories of the system into almost straight segments so that every segment of a reach pipe in a polyhedral cone tends to be straight as well, and hence can be over-approximated tightly by polyhedra using similar techniques as HyTech or PHAVer. In particular, for diagonalizable affine systems, our approach can guarantee to find an invariant for unbounded reachable sets, which is beyond the capability of bounded-time reachability analysis tools. We implemented the approach in a tool and experiments on benchmarks show that our approach is more powerful than SpaceEx and PHAVer in dealing with diagonalizable systems. AU - Bogomolov, Sergiy AU - Giacobbe, Mirco AU - Henzinger, Thomas A AU - Kong, Hui ID - 647 SN - 978-331965764-6 TI - Conic abstractions for hybrid systems VL - 10419 ER - TY - CONF AB - Template polyhedra generalize intervals and octagons to polyhedra whose facets are orthogonal to a given set of arbitrary directions. They have been employed in the abstract interpretation of programs and, with particular success, in the reachability analysis of hybrid automata. While previously, the choice of directions has been left to the user or a heuristic, we present a method for the automatic discovery of directions that generalize and eliminate spurious counterexamples. We show that for the class of convex hybrid automata, i.e., hybrid automata with (possibly nonlinear) convex constraints on derivatives, such directions always exist and can be found using convex optimization. We embed our method inside a CEGAR loop, thus enabling the time-unbounded reachability analysis of an important and richer class of hybrid automata than was previously possible. We evaluate our method on several benchmarks, demonstrating also its superior efficiency for the special case of linear hybrid automata. AU - Bogomolov, Sergiy AU - Frehse, Goran AU - Giacobbe, Mirco AU - Henzinger, Thomas A ID - 631 SN - 978-366254576-8 TI - Counterexample guided refinement of template polyhedra VL - 10205 ER - TY - JOUR AB - We show that matrix elements of functions of N × N Wigner matrices fluctuate on a scale of order N−1/2 and we identify the limiting fluctuation. Our result holds for any function f of the matrix that has bounded variation thus considerably relaxing the regularity requirement imposed in [7, 11]. AU - Erdös, László AU - Schröder, Dominik J ID - 1144 JF - Electronic Communications in Probability TI - Fluctuations of functions of Wigner matrices VL - 21 ER - TY - JOUR AB - Color texture reproduction in 3D printing commonly ignores volumetric light transport (cross-talk) between surface points on a 3D print. Such light diffusion leads to significant blur of details and color bleeding, and is particularly severe for highly translucent resin-based print materials. Given their widely varying scattering properties, this cross-talk between surface points strongly depends on the internal structure of the volume surrounding each surface point. Existing scattering-aware methods use simplified models for light diffusion, and often accept the visual blur as an immutable property of the print medium. In contrast, our work counteracts heterogeneous scattering to obtain the impression of a crisp albedo texture on top of the 3D print, by optimizing for a fully volumetric material distribution that preserves the target appearance. Our method employs an efficient numerical optimizer on top of a general Monte-Carlo simulation of heterogeneous scattering, supported by a practical calibration procedure to obtain scattering parameters from a given set of printer materials. Despite the inherent translucency of the medium, we reproduce detailed surface textures on 3D prints. We evaluate our system using a commercial, five-tone 3D print process and compare against the printer’s native color texturing mode, demonstrating that our method preserves high-frequency features well without having to compromise on color gamut. AU - Elek, Oskar AU - Sumin, Denis AU - Zhang, Ran AU - Weyrich, Tim AU - Myszkowski, Karol AU - Bickel, Bernd AU - Wilkie, Alexander AU - Krivanek, Jaroslav ID - 486 IS - 6 JF - ACM Transactions on Graphics SN - 07300301 TI - Scattering-aware texture reproduction for 3D printing VL - 36 ER - TY - CONF AB - For many cryptographic primitives, it is relatively easy to achieve selective security (where the adversary commits a-priori to some of the choices to be made later in the attack) but appears difficult to achieve the more natural notion of adaptive security (where the adversary can make all choices on the go as the attack progresses). A series of several recent works shows how to cleverly achieve adaptive security in several such scenarios including generalized selective decryption (Panjwani, TCC ’07 and Fuchsbauer et al., CRYPTO ’15), constrained PRFs (Fuchsbauer et al., ASIACRYPT ’14), and Yao garbled circuits (Jafargholi and Wichs, TCC ’16b). Although the above works expressed vague intuition that they share a common technique, the connection was never made precise. In this work we present a new framework that connects all of these works and allows us to present them in a unified and simplified fashion. Moreover, we use the framework to derive a new result for adaptively secure secret sharing over access structures defined via monotone circuits. We envision that further applications will follow in the future. Underlying our framework is the following simple idea. It is well known that selective security, where the adversary commits to n-bits of information about his future choices, automatically implies adaptive security at the cost of amplifying the adversary’s advantage by a factor of up to 2n. However, in some cases the proof of selective security proceeds via a sequence of hybrids, where each pair of adjacent hybrids locally only requires some smaller partial information consisting of m ≪ n bits. The partial information needed might be completely different between different pairs of hybrids, and if we look across all the hybrids we might rely on the entire n-bit commitment. Nevertheless, the above is sufficient to prove adaptive security, at the cost of amplifying the adversary’s advantage by a factor of only 2m ≪ 2n. In all of our examples using the above framework, the different hybrids are captured by some sort of a graph pebbling game and the amount of information that the adversary needs to commit to in each pair of hybrids is bounded by the maximum number of pebbles in play at any point in time. Therefore, coming up with better strategies for proving adaptive security translates to various pebbling strategies for different types of graphs. AU - Jafargholi, Zahra AU - Kamath Hosdurg, Chethan AU - Klein, Karen AU - Komargodski, Ilan AU - Pietrzak, Krzysztof Z AU - Wichs, Daniel ED - Katz, Jonathan ED - Shacham, Hovav ID - 637 SN - 978-331963687-0 TI - Be adaptive avoid overcommitting VL - 10401 ER - TY - GEN AB - Mathematica notebooks used to generate figures. AU - Etheridge, Alison AU - Barton, Nicholas H ID - 9842 TI - Data for: Establishment in a new habitat by polygenic adaptation ER - TY - CONF AB - Greedy optimization methods such as Matching Pursuit (MP) and Frank-Wolfe (FW) algorithms regained popularity in recent years due to their simplicity, effectiveness and theoretical guarantees. MP and FW address optimization over the linear span and the convex hull of a set of atoms, respectively. In this paper, we consider the intermediate case of optimization over the convex cone, parametrized as the conic hull of a generic atom set, leading to the first principled definitions of non-negative MP algorithms for which we give explicit convergence rates and demonstrate excellent empirical performance. In particular, we derive sublinear (O(1/t)) convergence on general smooth and convex objectives, and linear convergence (O(e−t)) on strongly convex objectives, in both cases for general sets of atoms. Furthermore, we establish a clear correspondence of our algorithms to known algorithms from the MP and FW literature. Our novel algorithms and analyses target general atom sets and general objective functions, and hence are directly applicable to a large variety of learning settings. AU - Locatello, Francesco AU - Tschannen, Michael AU - Rätsch, Gunnar AU - Jaggi, Martin ID - 14206 SN - 9781510860964 T2 - Advances in Neural Information Processing Systems TI - Greedy algorithms for cone constrained optimization with convergence guarantees ER - TY - CONF AB - Two of the most fundamental prototypes of greedy optimization are the matching pursuit and Frank-Wolfe algorithms. In this paper, we take a unified view on both classes of methods, leading to the first explicit convergence rates of matching pursuit methods in an optimization sense, for general sets of atoms. We derive sublinear (1/t) convergence for both classes on general smooth objectives, and linear convergence on strongly convex objectives, as well as a clear correspondence of algorithm variants. Our presented algorithms and rates are affine invariant, and do not need any incoherence or sparsity assumptions. AU - Locatello, Francesco AU - Khanna, Rajiv AU - Tschannen, Michael AU - Jaggi, Martin ID - 14205 T2 - Proceedings of the 20th International Conference on Artificial Intelligence and Statistics TI - A unified optimization view on generalized matching pursuit and Frank-Wolfe VL - 54 ER - TY - THES AB - Restriction-modification (RM) represents the simplest and possibly the most widespread mechanism of self/non-self discrimination in nature. In order to provide bacteria with immunity against bacteriophages and other parasitic genetic elements, RM systems rely on a balance between two enzymes: the restriction enzyme, which cleaves non-self DNA at specific restriction sites, and the modification enzyme, which tags the host’s DNA as self and thus protects it from cleavage. In this thesis, I use population and single-cell level experiments in combination with mathematical modeling to study different aspects of the interplay between RM systems, bacteria and bacteriophages. First, I analyze how mutations in phage restriction sites affect the probability of phage escape – an inherently stochastic process, during which phages accidently get modified instead of restricted. Next, I use single-cell experiments to show that RM systems can, with a low probability, attack the genome of their bacterial host and that this primitive form of autoimmunity leads to a tradeoff between the evolutionary cost and benefit of RM systems. Finally, I investigate the nature of interactions between bacteria, RM systems and temperate bacteriophages to find that, as a consequence of phage escape and its impact on population dynamics, RM systems can promote acquisition of symbiotic bacteriophages, rather than limit it. The results presented here uncover new fundamental biological properties of RM systems and highlight their importance in the ecology and evolution of bacteria, bacteriophages and their interactions. AU - Pleska, Maros ID - 202 SN - 2663-337X TI - Biology of restriction-modification systems at the single-cell and population level ER - TY - THES AB - The main objects considered in the present work are simplicial and CW-complexes with vertices forming a random point cloud. In particular, we consider a Poisson point process in R^n and study Delaunay and Voronoi complexes of the first and higher orders and weighted Delaunay complexes obtained as sections of Delaunay complexes, as well as the Čech complex. Further, we examine theDelaunay complex of a Poisson point process on the sphere S^n, as well as of a uniform point cloud, which is equivalent to the convex hull, providing a connection to the theory of random polytopes. Each of the complexes in question can be endowed with a radius function, which maps its cells to the radii of appropriately chosen circumspheres, called the radius of the cell. Applying and developing discrete Morse theory for these functions, joining it together with probabilistic and sometimes analytic machinery, and developing several integral geometric tools, we aim at getting the distributions of circumradii of typical cells. For all considered complexes, we are able to generalize and obtain up to constants the distribution of radii of typical intervals of all types. In low dimensions the constants can be computed explicitly, thus providing the explicit expressions for the expected numbers of cells. In particular, it allows to find the expected density of simplices of every dimension for a Poisson point process in R^4, whereas the result for R^3 was known already in 1970's. AU - Nikitenko, Anton ID - 6287 SN - 2663-337X TI - Discrete Morse theory for random complexes ER - TY - THES AB - Plant hormone auxin and its transport between cells belong to the most important mechanisms controlling plant development. Auxin itself could change localization of PINs and thereby control direction of its own flow. We performed an expression profiling experiment in Arabidopsis roots to identify potential regulators of PIN polarity which are transcriptionally regulated by auxin signalling. We identified several novel regulators and performed a detailed characterization of the transcription factor WRKY23 (At2g47260) and its role in auxin feedback on PIN polarity. Gain-of-function and dominant-negative mutants revealed that WRKY23 plays a crucial role in mediating the auxin effect on PIN polarity. In concordance, typical polar auxin transport processes such as gravitropism and leaf vascular pattern formation were disturbed by interfering with WRKY23 function. In order to identify direct targets of WRKY23, we performed consequential expression profiling experiments using a WRKY23 inducible gain-of-function line and dominant-negative WRKY23 line that is defunct in PIN re-arrangement. Among several genes mostly related to the groups of cell wall and defense process regulators, we identified LYSINE-HISTIDINE TRANSPORTER 1 (LHT1; At5g40780), a small amino acid permease gene from the amino acid/auxin permease family (AAAP), we present its detailed characterisation in auxin feedback on PIN repolarization, identified its transcriptional regulation, we propose a potential mechanism of its action. Moreover, we identified also a member of receptor-like protein kinase LRR-RLK (LEUCINE-RICH REPEAT TRANSMEMBRANE PROTEIN KINASE PROTEIN 1; LRRK1; At1g05700), which also affects auxin-dependent PIN re-arrangement. We described its transcriptional behaviour, subcellular localization. Based on global expression data, we tried to identify ligand responsible for mechanism of signalling and suggest signalling partner and interactors. Additionally, we described role of novel phytohormone group, strigolactone, in auxin-dependent PIN re-arrangement, that could be a fundament for future studies in this field. Our results provide first insights into an auxin transcriptional network targeting PIN localization and thus regulating plant development. We highlighted WRKY23 transcriptional network and characterised its mediatory role in plant development. We identified direct effectors of this network, LHT1 and LRRK1, and describe their roles in PIN re-arrangement and PIN-dependent auxin transport processes. AU - Prat, Tomas ID - 1127 SN - 2663-337X TI - Identification of novel regulators of PIN polarity and development of novel auxin sensor ER - TY - JOUR AB - The Ising model is one of the simplest and most famous models of interacting systems. It was originally proposed to model ferromagnetic interactions in statistical physics and is now widely used to model spatial processes in many areas such as ecology, sociology, and genetics, usually without testing its goodness-of-fit. Here, we propose an exact goodness-of-fit test for the finite-lattice Ising model. The theory of Markov bases has been developed in algebraic statistics for exact goodness-of-fit testing using a Monte Carlo approach. However, this beautiful theory has fallen short of its promise for applications, because finding a Markov basis is usually computationally intractable. We develop a Monte Carlo method for exact goodness-of-fit testing for the Ising model which avoids computing a Markov basis and also leads to a better connectivity of the Markov chain and hence to a faster convergence. We show how this method can be applied to analyze the spatial organization of receptors on the cell membrane. AU - Martin Del Campo Sanchez, Abraham AU - Cepeda Humerez, Sarah A AU - Uhler, Caroline ID - 2016 IS - 2 JF - Scandinavian Journal of Statistics SN - 03036898 TI - Exact goodness-of-fit testing for the Ising model VL - 44 ER - TY - JOUR AB - We consider N×N Hermitian random matrices H consisting of blocks of size M≥N6/7. The matrix elements are i.i.d. within the blocks, close to a Gaussian in the four moment matching sense, but their distribution varies from block to block to form a block-band structure, with an essential band width M. We show that the entries of the Green’s function G(z)=(H−z)−1 satisfy the local semicircle law with spectral parameter z=E+iη down to the real axis for any η≫N−1, using a combination of the supersymmetry method inspired by Shcherbina (J Stat Phys 155(3): 466–499, 2014) and the Green’s function comparison strategy. Previous estimates were valid only for η≫M−1. The new estimate also implies that the eigenvectors in the middle of the spectrum are fully delocalized. AU - Bao, Zhigang AU - Erdös, László ID - 1528 IS - 3-4 JF - Probability Theory and Related Fields SN - 01788051 TI - Delocalization for a class of random block band matrices VL - 167 ER - TY - JOUR AB - Phat is an open-source C. ++ library for the computation of persistent homology by matrix reduction, targeted towards developers of software for topological data analysis. We aim for a simple generic design that decouples algorithms from data structures without sacrificing efficiency or user-friendliness. We provide numerous different reduction strategies as well as data types to store and manipulate the boundary matrix. We compare the different combinations through extensive experimental evaluation and identify optimization techniques that work well in practical situations. We also compare our software with various other publicly available libraries for persistent homology. AU - Bauer, Ulrich AU - Kerber, Michael AU - Reininghaus, Jan AU - Wagner, Hubert ID - 1433 JF - Journal of Symbolic Computation SN - 07477171 TI - Phat - Persistent homology algorithms toolbox VL - 78 ER - TY - JOUR AB - We consider the problem of computing the set of initial states of a dynamical system such that there exists a control strategy to ensure that the trajectories satisfy a temporal logic specification with probability 1 (almost-surely). We focus on discrete-time, stochastic linear dynamics and specifications given as formulas of the Generalized Reactivity(1) fragment of Linear Temporal Logic over linear predicates in the states of the system. We propose a solution based on iterative abstraction-refinement, and turn-based 2-player probabilistic games. While the theoretical guarantee of our algorithm after any finite number of iterations is only a partial solution, we show that if our algorithm terminates, then the result is the set of all satisfying initial states. Moreover, for any (partial) solution our algorithm synthesizes witness control strategies to ensure almost-sure satisfaction of the temporal logic specification. While the proposed algorithm guarantees progress and soundness in every iteration, it is computationally demanding. We offer an alternative, more efficient solution for the reachability properties that decomposes the problem into a series of smaller problems of the same type. All algorithms are demonstrated on an illustrative case study. AU - Svoreňová, Mária AU - Kretinsky, Jan AU - Chmelik, Martin AU - Chatterjee, Krishnendu AU - Cěrná, Ivana AU - Belta, Cǎlin ID - 1407 IS - 2 JF - Nonlinear Analysis: Hybrid Systems TI - Temporal logic control for stochastic linear systems using abstraction refinement of probabilistic games VL - 23 ER - TY - JOUR AB - One of the major challenges in physically based modelling is making simulations efficient. Adaptive models provide an essential solution to these efficiency goals. These models are able to self-adapt in space and time, attempting to provide the best possible compromise between accuracy and speed. This survey reviews the adaptive solutions proposed so far in computer graphics. Models are classified according to the strategy they use for adaptation, from time-stepping and freezing techniques to geometric adaptivity in the form of structured grids, meshes and particles. Applications range from fluids, through deformable bodies, to articulated solids. AU - Manteaux, Pierre AU - Wojtan, Christopher J AU - Narain, Rahul AU - Redon, Stéphane AU - Faure, François AU - Cani, Marie ID - 1367 IS - 6 JF - Computer Graphics Forum SN - 01677055 TI - Adaptive physically based models in computer graphics VL - 36 ER - TY - JOUR AB - We present a computer-aided programming approach to concurrency. The approach allows programmers to program assuming a friendly, non-preemptive scheduler, and our synthesis procedure inserts synchronization to ensure that the final program works even with a preemptive scheduler. The correctness specification is implicit, inferred from the non-preemptive behavior. Let us consider sequences of calls that the program makes to an external interface. The specification requires that any such sequence produced under a preemptive scheduler should be included in the set of sequences produced under a non-preemptive scheduler. We guarantee that our synthesis does not introduce deadlocks and that the synchronization inserted is optimal w.r.t. a given objective function. The solution is based on a finitary abstraction, an algorithm for bounded language inclusion modulo an independence relation, and generation of a set of global constraints over synchronization placements. Each model of the global constraints set corresponds to a correctness-ensuring synchronization placement. The placement that is optimal w.r.t. the given objective function is chosen as the synchronization solution. We apply the approach to device-driver programming, where the driver threads call the software interface of the device and the API provided by the operating system. Our experiments demonstrate that our synthesis method is precise and efficient. The implicit specification helped us find one concurrency bug previously missed when model-checking using an explicit, user-provided specification. We implemented objective functions for coarse-grained and fine-grained locking and observed that different synchronization placements are produced for our experiments, favoring a minimal number of synchronization operations or maximum concurrency, respectively. AU - Cerny, Pavol AU - Clarke, Edmund AU - Henzinger, Thomas A AU - Radhakrishna, Arjun AU - Ryzhyk, Leonid AU - Samanta, Roopsha AU - Tarrach, Thorsten ID - 1338 IS - 2-3 JF - Formal Methods in System Design TI - From non-preemptive to preemptive scheduling using synchronization synthesis VL - 50 ER - TY - JOUR AB - The behaviour of gene regulatory networks (GRNs) is typically analysed using simulation-based statistical testing-like methods. In this paper, we demonstrate that we can replace this approach by a formal verification-like method that gives higher assurance and scalability. We focus on Wagner’s weighted GRN model with varying weights, which is used in evolutionary biology. In the model, weight parameters represent the gene interaction strength that may change due to genetic mutations. For a property of interest, we synthesise the constraints over the parameter space that represent the set of GRNs satisfying the property. We experimentally show that our parameter synthesis procedure computes the mutational robustness of GRNs—an important problem of interest in evolutionary biology—more efficiently than the classical simulation method. We specify the property in linear temporal logic. We employ symbolic bounded model checking and SMT solving to compute the space of GRNs that satisfy the property, which amounts to synthesizing a set of linear constraints on the weights. AU - Giacobbe, Mirco AU - Guet, Calin C AU - Gupta, Ashutosh AU - Henzinger, Thomas A AU - Paixao, Tiago AU - Petrov, Tatjana ID - 1351 IS - 8 JF - Acta Informatica SN - 00015903 TI - Model checking the evolution of gene regulatory networks VL - 54 ER - TY - JOUR AB - Evolutionary algorithms (EAs) form a popular optimisation paradigm inspired by natural evolution. In recent years the field of evolutionary computation has developed a rigorous analytical theory to analyse the runtimes of EAs on many illustrative problems. Here we apply this theory to a simple model of natural evolution. In the Strong Selection Weak Mutation (SSWM) evolutionary regime the time between occurrences of new mutations is much longer than the time it takes for a mutated genotype to take over the population. In this situation, the population only contains copies of one genotype and evolution can be modelled as a stochastic process evolving one genotype by means of mutation and selection between the resident and the mutated genotype. The probability of accepting the mutated genotype then depends on the change in fitness. We study this process, SSWM, from an algorithmic perspective, quantifying its expected optimisation time for various parameters and investigating differences to a similar evolutionary algorithm, the well-known (1+1) EA. We show that SSWM can have a moderate advantage over the (1+1) EA at crossing fitness valleys and study an example where SSWM outperforms the (1+1) EA by taking advantage of information on the fitness gradient. AU - Paixao, Tiago AU - Pérez Heredia, Jorge AU - Sudholt, Dirk AU - Trubenova, Barbora ID - 1336 IS - 2 JF - Algorithmica SN - 01784617 TI - Towards a runtime comparison of natural and artificial evolution VL - 78 ER - TY - JOUR AB - We consider the local eigenvalue distribution of large self-adjoint N×N random matrices H=H∗ with centered independent entries. In contrast to previous works the matrix of variances sij=\mathbbmE|hij|2 is not assumed to be stochastic. Hence the density of states is not the Wigner semicircle law. Its possible shapes are described in the companion paper (Ajanki et al. in Quadratic Vector Equations on the Complex Upper Half Plane. arXiv:1506.05095). We show that as N grows, the resolvent, G(z)=(H−z)−1, converges to a diagonal matrix, diag(m(z)), where m(z)=(m1(z),…,mN(z)) solves the vector equation −1/mi(z)=z+∑jsijmj(z) that has been analyzed in Ajanki et al. (Quadratic Vector Equations on the Complex Upper Half Plane. arXiv:1506.05095). We prove a local law down to the smallest spectral resolution scale, and bulk universality for both real symmetric and complex hermitian symmetry classes. AU - Ajanki, Oskari H AU - Erdös, László AU - Krüger, Torben H ID - 1337 IS - 3-4 JF - Probability Theory and Related Fields SN - 01788051 TI - Universality for general Wigner-type matrices VL - 169 ER - TY - JOUR AB - We study controller synthesis problems for finite-state Markov decision processes, where the objective is to optimize the expected mean-payoff performance and stability (also known as variability in the literature). We argue that the basic notion of expressing the stability using the statistical variance of the mean payoff is sometimes insufficient, and propose an alternative definition. We show that a strategy ensuring both the expected mean payoff and the variance below given bounds requires randomization and memory, under both the above definitions. We then show that the problem of finding such a strategy can be expressed as a set of constraints. AU - Brázdil, Tomáš AU - Chatterjee, Krishnendu AU - Forejt, Vojtěch AU - Kučera, Antonín ID - 1294 JF - Journal of Computer and System Sciences TI - Trading performance for stability in Markov decision processes VL - 84 ER - TY - JOUR AB - Since 2006, reprogrammed cells have increasingly been used as a biomedical research technique in addition to neuro-psychiatric methods. These rapidly evolving techniques allow for the generation of neuronal sub-populations, and have sparked interest not only in monogenetic neuro-psychiatric diseases, but also in poly-genetic and poly-aetiological disorders such as schizophrenia (SCZ) and bipolar disorder (BPD). This review provides a summary of 19 publications on reprogrammed adult somatic cells derived from patients with SCZ, and five publications using this technique in patients with BPD. As both disorders are complex and heterogeneous, there is a plurality of hypotheses to be tested in vitro. In SCZ, data on alterations of dopaminergic transmission in vitro are sparse, despite the great explanatory power of the so-called DA hypothesis of SCZ. Some findings correspond to perturbations of cell energy metabolism, and observations in reprogrammed cells suggest neuro-developmental alterations. Some studies also report on the efficacy of medicinal compounds to revert alterations observed in cellular models. However, due to the paucity of replication studies, no comprehensive conclusions can be drawn from studies using reprogrammed cells at the present time. In the future, findings from cell culture methods need to be integrated with clinical, epidemiological, pharmacological and imaging data in order to generate a more comprehensive picture of SCZ and BPD. AU - Sauerzopf, Ulrich AU - Sacco, Roberto AU - Novarino, Gaia AU - Niello, Marco AU - Weidenauer, Ana AU - Praschak Rieder, Nicole AU - Sitte, Harald AU - Willeit, Matthaeus ID - 1228 IS - 1 JF - European Journal of Neuroscience TI - Are reprogrammed cells a useful tool for studying dopamine dysfunction in psychotic disorders? A review of the current evidence VL - 45 ER -