@article{1026, abstract = {The optogenetic revolution enabled spatially-precise and temporally-precise control over protein function, signaling pathway activation, and animal behavior with tremendous success in the dissection of signaling networks and neural circuits. Very recently, optogenetic methods have been paired with optical reporters in novel drug screening platforms. In these all-optical platforms, light remotely activated ion channels and kinases thereby obviating the use of electrophysiology or reagents. Consequences were remarkable operational simplicity, throughput, and cost-effectiveness that culminated in the identification of new drug candidates. These blueprints for all-optical assays also revealed potential pitfalls and inspire all-optical variants of other screens, such as those that aim at better understanding dynamic drug action or orphan protein function.}, author = {Agus, Viviana and Janovjak, Harald L}, issn = {09581669}, journal = {Current Opinion in Biotechnology}, pages = {8 -- 14}, publisher = {Elsevier}, title = {{Optogenetic methods in drug screening: Technologies and applications}}, doi = {10.1016/j.copbio.2017.02.006}, volume = {48}, year = {2017}, } @article{1027, abstract = {The rising prevalence of antibiotic resistant bacteria is an increasingly serious public health challenge. To address this problem, recent work ranging from clinical studies to theoretical modeling has provided valuable insights into the mechanisms of resistance, its emergence and spread, and ways to counteract it. A deeper understanding of the underlying dynamics of resistance evolution will require a combination of experimental and theoretical expertise from different disciplines and new technology for studying evolution in the laboratory. Here, we review recent advances in the quantitative understanding of the mechanisms and evolution of antibiotic resistance. We focus on key theoretical concepts and new technology that enables well-controlled experiments. We further highlight key challenges that can be met in the near future to ultimately develop effective strategies for combating resistance.}, author = {Lukacisinova, Marta and Bollenbach, Mark Tobias}, journal = {Current Opinion in Biotechnology}, pages = {90 -- 97}, publisher = {Elsevier}, title = {{Toward a quantitative understanding of antibiotic resistance evolution}}, doi = {10.1016/j.copbio.2017.02.013}, volume = {46}, year = {2017}, } @article{1028, abstract = {Optogenetics and photopharmacology provide spatiotemporally precise control over protein interactions and protein function in cells and animals. Optogenetic methods that are sensitive to green light and can be used to break protein complexes are not broadly available but would enable multichromatic experiments with previously inaccessible biological targets. Herein, we repurposed cobalamin (vitamin B12) binding domains of bacterial CarH transcription factors for green-light-induced receptor dissociation. In cultured cells, we observed oligomerization-induced cell signaling for the fibroblast growth factor receptor 1 fused to cobalamin-binding domains in the dark that was rapidly eliminated upon illumination. In zebrafish embryos expressing fusion receptors, green light endowed control over aberrant fibroblast growth factor signaling during development. Green-light-induced domain dissociation and light-inactivated receptors will critically expand the optogenetic toolbox for control of biological processes.}, author = {Kainrath, Stephanie and Stadler, Manuela and Gschaider-Reichhart, Eva and Distel, Martin and Janovjak, Harald L}, issn = {14337851}, journal = {Angewandte Chemie - International Edition}, number = {16}, pages = {4608--4611}, publisher = {Wiley-Blackwell}, title = {{Green-light-induced inactivation of receptor signaling using cobalamin-binding domains}}, doi = {10.1002/anie.201611998}, volume = {56}, year = {2017}, } @article{1029, abstract = {RNA Polymerase II pauses and backtracks during transcription, with many consequences for gene expression and cellular physiology. Here, we show that the energy required to melt double-stranded nucleic acids in the transcription bubble predicts pausing in Saccharomyces cerevisiae far more accurately than nucleosome roadblocks do. In addition, the same energy difference also determines when the RNA polymerase backtracks instead of continuing to move forward. This data-driven model corroborates—in a genome wide and quantitative manner—previous evidence that sequence-dependent thermodynamic features of nucleic acids influence both transcriptional pausing and backtracking.}, author = {Lukacisin, Martin and Landon, Matthieu and Jajoo, Rishi}, issn = {19326203}, journal = {PLoS One}, number = {3}, publisher = {Public Library of Science}, title = {{Sequence-specific thermodynamic properties of nucleic acids influence both transcriptional pausing and backtracking in yeast}}, doi = {10.1371/journal.pone.0174066}, volume = {12}, year = {2017}, } @article{1030, abstract = {Auf der Suche nach einem Bibliothekssystem entschied sich die Forschungseinrichtung IST Austria im Jahr 2014 für das Open-Source-Produkt Koha. In einem ersten Schritt wurden zunächst Grundfunktionen aktiviert um im Anschluss diverse zusätzliche Tools zum Einsatz zu bringen. Die große Flexibilität des Systems erlaubt maßgeschneiderte Lösungen für unterschiedlichste Institutionen. Trotz Herausforderungen kann die Bibliothek auf eine erfolgreiche Implementierung zurückblicken.}, author = {Villányi, Márton}, issn = {2297-3249}, journal = {Informationspraxis}, number = {1}, publisher = {Verein Informationspraxis }, title = {{Ein freies Bibliothekssystem für wissenschaftliche Bibliotheken – Werkstattbericht der IST Austria Library}}, doi = {10.11588/ip.2017.1.35227}, volume = {3}, year = {2017}, } @article{10416, abstract = {A fundamental algorithmic problem at the heart of static analysis is Dyck reachability. The input is a graph where the edges are labeled with different types of opening and closing parentheses, and the reachability information is computed via paths whose parentheses are properly matched. We present new results for Dyck reachability problems with applications to alias analysis and data-dependence analysis. Our main contributions, that include improved upper bounds as well as lower bounds that establish optimality guarantees, are as follows: First, we consider Dyck reachability on bidirected graphs, which is the standard way of performing field-sensitive points-to analysis. Given a bidirected graph with n nodes and m edges, we present: (i) an algorithm with worst-case running time O(m + n · α(n)), where α(n) is the inverse Ackermann function, improving the previously known O(n2) time bound; (ii) a matching lower bound that shows that our algorithm is optimal wrt to worst-case complexity; and (iii) an optimal average-case upper bound of O(m) time, improving the previously known O(m · logn) bound. Second, we consider the problem of context-sensitive data-dependence analysis, where the task is to obtain analysis summaries of library code in the presence of callbacks. Our algorithm preprocesses libraries in almost linear time, after which the contribution of the library in the complexity of the client analysis is only linear, and only wrt the number of call sites. Third, we prove that combinatorial algorithms for Dyck reachability on general graphs with truly sub-cubic bounds cannot be obtained without obtaining sub-cubic combinatorial algorithms for Boolean Matrix Multiplication, which is a long-standing open problem. Thus we establish that the existing combinatorial algorithms for Dyck reachability are (conditionally) optimal for general graphs. We also show that the same hardness holds for graphs of constant treewidth. Finally, we provide a prototype implementation of our algorithms for both alias analysis and data-dependence analysis. Our experimental evaluation demonstrates that the new algorithms significantly outperform all existing methods on the two problems, over real-world benchmarks.}, author = {Chatterjee, Krishnendu and Choudhary, Bhavya and Pavlogiannis, Andreas}, issn = {2475-1421}, journal = {Proceedings of the ACM on Programming Languages}, location = {Los Angeles, CA, United States}, number = {POPL}, publisher = {Association for Computing Machinery}, title = {{Optimal Dyck reachability for data-dependence and Alias analysis}}, doi = {10.1145/3158118}, volume = {2}, year = {2017}, } @article{10417, abstract = {We present a new dynamic partial-order reduction method for stateless model checking of concurrent programs. A common approach for exploring program behaviors relies on enumerating the traces of the program, without storing the visited states (aka stateless exploration). As the number of distinct traces grows exponentially, dynamic partial-order reduction (DPOR) techniques have been successfully used to partition the space of traces into equivalence classes (Mazurkiewicz partitioning), with the goal of exploring only few representative traces from each class. We introduce a new equivalence on traces under sequential consistency semantics, which we call the observation equivalence. Two traces are observationally equivalent if every read event observes the same write event in both traces. While the traditional Mazurkiewicz equivalence is control-centric, our new definition is data-centric. We show that our observation equivalence is coarser than the Mazurkiewicz equivalence, and in many cases even exponentially coarser. We devise a DPOR exploration of the trace space, called data-centric DPOR, based on the observation equivalence.}, author = {Chalupa, Marek and Chatterjee, Krishnendu and Pavlogiannis, Andreas and Sinha, Nishant and Vaidya, Kapil}, issn = {2475-1421}, journal = {Proceedings of the ACM on Programming Languages}, location = {Los Angeles, CA, United States}, number = {POPL}, publisher = {Association for Computing Machinery}, title = {{Data-centric dynamic partial order reduction}}, doi = {10.1145/3158119}, volume = {2}, year = {2017}, } @article{10418, abstract = {We present a new proof rule for proving almost-sure termination of probabilistic programs, including those that contain demonic non-determinism. An important question for a probabilistic program is whether the probability mass of all its diverging runs is zero, that is that it terminates "almost surely". Proving that can be hard, and this paper presents a new method for doing so. It applies directly to the program's source code, even if the program contains demonic choice. Like others, we use variant functions (a.k.a. "super-martingales") that are real-valued and decrease randomly on each loop iteration; but our key innovation is that the amount as well as the probability of the decrease are parametric. We prove the soundness of the new rule, indicate where its applicability goes beyond existing rules, and explain its connection to classical results on denumerable (non-demonic) Markov chains.}, author = {Mciver, Annabelle and Morgan, Carroll and Kaminski, Benjamin Lucien and Katoen, Joost P}, issn = {2475-1421}, journal = {Proceedings of the ACM on Programming Languages}, location = {Los Angeles, CA, United States}, number = {POPL}, publisher = {Association for Computing Machinery}, title = {{A new proof rule for almost-sure termination}}, doi = {10.1145/3158121}, volume = {2}, year = {2017}, } @article{1063, abstract = {Severe environmental change can drive a population extinct unless the population adapts in time to the new conditions (“evolutionary rescue”). How does biparental sexual reproduction influence the chances of population persistence compared to clonal reproduction or selfing? In this article, we set up a one‐locus two‐allele model for adaptation in diploid species, where rescue is contingent on the establishment of the mutant homozygote. Reproduction can occur by random mating, selfing, or clonally. Random mating generates and destroys the rescue mutant; selfing is efficient at generating it but at the same time depletes the heterozygote, which can lead to a low mutant frequency in the standing genetic variation. Due to these (and other) antagonistic effects, we find a nontrivial dependence of population survival on the rate of sex/selfing, which is strongly influenced by the dominance coefficient of the mutation before and after the environmental change. Importantly, since mating with the wild‐type breaks the mutant homozygote up, a slow decay of the wild‐type population size can impede rescue in randomly mating populations.}, author = {Uecker, Hildegard}, issn = {00143820}, journal = {Evolution}, number = {4}, pages = {845 -- 858}, publisher = {Wiley-Blackwell}, title = {{Evolutionary rescue in randomly mating, selfing, and clonal populations}}, doi = {10.1111/evo.13191}, volume = {71}, year = {2017}, } @article{1065, abstract = {We consider the problem of reachability in pushdown graphs. We study the problem for pushdown graphs with constant treewidth. Even for pushdown graphs with treewidth 1, for the reachability problem we establish the following: (i) the problem is PTIME-complete, and (ii) any subcubic algorithm for the problem would contradict the k-clique conjecture and imply faster combinatorial algorithms for cliques in graphs.}, author = {Chatterjee, Krishnendu and Osang, Georg F}, issn = {00200190}, journal = {Information Processing Letters}, pages = {25 -- 29}, publisher = {Elsevier}, title = {{Pushdown reachability with constant treewidth}}, doi = {10.1016/j.ipl.2017.02.003}, volume = {122}, year = {2017}, } @article{1180, abstract = {In this article we define an algebraic vertex of a generalized polyhedron and show that the set of algebraic vertices is the smallest set of points needed to define the polyhedron. We prove that the indicator function of a generalized polytope P is a linear combination of indicator functions of simplices whose vertices are algebraic vertices of P. We also show that the indicator function of any generalized polyhedron is a linear combination, with integer coefficients, of indicator functions of cones with apices at algebraic vertices and line-cones. The concept of an algebraic vertex is closely related to the Fourier–Laplace transform. We show that a point v is an algebraic vertex of a generalized polyhedron P if and only if the tangent cone of P, at v, has non-zero Fourier–Laplace transform.}, author = {Akopyan, Arseniy and Bárány, Imre and Robins, Sinai}, issn = {00018708}, journal = {Advances in Mathematics}, pages = {627 -- 644}, publisher = {Academic Press}, title = {{Algebraic vertices of non-convex polyhedra}}, doi = {10.1016/j.aim.2016.12.026}, volume = {308}, year = {2017}, } @article{1187, abstract = {We construct efficient authentication protocols and message authentication codes (MACs) whose security can be reduced to the learning parity with noise (LPN) problem. Despite a large body of work—starting with the (Formula presented.) protocol of Hopper and Blum in 2001—until now it was not even known how to construct an efficient authentication protocol from LPN which is secure against man-in-the-middle attacks. A MAC implies such a (two-round) protocol.}, author = {Kiltz, Eike and Pietrzak, Krzysztof Z and Venturi, Daniele and Cash, David and Jain, Abhishek}, journal = {Journal of Cryptology}, number = {4}, pages = {1238 -- 1275}, publisher = {Springer}, title = {{Efficient authentication from hard learning problems}}, doi = {10.1007/s00145-016-9247-3}, volume = {30}, year = {2017}, } @article{1191, abstract = {Variation in genotypes may be responsible for differences in dispersal rates, directional biases, and growth rates of individuals. These traits may favor certain genotypes and enhance their spatiotemporal spreading into areas occupied by the less advantageous genotypes. We study how these factors influence the speed of spreading in the case of two competing genotypes under the assumption that spatial variation of the total population is small compared to the spatial variation of the frequencies of the genotypes in the population. In that case, the dynamics of the frequency of one of the genotypes is approximately described by a generalized Fisher–Kolmogorov–Petrovskii–Piskunov (F–KPP) equation. This generalized F–KPP equation with (nonlinear) frequency-dependent diffusion and advection terms admits traveling wave solutions that characterize the invasion of the dominant genotype. Our existence results generalize the classical theory for traveling waves for the F–KPP with constant coefficients. Moreover, in the particular case of the quadratic (monostable) nonlinear growth–decay rate in the generalized F–KPP we study in detail the influence of the variance in diffusion and mean displacement rates of the two genotypes on the minimal wave propagation speed.}, author = {Kollár, Richard and Novak, Sebastian}, journal = {Bulletin of Mathematical Biology}, number = {3}, pages = {525--559}, publisher = {Springer}, title = {{Existence of traveling waves for the generalized F–KPP equation}}, doi = {10.1007/s11538-016-0244-3}, volume = {79}, year = {2017}, } @inproceedings{1192, abstract = {The main result of this paper is a generalization of the classical blossom algorithm for finding perfect matchings. Our algorithm can efficiently solve Boolean CSPs where each variable appears in exactly two constraints (we call it edge CSP) and all constraints are even Δ-matroid relations (represented by lists of tuples). As a consequence of this, we settle the complexity classification of planar Boolean CSPs started by Dvorak and Kupec. Knowing that edge CSP is tractable for even Δ-matroid constraints allows us to extend the tractability result to a larger class of Δ-matroids that includes many classes that were known to be tractable before, namely co-independent, compact, local and binary.}, author = {Kazda, Alexandr and Kolmogorov, Vladimir and Rolinek, Michal}, isbn = {978-161197478-2}, location = {Barcelona, Spain}, pages = {307 -- 326}, publisher = {SIAM}, title = {{Even delta-matroids and the complexity of planar Boolean CSPs}}, doi = {10.1137/1.9781611974782.20}, year = {2017}, } @inproceedings{1194, abstract = {Termination is one of the basic liveness properties, and we study the termination problem for probabilistic programs with real-valued variables. Previous works focused on the qualitative problem that asks whether an input program terminates with probability~1 (almost-sure termination). A powerful approach for this qualitative problem is the notion of ranking supermartingales with respect to a given set of invariants. The quantitative problem (probabilistic termination) asks for bounds on the termination probability. A fundamental and conceptual drawback of the existing approaches to address probabilistic termination is that even though the supermartingales consider the probabilistic behavior of the programs, the invariants are obtained completely ignoring the probabilistic aspect. In this work we address the probabilistic termination problem for linear-arithmetic probabilistic programs with nondeterminism. We define the notion of {\em stochastic invariants}, which are constraints along with a probability bound that the constraints hold. We introduce a concept of {\em repulsing supermartingales}. First, we show that repulsing supermartingales can be used to obtain bounds on the probability of the stochastic invariants. Second, we show the effectiveness of repulsing supermartingales in the following three ways: (1)~With a combination of ranking and repulsing supermartingales we can compute lower bounds on the probability of termination; (2)~repulsing supermartingales provide witnesses for refutation of almost-sure termination; and (3)~with a combination of ranking and repulsing supermartingales we can establish persistence properties of probabilistic programs. We also present results on related computational problems and an experimental evaluation of our approach on academic examples. }, author = {Chatterjee, Krishnendu and Novotny, Petr and Zikelic, Djordje}, issn = {07308566}, location = {Paris, France}, number = {1}, pages = {145 -- 160}, publisher = {ACM}, title = {{Stochastic invariants for probabilistic termination}}, doi = {10.1145/3009837.3009873}, volume = {52}, year = {2017}, } @article{1196, abstract = {We define the . model-measuring problem: given a model . M and specification . ϕ, what is the maximal distance . ρ such that all models . M' within distance . ρ from . M satisfy (or violate) . ϕ. The model-measuring problem presupposes a distance function on models. We concentrate on . automatic distance functions, which are defined by weighted automata. The model-measuring problem subsumes several generalizations of the classical model-checking problem, in particular, quantitative model-checking problems that measure the degree of satisfaction of a specification; robustness problems that measure how much a model can be perturbed without violating the specification; and parameter synthesis for hybrid systems. We show that for automatic distance functions, and (a) . ω-regular linear-time, (b) . ω-regular branching-time, and (c) hybrid specifications, the model-measuring problem can be solved.We use automata-theoretic model-checking methods for model measuring, replacing the emptiness question for word, tree, and hybrid automata by the . optimal-value question for the weighted versions of these automata. For automata over words and trees, we consider weighted automata that accumulate weights by maximizing, summing, discounting, and limit averaging. For hybrid automata, we consider monotonic (parametric) hybrid automata, a hybrid counterpart of (discrete) weighted automata.We give several examples of using the model-measuring problem to compute various notions of robustness and quantitative satisfaction for temporal specifications. Further, we propose the modeling framework for model measuring to ease the specification and reduce the likelihood of errors in modeling.Finally, we present a variant of the model-measuring problem, called the . model-repair problem. The model-repair problem applies to models that do not satisfy the specification; it can be used to derive restrictions, under which the model satisfies the specification, i.e., to repair the model.}, author = {Henzinger, Thomas A and Otop, Jan}, journal = {Nonlinear Analysis: Hybrid Systems}, pages = {166 -- 190}, publisher = {Elsevier}, title = {{Model measuring for discrete and hybrid systems}}, doi = {10.1016/j.nahs.2016.09.001}, volume = {23}, year = {2017}, } @article{1198, abstract = {We consider a model of fermions interacting via point interactions, defined via a certain weighted Dirichlet form. While for two particles the interaction corresponds to infinite scattering length, the presence of further particles effectively decreases the interaction strength. We show that the model becomes trivial in the thermodynamic limit, in the sense that the free energy density at any given particle density and temperature agrees with the corresponding expression for non-interacting particles.}, author = {Moser, Thomas and Seiringer, Robert}, issn = {03779017}, journal = {Letters in Mathematical Physics}, number = {3}, pages = { 533 -- 552}, publisher = {Springer}, title = {{Triviality of a model of particles with point interactions in the thermodynamic limit}}, doi = {10.1007/s11005-016-0915-x}, volume = {107}, year = {2017}, } @article{1199, abstract = {Much of quantitative genetics is based on the ‘infinitesimal model’, under which selection has a negligible effect on the genetic variance. This is typically justified by assuming a very large number of loci with additive effects. However, it applies even when genes interact, provided that the number of loci is large enough that selection on each of them is weak relative to random drift. In the long term, directional selection will change allele frequencies, but even then, the effects of epistasis on the ultimate change in trait mean due to selection may be modest. Stabilising selection can maintain many traits close to their optima, even when the underlying alleles are weakly selected. However, the number of traits that can be optimised is apparently limited to ~4Ne by the ‘drift load’, and this is hard to reconcile with the apparent complexity of many organisms. Just as for the mutation load, this limit can be evaded by a particular form of negative epistasis. A more robust limit is set by the variance in reproductive success. This suggests that selection accumulates information most efficiently in the infinitesimal regime, when selection on individual alleles is weak, and comparable with random drift. A review of evidence on selection strength suggests that although most variance in fitness may be because of alleles with large Nes, substantial amounts of adaptation may be because of alleles in the infinitesimal regime, in which epistasis has modest effects.}, author = {Barton, Nicholas H}, journal = {Heredity}, pages = {96 -- 109}, publisher = {Nature Publishing Group}, title = {{How does epistasis influence the response to selection?}}, doi = {10.1038/hdy.2016.109}, volume = {118}, year = {2017}, } @article{1207, abstract = {The eigenvalue distribution of the sum of two large Hermitian matrices, when one of them is conjugated by a Haar distributed unitary matrix, is asymptotically given by the free convolution of their spectral distributions. We prove that this convergence also holds locally in the bulk of the spectrum, down to the optimal scales larger than the eigenvalue spacing. The corresponding eigenvectors are fully delocalized. Similar results hold for the sum of two real symmetric matrices, when one is conjugated by Haar orthogonal matrix.}, author = {Bao, Zhigang and Erdös, László and Schnelli, Kevin}, issn = {00103616}, journal = {Communications in Mathematical Physics}, number = {3}, pages = {947 -- 990}, publisher = {Springer}, title = {{Local law of addition of random matrices on optimal scale}}, doi = {10.1007/s00220-016-2805-6}, volume = {349}, year = {2017}, } @article{1208, abstract = {We study parameter estimation in linear Gaussian covariance models, which are p-dimensional Gaussian models with linear constraints on the covariance matrix. Maximum likelihood estimation for this class of models leads to a non-convex optimization problem which typically has many local maxima. Using recent results on the asymptotic distribution of extreme eigenvalues of the Wishart distribution, we provide sufficient conditions for any hill climbing method to converge to the global maximum. Although we are primarily interested in the case in which n≫p, the proofs of our results utilize large sample asymptotic theory under the scheme n/p→γ>1. Remarkably, our numerical simulations indicate that our results remain valid for p as small as 2. An important consequence of this analysis is that, for sample sizes n≃14p, maximum likelihood estimation for linear Gaussian covariance models behaves as if it were a convex optimization problem. © 2016 The Royal Statistical Society and Blackwell Publishing Ltd.}, author = {Zwiernik, Piotr and Uhler, Caroline and Richards, Donald}, issn = {13697412}, journal = {Journal of the Royal Statistical Society. Series B: Statistical Methodology}, number = {4}, pages = {1269 -- 1292}, publisher = {Wiley-Blackwell}, title = {{Maximum likelihood estimation for linear Gaussian covariance models}}, doi = {10.1111/rssb.12217}, volume = {79}, year = {2017}, }