TY - JOUR
AB - We study synthesis of controllers for real-time systems, where the objective is to stay in a given safe set. The problem is solved by obtaining winning strategies in the setting of concurrent two player timed automaton games with safety objectives. To prevent a player from winning by blocking time, we restrict each player to strategies that ensure that the player cannot be responsible for causing a Zeno run. We construct winning strategies for the controller which require access only to (1) the system clocks (thus, controllers which require their own internal infinitely precise clocks are not necessary), and (2) a logarithmic (in the number of clocks) number of memory bits (i.e. a linear number of memory states). Precisely, we show that for safety objectives, a memory of size (3 + lg (| C | + 1)) bits suffices for winning controller strategies, where C is the set of clocks of the timed automaton game, significantly improving the previous known exponential memory states bound. We also settle the open question of whether winning region-based strategies require memory for safety objectives by showing with an example the necessity of memory for such strategies to win for safety objectives. Finally, we show that the decision problem of determining if there exists a receptive player-1 winning strategy for safety objectives is EXPTIME-complete over timed automaton games.
AU - Chatterjee, Krishnendu
AU - Prabhu, Vinayak
ID - 2824
JF - Information and Computation
TI - Synthesis of memory-efficient, clock-memory free, and non-Zeno safety controllers for timed systems
VL - 228-229
ER -
TY - JOUR
AB - Myopia, or near-sightedness, is an ocular refractive error of unfocused image quality in front of the retinal plane. Individuals with high-grade myopia (dioptric power greater than -6.00) are predisposed to ocular morbidities such as glaucoma, retinal detachment, and myopic maculopathy. Nonsyndromic, high-grade myopia is highly heritable, and to date multiple gene loci have been reported. We performed exome sequencing in 4 individuals from an 11-member family of European descent from the United States. Affected individuals had a mean dioptric spherical equivalent of -22.00 sphere. A premature stop codon mutation c.157C>T (p.Gln53*) cosegregating with disease was discovered within SCO2 that maps to chromosome 22q13.33. Subsequent analyses identified three additional mutations in three highly myopic unrelated individuals (c.341G>A, c.418G>A, and c.776C>T). To determine differential gene expression in a developmental mouse model, we induced myopia by applying a -15.00D lens over one eye. Messenger RNA levels of SCO2 were significantly downregulated in myopic mouse retinae. Immunohistochemistry in mouse eyes confirmed SCO2 protein localization in retina, retinal pigment epithelium, and sclera. SCO2 encodes for a copper homeostasis protein influential in mitochondrial cytochrome c oxidase activity. Copper deficiencies have been linked with photoreceptor loss and myopia with increased scleral wall elasticity. Retinal thinning has been reported with an SC02 variant. Human mutation identification with support from an induced myopic animal provides biological insights of myopic development.
AU - Tran Viet, Khanh
AU - Powell, Caldwell
AU - Barathi, Veluchamy
AU - Klemm, Thomas
AU - Maurer Stroh, Sebastian
AU - Limviphuvadh, Vachiranee
AU - Soler, Vincent
AU - Ho, Candice
AU - Yanovitch, Tammy
AU - Schneider, Georg
AU - Li, Yi
AU - Nading, Erica
AU - Metlapally, Ravikanth
AU - Saw, Seang
AU - Goh, Liang
AU - Rozen, Steve
AU - Young, Terri
ID - 2826
IS - 5
JF - American Journal of Human Genetics
TI - Mutations in SCO2 are associated with autosomal-dominant high-grade myopia
VL - 92
ER -
TY - JOUR
AB - Removal of cargos from the cell surface via endocytosis is an efficient mechanism to regulate activities of plasma membrane (PM)-resident proteins, such as receptors or transporters. Salicylic acid (SA) is an important plant hormone that is traditionally associated with pathogen defense. Here, we describe an unanticipated effect of SA on subcellular endocytic cycling of proteins. Both exogenous treatments and endogenously enhanced SA levels repressed endocytosis of different PM proteins. The SA effect on endocytosis did not involve transcription or known components of the SA signaling pathway for transcriptional regulation. SA likely targets an endocytic mechanism that involves the coat protein clathrin, because SA interfered with the clathrin incidence at the PM and clathrin-deficient mutants were less sensitive to the impact of SA on the auxin distribution and root bending during the gravitropic response. By contrast, SA did not affect the ligand-induced endocytosis of the FLAGELLIN SENSING2 (FLS2) receptor during pathogen responses. Our data suggest that the established SA impact on transcription in plant immunity and the nontranscriptional effect of SA on clathrin-mediated endocytosis are independent mechanisms by which SA regulates distinct aspects of plant physiology.
AU - Du, Yunlong
AU - Tejos, Ricardo
AU - Beck, Martina
AU - Himschoot, Ellie
AU - Li, Hongjiang
AU - Robatzek, Silke
AU - Vanneste, Steffen
AU - Friml, Jirí
ID - 2827
IS - 19
JF - PNAS
TI - Salicylic acid interferes with clathrin-mediated endocytic protein trafficking
VL - 110
ER -
TY - JOUR
AB - We study the complexity of valued constraint satisfaction problems (VCSPs) parametrized by a constraint language, a fixed set of cost functions over a finite domain. An instance of the problem is specified by a sum of cost functions from the language and the goal is to minimize the sum. Under the unique games conjecture, the approximability of finite-valued VCSPs is well understood, see Raghavendra [2008]. However, there is no characterization of finite-valued VCSPs, let alone general-valued VCSPs, that can be solved exactly in polynomial time, thus giving insights from a combinatorial optimization perspective. We consider the case of languages containing all possible unary cost functions. In the case of languages consisting of only {0, ∞}-valued cost functions (i.e., relations), such languages have been called conservative and studied by Bulatov [2003, 2011] and recently by Barto [2011]. Since we study valued languages, we call a language conservative if it contains all finite-valued unary cost functions. The computational complexity of conservative valued languages has been studied by Cohen et al. [2006] for languages over Boolean domains, by Deineko et al. [2008] for {0, 1}-valued languages (a.k.a Max-CSP), and by Takhanov [2010a] for {0, ∞}-valued languages containing all finite-valued unary cost functions (a.k.a. Min-Cost-Hom). We prove a Schaefer-like dichotomy theorem for conservative valued languages: if all cost functions in the language satisfy a certain condition (specified by a complementary combination of STP and MJN multimor-phisms), then any instance can be solved in polynomial time (via a new algorithm developed in this article), otherwise the language is NP-hard. This is the first complete complexity classification of general-valued constraint languages over non-Boolean domains. It is a common phenomenon that complexity classifications of problems over non-Boolean domains are significantly harder than the Boolean cases. The polynomial-time algorithm we present for the tractable cases is a generalization of the submodular minimization problem and a result of Cohen et al. [2008]. Our results generalize previous results by Takhanov [2010a] and (a subset of results) by Cohen et al. [2006] and Deineko et al. [2008]. Moreover, our results do not rely on any computer-assisted search as in Deineko et al. [2008], and provide a powerful tool for proving hardness of finite-valued and general-valued languages.
AU - Kolmogorov, Vladimir
AU - Živný, Stanislav
ID - 2828
IS - 2
JF - Journal of the ACM
TI - The complexity of conservative valued CSPs
VL - 60
ER -
TY - JOUR
AB - Laminar-turbulent intermittency is intrinsic to the transitional regime of a wide range of fluid flows including pipe, channel, boundary layer, and Couette flow. In the latter turbulent spots can grow and form continuous stripes, yet in the stripe-normal direction they remain interspersed by laminar fluid. We carry out direct numerical simulations in a long narrow domain and observe that individual turbulent stripes are transient. In agreement with recent observations in pipe flow, we find that turbulence becomes sustained at a distinct critical point once the spatial proliferation outweighs the inherent decaying process. By resolving the asymptotic size distributions close to criticality we can for the first time demonstrate scale invariance at the onset of turbulence.
AU - Shi, Liang
AU - Avila, Marc
AU - Hof, Björn
ID - 2829
IS - 20
JF - Physical Review Letters
TI - Scale invariance at the onset of turbulence in couette flow
VL - 110
ER -
TY - JOUR
AU - Moussion, Christine
AU - Sixt, Michael K
ID - 2830
IS - 5
JF - Immunity
TI - A conduit to amplify innate immunity
VL - 38
ER -
TY - JOUR
AB - We consider Markov decision processes (MDPs) with Büchi (liveness) objectives. We consider the problem of computing the set of almost-sure winning states from where the objective can be ensured with probability 1. Our contributions are as follows: First, we present the first subquadratic symbolic algorithm to compute the almost-sure winning set for MDPs with Büchi objectives; our algorithm takes O(n · √ m) symbolic steps as compared to the previous known algorithm that takes O(n 2) symbolic steps, where n is the number of states and m is the number of edges of the MDP. In practice MDPs have constant out-degree, and then our symbolic algorithm takes O(n · √ n) symbolic steps, as compared to the previous known O(n 2) symbolic steps algorithm. Second, we present a new algorithm, namely win-lose algorithm, with the following two properties: (a) the algorithm iteratively computes subsets of the almost-sure winning set and its complement, as compared to all previous algorithms that discover the almost-sure winning set upon termination; and (b) requires O(n · √ K) symbolic steps, where K is the maximal number of edges of strongly connected components (scc's) of the MDP. The win-lose algorithm requires symbolic computation of scc's. Third, we improve the algorithm for symbolic scc computation; the previous known algorithm takes linear symbolic steps, and our new algorithm improves the constants associated with the linear number of steps. In the worst case the previous known algorithm takes 5×n symbolic steps, whereas our new algorithm takes 4×n symbolic steps.
AU - Chatterjee, Krishnendu
AU - Henzinger, Monika
AU - Joglekar, Manas
AU - Shah, Nisarg
ID - 2831
IS - 3
JF - Formal Methods in System Design
TI - Symbolic algorithms for qualitative analysis of Markov decision processes with Büchi objectives
VL - 42
ER -
TY - JOUR
AB - PIN-FORMED (PIN) proteins localize asymmetrically at the plasma membrane and mediate intercellular polar transport of the plant hormone auxin that is crucial for a multitude of developmental processes in plants. PIN localization is under extensive control by environmental or developmental cues, but mechanisms regulating PIN localization are not fully understood. Here we show that early endosomal components ARF GEF BEN1 and newly identified Sec1/Munc18 family protein BEN2 are involved in distinct steps of early endosomal trafficking. BEN1 and BEN2 are collectively required for polar PIN localization, for their dynamic repolarization, and consequently for auxin activity gradient formation and auxin-related developmental processes including embryonic patterning, organogenesis, and vasculature venation patterning. These results show that early endosomal trafficking is crucial for cell polarity and auxin-dependent regulation of plant architecture.
AU - Tanaka, Hirokazu
AU - Kitakura, Saeko
AU - Rakusová, Hana
AU - Uemura, Tomohiro
AU - Feraru, Mugurel
AU - De Rycke, Riet
AU - Robert, Stéphanie
AU - Kakimoto, Tatsuo
AU - Friml, Jirí
ID - 2832
IS - 5
JF - PLoS Genetics
TI - Cell polarity and patterning by PIN trafficking through early endosomal compartments in arabidopsis thaliana
VL - 9
ER -
TY - JOUR
AB - During development, mechanical forces cause changes in size, shape, number, position, and gene expression of cells. They are therefore integral to any morphogenetic processes. Force generation by actin-myosin networks and force transmission through adhesive complexes are two self-organizing phenomena driving tissue morphogenesis. Coordination and integration of forces by long-range force transmission and mechanosensing of cells within tissues produce large-scale tissue shape changes. Extrinsic mechanical forces also control tissue patterning by modulating cell fate specification and differentiation. Thus, the interplay between tissue mechanics and biochemical signaling orchestrates tissue morphogenesis and patterning in development.
AU - Heisenberg, Carl-Philipp J
AU - Bellaïche, Yohanns
ID - 2833
IS - 5
JF - Cell
TI - Forces in tissue morphogenesis and patterning
VL - 153
ER -
TY - JOUR
AB - Although the equations governing fluid flow are well known, there are no analytical expressions that describe the complexity of turbulent motion. A recent proposition is that in analogy to low dimensional chaotic systems, turbulence is organized around unstable solutions of the governing equations which provide the building blocks of the disordered dynamics. We report the discovery of periodic solutions which just like intermittent turbulence are spatially localized and show that turbulent transients arise from one such solution branch.
AU - Avila, Marc
AU - Mellibovsky, Fernando
AU - Roland, Nicolas
AU - Hof, Björn
ID - 2834
IS - 22
JF - Physical Review Letters
TI - Streamwise-localized solutions at the onset of turbulence in pipe flow
VL - 110
ER -
TY - JOUR
AB - The phytohormone auxin regulates virtually every aspect of plant development. To identify new genes involved in auxin activity, a genetic screen was performed for Arabidopsis (Arabidopsis thaliana) mutants with altered expression of the auxin-responsive reporter DR5rev:GFP. One of the mutants recovered in the screen, designated as weak auxin response3 (wxr3), exhibits much lower DR5rev:GFP expression when treated with the synthetic auxin 2,4-dichlorophenoxyacetic acid and displays severe defects in root development. The wxr3 mutant decreases polar auxin transport and results in a disruption of the asymmetric auxin distribution. The levels of the auxin transporters AUXIN1 and PIN-FORMED are dramatically reduced in the wxr3 root tip. Molecular analyses demonstrate that WXR3 is ROOT ULTRAVIOLET B-SENSITIVE1 (RUS1), a member of the conserved Domain of Unknown Function647 protein family found in diverse eukaryotic organisms. Our data suggest that RUS1/WXR3 plays an essential role in the regulation of polar auxin transport by maintaining the proper level of auxin transporters on the plasma membrane.
AU - Yu, Hong
AU - Karampelias, Michael
AU - Robert, Stéphanie
AU - Peer, Wendy
AU - Swarup, Ranjan
AU - Ye, Songqing
AU - Ge, Lei
AU - Cohen, Jerry
AU - Murphy, Angus
AU - Friml, Jirí
AU - Estelle, Mark
ID - 2835
IS - 2
JF - Plant Physiology
TI - Root ultraviolet b-sensitive1/weak auxin response3 is essential for polar auxin transport in arabidopsis
VL - 162
ER -
TY - JOUR
AB - We study the automatic synthesis of fair non-repudiation protocols, a class of fair exchange protocols, used for digital contract signing. First, we show how to specify the objectives of the participating agents and the trusted third party as path formulas in linear temporal logic and prove that the satisfaction of these objectives imply fairness; a property required of fair exchange protocols. We then show that weak (co-operative) co-synthesis and classical (strictly competitive) co-synthesis fail, whereas assume-guarantee synthesis (AGS) succeeds. We demonstrate the success of AGS as follows: (a) any solution of AGS is attack-free; no subset of participants can violate the objectives of the other participants; (b) the Asokan-Shoup-Waidner certified mail protocol that has known vulnerabilities is not a solution of AGS; (c) the Kremer-Markowitch non-repudiation protocol is a solution of AGS; and (d) AGS presents a new and symmetric fair non-repudiation protocol that is attack-free. To our knowledge this is the first application of synthesis to fair non-repudiation protocols, and our results show how synthesis can both automatically discover vulnerabilities in protocols and generate correct protocols. The solution to AGS can be computed efficiently as the secure equilibrium solution of three-player graph games.
AU - Chatterjee, Krishnendu
AU - Raman, Vishwanath
ID - 2836
IS - 4
JF - Formal Aspects of Computing
TI - Assume-guarantee synthesis for digital contract signing
VL - 26
ER -
TY - JOUR
AB - We consider a general class of N × N random matrices whose entries hij are independent up to a symmetry constraint, but not necessarily identically distributed. Our main result is a local semicircle law which improves previous results [17] both in the bulk and at the edge. The error bounds are given in terms of the basic small parameter of the model, maxi,j E|hij|2. As a consequence, we prove the universality of the local n-point correlation functions in the bulk spectrum for a class of matrices whose entries do not have comparable variances, including random band matrices with band width W ≫N1-εn with some εn > 0 and with a negligible mean-field component. In addition, we provide a coherent and pedagogical proof of the local semicircle law, streamlining and strengthening previous arguments from [17, 19, 6].
AU - Erdös, László
AU - Knowles, Antti
AU - Yau, Horng
AU - Yin, Jun
ID - 2837
IS - 59
JF - Electronic Journal of Probability
TI - The local semicircle law for a general class of random matrices
VL - 18
ER -
TY - JOUR
AB - Individuals with Down syndrome (DS) present important motor deficits that derive from altered motor development of infants and young children. DYRK1A, a candidate gene for DS abnormalities has been implicated in motor function due to its expression in motor nuclei in the adult brain, and its overexpression in DS mouse models leads to hyperactivity and altered motor learning. However, its precise role in the adult motor system, or its possible involvement in postnatal locomotor development has not yet been clarified. During the postnatal period we observed time-specific expression of Dyrk1A in discrete subsets of brainstem nuclei and spinal cord motor neurons. Interestingly, we describe for the first time the presence of Dyrk1A in the presynaptic terminal of the neuromuscular junctions and its axonal transport from the facial nucleus, suggesting a function for Dyrk1A in these structures. Relevant to DS, Dyrk1A overexpression in transgenic mice (TgDyrk1A) produces motor developmental alterations possibly contributing to DS motor phenotypes and modifies the numbers of motor cholinergic neurons, suggesting that the kinase may have a role in the development of the brainstem and spinal cord motor system.
AU - Arquè Fuste, Gloria
AU - Casanovas, Anna
AU - Dierssen, Mara
ID - 2838
IS - 1
JF - PLoS One
TI - Dyrk1A is dynamically expressed on subsets of motor neurons and in the neuromuscular junction: Possible role in Down syndrome
VL - 8
ER -
TY - JOUR
AB - Directional guidance of cells via gradients of chemokines is considered crucial for embryonic development, cancer dissemination, and immune responses. Nevertheless, the concept still lacks direct experimental confirmation in vivo. Here, we identify endogenous gradients of the chemokine CCL21 within mouse skin and show that they guide dendritic cells toward lymphatic vessels. Quantitative imaging reveals depots of CCL21 within lymphatic endothelial cells and steeply decaying gradients within the perilymphatic interstitium. These gradients match the migratory patterns of the dendritic cells, which directionally approach vessels from a distance of up to 90-micrometers. Interstitial CCL21 is immobilized to heparan sulfates, and its experimental delocalization or swamping the endogenous gradients abolishes directed migration. These findings functionally establish the concept of haptotaxis, directed migration along immobilized gradients, in tissues.
AU - Weber, Michele
AU - Hauschild, Robert
AU - Schwarz, Jan
AU - Moussion, Christine
AU - De Vries, Ingrid
AU - Legler, Daniel
AU - Luther, Sanjiv
AU - Bollenbach, Mark Tobias
AU - Sixt, Michael K
ID - 2839
IS - 6117
JF - Science
TI - Interstitial dendritic cell guidance by haptotactic chemokine gradients
VL - 339
ER -
TY - JOUR
AB - It is known that the entorhinal cortex plays a crucial role in spatial cognition in rodents. Neuroanatomical and electrophysiological data suggest that there is a functional distinction between 2 subregions within the entorhinal cortex, the medial entorhinal cortex (MEC), and the lateral entorhinal cortex (LEC). Rats with MEC or LEC lesions were trained in 2 navigation tasks requiring allothetic (water maze task) or idiothetic (path integration) information processing and 2-object exploration tasks allowing testing of spatial and nonspatial processing of intramaze objects. MEC lesions mildly affected place navigation in the water maze and produced a path integration deficit. They also altered the processing of spatial information in both exploration tasks while sparing the processing of nonspatial information. LEC lesions did not affect navigation abilities in both the water maze and the path integration tasks. They altered spatial and nonspatial processing in the object exploration task but not in the one-trial recognition task. Overall, these results indicate that the MEC is important for spatial processing and path integration. The LEC has some influence on both spatial and nonspatial processes, suggesting that the 2 kinds of information interact at the level of the EC.
AU - Van Cauter, Tiffany
AU - Camon, Jeremy
AU - Alvernhe, Alice
AU - Elduayen, Coralie
AU - Sargolini, Francesca
AU - Save, Étienne
ID - 2840
IS - 2
JF - Cerebral Cortex
TI - Distinct roles of medial and lateral entorhinal cortex in spatial cognition
VL - 23
ER -
TY - JOUR
AB - In zebrafish early development, blastoderm cells undergo extensive radial intercalations, triggering the spreading of the blastoderm over the yolk cell and thereby initiating embryonic body axis formation. Now reporting in Developmental Cell, Song et al. (2013) demonstrate a critical function for EGF-dependent E-cadherin endocytosis in promoting blastoderm cell intercalations.
AU - Morita, Hitoshi
AU - Heisenberg, Carl-Philipp J
ID - 2841
IS - 6
JF - Developmental Cell
TI - Holding on and letting go: Cadherin turnover in cell intercalation
VL - 24
ER -
TY - JOUR
AB - We outline two approaches to inference of neighbourhood size, N, and dispersal rate, σ2, based on either allele frequencies or on the lengths of sequence blocks that are shared between genomes. Over intermediate timescales (10-100 generations, say), populations that live in two dimensions approach a quasi-equilibrium that is independent of both their local structure and their deeper history. Over such scales, the standardised covariance of allele frequencies (i.e. pairwise FS T) falls with the logarithm of distance, and depends only on neighbourhood size, N, and a 'local scale', κ; the rate of gene flow, σ2, cannot be inferred. We show how spatial correlations can be accounted for, assuming a Gaussian distribution of allele frequencies, giving maximum likelihood estimates of N and κ. Alternatively, inferences can be based on the distribution of the lengths of sequence that are identical between blocks of genomes: long blocks (>0.1 cM, say) tell us about intermediate timescales, over which we assume a quasi-equilibrium. For large neighbourhood size, the distribution of long blocks is given directly by the classical Wright-Malécot formula; this relationship can be used to infer both N and σ2. With small neighbourhood size, there is an appreciable chance that recombinant lineages will coalesce back before escaping into the distant past. For this case, we show that if genomes are sampled from some distance apart, then the distribution of lengths of blocks that are identical in state is geometric, with a mean that depends on N and σ2.
AU - Barton, Nicholas H
AU - Etheridge, Alison
AU - Kelleher, Jerome
AU - Véber, Amandine
ID - 2842
IS - 1
JF - Theoretical Population Biology
TI - Inference in two dimensions: Allele frequencies versus lengths of shared sequence blocks
VL - 87
ER -
TY - CONF
AB - Mathematical objects can be measured unambiguously, but not so objects from our physical world. Even the total length of tubelike shapes has its difficulties. We introduce a combination of geometric, probabilistic, and topological methods to design a stable length estimate for tube-like shapes; that is: one that is insensitive to small shape changes.
AU - Edelsbrunner, Herbert
AU - Pausinger, Florian
ID - 2843
T2 - 17th IAPR International Conference on Discrete Geometry for Computer Imagery
TI - Stable length estimates of tube-like shapes
VL - 7749
ER -
TY - JOUR
AB - As soon as a seed germinates, plant growth relates to gravity to ensure that the root penetrates the soil and the shoot expands aerially. Whereas mechanisms of positive and negative orthogravitropism of primary roots and shoots are relatively well understood [1-3], lateral organs often show more complex growth behavior [4]. Lateral roots (LRs) seemingly suppress positive gravitropic growth and show a defined gravitropic set-point angle (GSA) that allows radial expansion of the root system (plagiotropism) [3, 4]. Despite its eminent importance for root architecture, it so far remains completely unknown how lateral organs partially suppress positive orthogravitropism. Here we show that the phytohormone auxin steers GSA formation and limits positive orthogravitropism in LR. Low and high auxin levels/signaling lead to radial or axial root systems, respectively. At a cellular level, it is the auxin transport-dependent regulation of asymmetric growth in the elongation zone that determines GSA. Our data suggest that strong repression of PIN4/PIN7 and transient PIN3 expression limit auxin redistribution in young LR columella cells. We conclude that PIN activity, by temporally limiting the asymmetric auxin fluxes in the tip of LRs, induces transient, differential growth responses in the elongation zone and, consequently, controls root architecture.
AU - Rosquete, Michel
AU - Von Wangenheim, Daniel
AU - Marhavy, Peter
AU - Barbez, Elke
AU - Stelzer, Ernst
AU - Benková, Eva
AU - Maizel, Alexis
AU - Kleine Vehn, Jürgen
ID - 2844
IS - 9
JF - Current Biology
TI - An auxin transport mechanism restricts positive orthogravitropism in lateral roots
VL - 23
ER -