TY - CONF AB - We consider the core algorithmic problems related to verification of systems with respect to three classical quantitative properties, namely, the mean-payoff property, the ratio property, and the minimum initial credit for energy property. The algorithmic problem given a graph and a quantitative property asks to compute the optimal value (the infimum value over all traces) from every node of the graph. We consider graphs with constant treewidth, and it is well-known that the control-flow graphs of most programs have constant treewidth. Let n denote the number of nodes of a graph, m the number of edges (for constant treewidth graphs m=O(n)) and W the largest absolute value of the weights. Our main theoretical results are as follows. First, for constant treewidth graphs we present an algorithm that approximates the mean-payoff value within a multiplicative factor of ϵ in time O(n⋅log(n/ϵ)) and linear space, as compared to the classical algorithms that require quadratic time. Second, for the ratio property we present an algorithm that for constant treewidth graphs works in time O(n⋅log(|a⋅b|))=O(n⋅log(n⋅W)), when the output is ab, as compared to the previously best known algorithm with running time O(n2⋅log(n⋅W)). Third, for the minimum initial credit problem we show that (i) for general graphs the problem can be solved in O(n2⋅m) time and the associated decision problem can be solved in O(n⋅m) time, improving the previous known O(n3⋅m⋅log(n⋅W)) and O(n2⋅m) bounds, respectively; and (ii) for constant treewidth graphs we present an algorithm that requires O(n⋅logn) time, improving the previous known O(n4⋅log(n⋅W)) bound. We have implemented some of our algorithms and show that they present a significant speedup on standard benchmarks. AU - Chatterjee, Krishnendu AU - Ibsen-Jensen, Rasmus AU - Pavlogiannis, Andreas ID - 1607 TI - Faster algorithms for quantitative verification in constant treewidth graphs VL - 9206 ER - TY - CONF AB - We present a flexible framework for the automated competitive analysis of on-line scheduling algorithms for firm-deadline real-time tasks based on multi-objective graphs: Given a task set and an on-line scheduling algorithm specified as a labeled transition system, along with some optional safety, liveness, and/or limit-average constraints for the adversary, we automatically compute the competitive ratio of the algorithm w.r.t. A clairvoyant scheduler. We demonstrate the flexibility and power of our approach by comparing the competitive ratio of several on-line algorithms, including Dover, that have been proposed in the past, for various task sets. Our experimental results reveal that none of these algorithms is universally optimal, in the sense that there are task sets where other schedulers provide better performance. Our framework is hence a very useful design tool for selecting optimal algorithms for a given application. AU - Chatterjee, Krishnendu AU - Pavlogiannis, Andreas AU - Kößler, Alexander AU - Schmid, Ulrich ID - 1714 IS - January T2 - Real-Time Systems Symposium TI - A framework for automated competitive analysis of on-line scheduling of firm-deadline tasks VL - 2015 ER - TY - CONF AB - We present a method for simulating brittle fracture under the assumptions of quasi-static linear elastic fracture mechanics (LEFM). Using the boundary element method (BEM) and Lagrangian crack-fronts, we produce highly detailed fracture surfaces. The computational cost of the BEM is alleviated by using a low-resolution mesh and interpolating the resulting stress intensity factors when propagating the high-resolution crack-front. Our system produces physics-based fracture surfaces with high spatial and temporal resolution, taking spatial variation of material toughness and/or strength into account. It also allows for crack initiation to be handled separately from crack propagation, which is not only more reasonable from a physics perspective, but can also be used to control the simulation. Separating the resolution of the crack-front from the resolution of the computational mesh increases the efficiency and therefore the amount of visual detail on the resulting fracture surfaces. The BEM also allows us to re-use previously computed blocks of the system matrix. AU - Hahn, David AU - Wojtan, Christopher J ID - 1633 IS - 4 TI - High-resolution brittle fracture simulation with boundary elements VL - 34 ER - TY - JOUR AB - 3D amoeboid cell migration is central to many developmental and disease-related processes such as cancer metastasis. Here, we identify a unique prototypic amoeboid cell migration mode in early zebrafish embryos, termed stable-bleb migration. Stable-bleb cells display an invariant polarized balloon-like shape with exceptional migration speed and persistence. Progenitor cells can be reversibly transformed into stable-bleb cells irrespective of their primary fate and motile characteristics by increasing myosin II activity through biochemical or mechanical stimuli. Using a combination of theory and experiments, we show that, in stable-bleb cells, cortical contractility fluctuations trigger a stochastic switch into amoeboid motility, and a positive feedback between cortical flows and gradients in contractility maintains stable-bleb cell polarization. We further show that rearward cortical flows drive stable-bleb cell migration in various adhesive and non-adhesive environments, unraveling a highly versatile amoeboid migration phenotype. AU - Ruprecht, Verena AU - Wieser, Stefan AU - Callan Jones, Andrew AU - Smutny, Michael AU - Morita, Hitoshi AU - Sako, Keisuke AU - Barone, Vanessa AU - Ritsch Marte, Monika AU - Sixt, Michael K AU - Voituriez, Raphaël AU - Heisenberg, Carl-Philipp J ID - 1537 IS - 4 JF - Cell TI - Cortical contractility triggers a stochastic switch to fast amoeboid cell motility VL - 160 ER - TY - JOUR AB - Auxin participates in a multitude of developmental processes, as well as responses to environmental cues. Compared with other plant hormones, auxin exhibits a unique property, as it undergoes directional, cell-to-cell transport facilitated by plasma membrane-localized transport proteins. Among them, a prominent role has been ascribed to the PIN family of auxin efflux facilitators. PIN proteins direct polar auxin transport on account of their asymmetric subcellular localizations. In this review, we provide an overview of the multiple developmental roles of PIN proteins, including the atypical endoplasmic reticulum-localized members of the family, and look at the family from an evolutionary perspective. Next, we cover the cell biological and molecular aspects of PIN function, in particular the establishment of their polar subcellular localization. Hormonal and environmental inputs into the regulation of PIN action are summarized as well. AU - Adamowski, Maciek AU - Friml, Jirí ID - 1591 IS - 1 JF - Plant Cell TI - PIN-dependent auxin transport: Action, regulation, and evolution VL - 27 ER - TY - JOUR AB - We consider real symmetric and complex Hermitian random matrices with the additional symmetry hxy = hN-y,N-x. The matrix elements are independent (up to the fourfold symmetry) and not necessarily identically distributed. This ensemble naturally arises as the Fourier transform of a Gaussian orthogonal ensemble. Italso occurs as the flip matrix model - an approximation of the two-dimensional Anderson model at small disorder. We show that the density of states converges to the Wigner semicircle law despite the new symmetry type. We also prove the local version of the semicircle law on the optimal scale. AU - Alt, Johannes ID - 1677 IS - 10 JF - Journal of Mathematical Physics TI - The local semicircle law for random matrices with a fourfold symmetry VL - 56 ER - TY - JOUR AB - High-throughput live-cell screens are intricate elements of systems biology studies and drug discovery pipelines. Here, we demonstrate an optogenetics-assisted method that avoids the need for chemical activators and reporters, reduces the number of operational steps and increases information content in a cell-based small-molecule screen against human protein kinases, including an orphan receptor tyrosine kinase. This blueprint for all-optical screening can be adapted to many drug targets and cellular processes. AU - Inglés Prieto, Álvaro AU - Gschaider-Reichhart, Eva AU - Muellner, Markus AU - Nowak, Matthias AU - Nijman, Sebastian AU - Grusch, Michael AU - Janovjak, Harald L ID - 1678 IS - 12 JF - Nature Chemical Biology TI - Light-assisted small-molecule screening against protein kinases VL - 11 ER - TY - JOUR AB - Gene expression is controlled primarily by interactions between transcription factor proteins (TFs) and the regulatory DNA sequence, a process that can be captured well by thermodynamic models of regulation. These models, however, neglect regulatory crosstalk: the possibility that noncognate TFs could initiate transcription, with potentially disastrous effects for the cell. Here, we estimate the importance of crosstalk, suggest that its avoidance strongly constrains equilibrium models of TF binding, and propose an alternative nonequilibrium scheme that implements kinetic proofreading to suppress erroneous initiation. This proposal is consistent with the observed covalent modifications of the transcriptional apparatus and predicts increased noise in gene expression as a trade-off for improved specificity. Using information theory, we quantify this trade-off to find when optimal proofreading architectures are favored over their equilibrium counterparts. Such architectures exhibit significant super-Poisson noise at low expression in steady state. AU - Cepeda Humerez, Sarah A AU - Rieckh, Georg AU - Tkacik, Gasper ID - 1576 IS - 24 JF - Physical Review Letters TI - Stochastic proofreading mechanism alleviates crosstalk in transcriptional regulation VL - 115 ER - TY - GEN AB - We study conditions under which a finite simplicial complex $K$ can be mapped to $\mathbb R^d$ without higher-multiplicity intersections. An almost $r$-embedding is a map $f: K\to \mathbb R^d$ such that the images of any $r$ pairwise disjoint simplices of $K$ do not have a common point. We show that if $r$ is not a prime power and $d\geq 2r+1$, then there is a counterexample to the topological Tverberg conjecture, i.e., there is an almost $r$-embedding of the $(d+1)(r-1)$-simplex in $\mathbb R^d$. This improves on previous constructions of counterexamples (for $d\geq 3r$) based on a series of papers by M. \"Ozaydin, M. Gromov, P. Blagojevi\'c, F. Frick, G. Ziegler, and the second and fourth present authors. The counterexamples are obtained by proving the following algebraic criterion in codimension 2: If $r\ge3$ and if $K$ is a finite $2(r-1)$-complex then there exists an almost $r$-embedding $K\to \mathbb R^{2r}$ if and only if there exists a general position PL map $f:K\to \mathbb R^{2r}$ such that the algebraic intersection number of the $f$-images of any $r$ pairwise disjoint simplices of $K$ is zero. This result can be restated in terms of cohomological obstructions or equivariant maps, and extends an analogous codimension 3 criterion by the second and fourth authors. As another application we classify ornaments $f:S^3 \sqcup S^3\sqcup S^3\to \mathbb R^5$ up to ornament concordance. It follows from work of M. Freedman, V. Krushkal and P. Teichner that the analogous criterion for $r=2$ is false. We prove a lemma on singular higher-dimensional Borromean rings, yielding an elementary proof of the counterexample. AU - Avvakumov, Sergey AU - Mabillard, Isaac AU - Skopenkov, A. AU - Wagner, Uli ID - 8183 T2 - arXiv TI - Eliminating higher-multiplicity intersections, III. Codimension 2 ER - TY - GEN AB - We study algorithmic questions for concurrent systems where the transitions are labeled from a complete, closed semiring, and path properties are algebraic with semiring operations. The algebraic path properties can model dataflow analysis problems, the shortest path problem, and many other natural problems that arise in program analysis. We consider that each component of the concurrent system is a graph with constant treewidth, a property satisfied by the controlflow graphs of most programs. We allow for multiple possible queries, which arise naturally in demand driven dataflow analysis. The study of multiple queries allows us to consider the tradeoff between the resource usage of the one-time preprocessing and for each individual query. The traditional approach constructs the product graph of all components and applies the best-known graph algorithm on the product. In this approach, even the answer to a single query requires the transitive closure (i.e., the results of all possible queries), which provides no room for tradeoff between preprocessing and query time. Our main contributions are algorithms that significantly improve the worst-case running time of the traditional approach, and provide various tradeoffs depending on the number of queries. For example, in a concurrent system of two components, the traditional approach requires hexic time in the worst case for answering one query as well as computing the transitive closure, whereas we show that with one-time preprocessing in almost cubic time, each subsequent query can be answered in at most linear time, and even the transitive closure can be computed in almost quartic time. Furthermore, we establish conditional optimality results showing that the worst-case running time of our algorithms cannot be improved without achieving major breakthroughs in graph algorithms (i.e., improving the worst-case bound for the shortest path problem in general graphs). Preliminary experimental results show that our algorithms perform favorably on several benchmarks. AU - Chatterjee, Krishnendu AU - Ibsen-Jensen, Rasmus AU - Goharshady, Amir AU - Pavlogiannis, Andreas ID - 5441 SN - 2664-1690 TI - Algorithms for algebraic path properties in concurrent systems of constant treewidth components ER - TY - GEN AB - We study algorithmic questions for concurrent systems where the transitions are labeled from a complete, closed semiring, and path properties are algebraic with semiring operations. The algebraic path properties can model dataflow analysis problems, the shortest path problem, and many other natural properties that arise in program analysis. We consider that each component of the concurrent system is a graph with constant treewidth, and it is known that the controlflow graphs of most programs have constant treewidth. We allow for multiple possible queries, which arise naturally in demand driven dataflow analysis problems (e.g., alias analysis). The study of multiple queries allows us to consider the tradeoff between the resource usage of the \emph{one-time} preprocessing and for \emph{each individual} query. The traditional approaches construct the product graph of all components and apply the best-known graph algorithm on the product. In the traditional approach, even the answer to a single query requires the transitive closure computation (i.e., the results of all possible queries), which provides no room for tradeoff between preprocessing and query time. Our main contributions are algorithms that significantly improve the worst-case running time of the traditional approach, and provide various tradeoffs depending on the number of queries. For example, in a concurrent system of two components, the traditional approach requires hexic time in the worst case for answering one query as well as computing the transitive closure, whereas we show that with one-time preprocessing in almost cubic time, each subsequent query can be answered in at most linear time, and even the transitive closure can be computed in almost quartic time. Furthermore, we establish conditional optimality results that show that the worst-case running times of our algorithms cannot be improved without achieving major breakthroughs in graph algorithms (such as improving the worst-case bounds for the shortest path problem in general graphs whose current best-known bound has not been improved in five decades). Finally, we provide a prototype implementation of our algorithms which significantly outperforms the existing algorithmic methods on several benchmarks. AU - Anonymous, 1 AU - Anonymous, 2 AU - Anonymous, 3 AU - Anonymous, 4 ID - 5442 SN - 2664-1690 TI - Algorithms for algebraic path properties in concurrent systems of constant treewidth components ER - TY - CONF 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 satisfying initial states. Moreover, for any (partial) solution our algorithm synthesizes witness control strategies to ensure almost-sure satisfaction of the temporal logic specification. We demonstrate our approach on an illustrative case study. AU - Svoreňová, Mária AU - Kretinsky, Jan AU - Chmelik, Martin AU - Chatterjee, Krishnendu AU - Cěrná, Ivana AU - Belta, Cǎlin ID - 1689 T2 - Proceedings of the 18th International Conference on Hybrid Systems: Computation and Control TI - Temporal logic control for stochastic linear systems using abstraction refinement of probabilistic games ER - TY - CONF 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 such sequences produced under a non-preemptive scheduler. The solution is based on a finitary abstraction, an algorithm for bounded language inclusion modulo an independence relation, and rules for inserting synchronization. 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, and, since it does not require explicit specifications, is more practical than the conventional approach based on user-provided assertions. AU - Cerny, Pavol AU - Clarke, Edmund AU - Henzinger, Thomas A AU - Radhakrishna, Arjun AU - Ryzhyk, Leonid AU - Samanta, Roopsha AU - Tarrach, Thorsten ID - 1729 TI - From non-preemptive to preemptive scheduling using synchronization synthesis VL - 9207 ER - TY - CONF 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 logics. 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 - 1835 TI - Model checking gene regulatory networks VL - 9035 ER - TY - JOUR AB - The Auxin Binding Protein1 (ABP1) has been identified based on its ability to bind auxin with high affinity and studied for a long time as a prime candidate for the extracellular auxin receptor responsible for mediating in particular the fast non-transcriptional auxin responses. However, the contradiction between the embryo-lethal phenotypes of the originally described Arabidopsis T-DNA insertional knock-out alleles (abp1-1 and abp1-1s) and the wild type-like phenotypes of other recently described loss-of-function alleles (abp1-c1 and abp1-TD1) questions the biological importance of ABP1 and relevance of the previous genetic studies. Here we show that there is no hidden copy of the ABP1 gene in the Arabidopsis genome but the embryo-lethal phenotypes of abp1-1 and abp1-1s alleles are very similar to the knock-out phenotypes of the neighboring gene, BELAYA SMERT (BSM). Furthermore, the allelic complementation test between bsm and abp1 alleles shows that the embryo-lethality in the abp1-1 and abp1-1s alleles is caused by the off-target disruption of the BSM locus by the T-DNA insertions. This clarifies the controversy of different phenotypes among published abp1 knock-out alleles and asks for reflections on the developmental role of ABP1. AU - Michalko, Jaroslav AU - Dravecka, Marta AU - Bollenbach, Tobias AU - Friml, Jirí ID - 1509 JF - F1000 Research TI - Embryo-lethal phenotypes in early abp1 mutants are due to disruption of the neighboring BSM gene VL - 4 ER - TY - JOUR AB - In many social situations, individuals endeavor to find the single best possible partner, but are constrained to evaluate the candidates in sequence. Examples include the search for mates, economic partnerships, or any other long-term ties where the choice to interact involves two parties. Surprisingly, however, previous theoretical work on mutual choice problems focuses on finding equilibrium solutions, while ignoring the evolutionary dynamics of decisions. Empirically, this may be of high importance, as some equilibrium solutions can never be reached unless the population undergoes radical changes and a sufficient number of individuals change their decisions simultaneously. To address this question, we apply a mutual choice sequential search problem in an evolutionary game-theoretical model that allows one to find solutions that are favored by evolution. As an example, we study the influence of sequential search on the evolutionary dynamics of cooperation. For this, we focus on the classic snowdrift game and the prisoner’s dilemma game. AU - Priklopil, Tadeas AU - Chatterjee, Krishnendu ID - 1681 IS - 4 JF - Games TI - Evolution of decisions in population games with sequentially searching individuals VL - 6 ER - TY - JOUR AB - Quantifying behaviors of robots which were generated autonomously from task-independent objective functions is an important prerequisite for objective comparisons of algorithms and movements of animals. The temporal sequence of such a behavior can be considered as a time series and hence complexity measures developed for time series are natural candidates for its quantification. The predictive information and the excess entropy are such complexity measures. They measure the amount of information the past contains about the future and thus quantify the nonrandom structure in the temporal sequence. However, when using these measures for systems with continuous states one has to deal with the fact that their values will depend on the resolution with which the systems states are observed. For deterministic systems both measures will diverge with increasing resolution. We therefore propose a new decomposition of the excess entropy in resolution dependent and resolution independent parts and discuss how they depend on the dimensionality of the dynamics, correlations and the noise level. For the practical estimation we propose to use estimates based on the correlation integral instead of the direct estimation of the mutual information based on next neighbor statistics because the latter allows less control of the scale dependencies. Using our algorithm we are able to show how autonomous learning generates behavior of increasing complexity with increasing learning duration. AU - Martius, Georg S AU - Olbrich, Eckehard ID - 1655 IS - 10 JF - Entropy TI - Quantifying emergent behavior of autonomous robots VL - 17 ER - TY - JOUR AB - Huge body of evidences demonstrated that volatile anesthetics affect the hippocampal neurogenesis and neurocognitive functions, and most of them showed impairment at anesthetic dose. Here, we investigated the effect of low dose (1.8%) sevoflurane on hippocampal neurogenesis and dentate gyrus-dependent learning. Neonatal rats at postnatal day 4 to 6 (P4-6) were treated with 1.8% sevoflurane for 6 hours. Neurogenesis was quantified by bromodeoxyuridine labeling and electrophysiology recording. Four and seven weeks after treatment, the Morris water maze and contextual-fear discrimination learning tests were performed to determine the influence on spatial learning and pattern separation. A 6-hour treatment with 1.8% sevoflurane promoted hippocampal neurogenesis and increased the survival of newborn cells and the proportion of immature granular cells in the dentate gyrus of neonatal rats. Sevoflurane-treated rats performed better during the training days of the Morris water maze test and in contextual-fear discrimination learning test. These results suggest that a subanesthetic dose of sevoflurane promotes hippocampal neurogenesis in neonatal rats and facilitates their performance in dentate gyrus-dependent learning tasks. AU - Chen, Chong AU - Wang, Chao AU - Zhao, Xuan AU - Zhou, Tao AU - Xu, Dao AU - Wang, Zhi AU - Wang, Ying ID - 1834 IS - 2 JF - ASN Neuro TI - Low-dose sevoflurane promoteshippocampal neurogenesis and facilitates the development of dentate gyrus-dependent learning in neonatal rats VL - 7 ER - TY - JOUR AB - We calculate a Ricci curvature lower bound for some classical examples of random walks, namely, a chain on a slice of the n-dimensional discrete cube (the so-called Bernoulli-Laplace model) and the random transposition shuffle of the symmetric group of permutations on n letters. AU - Erbar, Matthias AU - Maas, Jan AU - Tetali, Prasad ID - 1635 IS - 4 JF - Annales de la faculté des sciences de Toulouse TI - Discrete Ricci curvature bounds for Bernoulli-Laplace and random transposition models VL - 24 ER - TY - JOUR AB - Scaffolded DNA origami enables the fabrication of a variety of complex nanostructures that promise utility in diverse fields of application, ranging from biosensing over advanced therapeutics to metamaterials. The broad applicability of DNA origami as a material beyond the level of proof-of-concept studies critically depends, among other factors, on the availability of large amounts of pure single-stranded scaffold DNA. Here, we present a method for the efficient production of M13 bacteriophage-derived genomic DNA using high-cell-density fermentation of Escherichia coli in stirred-tank bioreactors. We achieve phage titers of up to 1.6 × 1014 plaque-forming units per mL. Downstream processing yields up to 410 mg of high-quality single-stranded DNA per one liter reaction volume, thus upgrading DNA origami-based nanotechnology from the milligram to the gram scale. AU - Kick, B AU - Praetorius, Florian M AU - Dietz, H AU - Weuster-Botz, D ID - 14303 IS - 7 JF - Nano Letters SN - 1530-6984 TI - Efficient production of single-stranded phage DNA as scaffolds for DNA origami VL - 15 ER - TY - CONF AB - For deterministic systems, a counterexample to a property can simply be an error trace, whereas counterexamples in probabilistic systems are necessarily more complex. For instance, a set of erroneous traces with a sufficient cumulative probability mass can be used. Since these are too large objects to understand and manipulate, compact representations such as subchains have been considered. In the case of probabilistic systems with non-determinism, the situation is even more complex. While a subchain for a given strategy (or scheduler, resolving non-determinism) is a straightforward choice, we take a different approach. Instead, we focus on the strategy itself, and extract the most important decisions it makes, and present its succinct representation. The key tools we employ to achieve this are (1) introducing a concept of importance of a state w.r.t. the strategy, and (2) learning using decision trees. There are three main consequent advantages of our approach. Firstly, it exploits the quantitative information on states, stressing the more important decisions. Secondly, it leads to a greater variability and degree of freedom in representing the strategies. Thirdly, the representation uses a self-explanatory data structure. In summary, our approach produces more succinct and more explainable strategies, as opposed to e.g. binary decision diagrams. Finally, our experimental results show that we can extract several rules describing the strategy even for very large systems that do not fit in memory, and based on the rules explain the erroneous behaviour. AU - Brázdil, Tomáš AU - Chatterjee, Krishnendu AU - Chmelik, Martin AU - Fellner, Andreas AU - Kretinsky, Jan ID - 1603 TI - Counterexample explanation by learning small strategies in Markov decision processes VL - 9206 ER - TY - DATA AB - This repository contains the experimental part of the CAV 2015 publication Counterexample Explanation by Learning Small Strategies in Markov Decision Processes. We extended the probabilistic model checker PRISM to represent strategies of Markov Decision Processes as Decision Trees. The archive contains a java executable version of the extended tool (prism_dectree.jar) together with a few examples of the PRISM benchmark library. To execute the program, please have a look at the README.txt, which provides instructions and further information on the archive. The archive contains scripts that (if run often enough) reproduces the data presented in the publication. AU - Fellner, Andreas ID - 5549 KW - Markov Decision Process KW - Decision Tree KW - Probabilistic Verification KW - Counterexample Explanation TI - Experimental part of CAV 2015 publication: Counterexample Explanation by Learning Small Strategies in Markov Decision Processes ER - TY - CONF AB - We show that very weak topological assumptions are enough to ensure the existence of a Helly-type theorem. More precisely, we show that for any non-negative integers b and d there exists an integer h(b,d) such that the following holds. If F is a finite family of subsets of R^d such that the ith reduced Betti number (with Z_2 coefficients in singular homology) of the intersection of any proper subfamily G of F is at most b for every non-negative integer i less or equal to (d-1)/2, then F has Helly number at most h(b,d). These topological conditions are sharp: not controlling any of these first Betti numbers allow for families with unbounded Helly number. Our proofs combine homological non-embeddability results with a Ramsey-based approach to build, given an arbitrary simplicial complex K, some well-behaved chain map from C_*(K) to C_*(R^d). Both techniques are of independent interest. AU - Goaoc, Xavier AU - Paták, Pavel AU - Patakova, Zuzana AU - Tancer, Martin AU - Wagner, Uli ID - 1512 TI - Bounding Helly numbers via Betti numbers VL - 34 ER - TY - JOUR AB - We show that a non-singular integral form of degree d is soluble non-trivially over the integers if and only if it is soluble non-trivially over the reals and the p-adic numbers, provided that the form has at least (d-\sqrt{d}/2)2^d variables. This improves on a longstanding result of Birch. AU - Browning, Timothy D AU - Prendiville, Sean ID - 271 IS - 731 JF - Journal fur die Reine und Angewandte Mathematik SN - 0075-4102 TI - Improvements in Birch's theorem on forms in many variables VL - 2017 ER - TY - CONF AB - Proofs of work (PoW) have been suggested by Dwork and Naor (Crypto’92) as protection to a shared resource. The basic idea is to ask the service requestor to dedicate some non-trivial amount of computational work to every request. The original applications included prevention of spam and protection against denial of service attacks. More recently, PoWs have been used to prevent double spending in the Bitcoin digital currency system. In this work, we put forward an alternative concept for PoWs - so-called proofs of space (PoS), where a service requestor must dedicate a significant amount of disk space as opposed to computation. We construct secure PoS schemes in the random oracle model (with one additional mild assumption required for the proof to go through), using graphs with high “pebbling complexity” and Merkle hash-trees. We discuss some applications, including follow-up work where a decentralized digital currency scheme called Spacecoin is constructed that uses PoS (instead of wasteful PoW like in Bitcoin) to prevent double spending. The main technical contribution of this work is the construction of (directed, loop-free) graphs on N vertices with in-degree O(log logN) such that even if one places Θ(N) pebbles on the nodes of the graph, there’s a constant fraction of nodes that needs Θ(N) steps to be pebbled (where in every step one can put a pebble on a node if all its parents have a pebble). AU - Dziembowski, Stefan AU - Faust, Sebastian AU - Kolmogorov, Vladimir AU - Pietrzak, Krzysztof Z ID - 1675 SN - 0302-9743 T2 - 35th Annual Cryptology Conference TI - Proofs of space VL - 9216 ER - TY - JOUR AB - The circadian clock orchestrates global changes in transcriptional regulation on a daily basis via the bHLH-PAS transcription factor CLOCK:BMAL1. Pathways driven by other bHLH-PAS transcription factors have a homologous repressor that modulates activity on a tissue-specific basis, but none have been identified for CLOCK:BMAL1. We show here that the cancer/testis antigen PASD1 fulfills this role to suppress circadian rhythms. PASD1 is evolutionarily related to CLOCK and interacts with the CLOCK:BMAL1 complex to repress transcriptional activation. Expression of PASD1 is restricted to germline tissues in healthy individuals but can be induced in cells of somatic origin upon oncogenic transformation. Reducing PASD1 in human cancer cells significantly increases the amplitude of transcriptional oscillations to generate more robust circadian rhythms. Our results describe a function for a germline-specific protein in regulation of the circadian clock and provide a molecular link from oncogenic transformation to suppression of circadian rhythms. AU - Michael, Alicia Kathleen AU - Harvey, Stacy L. AU - Sammons, Patrick J. AU - Anderson, Amanda P. AU - Kopalle, Hema M. AU - Banham, Alison H. AU - Partch, Carrie L. ID - 15160 IS - 5 JF - Molecular Cell KW - Cell Biology KW - Molecular Biology SN - 1097-2765 TI - Cancer/Testis antigen PASD1 silences the circadian clock VL - 58 ER - TY - JOUR AB - It is widely recognized that BMAL1 is an essential subunit of the primary transcription factor that drives rhythmic circadian transcription in the nucleus. In a surprising turn, Lipton et al. now show that BMAL1 rhythmically interacts with translational machinery in the cytosol to stimulate protein synthesis in response to mTOR signaling. AU - Michael, Alicia Kathleen AU - Asimgil, Hande AU - Partch, Carrie L. ID - 15159 IS - 9 JF - Trends in Biochemical Sciences KW - Molecular Biology KW - Biochemistry SN - 0968-0004 TI - Cytosolic BMAL1 moonlights as a translation factor VL - 40 ER - TY - JOUR AB - The emergence of drug resistant pathogens is a serious public health problem. It is a long-standing goal to predict rates of resistance evolution and design optimal treatment strategies accordingly. To this end, it is crucial to reveal the underlying causes of drug-specific differences in the evolutionary dynamics leading to resistance. However, it remains largely unknown why the rates of resistance evolution via spontaneous mutations and the diversity of mutational paths vary substantially between drugs. Here we comprehensively quantify the distribution of fitness effects (DFE) of mutations, a key determinant of evolutionary dynamics, in the presence of eight antibiotics representing the main modes of action. Using precise high-throughput fitness measurements for genome-wide Escherichia coli gene deletion strains, we find that the width of the DFE varies dramatically between antibiotics and, contrary to conventional wisdom, for some drugs the DFE width is lower than in the absence of stress. We show that this previously underappreciated divergence in DFE width among antibiotics is largely caused by their distinct drug-specific dose-response characteristics. Unlike the DFE, the magnitude of the changes in tolerated drug concentration resulting from genome-wide mutations is similar for most drugs but exceptionally small for the antibiotic nitrofurantoin, i.e., mutations generally have considerably smaller resistance effects for nitrofurantoin than for other drugs. A population genetics model predicts that resistance evolution for drugs with this property is severely limited and confined to reproducible mutational paths. We tested this prediction in laboratory evolution experiments using the “morbidostat”, a device for evolving bacteria in well-controlled drug environments. Nitrofurantoin resistance indeed evolved extremely slowly via reproducible mutations—an almost paradoxical behavior since this drug causes DNA damage and increases the mutation rate. Overall, we identified novel quantitative characteristics of the evolutionary landscape that provide the conceptual foundation for predicting the dynamics of drug resistance evolution. AU - Chevereau, Guillaume AU - Dravecka, Marta AU - Batur, Tugce AU - Guvenek, Aysegul AU - Ayhan, Dilay AU - Toprak, Erdal AU - Bollenbach, Mark Tobias ID - 1619 IS - 11 JF - PLoS Biology TI - Quantifying the determinants of evolutionary dynamics leading to drug resistance VL - 13 ER - TY - JOUR AB - Protein oligomers have been implicated as toxic agents in a wide range of amyloid-related diseases. However, it has remained unsolved whether the oligomers are a necessary step in the formation of amyloid fibrils or just a dangerous byproduct. Analogously, it has not been resolved if the amyloid nucleation process is a classical one-step nucleation process or a two-step process involving prenucleation clusters. We use coarse-grained computer simulations to study the effect of nonspecific attractions between peptides on the primary nucleation process underlying amyloid fibrillization. We find that, for peptides that do not attract, the classical one-step nucleation mechanism is possible but only at nonphysiologically high peptide concentrations. At low peptide concentrations, which mimic the physiologically relevant regime, attractive interpeptide interactions are essential for fibril formation. Nucleation then inevitably takes place through a two-step mechanism involving prefibrillar oligomers. We show that oligomers not only help peptides meet each other but also, create an environment that facilitates the conversion of monomers into the β-sheet–rich form characteristic of fibrils. Nucleation typically does not proceed through the most prevalent oligomers but through an oligomer size that is only observed in rare fluctuations, which is why such aggregates might be hard to capture experimentally. Finally, we find that the nucleation of amyloid fibrils cannot be described by classical nucleation theory: in the two-step mechanism, the critical nucleus size increases with increases in both concentration and interpeptide interactions, which is in direct contrast with predictions from classical nucleation theory. AU - Šarić, Anđela AU - Chebaro, Yassmine C. AU - Knowles, Tuomas P. J. AU - Frenkel, Daan ID - 10382 IS - 50 JF - Proceedings of the National Academy of Sciences KW - multidisciplinary SN - 0027-8424 TI - Crucial role of nonspecific interactions in amyloid nucleation VL - 111 ER - TY - JOUR AB - We use numerical simulations to compute the equation of state of a suspension of spherical self-propelled nanoparticles in two and three dimensions. We study in detail the effect of excluded volume interactions and confinement as a function of the system's temperature, concentration, and strength of the propulsion. We find a striking nonmonotonic dependence of the pressure on the temperature and provide simple scaling arguments to predict and explain the occurrence of such anomalous behavior. We explicitly show how our results have important implications for the effective forces on passive components suspended in a bath of active particles. AU - Mallory, S. A. AU - Šarić, Anđela AU - Valeriani, C. AU - Cacciuto, A. ID - 10383 IS - 5 JF - Physical Review E SN - 1539-3755 TI - Anomalous thermomechanical properties of a self-propelled colloidal fluid VL - 89 ER - TY - JOUR AB - Diffraction-unlimited far-field super-resolution fluorescence (nanoscopy) methods typically rely on transiently transferring fluorophores between two states, whereby this transfer is usually laid out as a switch. However, depending on whether this is induced in a spatially controlled manner using a pattern of light (coordinate-targeted) or stochastically on a single-molecule basis, specific requirements on the fluorophores are imposed. Therefore, the fluorophores are usually utilized just for one class of methods only. In this study we demonstrate that the reversibly switchable fluorescent protein Dreiklang enables live-cell recordings in both spatially controlled and stochastic modes. We show that the Dreiklang chromophore entails three different light-induced switching mechanisms, namely a reversible photochemical one, off-switching by stimulated emission, and a reversible transfer to a long-lived dark state from the S1 state, all of which can be utilized to overcome the diffraction barrier. We also find that for the single-molecule- based stochastic GSDIM approach (ground-state depletion followed by individual molecule return), Dreiklang provides a larger number of on-off localization events as compared to its progenitor Citrine. Altogether, Dreiklang is a versatile probe for essentially all popular forms of live-cell fluorescence nanoscopy. AU - Jensen, Nickels AU - Danzl, Johann G AU - Willig, Katrin AU - Lavoie Cardinal, Flavie AU - Brakemann, Tanja AU - Hell, Stefan AU - Jakobs, Stefan ID - 1058 IS - 4 JF - ChemPhysChem TI - Coordinate-targeted and coordinate-stochastic super-resolution microscopy with the reversibly switchable fluorescent protein dreiklang VL - 15 ER - TY - JOUR AB - In the last several decades, developmental biology has clarified the molecular mechanisms of embryogenesis and organogenesis. In particular, it has demonstrated that the “tool-kit genes” essential for regulating developmental processes are not only highly conserved among species, but are also used as systems at various times and places in an organism to control distinct developmental events. Therefore, mutations in many of these tool-kit genes may cause congenital diseases involving morphological abnormalities. This link between genes and abnormal morphological phenotypes underscores the importance of understanding how cells behave and contribute to morphogenesis as a result of gene function. Recent improvements in live imaging and in quantitative analyses of cellular dynamics will advance our understanding of the cellular pathogenesis of congenital diseases associated with aberrant morphologies. In these studies, it is critical to select an appropriate model organism for the particular phenomenon of interest. AU - Hashimoto, Masakazu AU - Morita, Hitoshi AU - Ueno, Naoto ID - 10815 IS - 1 JF - Congenital Anomalies KW - Developmental Biology KW - Embryology KW - General Medicine KW - Pediatrics KW - Perinatology KW - and Child Health SN - 0914-3505 TI - Molecular and cellular mechanisms of development underlying congenital diseases VL - 54 ER - TY - BOOK AB - Auxin is an important signaling compound in plants and vital for plant development and growth. The present book, Auxin and its Role in Plant Development, provides the reader with detailed and comprehensive insight into the functioning of the molecule on the whole and specifically in plant development. In the first part, the functioning, metabolism and signaling pathways of auxin in plants are explained, the second part depicts the specific role of auxin in plant development and the third part describes the interaction and functioning of the signaling compound upon stimuli of the environment. Each chapter is written by international experts in the respective field and designed for scientists and researchers in plant biology, plant development and cell biology to summarize the recent progress in understanding the role of auxin and suggest future perspectives for auxin research. ED - Zažímalová, Eva ED - Petrášek, Jan ED - Benková, Eva ID - 10811 SN - 9783709115251 TI - Auxin and Its Role in Plant Development ER - TY - CONF AB - We revisit the parameterized model checking problem for token-passing systems and specifications in indexed CTL  ∗ \X. Emerson and Namjoshi (1995, 2003) have shown that parameterized model checking of indexed CTL  ∗ \X in uni-directional token rings can be reduced to checking rings up to some cutoff size. Clarke et al. (2004) have shown a similar result for general topologies and indexed LTL \X, provided processes cannot choose the directions for sending or receiving the token. We unify and substantially extend these results by systematically exploring fragments of indexed CTL  ∗ \X with respect to general topologies. For each fragment we establish whether a cutoff exists, and for some concrete topologies, such as rings, cliques and stars, we infer small cutoffs. Finally, we show that the problem becomes undecidable, and thus no cutoffs exist, if processes are allowed to choose the directions in which they send or from which they receive the token. AU - Aminof, Benjamin AU - Jacobs, Swen AU - Khalimov, Ayrat AU - Rubin, Sasha ID - 10884 SN - 0302-9743 T2 - Verification, Model Checking, and Abstract Interpretation TI - Parameterized model checking of token-passing systems VL - 8318 ER - TY - CHAP AB - Saddle periodic orbits are an essential and stable part of the topological skeleton of a 3D vector field. Nevertheless, there is currently no efficient algorithm to robustly extract these features. In this chapter, we present a novel technique to extract saddle periodic orbits. Exploiting the analytic properties of such an orbit, we propose a scalar measure based on the finite-time Lyapunov exponent (FTLE) that indicates its presence. Using persistent homology, we can then extract the robust cycles of this field. These cycles thereby represent the saddle periodic orbits of the given vector field. We discuss the different existing FTLE approximation schemes regarding their applicability to this specific problem and propose an adapted version of FTLE called Normalized Velocity Separation. Finally, we evaluate our method using simple analytic vector field data. AU - Kasten, Jens AU - Reininghaus, Jan AU - Reich, Wieland AU - Scheuermann, Gerik ED - Bremer, Peer-Timo ED - Hotz, Ingrid ED - Pascucci, Valerio ED - Peikert, Ronald ID - 10893 SN - 1612-3786 T2 - Topological Methods in Data Analysis and Visualization III TI - Toward the extraction of saddle periodic orbits VL - 1 ER - TY - JOUR AB - The spindle assembly checkpoint prevents separation of sister chromatids until each kinetochore is attached to the mitotic spindle. Rodriguez-Bravo et al. report that the nuclear pore complex scaffolds spindle assembly checkpoint signaling in interphase, providing a store of inhibitory signals that limits the speed of the subsequent mitosis. AU - Buchwalter, Abigail AU - HETZER, Martin W ID - 11080 IS - 5 JF - Cell KW - General Biochemistry KW - Genetics and Molecular Biology SN - 0092-8674 TI - Nuclear pores set the speed limit for mitosis VL - 156 ER - TY - JOUR AB - The nuclear pore complex (NPC) plays a critical role in gene expression by mediating import of transcription regulators into the nucleus and export of RNA transcripts to the cytoplasm. Emerging evidence suggests that in addition to mediating transport, a subset of nucleoporins (Nups) engage in transcriptional activation and elongation at genomic loci that are not associated with NPCs. The underlying mechanism and regulation of Nup mobility on and off nuclear pores remain unclear. Here we show that Nup50 is a mobile Nup with a pronounced presence both at the NPC and in the nucleoplasm that can move between these different localizations. Strikingly, the dynamic behavior of Nup50 in both locations is dependent on active transcription by RNA polymerase II and requires the N-terminal half of the protein, which contains importin α– and Nup153-binding domains. However, Nup50 dynamics are independent of importin α, Nup153, and Nup98, even though the latter two proteins also exhibit transcription-dependent mobility. Of interest, depletion of Nup50 from C2C12 myoblasts does not affect cell proliferation but inhibits differentiation into myotubes. Taken together, our results suggest a transport-independent role for Nup50 in chromatin biology that occurs away from the NPC. AU - Buchwalter, Abigail L. AU - Liang, Yun AU - HETZER, Martin W ID - 11082 IS - 16 JF - Molecular Biology of the Cell KW - Cell Biology KW - Molecular Biology SN - 1059-1524 TI - Nup50 is required for cell differentiation and exhibits transcription-dependent dynamics VL - 25 ER - TY - JOUR AB - In eukaryotic cells the nuclear genome is enclosed by the nuclear envelope (NE). In metazoans, the NE breaks down in mitosis and it has been assumed that the physical barrier separating nucleoplasm and cytoplasm remains intact during the rest of the cell cycle and cell differentiation. However, recent studies suggest that nonmitotic NE remodeling plays a critical role in development, virus infection, laminopathies, and cancer. Although the mechanisms underlying these NE restructuring events are currently being defined, one common theme is activation of protein kinase C family members in the interphase nucleus to disrupt the nuclear lamina, demonstrating the importance of the lamina in maintaining nuclear integrity. AU - Hatch, Emily AU - HETZER, Martin W ID - 11081 IS - 2 JF - Journal of Cell Biology KW - Cell Biology SN - 1540-8140 TI - Breaching the nuclear envelope in development and disease VL - 205 ER - TY - JOUR AB - Candidate galaxies at redshifts of z ∼ 10 are now being found in extremely deep surveys, probing very small areas. As a consequence, candidates are very faint, making spectroscopic confirmation practically impossible. In order to overcome such limitations, we have undertaken the CF-HiZELS survey, which is a large-area, medium-depth near-infrared narrow-band survey targeted at z = 8.8 Lyman α (Lyα) emitters (LAEs) and covering 10 deg2 in part of the SSA22 field with the Canada–France–Hawaii Telescope (CFHT). We surveyed a comoving volume of 4.7 × 106 Mpc3 to a Lyα luminosity limit of 6.3 × 1043舁erg舁s−1. We look for Lyα candidates by applying the following criteria: (i) clear emission-line source, (ii) no optical detections (ugriz from CFHTLS), (iii) no visible detection in the optical stack (ugriz > 27), (iv) visually checked reliable NBJ and J detections and (v) J − K ≤ 0. We compute photometric redshifts and remove a significant amount of dusty lower redshift line-emitters at z ∼ 1.4 or 2.2. A total of 13 Lyα candidates were found, of which two are marked as strong candidates, but the majority have very weak constraints on their spectral energy distributions. Using follow-up observations with SINFONI/VLT, we are able to exclude the most robust candidates as LAEs. We put a strong constraint on the Lyα luminosity function at z ∼ 9 and make realistic predictions for ongoing and future surveys. Our results show that surveys for the highest redshift LAEs are susceptible of multiple contaminations and that spectroscopic follow-up is absolutely necessary. AU - Matthee, Jorryt J AU - Sobral, David AU - Swinbank, A. M. AU - Smail, Ian AU - Best, P. N. AU - Kim, Jae-Woo AU - Franx, Marijn AU - Milvang-Jensen, Bo AU - Fynbo, Johan ID - 11583 IS - 3 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - galaxies: evolution KW - galaxies: high-redshift KW - cosmology: observations KW - dark ages KW - reionization KW - first stars SN - 0035-8711 TI - A 10 deg2 Lyman α survey at z=8.8 with spectroscopic follow-up: Strong constraints on the luminosity function and implications for other surveys VL - 440 ER - TY - JOUR AB - We have observed a sample of typical z ∼ 1 star-forming galaxies, selected from the HiZELS survey, with the new K-band Multi-Object Spectrograph (KMOS) near-infrared, multi-integral field unit instrument on the Very Large Telescope (VLT), in order to obtain their dynamics and metallicity gradients. The majority of our galaxies have a metallicity gradient consistent with being flat or negative (i.e. higher metallicity cores than outskirts). Intriguingly, we find a trend between metallicity gradient and specific star formation rate (sSFR), such that galaxies with a high sSFR tend to have relatively metal poor centres, a result which is strengthened when combined with data sets from the literature. This result appears to explain the discrepancies reported between different high-redshift studies and varying claims for evolution. From a galaxy evolution perspective, the trend we see would mean that a galaxy's sSFR is governed by the amount of metal-poor gas that can be funnelled into its core, triggered either by merging or through efficient accretion. In fact, merging may play a significant role as it is the starburst galaxies at all epochs, which have the more positive metallicity gradients. Our results may help to explain the origin of the fundamental metallicity relation, in which galaxies at a fixed mass are observed to have lower metallicities at higher star formation rates, especially if the metallicity is measured in an aperture encompassing only the central regions of the galaxy. Finally, we note that this study demonstrates the power of KMOS as an efficient instrument for large-scale resolved galaxy surveys. AU - Stott, John P. AU - Sobral, David AU - Swinbank, A. M. AU - Smail, Ian AU - Bower, Richard AU - Best, Philip N. AU - Sharples, Ray M. AU - Geach, James E. AU - Matthee, Jorryt J ID - 11582 IS - 3 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - galaxies: abundances KW - galaxies: evolution KW - galaxies: kinematics and dynamics SN - 0035-8711 TI - A relationship between specific star formation rate and metallicity gradient within z ∼ 1 galaxies from KMOS-HiZELS VL - 443 ER - TY - JOUR AB - We report on the magnetic properties of a hot-pressed FeSb 2 sample. We find a significant increase in the magnetic susceptibility in our sample when compared with the values previously reported for the polycrystalline sample. The pronounced Curie tail at low temperature corresponds to 0.2% of Fe 2+ impurities per mole. In the intrinsic conductivity region, the susceptibility due to free carriers shows thermally activated behavior and is consistent with the data reported for single crystal FeSb 2 . Based on our data and analysis, while the enhanced magnetic susceptibility in our sample comes mainly from a small amount of unreacted Fe, the contribution from the enhanced carrier density due to lattice and strain defects arising from the ball milling process is also significant. Existence of an unreacted Fe phase is evidenced by small coercivity values of ~100 observed at 50 and 300 K. AU - Pokharel, Mani AU - Zhao, Huaizhou AU - Modic, Kimberly A AU - Ren, Zhifeng AU - Opeil, Cyril ID - 11750 IS - 5 JF - IEEE Transactions on Magnetics SN - 0018-9464 TI - Magnetic properties of hot-pressed FeSb2 VL - 50 ER - TY - CONF AB - We study a weighted online bipartite matching problem: G(V 1, V 2, E) is a weighted bipartite graph where V 1 is known beforehand and the vertices of V 2 arrive online. The goal is to match vertices of V 2 as they arrive to vertices in V 1, so as to maximize the sum of weights of edges in the matching. If assignments to V 1 cannot be changed, no bounded competitive ratio is achievable. We study the weighted online matching problem with free disposal, where vertices in V 1 can be assigned multiple times, but only get credit for the maximum weight edge assigned to them over the course of the algorithm. For this problem, the greedy algorithm is 0.5-competitive and determining whether a better competitive ratio is achievable is a well known open problem. We identify an interesting special case where the edge weights are decomposable as the product of two factors, one corresponding to each end point of the edge. This is analogous to the well studied related machines model in the scheduling literature, although the objective functions are different. For this case of decomposable edge weights, we design a 0.5664 competitive randomized algorithm in complete bipartite graphs. We show that such instances with decomposable weights are non-trivial by establishing upper bounds of 0.618 for deterministic and 0.8 for randomized algorithms. A tight competitive ratio of 1 − 1/e ≈ 0.632 was known previously for both the 0-1 case as well as the case where edge weights depend on the offline vertices only, but for these cases, reassignments cannot change the quality of the solution. Beating 0.5 for weighted matching where reassignments are necessary has been a significant challenge. We thus give the first online algorithm with competitive ratio strictly better than 0.5 for a non-trivial case of weighted matching with free disposal. AU - Charikar, Moses AU - Henzinger, Monika H AU - Nguyễn, Huy L. ID - 11789 SN - 0302-9743 T2 - 22nd Annual European Symposium on Algorithms TI - Online bipartite matching with decomposable weights VL - 8737 ER - TY - CONF AB - Assume a seller wants to sell a digital product in a social network where a buyer’s valuation of the item has positive network externalities from her neighbors that already have the item. The goal of the seller is to maximize his revenue. Previous work on this problem [7] studies the case where clients are offered the item in sequence and have to pay personalized prices. This is highly infeasible in large scale networks such as the Facebook graph: (1) Offering items to the clients one after the other consumes a large amount of time, and (2) price-discrimination of clients could appear unfair to them and result in negative client reaction or could conflict with legal requirements. We study a setting dealing with these issues. Specifically, the item is offered in parallel to multiple clients at the same time and at the same price. This is called a round. We show that with O(logn) rounds, where n is the number of clients, a constant factor of the revenue with price discrimination can be achieved and that this is not possible with o(logn) rounds. Moreover we show that it is APX-hard to maximize the revenue and we give constant factor approximation algorithms for various further settings of limited price discrimination. AU - Cigler, Luděk AU - Dvořák, Wolfgang AU - Henzinger, Monika H AU - Starnberger, Martin ID - 11790 SN - 0302-9743 T2 - 10th International Conference of Web and Internet Economics TI - Limiting price discrimination when selling products with positive network externalities VL - 8877 ER - TY - JOUR AB - While the penetration of objects into granular media is well-studied, there is little understanding of how objects settle in gravities, geff, different from that of Earth - a scenario potentially relevant to the geomorphology of planets and asteroids and also to their exploration using man-made devices. By conducting experiments in an accelerating frame, we explore geff ranging from 0.4 g to 1.2 g. Surprisingly, we find that the rest depth is independent of geff and also that the time required for the object to come to rest scales like geff-1/2. With discrete element modeling simulations, we reproduce the experimental results and extend the range of geff to objects as small as asteroids and as large as Jupiter. Our results shed light on the initial stage of sedimentation into dry granular media across a range of celestial bodies and also have implications for the design of man-made, extraterrestrial vehicles and structures. Key Points The settling depth in granular media is independent of gravity The settling time scales like g-1/2 Layering driven by granular sedimentation should be similar. AU - Altshuler, Ernesto AU - Torres, H AU - González_Pita, A AU - Sánchez, Colina G AU - Pérez Penichet, Carlos AU - Waitukaitis, Scott R AU - Hidalgo, Rauól ID - 118 IS - 9 JF - Geophysical Research Letters TI - Settling into dry granular media in different gravities VL - 41 ER - TY - CONF AB - The decremental single-source shortest paths (SSSP) problem concerns maintaining the distances between a given source node s to every node in an n-node m-edge graph G undergoing edge deletions. While its static counterpart can be easily solved in near-linear time, this decremental problem is much more challenging even in the undirected unweighted case. In this case, the classic O(mn) total update time of Even and Shiloach (JACM 1981) has been the fastest known algorithm for three decades. With the loss of a (1 + ε)-approximation factor, the running time was recently improved to O(n 2+o(1) ) by Bernstein and Roditty (SODA 2011), and more recently to O(n 1.8+o(1) + m 1+o(1) ) by Henzinger, Krinninger, and Nanongkai (SODA 2014). In this paper, we finally bring the running time of this case down to near-linear: We give a (1 + ε)-approximation algorithm with O(m 1+o(1) ) total update time, thus obtaining near-linear time. Moreover, we obtain O(m 1+o(1) log W) time for the weighted case, where the edge weights are integers from 1 to W. The only prior work on weighted graphs in o(mn log W) time is the O(mn 0.986 log W)-time algorithm by Henzinger, Krinninger, and Nanongkai (STOC 2014) which works for the general weighted directed case. In contrast to the previous results which rely on maintaining a sparse emulator, our algorithm relies on maintaining a so-called sparse (d, ε)-hop set introduced by Cohen (JACM 2000) in the PRAM literature. A (d, ε)-hop set of a graph G = (V, E) is a set E' of weighted edges such that the distance between any pair of nodes in G can be (1 + ε)-approximated by their d-hop distance (given by a path containing at most d edges) on G'=(V, E∪E'). Our algorithm can maintain an (n o(1) , ε)-hop set of near-linear size in near-linear time under edge deletions. It is the first of its kind to the best of our knowledge. To maintain the distances on this hop set, we develop a monotone bounded-hop Even-Shiloach tree. It results from extending and combining the monotone Even-Shiloach tree of Henzinger, Krinninger, and Nanongkai (FOCS 2013) with the bounded-hop SSSP technique of Bernstein (STOC 2013). These two new tools might be of independent interest. AU - Henzinger, Monika H AU - Krinninger, Sebastian AU - Nanongkai, Danupon ID - 11855 SN - 0272-5428 T2 - 55th Annual Symposium on Foundations of Computer Science TI - Decremental single-source shortest paths on undirected graphs in near-linear total update time ER - TY - CONF AB - We consider dynamic algorithms for maintaining Single-Source Reachability (SSR) and approximate Single-Source Shortest Paths (SSSP) on n-node m-edge directed graphs under edge deletions (decremental algorithms). The previous fastest algorithm for SSR and SSSP goes back three decades to Even and Shiloach (JACM 1981); it has O(1) query time and O(mn) total update time (i.e., linear amortized update time if all edges are deleted). This algorithm serves as a building block for several other dynamic algorithms. The question whether its total update time can be improved is a major, long standing, open problem. In this paper, we answer this question affirmatively. We obtain a randomized algorithm which, in a simplified form, achieves an Õ(mn0.984) expected total update time for SSR and (1 + ε)-approximate SSSP, where Õ(·) hides poly log n. We also extend our algorithm to achieve roughly the same running time for Strongly Connected Components (SCC), improving the algorithm of Roditty and Zwick (FOCS 2002), and an algorithm that improves the Õ (mn log W)-time algorithm of Bernstein (STOC 2013) for approximating SSSP on weighted directed graphs, where the edge weights are integers from 1 to W. All our algorithms have constant query time in the worst case. AU - Henzinger, Monika H AU - Krinninger, Sebastian AU - Nanongkai, Danupon ID - 11870 SN - 0737-8017 T2 - 46th Annual ACM Symposium on Theory of Computing TI - Sublinear-time decremental algorithms for single-source reachability and shortest paths on directed graphs ER - TY - CONF AB - We study dynamic (1 + ∊)-approximation algorithms for the single-source shortest paths problem in an unweighted undirected n-node m-edge graph under edge deletions. The fastest algorithm for this problem is an algorithm with O(n2+o(1)) total update time and constant query time by Bernstein and Roditty (SODA 2011). In this paper, we improve the total update time to O(n1.8+o(1) + m1+o(1)) while keeping the query time constant. This running time is essentially tight when m = Ω(n1.8) since we need Ω(m) time even in the static setting. For smaller values of m, the running time of our algorithm is subquadratic, and is the first that breaks through the quadratic time barrier. In obtaining this result, we develop a fast algorithm for what we call center cover data structure. We also make non-trivial extensions to our previous techniques called lazy-update and monotone Even-Shiloach trees (ICALP 2013 and FOCS 2013). As by-products of our new techniques, we obtain two new results for the decremental all-pairs shortest-paths problem. Our first result is the first approximation algorithm whose total update time is faster than Õ(mn) for all values of m. Our second result is a new trade-off between the total update time and the additive approximation guarantee. AU - Henzinger, Monika H AU - Krinninger, Sebastian AU - Nanongkai, Danupon ID - 11876 SN - 978-1-61197-338-9 T2 - 25th Annual ACM-SIAM Symposium on Discrete Algorithms TI - A subquadratic-time algorithm for decremental single-source shortest paths ER - TY - CONF AB - We present the first deterministic data structures for maintaining approximate minimum vertex cover and maximum matching in a fully dynamic graph in time per update. In particular, for minimum vertex cover we provide deterministic data structures for maintaining a (2 + ε) approximation in O(log n/ε2) amortized time per update. For maximum matching, we show how to maintain a (3 + e) approximation in O(m1/3/ε2) amortized time per update, and a (4 + ε) approximation in O(m1/3/ε2) worst-case time per update. Our data structure for fully dynamic minimum vertex cover is essentially near-optimal and settles an open problem by Onak and Rubinfeld [13]. AU - Bhattacharya, Sayan AU - Henzinger, Monika H AU - Italiano, Giuseppe F. ID - 11875 SN - 978-1-61197-374-7 T2 - 26th Annual ACM-SIAM Symposium on Discrete Algorithms TI - Deterministic fully dynamic data structures for vertex cover and matching ER - TY - JOUR AB - Observations of flowing granular matter have suggested that same-material tribocharging depends on particle size, typically rendering large grains positive and small ones negative. Models assuming the transfer of trapped electrons can account for this trend, but have not been validated. Tracking individual grains in an electric field, we show quantitatively that charge is transferred based on size between materially identical grains. However, the surface density of trapped electrons, measured independently by thermoluminescence techniques, is orders of magnitude too small to account for the scale of charge transferred. This reveals that trapped electrons are not a necessary ingredient for same-material tribocharging. AU - Waitukaitis, Scott R AU - Lee, Victor AU - Pierson, James AU - Forman, Steven AU - Jaeger, Heinrich ID - 119 IS - 21 JF - APS Physics, Physical Review Letters TI - Size-dependent same-material tribocharging in insulating grains VL - 112 ER - TY - JOUR AB - Membrane phospholipids typically contain fatty acids (FAs) of 16 and 18 carbon atoms. This particular chain length is evolutionarily highly conserved and presumably provides maximum stability and dynamic properties to biological membranes in response to nutritional or environmental cues. Here, we show that the relative proportion of C16 versus C18 FAs is regulated by the activity of acetyl-CoA carboxylase (Acc1), the first and rate-limiting enzyme of FA de novo synthesis. Acc1 activity is attenuated by AMPK/Snf1-dependent phosphorylation, which is required to maintain an appropriate acyl-chain length distribution. Moreover, we find that the transcriptional repressor Opi1 preferentially binds to C16 over C18 phosphatidic acid (PA) species: thus, C16-chain containing PA sequesters Opi1 more effectively to the ER, enabling AMPK/Snf1 control of PA acyl-chain length to determine the degree of derepression of Opi1 target genes. These findings reveal an unexpected regulatory link between the major energy-sensing kinase, membrane lipid composition, and transcription. AU - Hofbauer, Harald F. AU - Schopf, Florian H. AU - Schleifer, Hannes AU - Knittelfelder, Oskar L. AU - Pieber, Bartholomäus AU - Rechberger, Gerald N. AU - Wolinski, Heimo AU - Gaspar, Maria L. AU - Kappe, C. Oliver AU - Stadlmann, Johannes AU - Mechtler, Karl AU - Zenz, Alexandra AU - Lohner, Karl AU - Tehlivets, Oksana AU - Henry, Susan A. AU - Kohlwein, Sepp D. ID - 11968 IS - 6 JF - Developmental Cell SN - 1534-5807 TI - Regulation of gene expression through a transcriptional repressor that senses acyl-chain length in membrane phospholipids VL - 29 ER - TY - JOUR AB - An experimentally easy to perform method for the generation of alumina-supported Fe3O4 nanoparticles [(6±1) nm size, 0.67 wt %]and the use of this material in hydrazine-mediated heterogeneously catalyzed reductions of nitroarenes to anilines under batch and continuous-flow conditions is presented. The bench-stable, reusable nano-Fe3O4@Al2O3 catalyst can selectively reduce functionalized nitroarenes at 1 mol % catalyst loading by using a 20 mol % excess of hydrazine hydrate in an elevated temperature regime (150 °C, reaction time 2–6 min in batch). For continuous-flow processing, the catalyst material is packed into dedicated cartridges and used in a commercially available high-temperature/-pressure flow device. In continuous mode, reaction times can be reduced to less than 1 min at 150 °C (30 bar back pressure) in a highly intensified process. The nano-Fe3O4@Al2O3 catalyst demonstrated stable reduction of nitrobenzene (0.5 M in MeOH) for more than 10 h on stream at a productivity of 30 mmol h−1 (0.72 mol per day). Importantly, virtually no leaching of the catalytically active material could be observed by inductively coupled plasma MS monitoring. AU - Moghaddam, Mojtaba Mirhosseini AU - Pieber, Bartholomäus AU - Glasnov, Toma AU - Kappe, C. Oliver ID - 11967 IS - 11 JF - ChemSusChem SN - 1864-5631 TI - Immobilized iron oxide nanoparticles as stable and reusable catalysts for hydrazine-mediated nitro reductions in continuous flow VL - 7 ER - TY - JOUR AB - A method for the direct lithiation of terminal alkynes and heterocycles with subsequent carboxylation in a continuous flow format was developed. This method provides carboxylic acids at ambient conditions within less than five seconds with only little excess of the organometallic base and CO2. AU - Pieber, Bartholomäus AU - Glasnov, Toma AU - Kappe, C. O. ID - 11987 IS - 26 JF - RSC Advances TI - Flash carboxylation: Fast lithiation–carboxylation sequence at room temperature in continuous flow VL - 4 ER - TY - JOUR AB - We show that weak solutions of the Derrida-Lebowitz-Speer-Spohn (DLSS) equation display infinite speed of support propagation. We apply our method to the case of the quantum drift-diffusion equation which augments the DLSS equation with a drift term and possibly a second-order diffusion term. The proof is accomplished using weighted entropy estimates, Hardy's inequality and a family of singular weight functions to derive a differential inequality; the differential inequality shows exponential growth of the weighted entropy, with the growth constant blowing up very fast as the singularity of the weight becomes sharper. To the best of our knowledge, this is the first example of a nonnegativity-preserving higher-order parabolic equation displaying infinite speed of support propagation. AU - Julian Fischer ID - 1309 IS - 1 JF - Nonlinear Differential Equations and Applications TI - Infinite speed of support propagation for the Derrida-Lebowitz-Speer-Spohn equation and quantum drift-diffusion models VL - 21 ER - TY - JOUR AB - We derive upper bounds on the waiting time of solutions to the thin-film equation in the regime of weak slippage n ∈ [2, 32\11). In particular, we give sufficient conditions on the initial data for instantaneous forward motion of the free boundary. For n ∈ (2, 32\11), our estimates are sharp, for n = 2, they are sharp up to a logarithmic correction term. Note that the case n = 2 corresponds-with a grain of salt-to the assumption of the Navier slip condition at the fluid-solid interface. We also obtain results in the regime of strong slippage n ∈ (1,2); however, in this regime we expect them not to be optimal. Our method is based on weighted backward entropy estimates, Hardy's inequality and singular weight functions; we deduce a differential inequality which would enforce blowup of the weighted entropy if the contact line were to remain stationary for too long. AU - Julian Fischer ID - 1312 IS - 3 JF - Archive for Rational Mechanics and Analysis TI - Upper bounds on waiting times for the Thin-film equation: The case of weak slippage VL - 211 ER - TY - JOUR AB - We consider directed graphs where each edge is labeled with an integer weight and study the fundamental algorithmic question of computing the value of a cycle with minimum mean weight. Our contributions are twofold: (1) First we show that the algorithmic question is reducible to the problem of a logarithmic number of min-plus matrix multiplications of n×n-matrices, where n is the number of vertices of the graph. (2) Second, when the weights are nonnegative, we present the first (1+ε)-approximation algorithm for the problem and the running time of our algorithm is Õ(nωlog3(nW/ε)/ε),1 where O(nω) is the time required for the classic n×n-matrix multiplication and W is the maximum value of the weights. With an additional O(log(nW/ε)) factor in space a cycle with approximately optimal weight can be computed within the same time bound. AU - Chatterjee, Krishnendu AU - Henzinger, Monika H AU - Krinninger, Sebastian AU - Loitzenbauer, Veronika AU - Raskin, Michael ID - 1375 IS - C JF - Theoretical Computer Science TI - Approximating the minimum cycle mean VL - 547 ER - TY - CONF AB - Fault-tolerant distributed algorithms play an important role in ensuring the reliability of many software applications. In this paper we consider distributed algorithms whose computations are organized in rounds. To verify the correctness of such algorithms, we reason about (i) properties (such as invariants) of the state, (ii) the transitions controlled by the algorithm, and (iii) the communication graph. We introduce a logic that addresses these points, and contains set comprehensions with cardinality constraints, function symbols to describe the local states of each process, and a limited form of quantifier alternation to express the verification conditions. We show its use in automating the verification of consensus algorithms. In particular, we give a semi-decision procedure for the unsatisfiability problem of the logic and identify a decidable fragment. We successfully applied our framework to verify the correctness of a variety of consensus algorithms tolerant to both benign faults (message loss, process crashes) and value faults (message corruption). AU - Dragoi, Cezara AU - Henzinger, Thomas A AU - Veith, Helmut AU - Widder, Josef AU - Zufferey, Damien ID - 1392 TI - A logic-based framework for verifying consensus algorithms VL - 8318 ER - TY - CONF AB - Probabilistic programs are usual functional or imperative programs with two added constructs: (1) the ability to draw values at random from distributions, and (2) the ability to condition values of variables in a program via observations. Models from diverse application areas such as computer vision, coding theory, cryptographic protocols, biology and reliability analysis can be written as probabilistic programs. Probabilistic inference is the problem of computing an explicit representation of the probability distribution implicitly specified by a probabilistic program. Depending on the application, the desired output from inference may vary-we may want to estimate the expected value of some function f with respect to the distribution, or the mode of the distribution, or simply a set of samples drawn from the distribution. In this paper, we describe connections this research area called \Probabilistic Programming" has with programming languages and software engineering, and this includes language design, and the static and dynamic analysis of programs. We survey current state of the art and speculate on promising directions for future research. AU - Gordon, Andrew AU - Henzinger, Thomas A AU - Nori, Aditya AU - Rajamani, Sriram ID - 1393 T2 - Proceedings of the on Future of Software Engineering TI - Probabilistic programming ER - TY - THES AB - The co-evolution of hosts and pathogens is characterized by continuous adaptations of both parties. Pathogens of social insects need to adapt towards disease defences at two levels: 1) individual immunity of each colony member consisting of behavioural defence strategies as well as humoral and cellular immune responses and 2) social immunity that is collectively performed by all group members comprising behavioural, physiological and organisational defence strategies. To disentangle the selection pressure on pathogens by the collective versus individual level of disease defence in social insects, we performed an evolution experiment using the Argentine Ant, Linepithema humile, as a host and a mixture of the general insect pathogenic fungus Metarhizium spp. (6 strains) as a pathogen. We allowed pathogen evolution over 10 serial host passages to two different evolution host treatments: (1) only individual host immunity in a single host treatment, and (2) simultaneously acting individual and social immunity in a social host treatment, in which an exposed ant was accompanied by two untreated nestmates. Before starting the pathogen evolution experiment, the 6 Metarhizium spp. strains were characterised concerning conidiospore size killing rates in singly and socially reared ants, their competitiveness under coinfecting conditions and their influence on ant behaviour. We analysed how the ancestral atrain mixture changed in conidiospere size, killing rate and strain composition dependent on host treatment (single or social hosts) during 10 passages and found that killing rate and conidiospere size of the pathogen increased under both evolution regimes, but different depending on host treatment. Testing the evolved strain mixtures that evolved under either the single or social host treatment under both single and social current rearing conditions in a full factorial design experiment revealed that the additional collective defences in insect societies add new selection pressure for their coevolving pathogens that compromise their ability to adapt to its host at the group level. To our knowledge, this is the first study directly measuring the influence of social immunity on pathogen evolution. AU - Stock, Miriam ID - 1404 TI - Evolution of a fungal pathogen towards individual versus social immunity in ants ER - TY - CONF AB - We present a rigorous derivation of the BCS gap equation for superfluid fermionic gases with point interactions. Our starting point is the BCS energy functional, whose minimizer we investigate in the limit when the range of the interaction potential goes to zero. AU - Bräunlich, Gerhard AU - Hainzl, Christian AU - Seiringer, Robert ID - 1516 T2 - Proceedings of the QMath12 Conference TI - On the BCS gap equation for superfluid fermionic gases ER - TY - JOUR AB - We propose a method for propagating edit operations in 2D vector graphics, based on geometric relationship functions. These functions quantify the geometric relationship of a point to a polygon, such as the distance to the boundary or the direction to the closest corner vertex. The level sets of the relationship functions describe points with the same relationship to a polygon. For a given query point, we first determine a set of relationships to local features, construct all level sets for these relationships, and accumulate them. The maxima of the resulting distribution are points with similar geometric relationships. We show extensions to handle mirror symmetries, and discuss the use of relationship functions as local coordinate systems. Our method can be applied, for example, to interactive floorplan editing, and it is especially useful for large layouts, where individual edits would be cumbersome. We demonstrate populating 2D layouts with tens to hundreds of objects by propagating relatively few edit operations. AU - Guerrero, Paul AU - Jeschke, Stefan AU - Wimmer, Michael AU - Wonka, Peter ID - 1629 IS - 2 JF - ACM Transactions on Graphics TI - Edit propagation using geometric relationship functions VL - 33 ER - TY - CONF AB - The Hanani–Tutte theorem is a classical result proved for the first time in the 1930s that characterizes planar graphs as graphs that admit a drawing in the plane in which every pair of edges not sharing a vertex cross an even number of times. We generalize this classical result to clustered graphs with two disjoint clusters, and show that a straightforward extension of our result to flat clustered graphs with three or more disjoint clusters is not possible. We also give a new and short proof for a related result by Di Battista and Frati based on the matroid intersection algorithm. AU - Fulek, Radoslav AU - Kynčl, Jan AU - Malinović, Igor AU - Pálvölgyi, Dömötör ID - 10793 SN - 0302-9743 T2 - International Symposium on Graph Drawing TI - Clustered planarity testing revisited VL - 8871 ER - TY - CONF AB - We extend the notion of verifiable random functions (VRF) to constrained VRFs, which generalize the concept of constrained pseudorandom functions, put forward by Boneh and Waters (Asiacrypt’13), and independently by Kiayias et al. (CCS’13) and Boyle et al. (PKC’14), who call them delegatable PRFs and functional PRFs, respectively. In a standard VRF the secret key sk allows one to evaluate a pseudorandom function at any point of its domain; in addition, it enables computation of a non-interactive proof that the function value was computed correctly. In a constrained VRF from the key sk one can derive constrained keys skS for subsets S of the domain, which allow computation of function values and proofs only at points in S. After formally defining constrained VRFs, we derive instantiations from the multilinear-maps-based constrained PRFs by Boneh and Waters, yielding a VRF with constrained keys for any set that can be decided by a polynomial-size circuit. Our VRFs have the same function values as the Boneh-Waters PRFs and are proved secure under the same hardness assumption, showing that verifiability comes at no cost. Constrained (functional) VRFs were stated as an open problem by Boyle et al. AU - Fuchsbauer, Georg ED - Abdalla, Michel ED - De Prisco, Roberto ID - 1643 T2 - SCN 2014 TI - Constrained Verifiable Random Functions VL - 8642 ER - TY - CONF AB - In this paper we present INTERHORN, a solver for recursion-free Horn clauses. The main application domain of INTERHORN lies in solving interpolation problems arising in software verification. We show how a range of interpolation problems, including path, transition, nested, state/transition and well-founded interpolation can be handled directly by INTERHORN. By detailing these interpolation problems and their Horn clause representations, we hope to encourage the emergence of a common back-end interpolation interface useful for diverse verification tools. AU - Gupta, Ashutosh AU - Popeea, Corneliu AU - Rybalchenko, Andrey ID - 1702 T2 - Electronic Proceedings in Theoretical Computer Science, EPTCS TI - Generalised interpolation by solving recursion free-horn clauses VL - 169 ER - TY - CONF AB - It has been long argued that, because of inherent ambiguity and noise, the brain needs to represent uncertainty in the form of probability distributions. The neural encoding of such distributions remains however highly controversial. Here we present a novel circuit model for representing multidimensional real-valued distributions using a spike based spatio-temporal code. Our model combines the computational advantages of the currently competing models for probabilistic codes and exhibits realistic neural responses along a variety of classic measures. Furthermore, the model highlights the challenges associated with interpreting neural activity in relation to behavioral uncertainty and points to alternative population-level approaches for the experimental validation of distributed representations. AU - Savin, Cristina AU - Denève, Sophie ID - 1708 IS - January TI - Spatio-temporal representations of uncertainty in spiking neural networks VL - 3 ER - TY - JOUR AB - Metal silicides formed by means of thermal annealing processes are employed as contact materials in microelectronics. Control of the structure of silicide/silicon interfaces becomes a critical issue when the characteristic size of the device is reduced below a few tens of nanometers. Here, we report on silicide clustering occurring within the channel of PtSi/Si/PtSi Schottky-barrier transistors. This phenomenon is investigated through atomistic simulations and low-temperature resonant-tunneling spectroscopy. Our results provide evidence for the segregation of a PtSi cluster with a diameter of a few nanometers from the silicide contact. The cluster acts as a metallic quantum dot giving rise to distinct signatures of quantum transport through its discrete energy states. AU - Mongillo, Massimo AU - Spathis, Panayotis N AU - Georgios Katsaros AU - De Franceschi, Silvano AU - Gentile, Pascal AU - Rurali, Riccardo AU - Cartoixà, Xavier ID - 1761 IS - 4 JF - Physical Review X TI - PtSi clustering in silicon probed by transport spectroscopy VL - 3 ER - TY - JOUR AB - Acute gene inactivation using short hairpin RNA (shRNA, knockdown) in developing brain is a powerful technique to study genetic function; however, discrepancies between knockdown and knockout murine phenotypes have left unanswered questions. For example, doublecortin (Dcx) knockdown but not knockout shows a neocortical neuronal migration phenotype. Here we report that in utero electroporation of shRNA, but not siRNA or miRNA, to Dcx demonstrates a migration phenotype in Dcx knockouts akin to the effect in wild-type mice, suggestingshRNA-mediated off-target toxicity. This effect wasnot limited to Dcx, as it was observed in Dclk1 knockouts, as well as with a fraction of scrambled shRNAs, suggesting a sequence-dependent but not sequence-specific effect. Profiling RNAs from electroporated cells showed a defect in endogenous let7 miRNA levels, and disruption of let7 or Dicer recapitulated the migration defect. The results suggest that shRNA-mediated knockdown can produce untoward migration effects by altering endogenous miRNA pathways. AU - Baek, SeungTae AU - Kerjan, Géraldine AU - Bielas, Stephanie L AU - Lee, Jieun AU - Fenstermaker, Ali G AU - Gaia Novarino AU - Gleeson, Joseph G ID - 1791 IS - 6 JF - Neuron TI - Off-target effect of doublecortin family shRNA on neuronal migration associated with endogenous MicroRNA dysregulation VL - 82 ER - TY - CHAP AB - The generation of asymmetry, at both cellular and tissue level, is one of the most essential capabilities of all eukaryotic organisms. It mediates basically all multicellular development ranging from embryogenesis and de novo organ formation till responses to various environmental stimuli. In plants, the awe-inspiring number of such processes is regulated by phytohormone auxin and its directional, cell-to-cell transport. The mediators of this transport, PIN auxin transporters, are asymmetrically localized at the plasma membrane, and this polar localization determines the directionality of intercellular auxin flow. Thus, auxin transport contributes crucially to the generation of local auxin gradients or maxima, which instruct given cell to change its developmental program. Here, we introduce and discuss the molecular components and cellular mechanisms regulating the generation and maintenance of cellular PIN polarity, as the general hallmarks of cell polarity in plants. AU - Baster, Pawel AU - Friml, Jiří ED - Zažímalová, Eva ED - Petrášek, Jan ED - Benková, Eva ID - 1806 T2 - Auxin and Its Role in Plant Development TI - Auxin on the road navigated by cellular PIN polarity ER - TY - JOUR AB - Watermarking techniques for vector graphics dislocate vertices in order to embed imperceptible, yet detectable, statistical features into the input data. The embedding process may result in a change of the topology of the input data, e.g., by introducing self-intersections, which is undesirable or even disastrous for many applications. In this paper we present a watermarking framework for two-dimensional vector graphics that employs conventional watermarking techniques but still provides the guarantee that the topology of the input data is preserved. The geometric part of this framework computes so-called maximum perturbation regions (MPR) of vertices. We propose two efficient algorithms to compute MPRs based on Voronoi diagrams and constrained triangulations. Furthermore, we present two algorithms to conditionally correct the watermarked data in order to increase the watermark embedding capacity and still guarantee topological correctness. While we focus on the watermarking of input formed by straight-line segments, one of our approaches can also be extended to circular arcs. We conclude the paper by demonstrating and analyzing the applicability of our framework in conjunction with two well-known watermarking techniques. AU - Huber, Stefan AU - Held, Martin AU - Meerwald, Peter AU - Kwitt, Roland ID - 1816 IS - 1 JF - International Journal of Computational Geometry and Applications TI - Topology-preserving watermarking of vector graphics VL - 24 ER - TY - JOUR AB - We review recent progress towards a rigorous understanding of the Bogoliubov approximation for bosonic quantum many-body systems. We focus, in particular, on the excitation spectrum of a Bose gas in the mean-field (Hartree) limit. A list of open problems will be discussed at the end. AU - Seiringer, Robert ID - 1821 IS - 7 JF - Journal of Mathematical Physics TI - Bose gases, Bose-Einstein condensation, and the Bogoliubov approximation VL - 55 ER - TY - JOUR AU - Jakšić, Vojkan AU - Pillet, Claude AU - Seiringer, Robert ID - 1822 IS - 7 JF - Journal of Mathematical Physics TI - Introduction VL - 55 ER - TY - CHAP AB - Hitting and batting tasks, such as tennis forehands, ping-pong strokes, or baseball batting, depend on predictions where the ball can be intercepted and how it can properly be returned to the opponent. These predictions get more accurate over time, hence the behaviors need to be continuously modified. As a result, movement templates with a learned global shape need to be adapted during the execution so that the racket reaches a target position and velocity that will return the ball over to the other side of the net or court. It requires altering learned movements to hit a varying target with the necessary velocity at a specific instant in time. Such a task cannot be incorporated straightforwardly in most movement representations suitable for learning. For example, the standard formulation of the dynamical system based motor primitives (introduced by Ijspeert et al (2002b)) does not satisfy this property despite their flexibility which has allowed learning tasks ranging from locomotion to kendama. In order to fulfill this requirement, we reformulate the Ijspeert framework to incorporate the possibility of specifying a desired hitting point and a desired hitting velocity while maintaining all advantages of the original formulation.We show that the proposed movement template formulation works well in two scenarios, i.e., for hitting a ball on a string with a table tennis racket at a specified velocity and for returning balls launched by a ball gun successfully over the net using forehand movements. AU - Muelling, Katharina AU - Kroemer, Oliver AU - Lampert, Christoph AU - Schölkopf, Bernhard ED - Kober, Jens ED - Peters, Jan ID - 1829 T2 - Learning Motor Skills TI - Movement templates for learning of hitting and batting VL - 97 ER - TY - JOUR AB - Local protein interactions ("molecular context" effects) dictate amino acid replacements and can be described in terms of site-specific, energetic preferences for any different amino acid. It has been recently debated whether these preferences remain approximately constant during evolution or whether, due to coevolution of sites, they change strongly. Such research highlights an unresolved and fundamental issue with far-reaching implications for phylogenetic analysis and molecular evolution modeling. Here, we take advantage of the recent availability of phenotypically supported laboratory resurrections of Precambrian thioredoxins and β-lactamases to experimentally address the change of site-specific amino acid preferences over long geological timescales. Extensive mutational analyses support the notion that evolutionary adjustment to a new amino acid may occur, but to a large extent this is insufficient to erase the primitive preference for amino acid replacements. Generally, site-specific amino acid preferences appear to remain conserved throughout evolutionary history despite local sequence divergence. We show such preference conservation to be readily understandable in molecular terms and we provide crystallographic evidence for an intriguing structural-switch mechanism: Energetic preference for an ancestral amino acid in a modern protein can be linked to reorganization upon mutation to the ancestral local structure around the mutated site. Finally, we point out that site-specific preference conservation naturally leads to one plausible evolutionary explanation for the existence of intragenic global suppressor mutations. AU - Risso, Valeria AU - Manssour Triedo, Fadia AU - Delgado Delgado, Asuncion AU - Arco, Rocio AU - Barroso Deljesús, Alicia AU - Inglés Prieto, Álvaro AU - Godoy Ruiz, Raquel AU - Gavira, Josè AU - Gaucher, Eric AU - Ibarra Molero, Beatriz AU - Sánchez Ruiz, Jose ID - 1844 IS - 2 JF - Molecular Biology and Evolution TI - Mutational studies on resurrected ancestral proteins reveal conservation of site-specific amino acid preferences throughout evolutionary history VL - 32 ER - TY - JOUR AB - We prove polynomial upper bounds of geometric Ramsey numbers of pathwidth-2 outerplanar triangulations in both convex and general cases. We also prove that the geometric Ramsey numbers of the ladder graph on 2n vertices are bounded by O(n3) and O(n10), in the convex and general case, respectively. We then apply similar methods to prove an (Formula presented.) upper bound on the Ramsey number of a path with n ordered vertices. AU - Cibulka, Josef AU - Gao, Pu AU - Krcál, Marek AU - Valla, Tomáš AU - Valtr, Pavel ID - 1842 IS - 1 JF - Discrete & Computational Geometry TI - On the geometric ramsey number of outerplanar graphs VL - 53 ER - TY - JOUR AB - In this paper, we present a method for non-rigid, partial shape matching in vector graphics. Given a user-specified query region in a 2D shape, similar regions are found, even if they are non-linearly distorted. Furthermore, a non-linear mapping is established between the query regions and these matches, which allows the automatic transfer of editing operations such as texturing. This is achieved by a two-step approach. First, pointwise correspondences between the query region and the whole shape are established. The transformation parameters of these correspondences are registered in an appropriate transformation space. For transformations between similar regions, these parameters form surfaces in transformation space, which are extracted in the second step of our method. The extracted regions may be related to the query region by a non-rigid transform, enabling non-rigid shape matching. In this paper, we present a method for non-rigid, partial shape matching in vector graphics. Given a user-specified query region in a 2D shape, similar regions are found, even if they are non-linearly distorted. Furthermore, a non-linear mapping is established between the query regions and these matches, which allows the automatic transfer of editing operations such as texturing. This is achieved by a two-step approach. First, pointwise correspondences between the query region and the whole shape are established. The transformation parameters of these correspondences are registered in an appropriate transformation space. For transformations between similar regions, these parameters form surfaces in transformation space, which are extracted in the second step of our method. The extracted regions may be related to the query region by a non-rigid transform, enabling non-rigid shape matching. AU - Guerrero, Paul AU - Auzinger, Thomas AU - Wimmer, Michael AU - Jeschke, Stefan ID - 1854 IS - 1 JF - Computer Graphics Forum TI - Partial shape matching using transformation parameter similarity VL - 34 ER - TY - JOUR AB - To control morphogenesis, molecular regulatory networks have to interfere with the mechanical properties of the individual cells of developing organs and tissues, but how this is achieved is not well known. We study this issue here in the shoot meristem of higher plants, a group of undifferentiated cells where complex changes in growth rates and directions lead to the continuous formation of new organs [1, 2]. Here, we show that the plant hormone auxin plays an important role in this process via a dual, local effect on the extracellular matrix, the cell wall, which determines cell shape. Our study reveals that auxin not only causes a limited reduction in wall stiffness but also directly interferes with wall anisotropy via the regulation of cortical microtubule dynamics. We further show that to induce growth isotropy and organ outgrowth, auxin somehow interferes with the cortical microtubule-ordering activity of a network of proteins, including AUXIN BINDING PROTEIN 1 and KATANIN 1. Numerical simulations further indicate that the induced isotropy is sufficient to amplify the effects of the relatively minor changes in wall stiffness to promote organogenesis and the establishment of new growth axes in a robust manner. AU - Sassi, Massimiliano AU - Ali, Olivier AU - Boudon, Frédéric AU - Cloarec, Gladys AU - Abad, Ursula AU - Cellier, Coralie AU - Chen, Xu AU - Gilles, Benjamin AU - Milani, Pascale AU - Friml, Jirí AU - Vernoux, Teva AU - Godin, Christophe AU - Hamant, Olivier AU - Traas, Jan ID - 1852 IS - 19 JF - Current Biology TI - An auxin-mediated shift toward growth isotropy promotes organ formation at the shoot meristem in Arabidopsis VL - 24 ER - TY - CONF AB - Wireless sensor networks (WSNs) composed of low-power, low-cost sensor nodes are expected to form the backbone of future intelligent networks for a broad range of civil, industrial and military applications. These sensor nodes are often deployed through random spreading, and function in dynamic environments. Many applications of WSNs such as pollution tracking, forest fire detection, and military surveillance require knowledge of the location of constituent nodes. But the use of technologies such as GPS on all nodes is prohibitive due to power and cost constraints. So, the sensor nodes need to autonomously determine their locations. Most localization techniques use anchor nodes with known locations to determine the position of remaining nodes. Localization techniques have two conflicting requirements. On one hand, an ideal localization technique should be computationally simple and on the other hand, it must be resistant to attacks that compromise anchor nodes. In this paper, we propose a computationally light-weight game theoretic secure localization technique and demonstrate its effectiveness in comparison to existing techniques. AU - Jha, Susmit AU - Tripakis, Stavros AU - Seshia, Sanjit AU - Chatterjee, Krishnendu ID - 1853 TI - Game theoretic secure localization in wireless sensor networks ER - TY - JOUR AB - The prominent and evolutionarily ancient role of the plant hormone auxin is the regulation of cell expansion. Cell expansion requires ordered arrangement of the cytoskeleton but molecular mechanisms underlying its regulation by signalling molecules including auxin are unknown. Here we show in the model plant Arabidopsis thaliana that in elongating cells exogenous application of auxin or redistribution of endogenous auxin induces very rapid microtubule re-orientation from transverse to longitudinal, coherent with the inhibition of cell expansion. This fast auxin effect requires auxin binding protein 1 (ABP1) and involves a contribution of downstream signalling components such as ROP6 GTPase, ROP-interactive protein RIC1 and the microtubule-severing protein katanin. These components are required for rapid auxin-and ABP1-mediated re-orientation of microtubules to regulate cell elongation in roots and dark-grown hypocotyls as well as asymmetric growth during gravitropic responses. AU - Chen, Xu AU - Grandont, Laurie AU - Li, Hongjiang AU - Hauschild, Robert AU - Paque, Sébastien AU - Abuzeineh, Anas AU - Rakusova, Hana AU - Benková, Eva AU - Perrot Rechenmann, Catherine AU - Friml, Jirí ID - 1862 IS - 729 JF - Nature SN - 0028-0836 TI - Inhibition of cell expansion by rapid ABP1-mediated auxin effect on microtubules VL - 516 ER - TY - CONF AB - Boolean controllers for systems with complex datapaths are often very difficult to implement correctly, in particular when concurrency is involved. Yet, in many instances it is easy to formally specify correctness. For example, the specification for the controller of a pipelined processor only has to state that the pipelined processor gives the same results as a non-pipelined reference design. This makes such controllers a good target for automated synthesis. However, an efficient abstraction for the complex datapath elements is needed, as a bit-precise description is often infeasible. We present Suraq, the first controller synthesis tool which uses uninterpreted functions for the abstraction. Quantified firstorder formulas (with specific quantifier structure) serve as the specification language from which Suraq synthesizes Boolean controllers. Suraq transforms the specification into an unsatisfiable SMT formula, and uses Craig interpolation to compute its results. Using Suraq, we were able to synthesize a controller (consisting of two Boolean signals) for a five-stage pipelined DLX processor in roughly one hour and 15 minutes. AU - Hofferek, Georg AU - Gupta, Ashutosh ED - Yahav, Eran ID - 1869 T2 - HVC 2014 TI - Suraq - a controller synthesis tool using uninterpreted functions VL - 8855 ER - TY - CONF AB - Extensionality axioms are common when reasoning about data collections, such as arrays and functions in program analysis, or sets in mathematics. An extensionality axiom asserts that two collections are equal if they consist of the same elements at the same indices. Using extensionality is often required to show that two collections are equal. A typical example is the set theory theorem (∀x)(∀y)x∪y = y ∪x. Interestingly, while humans have no problem with proving such set identities using extensionality, they are very hard for superposition theorem provers because of the calculi they use. In this paper we show how addition of a new inference rule, called extensionality resolution, allows first-order theorem provers to easily solve problems no modern first-order theorem prover can solve. We illustrate this by running the VAMPIRE theorem prover with extensionality resolution on a number of set theory and array problems. Extensionality resolution helps VAMPIRE to solve problems from the TPTP library of first-order problems that were never solved before by any prover. AU - Gupta, Ashutosh AU - Kovács, Laura AU - Kragl, Bernhard AU - Voronkov, Andrei ED - Cassez, Franck ED - Raskin, Jean-François ID - 1872 T2 - ATVA 2014 TI - Extensional crisis and proving identity VL - 8837 ER - TY - CONF AB - We investigate the problem of checking if a finite-state transducer is robust to uncertainty in its input. Our notion of robustness is based on the analytic notion of Lipschitz continuity - a transducer is K-(Lipschitz) robust if the perturbation in its output is at most K times the perturbation in its input. We quantify input and output perturbation using similarity functions. We show that K-robustness is undecidable even for deterministic transducers. We identify a class of functional transducers, which admits a polynomial time automata-theoretic decision procedure for K-robustness. This class includes Mealy machines and functional letter-to-letter transducers. We also study K-robustness of nondeterministic transducers. Since a nondeterministic transducer generates a set of output words for each input word, we quantify output perturbation using setsimilarity functions. We show that K-robustness of nondeterministic transducers is undecidable, even for letter-to-letter transducers. We identify a class of set-similarity functions which admit decidable K-robustness of letter-to-letter transducers. AU - Henzinger, Thomas A AU - Otop, Jan AU - Samanta, Roopsha ID - 1870 T2 - Leibniz International Proceedings in Informatics, LIPIcs TI - Lipschitz robustness of finite-state transducers VL - 29 ER - TY - CONF AB - We present a formal framework for repairing infinite-state, imperative, sequential programs, with (possibly recursive) procedures and multiple assertions; the framework can generate repaired programs by modifying the original erroneous program in multiple program locations, and can ensure the readability of the repaired program using user-defined expression templates; the framework also generates a set of inductive assertions that serve as a proof of correctness of the repaired program. As a step toward integrating programmer intent and intuition in automated program repair, we present a cost-aware formulation - given a cost function associated with permissible statement modifications, the goal is to ensure that the total program modification cost does not exceed a given repair budget. As part of our predicate abstractionbased solution framework, we present a sound and complete algorithm for repair of Boolean programs. We have developed a prototype tool based on SMT solving and used it successfully to repair diverse errors in benchmark C programs. AU - Samanta, Roopsha AU - Olivo, Oswaldo AU - Allen, Emerson ED - Müller-Olm, Markus ED - Seidl, Helmut ID - 1875 TI - Cost-aware automatic program repair VL - 8723 ER - TY - JOUR AB - We study densities of functionals over uniformly bounded triangulations of a Delaunay set of vertices, and prove that the minimum is attained for the Delaunay triangulation if this is the case for finite sets. AU - Dolbilin, Nikolai AU - Edelsbrunner, Herbert AU - Glazyrin, Alexey AU - Musin, Oleg ID - 1876 IS - 3 JF - Moscow Mathematical Journal SN - 16093321 TI - Functionals on triangulations of delaunay sets VL - 14 ER - TY - JOUR AB - During inflammation, lymph nodes swell with an influx of immune cells. New findings identify a signalling pathway that induces relaxation in the contractile cells that give structure to these organs. AU - Sixt, Michael K AU - Vaahtomeri, Kari ID - 1877 IS - 7523 JF - Nature TI - Physiology: Relax and come in VL - 514 ER - TY - JOUR AB - Information processing in the sensory periphery is shaped by natural stimulus statistics. In the periphery, a transmission bottleneck constrains performance; thus efficient coding implies that natural signal components with a predictably wider range should be compressed. In a different regime—when sampling limitations constrain performance—efficient coding implies that more resources should be allocated to informative features that are more variable. We propose that this regime is relevant for sensory cortex when it extracts complex features from limited numbers of sensory samples. To test this prediction, we use central visual processing as a model: we show that visual sensitivity for local multi-point spatial correlations, described by dozens of independently-measured parameters, can be quantitatively predicted from the structure of natural images. This suggests that efficient coding applies centrally, where it extends to higher-order sensory features and operates in a regime in which sensitivity increases with feature variability. AU - Hermundstad, Ann AU - Briguglio, John AU - Conte, Mary AU - Victor, Jonathan AU - Balasubramanian, Vijay AU - Tkacik, Gasper ID - 1886 IS - November JF - eLife TI - Variance predicts salience in central sensory processing ER - TY - JOUR AB - To search for a target in a complex environment is an everyday behavior that ends with finding the target. When we search for two identical targets, however, we must continue the search after finding the first target and memorize its location. We used fixation-related potentials to investigate the neural correlates of different stages of the search, that is, before and after finding the first target. Having found the first target influenced subsequent distractor processing. Compared to distractor fixations before the first target fixation, a negative shift was observed for three subsequent distractor fixations. These results suggest that processing a target in continued search modulates the brain's response, either transiently by reflecting temporary working memory processes or permanently by reflecting working memory retention. AU - Körner, Christof AU - Braunstein, Verena AU - Stangl, Matthias AU - Schlögl, Alois AU - Neuper, Christa AU - Ischebeck, Anja ID - 1890 IS - 4 JF - Psychophysiology TI - Sequential effects in continued visual search: Using fixation-related potentials to compare distractor processing before and after target detection VL - 51 ER - TY - JOUR AB - Behavioural variation among conspecifics is typically contingent on individual state or environmental conditions. Sex-specific genetic polymorphisms are enigmatic because they lack conditionality, and genes causing adaptive trait variation in one sex may reduce Darwinian fitness in the other. One way to avoid such genetic antagonism is to control sex-specific traits by inheritance via sex chromosomes. Here, controlled laboratory crossings suggest that in snail-brooding cichlid fish a single locus, two-allele polymorphism located on a sex-linked chromosome of heterogametic males generates an extreme reproductive dimorphism. Both natural and sexual selection are responsible for exceptionally large body size of bourgeois males, creating a niche for a miniature male phenotype to evolve. This extreme intrasexual dimorphism results from selection on opposite size thresholds caused by a single ecological factor, empty snail shells used as breeding substrate. Paternity analyses reveal that in the field parasitic dwarf males sire the majority of offspring in direct sperm competition with large nest owners exceeding their size more than 40 times. Apparently, use of empty snail shells as breeding substrate and single locus sex-linked inheritance of growth are the major ecological and genetic mechanisms responsible for the extreme intrasexual diversity observed in Lamprologus callipterus. AU - Ocana, Sabine AU - Meidl, Patrick AU - Bonfils, Danielle AU - Taborsky, Michael ID - 1892 IS - 1794 JF - Proceedings of the Royal Society of London Series B Biological Sciences TI - Y-linked Mendelian inheritance of giant and dwarf male morphs in shell-brooding cichlids VL - 281 ER - TY - JOUR AB - We provide theoretical tests of a novel experimental technique to determine mechanostability of proteins based on stretching a mechanically protected protein by single-molecule force spectroscopy. This technique involves stretching a homogeneous or heterogeneous chain of reference proteins (single-molecule markers) in which one of them acts as host to the guest protein under study. The guest protein is grafted into the host through genetic engineering. It is expected that unraveling of the host precedes the unraveling of the guest removing ambiguities in the reading of the force-extension patterns of the guest protein. We study examples of such systems within a coarse-grained structure-based model. We consider systems with various ratios of mechanostability for the host and guest molecules and compare them to experimental results involving cohesin I as the guest molecule. For a comparison, we also study the force-displacement patterns in proteins that are linked in a serial fashion. We find that the mechanostability of the guest is similar to that of the isolated or serially linked protein. We also demonstrate that the ideal configuration of this strategy would be one in which the host is much more mechanostable than the single-molecule markers. We finally show that it is troublesome to use the highly stable cystine knot proteins as a host to graft a guest in stretching studies because this would involve a cleaving procedure. AU - Chwastyk, Mateusz AU - Galera Prat, Albert AU - Sikora, Mateusz K AU - Gómez Sicilia, Àngel AU - Carrión Vázquez, Mariano AU - Cieplak, Marek ID - 1891 IS - 5 JF - Proteins: Structure, Function and Bioinformatics TI - Theoretical tests of the mechanical protection strategy in protein nanomechanics VL - 82 ER - TY - JOUR AB - Unbiased high-throughput massively parallel sequencing methods have transformed the process of discovery of novel putative driver gene mutations in cancer. In chronic lymphocytic leukemia (CLL), these methods have yielded several unexpected findings, including the driver genes SF3B1, NOTCH1 and POT1. Recent analysis, utilizing down-sampling of existing datasets, has shown that the discovery process of putative drivers is far from complete across cancer. In CLL, while driver gene mutations affecting >10% of patients were efficiently discovered with previously published CLL cohorts of up to 160 samples subjected to whole exome sequencing (WES), this sample size has only 0.78 power to detect drivers affecting 5% of patients, and only 0.12 power for drivers affecting 2% of patients. These calculations emphasize the need to apply unbiased WES to larger patient cohorts. AU - Landau, Dan AU - Stewart, Chip AU - Reiter, Johannes AU - Lawrence, Michael AU - Sougnez, Carrie AU - Brown, Jennifer AU - Lopez Guillermo, Armando AU - Gabriel, Stacey AU - Lander, Eric AU - Neuberg, Donna AU - López Otín, Carlos AU - Campo, Elias AU - Getz, Gad AU - Wu, Catherine ID - 1884 IS - 21 JF - Blood TI - Novel putative driver gene mutations in chronic lymphocytic leukemia (CLL): results from a combined analysis of whole exome sequencing of 262 primary CLL aamples VL - 124 ER - TY - JOUR AB - We study translation-invariant quasi-free states for a system of fermions with two-particle interactions. The associated energy functional is similar to the BCS functional but also includes direct and exchange energies. We show that for suitable short-range interactions, these latter terms only lead to a renormalization of the chemical potential, with the usual properties of the BCS functional left unchanged. Our analysis thus represents a rigorous justification of part of the BCS approximation. We give bounds on the critical temperature below which the system displays superfluidity. AU - Bräunlich, Gerhard AU - Hainzl, Christian AU - Seiringer, Robert ID - 1889 IS - 7 JF - Reviews in Mathematical Physics TI - Translation-invariant quasi-free states for fermionic systems and the BCS approximation VL - 26 ER - TY - JOUR AB - Background: Bacterial Dsb enzymes are involved in the oxidative folding of many proteins, through the formation of disulfide bonds between their cysteine residues. The Dsb protein network has been well characterized in cells of the model microorganism Escherichia coli. To gain insight into the functioning of the Dsb system in epsilon-Proteobacteria, where it plays an important role in the colonization process, we studied two homologs of the main Escherichia coli Dsb oxidase (EcDsbA) that are present in the cells of the enteric pathogen Campylobacter jejuni, the most frequently reported bacterial cause of human enteritis in the world. Methods and Results: Phylogenetic analysis suggests the horizontal transfer of the epsilon-Proteobacterial DsbAs from a common ancestor to gamma-Proteobacteria, which then gave rise to the DsbL lineage. Phenotype and enzymatic assays suggest that the two C. jejuni DsbAs play different roles in bacterial cells and have divergent substrate spectra. CjDsbA1 is essential for the motility and autoagglutination phenotypes, while CjDsbA2 has no impact on those processes. CjDsbA1 plays a critical role in the oxidative folding that ensures the activity of alkaline phosphatase CjPhoX, whereas CjDsbA2 is crucial for the activity of arylsulfotransferase CjAstA, encoded within the dsbA2-dsbB-astA operon. Conclusions: Our results show that CjDsbA1 is the primary thiol-oxidoreductase affecting life processes associated with bacterial spread and host colonization, as well as ensuring the oxidative folding of particular protein substrates. In contrast, CjDsbA2 activity does not affect the same processes and so far its oxidative folding activity has been demonstrated for one substrate, arylsulfotransferase CjAstA. The results suggest the cooperation between CjDsbA2 and CjDsbB. In the case of the CjDsbA1, this cooperation is not exclusive and there is probably another protein to be identified in C. jejuni cells that acts to re-oxidize CjDsbA1. Altogether the data presented here constitute the considerable insight to the Epsilonproteobacterial Dsb systems, which have been poorly understood so far. AU - Grabowska, Anna AU - Wywiał, Ewa AU - Dunin Horkawicz, Stanislaw AU - Łasica, Anna AU - Wösten, Marc AU - Nagy-Staron, Anna A AU - Godlewska, Renata AU - Bocian Ostrzycka, Katarzyna AU - Pieńkowska, Katarzyna AU - Łaniewski, Paweł AU - Bujnicki, Janusz AU - Van Putten, Jos AU - Jagusztyn Krynicka, Elzbieta ID - 1894 IS - 9 JF - PLoS One TI - Functional and bioinformatics analysis of two Campylobacter jejuni homologs of the thiol-disulfide oxidoreductase, DsbA VL - 9 ER - TY - JOUR AB - Major histocompatibility complex class I (MHCI) molecules were recently identified as novel regulators of synaptic plasticity. These molecules are expressed in various brain areas, especially in regions undergoing activity-dependent synaptic plasticity, but their role in the nucleus accumbens (NAc) is unknown. In this study, we investigated the effects of genetic disruption of MHCI function, through deletion of β2-microblobulin, which causes lack of cell surface expression of MHCI. First, we confirmed that MHCI molecules are expressed in the NAc core in wild-type mice. Second, we performed electrophysiological recordings with NAc core slices from wild-type and β2-microglobulin knock-out mice lacking cell surface expression of MHCI. We found that low frequency stimulation induced long-term depression in wild-type but not knock-out mice, whereas high frequency stimulation induced long-term potentiation in both genotypes, with a larger magnitude in knock-out mice. Furthermore, we demonstrated that knock-out mice showed more persistent behavioral sensitization to cocaine, which is a NAc-related behavior. Using this model, we analyzed the density of total AMPA receptors and their subunits GluR1 and GluR2 in the NAc core, by SDS-digested freeze-fracture replica labeling. After repeated cocaine exposure, the density of GluR1 was increased, but there was no change in total AMPA receptors and GluR2 levels in wildtype mice. In contrast, following repeated cocaine exposure, increased densities of total AMPA receptors, GluR1 and GluR2 were observed in knock-out mice. These results indicate that functional deficiency of MHCI enhances synaptic potentiation, induced by electrical and pharmacological stimulation. AU - Edamura, Mitsuhiro AU - Murakami, Gen AU - Meng, Hongrui AU - Itakura, Makoto AU - Shigemoto, Ryuichi AU - Fukuda, Atsuo AU - Nakahara, Daiichiro ID - 1895 IS - 9 JF - PLoS One TI - Functional deficiency of MHC class i enhances LTP and abolishes LTD in the nucleus accumbens of mice VL - 9 ER - TY - JOUR AB - Phosphatidylinositol (PtdIns) is a structural phospholipid that can be phosphorylated into various lipid signaling molecules, designated polyphosphoinositides (PPIs). The reversible phosphorylation of PPIs on the 3, 4, or 5 position of inositol is performed by a set of organelle-specific kinases and phosphatases, and the characteristic head groups make these molecules ideal for regulating biological processes in time and space. In yeast and mammals, PtdIns3P and PtdIns(3,5)P2 play crucial roles in trafficking toward the lytic compartments, whereas the role in plants is not yet fully understood. Here we identified the role of a land plant-specific subgroup of PPI phosphatases, the suppressor of actin 2 (SAC2) to SAC5, during vacuolar trafficking and morphogenesis in Arabidopsis thaliana. SAC2-SAC5 localize to the tonoplast along with PtdIns3P, the presumable product of their activity. In SAC gain- and loss-of-function mutants, the levels of PtdIns monophosphates and bisphosphates were changed, with opposite effects on the morphology of storage and lytic vacuoles, and the trafficking toward the vacuoles was defective. Moreover, multiple sac knockout mutants had an increased number of smaller storage and lytic vacuoles, whereas extralarge vacuoles were observed in the overexpression lines, correlating with various growth and developmental defects. The fragmented vacuolar phenotype of sac mutants could be mimicked by treating wild-type seedlings with PtdIns(3,5)P2, corroborating that this PPI is important for vacuole morphology. Taken together, these results provide evidence that PPIs, together with their metabolic enzymes SAC2-SAC5, are crucial for vacuolar trafficking and for vacuolar morphology and function in plants. AU - Nováková, Petra AU - Hirsch, Sibylle AU - Feraru, Elena AU - Tejos, Ricardo AU - Van Wijk, Ringo AU - Viaene, Tom AU - Heilmann, Mareike AU - Lerche, Jennifer AU - De Rycke, Riet AU - Feraru, Mugurel AU - Grones, Peter AU - Van Montagu, Marc AU - Heilmann, Ingo AU - Munnik, Teun AU - Friml, Jirí ID - 1893 IS - 7 JF - PNAS TI - SAC phosphoinositide phosphatases at the tonoplast mediate vacuolar function in Arabidopsis VL - 111 ER - TY - JOUR AB - Biopolymer length regulation is a complex process that involves a large number of biological, chemical, and physical subprocesses acting simultaneously across multiple spatial and temporal scales. An illustrative example important for genomic stability is the length regulation of telomeres - nucleoprotein structures at the ends of linear chromosomes consisting of tandemly repeated DNA sequences and a specialized set of proteins. Maintenance of telomeres is often facilitated by the enzyme telomerase but, particularly in telomerase-free systems, the maintenance of chromosomal termini depends on alternative lengthening of telomeres (ALT) mechanisms mediated by recombination. Various linear and circular DNA structures were identified to participate in ALT, however, dynamics of the whole process is still poorly understood. We propose a chemical kinetics model of ALT with kinetic rates systematically derived from the biophysics of DNA diffusion and looping. The reaction system is reduced to a coagulation-fragmentation system by quasi-steady-state approximation. The detailed treatment of kinetic rates yields explicit formulas for expected size distributions of telomeres that demonstrate the key role played by the J factor, a quantitative measure of bending of polymers. The results are in agreement with experimental data and point out interesting phenomena: an appearance of very long telomeric circles if the total telomere density exceeds a critical value (excess mass) and a nonlinear response of the telomere size distributions to the amount of telomeric DNA in the system. The results can be of general importance for understanding dynamics of telomeres in telomerase-independent systems as this mode of telomere maintenance is similar to the situation in tumor cells lacking telomerase activity. Furthermore, due to its universality, the model may also serve as a prototype of an interaction between linear and circular DNA structures in various settings. AU - Kollár, Richard AU - Bod'ová, Katarína AU - Nosek, Jozef AU - Tomáška, Ľubomír ID - 1896 IS - 3 JF - Physical Review E Statistical Nonlinear and Soft Matter Physics TI - Mathematical model of alternative mechanism of telomere length maintenance VL - 89 ER - TY - JOUR AB - GNOM is one of the most characterized membrane trafficking regulators in plants, with crucial roles in development. GNOM encodes an ARF-guanine nucleotide exchange factor (ARF-GEF) that activates small GTPases of the ARF (ADP ribosylation factor) class to mediate vesicle budding at endomembranes. The crucial role of GNOM in recycling of PIN auxin transporters and other proteins to the plasma membrane was identified in studies using the ARF-GEF inhibitor brefeldin A (BFA). GNOM, the most prominent regulator of recycling in plants, has been proposed to act and localize at so far elusive recycling endosomes. Here, we report the GNOM localization in context of its cellular function in Arabidopsis thaliana. State-of-the-art imaging, pharmacological interference, and ultrastructure analysis show that GNOM predominantly localizes to Golgi apparatus. Super-resolution confocal live imaging microscopy identified GNOM and its closest homolog GNOM-like 1 at distinct subdomains on Golgi cisternae. Short-term BFA treatment stabilizes GNOM at the Golgi apparatus, whereas prolonged exposures results in GNOM translocation to trans-Golgi network (TGN)/early endosomes (EEs). Malformed TGN/EE in gnom mutants suggests a role for GNOM in maintaining TGN/EE function. Our results redefine the subcellular action of GNOM and reevaluate the identity and function of recycling endosomes in plants. AU - Naramoto, Satoshi AU - Otegui, Marisa AU - Kutsuna, Natsumaro AU - De Rycke, Riet AU - Dainobu, Tomoko AU - Karampelias, Michael AU - Fujimoto, Masaru AU - Feraru, Elena AU - Miki, Daisuke AU - Fukuda, Hiroo AU - Nakano, Akihiko AU - Friml, Jirí ID - 1897 IS - 7 JF - Plant Cell TI - Insights into the localization and function of the membrane trafficking regulator GNOM ARF-GEF at the Golgi apparatus in Arabidopsis VL - 26 ER - TY - JOUR AB - Asymmetric cell divisions allow stem cells to balance proliferation and differentiation. During embryogenesis, murine epidermis expands rapidly from a single layer of unspecified basal layer progenitors to a stratified, differentiated epithelium. Morphogenesis involves perpendicular (asymmetric) divisions and the spindle orientation protein LGN, but little is known about how the apical localization of LGN is regulated. Here, we combine conventional genetics and lentiviral-mediated in vivo RNAi to explore the functions of the LGN-interacting proteins Par3, mInsc and Gα i3. Whereas loss of each gene alone leads to randomized division angles, combined loss of Gnai3 and mInsc causes a phenotype of mostly planar divisions, akin to loss of LGN. These findings lend experimental support for the hitherto untested model that Par3-mInsc and Gα i3 act cooperatively to polarize LGN and promote perpendicular divisions. Finally, we uncover a developmental switch between delamination-driven early stratification and spindle-orientation-dependent differentiation that occurs around E15, revealing a two-step mechanism underlying epidermal maturation. AU - Williams, Scott AU - Ratliff, Lyndsay AU - Postiglione, Maria P AU - Knoblich, Juergen AU - Fuchs, Elaine ID - 1899 IS - 8 JF - Nature Cell Biology TI - Par3-mInsc and Gα i3 cooperate to promote oriented epidermal cell divisions through LGN VL - 16 ER - TY - JOUR AB - Fast synaptic transmission is important for rapid information processing. To explore the maximal rate of neuronal signaling and to analyze the presynaptic mechanisms, we focused on the input layer of the cerebellar cortex, where exceptionally high action potential (AP) frequencies have been reported invivo. With paired recordings between presynaptic cerebellar mossy fiber boutons and postsynaptic granule cells, we demonstrate reliable neurotransmission upto ~1 kHz. Presynaptic APs are ultrafast, with ~100μs half-duration. Both Kv1 and Kv3 potassium channels mediate the fast repolarization, rapidly inactivating sodium channels ensure metabolic efficiency, and little AP broadening occurs during bursts of up to 1.5 kHz. Presynaptic Cav2.1 (P/Q-type) calcium channels open efficiently during ultrafast APs. Furthermore, a subset of synaptic vesicles is tightly coupled to Ca2+ channels, and vesicles are rapidly recruited to the release site. These data reveal mechanisms of presynaptic AP generation and transmitter release underlying neuronal kHz signaling. AU - Ritzau Jost, Andreas AU - Delvendahl, Igor AU - Rings, Annika AU - Byczkowicz, Niklas AU - Harada, Harumi AU - Shigemoto, Ryuichi AU - Hirrlinger, Johannes AU - Eilers, Jens AU - Hallermann, Stefan ID - 1898 IS - 1 JF - Neuron TI - Ultrafast action potentials mediate kilohertz signaling at a central synapse VL - 84 ER - TY - JOUR AB - In this paper, we introduce a novel scene representation for the visualization of large-scale point clouds accompanied by a set of high-resolution photographs. Many real-world applications deal with very densely sampled point-cloud data, which are augmented with photographs that often reveal lighting variations and inaccuracies in registration. Consequently, the high-quality representation of the captured data, i.e., both point clouds and photographs together, is a challenging and time-consuming task. We propose a two-phase approach, in which the first (preprocessing) phase generates multiple overlapping surface patches and handles the problem of seamless texture generation locally for each patch. The second phase stitches these patches at render-time to produce a high-quality visualization of the data. As a result of the proposed localization of the global texturing problem, our algorithm is more than an order of magnitude faster than equivalent mesh-based texturing techniques. Furthermore, since our preprocessing phase requires only a minor fraction of the whole data set at once, we provide maximum flexibility when dealing with growing data sets. AU - Arikan, Murat AU - Preiner, Reinhold AU - Scheiblauer, Claus AU - Jeschke, Stefan AU - Wimmer, Michael ID - 1906 IS - 9 JF - IEEE Transactions on Visualization and Computer Graphics TI - Large-scale point-cloud visualization through localized textured surface reconstruction VL - 20 ER - TY - JOUR AB - The unprecedented polymorphism in the major histocompatibility complex (MHC) genes is thought to be maintained by balancing selection from parasites. However, do parasites also drive divergence at MHC loci between host populations, or do the effects of balancing selection maintain similarities among populations? We examined MHC variation in populations of the livebearing fish Poecilia mexicana and characterized their parasite communities. Poecilia mexicana populations in the Cueva del Azufre system are locally adapted to darkness and the presence of toxic hydrogen sulphide, representing highly divergent ecotypes or incipient species. Parasite communities differed significantly across populations, and populations with higher parasite loads had higher levels of diversity at class II MHC genes. However, despite different parasite communities, marked divergence in adaptive traits and in neutral genetic markers, we found MHC alleles to be remarkably similar among host populations. Our findings indicate that balancing selection from parasites maintains immunogenetic diversity of hosts, but this process does not promote MHC divergence in this system. On the contrary, we suggest that balancing selection on immunogenetic loci may outweigh divergent selection causing divergence, thereby hindering host divergence and speciation. Our findings support the hypothesis that balancing selection maintains MHC similarities among lineages during and after speciation (trans-species evolution). AU - Tobler, Michael AU - Plath, Martin AU - Riesch, Rüdiger AU - Schlupp, Ingo AU - Grasse, Anna V AU - Munimanda, Gopi AU - Setzer, C AU - Penn, Dustin AU - Moodley, Yoshan ID - 1905 IS - 5 JF - Journal of Evolutionary Biology SN - 1010-061X TI - Selection from parasites favours immunogenetic diversity but not divergence among locally adapted host populations VL - 27 ER - TY - JOUR AB - In the 1960s-1980s, determination of bacterial growth rates was an important tool in microbial genetics, biochemistry, molecular biology, and microbial physiology. The exciting technical developments of the 1990s and the 2000s eclipsed that tool; as a result, many investigators today lack experience with growth rate measurements. Recently, investigators in a number of areas have started to use measurements of bacterial growth rates for a variety of purposes. Those measurements have been greatly facilitated by the availability of microwell plate readers that permit the simultaneous measurements on up to 384 different cultures. Only the exponential (logarithmic) portions of the resulting growth curves are useful for determining growth rates, and manual determination of that portion and calculation of growth rates can be tedious for high-throughput purposes. Here, we introduce the program GrowthRates that uses plate reader output files to automatically determine the exponential portion of the curve and to automatically calculate the growth rate, the maximum culture density, and the duration of the growth lag phase. GrowthRates is freely available for Macintosh, Windows, and Linux.We discuss the effects of culture volume, the classical bacterial growth curve, and the differences between determinations in rich media and minimal (mineral salts) media. This protocol covers calibration of the plate reader, growth of culture inocula for both rich and minimal media, and experimental setup. As a guide to reliability, we report typical day-to-day variation in growth rates and variation within experiments with respect to position of wells within the plates. AU - Hall, Barry AU - Acar, Hande AU - Nandipati, Anna AU - Barlow, Miriam ID - 1902 IS - 1 JF - Molecular Biology and Evolution SN - 0737-4038 TI - Growth rates made easy VL - 31 ER - TY - JOUR AB - In plants, the patterning of stem cell-enriched meristems requires a graded auxin response maximum that emerges from the concerted action of polar auxin transport, auxin biosynthesis, auxin metabolism, and cellular auxin response machinery. However, mechanisms underlying this auxin response maximum-mediated root stem cell maintenance are not fully understood. Here, we present unexpected evidence that WUSCHEL-RELATED HOMEOBOX 5 (WOX5) transcription factor modulates expression of auxin biosynthetic genes in the quiescent center (QC) of the root and thus provides a robust mechanism for the maintenance of auxin response maximum in the root tip. This WOX5 action is balanced through the activity of indole-3-acetic acid 17 (IAA17) auxin response repressor. Our combined genetic, cell biology, and computational modeling studies revealed a previously uncharacterized feedback loop linking WOX5-mediated auxin production to IAA17-dependent repression of auxin responses. This WOX5-IAA17 feedback circuit further assures the maintenance of auxin response maximum in the root tip and thereby contributes to the maintenance of distal stem cell (DSC) populations. Our experimental studies and in silico computer simulations both demonstrate that the WOX5-IAA17 feedback circuit is essential for the maintenance of auxin gradient in the root tip and the auxin-mediated root DSC differentiation. AU - Tian, Huiyu AU - Wabnik, Krzysztof T AU - Niu, Tiantian AU - Li, Hongjiang AU - Yu, Qianqian AU - Pollmann, Stephan AU - Vanneste, Steffen AU - Govaerts, Willy AU - Rolčík, Jakub AU - Geisler, Markus AU - Friml, Jirí AU - Ding, Zhaojun ID - 1901 IS - 2 JF - Molecular Plant TI - WOX5-IAA17 feedback circuit-mediated cellular auxin response is crucial for the patterning of root stem cell niches in arabidopsis VL - 7 ER -