@article{643, abstract = {It has been reported that nicotinamide-overload induces oxidative stress associated with insulin resistance, the key feature of type 2 diabetes mellitus (T2DM). This study aimed to investigate the effects of B vitamins in T2DM. Glucose tolerance tests (GTT) were carried out in adult Sprague-Dawley rats treated with or without cumulative doses of B vitamins. More specifically, insulin tolerance tests (ITT) were also carried out in adult Sprague-Dawley rats treated with or without cumulative doses of Vitamin B3. We found that cumulative Vitamin B1 and Vitamin B3 administration significantly increased the plasma H2O2 levels associated with high insulin levels. Only Vitamin B3 reduced muscular and hepatic glycogen contents. Cumulative administration of nicotinic acid, another form of Vitamin B3, also significantly increased plasma insulin level and H2O2 generation. Moreover, cumulative administration of nicotinic acid or nicotinamide impaired glucose metabolism. This study suggested that excess Vitamin B1 and Vitamin B3 caused oxidative stress and insulin resistance.}, author = {Sun, Wuping and Zhai, Ming-Zhu and Zhou, Qian and Qian, Chengrui and Jiang, Changyu}, issn = {03044920}, journal = {Chinese Journal of Physiology}, number = {4}, pages = {207 -- 214}, publisher = {Chinese Physiological Society}, title = {{Effects of B vitamins overload on plasma insulin level and hydrogen peroxide generation in rats}}, doi = {10.4077/CJP.2017.BAF469}, volume = {60}, year = {2017}, } @article{642, abstract = {Cauchy problems with SPDEs on the whole space are localized to Cauchy problems on a ball of radius R. This localization reduces various kinds of spatial approximation schemes to finite dimensional problems. The error is shown to be exponentially small. As an application, a numerical scheme is presented which combines the localization and the space and time discretization, and thus is fully implementable.}, author = {Gerencser, Mate and Gyöngy, István}, issn = {00255718}, journal = {Mathematics of Computation}, number = {307}, pages = {2373 -- 2397}, publisher = {American Mathematical Society}, title = {{Localization errors in solving stochastic partial differential equations in the whole space}}, doi = {10.1090/mcom/3201}, volume = {86}, year = {2017}, } @inproceedings{645, abstract = {Markov decision processes (MDPs) are standard models for probabilistic systems with non-deterministic behaviours. Long-run average rewards provide a mathematically elegant formalism for expressing long term performance. Value iteration (VI) is one of the simplest and most efficient algorithmic approaches to MDPs with other properties, such as reachability objectives. Unfortunately, a naive extension of VI does not work for MDPs with long-run average rewards, as there is no known stopping criterion. In this work our contributions are threefold. (1) We refute a conjecture related to stopping criteria for MDPs with long-run average rewards. (2) We present two practical algorithms for MDPs with long-run average rewards based on VI. First, we show that a combination of applying VI locally for each maximal end-component (MEC) and VI for reachability objectives can provide approximation guarantees. Second, extending the above approach with a simulation-guided on-demand variant of VI, we present an anytime algorithm that is able to deal with very large models. (3) Finally, we present experimental results showing that our methods significantly outperform the standard approaches on several benchmarks.}, author = {Ashok, Pranav and Chatterjee, Krishnendu and Daca, Przemyslaw and Kretinsky, Jan and Meggendorfer, Tobias}, editor = {Majumdar, Rupak and Kunčak, Viktor}, isbn = {978-331963386-2}, location = {Heidelberg, Germany}, pages = {201 -- 221}, publisher = {Springer}, title = {{Value iteration for long run average reward in markov decision processes}}, doi = {10.1007/978-3-319-63387-9_10}, volume = {10426}, year = {2017}, } @article{644, abstract = {An instance of the valued constraint satisfaction problem (VCSP) is given by a finite set of variables, a finite domain of labels, and a sum of functions, each function depending on a subset of the variables. Each function can take finite values specifying costs of assignments of labels to its variables or the infinite value, which indicates an infeasible assignment. The goal is to find an assignment of labels to the variables that minimizes the sum. We study, assuming that P 6= NP, how the complexity of this very general problem depends on the set of functions allowed in the instances, the so-called constraint language. The case when all allowed functions take values in f0;1g corresponds to ordinary CSPs, where one deals only with the feasibility issue, and there is no optimization. This case is the subject of the algebraic CSP dichotomy conjecture predicting for which constraint languages CSPs are tractable (i.e., solvable in polynomial time) and for which they are NP-hard. The case when all allowed functions take only finite values corresponds to a finitevalued CSP, where the feasibility aspect is trivial and one deals only with the optimization issue. The complexity of finite-valued CSPs was fully classified by Thapper and Živný. An algebraic necessary condition for tractability of a general-valued CSP with a fixed constraint language was recently given by Kozik and Ochremiak. As our main result, we prove that if a constraint language satisfies this algebraic necessary condition, and the feasibility CSP (i.e., the problem of deciding whether a given instance has a feasible solution) corresponding to the VCSP with this language is tractable, then the VCSP is tractable. The algorithm is a simple combination of the assumed algorithm for the feasibility CSP and the standard LP relaxation. As a corollary, we obtain that a dichotomy for ordinary CSPs would imply a dichotomy for general-valued CSPs.}, author = {Kolmogorov, Vladimir and Krokhin, Andrei and Rolinek, Michal}, journal = {SIAM Journal on Computing}, number = {3}, pages = {1087 -- 1110}, publisher = {SIAM}, title = {{The complexity of general-valued CSPs}}, doi = {10.1137/16M1091836}, volume = {46}, year = {2017}, } @inproceedings{646, abstract = {We present a novel convex relaxation and a corresponding inference algorithm for the non-binary discrete tomography problem, that is, reconstructing discrete-valued images from few linear measurements. In contrast to state of the art approaches that split the problem into a continuous reconstruction problem for the linear measurement constraints and a discrete labeling problem to enforce discrete-valued reconstructions, we propose a joint formulation that addresses both problems simultaneously, resulting in a tighter convex relaxation. For this purpose a constrained graphical model is set up and evaluated using a novel relaxation optimized by dual decomposition. We evaluate our approach experimentally and show superior solutions both mathematically (tighter relaxation) and experimentally in comparison to previously proposed relaxations.}, author = {Kuske, Jan and Swoboda, Paul and Petra, Stefanie}, editor = {Lauze, François and Dong, Yiqiu and Bjorholm Dahl, Anders}, isbn = {978-331958770-7}, location = {Kolding, Denmark}, pages = {235 -- 246}, publisher = {Springer}, title = {{A novel convex relaxation for non binary discrete tomography}}, doi = {10.1007/978-3-319-58771-4_19}, volume = {10302}, year = {2017}, } @inproceedings{648, abstract = {Pseudoentropy has found a lot of important applications to cryptography and complexity theory. In this paper we focus on the foundational problem that has not been investigated so far, namely by how much pseudoentropy (the amount seen by computationally bounded attackers) differs from its information-theoretic counterpart (seen by unbounded observers), given certain limits on attacker’s computational power? We provide the following answer for HILL pseudoentropy, which exhibits a threshold behavior around the size exponential in the entropy amount:– If the attacker size (s) and advantage () satisfy s (formula presented) where k is the claimed amount of pseudoentropy, then the pseudoentropy boils down to the information-theoretic smooth entropy. – If s (formula presented) then pseudoentropy could be arbitrarily bigger than the information-theoretic smooth entropy. Besides answering the posted question, we show an elegant application of our result to the complexity theory, namely that it implies the clas-sical result on the existence of functions hard to approximate (due to Pippenger). In our approach we utilize non-constructive techniques: the duality of linear programming and the probabilistic method.}, author = {Skórski, Maciej}, editor = {Jäger, Gerhard and Steila, Silvia}, isbn = {978-331955910-0}, location = {Bern, Switzerland}, pages = {600 -- 613}, publisher = {Springer}, title = {{On the complexity of breaking pseudoentropy}}, doi = {10.1007/978-3-319-55911-7_43}, volume = {10185}, year = {2017}, } @inbook{649, abstract = {We give a short overview on a recently developed notion of Ricci curvature for discrete spaces. This notion relies on geodesic convexity properties of the relative entropy along geodesics in the space of probability densities, for a metric which is similar to (but different from) the 2-Wasserstein metric. The theory can be considered as a discrete counterpart to the theory of Ricci curvature for geodesic measure spaces developed by Lott–Sturm–Villani.}, author = {Maas, Jan}, booktitle = {Modern Approaches to Discrete Curvature}, editor = {Najman, Laurent and Romon, Pascal}, isbn = {978-3-319-58001-2}, issn = {978-3-319-58002-9}, pages = {159 -- 174}, publisher = {Springer}, title = {{Entropic Ricci curvature for discrete spaces}}, doi = {10.1007/978-3-319-58002-9_5}, volume = {2184}, year = {2017}, } @inproceedings{650, abstract = {In this work we present a short and unified proof for the Strong and Weak Regularity Lemma, based on the cryptographic tech-nique called low-complexity approximations. In short, both problems reduce to a task of finding constructively an approximation for a certain target function under a class of distinguishers (test functions), where dis-tinguishers are combinations of simple rectangle-indicators. In our case these approximations can be learned by a simple iterative procedure, which yields a unified and simple proof, achieving for any graph with density d and any approximation parameter the partition size. The novelty in our proof is: (a) a simple approach which yields both strong and weaker variant, and (b) improvements when d = o(1). At an abstract level, our proof can be seen a refinement and simplification of the “analytic” proof given by Lovasz and Szegedy.}, author = {Skórski, Maciej}, editor = {Jäger, Gerhard and Steila, Silvia}, issn = {03029743}, location = {Bern, Switzerland}, pages = {586 -- 599}, publisher = {Springer}, title = {{A cryptographic view of regularity lemmas: Simpler unified proofs and refined bounds}}, doi = {10.1007/978-3-319-55911-7_42}, volume = {10185}, year = {2017}, } @inproceedings{6519, abstract = {Graph games with omega-regular winning conditions provide a mathematical framework to analyze a wide range of problems in the analysis of reactive systems and programs (such as the synthesis of reactive systems, program repair, and the verification of branching time properties). Parity conditions are canonical forms to specify omega-regular winning conditions. Graph games with parity conditions are equivalent to mu-calculus model checking, and thus a very important algorithmic problem. Symbolic algorithms are of great significance because they provide scalable algorithms for the analysis of large finite-state systems, as well as algorithms for the analysis of infinite-state systems with finite quotient. A set-based symbolic algorithm uses the basic set operations and the one-step predecessor operators. We consider graph games with n vertices and parity conditions with c priorities (equivalently, a mu-calculus formula with c alternations of least and greatest fixed points). While many explicit algorithms exist for graph games with parity conditions, for set-based symbolic algorithms there are only two algorithms (notice that we use space to refer to the number of sets stored by a symbolic algorithm): (a) the basic algorithm that requires O(n^c) symbolic operations and linear space; and (b) an improved algorithm that requires O(n^{c/2+1}) symbolic operations but also O(n^{c/2+1}) space (i.e., exponential space). In this work we present two set-based symbolic algorithms for parity games: (a) our first algorithm requires O(n^{c/2+1}) symbolic operations and only requires linear space; and (b) developing on our first algorithm, we present an algorithm that requires O(n^{c/3+1}) symbolic operations and only linear space. We also present the first linear space set-based symbolic algorithm for parity games that requires at most a sub-exponential number of symbolic operations. }, author = {Chatterjee, Krishnendu and Dvorák, Wolfgang and Henzinger, Monika H and Loitzenbauer, Veronika}, location = {Stockholm, Sweden}, publisher = {Schloss Dagstuhl -Leibniz-Zentrum fuer Informatik}, title = {{Improved set-based symbolic algorithms for parity games}}, doi = {10.4230/LIPICS.CSL.2017.18}, volume = {82}, year = {2017}, } @inproceedings{6517, abstract = {A (possibly degenerate) drawing of a graph G in the plane is approximable by an embedding if it can be turned into an embedding by an arbitrarily small perturbation. We show that testing, whether a drawing of a planar graph G in the plane is approximable by an embedding, can be carried out in polynomial time, if a desired embedding of G belongs to a fixed isotopy class, i.e., the rotation system (or equivalently the faces) of the embedding of G and the choice of outer face are fixed. In other words, we show that c-planarity with embedded pipes is tractable for graphs with fixed embeddings. To the best of our knowledge an analogous result was previously known essentially only when G is a cycle.}, author = {Fulek, Radoslav}, location = {Phuket, Thailand}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Embedding graphs into embedded graphs}}, doi = {10.4230/LIPICS.ISAAC.2017.34}, volume = {92}, year = {2017}, } @inproceedings{652, abstract = {We present an approach that enables robots to self-organize their sensorimotor behavior from scratch without providing specific information about neither the robot nor its environment. This is achieved by a simple neural control law that increases the consistency between external sensor dynamics and internal neural dynamics of the utterly simple controller. In this way, the embodiment and the agent-environment coupling are the only source of individual development. We show how an anthropomorphic tendon driven arm-shoulder system develops different behaviors depending on that coupling. For instance: Given a bottle half-filled with water, the arm starts to shake it, driven by the physical response of the water. When attaching a brush, the arm can be manipulated into wiping a table, and when connected to a revolvable wheel it finds out how to rotate it. Thus, the robot may be said to discover the affordances of the world. When allowing two (simulated) humanoid robots to interact physically, they engage into a joint behavior development leading to, for instance, spontaneous cooperation. More social effects are observed if the robots can visually perceive each other. Although, as an observer, it is tempting to attribute an apparent intentionality, there is nothing of the kind put in. As a conclusion, we argue that emergent behavior may be much less rooted in explicit intentions, internal motivations, or specific reward systems than is commonly believed.}, author = {Der, Ralf and Martius, Georg S}, isbn = {978-150905069-7}, location = {Cergy-Pontoise, France}, publisher = {IEEE}, title = {{Dynamical self consistency leads to behavioral development and emergent social interactions in robots}}, doi = {10.1109/DEVLRN.2016.7846789}, year = {2017}, } @article{651, abstract = {Superhydrophobic surfaces reduce the frictional drag between water and solid materials, but this effect is often temporary. The realization of sustained drag reduction has applications for water vehicles and pipeline flows. }, author = {Hof, Björn}, issn = {00280836}, journal = {Nature}, number = {7636}, pages = {161 -- 162}, publisher = {Nature Publishing Group}, title = {{Fluid dynamics: Water flows out of touch}}, doi = {10.1038/541161a}, volume = {541}, year = {2017}, } @article{653, abstract = {The extent of heterogeneity among driver gene mutations present in naturally occurring metastases - that is, treatment-naive metastatic disease - is largely unknown. To address this issue, we carried out 60× whole-genome sequencing of 26 metastases from four patients with pancreatic cancer. We found that identical mutations in known driver genes were present in every metastatic lesion for each patient studied. Passenger gene mutations, which do not have known or predicted functional consequences, accounted for all intratumoral heterogeneity. Even with respect to these passenger mutations, our analysis suggests that the genetic similarity among the founding cells of metastases was higher than that expected for any two cells randomly taken from a normal tissue. The uniformity of known driver gene mutations among metastases in the same patient has critical and encouraging implications for the success of future targeted therapies in advanced-stage disease.}, author = {Makohon Moore, Alvin and Zhang, Ming and Reiter, Johannes and Božić, Ivana and Allen, Benjamin and Kundu, Deepanjan and Chatterjee, Krishnendu and Wong, Fay and Jiao, Yuchen and Kohutek, Zachary and Hong, Jungeui and Attiyeh, Marc and Javier, Breanna and Wood, Laura and Hruban, Ralph and Nowak, Martin and Papadopoulos, Nickolas and Kinzler, Kenneth and Vogelstein, Bert and Iacobuzio Donahue, Christine}, issn = {10614036}, journal = {Nature Genetics}, number = {3}, pages = {358 -- 366}, publisher = {Nature Publishing Group}, title = {{Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer}}, doi = {10.1038/ng.3764}, volume = {49}, year = {2017}, } @inproceedings{6527, abstract = {A memory-hard function (MHF) ƒn with parameter n can be computed in sequential time and space n. Simultaneously, a high amortized parallel area-time complexity (aAT) is incurred per evaluation. In practice, MHFs are used to limit the rate at which an adversary (using a custom computational device) can evaluate a security sensitive function that still occasionally needs to be evaluated by honest users (using an off-the-shelf general purpose device). The most prevalent examples of such sensitive functions are Key Derivation Functions (KDFs) and password hashing algorithms where rate limits help mitigate off-line dictionary attacks. As the honest users' inputs to these functions are often (low-entropy) passwords special attention is given to a class of side-channel resistant MHFs called iMHFs. Essentially all iMHFs can be viewed as some mode of operation (making n calls to some round function) given by a directed acyclic graph (DAG) with very low indegree. Recently, a combinatorial property of a DAG has been identified (called "depth-robustness") which results in good provable security for an iMHF based on that DAG. Depth-robust DAGs have also proven useful in other cryptographic applications. Unfortunately, up till now, all known very depth-robust DAGs are impractically complicated and little is known about their exact (i.e. non-asymptotic) depth-robustness both in theory and in practice. In this work we build and analyze (both formally and empirically) several exceedingly simple and efficient to navigate practical DAGs for use in iMHFs and other applications. For each DAG we: *Prove that their depth-robustness is asymptotically maximal. *Prove bounds of at least 3 orders of magnitude better on their exact depth-robustness compared to known bounds for other practical iMHF. *Implement and empirically evaluate their depth-robustness and aAT against a variety of state-of-the art (and several new) depth-reduction and low aAT attacks. We find that, against all attacks, the new DAGs perform significantly better in practice than Argon2i, the most widely deployed iMHF in practice. Along the way we also improve the best known empirical attacks on the aAT of Argon2i by implementing and testing several heuristic versions of a (hitherto purely theoretical) depth-reduction attack. Finally, we demonstrate practicality of our constructions by modifying the Argon2i code base to use one of the new high aAT DAGs. Experimental benchmarks on a standard off-the-shelf CPU show that the new modifications do not adversely affect the impressive throughput of Argon2i (despite seemingly enjoying significantly higher aAT). }, author = {Alwen, Joel F and Blocki, Jeremiah and Harsha, Ben}, booktitle = {Proceedings of the 2017 ACM SIGSAC Conference on Computer and Communications Security}, isbn = {9781450349468}, location = {Dallas, TX, USA}, pages = {1001--1017}, publisher = {ACM Press}, title = {{Practical graphs for optimal side-channel resistant memory-hard functions}}, doi = {10.1145/3133956.3134031}, year = {2017}, } @article{654, abstract = {In November 2016, developmental biologists, synthetic biologists and engineers gathered in Paris for a meeting called ‘Engineering the embryo’. The participants shared an interest in exploring how synthetic systems can reveal new principles of embryonic development, and how the in vitro manipulation and modeling of development using stem cells can be used to integrate ideas and expertise from physics, developmental biology and tissue engineering. As we review here, the conference pinpointed some of the challenges arising at the intersection of these fields, along with great enthusiasm for finding new approaches and collaborations.}, author = {Kicheva, Anna and Rivron, Nicolas}, issn = {09501991}, journal = {Development}, number = {5}, pages = {733 -- 736}, publisher = {Company of Biologists}, title = {{Creating to understand – developmental biology meets engineering in Paris}}, doi = {10.1242/dev.144915}, volume = {144}, year = {2017}, } @inproceedings{6526, abstract = {This paper studies the complexity of estimating Rényi divergences of discrete distributions: p observed from samples and the baseline distribution q known a priori. Extending the results of Acharya et al. (SODA'15) on estimating Rényi entropy, we present improved estimation techniques together with upper and lower bounds on the sample complexity. We show that, contrarily to estimating Rényi entropy where a sublinear (in the alphabet size) number of samples suffices, the sample complexity is heavily dependent on events occurring unlikely in q, and is unbounded in general (no matter what an estimation technique is used). For any divergence of integer order bigger than 1, we provide upper and lower bounds on the number of samples dependent on probabilities of p and q (the lower bounds hold for non-integer orders as well). We conclude that the worst-case sample complexity is polynomial in the alphabet size if and only if the probabilities of q are non-negligible. This gives theoretical insights into heuristics used in the applied literature to handle numerical instability, which occurs for small probabilities of q. Our result shows that they should be handled with care not only because of numerical issues, but also because of a blow up in the sample complexity.}, author = {Skórski, Maciej}, booktitle = {2017 IEEE International Symposium on Information Theory (ISIT)}, isbn = {9781509040964}, location = {Aachen, Germany}, publisher = {IEEE}, title = {{On the complexity of estimating Rènyi divergences}}, doi = {10.1109/isit.2017.8006529}, year = {2017}, } @article{655, abstract = {The bacterial flagellum is a self-assembling nanomachine. The external flagellar filament, several times longer than a bacterial cell body, is made of a few tens of thousands subunits of a single protein: flagellin. A fundamental problem concerns the molecular mechanism of how the flagellum grows outside the cell, where no discernible energy source is available. Here, we monitored the dynamic assembly of individual flagella using in situ labelling and real-time immunostaining of elongating flagellar filaments. We report that the rate of flagellum growth, initially ~1,700 amino acids per second, decreases with length and that the previously proposed chain mechanism does not contribute to the filament elongation dynamics. Inhibition of the proton motive force-dependent export apparatus revealed a major contribution of substrate injection in driving filament elongation. The combination of experimental and mathematical evidence demonstrates that a simple, injection-diffusion mechanism controls bacterial flagella growth outside the cell.}, author = {Renault, Thibaud and Abraham, Anthony and Bergmiller, Tobias and Paradis, Guillaume and Rainville, Simon and Charpentier, Emmanuelle and Guet, Calin C and Tu, Yuhai and Namba, Keiichi and Keener, James and Minamino, Tohru and Erhardt, Marc}, issn = {2050084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Bacterial flagella grow through an injection diffusion mechanism}}, doi = {10.7554/eLife.23136}, volume = {6}, year = {2017}, } @article{657, abstract = {Plant organs are typically organized into three main tissue layers. The middle ground tissue layer comprises the majority of the plant body and serves a wide range of functions, including photosynthesis, selective nutrient uptake and storage, and gravity sensing. Ground tissue patterning and maintenance in Arabidopsis are controlled by a well-established gene network revolving around the key regulator SHORT-ROOT (SHR). In contrast, it is completely unknown how ground tissue identity is first specified from totipotent precursor cells in the embryo. The plant signaling molecule auxin, acting through AUXIN RESPONSE FACTOR (ARF) transcription factors, is critical for embryo patterning. The auxin effector ARF5/MONOPTEROS (MP) acts both cell-autonomously and noncell-autonomously to control embryonic vascular tissue formation and root initiation, respectively. Here we show that auxin response and ARF activity cell-autonomously control the asymmetric division of the first ground tissue cells. By identifying embryonic target genes, we show that MP transcriptionally initiates the ground tissue lineage and acts upstream of the regulatory network that controls ground tissue patterning and maintenance. Strikingly, whereas the SHR network depends on MP, this MP function is, at least in part, SHR independent. Our study therefore identifies auxin response as a regulator of ground tissue specification in the embryonic root, and reveals that ground tissue initiation and maintenance use different regulators and mechanisms. Moreover, our data provide a framework for the simultaneous formation of multiple cell types by the same transcriptional regulator.}, author = {Möller, Barbara and Ten Hove, Colette and Xiang, Daoquan and Williams, Nerys and López, Lorena and Yoshida, Saiko and Smit, Margot and Datla, Raju and Weijers, Dolf}, issn = {00278424}, journal = {PNAS}, number = {12}, pages = {E2533 -- E2539}, publisher = {National Academy of Sciences}, title = {{Auxin response cell autonomously controls ground tissue initiation in the early arabidopsis embryo}}, doi = {10.1073/pnas.1616493114}, volume = {114}, year = {2017}, } @article{656, abstract = {Human neurons transplanted into a mouse model for Alzheimer’s disease show human-specific vulnerability to β-amyloid plaques and may help to identify new therapeutic targets.}, author = {Novarino, Gaia}, issn = {19466234}, journal = {Science Translational Medicine}, number = {381}, publisher = {American Association for the Advancement of Science}, title = {{Modeling Alzheimer's disease in mice with human neurons}}, doi = {10.1126/scitranslmed.aam9867}, volume = {9}, year = {2017}, } @article{658, abstract = {With the accelerated development of robot technologies, control becomes one of the central themes of research. In traditional approaches, the controller, by its internal functionality, finds appropriate actions on the basis of specific objectives for the task at hand. While very successful in many applications, self-organized control schemes seem to be favored in large complex systems with unknown dynamics or which are difficult to model. Reasons are the expected scalability, robustness, and resilience of self-organizing systems. The paper presents a self-learning neurocontroller based on extrinsic differential plasticity introduced recently, applying it to an anthropomorphic musculoskeletal robot arm with attached objects of unknown physical dynamics. The central finding of the paper is the following effect: by the mere feedback through the internal dynamics of the object, the robot is learning to relate each of the objects with a very specific sensorimotor pattern. Specifically, an attached pendulum pilots the arm into a circular motion, a half-filled bottle produces axis oriented shaking behavior, a wheel is getting rotated, and wiping patterns emerge automatically in a table-plus-brush setting. By these object-specific dynamical patterns, the robot may be said to recognize the object's identity, or in other words, it discovers dynamical affordances of objects. Furthermore, when including hand coordinates obtained from a camera, a dedicated hand-eye coordination self-organizes spontaneously. These phenomena are discussed from a specific dynamical system perspective. Central is the dedicated working regime at the border to instability with its potentially infinite reservoir of (limit cycle) attractors "waiting" to be excited. Besides converging toward one of these attractors, variate behavior is also arising from a self-induced attractor morphing driven by the learning rule. We claim that experimental investigations with this anthropomorphic, self-learning robot not only generate interesting and potentially useful behaviors, but may also help to better understand what subjective human muscle feelings are, how they can be rooted in sensorimotor patterns, and how these concepts may feed back on robotics.}, author = {Der, Ralf and Martius, Georg S}, issn = {16625218}, journal = {Frontiers in Neurorobotics}, number = {MAR}, publisher = {Frontiers Research Foundation}, title = {{Self organized behavior generation for musculoskeletal robots}}, doi = {10.3389/fnbot.2017.00008}, volume = {11}, year = {2017}, } @article{659, abstract = {Migration frequently involves Rac-mediated protrusion of lamellipodia, formed by Arp2/3 complex-dependent branching thought to be crucial for force generation and stability of these networks. The formins FMNL2 and FMNL3 are Cdc42 effectors targeting to the lamellipodium tip and shown here to nucleate and elongate actin filaments with complementary activities in vitro. In migrating B16-F1 melanoma cells, both formins contribute to the velocity of lamellipodium protrusion. Loss of FMNL2/3 function in melanoma cells and fibroblasts reduces lamellipodial width, actin filament density and -bundling, without changing patterns of Arp2/3 complex incorporation. Strikingly, in melanoma cells, FMNL2/3 gene inactivation almost completely abolishes protrusion forces exerted by lamellipodia and modifies their ultrastructural organization. Consistently, CRISPR/Cas-mediated depletion of FMNL2/3 in fibroblasts reduces both migration and capability of cells to move against viscous media. Together, we conclude that force generation in lamellipodia strongly depends on FMNL formin activity, operating in addition to Arp2/3 complex-dependent filament branching.}, author = {Kage, Frieda and Winterhoff, Moritz and Dimchev, Vanessa and Müller, Jan and Thalheim, Tobias and Freise, Anika and Brühmann, Stefan and Kollasser, Jana and Block, Jennifer and Dimchev, Georgi A and Geyer, Matthias and Schnittler, Hams and Brakebusch, Cord and Stradal, Theresia and Carlier, Marie and Sixt, Michael K and Käs, Josef and Faix, Jan and Rottner, Klemens}, issn = {20411723}, journal = {Nature Communications}, publisher = {Nature Publishing Group}, title = {{FMNL formins boost lamellipodial force generation}}, doi = {10.1038/ncomms14832}, volume = {8}, year = {2017}, } @article{660, abstract = {Growing microtubules are protected from depolymerization by the presence of a GTP or GDP/Pi cap. End-binding proteins of the EB1 family bind to the stabilizing cap, allowing monitoring of its size in real time. The cap size has been shown to correlate with instantaneous microtubule stability. Here we have quantitatively characterized the properties of cap size fluctuations during steadystate growth and have developed a theory predicting their timescale and amplitude from the kinetics of microtubule growth and cap maturation. In contrast to growth speed fluctuations, cap size fluctuations show a characteristic timescale, which is defined by the lifetime of the cap sites. Growth fluctuations affect the amplitude of cap size fluctuations; however, cap size does not affect growth speed, indicating that microtubules are far from instability during most of their time of growth. Our theory provides the basis for a quantitative understanding of microtubule stability fluctuations during steady-state growth.}, author = {Rickman, Jamie and Düllberg, Christian F and Cade, Nicholas and Griffin, Lewis and Surrey, Thomas}, issn = {00278424}, journal = {PNAS}, number = {13}, pages = {3427 -- 3432}, publisher = {National Academy of Sciences}, title = {{Steady state EB cap size fluctuations are determined by stochastic microtubule growth and maturation}}, doi = {10.1073/pnas.1620274114}, volume = {114}, year = {2017}, } @article{662, abstract = {We report a direct-numerical-simulation study of the Taylor-Couette flow in the quasi-Keplerian regime at shear Reynolds numbers up to (105). Quasi-Keplerian rotating flow has been investigated for decades as a simplified model system to study the origin of turbulence in accretion disks that is not fully understood. The flow in this study is axially periodic and thus the experimental end-wall effects on the stability of the flow are avoided. Using optimal linear perturbations as initial conditions, our simulations find no sustained turbulence: the strong initial perturbations distort the velocity profile and trigger turbulence that eventually decays.}, author = {Shi, Liang and Hof, Björn and Rampp, Markus and Avila, Marc}, issn = {10706631}, journal = {Physics of Fluids}, number = {4}, publisher = {American Institute of Physics}, title = {{Hydrodynamic turbulence in quasi Keplerian rotating flows}}, doi = {10.1063/1.4981525}, volume = {29}, year = {2017}, } @inproceedings{663, abstract = {In this paper, we propose an approach to automatically compute invariant clusters for nonlinear semialgebraic hybrid systems. An invariant cluster for an ordinary differential equation (ODE) is a multivariate polynomial invariant g(u→, x→) = 0, parametric in u→, which can yield an infinite number of concrete invariants by assigning different values to u→ so that every trajectory of the system can be overapproximated precisely by the intersection of a group of concrete invariants. For semialgebraic systems, which involve ODEs with multivariate polynomial right-hand sides, given a template multivariate polynomial g(u→, x→), an invariant cluster can be obtained by first computing the remainder of the Lie derivative of g(u→, x→) divided by g(u→, x→) and then solving the system of polynomial equations obtained from the coefficients of the remainder. Based on invariant clusters and sum-of-squares (SOS) programming, we present a new method for the safety verification of hybrid systems. Experiments on nonlinear benchmark systems from biology and control theory show that our approach is efficient. }, author = {Kong, Hui and Bogomolov, Sergiy and Schilling, Christian and Jiang, Yu and Henzinger, Thomas A}, booktitle = {Proceedings of the 20th International Conference on Hybrid Systems}, isbn = {978-145034590-3}, location = {Pittsburgh, PA, United States}, pages = {163 -- 172}, publisher = {ACM}, title = {{Safety verification of nonlinear hybrid systems based on invariant clusters}}, doi = {10.1145/3049797.3049814}, year = {2017}, } @article{667, abstract = {Perinatal exposure to penicillin may result in longlasting gut and behavioral changes.}, author = {Novarino, Gaia}, issn = {19466234}, journal = {Science Translational Medicine}, number = {387}, publisher = {American Association for the Advancement of Science}, title = {{The antisocial side of antibiotics}}, doi = {10.1126/scitranslmed.aan2786}, volume = {9}, year = {2017}, } @article{668, abstract = {Macrophage filopodia, finger-like membrane protrusions, were first implicated in phagocytosis more than 100 years ago, but little is still known about the involvement of these actin-dependent structures in particle clearance. Using spinning disk confocal microscopy to image filopodial dynamics in mouse resident Lifeact-EGFP macrophages, we show that filopodia, or filopodia-like structures, support pathogen clearance by multiple means. Filopodia supported the phagocytic uptake of bacterial (Escherichia coli) particles by (i) capturing along the filopodial shaft and surfing toward the cell body, the most common mode of capture; (ii) capturing via the tip followed by retraction; (iii) combinations of surfing and retraction; or (iv) sweeping actions. In addition, filopodia supported the uptake of zymosan (Saccharomyces cerevisiae) particles by (i) providing fixation, (ii) capturing at the tip and filopodia-guided actin anterograde flow with phagocytic cup formation, and (iii) the rapid growth of new protrusions. To explore the role of filopodia-inducing Cdc42, we generated myeloid-restricted Cdc42 knock-out mice. Cdc42-deficient macrophages exhibited rapid phagocytic cup kinetics, but reduced particle clearance, which could be explained by the marked rounded-up morphology of these cells. Macrophages lacking Myo10, thought to act downstream of Cdc42, had normal morphology, motility, and phagocytic cup formation, but displayed markedly reduced filopodia formation. In conclusion, live-cell imaging revealed multiple mechanisms involving macrophage filopodia in particle capture and engulfment. Cdc42 is not critical for filopodia or phagocytic cup formation, but plays a key role in driving macrophage lamellipodial spreading.}, author = {Horsthemke, Markus and Bachg, Anne and Groll, Katharina and Moyzio, Sven and Müther, Barbara and Hemkemeyer, Sandra and Wedlich Söldner, Roland and Sixt, Michael K and Tacke, Sebastian and Bähler, Martin and Hanley, Peter}, issn = {00219258}, journal = {Journal of Biological Chemistry}, number = {17}, pages = {7258 -- 7273}, publisher = {American Society for Biochemistry and Molecular Biology}, title = {{Multiple roles of filopodial dynamics in particle capture and phagocytosis and phenotypes of Cdc42 and Myo10 deletion}}, doi = {10.1074/jbc.M116.766923}, volume = {292}, year = {2017}, } @article{669, abstract = {The exocyst, a eukaryotic tethering complex, coregulates targeted exocytosis as an effector of small GTPases in polarized cell growth. In land plants, several exocyst subunits are encoded by double or triple paralogs, culminating in tens of EXO70 paralogs. Out of 23 Arabidopsis thaliana EXO70 isoforms, we analyzed seven isoforms expressed in pollen. Genetic and microscopic analyses of single mutants in EXO70A2, EXO70C1, EXO70C2, EXO70F1, EXO70H3, EXO70H5, and EXO70H6 genes revealed that only a loss-of-function EXO70C2 allele resulted in a significant male-specific transmission defect (segregation 40%:51%:9%) due to aberrant pollen tube growth. Mutant pollen tubes grown in vitro exhibited an enhanced growth rate and a decreased thickness of the tip cell wall, causing tip bursts. However, exo70C2 pollen tubes could frequently recover and restart their speedy elongation, resulting in a repetitive stop-and-go growth dynamics. A pollenspecific depletion of the closest paralog, EXO70C1, using artificial microRNA in the exo70C2 mutant background, resulted in a complete pollen-specific transmission defect, suggesting redundant functions of EXO70C1 and EXO70C2. Both EXO70C1 and EXO70C2, GFP tagged and expressed under the control of their native promoters, localized in the cytoplasm of pollen grains, pollen tubes, and also root trichoblast cells. The expression of EXO70C2-GFP complemented the aberrant growth of exo70C2 pollen tubes. The absent EXO70C2 interactions with core exocyst subunits in the yeast two-hybrid assay, cytoplasmic localization, and genetic effect suggest an unconventional EXO70 function possibly as a regulator of exocytosis outside the exocyst complex. In conclusion, EXO70C2 is a novel factor contributing to the regulation of optimal tip growth of Arabidopsis pollen tubes. }, author = {Synek, Lukáš and Vukašinović, Nemanja and Kulich, Ivan and Hála, Michal and Aldorfová, Klára and Fendrych, Matyas and Žárský, Viktor}, issn = {00320889}, journal = {Plant Physiology}, number = {1}, pages = {223 -- 240}, publisher = {American Society of Plant Biologists}, title = {{EXO70C2 is a key regulatory factor for optimal tip growth of pollen}}, doi = {10.1104/pp.16.01282}, volume = {174}, year = {2017}, } @article{671, abstract = {Humans routinely use conditionally cooperative strategies when interacting in repeated social dilemmas. They are more likely to cooperate if others cooperated before, and are ready to retaliate if others defected. To capture the emergence of reciprocity, most previous models consider subjects who can only choose from a restricted set of representative strategies, or who react to the outcome of the very last round only. As players memorize more rounds, the dimension of the strategy space increases exponentially. This increasing computational complexity renders simulations for individuals with higher cognitive abilities infeasible, especially if multiplayer interactions are taken into account. Here, we take an axiomatic approach instead. We propose several properties that a robust cooperative strategy for a repeated multiplayer dilemma should have. These properties naturally lead to a unique class of cooperative strategies, which contains the classical Win-Stay Lose-Shift rule as a special case. A comprehensive numerical analysis for the prisoner's dilemma and for the public goods game suggests that strategies of this class readily evolve across various memory-n spaces. Our results reveal that successful strategies depend not only on how cooperative others were in the past but also on the respective context of cooperation.}, author = {Hilbe, Christian and Martinez, Vaquero and Chatterjee, Krishnendu and Nowak, Martin}, issn = {00278424}, journal = {PNAS}, number = {18}, pages = {4715 -- 4720}, publisher = {National Academy of Sciences}, title = {{Memory-n strategies of direct reciprocity}}, doi = {10.1073/pnas.1621239114}, volume = {114}, year = {2017}, } @article{670, abstract = {We propose an efficient method to model paper tearing in the context of interactive modeling. The method uses geometrical information to automatically detect potential starting points of tears. We further introduce a new hybrid geometrical and physical-based method to compute the trajectory of tears while procedurally synthesizing high resolution details of the tearing path using a texture based approach. The results obtained are compared with real paper and with previous studies on the expected geometric paths of paper that tears.}, author = {Schreck, Camille and Rohmer, Damien and Hahmann, Stefanie}, issn = {01677055}, journal = {Computer Graphics Forum}, number = {2}, pages = {95 -- 106}, publisher = {Wiley}, title = {{Interactive paper tearing}}, doi = {10.1111/cgf.13110}, volume = {36}, year = {2017}, } @article{672, abstract = {Trafficking cells frequently transmigrate through epithelial and endothelial monolayers. How monolayers cooperate with the penetrating cells to support their transit is poorly understood. We studied dendritic cell (DC) entry into lymphatic capillaries as a model system for transendothelial migration. We find that the chemokine CCL21, which is the decisive guidance cue for intravasation, mainly localizes in the trans-Golgi network and intracellular vesicles of lymphatic endothelial cells. Upon DC transmigration, these Golgi deposits disperse and CCL21 becomes extracellularly enriched at the sites of endothelial cell-cell junctions. When we reconstitute the transmigration process in vitro, we find that secretion of CCL21-positive vesicles is triggered by a DC contact-induced calcium signal, and selective calcium chelation in lymphatic endothelium attenuates transmigration. Altogether, our data demonstrate a chemokine-mediated feedback between DCs and lymphatic endothelium, which facilitates transendothelial migration.}, author = {Vaahtomeri, Kari and Brown, Markus and Hauschild, Robert and De Vries, Ingrid and Leithner, Alexander F and Mehling, Matthias and Kaufmann, Walter and Sixt, Michael K}, issn = {22111247}, journal = {Cell Reports}, number = {5}, pages = {902 -- 909}, publisher = {Cell Press}, title = {{Locally triggered release of the chemokine CCL21 promotes dendritic cell transmigration across lymphatic endothelia}}, doi = {10.1016/j.celrep.2017.04.027}, volume = {19}, year = {2017}, } @article{674, abstract = {Navigation of cells along gradients of guidance cues is a determining step in many developmental and immunological processes. Gradients can either be soluble or immobilized to tissues as demonstrated for the haptotactic migration of dendritic cells (DCs) toward higher concentrations of immobilized chemokine CCL21. To elucidate how gradient characteristics govern cellular response patterns, we here introduce an in vitro system allowing to track migratory responses of DCs to precisely controlled immobilized gradients of CCL21. We find that haptotactic sensing depends on the absolute CCL21 concentration and local steepness of the gradient, consistent with a scenario where DC directionality is governed by the signal-to-noise ratio of CCL21 binding to the receptor CCR7. We find that the conditions for optimal DC guidance are perfectly provided by the CCL21 gradients we measure in vivo. Furthermore, we find that CCR7 signal termination by the G-protein-coupled receptor kinase 6 (GRK6) is crucial for haptotactic but dispensable for chemotactic CCL21 gradient sensing in vitro and confirm those observations in vivo. These findings suggest that stable, tissue-bound CCL21 gradients as sustainable “roads” ensure optimal guidance in vivo.}, author = {Schwarz, Jan and Bierbaum, Veronika and Vaahtomeri, Kari and Hauschild, Robert and Brown, Markus and De Vries, Ingrid and Leithner, Alexander F and Reversat, Anne and Merrin, Jack and Tarrant, Teresa and Bollenbach, Tobias and Sixt, Michael K}, issn = {09609822}, journal = {Current Biology}, number = {9}, pages = {1314 -- 1325}, publisher = {Cell Press}, title = {{Dendritic cells interpret haptotactic chemokine gradients in a manner governed by signal to noise ratio and dependent on GRK6}}, doi = {10.1016/j.cub.2017.04.004}, volume = {27}, year = {2017}, } @article{677, abstract = {The INO80 complex (INO80-C) is an evolutionarily conserved nucleosome remodeler that acts in transcription, replication, and genome stability. It is required for resistance against genotoxic agents and is involved in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR). However, the causes of the HR defect in INO80-C mutant cells are controversial. Here, we unite previous findings using a system to study HR with high spatial resolution in budding yeast. We find that INO80-C has at least two distinct functions during HR—DNA end resection and presynaptic filament formation. Importantly, the second function is linked to the histone variant H2A.Z. In the absence of H2A.Z, presynaptic filament formation and HR are restored in INO80-C-deficient mutants, suggesting that presynaptic filament formation is the crucial INO80-C function during HR.}, author = {Lademann, Claudio and Renkawitz, Jörg and Pfander, Boris and Jentsch, Stefan}, issn = {22111247}, journal = {Cell Reports}, number = {7}, pages = {1294 -- 1303}, publisher = {Cell Press}, title = {{The INO80 complex removes H2A.Z to promote presynaptic filament formation during homologous recombination}}, doi = {10.1016/j.celrep.2017.04.051}, volume = {19}, year = {2017}, } @article{678, abstract = {The seminal observation that mechanical signals can elicit changes in biochemical signalling within cells, a process commonly termed mechanosensation and mechanotransduction, has revolutionized our understanding of the role of cell mechanics in various fundamental biological processes, such as cell motility, adhesion, proliferation and differentiation. In this Review, we will discuss how the interplay and feedback between mechanical and biochemical signals control tissue morphogenesis and cell fate specification in embryonic development.}, author = {Petridou, Nicoletta and Spiro, Zoltan P and Heisenberg, Carl-Philipp J}, issn = {14657392}, journal = {Nature Cell Biology}, number = {6}, pages = {581 -- 588}, publisher = {Nature Publishing Group}, title = {{Multiscale force sensing in development}}, doi = {10.1038/ncb3524}, volume = {19}, year = {2017}, } @article{681, abstract = {Two-player games on graphs provide the theoretical framework for many important problems such as reactive synthesis. While the traditional study of two-player zero-sum games has been extended to multi-player games with several notions of equilibria, they are decidable only for perfect-information games, whereas several applications require imperfect-information. In this paper we propose a new notion of equilibria, called doomsday equilibria, which is a strategy profile where all players satisfy their own objective, and if any coalition of players deviates and violates even one of the players' objective, then the objective of every player is violated. We present algorithms and complexity results for deciding the existence of doomsday equilibria for various classes of ω-regular objectives, both for imperfect-information games, and for perfect-information games. We provide optimal complexity bounds for imperfect-information games, and in most cases for perfect-information games.}, author = {Chatterjee, Krishnendu and Doyen, Laurent and Filiot, Emmanuel and Raskin, Jean}, issn = {08905401}, journal = {Information and Computation}, pages = {296 -- 315}, publisher = {Elsevier}, title = {{Doomsday equilibria for omega-regular games}}, doi = {10.1016/j.ic.2016.10.012}, volume = {254}, year = {2017}, } @inproceedings{6841, abstract = {In classical machine learning, regression is treated as a black box process of identifying a suitable function from a hypothesis set without attempting to gain insight into the mechanism connecting inputs and outputs. In the natural sciences, however, finding an interpretable function for a phenomenon is the prime goal as it allows to understand and generalize results. This paper proposes a novel type of function learning network, called equation learner (EQL), that can learn analytical expressions and is able to extrapolate to unseen domains. It is implemented as an end-to-end differentiable feed-forward network and allows for efficient gradient based training. Due to sparsity regularization concise interpretable expressions can be obtained. Often the true underlying source expression is identified.}, author = {Martius, Georg S and Lampert, Christoph}, booktitle = {5th International Conference on Learning Representations, ICLR 2017 - Workshop Track Proceedings}, location = {Toulon, France}, publisher = {International Conference on Learning Representations}, title = {{Extrapolation and learning equations}}, year = {2017}, } @article{684, abstract = {We generalize winning conditions in two-player games by adding a structural acceptance condition called obligations. Obligations are orthogonal to the linear winning conditions that define whether a play is winning. Obligations are a declaration that player 0 can achieve a certain value from a configuration. If the obligation is met, the value of that configuration for player 0 is 1. We define the value in such games and show that obligation games are determined. For Markov chains with Borel objectives and obligations, and finite turn-based stochastic parity games with obligations we give an alternative and simpler characterization of the value function. Based on this simpler definition we show that the decision problem of winning finite turn-based stochastic parity games with obligations is in NP∩co-NP. We also show that obligation games provide a game framework for reasoning about p-automata. © 2017 The Association for Symbolic Logic.}, author = {Chatterjee, Krishnendu and Piterman, Nir}, issn = {1943-5886}, journal = {Journal of Symbolic Logic}, number = {2}, pages = {420 -- 452}, publisher = {Cambridge University Press}, title = {{Obligation blackwell games and p-automata}}, doi = {10.1017/jsl.2016.71}, volume = {82}, year = {2017}, } @article{685, abstract = {By applying methods and principles from the physical sciences to biological problems, D'Arcy Thompson's On Growth and Form demonstrated how mathematical reasoning reveals elegant, simple explanations for seemingly complex processes. This has had a profound influence on subsequent generations of developmental biologists. We discuss how this influence can be traced through twentieth century morphologists, embryologists and theoreticians to current research that explores the molecular and cellular mechanisms of tissue growth and patterning, including our own studies of the vertebrate neural tube.}, author = {Briscoe, James and Kicheva, Anna}, issn = {09254773}, journal = {Mechanisms of Development}, pages = {26 -- 31}, publisher = {Elsevier}, title = {{The physics of development 100 years after D'Arcy Thompson's “on growth and form”}}, doi = {10.1016/j.mod.2017.03.005}, volume = {145}, year = {2017}, } @inproceedings{688, abstract = {We show that the framework of topological data analysis can be extended from metrics to general Bregman divergences, widening the scope of possible applications. Examples are the Kullback - Leibler divergence, which is commonly used for comparing text and images, and the Itakura - Saito divergence, popular for speech and sound. In particular, we prove that appropriately generalized čech and Delaunay (alpha) complexes capture the correct homotopy type, namely that of the corresponding union of Bregman balls. Consequently, their filtrations give the correct persistence diagram, namely the one generated by the uniformly growing Bregman balls. Moreover, we show that unlike the metric setting, the filtration of Vietoris-Rips complexes may fail to approximate the persistence diagram. We propose algorithms to compute the thus generalized čech, Vietoris-Rips and Delaunay complexes and experimentally test their efficiency. Lastly, we explain their surprisingly good performance by making a connection with discrete Morse theory. }, author = {Edelsbrunner, Herbert and Wagner, Hubert}, issn = {18688969}, location = {Brisbane, Australia}, pages = {391--3916}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Topological data analysis with Bregman divergences}}, doi = {10.4230/LIPIcs.SoCG.2017.39}, volume = {77}, year = {2017}, } @article{687, abstract = {Pursuing the similarity between the Kontsevich-Soibelman construction of the cohomological Hall algebra (CoHA) of BPS states and Lusztig's construction of canonical bases for quantum enveloping algebras, and the similarity between the integrality conjecture for motivic Donaldson-Thomas invariants and the PBW theorem for quantum enveloping algebras, we build a coproduct on the CoHA associated to a quiver with potential. We also prove a cohomological dimensional reduction theorem, further linking a special class of CoHAs with Yangians, and explaining how to connect the study of character varieties with the study of CoHAs.}, author = {Davison, Ben}, issn = {00335606}, journal = {Quarterly Journal of Mathematics}, number = {2}, pages = {635 -- 703}, publisher = {Oxford University Press}, title = {{The critical CoHA of a quiver with potential}}, doi = {10.1093/qmath/haw053}, volume = {68}, year = {2017}, } @article{686, abstract = {Tissues are thought to behave like fluids with a given surface tension. Differences in tissue surface tension (TST) have been proposed to trigger cell sorting and tissue envelopment. D'Arcy Thompson in his seminal book ‘On Growth and Form’ has introduced this concept of differential TST as a key physical mechanism dictating tissue formation and organization within the developing organism. Over the past century, many studies have picked up the concept of differential TST and analyzed the role and cell biological basis of TST in development, underlining the importance and influence of this concept in developmental biology.}, author = {Heisenberg, Carl-Philipp J}, issn = {09254773}, journal = {Mechanisms of Development}, pages = {32 -- 37}, publisher = {Elsevier}, title = {{D'Arcy Thompson's ‘on growth and form’: From soap bubbles to tissue self organization}}, doi = {10.1016/j.mod.2017.03.006}, volume = {145}, year = {2017}, } @article{689, abstract = {Rett syndrome modeling in monkey mirrors the human disorder.}, author = {Novarino, Gaia}, issn = {19466234}, journal = {Science Translational Medicine}, number = {393}, publisher = {American Association for the Advancement of Science}, title = {{Rett syndrome modeling goes simian}}, doi = {10.1126/scitranslmed.aan8196}, volume = {9}, year = {2017}, } @article{693, abstract = {Many central synapses contain a single presynaptic active zone and a single postsynaptic density. Vesicular release statistics at such “simple synapses” indicate that they contain a small complement of docking sites where vesicles repetitively dock and fuse. In this work, we investigate functional and morphological aspects of docking sites at simple synapses made between cerebellar parallel fibers and molecular layer interneurons. Using immunogold labeling of SDS-treated freeze-fracture replicas, we find that Cav2.1 channels form several clusters per active zone with about nine channels per cluster. The mean value and range of intersynaptic variation are similar for Cav2.1 cluster numbers and for functional estimates of docking-site numbers obtained from the maximum numbers of released vesicles per action potential. Both numbers grow in relation with synaptic size and decrease by a similar extent with age between 2 wk and 4 wk postnatal. Thus, the mean docking-site numbers were 3.15 at 2 wk (range: 1–10) and 2.03 at 4 wk (range: 1–4), whereas the mean numbers of Cav2.1 clusters were 2.84 at 2 wk (range: 1–8) and 2.37 at 4 wk (range: 1–5). These changes were accompanied by decreases of miniature current amplitude (from 93 pA to 56 pA), active-zone surface area (from 0.0427 μm2 to 0.0234 μm2), and initial success rate (from 0.609 to 0.353), indicating a tightening of synaptic transmission with development. Altogether, these results suggest a close correspondence between the number of functionally defined vesicular docking sites and that of clusters of voltage-gated calcium channels. }, author = {Miki, Takafumi and Kaufmann, Walter and Malagon, Gerardo and Gomez, Laura and Tabuchi, Katsuhiko and Watanabe, Masahiko and Shigemoto, Ryuichi and Marty, Alain}, issn = {00278424}, journal = {PNAS}, number = {26}, pages = {E5246 -- E5255}, publisher = {National Academy of Sciences}, title = {{Numbers of presynaptic Ca2+ channel clusters match those of functionally defined vesicular docking sites in single central synapses}}, doi = {10.1073/pnas.1704470114}, volume = {114}, year = {2017}, } @article{694, abstract = {A change regarding the extent of adhesion - hereafter referred to as adhesion plasticity - between adhesive and less-adhesive states of mammalian cells is important for their behavior. To investigate adhesion plasticity, we have selected a stable isogenic subpopulation of human MDA-MB-468 breast carcinoma cells growing in suspension. These suspension cells are unable to re-adhere to various matrices or to contract three-dimensional collagen lattices. By using transcriptome analysis, we identified the focal adhesion protein tensin3 (Tns3) as a determinant of adhesion plasticity. Tns3 is strongly reduced at mRNA and protein levels in suspension cells. Furthermore, by transiently challenging breast cancer cells to grow under non-adherent conditions markedly reduces Tns3 protein expression, which is regained upon re-adhesion. Stable knockdown of Tns3 in parental MDA-MB-468 cells results in defective adhesion, spreading and migration. Tns3-knockdown cells display impaired structure and dynamics of focal adhesion complexes as determined by immunostaining. Restoration of Tns3 protein expression in suspension cells partially rescues adhesion and focal contact composition. Our work identifies Tns3 as a crucial focal adhesion component regulated by, and functionally contributing to, the switch between adhesive and non-adhesive states in MDA-MB-468 cancer cells.}, author = {Veß, Astrid and Blache, Ulrich and Leitner, Laura and Kurz, Angela and Ehrenpfordt, Anja and Sixt, Michael K and Posern, Guido}, issn = {00219533}, journal = {Journal of Cell Science}, number = {13}, pages = {2172 -- 2184}, publisher = {Company of Biologists}, title = {{A dual phenotype of MDA MB 468 cancer cells reveals mutual regulation of tensin3 and adhesion plasticity}}, doi = {10.1242/jcs.200899}, volume = {130}, year = {2017}, } @inproceedings{697, abstract = {De, Trevisan and Tulsiani [CRYPTO 2010] show that every distribution over n-bit strings which has constant statistical distance to uniform (e.g., the output of a pseudorandom generator mapping n-1 to n bit strings), can be distinguished from the uniform distribution with advantage epsilon by a circuit of size O( 2^n epsilon^2). We generalize this result, showing that a distribution which has less than k bits of min-entropy, can be distinguished from any distribution with k bits of delta-smooth min-entropy with advantage epsilon by a circuit of size O(2^k epsilon^2/delta^2). As a special case, this implies that any distribution with support at most 2^k (e.g., the output of a pseudoentropy generator mapping k to n bit strings) can be distinguished from any given distribution with min-entropy k+1 with advantage epsilon by a circuit of size O(2^k epsilon^2). Our result thus shows that pseudoentropy distributions face basically the same non-uniform attacks as pseudorandom distributions. }, author = {Pietrzak, Krzysztof Z and Skórski, Maciej}, issn = {18688969}, location = {Warsaw, Poland}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Non uniform attacks against pseudoentropy}}, doi = {10.4230/LIPIcs.ICALP.2017.39}, volume = {80}, year = {2017}, } @article{698, abstract = {Extracellular matrix signals from the microenvironment regulate gene expression patterns and cell behavior. Using a combination of experiments and geometric models, we demonstrate correlations between cell geometry, three-dimensional (3D) organization of chromosome territories, and gene expression. Fluorescence in situ hybridization experiments showed that micropatterned fibroblasts cultured on anisotropic versus isotropic substrates resulted in repositioning of specific chromosomes, which contained genes that were differentially regulated by cell geometries. Experiments combined with ellipsoid packing models revealed that the mechanosensitivity of chromosomes was correlated with their orientation in the nucleus. Transcription inhibition experiments suggested that the intermingling degree was more sensitive to global changes in transcription than to chromosome radial positioning and its orientations. These results suggested that cell geometry modulated 3D chromosome arrangement, and their neighborhoods correlated with gene expression patterns in a predictable manner. This is central to understanding geometric control of genetic programs involved in cellular homeostasis and the associated diseases. }, author = {Wang, Yejun and Nagarajan, Mallika and Uhler, Caroline and Shivashankar, Gv}, issn = {10591524}, journal = {Molecular Biology of the Cell}, number = {14}, pages = {1997 -- 2009}, publisher = {American Society for Cell Biology}, title = {{Orientation and repositioning of chromosomes correlate with cell geometry dependent gene expression}}, doi = {10.1091/mbc.E16-12-0825}, volume = {28}, year = {2017}, } @article{699, abstract = {In antagonistic symbioses, such as host–parasite interactions, one population’s success is the other’s loss. In mutualistic symbioses, such as division of labor, both parties can gain, but they might have different preferences over the possible mutualistic arrangements. The rates of evolution of the two populations in a symbiosis are important determinants of which population will be more successful: Faster evolution is thought to be favored in antagonistic symbioses (the “Red Queen effect”), but disfavored in certain mutualistic symbioses (the “Red King effect”). However, it remains unclear which biological parameters drive these effects. Here, we analyze the effects of the various determinants of evolutionary rate: generation time, mutation rate, population size, and the intensity of natural selection. Our main results hold for the case where mutation is infrequent. Slower evolution causes a long-term advantage in an important class of mutualistic interactions. Surprisingly, less intense selection is the strongest driver of this Red King effect, whereas relative mutation rates and generation times have little effect. In antagonistic interactions, faster evolution by any means is beneficial. Our results provide insight into the demographic evolution of symbionts. }, author = {Veller, Carl and Hayward, Laura and Nowak, Martin and Hilbe, Christian}, issn = {00278424}, journal = {PNAS}, number = {27}, pages = {E5396 -- E5405}, publisher = {National Academy of Sciences}, title = {{The red queen and king in finite populations}}, doi = {10.1073/pnas.1702020114}, volume = {114}, year = {2017}, } @article{700, abstract = {Microtubules provide the mechanical force required for chromosome separation during mitosis. However, little is known about the dynamic (high-frequency) mechanical properties of microtubules. Here, we theoretically propose to control the vibrations of a doubly clamped microtubule by tip electrodes and to detect its motion via the optomechanical coupling between the vibrational modes of the microtubule and an optical cavity. In the presence of a red-detuned strong pump laser, this coupling leads to optomechanical-induced transparency of an optical probe field, which can be detected with state-of-the art technology. The center frequency and line width of the transparency peak give the resonance frequency and damping rate of the microtubule, respectively, while the height of the peak reveals information about the microtubule-cavity field coupling. Our method opens the new possibilities to gain information about the physical properties of microtubules, which will enhance our capability to design physical cancer treatment protocols as alternatives to chemotherapeutic drugs.}, author = {Barzanjeh, Shabir and Salari, Vahid and Tuszynski, Jack and Cifra, Michal and Simon, Christoph}, issn = {24700045}, journal = { Physical Review E Statistical Nonlinear and Soft Matter Physics }, number = {1}, publisher = {American Institute of Physics}, title = {{Optomechanical proposal for monitoring microtubule mechanical vibrations}}, doi = {10.1103/PhysRevE.96.012404}, volume = {96}, year = {2017}, } @article{701, abstract = {A d-dimensional simplex S is called a k-reptile (or a k-reptile simplex) if it can be tiled by k simplices with disjoint interiors that are all mutually congruent and similar to S. For d = 2, triangular k-reptiles exist for all k of the form a^2, 3a^2 or a^2+b^2 and they have been completely characterized by Snover, Waiveris, and Williams. On the other hand, the only k-reptile simplices that are known for d ≥ 3, have k = m^d, where m is a positive integer. We substantially simplify the proof by Matoušek and the second author that for d = 3, k-reptile tetrahedra can exist only for k = m^3. We then prove a weaker analogue of this result for d = 4 by showing that four-dimensional k-reptile simplices can exist only for k = m^2.}, author = {Kynčl, Jan and Patakova, Zuzana}, issn = {10778926}, journal = {The Electronic Journal of Combinatorics}, number = {3}, pages = {1--44}, publisher = {International Press}, title = {{On the nonexistence of k reptile simplices in ℝ^3 and ℝ^4}}, volume = {24}, year = {2017}, } @article{702, abstract = {Leading autism-associated mutation in mouse partially mimics human disorder. }, author = {Novarino, Gaia}, issn = {19466234}, journal = {Science Translational Medicine}, number = {399}, pages = {eaao0972}, publisher = {American Association for the Advancement of Science}, title = {{The riddle of CHD8 haploinsufficiency in autism spectrum disorder}}, doi = {10.1126/scitranslmed.aao0972}, volume = {9}, year = {2017}, } @article{706, abstract = {A hippocampal mossy fiber synapse has a complex structure and is implicated in learning and memory. In this synapse, the mossy fiber boutons attach to the dendritic shaft by puncta adherentia junctions and wrap around a multiply-branched spine, forming synaptic junctions. We have recently shown using transmission electron microscopy, immunoelectron microscopy and serial block face-scanning electron microscopy that atypical puncta adherentia junctions are formed in the afadin-deficient mossy fiber synapse and that the complexity of postsynaptic spines and mossy fiber boutons, the number of spine heads, the area of postsynaptic densities and the density of synaptic vesicles docked to active zones are decreased in the afadin-deficient synapse. We investigated here the roles of afadin in the functional differentiations of the mossy fiber synapse using the afadin-deficient mice. The electrophysiological studies showed that both the release probability of glutamate and the postsynaptic responsiveness to glutamate were markedly reduced, but not completely lost, in the afadin-deficient mossy fiber synapse, whereas neither long-term potentiation nor long-term depression was affected. These results indicate that afadin plays roles in the functional differentiations of the presynapse and the postsynapse of the hippocampal mossy fiber synapse.}, author = {Geng, Xiaoqi and Maruo, Tomohiko and Mandai, Kenji and Supriyanto, Irwan and Miyata, Muneaki and Sakakibara, Shotaro and Mizoguchi, Akira and Takai, Yoshimi and Mori, Masahiro}, issn = {13569597}, journal = {Genes to Cells}, number = {8}, pages = {715 -- 722}, publisher = {Wiley-Blackwell}, title = {{Roles of afadin in functional differentiations of hippocampal mossy fiber synapse}}, doi = {10.1111/gtc.12508}, volume = {22}, year = {2017}, } @article{707, abstract = {We answer a question of M. Gromov on the waist of the unit ball.}, author = {Akopyan, Arseniy and Karasev, Roman}, issn = {00246093}, journal = {Bulletin of the London Mathematical Society}, number = {4}, pages = {690 -- 693}, publisher = {Wiley-Blackwell}, title = {{A tight estimate for the waist of the ball }}, doi = {10.1112/blms.12062}, volume = {49}, year = {2017}, } @article{708, abstract = {In the developing and adult brain, oligodendrocyte precursor cells (OPCs) are influenced by neuronal activity: they are involved in synaptic signaling with neurons, and their proliferation and differentiation into myelinating glia can be altered by transient changes in neuronal firing. An important question that has been unanswered is whether OPCs can discriminate different patterns of neuronal activity and respond to them in a distinct way. Here, we demonstrate in brain slices that the pattern of neuronal activity determines the functional changes triggered at synapses between axons and OPCs. Furthermore, we show that stimulation of the corpus callosum at different frequencies in vivo affects proliferation and differentiation of OPCs in a dissimilar way. Our findings suggest that neurons do not influence OPCs in “all-or-none” fashion but use their firing pattern to tune the response and behavior of these nonneuronal cells.}, author = {Nagy, Balint and Hovhannisyan, Anahit and Barzan, Ruxandra and Chen, Ting and Kukley, Maria}, issn = {15449173}, journal = {PLoS Biology}, number = {8}, publisher = {Public Library of Science}, title = {{Different patterns of neuronal activity trigger distinct responses of oligodendrocyte precursor cells in the corpus callosum}}, doi = {10.1371/journal.pbio.2001993}, volume = {15}, year = {2017}, } @article{709, abstract = {Adipose tissues play key roles in energy homeostasis. Brown adipocytes and beige adipocytes in white adipose tissue (WAT) share the similar characters of thermogenesis, both of them could be potential targets for obesity management. Several thermo-sensitive transient receptor potential channels (thermoTRPs) are shown to be involved in adipocyte biology. However, the expression pattern of thermoTRPs in adipose tissues from obese mice is still unknown. The mRNA expression of thermoTRPs in subcutaneous WAT (sWAT) and interscapular brown adipose tissue (iBAT) from lean and obese mice were measured using reverse transcriptase-quantitative PCRs (RT-qPCR). The results demonstrated that all 10 thermoTRPs are expressed in both iBAT and sWAT, and without significant difference in the mRNA expression level of thermoTRPs between these two tissues. Moreover, Trpv1 and Trpv3 mRNA expression levels in both iBAT and sWAT were significantly decreased in high fat diet (HFD)-induced obese mice and db/db (leptin receptor deficient) mice. Trpm2 mRNA expression level was significantly decreased only in sWAT from HFD-induced obese mice and db/db mice. On the other hand, Trpv2 and Trpv4 mRNA expression levels in iBAT and sWAT were significantly increased in HFD-induced obese mice and db/db mice. Taken together, we conclude that all 10 thermoTRPs are expressed in iBAT and sWAT. And several thermoTRPs differentially expressed in adipose tissues from HFD-induced obese mice and db/db mice, suggesting a potential involvement in anti-obesity regulations.}, author = {Sun, Wuping and Li, Chen and Zhang, Yonghong and Jiang, Changyu and Zhai, Ming-Zhu and Zhou, Qian and Xiao, Lizu and Deng, Qiwen}, issn = {10656995}, journal = {Cell Biology International}, number = {8}, pages = {908 -- 913}, publisher = {Wiley-Blackwell}, title = {{Gene expression changes of thermo sensitive transient receptor potential channels in obese mice}}, doi = {10.1002/cbin.10783}, volume = {41}, year = {2017}, } @inproceedings{710, abstract = {We revisit the problem of estimating entropy of discrete distributions from independent samples, studied recently by Acharya, Orlitsky, Suresh and Tyagi (SODA 2015), improving their upper and lower bounds on the necessary sample size n. For estimating Renyi entropy of order alpha, up to constant accuracy and error probability, we show the following * Upper bounds n = O(1) 2^{(1-1/alpha)H_alpha} for integer alpha>1, as the worst case over distributions with Renyi entropy equal to H_alpha. * Lower bounds n = Omega(1) K^{1-1/alpha} for any real alpha>1, with the constant being an inverse polynomial of the accuracy, as the worst case over all distributions on K elements. Our upper bounds essentially replace the alphabet size by a factor exponential in the entropy, which offers improvements especially in low or medium entropy regimes (interesting for example in anomaly detection). As for the lower bounds, our proof explicitly shows how the complexity depends on both alphabet and accuracy, partially solving the open problem posted in previous works. The argument for upper bounds derives a clean identity for the variance of falling-power sum of a multinomial distribution. Our approach for lower bounds utilizes convex optimization to find a distribution with possibly worse estimation performance, and may be of independent interest as a tool to work with Le Cam’s two point method. }, author = {Obremski, Maciej and Skórski, Maciej}, issn = {18688969}, location = {Berkeley, USA}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Renyi entropy estimation revisited}}, doi = {10.4230/LIPIcs.APPROX-RANDOM.2017.20}, volume = {81}, year = {2017}, } @article{713, abstract = {To determine the dynamics of allelic-specific expression during mouse development, we analyzed RNA-seq data from 23 F1 tissues from different developmental stages, including 19 female tissues allowing X chromosome inactivation (XCI) escapers to also be detected. We demonstrate that allelic expression arising from genetic or epigenetic differences is highly tissue-specific. We find that tissue-specific strain-biased gene expression may be regulated by tissue-specific enhancers or by post-transcriptional differences in stability between the alleles. We also find that escape from X-inactivation is tissue-specific, with leg muscle showing an unexpectedly high rate of XCI escapers. By surveying a range of tissues during development, and performing extensive validation, we are able to provide a high confidence list of mouse imprinted genes including 18 novel genes. This shows that cluster size varies dynamically during development and can be substantially larger than previously thought, with the Igf2r cluster extending over 10 Mb in placenta.}, author = {Andergassen, Daniel and Dotter, Christoph and Wenzel, Dyniel and Sigl, Verena and Bammer, Philipp and Muckenhuber, Markus and Mayer, Daniela and Kulinski, Tomasz and Theussl, Hans and Penninger, Josef and Bock, Christoph and Barlow, Denise and Pauler, Florian and Hudson, Quanah}, issn = {2050084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Mapping the mouse Allelome reveals tissue specific regulation of allelic expression}}, doi = {10.7554/eLife.25125}, volume = {6}, year = {2017}, } @inproceedings{711, abstract = {Nested weighted automata (NWA) present a robust and convenient automata-theoretic formalism for quantitative specifications. Previous works have considered NWA that processed input words only in the forward direction. It is natural to allow the automata to process input words backwards as well, for example, to measure the maximal or average time between a response and the preceding request. We therefore introduce and study bidirectional NWA that can process input words in both directions. First, we show that bidirectional NWA can express interesting quantitative properties that are not expressible by forward-only NWA. Second, for the fundamental decision problems of emptiness and universality, we establish decidability and complexity results for the new framework which match the best-known results for the special case of forward-only NWA. Thus, for NWA, the increased expressiveness of bidirectionality is achieved at no additional computational complexity. This is in stark contrast to the unweighted case, where bidirectional finite automata are no more expressive but exponentially more succinct than their forward-only counterparts.}, author = {Chatterjee, Krishnendu and Henzinger, Thomas A and Otop, Jan}, issn = {18688969}, location = {Berlin, Germany}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Bidirectional nested weighted automata}}, doi = {10.4230/LIPIcs.CONCUR.2017.5}, volume = {85}, year = {2017}, } @article{712, abstract = {We establish a weak–strong uniqueness principle for solutions to entropy-dissipating reaction–diffusion equations: As long as a strong solution to the reaction–diffusion equation exists, any weak solution and even any renormalized solution must coincide with this strong solution. Our assumptions on the reaction rates are just the entropy condition and local Lipschitz continuity; in particular, we do not impose any growth restrictions on the reaction rates. Therefore, our result applies to any single reversible reaction with mass-action kinetics as well as to systems of reversible reactions with mass-action kinetics satisfying the detailed balance condition. Renormalized solutions are known to exist globally in time for reaction–diffusion equations with entropy-dissipating reaction rates; in contrast, the global-in-time existence of weak solutions is in general still an open problem–even for smooth data–, thereby motivating the study of renormalized solutions. The key ingredient of our result is a careful adjustment of the usual relative entropy functional, whose evolution cannot be controlled properly for weak solutions or renormalized solutions.}, author = {Fischer, Julian L}, issn = {0362546X}, journal = {Nonlinear Analysis: Theory, Methods and Applications}, pages = {181 -- 207}, publisher = {Elsevier}, title = {{Weak–strong uniqueness of solutions to entropy dissipating reaction–diffusion equations}}, doi = {10.1016/j.na.2017.03.001}, volume = {159}, year = {2017}, } @article{714, abstract = {Background HIV-1 infection and drug abuse are frequently co-morbid and their association greatly increases the severity of HIV-1-induced neuropathology. While nucleus accumbens (NAcc) function is severely perturbed by drugs of abuse, little is known about how HIV-1 infection affects NAcc. Methods We used calcium and voltage imaging to investigate the effect of HIV-1 trans-activator of transcription (Tat) on rat NAcc. Based on previous neuronal studies, we hypothesized that Tat modulates intracellular Ca2+ homeostasis of NAcc neurons. Results We provide evidence that Tat triggers a Ca2+ signaling cascade in NAcc medium spiny neurons (MSN) expressing D1-like dopamine receptors leading to neuronal depolarization. Firstly, Tat induced inositol 1,4,5-trisphsophate (IP3) receptor-mediated Ca2+ release from endoplasmic reticulum, followed by Ca2+ and Na+ influx via transient receptor potential canonical channels. The influx of cations depolarizes the membrane promoting additional Ca2+ entry through voltage-gated P/Q-type Ca2+ channels and opening of tetrodotoxin-sensitive Na+ channels. By activating this mechanism, Tat elicits a feed-forward depolarization increasing the excitability of D1-phosphatidylinositol-linked NAcc MSN. We previously found that cocaine targets NAcc neurons directly (independent of the inhibition of dopamine transporter) only when IP3-generating mechanisms are concomitantly initiated. When tested here, cocaine produced a dose-dependent potentiation of the effect of Tat on cytosolic Ca2+. Conclusion We describe for the first time a HIV-1 Tat-triggered Ca2+ signaling in MSN of NAcc involving TRPC and depolarization and a potentiation of the effect of Tat by cocaine, which may be relevant for the reward axis in cocaine-abusing HIV-1-positive patients.}, author = {Brailoiu, Gabriela and Deliu, Elena and Barr, Jeffrey and Console Bram, Linda and Ciuciu, Alexandra and Abood, Mary and Unterwald, Ellen and Brǎiloiu, Eugen}, issn = {03768716}, journal = {Drug and Alcohol Dependence}, pages = {7 -- 14}, publisher = {Elsevier}, title = {{HIV Tat excites D1 receptor-like expressing neurons from rat nucleus accumbens}}, doi = {10.1016/j.drugalcdep.2017.04.015}, volume = {178}, year = {2017}, } @article{715, abstract = {D-cycloserine ameliorates breathing abnormalities and survival rate in a mouse model of Rett syndrome.}, author = {Novarino, Gaia}, issn = {19466234}, journal = {Science Translational Medicine}, number = {405}, publisher = {American Association for the Advancement of Science}, title = {{More excitation for Rett syndrome}}, doi = {10.1126/scitranslmed.aao4218}, volume = {9}, year = {2017}, } @article{716, abstract = {Two-player games on graphs are central in many problems in formal verification and program analysis, such as synthesis and verification of open systems. In this work, we consider solving recursive game graphs (or pushdown game graphs) that model the control flow of sequential programs with recursion.While pushdown games have been studied before with qualitative objectives-such as reachability and ?-regular objectives- in this work, we study for the first time such games with the most well-studied quantitative objective, the mean-payoff objective. In pushdown games, two types of strategies are relevant: (1) global strategies, which depend on the entire global history; and (2) modular strategies, which have only local memory and thus do not depend on the context of invocation but rather only on the history of the current invocation of the module. Our main results are as follows: (1) One-player pushdown games with mean-payoff objectives under global strategies are decidable in polynomial time. (2) Two-player pushdown games with mean-payoff objectives under global strategies are undecidable. (3) One-player pushdown games with mean-payoff objectives under modular strategies are NP-hard. (4) Two-player pushdown games with mean-payoff objectives under modular strategies can be solved in NP (i.e., both one-player and two-player pushdown games with mean-payoff objectives under modular strategies are NP-complete). We also establish the optimal strategy complexity by showing that global strategies for mean-payoff objectives require infinite memory even in one-player pushdown games and memoryless modular strategies are sufficient in two-player pushdown games. Finally, we also show that all the problems have the same complexity if the stack boundedness condition is added, where along with the mean-payoff objective the player must also ensure that the stack height is bounded.}, author = {Chatterjee, Krishnendu and Velner, Yaron}, issn = {00045411}, journal = {Journal of the ACM}, number = {5}, pages = {34}, publisher = {ACM}, title = {{The complexity of mean-payoff pushdown games}}, doi = {10.1145/3121408}, volume = {64}, year = {2017}, } @article{717, abstract = {We consider finite-state and recursive game graphs with multidimensional mean-payoff objectives. In recursive games two types of strategies are relevant: global strategies and modular strategies. Our contributions are: (1) We show that finite-state multidimensional mean-payoff games can be solved in polynomial time if the number of dimensions and the maximal absolute value of weights are fixed; whereas for arbitrary dimensions the problem is coNP-complete. (2) We show that one-player recursive games with multidimensional mean-payoff objectives can be solved in polynomial time. Both above algorithms are based on hyperplane separation technique. (3) For recursive games we show that under modular strategies the multidimensional problem is undecidable. We show that if the number of modules, exits, and the maximal absolute value of the weights are fixed, then one-dimensional recursive mean-payoff games under modular strategies can be solved in polynomial time, whereas for unbounded number of exits or modules the problem is NP-hard.}, author = {Chatterjee, Krishnendu and Velner, Yaron}, journal = {Journal of Computer and System Sciences}, pages = {236 -- 259}, publisher = {Academic Press}, title = {{Hyperplane separation technique for multidimensional mean-payoff games}}, doi = {10.1016/j.jcss.2017.04.005}, volume = {88}, year = {2017}, } @article{719, abstract = {The ubiquity of computation in modern machines and devices imposes a need to assert the correctness of their behavior. Especially in the case of safety-critical systems, their designers need to take measures that enforce their safe operation. Formal methods has emerged as a research field that addresses this challenge: by rigorously proving that all system executions adhere to their specifications, the correctness of an implementation under concern can be assured. To achieve this goal, a plethora of techniques are nowadays available, all of which are optimized for different system types and application domains.}, author = {Chatterjee, Krishnendu and Ehlers, Rüdiger}, issn = {00015903}, journal = {Acta Informatica}, number = {6}, pages = {543 -- 544}, publisher = {Springer}, title = {{Special issue: Synthesis and SYNT 2014}}, doi = {10.1007/s00236-017-0299-0}, volume = {54}, year = {2017}, } @article{720, abstract = {Advances in multi-unit recordings pave the way for statistical modeling of activity patterns in large neural populations. Recent studies have shown that the summed activity of all neurons strongly shapes the population response. A separate recent finding has been that neural populations also exhibit criticality, an anomalously large dynamic range for the probabilities of different population activity patterns. Motivated by these two observations, we introduce a class of probabilistic models which takes into account the prior knowledge that the neural population could be globally coupled and close to critical. These models consist of an energy function which parametrizes interactions between small groups of neurons, and an arbitrary positive, strictly increasing, and twice differentiable function which maps the energy of a population pattern to its probability. We show that: 1) augmenting a pairwise Ising model with a nonlinearity yields an accurate description of the activity of retinal ganglion cells which outperforms previous models based on the summed activity of neurons; 2) prior knowledge that the population is critical translates to prior expectations about the shape of the nonlinearity; 3) the nonlinearity admits an interpretation in terms of a continuous latent variable globally coupling the system whose distribution we can infer from data. Our method is independent of the underlying system’s state space; hence, it can be applied to other systems such as natural scenes or amino acid sequences of proteins which are also known to exhibit criticality.}, author = {Humplik, Jan and Tkacik, Gasper}, issn = {1553734X}, journal = {PLoS Computational Biology}, number = {9}, publisher = {Public Library of Science}, title = {{Probabilistic models for neural populations that naturally capture global coupling and criticality}}, doi = {10.1371/journal.pcbi.1005763}, volume = {13}, year = {2017}, } @article{721, abstract = {Let S be a positivity-preserving symmetric linear operator acting on bounded functions. The nonlinear equation -1/m=z+Sm with a parameter z in the complex upper half-plane ℍ has a unique solution m with values in ℍ. We show that the z-dependence of this solution can be represented as the Stieltjes transforms of a family of probability measures v on ℝ. Under suitable conditions on S, we show that v has a real analytic density apart from finitely many algebraic singularities of degree at most 3. Our motivation comes from large random matrices. The solution m determines the density of eigenvalues of two prominent matrix ensembles: (i) matrices with centered independent entries whose variances are given by S and (ii) matrices with correlated entries with a translation-invariant correlation structure. Our analysis shows that the limiting eigenvalue density has only square root singularities or cubic root cusps; no other singularities occur.}, author = {Ajanki, Oskari H and Krüger, Torben H and Erdös, László}, issn = {00103640}, journal = {Communications on Pure and Applied Mathematics}, number = {9}, pages = {1672 -- 1705}, publisher = {Wiley-Blackwell}, title = {{Singularities of solutions to quadratic vector equations on the complex upper half plane}}, doi = {10.1002/cpa.21639}, volume = {70}, year = {2017}, } @article{722, abstract = {Plants are sessile organisms rooted in one place. The soil resources that plants require are often distributed in a highly heterogeneous pattern. To aid foraging, plants have evolved roots whose growth and development are highly responsive to soil signals. As a result, 3D root architecture is shaped by myriad environmental signals to ensure resource capture is optimised and unfavourable environments are avoided. The first signals sensed by newly germinating seeds — gravity and light — direct root growth into the soil to aid seedling establishment. Heterogeneous soil resources, such as water, nitrogen and phosphate, also act as signals that shape 3D root growth to optimise uptake. Root architecture is also modified through biotic interactions that include soil fungi and neighbouring plants. This developmental plasticity results in a ‘custom-made’ 3D root system that is best adapted to forage for resources in each soil environment that a plant colonises.}, author = {Morris, Emily and Griffiths, Marcus and Golebiowska, Agata and Mairhofer, Stefan and Burr Hersey, Jasmine and Goh, Tatsuaki and Von Wangenheim, Daniel and Atkinson, Brian and Sturrock, Craig and Lynch, Jonathan and Vissenberg, Kris and Ritz, Karl and Wells, Darren and Mooney, Sacha and Bennett, Malcolm}, issn = {09609822}, journal = {Current Biology}, number = {17}, pages = {R919 -- R930}, publisher = {Cell Press}, title = {{Shaping 3D root system architecture}}, doi = {10.1016/j.cub.2017.06.043}, volume = {27}, year = {2017}, } @article{725, abstract = {Individual computations and social interactions underlying collective behavior in groups of animals are of great ethological, behavioral, and theoretical interest. While complex individual behaviors have successfully been parsed into small dictionaries of stereotyped behavioral modes, studies of collective behavior largely ignored these findings; instead, their focus was on inferring single, mode-independent social interaction rules that reproduced macroscopic and often qualitative features of group behavior. Here, we bring these two approaches together to predict individual swimming patterns of adult zebrafish in a group. We show that fish alternate between an “active” mode, in which they are sensitive to the swimming patterns of conspecifics, and a “passive” mode, where they ignore them. Using a model that accounts for these two modes explicitly, we predict behaviors of individual fish with high accuracy, outperforming previous approaches that assumed a single continuous computation by individuals and simple metric or topological weighing of neighbors’ behavior. At the group level, switching between active and passive modes is uncorrelated among fish, but correlated directional swimming behavior still emerges. Our quantitative approach for studying complex, multi-modal individual behavior jointly with emergent group behavior is readily extensible to additional behavioral modes and their neural correlates as well as to other species.}, author = {Harpaz, Roy and Tkacik, Gasper and Schneidman, Elad}, issn = {00278424}, journal = {PNAS}, number = {38}, pages = {10149 -- 10154}, publisher = {National Academy of Sciences}, title = {{Discrete modes of social information processing predict individual behavior of fish in a group}}, doi = {10.1073/pnas.1703817114}, volume = {114}, year = {2017}, } @article{724, abstract = {We investigate the stationary and dynamical behavior of an Anderson localized chain coupled to a single central bound state. Although this coupling partially dilutes the Anderson localized peaks towards nearly resonant sites, the most weight of the original peaks remains unchanged. This leads to multifractal wave functions with a frozen spectrum of fractal dimensions, which is characteristic for localized phases in models with power-law hopping. Using a perturbative approach we identify two different dynamical regimes. At weak couplings to the central site, the transport of particles and information is logarithmic in time, a feature usually attributed to many-body localization. We connect such transport to the persistence of the Poisson statistics of level spacings in parts of the spectrum. In contrast, at stronger couplings the level repulsion is established in the entire spectrum, the problem can be mapped to the Fano resonance, and the transport is ballistic.}, author = {Hetterich, Daniel and Serbyn, Maksym and Domínguez, Fernando and Pollmann, Frank and Trauzettel, Björn}, issn = {24699950}, journal = {Physical Review B}, number = {10}, publisher = {American Physical Society}, title = {{Noninteracting central site model localization and logarithmic entanglement growth}}, doi = {10.1103/PhysRevB.96.104203}, volume = {96}, year = {2017}, } @article{731, abstract = {Genetic variations in the oxytocin receptor gene affect patients with ASD and ADHD differently.}, author = {Novarino, Gaia}, issn = {19466234}, journal = {Science Translational Medicine}, number = {411}, publisher = {American Association for the Advancement of Science}, title = {{The science of love in ASD and ADHD}}, doi = {10.1126/scitranslmed.aap8168}, volume = {9}, year = {2017}, } @article{7360, abstract = {Inflammation, which is a highly regulated host response against danger signals, may be harmful if it is excessive and deregulated. Ideally, anti-inflammatory therapy should autonomously commence as soon as possible after the onset of inflammation, should be controllable by a physician, and should not systemically block beneficial immune response in the long term. We describe a genetically encoded anti-inflammatory mammalian cell device based on a modular engineered genetic circuit comprising a sensor, an amplifier, a “thresholder” to restrict activation of a positive-feedback loop, a combination of advanced clinically used biopharmaceutical proteins, and orthogonal regulatory elements that linked modules into the functional device. This genetic circuit was autonomously activated by inflammatory signals, including endogenous cecal ligation and puncture (CLP)-induced inflammation in mice and serum from a systemic juvenile idiopathic arthritis (sIJA) patient, and could be reset externally by a chemical signal. The microencapsulated anti-inflammatory device significantly reduced the pathology in dextran sodium sulfate (DSS)-induced acute murine colitis, demonstrating a synthetic immunological approach for autonomous anti-inflammatory therapy.}, author = {Smole, Anže and Lainšček, Duško and Bezeljak, Urban and Horvat, Simon and Jerala, Roman}, issn = {1525-0016}, journal = {Molecular Therapy}, number = {1}, pages = {102--119}, publisher = {Elsevier}, title = {{A synthetic mammalian therapeutic gene circuit for sensing and suppressing inflammation}}, doi = {10.1016/j.ymthe.2016.10.005}, volume = {25}, year = {2017}, } @inproceedings{750, abstract = {Modern communication technologies allow first responders to contact thousands of potential volunteers simultaneously for support during a crisis or disaster event. However, such volunteer efforts must be well coordinated and monitored, in order to offer an effective relief to the professionals. In this paper we extend earlier work on optimally assigning volunteers to selected landmark locations. In particular, we emphasize the aspect that obtaining good assignments requires not only advanced computational tools, but also a realistic measure of distance between volunteers and landmarks. Specifically, we propose the use of the Open Street Map (OSM) driving distance instead of he previously used flight distance. We find the OSM driving distance to be better aligned with the interests of volunteers and first responders. Furthermore, we show that relying on the flying distance leads to a substantial underestimation of the number of required volunteers, causing negative side effects in case of an actual crisis situation.}, author = {Pielorz, Jasmin and Prandtstetter, Matthias and Straub, Markus and Lampert, Christoph}, booktitle = {2017 IEEE International Conference on Big Data}, isbn = {978-153862714-3}, location = {Boston, MA, United States}, pages = {3760 -- 3763}, publisher = {IEEE}, title = {{Optimal geospatial volunteer allocation needs realistic distances}}, doi = {10.1109/BigData.2017.8258375}, year = {2017}, } @article{795, abstract = {We introduce a common generalization of the strong Hanani–Tutte theorem and the weak Hanani–Tutte theorem: if a graph G has a drawing D in the plane where every pair of independent edges crosses an even number of times, then G has a planar drawing preserving the rotation of each vertex whose incident edges cross each other evenly in D. The theorem is implicit in the proof of the strong Hanani–Tutte theorem by Pelsmajer, Schaefer and Štefankovič. We give a new, somewhat simpler proof.}, author = {Fulek, Radoslav and Kynčl, Jan and Pálvölgyi, Dömötör}, issn = {10778926}, journal = {Electronic Journal of Combinatorics}, number = {3}, publisher = {International Press}, title = {{Unified Hanani Tutte theorem}}, doi = {10.37236/6663}, volume = {24}, year = {2017}, } @article{797, abstract = {Phasenübergänge helfen beim Verständnis von Vielteilchensystemen in der Festkörperphysik und Fluiddynamik bis hin zur Teilchenphysik. Unserer internationalen Kollaboration ist es gelungen, einen neuartigen Phasenübergang in einem Quantensystem zu beobachten [1]. In einem Mikrowellenresonator konnte erstmals die spontane Zustandsänderung von undurchsichtig zu transparent nachgewiesen werden.}, author = {Fink, Johannes M}, journal = {Physik in unserer Zeit}, number = {3}, pages = {111 -- 113}, publisher = {Wiley}, title = {{Photonenblockade aufgelöst}}, doi = {10.1002/piuz.201770305}, volume = {48}, year = {2017}, } @article{9445, abstract = {Cytosine methylation regulates essential genome functions across eukaryotes, but the fundamental question of whether nucleosomal or naked DNA is the preferred substrate of plant and animal methyltransferases remains unresolved. Here, we show that genetic inactivation of a single DDM1/Lsh family nucleosome remodeler biases methylation toward inter-nucleosomal linker DNA in Arabidopsis thaliana and mouse. We find that DDM1 enables methylation of DNA bound to the nucleosome, suggesting that nucleosome-free DNA is the preferred substrate of eukaryotic methyltransferases in vivo. Furthermore, we show that simultaneous mutation of DDM1 and linker histone H1 in Arabidopsis reproduces the strong linker-specific methylation patterns of species that diverged from flowering plants and animals over a billion years ago. Our results indicate that in the absence of remodeling, nucleosomes are strong barriers to DNA methyltransferases. Linker-specific methylation can evolve simply by breaking the connection between nucleosome remodeling and DNA methylation.}, author = {Lyons, David B and Zilberman, Daniel}, issn = {2050-084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{DDM1 and Lsh remodelers allow methylation of DNA wrapped in nucleosomes}}, doi = {10.7554/elife.30674}, volume = {6}, year = {2017}, } @inbook{957, abstract = {Small molecule biosensors based on Forster resonance energy transfer (FRET) enable small molecule signaling to be monitored with high spatial and temporal resolution in complex cellular environments. FRET sensors can be constructed by fusing a pair of fluorescent proteins to a suitable recognition domain, such as a member of the solute-binding protein (SBP) superfamily. However, naturally occurring SBPs may be unsuitable for incorporation into FRET sensors due to their low thermostability, which may preclude imaging under physiological conditions, or because the positions of their N- and C-termini may be suboptimal for fusion of fluorescent proteins, which may limit the dynamic range of the resulting sensors. Here, we show how these problems can be overcome using ancestral protein reconstruction and circular permutation. Ancestral protein reconstruction, used as a protein engineering strategy, leverages phylogenetic information to improve the thermostability of proteins, while circular permutation enables the termini of an SBP to be repositioned to maximize the dynamic range of the resulting FRET sensor. We also provide a protocol for cloning the engineered SBPs into FRET sensor constructs using Golden Gate assembly and discuss considerations for in situ characterization of the FRET sensors.}, author = {Clifton, Ben and Whitfield, Jason and Sanchez Romero, Inmaculada and Herde, Michel and Henneberger, Christian and Janovjak, Harald L and Jackson, Colin}, booktitle = {Synthetic Protein Switches}, editor = {Stein, Viktor}, issn = {10643745}, pages = {71 -- 87}, publisher = {Springer}, title = {{Ancestral protein reconstruction and circular permutation for improving the stability and dynamic range of FRET sensors}}, doi = {10.1007/978-1-4939-6940-1_5}, volume = {1596}, year = {2017}, } @inproceedings{963, abstract = {Network games are widely used as a model for selfish resource-allocation problems. In the classical model, each player selects a path connecting her source and target vertex. The cost of traversing an edge depends on the number of players that traverse it. Thus, it abstracts the fact that different users may use a resource at different times and for different durations, which plays an important role in defining the costs of the users in reality. For example, when transmitting packets in a communication network, routing traffic in a road network, or processing a task in a production system, the traversal of the network involves an inherent delay, and so sharing and congestion of resources crucially depends on time. We study timed network games , which add a time component to network games. Each vertex v in the network is associated with a cost function, mapping the load on v to the price that a player pays for staying in v for one time unit with this load. In addition, each edge has a guard, describing time intervals in which the edge can be traversed, forcing the players to spend time on vertices. Unlike earlier work that add a time component to network games, the time in our model is continuous and cannot be discretized. In particular, players have uncountably many strategies, and a game may have uncountably many pure Nash equilibria. We study properties of timed network games with cost-sharing or congestion cost functions: their stability, equilibrium inefficiency, and complexity. In particular, we show that the answer to the question whether we can restrict attention to boundary strategies, namely ones in which edges are traversed only at the boundaries of guards, is mixed. }, author = {Avni, Guy and Guha, Shibashis and Kupferman, Orna}, issn = {18688969}, location = {Aalborg, Denmark}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Timed network games with clocks}}, doi = {10.4230/LIPIcs.MFCS.2017.37}, volume = {83}, year = {2017}, } @misc{9709, abstract = {Across the nervous system, certain population spiking patterns are observed far more frequently than others. A hypothesis about this structure is that these collective activity patterns function as population codewords–collective modes–carrying information distinct from that of any single cell. We investigate this phenomenon in recordings of ∼150 retinal ganglion cells, the retina’s output. We develop a novel statistical model that decomposes the population response into modes; it predicts the distribution of spiking activity in the ganglion cell population with high accuracy. We found that the modes represent localized features of the visual stimulus that are distinct from the features represented by single neurons. Modes form clusters of activity states that are readily discriminated from one another. When we repeated the same visual stimulus, we found that the same mode was robustly elicited. These results suggest that retinal ganglion cells’ collective signaling is endowed with a form of error-correcting code–a principle that may hold in brain areas beyond retina.}, author = {Prentice, Jason and Marre, Olivier and Ioffe, Mark and Loback, Adrianna and Tkačik, Gašper and Berry, Michael}, publisher = {Dryad}, title = {{Data from: Error-robust modes of the retinal population code}}, doi = {10.5061/dryad.1f1rc}, year = {2017}, } @article{541, abstract = {While we have good understanding of bacterial metabolism at the population level, we know little about the metabolic behavior of individual cells: do single cells in clonal populations sometimes specialize on different metabolic pathways? Such metabolic specialization could be driven by stochastic gene expression and could provide individual cells with growth benefits of specialization. We measured the degree of phenotypic specialization in two parallel metabolic pathways, the assimilation of glucose and arabinose. We grew Escherichia coli in chemostats, and used isotope-labeled sugars in combination with nanometer-scale secondary ion mass spectrometry and mathematical modeling to quantify sugar assimilation at the single-cell level. We found large variation in metabolic activities between single cells, both in absolute assimilation and in the degree to which individual cells specialize in the assimilation of different sugars. Analysis of transcriptional reporters indicated that this variation was at least partially based on cell-to-cell variation in gene expression. Metabolic differences between cells in clonal populations could potentially reduce metabolic incompatibilities between different pathways, and increase the rate at which parallel reactions can be performed.}, author = {Nikolic, Nela and Schreiber, Frank and Dal Co, Alma and Kiviet, Daniel and Bergmiller, Tobias and Littmann, Sten and Kuypers, Marcel and Ackermann, Martin}, issn = {15537390}, journal = {PLoS Genetics}, number = {12}, publisher = {Public Library of Science}, title = {{Cell-to-cell variation and specialization in sugar metabolism in clonal bacterial populations}}, doi = {10.1371/journal.pgen.1007122}, volume = {13}, year = {2017}, } @misc{9847, abstract = {information on culture conditions, phage mutagenesis, verification and lysate preparation; Raw data}, author = {Pleska, Maros and Guet, Calin C}, publisher = {The Royal Society}, title = {{Supplementary materials and methods; Full data set from effects of mutations in phage restriction sites during escape from restriction–modification}}, doi = {10.6084/m9.figshare.5633917.v1}, year = {2017}, } @misc{9845, abstract = {Estimates of 13 C-arabinose and 2 H-glucose uptake from the fractions of heavy isotopes measured in single cells}, author = {Nikolic, Nela and Schreiber, Frank and Dal Co, Alma and Kiviet, Daniel and Bergmiller, Tobias and Littmann, Sten and Kuypers, Marcel and Ackermann, Martin}, publisher = {Public Library of Science}, title = {{Mathematical model}}, doi = {10.1371/journal.pgen.1007122.s017}, year = {2017}, } @misc{9849, abstract = {This text provides additional information about the model, a derivation of the analytic results in Eq (4), and details about simulations of an additional parameter set.}, author = {Lukacisinova, Marta and Novak, Sebastian and Paixao, Tiago}, publisher = {Public Library of Science}, title = {{Modelling and simulation details}}, doi = {10.1371/journal.pcbi.1005609.s001}, year = {2017}, } @misc{9850, abstract = {In this text, we discuss how a cost of resistance and the possibility of lethal mutations impact our model.}, author = {Lukacisinova, Marta and Novak, Sebastian and Paixao, Tiago}, publisher = {Public Library of Science}, title = {{Extensions of the model}}, doi = {10.1371/journal.pcbi.1005609.s002}, year = {2017}, } @misc{9846, author = {Nikolic, Nela and Schreiber, Frank and Dal Co, Alma and Kiviet, Daniel and Bergmiller, Tobias and Littmann, Sten and Kuypers, Marcel and Ackermann, Martin}, publisher = {Public Library of Science}, title = {{Supplementary methods}}, doi = {10.1371/journal.pgen.1007122.s016}, year = {2017}, } @article{680, abstract = {In order to respond reliably to specific features of their environment, sensory neurons need to integrate multiple incoming noisy signals. Crucially, they also need to compete for the interpretation of those signals with other neurons representing similar features. The form that this competition should take depends critically on the noise corrupting these signals. In this study we show that for the type of noise commonly observed in sensory systems, whose variance scales with the mean signal, sensory neurons should selectively divide their input signals by their predictions, suppressing ambiguous cues while amplifying others. Any change in the stimulus context alters which inputs are suppressed, leading to a deep dynamic reshaping of neural receptive fields going far beyond simple surround suppression. Paradoxically, these highly variable receptive fields go alongside and are in fact required for an invariant representation of external sensory features. In addition to offering a normative account of context-dependent changes in sensory responses, perceptual inference in the presence of signal-dependent noise accounts for ubiquitous features of sensory neurons such as divisive normalization, gain control and contrast dependent temporal dynamics.}, author = {Chalk, Matthew J and Masset, Paul and Gutkin, Boris and Denève, Sophie}, issn = {1553734X}, journal = {PLoS Computational Biology}, number = {6}, publisher = {Public Library of Science}, title = {{Sensory noise predicts divisive reshaping of receptive fields}}, doi = {10.1371/journal.pcbi.1005582}, volume = {13}, year = {2017}, } @misc{9851, abstract = {Based on the intuitive derivation of the dynamics of SIM allele frequency pM in the main text, we present a heuristic prediction for the long-term SIM allele frequencies with χ > 1 stresses and compare it to numerical simulations.}, author = {Lukacisinova, Marta and Novak, Sebastian and Paixao, Tiago}, publisher = {Public Library of Science}, title = {{Heuristic prediction for multiple stresses}}, doi = {10.1371/journal.pcbi.1005609.s003}, year = {2017}, } @misc{9852, abstract = {We show how different combination strategies affect the fraction of individuals that are multi-resistant.}, author = {Lukacisinova, Marta and Novak, Sebastian and Paixao, Tiago}, publisher = {Public Library of Science}, title = {{Resistance frequencies for different combination strategies}}, doi = {10.1371/journal.pcbi.1005609.s004}, year = {2017}, } @misc{9855, abstract = {Includes derivation of optimal estimation algorithm, generalisation to non-poisson noise statistics, correlated input noise, and implementation of in a multi-layer neural network.}, author = {Chalk, Matthew J and Masset, Paul and Gutkin, Boris and Denève, Sophie}, publisher = {Public Library of Science}, title = {{Supplementary appendix}}, doi = {10.1371/journal.pcbi.1005582.s001}, year = {2017}, } @inproceedings{941, abstract = {Recently there has been a proliferation of automated program repair (APR) techniques, targeting various programming languages. Such techniques can be generally classified into two families: syntactic- and semantics-based. Semantics-based APR, on which we focus, typically uses symbolic execution to infer semantic constraints and then program synthesis to construct repairs conforming to them. While syntactic-based APR techniques have been shown successful on bugs in real-world programs written in both C and Java, semantics-based APR techniques mostly target C programs. This leaves empirical comparisons of the APR families not fully explored, and developers without a Java-based semantics APR technique. We present JFix, a semantics-based APR framework that targets Java, and an associated Eclipse plugin. JFix is implemented atop Symbolic PathFinder, a well-known symbolic execution engine for Java programs. It extends one particular APR technique (Angelix), and is designed to be sufficiently generic to support a variety of such techniques. We demonstrate that semantics-based APR can indeed efficiently and effectively repair a variety of classes of bugs in large real-world Java programs. This supports our claim that the framework can both support developers seeking semantics-based repair of bugs in Java programs, as well as enable larger scale empirical studies comparing syntactic- and semantics-based APR targeting Java. The demonstration of our tool is available via the project website at: https://xuanbachle.github.io/semanticsrepair/ }, author = {Le, Xuan and Chu, Duc Hiep and Lo, David and Le Goues, Claire and Visser, Willem}, booktitle = {Proceedings of the 26th ACM SIGSOFT International Symposium on Software Testing and Analysis}, location = {Santa Barbara, CA, United States}, pages = {376 -- 379 }, publisher = {ACM}, title = {{JFIX: Semantics-based repair of Java programs via symbolic PathFinder}}, doi = {10.1145/3092703.3098225}, year = {2017}, } @article{9506, abstract = {Methylation in the bodies of active genes is common in animals and vascular plants. Evolutionary patterns indicate homeostatic functions for this type of methylation.}, author = {Zilberman, Daniel}, issn = {1465-6906}, journal = {Genome Biology}, number = {1}, publisher = {Springer Nature}, title = {{An evolutionary case for functional gene body methylation in plants and animals}}, doi = {10.1186/s13059-017-1230-2}, volume = {18}, year = {2017}, } @inbook{958, abstract = {Biosensors that exploit Forster resonance energy transfer (FRET) can be used to visualize biological and physiological processes and are capable of providing detailed information in both spatial and temporal dimensions. In a FRET-based biosensor, substrate binding is associated with a change in the relative positions of two fluorophores, leading to a change in FRET efficiency that may be observed in the fluorescence spectrum. As a result, their design requires a ligand-binding protein that exhibits a conformational change upon binding. However, not all ligand-binding proteins produce responsive sensors upon conjugation to fluorescent proteins or dyes, and identifying the optimum locations for the fluorophores often involves labor-intensive iterative design or high-throughput screening. Combining the genetic fusion of a fluorescent protein to the ligand-binding protein with site-specific covalent attachment of a fluorescent dye can allow fine control over the positions of the two fluorophores, allowing the construction of very sensitive sensors. This relies upon the accurate prediction of the locations of the two fluorophores in bound and unbound states. In this chapter, we describe a method for computational identification of dye-attachment sites that allows the use of cysteine modification to attach synthetic dyes that can be paired with a fluorescent protein for the purposes of creating FRET sensors.}, author = {Mitchell, Joshua and Zhang, William and Herde, Michel and Henneberger, Christian and Janovjak, Harald L and O'Mara, Megan and Jackson, Colin}, booktitle = {Synthetic Protein Switches}, editor = {Stein, Viktor}, issn = {10643745}, pages = {89 -- 99}, publisher = {Springer}, title = {{Method for developing optical sensors using a synthetic dye fluorescent protein FRET pair and computational modeling and assessment}}, doi = {10.1007/978-1-4939-6940-1_6}, volume = {1596}, year = {2017}, } @misc{9707, abstract = {Branching morphogenesis of the epithelial ureteric bud forms the renal collecting duct system and is critical for normal nephron number, while low nephron number is implicated in hypertension and renal disease. Ureteric bud growth and branching requires GDNF signaling from the surrounding mesenchyme to cells at the ureteric bud tips, via the Ret receptor tyrosine kinase and coreceptor Gfrα1; Ret signaling up-regulates transcription factors Etv4 and Etv5, which are also critical for branching. Despite extensive knowledge of the genetic control of these events, it is not understood, at the cellular level, how renal branching morphogenesis is achieved or how Ret signaling influences epithelial cell behaviors to promote this process. Analysis of chimeric embryos previously suggested a role for Ret signaling in promoting cell rearrangements in the nephric duct, but this method was unsuited to study individual cell behaviors during ureteric bud branching. Here, we use Mosaic Analysis with Double Markers (MADM), combined with organ culture and time-lapse imaging, to trace the movements and divisions of individual ureteric bud tip cells. We first examine wild-type clones and then Ret or Etv4 mutant/wild-type clones in which the mutant and wild-type sister cells are differentially and heritably marked by green and red fluorescent proteins. We find that, in normal kidneys, most individual tip cells behave as self-renewing progenitors, some of whose progeny remain at the tips while others populate the growing UB trunks. In Ret or Etv4 MADM clones, the wild-type cells generated at a UB tip are much more likely to remain at, or move to, the new tips during branching and elongation, while their Ret−/− or Etv4−/− sister cells tend to lag behind and contribute only to the trunks. By tracking successive mitoses in a cell lineage, we find that Ret signaling has little effect on proliferation, in contrast to its effects on cell movement. Our results show that Ret/Etv4 signaling promotes directed cell movements in the ureteric bud tips, and suggest a model in which these cell movements mediate branching morphogenesis.}, author = {Riccio, Paul and Cebrián, Christina and Zong, Hui and Hippenmeyer, Simon and Costantini, Frank}, publisher = {Dryad}, title = {{Data from: Ret and Etv4 promote directed movements of progenitor cells during renal branching morphogenesis}}, doi = {10.5061/dryad.pk16b}, year = {2017}, } @misc{9844, author = {Nikolic, Nela and Schreiber, Frank and Dal Co, Alma and Kiviet, Daniel and Bergmiller, Tobias and Littmann, Sten and Kuypers, Marcel and Ackermann, Martin}, publisher = {Public Library of Science}, title = {{Source data for figures and tables}}, doi = {10.1371/journal.pgen.1007122.s018}, year = {2017}, } @inproceedings{13160, abstract = {Transforming deterministic ω -automata into deterministic parity automata is traditionally done using variants of appearance records. We present a more efficient variant of this approach, tailored to Rabin automata, and several optimizations applicable to all appearance records. We compare the methods experimentally and find out that our method produces smaller automata than previous approaches. Moreover, the experiments demonstrate the potential of our method for LTL synthesis, using LTL-to-Rabin translators. It leads to significantly smaller parity automata when compared to state-of-the-art approaches on complex formulae.}, author = {Kretinsky, Jan and Meggendorfer, Tobias and Waldmann, Clara and Weininger, Maximilian}, booktitle = {Tools and Algorithms for the Construction and Analysis of Systems}, isbn = {9783662545768}, issn = {1611-3349}, location = {Uppsala, Sweden}, pages = {443--460}, publisher = {Springer}, title = {{Index appearance record for transforming Rabin automata into parity automata}}, doi = {10.1007/978-3-662-54577-5_26}, volume = {10205}, year = {2017}, } @inproceedings{950, abstract = {Two-player games on graphs are widely studied in formal methods as they model the interaction between a system and its environment. The game is played by moving a token throughout a graph to produce an infinite path. There are several common modes to determine how the players move the token through the graph; e.g., in turn-based games the players alternate turns in moving the token. We study the bidding mode of moving the token, which, to the best of our knowledge, has never been studied in infinite-duration games. Both players have separate budgets, which sum up to $1$. In each turn, a bidding takes place. Both players submit bids simultaneously, and a bid is legal if it does not exceed the available budget. The winner of the bidding pays his bid to the other player and moves the token. For reachability objectives, repeated bidding games have been studied and are called Richman games. There, a central question is the existence and computation of threshold budgets; namely, a value t\in [0,1] such that if\PO's budget exceeds $t$, he can win the game, and if\PT's budget exceeds 1-t, he can win the game. We focus on parity games and mean-payoff games. We show the existence of threshold budgets in these games, and reduce the problem of finding them to Richman games. We also determine the strategy-complexity of an optimal strategy. Our most interesting result shows that memoryless strategies suffice for mean-payoff bidding games. }, author = {Avni, Guy and Henzinger, Thomas A and Chonev, Ventsislav K}, issn = {1868-8969}, location = {Berlin, Germany}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Infinite-duration bidding games}}, doi = {10.4230/LIPIcs.CONCUR.2017.21}, volume = {85}, year = {2017}, } @inproceedings{683, abstract = {Given a triangulation of a point set in the plane, a flip deletes an edge e whose removal leaves a convex quadrilateral, and replaces e by the opposite diagonal of the quadrilateral. It is well known that any triangulation of a point set can be reconfigured to any other triangulation by some sequence of flips. We explore this question in the setting where each edge of a triangulation has a label, and a flip transfers the label of the removed edge to the new edge. It is not true that every labelled triangulation of a point set can be reconfigured to every other labelled triangulation via a sequence of flips, but we characterize when this is possible. There is an obvious necessary condition: for each label l, if edge e has label l in the first triangulation and edge f has label l in the second triangulation, then there must be some sequence of flips that moves label l from e to f, ignoring all other labels. Bose, Lubiw, Pathak and Verdonschot formulated the Orbit Conjecture, which states that this necessary condition is also sufficient, i.e. that all labels can be simultaneously mapped to their destination if and only if each label individually can be mapped to its destination. We prove this conjecture. Furthermore, we give a polynomial-time algorithm to find a sequence of flips to reconfigure one labelled triangulation to another, if such a sequence exists, and we prove an upper bound of O(n7) on the length of the flip sequence. Our proof uses the topological result that the sets of pairwise non-crossing edges on a planar point set form a simplicial complex that is homeomorphic to a high-dimensional ball (this follows from a result of Orden and Santos; we give a different proof based on a shelling argument). The dual cell complex of this simplicial ball, called the flip complex, has the usual flip graph as its 1-skeleton. We use properties of the 2-skeleton of the flip complex to prove the Orbit Conjecture.}, author = {Lubiw, Anna and Masárová, Zuzana and Wagner, Uli}, location = {Brisbane, Australia}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{A proof of the orbit conjecture for flipping edge labelled triangulations}}, doi = {10.4230/LIPIcs.SoCG.2017.49}, volume = {77}, year = {2017}, } @phdthesis{1155, abstract = {This dissertation concerns the automatic verification of probabilistic systems and programs with arrays by statistical and logical methods. Although statistical and logical methods are different in nature, we show that they can be successfully combined for system analysis. In the first part of the dissertation we present a new statistical algorithm for the verification of probabilistic systems with respect to unbounded properties, including linear temporal logic. Our algorithm often performs faster than the previous approaches, and at the same time requires less information about the system. In addition, our method can be generalized to unbounded quantitative properties such as mean-payoff bounds. In the second part, we introduce two techniques for comparing probabilistic systems. Probabilistic systems are typically compared using the notion of equivalence, which requires the systems to have the equal probability of all behaviors. However, this notion is often too strict, since probabilities are typically only empirically estimated, and any imprecision may break the relation between processes. On the one hand, we propose to replace the Boolean notion of equivalence by a quantitative distance of similarity. For this purpose, we introduce a statistical framework for estimating distances between Markov chains based on their simulation runs, and we investigate which distances can be approximated in our framework. On the other hand, we propose to compare systems with respect to a new qualitative logic, which expresses that behaviors occur with probability one or a positive probability. This qualitative analysis is robust with respect to modeling errors and applicable to many domains. In the last part, we present a new quantifier-free logic for integer arrays, which allows us to express counting. Counting properties are prevalent in array-manipulating programs, however they cannot be expressed in the quantified fragments of the theory of arrays. We present a decision procedure for our logic, and provide several complexity results.}, author = {Daca, Przemyslaw}, issn = {2663-337X}, pages = {163}, publisher = {Institute of Science and Technology Austria}, title = {{Statistical and logical methods for property checking}}, doi = {10.15479/AT:ISTA:TH_730}, year = {2017}, } @phdthesis{6291, abstract = {Bacteria and their pathogens – phages – are the most abundant living entities on Earth. Throughout their coevolution, bacteria have evolved multiple immune systems to overcome the ubiquitous threat from the phages. Although the molecu- lar details of these immune systems’ functions are relatively well understood, their epidemiological consequences for the phage-bacterial communities have been largely neglected. In this thesis we employed both experimental and theoretical methods to explore whether herd and social immunity may arise in bacterial popu- lations. Using our experimental system consisting of Escherichia coli strains with a CRISPR based immunity to the T7 phage we show that herd immunity arises in phage-bacterial communities and that it is accentuated when the populations are spatially structured. By fitting a mathematical model, we inferred expressions for the herd immunity threshold and the velocity of spread of a phage epidemic in partially resistant bacterial populations, which both depend on the bacterial growth rate, phage burst size and phage latent period. We also investigated the poten- tial for social immunity in Streptococcus thermophilus and its phage 2972 using a bioinformatic analysis of potentially coding short open reading frames with a signalling signature, encoded within the CRISPR associated genes. Subsequently, we tested one identified potentially signalling peptide and found that its addition to a phage-challenged culture increases probability of survival of bacteria two fold, although the results were only marginally significant. Together, these results demonstrate that the ubiquitous arms races between bacteria and phages have further consequences at the level of the population.}, author = {Payne, Pavel}, issn = {2663-337X}, pages = {83}, publisher = {Institute of Science and Technology Austria}, title = {{Bacterial herd and social immunity to phages}}, year = {2017}, } @article{561, abstract = {Restriction–modification systems are widespread genetic elements that protect bacteria from bacteriophage infections by recognizing and cleaving heterologous DNA at short, well-defined sequences called restriction sites. Bioinformatic evidence shows that restriction sites are significantly underrepresented in bacteriophage genomes, presumably because bacteriophages with fewer restriction sites are more likely to escape cleavage by restriction–modification systems. However, how mutations in restriction sites affect the likelihood of bacteriophage escape is unknown. Using the bacteriophage l and the restriction–modification system EcoRI, we show that while mutation effects at different restriction sites are unequal, they are independent. As a result, the probability of bacteriophage escape increases with each mutated restriction site. Our results experimentally support the role of restriction site avoidance as a response to selection imposed by restriction–modification systems and offer an insight into the events underlying the process of bacteriophage escape.}, author = {Pleska, Maros and Guet, Calin C}, issn = {1744-9561}, journal = {Biology Letters}, number = {12}, publisher = {The Royal Society}, title = {{Effects of mutations in phage restriction sites during escape from restriction–modification}}, doi = {10.1098/rsbl.2017.0646}, volume = {13}, year = {2017}, } @phdthesis{818, abstract = {Antibiotics have diverse effects on bacteria, including massive changes in bacterial gene expression. Whereas the gene expression changes under many antibiotics have been measured, the temporal organization of these responses and their dependence on the bacterial growth rate are unclear. As described in Chapter 1, we quantified the temporal gene expression changes in the bacterium Escherichia coli in response to the sudden exposure to antibiotics using a fluorescent reporter library and a robotic system. Our data show temporally structured gene expression responses, with response times for individual genes ranging from tens of minutes to several hours. We observed that many stress response genes were activated in response to antibiotics. As certain stress responses cross-protect bacteria from other stressors, we then asked whether cellular responses to antibiotics have a similar protective role in Chapter 2. Indeed, we found that the trimethoprim-induced acid stress response protects bacteria from subsequent acid stress. We combined microfluidics with time-lapse imaging to monitor survival, intracellular pH, and acid stress response in single cells. This approach revealed that the variable expression of the acid resistance operon gadBC strongly correlates with single-cell survival time. Cells with higher gadBC expression following trimethoprim maintain higher intracellular pH and survive the acid stress longer. Overall, we provide a way to identify single-cell cross-protection between antibiotics and environmental stressors from temporal gene expression data, and show how antibiotics can increase bacterial fitness in changing environments. While gene expression changes to antibiotics show a clear temporal structure at the population-level, it is unclear whether this clear temporal order is followed by every single cell. Using dual-reporter strains described in Chapter 3, we measured gene expression dynamics of promoter pairs in the same cells using microfluidics and microscopy. Chapter 4 shows that the oxidative stress response and the DNA stress response showed little timing variability and a clear temporal order under the antibiotic nitrofurantoin. In contrast, the acid stress response under trimethoprim ran independently from all other activated response programs including the DNA stress response, which showed particularly high timing variability in this stress condition. In summary, this approach provides insight into the temporal organization of gene expression programs at the single-cell level and suggests dependencies between response programs and the underlying variability-introducing mechanisms. Altogether, this work advances our understanding of the diverse effects that antibiotics have on bacteria. These results were obtained by taking into account gene expression dynamics, which allowed us to identify general principles, molecular mechanisms, and dependencies between genes. Our findings may have implications for infectious disease treatments, and microbial communities in the human body and in nature. }, author = {Mitosch, Karin}, issn = {2663-337X}, pages = {113}, publisher = {Institute of Science and Technology Austria}, title = {{Timing, variability and cross-protection in bacteria – insights from dynamic gene expression responses to antibiotics}}, doi = {10.15479/AT:ISTA:th_862}, year = {2017}, } @article{666, abstract = {Antibiotics elicit drastic changes in microbial gene expression, including the induction of stress response genes. While certain stress responses are known to “cross-protect” bacteria from other stressors, it is unclear whether cellular responses to antibiotics have a similar protective role. By measuring the genome-wide transcriptional response dynamics of Escherichia coli to four antibiotics, we found that trimethoprim induces a rapid acid stress response that protects bacteria from subsequent exposure to acid. Combining microfluidics with time-lapse imaging to monitor survival and acid stress response in single cells revealed that the noisy expression of the acid resistance operon gadBC correlates with single-cell survival. Cells with higher gadBC expression following trimethoprim maintain higher intracellular pH and survive the acid stress longer. The seemingly random single-cell survival under acid stress can therefore be predicted from gadBC expression and rationalized in terms of GadB/C molecular function. Overall, we provide a roadmap for identifying the molecular mechanisms of single-cell cross-protection between antibiotics and other stressors.}, author = {Mitosch, Karin and Rieckh, Georg and Bollenbach, Tobias}, issn = {24054712}, journal = {Cell Systems}, number = {4}, pages = {393 -- 403}, publisher = {Cell Press}, title = {{Noisy response to antibiotic stress predicts subsequent single cell survival in an acidic environment}}, doi = {10.1016/j.cels.2017.03.001}, volume = {4}, year = {2017}, } @phdthesis{821, abstract = {This dissertation focuses on algorithmic aspects of program verification, and presents modeling and complexity advances on several problems related to the static analysis of programs, the stateless model checking of concurrent programs, and the competitive analysis of real-time scheduling algorithms. Our contributions can be broadly grouped into five categories. Our first contribution is a set of new algorithms and data structures for the quantitative and data-flow analysis of programs, based on the graph-theoretic notion of treewidth. It has been observed that the control-flow graphs of typical programs have special structure, and are characterized as graphs of small treewidth. We utilize this structural property to provide faster algorithms for the quantitative and data-flow analysis of recursive and concurrent programs. In most cases we make an algebraic treatment of the considered problem, where several interesting analyses, such as the reachability, shortest path, and certain kind of data-flow analysis problems follow as special cases. We exploit the constant-treewidth property to obtain algorithmic improvements for on-demand versions of the problems, and provide data structures with various tradeoffs between the resources spent in the preprocessing and querying phase. We also improve on the algorithmic complexity of quantitative problems outside the algebraic path framework, namely of the minimum mean-payoff, minimum ratio, and minimum initial credit for energy problems. Our second contribution is a set of algorithms for Dyck reachability with applications to data-dependence analysis and alias analysis. In particular, we develop an optimal algorithm for Dyck reachability on bidirected graphs, which are ubiquitous in context-insensitive, field-sensitive points-to analysis. Additionally, we develop an efficient algorithm for context-sensitive data-dependence analysis via Dyck reachability, where the task is to obtain analysis summaries of library code in the presence of callbacks. Our algorithm preprocesses libraries in almost linear time, after which the contribution of the library in the complexity of the client analysis is (i)~linear in the number of call sites and (ii)~only logarithmic in the size of the whole library, as opposed to linear in the size of the whole library. Finally, we prove that Dyck reachability is Boolean Matrix Multiplication-hard in general, and the hardness also holds for graphs of constant treewidth. This hardness result strongly indicates that there exist no combinatorial algorithms for Dyck reachability with truly subcubic complexity. Our third contribution is the formalization and algorithmic treatment of the Quantitative Interprocedural Analysis framework. In this framework, the transitions of a recursive program are annotated as good, bad or neutral, and receive a weight which measures the magnitude of their respective effect. The Quantitative Interprocedural Analysis problem asks to determine whether there exists an infinite run of the program where the long-run ratio of the bad weights over the good weights is above a given threshold. We illustrate how several quantitative problems related to static analysis of recursive programs can be instantiated in this framework, and present some case studies to this direction. Our fourth contribution is a new dynamic partial-order reduction for the stateless model checking of concurrent programs. Traditional approaches rely on the standard Mazurkiewicz equivalence between traces, by means of partitioning the trace space into equivalence classes, and attempting to explore a few representatives from each class. We present a new dynamic partial-order reduction method called the Data-centric Partial Order Reduction (DC-DPOR). Our algorithm is based on a new equivalence between traces, called the observation equivalence. DC-DPOR explores a coarser partitioning of the trace space than any exploration method based on the standard Mazurkiewicz equivalence. Depending on the program, the new partitioning can be even exponentially coarser. Additionally, DC-DPOR spends only polynomial time in each explored class. Our fifth contribution is the use of automata and game-theoretic verification techniques in the competitive analysis and synthesis of real-time scheduling algorithms for firm-deadline tasks. On the analysis side, we leverage automata on infinite words to compute the competitive ratio of real-time schedulers subject to various environmental constraints. On the synthesis side, we introduce a new instance of two-player mean-payoff partial-information games, and show how the synthesis of an optimal real-time scheduler can be reduced to computing winning strategies in this new type of games.}, author = {Pavlogiannis, Andreas}, issn = {2663-337X}, pages = {418}, publisher = {Institute of Science and Technology Austria}, title = {{Algorithmic advances in program analysis and their applications}}, doi = {10.15479/AT:ISTA:th_854}, year = {2017}, }