TY - JOUR AB - SETD5 gene mutations have been identified as a frequent cause of idiopathic intellectual disability. Here we show that Setd5-haploinsufficient mice present developmental defects such as abnormal brain-to-body weight ratios and neural crest defect-associated phenotypes. Furthermore, Setd5-mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic profile of ultrasonic vocalization, and behavioral inflexibility. Behavioral issues are accompanied by abnormal expression of postsynaptic density proteins previously associated with cognition. Our data additionally indicate that Setd5 regulates RNA polymerase II dynamics and gene transcription via its interaction with the Hdac3 and Paf1 complexes, findings potentially explaining the gene expression defects observed in Setd5-haploinsufficient mice. Our results emphasize the decisive role of Setd5 in a biological pathway found to be disrupted in humans with intellectual disability and autism spectrum disorder. AU - Deliu, Elena AU - Arecco, Niccoló AU - Morandell, Jasmin AU - Dotter, Christoph AU - Contreras, Ximena AU - Girardot, Charles AU - Käsper, Eva AU - Kozlova, Alena AU - Kishi, Kasumi AU - Chiaradia, Ilaria AU - Noh, Kyung AU - Novarino, Gaia ID - 3 IS - 12 JF - Nature Neuroscience TI - Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition VL - 21 ER - TY - JOUR AB - Indirect reciprocity explores how humans act when their reputation is at stake, and which social norms they use to assess the actions of others. A crucial question in indirect reciprocity is which social norms can maintain stable cooperation in a society. Past research has highlighted eight such norms, called “leading-eight” strategies. This past research, however, is based on the assumption that all relevant information about other population members is publicly available and that everyone agrees on who is good or bad. Instead, here we explore the reputation dynamics when information is private and noisy. We show that under these conditions, most leading-eight strategies fail to evolve. Those leading-eight strategies that do evolve are unable to sustain full cooperation.Indirect reciprocity is a mechanism for cooperation based on shared moral systems and individual reputations. It assumes that members of a community routinely observe and assess each other and that they use this information to decide who is good or bad, and who deserves cooperation. When information is transmitted publicly, such that all community members agree on each other’s reputation, previous research has highlighted eight crucial moral systems. These “leading-eight” strategies can maintain cooperation and resist invasion by defectors. However, in real populations individuals often hold their own private views of others. Once two individuals disagree about their opinion of some third party, they may also see its subsequent actions in a different light. Their opinions may further diverge over time. Herein, we explore indirect reciprocity when information transmission is private and noisy. We find that in the presence of perception errors, most leading-eight strategies cease to be stable. Even if a leading-eight strategy evolves, cooperation rates may drop considerably when errors are common. Our research highlights the role of reliable information and synchronized reputations to maintain stable moral systems. AU - Hilbe, Christian AU - Schmid, Laura AU - Tkadlec, Josef AU - Chatterjee, Krishnendu AU - Nowak, Martin ID - 2 IS - 48 JF - PNAS TI - Indirect reciprocity with private, noisy, and incomplete information VL - 115 ER - TY - JOUR AB - Gene regulatory networks evolve through rewiring of individual components—that is, through changes in regulatory connections. However, the mechanistic basis of regulatory rewiring is poorly understood. Using a canonical gene regulatory system, we quantify the properties of transcription factors that determine the evolutionary potential for rewiring of regulatory connections: robustness, tunability and evolvability. In vivo repression measurements of two repressors at mutated operator sites reveal their contrasting evolutionary potential: while robustness and evolvability were positively correlated, both were in trade-off with tunability. Epistatic interactions between adjacent operators alleviated this trade-off. A thermodynamic model explains how the differences in robustness, tunability and evolvability arise from biophysical characteristics of repressor–DNA binding. The model also uncovers that the energy matrix, which describes how mutations affect repressor–DNA binding, encodes crucial information about the evolutionary potential of a repressor. The biophysical determinants of evolutionary potential for regulatory rewiring constitute a mechanistic framework for understanding network evolution. AU - Igler, Claudia AU - Lagator, Mato AU - Tkacik, Gasper AU - Bollback, Jonathan P AU - Guet, Calin C ID - 67 IS - 10 JF - Nature Ecology and Evolution TI - Evolutionary potential of transcription factors for gene regulatory rewiring VL - 2 ER - TY - DATA AB - Mean repression values and standard error of the mean are given for all operator mutant libraries. AU - Igler, Claudia AU - Lagator, Mato AU - Tkacik, Gasper AU - Bollback, Jonathan P AU - Guet, Calin C ID - 5585 TI - Data for the paper Evolutionary potential of transcription factors for gene regulatory rewiring ER - TY - JOUR AB - From microwave ovens to satellite television to the GPS and data services on our mobile phones, microwave technology is everywhere today. But one technology that has so far failed to prove its worth in this wavelength regime is quantum communication that uses the states of single photons as information carriers. This is because single microwave photons, as opposed to classical microwave signals, are extremely vulnerable to noise from thermal excitations in the channels through which they travel. Two new independent studies, one by Ze-Liang Xiang at Technische Universität Wien (Vienna), Austria, and colleagues [1] and another by Benoît Vermersch at the University of Innsbruck, also in Austria, and colleagues [2] now describe a theoretical protocol for microwave quantum communication that is resilient to thermal and other types of noise. Their approach could become a powerful technique to establish fast links between superconducting data processors in a future all-microwave quantum network. AU - Fink, Johannes M ID - 1013 IS - 32 JF - Physics TI - Viewpoint: Microwave quantum states beat the heat VL - 10 ER - TY - JOUR AB - We present a new proof rule for proving almost-sure termination of probabilistic programs, including those that contain demonic non-determinism. An important question for a probabilistic program is whether the probability mass of all its diverging runs is zero, that is that it terminates "almost surely". Proving that can be hard, and this paper presents a new method for doing so. It applies directly to the program's source code, even if the program contains demonic choice. Like others, we use variant functions (a.k.a. "super-martingales") that are real-valued and decrease randomly on each loop iteration; but our key innovation is that the amount as well as the probability of the decrease are parametric. We prove the soundness of the new rule, indicate where its applicability goes beyond existing rules, and explain its connection to classical results on denumerable (non-demonic) Markov chains. AU - Mciver, Annabelle AU - Morgan, Carroll AU - Kaminski, Benjamin Lucien AU - Katoen, Joost P ID - 10418 IS - POPL JF - Proceedings of the ACM on Programming Languages TI - A new proof rule for almost-sure termination VL - 2 ER - TY - CONF AB - There has been renewed interest in modelling the behaviour of evolutionary algorithms by more traditional mathematical objects, such as ordinary differential equations or Markov chains. The advantage is that the analysis becomes greatly facilitated due to the existence of well established methods. However, this typically comes at the cost of disregarding information about the process. Here, we introduce the use of stochastic differential equations (SDEs) for the study of EAs. SDEs can produce simple analytical results for the dynamics of stochastic processes, unlike Markov chains which can produce rigorous but unwieldy expressions about the dynamics. On the other hand, unlike ordinary differential equations (ODEs), they do not discard information about the stochasticity of the process. We show that these are especially suitable for the analysis of fixed budget scenarios and present analogs of the additive and multiplicative drift theorems for SDEs. We exemplify the use of these methods for two model algorithms ((1+1) EA and RLS) on two canonical problems(OneMax and LeadingOnes). AU - Paixao, Tiago AU - Pérez Heredia, Jorge ID - 1112 SN - 978-145034651-1 T2 - Proceedings of the 14th ACM/SIGEVO Conference on Foundations of Genetic Algorithms TI - An application of stochastic differential equations to evolutionary algorithms ER - TY - CONF AB - We study space complexity and time-space trade-offs with a focus not on peak memory usage but on overall memory consumption throughout the computation. Such a cumulative space measure was introduced for the computational model of parallel black pebbling by [Alwen and Serbinenko ’15] as a tool for obtaining results in cryptography. We consider instead the non- deterministic black-white pebble game and prove optimal cumulative space lower bounds and trade-offs, where in order to minimize pebbling time the space has to remain large during a significant fraction of the pebbling. We also initiate the study of cumulative space in proof complexity, an area where other space complexity measures have been extensively studied during the last 10–15 years. Using and extending the connection between proof complexity and pebble games in [Ben-Sasson and Nordström ’08, ’11] we obtain several strong cumulative space results for (even parallel versions of) the resolution proof system, and outline some possible future directions of study of this, in our opinion, natural and interesting space measure. AU - Alwen, Joel F AU - De Rezende, Susanna AU - Nordstrom, Jakob AU - Vinyals, Marc ED - Papadimitriou, Christos ID - 1175 SN - 18688969 TI - Cumulative space in black-white pebbling and resolution VL - 67 ER - TY - JOUR AB - Variation in genotypes may be responsible for differences in dispersal rates, directional biases, and growth rates of individuals. These traits may favor certain genotypes and enhance their spatiotemporal spreading into areas occupied by the less advantageous genotypes. We study how these factors influence the speed of spreading in the case of two competing genotypes under the assumption that spatial variation of the total population is small compared to the spatial variation of the frequencies of the genotypes in the population. In that case, the dynamics of the frequency of one of the genotypes is approximately described by a generalized Fisher–Kolmogorov–Petrovskii–Piskunov (F–KPP) equation. This generalized F–KPP equation with (nonlinear) frequency-dependent diffusion and advection terms admits traveling wave solutions that characterize the invasion of the dominant genotype. Our existence results generalize the classical theory for traveling waves for the F–KPP with constant coefficients. Moreover, in the particular case of the quadratic (monostable) nonlinear growth–decay rate in the generalized F–KPP we study in detail the influence of the variance in diffusion and mean displacement rates of the two genotypes on the minimal wave propagation speed. AU - Kollár, Richard AU - Novak, Sebastian ID - 1191 IS - 3 JF - Bulletin of Mathematical Biology TI - Existence of traveling waves for the generalized F–KPP equation VL - 79 ER - TY - JOUR AB - Systems such as fluid flows in channels and pipes or the complex Ginzburg–Landau system, defined over periodic domains, exhibit both continuous symmetries, translational and rotational, as well as discrete symmetries under spatial reflections or complex conjugation. The simplest, and very common symmetry of this type is the equivariance of the defining equations under the orthogonal group O(2). We formulate a novel symmetry reduction scheme for such systems by combining the method of slices with invariant polynomial methods, and show how it works by applying it to the Kuramoto–Sivashinsky system in one spatial dimension. As an example, we track a relative periodic orbit through a sequence of bifurcations to the onset of chaos. Within the symmetry-reduced state space we are able to compute and visualize the unstable manifolds of relative periodic orbits, their torus bifurcations, a transition to chaos via torus breakdown, and heteroclinic connections between various relative periodic orbits. It would be very hard to carry through such analysis in the full state space, without a symmetry reduction such as the one we present here. AU - Budanur, Nazmi B AU - Cvitanović, Predrag ID - 1211 IS - 3-4 JF - Journal of Statistical Physics TI - Unstable manifolds of relative periodic orbits in the symmetry reduced state space of the Kuramoto–Sivashinsky system VL - 167 ER - TY - JOUR AB - A drawing of a graph G is radial if the vertices of G are placed on concentric circles C 1 , . . . , C k with common center c , and edges are drawn radially : every edge intersects every circle centered at c at most once. G is radial planar if it has a radial embedding, that is, a crossing-free radial drawing. If the vertices of G are ordered or partitioned into ordered levels (as they are for leveled graphs), we require that the assignment of vertices to circles corresponds to the given ordering or leveling. We show that a graph G is radial planar if G has a radial drawing in which every two edges cross an even number of times; the radial embedding has the same leveling as the radial drawing. In other words, we establish the weak variant of the Hanani-Tutte theorem for radial planarity. This generalizes a result by Pach and Toth. AU - Fulek, Radoslav AU - Pelsmajer, Michael AU - Schaefer, Marcus ID - 1113 IS - 1 JF - Journal of Graph Algorithms and Applications TI - Hanani-Tutte for radial planarity VL - 21 ER - TY - CHAP AB - Complex I (NADH:ubiquinone oxidoreductase) plays a central role in cellular energy generation, contributing to the proton motive force used to produce ATP. It couples the transfer of two electrons between NADH and quinone to translocation of four protons across the membrane. It is the largest protein assembly of bacterial and mitochondrial respiratory chains, composed, in mammals, of up to 45 subunits with a total molecular weight of ∼1 MDa. Bacterial enzyme is about half the size, providing the important “minimal” model of complex I. The l-shaped complex consists of a hydrophilic arm, where electron transfer occurs, and a membrane arm, where proton translocation takes place. Previously, we have solved the crystal structures of the hydrophilic domain of complex I from Thermus thermophilus and of the membrane domain from Escherichia coli, followed by the atomic structure of intact, entire complex I from T. thermophilus. Recently, we have solved by cryo-EM a first complete atomic structure of mammalian (ovine) mitochondrial complex I. Core subunits are well conserved from the bacterial version, whilst supernumerary subunits form an interlinked, stabilizing shell around the core. Subunits containing additional cofactors, including Zn ion, NADPH and phosphopantetheine, probably have regulatory roles. Dysfunction of mitochondrial complex I is implicated in many human neurodegenerative diseases. The structure of mammalian enzyme provides many insights into complex I mechanism, assembly, maturation and dysfunction, allowing detailed molecular analysis of disease-causing mutations. AU - Sazanov, Leonid A ED - Wikström, Mårten ID - 444 SN - 978-1-78262-865-1 T2 - Mechanisms of primary energy transduction in biology TI - Structure of respiratory complex I: “Minimal” bacterial and “de luxe” mammalian versions ER - TY - JOUR AB - Most kinesin motors move in only one direction along microtubules. Members of the kinesin-5 subfamily were initially described as unidirectional plus-end-directed motors and shown to produce piconewton forces. However, some fungal kinesin-5 motors are bidirectional. The force production of a bidirectional kinesin-5 has not yet been measured. Therefore, it remains unknown whether the mechanism of the unconventional minus-end-directed motility differs fundamentally from that of plus-end-directed stepping. Using force spectroscopy, we have measured here the forces that ensembles of purified budding yeast kinesin-5 Cin8 produce in microtubule gliding assays in both plus- and minus-end direction. Correlation analysis of pause forces demonstrated that individual Cin8 molecules produce additive forces in both directions of movement. In ensembles, Cin8 motors were able to produce single-motor forces up to a magnitude of ∼1.5 pN. Hence, these properties appear to be conserved within the kinesin-5 subfamily. Force production was largely independent of the directionality of movement, indicating similarities between the motility mechanisms for both directions. These results provide constraints for the development of models for the bidirectional motility mechanism of fission yeast kinesin-5 and provide insight into the function of this mitotic motor. AU - Fallesen, Todd AU - Roostalu, Johanna AU - Düllberg, Christian F AU - Pruessner, Gunnar AU - Surrey, Thomas ID - 453 IS - 9 JF - Biophysical Journal TI - Ensembles of bidirectional kinesin Cin8 produce additive forces in both directions of movement VL - 113 ER - TY - JOUR AB - The computation of the winning set for parity objectives and for Streett objectives in graphs as well as in game graphs are central problems in computer-aided verification, with application to the verification of closed systems with strong fairness conditions, the verification of open systems, checking interface compatibility, well-formedness of specifications, and the synthesis of reactive systems. We show how to compute the winning set on n vertices for (1) parity-3 (aka one-pair Streett) objectives in game graphs in time O(n5/2) and for (2) k-pair Streett objectives in graphs in time O(n2+nklogn). For both problems this gives faster algorithms for dense graphs and represents the first improvement in asymptotic running time in 15 years. AU - Chatterjee, Krishnendu AU - Henzinger, Monika H AU - Loitzenbauer, Veronika ID - 464 IS - 3 JF - Logical Methods in Computer Science SN - 1860-5974 TI - Improved algorithms for parity and Streett objectives VL - 13 ER - TY - JOUR AB - This paper presents a method for simulating water surface waves as a displacement field on a 2D domain. Our method relies on Lagrangian particles that carry packets of water wave energy; each packet carries information about an entire group of wave trains, as opposed to only a single wave crest. Our approach is unconditionally stable and can simulate high resolution geometric details. This approach also presents a straightforward interface for artistic control, because it is essentially a particle system with intuitive parameters like wavelength and amplitude. Our implementation parallelizes well and runs in real time for moderately challenging scenarios. AU - Jeschke, Stefan AU - Wojtan, Christopher J ID - 470 IS - 4 JF - ACM Transactions on Graphics SN - 07300301 TI - Water wave packets VL - 36 ER - TY - JOUR AB - We present a new algorithm for the statistical model checking of Markov chains with respect to unbounded temporal properties, including full linear temporal logic. The main idea is that we monitor each simulation run on the fly, in order to detect quickly if a bottom strongly connected component is entered with high probability, in which case the simulation run can be terminated early. As a result, our simulation runs are often much shorter than required by termination bounds that are computed a priori for a desired level of confidence on a large state space. In comparison to previous algorithms for statistical model checking our method is not only faster in many cases but also requires less information about the system, namely, only the minimum transition probability that occurs in the Markov chain. In addition, our method can be generalised to unbounded quantitative properties such as mean-payoff bounds. AU - Daca, Przemyslaw AU - Henzinger, Thomas A AU - Kretinsky, Jan AU - Petrov, Tatjana ID - 471 IS - 2 JF - ACM Transactions on Computational Logic (TOCL) SN - 15293785 TI - Faster statistical model checking for unbounded temporal properties VL - 18 ER - TY - JOUR AB - We introduce planar matchings on directed pseudo-line arrangements, which yield a planar set of pseudo-line segments such that only matching-partners are adjacent. By translating the planar matching problem into a corresponding stable roommates problem we show that such matchings always exist. Using our new framework, we establish, for the first time, a complete, rigorous definition of weighted straight skeletons, which are based on a so-called wavefront propagation process. We present a generalized and unified approach to treat structural changes in the wavefront that focuses on the restoration of weak planarity by finding planar matchings. AU - Biedl, Therese AU - Huber, Stefan AU - Palfrader, Peter ID - 481 IS - 3-4 JF - International Journal of Computational Geometry and Applications TI - Planar matchings for weighted straight skeletons VL - 26 ER - TY - JOUR AB - We consider the dynamics of a large quantum system of N identical bosons in 3D interacting via a two-body potential of the form N3β-1w(Nβ(x - y)). For fixed 0 = β < 1/3 and large N, we obtain a norm approximation to the many-body evolution in the Nparticle Hilbert space. The leading order behaviour of the dynamics is determined by Hartree theory while the second order is given by Bogoliubov theory. AU - Nam, Phan AU - Napiórkowski, Marcin M ID - 484 IS - 3 JF - Advances in Theoretical and Mathematical Physics SN - 10950761 TI - Bogoliubov correction to the mean-field dynamics of interacting bosons VL - 21 ER - TY - JOUR AB - We prove the universality for the eigenvalue gap statistics in the bulk of the spectrum for band matrices, in the regime where the band width is comparable with the dimension of the matrix, W ~ N. All previous results concerning universality of non-Gaussian random matrices are for mean-field models. By relying on a new mean-field reduction technique, we deduce universality from quantum unique ergodicity for band matrices. AU - Bourgade, Paul AU - Erdös, László AU - Yau, Horng AU - Yin, Jun ID - 483 IS - 3 JF - Advances in Theoretical and Mathematical Physics SN - 10950761 TI - Universality for a class of random band matrices VL - 21 ER - TY - CONF AB - In this paper we study network architecture for unlicensed cellular networking for outdoor coverage in TV white spaces. The main technology proposed for TV white spaces is 802.11af, a Wi-Fi variant adapted for TV frequencies. However, 802.11af is originally designed for improved indoor propagation. We show that long links, typical for outdoor use, exacerbate known Wi-Fi issues, such as hidden and exposed terminal, and significantly reduce its efficiency. Instead, we propose CellFi, an alternative architecture based on LTE. LTE is designed for long-range coverage and throughput efficiency, but it is also designed to operate in tightly controlled and centrally managed networks. CellFi overcomes these problems by designing an LTE-compatible spectrum database component, mandatory for TV white space networking, and introducing an interference management component for distributed coordination. CellFi interference management is compatible with existing LTE mechanisms, requires no explicit communication between base stations, and is more efficient than CSMA for long links. We evaluate our design through extensive real world evaluation on of-the-shelf LTE equipment and simulations. We show that, compared to 802.11af, it increases coverage by 40% and reduces median flow completion times by 2.3x. AU - Baig, Ghufran AU - Radunovic, Bozidar AU - Alistarh, Dan-Adrian AU - Balkwill, Matthew AU - Karagiannis, Thomas AU - Qiu, Lili ID - 487 SN - 978-145035422-6 T2 - Proceedings of the 2017 13th International Conference on emerging Networking EXperiments and Technologies TI - Towards unlicensed cellular networks in TV white spaces ER - TY - JOUR AB - Orientation in space is represented in specialized brain circuits. Persistent head direction signals are transmitted from anterior thalamus to the presubiculum, but the identity of the presubicular target neurons, their connectivity and function in local microcircuits are unknown. Here, we examine how thalamic afferents recruit presubicular principal neurons and Martinotti interneurons, and the ensuing synaptic interactions between these cells. Pyramidal neuron activation of Martinotti cells in superficial layers is strongly facilitating such that high-frequency head directional stimulation efficiently unmutes synaptic excitation. Martinotti-cell feedback plays a dual role: precisely timed spikes may not inhibit the firing of in-tune head direction cells, while exerting lateral inhibition. Autonomous attractor dynamics emerge from a modelled network implementing wiring motifs and timing sensitive synaptic interactions in the pyramidal - Martinotti-cell feedback loop. This inhibitory microcircuit is therefore tuned to refine and maintain head direction information in the presubiculum. AU - Simonnet, Jean AU - Nassar, Mérie AU - Stella, Federico AU - Cohen, Ivan AU - Mathon, Bertrand AU - Boccara, Charlotte AU - Miles, Richard AU - Fricker, Desdemona ID - 514 JF - Nature Communications SN - 20411723 TI - Activity dependent feedback inhibition may maintain head direction signals in mouse presubiculum VL - 8 ER - TY - JOUR AB - The oxidative phosphorylation electron transport chain (OXPHOS-ETC) of the inner mitochondrial membrane is composed of five large protein complexes, named CI-CV. These complexes convert energy from the food we eat into ATP, a small molecule used to power a multitude of essential reactions throughout the cell. OXPHOS-ETC complexes are organized into supercomplexes (SCs) of defined stoichiometry: CI forms a supercomplex with CIII2 and CIV (SC I+III2+IV, known as the respirasome), as well as with CIII2 alone (SC I+III2). CIII2 forms a supercomplex with CIV (SC III2+IV) and CV forms dimers (CV2). Recent cryo-EM studies have revealed the structures of SC I+III2+IV and SC I+III2. Furthermore, recent work has shed light on the assembly and function of the SCs. Here we review and compare these recent studies and discuss how they have advanced our understanding of mitochondrial electron transport. AU - Letts, James A AU - Sazanov, Leonid A ID - 515 IS - 10 JF - Nature Structural and Molecular Biology SN - 15459993 TI - Clarifying the supercomplex: The higher-order organization of the mitochondrial electron transport chain VL - 24 ER - TY - JOUR AB - We present an experimental setup that creates a shear flow with zero mean advection velocity achieved by counterbalancing the nonzero streamwise pressure gradient by moving boundaries, which generates plane Couette-Poiseuille flow. We obtain experimental results in the transitional regime for this flow. Using flow visualization, we characterize the subcritical transition to turbulence in Couette-Poiseuille flow and show the existence of turbulent spots generated by a permanent perturbation. Due to the zero mean advection velocity of the base profile, these turbulent structures are nearly stationary. We distinguish two regions of the turbulent spot: the active turbulent core, which is characterized by waviness of the streaks similar to traveling waves, and the surrounding region, which includes in addition the weak undisturbed streaks and oblique waves at the laminar-turbulent interface. We also study the dependence of the size of these two regions on Reynolds number. Finally, we show that the traveling waves move in the downstream (Poiseuille) direction. AU - Klotz, Lukasz AU - Lemoult, Grégoire M AU - Frontczak, Idalia AU - Tuckerman, Laurette AU - Wesfreid, José ID - 513 IS - 4 JF - Physical Review Fluids TI - Couette-Poiseuille flow experiment with zero mean advection velocity: Subcritical transition to turbulence VL - 2 ER - TY - JOUR AB - Cyanobacteria are mostly engineered to be sustainable cell-factories by genetic manipulations alone. Here, by modulating the concentration of allosteric effectors, we focus on increasing product formation without further burdening the cells with increased expression of enzymes. Resorting to a novel 96-well microplate cultivation system for cyanobacteria, and using lactate-producing strains of Synechocystis PCC6803 expressing different l-lactate dehydrogenases (LDH), we titrated the effect of 2,5-anhydro-mannitol supplementation. The latter acts in cells as a nonmetabolizable analogue of fructose 1,6-bisphosphate, a known allosteric regulator of one of the tested LDHs. In this strain (SAA023), we achieved over 2-fold increase of lactate productivity. Furthermore, we observed that as carbon is increasingly deviated during growth toward product formation, there is an increased fixation rate in the population of spontaneous mutants harboring an impaired production pathway. This is a challenge in the development of green cell factories, which may be countered by the incorporation in biotechnological processes of strategies such as the one pioneered here. AU - Du, Wei AU - Angermayr, Andreas AU - Jongbloets, Joeri AU - Molenaar, Douwe AU - Bachmann, Herwig AU - Hellingwerf, Klaas AU - Branco Dos Santos, Filipe ID - 520 IS - 3 JF - ACS Synthetic Biology SN - 21615063 TI - Nonhierarchical flux regulation exposes the fitness burden associated with lactate production in Synechocystis sp. PCC6803 VL - 6 ER - TY - JOUR AB - Let X and Y be proper metric spaces. We show that a coarsely n-to-1 map f:X→Y induces an n-to-1 map of Higson coronas. This viewpoint turns out to be successful in showing that the classical dimension raising theorems hold in large scale; that is, if f:X→Y is a coarsely n-to-1 map between proper metric spaces X and Y then asdim(Y)≤asdim(X)+n−1. Furthermore we introduce coarsely open coarsely n-to-1 maps, which include the natural quotient maps via a finite group action, and prove that they preserve the asymptotic dimension. AU - Austin, Kyle AU - Virk, Ziga ID - 521 JF - Topology and its Applications SN - 01668641 TI - Higson compactification and dimension raising VL - 215 ER - TY - JOUR AB - We investigate the complexity of finding an embedded non-orientable surface of Euler genus g in a triangulated 3-manifold. This problem occurs both as a natural question in low-dimensional topology, and as a first non-trivial instance of embeddability of complexes into 3-manifolds. We prove that the problem is NP-hard, thus adding to the relatively few hardness results that are currently known in 3-manifold topology. In addition, we show that the problem lies in NP when the Euler genus g is odd, and we give an explicit algorithm in this case. AU - Burton, Benjamin AU - De Mesmay, Arnaud N AU - Wagner, Uli ID - 534 IS - 4 JF - Discrete & Computational Geometry SN - 01795376 TI - Finding non-orientable surfaces in 3-Manifolds VL - 58 ER - TY - JOUR AB - Optogenetik und Photopharmakologie ermöglichen präzise räumliche und zeitliche Kontrolle von Proteinwechselwirkung und -funktion in Zellen und Tieren. Optogenetische Methoden, die auf grünes Licht ansprechen und zum Trennen von Proteinkomplexen geeignet sind, sind nichtweitläufig verfügbar, würden jedoch mehrfarbige Experimente zur Beantwortung von biologischen Fragestellungen ermöglichen. Hier demonstrieren wir die Verwendung von Cobalamin(Vitamin B12)-bindenden Domänen von bakteriellen CarH-Transkriptionsfaktoren zur Grünlicht-induzierten Dissoziation von Rezeptoren. Fusioniert mit dem Fibroblasten-W achstumsfaktor-Rezeptor 1 führten diese im Dunkeln in kultivierten Zellen zu Signalaktivität durch Oligomerisierung, welche durch Beleuchten umgehend aufgehoben wurde. In Zebrafischembryonen, die einen derartigen Rezeptor exprimieren, ermöglichte grünes Licht die Kontrolle über abnormale Signalaktivität während der Embryonalentwicklung. AU - Kainrath, Stephanie AU - Stadler, Manuela AU - Gschaider-Reichhart, Eva AU - Distel, Martin AU - Janovjak, Harald L ID - 538 IS - 16 JF - Angewandte Chemie TI - Grünlicht-induzierte Rezeptorinaktivierung durch Cobalamin-bindende Domänen VL - 129 ER - TY - JOUR AB - RNA-dependent RNA polymerases (RdRps) play a key role in the life cycle of RNA viruses and impact their immunobiology. The arenavirus lymphocytic choriomeningitis virus (LCMV) strain Clone 13 provides a benchmark model for studying chronic infection. A major genetic determinant for its ability to persist maps to a single amino acid exchange in the viral L protein, which exhibits RdRp activity, yet its functional consequences remain elusive. To unravel the L protein interactions with the host proteome, we engineered infectious L protein-tagged LCMV virions by reverse genetics. A subsequent mass-spectrometric analysis of L protein pulldowns from infected human cells revealed a comprehensive network of interacting host proteins. The obtained LCMV L protein interactome was bioinformatically integrated with known host protein interactors of RdRps from other RNA viruses, emphasizing interconnected modules of human proteins. Functional characterization of selected interactors highlighted proviral (DDX3X) as well as antiviral (NKRF, TRIM21) host factors. To corroborate these findings, we infected Trim21-/-mice with LCMV and found impaired virus control in chronic infection. These results provide insights into the complex interactions of the arenavirus LCMV and other viral RdRps with the host proteome and contribute to a better molecular understanding of how chronic viruses interact with their host. AU - Khamina, Kseniya AU - Lercher, Alexander AU - Caldera, Michael AU - Schliehe, Christopher AU - Vilagos, Bojan AU - Sahin, Mehmet AU - Kosack, Lindsay AU - Bhattacharya, Anannya AU - Májek, Peter AU - Stukalov, Alexey AU - Sacco, Roberto AU - James, Leo AU - Pinschewer, Daniel AU - Bennett, Keiryn AU - Menche, Jörg AU - Bergthaler, Andreas ID - 540 IS - 12 JF - PLoS Pathogens SN - 15537366 TI - Characterization of host proteins interacting with the lymphocytic choriomeningitis virus L protein VL - 13 ER - TY - JOUR AB - We consider Markov decision processes (MDPs) with multiple limit-average (or mean-payoff) objectives. There exist two different views: (i) the expectation semantics, where the goal is to optimize the expected mean-payoff objective, and (ii) the satisfaction semantics, where the goal is to maximize the probability of runs such that the mean-payoff value stays above a given vector. We consider optimization with respect to both objectives at once, thus unifying the existing semantics. Precisely, the goal is to optimize the expectation while ensuring the satisfaction constraint. Our problem captures the notion of optimization with respect to strategies that are risk-averse (i.e., ensure certain probabilistic guarantee). Our main results are as follows: First, we present algorithms for the decision problems which are always polynomial in the size of the MDP. We also show that an approximation of the Pareto-curve can be computed in time polynomial in the size of the MDP, and the approximation factor, but exponential in the number of dimensions. Second, we present a complete characterization of the strategy complexity (in terms of memory bounds and randomization) required to solve our problem. AU - Chatterjee, Krishnendu AU - Křetínská, Zuzana AU - Kretinsky, Jan ID - 466 IS - 2 JF - Logical Methods in Computer Science SN - 18605974 TI - Unifying two views on multiple mean-payoff objectives in Markov decision processes VL - 13 ER - TY - JOUR AB - Recently there has been a significant effort to handle quantitative properties in formal verification and synthesis. While weighted automata over finite and infinite words provide a natural and flexible framework to express quantitative properties, perhaps surprisingly, some basic system properties such as average response time cannot be expressed using weighted automata or in any other known decidable formalism. In this work, we introduce nested weighted automata as a natural extension of weighted automata, which makes it possible to express important quantitative properties such as average response time. In nested weighted automata, a master automaton spins off and collects results from weighted slave automata, each of which computes a quantity along a finite portion of an infinite word. Nested weighted automata can be viewed as the quantitative analogue of monitor automata, which are used in runtime verification. We establish an almost-complete decidability picture for the basic decision problems about nested weighted automata and illustrate their applicability in several domains. In particular, nested weighted automata can be used to decide average response time properties. AU - Chatterjee, Krishnendu AU - Henzinger, Thomas A AU - Otop, Jan ID - 467 IS - 4 JF - ACM Transactions on Computational Logic (TOCL) SN - 15293785 TI - Nested weighted automata VL - 18 ER - TY - JOUR AB - The edit distance between two words w 1 , w 2 is the minimal number of word operations (letter insertions, deletions, and substitutions) necessary to transform w 1 to w 2 . The edit distance generalizes to languages L 1 , L 2 , where the edit distance from L 1 to L 2 is the minimal number k such that for every word from L 1 there exists a word in L 2 with edit distance at most k . We study the edit distance computation problem between pushdown automata and their subclasses. The problem of computing edit distance to a pushdown automaton is undecidable, and in practice, the interesting question is to compute the edit distance from a pushdown automaton (the implementation, a standard model for programs with recursion) to a regular language (the specification). In this work, we present a complete picture of decidability and complexity for the following problems: (1) deciding whether, for a given threshold k , the edit distance from a pushdown automaton to a finite automaton is at most k , and (2) deciding whether the edit distance from a pushdown automaton to a finite automaton is finite. AU - Chatterjee, Krishnendu AU - Henzinger, Thomas A AU - Ibsen-Jensen, Rasmus AU - Otop, Jan ID - 465 IS - 3 JF - Logical Methods in Computer Science SN - 18605974 TI - Edit distance for pushdown automata VL - 13 ER - TY - JOUR AB - The fixation probability is the probability that a new mutant introduced in a homogeneous population eventually takes over the entire population. The fixation probability is a fundamental quantity of natural selection, and known to depend on the population structure. Amplifiers of natural selection are population structures which increase the fixation probability of advantageous mutants, as compared to the baseline case of well-mixed populations. In this work we focus on symmetric population structures represented as undirected graphs. In the regime of undirected graphs, the strongest amplifier known has been the Star graph, and the existence of undirected graphs with stronger amplification properties has remained open for over a decade. In this work we present the Comet and Comet-swarm families of undirected graphs. We show that for a range of fitness values of the mutants, the Comet and Cometswarm graphs have fixation probability strictly larger than the fixation probability of the Star graph, for fixed population size and at the limit of large populations, respectively. AU - Pavlogiannis, Andreas AU - Tkadlec, Josef AU - Chatterjee, Krishnendu AU - Nowak, Martin ID - 512 IS - 1 JF - Scientific Reports SN - 20452322 TI - Amplification on undirected population structures: Comets beat stars VL - 7 ER - TY - JOUR AB - A fundamental algorithmic problem at the heart of static analysis is Dyck reachability. The input is a graph where the edges are labeled with different types of opening and closing parentheses, and the reachability information is computed via paths whose parentheses are properly matched. We present new results for Dyck reachability problems with applications to alias analysis and data-dependence analysis. Our main contributions, that include improved upper bounds as well as lower bounds that establish optimality guarantees, are as follows: First, we consider Dyck reachability on bidirected graphs, which is the standard way of performing field-sensitive points-to analysis. Given a bidirected graph with n nodes and m edges, we present: (i) an algorithm with worst-case running time O(m + n · α(n)), where α(n) is the inverse Ackermann function, improving the previously known O(n2) time bound; (ii) a matching lower bound that shows that our algorithm is optimal wrt to worst-case complexity; and (iii) an optimal average-case upper bound of O(m) time, improving the previously known O(m · logn) bound. Second, we consider the problem of context-sensitive data-dependence analysis, where the task is to obtain analysis summaries of library code in the presence of callbacks. Our algorithm preprocesses libraries in almost linear time, after which the contribution of the library in the complexity of the client analysis is only linear, and only wrt the number of call sites. Third, we prove that combinatorial algorithms for Dyck reachability on general graphs with truly sub-cubic bounds cannot be obtained without obtaining sub-cubic combinatorial algorithms for Boolean Matrix Multiplication, which is a long-standing open problem. Thus we establish that the existing combinatorial algorithms for Dyck reachability are (conditionally) optimal for general graphs. We also show that the same hardness holds for graphs of constant treewidth. Finally, we provide a prototype implementation of our algorithms for both alias analysis and data-dependence analysis. Our experimental evaluation demonstrates that the new algorithms significantly outperform all existing methods on the two problems, over real-world benchmarks. AU - Chatterjee, Krishnendu AU - Choudhary, Bhavya AU - Pavlogiannis, Andreas ID - 10416 IS - POPL JF - Proceedings of the ACM on Programming Languages TI - Optimal Dyck reachability for data-dependence and Alias analysis VL - 2 ER - TY - GEN AB - A fundamental algorithmic problem at the heart of static analysis is Dyck reachability. The input is a graphwhere the edges are labeled with different types of opening and closing parentheses, and the reachabilityinformation is computed via paths whose parentheses are properly matched. We present new results for Dyckreachability problems with applications to alias analysis and data-dependence analysis. Our main contributions,that include improved upper bounds as well as lower bounds that establish optimality guarantees, are asfollows:First, we consider Dyck reachability on bidirected graphs, which is the standard way of performing field-sensitive points-to analysis. Given a bidirected graph withnnodes andmedges, we present: (i) an algorithmwith worst-case running timeO(m+n·α(n)), whereα(n)is the inverse Ackermann function, improving thepreviously knownO(n2)time bound; (ii) a matching lower bound that shows that our algorithm is optimalwrt to worst-case complexity; and (iii) an optimal average-case upper bound ofO(m)time, improving thepreviously knownO(m·logn)bound.Second, we consider the problem of context-sensitive data-dependence analysis, where the task is to obtainanalysis summaries of library code in the presence of callbacks. Our algorithm preprocesses libraries in almostlinear time, after which the contribution of the library in the complexity of the client analysis is only linear,and only wrt the number of call sites.Third, we prove that combinatorial algorithms for Dyck reachability on general graphs with truly sub-cubic bounds cannot be obtained without obtaining sub-cubic combinatorial algorithms for Boolean MatrixMultiplication, which is a long-standing open problem. Thus we establish that the existing combinatorialalgorithms for Dyck reachability are (conditionally) optimal for general graphs. We also show that the samehardness holds for graphs of constant treewidth.Finally, we provide a prototype implementation of our algorithms for both alias analysis and data-dependenceanalysis. Our experimental evaluation demonstrates that the new algorithms significantly outperform allexisting methods on the two problems, over real-world benchmarks. AU - Chatterjee, Krishnendu AU - Choudhary, Bhavya AU - Pavlogiannis, Andreas ID - 5455 SN - 2664-1690 TI - Optimal Dyck reachability for data-dependence and alias analysis ER - TY - GEN AB - In this report the implementation of the institutional data repository IST DataRep at IST Austria will be covered: Starting with the research phase when requirements for a repository were established, the procedure of choosing a repository-software and its customization based on the results of user-testings will be discussed. Followed by reflections on the marketing strategies in regard of impact, and at the end sharing some experiences of one year operating IST DataRep. AU - Barbara Petritsch ID - 5450 TI - Implementing the institutional data repository IST DataRep ER - TY - JOUR AB - We present a new dynamic partial-order reduction method for stateless model checking of concurrent programs. A common approach for exploring program behaviors relies on enumerating the traces of the program, without storing the visited states (aka stateless exploration). As the number of distinct traces grows exponentially, dynamic partial-order reduction (DPOR) techniques have been successfully used to partition the space of traces into equivalence classes (Mazurkiewicz partitioning), with the goal of exploring only few representative traces from each class. We introduce a new equivalence on traces under sequential consistency semantics, which we call the observation equivalence. Two traces are observationally equivalent if every read event observes the same write event in both traces. While the traditional Mazurkiewicz equivalence is control-centric, our new definition is data-centric. We show that our observation equivalence is coarser than the Mazurkiewicz equivalence, and in many cases even exponentially coarser. We devise a DPOR exploration of the trace space, called data-centric DPOR, based on the observation equivalence. AU - Chalupa, Marek AU - Chatterjee, Krishnendu AU - Pavlogiannis, Andreas AU - Sinha, Nishant AU - Vaidya, Kapil ID - 10417 IS - POPL JF - Proceedings of the ACM on Programming Languages TI - Data-centric dynamic partial order reduction VL - 2 ER - TY - GEN AB - We present a new dynamic partial-order reduction method for stateless model checking of concurrent programs. A common approach for exploring program behaviors relies on enumerating the traces of the program, without storing the visited states (aka stateless exploration). As the number of distinct traces grows exponentially, dynamic partial-order reduction (DPOR) techniques have been successfully used to partition the space of traces into equivalence classes (Mazurkiewicz partitioning), with the goal of exploring only few representative traces from each class. We introduce a new equivalence on traces under sequential consistency semantics, which we call the observation equivalence. Two traces are observationally equivalent if every read event observes the same write event in both traces. While the traditional Mazurkiewicz equivalence is control-centric, our new definition is data-centric. We show that our observation equivalence is coarser than the Mazurkiewicz equivalence, and in many cases even exponentially coarser. We devise a DPOR exploration of the trace space, called data-centric DPOR, based on the observation equivalence. 1. For acyclic architectures, our algorithm is guaranteed to explore exactly one representative trace from each observation class, while spending polynomial time per class. Hence, our algorithm is optimal wrt the observation equivalence, and in several cases explores exponentially fewer traces than any enumerative method based on the Mazurkiewicz equivalence. 2. For cyclic architectures, we consider an equivalence between traces which is finer than the observation equivalence; but coarser than the Mazurkiewicz equivalence, and in some cases is exponentially coarser. Our data-centric DPOR algorithm remains optimal under this trace equivalence. Finally, we perform a basic experimental comparison between the existing Mazurkiewicz-based DPOR and our data-centric DPOR on a set of academic benchmarks. Our results show a significant reduction in both running time and the number of explored equivalence classes. AU - Chalupa, Marek AU - Chatterjee, Krishnendu AU - Pavlogiannis, Andreas AU - Sinha, Nishant AU - Vaidya, Kapil ID - 5456 SN - 2664-1690 TI - Data-centric dynamic partial order reduction ER - TY - CONF AB - Evolutionary graph theory studies the evolutionary dynamics in a population structure given as a connected graph. Each node of the graph represents an individual of the population, and edges determine how offspring are placed. We consider the classical birth-death Moran process where there are two types of individuals, namely, the residents with fitness 1 and mutants with fitness r. The fitness indicates the reproductive strength. The evolutionary dynamics happens as follows: in the initial step, in a population of all resident individuals a mutant is introduced, and then at each step, an individual is chosen proportional to the fitness of its type to reproduce, and the offspring replaces a neighbor uniformly at random. The process stops when all individuals are either residents or mutants. The probability that all individuals in the end are mutants is called the fixation probability, which is a key factor in the rate of evolution. We consider the problem of approximating the fixation probability. The class of algorithms that is extremely relevant for approximation of the fixation probabilities is the Monte-Carlo simulation of the process. Previous results present a polynomial-time Monte-Carlo algorithm for undirected graphs when r is given in unary. First, we present a simple modification: instead of simulating each step, we discard ineffective steps, where no node changes type (i.e., either residents replace residents, or mutants replace mutants). Using the above simple modification and our result that the number of effective steps is concentrated around the expected number of effective steps, we present faster polynomial-time Monte-Carlo algorithms for undirected graphs. Our algorithms are always at least a factor O(n2/ log n) faster as compared to the previous algorithms, where n is the number of nodes, and is polynomial even if r is given in binary. We also present lower bounds showing that the upper bound on the expected number of effective steps we present is asymptotically tight for undirected graphs. AU - Chatterjee, Krishnendu AU - Ibsen-Jensen, Rasmus AU - Nowak, Martin ID - 551 SN - 978-395977046-0 T2 - Leibniz International Proceedings in Informatics TI - Faster Monte Carlo algorithms for fixation probability of the Moran process on undirected graphs VL - 83 ER - TY - CONF AB - Graph games provide the foundation for modeling and synthesis of reactive processes. Such games are played over graphs where the vertices are controlled by two adversarial players. We consider graph games where the objective of the first player is the conjunction of a qualitative objective (specified as a parity condition) and a quantitative objective (specified as a meanpayoff condition). There are two variants of the problem, namely, the threshold problem where the quantitative goal is to ensure that the mean-payoff value is above a threshold, and the value problem where the quantitative goal is to ensure the optimal mean-payoff value; in both cases ensuring the qualitative parity objective. The previous best-known algorithms for game graphs with n vertices, m edges, parity objectives with d priorities, and maximal absolute reward value W for mean-payoff objectives, are as follows: O(nd+1 . m . w) for the threshold problem, and O(nd+2 · m · W) for the value problem. Our main contributions are faster algorithms, and the running times of our algorithms are as follows: O(nd-1 · m ·W) for the threshold problem, and O(nd · m · W · log(n · W)) for the value problem. For mean-payoff parity objectives with two priorities, our algorithms match the best-known bounds of the algorithms for mean-payoff games (without conjunction with parity objectives). Our results are relevant in synthesis of reactive systems with both functional requirement (given as a qualitative objective) and performance requirement (given as a quantitative objective). AU - Chatterjee, Krishnendu AU - Henzinger, Monika H AU - Svozil, Alexander ID - 552 SN - 978-395977046-0 T2 - Leibniz International Proceedings in Informatics TI - Faster algorithms for mean-payoff parity games VL - 83 ER - TY - CONF AB - We consider two player, zero-sum, finite-state concurrent reachability games, played for an infinite number of rounds, where in every round, each player simultaneously and independently of the other players chooses an action, whereafter the successor state is determined by a probability distribution given by the current state and the chosen actions. Player 1 wins iff a designated goal state is eventually visited. We are interested in the complexity of stationary strategies measured by their patience, which is defined as the inverse of the smallest non-zero probability employed. Our main results are as follows: We show that: (i) the optimal bound on the patience of optimal and -optimal strategies, for both players is doubly exponential; and (ii) even in games with a single non-absorbing state exponential (in the number of actions) patience is necessary. AU - Chatterjee, Krishnendu AU - Hansen, Kristofer AU - Ibsen-Jensen, Rasmus ID - 553 SN - 978-395977046-0 T2 - Leibniz International Proceedings in Informatics TI - Strategy complexity of concurrent safety games VL - 83 ER - TY - JOUR AB - In a recent article (Jentzen et al. 2016 Commun. Math. Sci. 14, 1477–1500 (doi:10.4310/CMS.2016.v14. n6.a1)), it has been established that, for every arbitrarily slow convergence speed and every natural number d ? {4, 5, . . .}, there exist d-dimensional stochastic differential equations with infinitely often differentiable and globally bounded coefficients such that no approximation method based on finitely many observations of the driving Brownian motion can converge in absolute mean to the solution faster than the given speed of convergence. In this paper, we strengthen the above result by proving that this slow convergence phenomenon also arises in two (d = 2) and three (d = 3) space dimensions. AU - Gerencser, Mate AU - Jentzen, Arnulf AU - Salimova, Diyora ID - 560 IS - 2207 JF - Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences SN - 13645021 TI - On stochastic differential equations with arbitrarily slow convergence rates for strong approximation in two space dimensions VL - 473 ER - TY - BOOK AB - This book is a concise and self-contained introduction of recent techniques to prove local spectral universality for large random matrices. Random matrix theory is a fast expanding research area, and this book mainly focuses on the methods that the authors participated in developing over the past few years. Many other interesting topics are not included, and neither are several new developments within the framework of these methods. The authors have chosen instead to present key concepts that they believe are the core of these methods and should be relevant for future applications. They keep technicalities to a minimum to make the book accessible to graduate students. With this in mind, they include in this book the basic notions and tools for high-dimensional analysis, such as large deviation, entropy, Dirichlet form, and the logarithmic Sobolev inequality. AU - Erdös, László AU - Yau, Horng ID - 567 SN - 9-781-4704-3648-3 TI - A Dynamical Approach to Random Matrix Theory VL - 28 ER - TY - JOUR AB - We study robust properties of zero sets of continuous maps f: X → ℝn. Formally, we analyze the family Z< r(f) := (g-1(0): ||g - f|| < r) of all zero sets of all continuous maps g closer to f than r in the max-norm. All of these sets are outside A := (x: |f(x)| ≥ r) and we claim that Z< r(f) is fully determined by A and an element of a certain cohomotopy group which (by a recent result) is computable whenever the dimension of X is at most 2n - 3. By considering all r > 0 simultaneously, the pointed cohomotopy groups form a persistence module-a structure leading to persistence diagrams as in the case of persistent homology or well groups. Eventually, we get a descriptor of persistent robust properties of zero sets that has better descriptive power (Theorem A) and better computability status (Theorem B) than the established well diagrams. Moreover, if we endow every point of each zero set with gradients of the perturbation, the robust description of the zero sets by elements of cohomotopy groups is in some sense the best possible (Theorem C). AU - Franek, Peter AU - Krcál, Marek ID - 568 IS - 2 JF - Homology, Homotopy and Applications SN - 15320073 TI - Persistence of zero sets VL - 19 ER - TY - JOUR AB - Most phenotypes are determined by molecular systems composed of specifically interacting molecules. However, unlike for individual components, little is known about the distributions of mutational effects of molecular systems as a whole. We ask how the distribution of mutational effects of a transcriptional regulatory system differs from the distributions of its components, by first independently, and then simultaneously, mutating a transcription factor and the associated promoter it represses. We find that the system distribution exhibits increased phenotypic variation compared to individual component distributions - an effect arising from intermolecular epistasis between the transcription factor and its DNA-binding site. In large part, this epistasis can be qualitatively attributed to the structure of the transcriptional regulatory system and could therefore be a common feature in prokaryotes. Counter-intuitively, intermolecular epistasis can alleviate the constraints of individual components, thereby increasing phenotypic variation that selection could act on and facilitating adaptive evolution. AU - Lagator, Mato AU - Sarikas, Srdjan AU - Acar, Hande AU - Bollback, Jonathan P AU - Guet, Calin C ID - 570 JF - eLife SN - 2050084X TI - Regulatory network structure determines patterns of intermolecular epistasis VL - 6 ER - TY - JOUR AB - The actomyosin ring generates force to ingress the cytokinetic cleavage furrow in animal cells, yet its filament organization and the mechanism of contractility is not well understood. We quantified actin filament order in human cells using fluorescence polarization microscopy and found that cleavage furrow ingression initiates by contraction of an equatorial actin network with randomly oriented filaments. The network subsequently gradually reoriented actin filaments along the cell equator. This strictly depended on myosin II activity, suggesting local network reorganization by mechanical forces. Cortical laser microsurgery revealed that during cytokinesis progression, mechanical tension increased substantially along the direction of the cell equator, while the network contracted laterally along the pole-to-pole axis without a detectable increase in tension. Our data suggest that an asymmetric increase in cortical tension promotes filament reorientation along the cytokinetic cleavage furrow, which might have implications for diverse other biological processes involving actomyosin rings. AU - Spira, Felix AU - Cuylen Haering, Sara AU - Mehta, Shalin AU - Samwer, Matthias AU - Reversat, Anne AU - Verma, Amitabh AU - Oldenbourg, Rudolf AU - Sixt, Michael K AU - Gerlich, Daniel ID - 569 JF - eLife SN - 2050084X TI - Cytokinesis in vertebrate cells initiates by contraction of an equatorial actomyosin network composed of randomly oriented filaments VL - 6 ER - TY - JOUR AB - Blood platelets are critical for hemostasis and thrombosis and play diverse roles during immune responses. Despite these versatile tasks in mammalian biology, their skills on a cellular level are deemed limited, mainly consisting in rolling, adhesion, and aggregate formation. Here, we identify an unappreciated asset of platelets and show that adherent platelets use adhesion receptors to mechanically probe the adhesive substrate in their local microenvironment. When actomyosin-dependent traction forces overcome substrate resistance, platelets migrate and pile up the adhesive substrate together with any bound particulate material. They use this ability to act as cellular scavengers, scanning the vascular surface for potential invaders and collecting deposited bacteria. Microbe collection by migrating platelets boosts the activity of professional phagocytes, exacerbating inflammatory tissue injury in sepsis. This assigns platelets a central role in innate immune responses and identifies them as potential targets to dampen inflammatory tissue damage in clinical scenarios of severe systemic infection. In addition to their role in thrombosis and hemostasis, platelets can also migrate to sites of infection to help trap bacteria and clear the vascular surface. AU - Gärtner, Florian R AU - Ahmad, Zerkah AU - Rosenberger, Gerhild AU - Fan, Shuxia AU - Nicolai, Leo AU - Busch, Benjamin AU - Yavuz, Gökce AU - Luckner, Manja AU - Ishikawa Ankerhold, Hellen AU - Hennel, Roman AU - Benechet, Alexandre AU - Lorenz, Michael AU - Chandraratne, Sue AU - Schubert, Irene AU - Helmer, Sebastian AU - Striednig, Bianca AU - Stark, Konstantin AU - Janko, Marek AU - Böttcher, Ralph AU - Verschoor, Admar AU - Leon, Catherine AU - Gachet, Christian AU - Gudermann, Thomas AU - Mederos Y Schnitzler, Michael AU - Pincus, Zachary AU - Iannacone, Matteo AU - Haas, Rainer AU - Wanner, Gerhard AU - Lauber, Kirsten AU - Sixt, Michael K AU - Massberg, Steffen ID - 571 IS - 6 JF - Cell Press SN - 00928674 TI - Migrating platelets are mechano scavengers that collect and bundle bacteria VL - 171 ER - TY - JOUR AB - In this review, we summarize the different biosynthesis-related pathways that contribute to the regulation of endogenous auxin in plants. We demonstrate that all known genes involved in auxin biosynthesis also have a role in root formation, from the initiation of a root meristem during embryogenesis to the generation of a functional root system with a primary root, secondary lateral root branches and adventitious roots. Furthermore, the versatile adaptation of root development in response to environmental challenges is mediated by both local and distant control of auxin biosynthesis. In conclusion, auxin homeostasis mediated by spatial and temporal regulation of auxin biosynthesis plays a central role in determining root architecture. AU - Olatunji, Damilola AU - Geelen, Danny AU - Verstraeten, Inge ID - 572 IS - 12 JF - International Journal of Molecular Sciences TI - Control of endogenous auxin levels in plant root development VL - 18 ER - TY - CHAP AB - Different distance metrics produce Voronoi diagrams with different properties. It is a well-known that on the (real) 2D plane or even on any 3D plane, a Voronoi diagram (VD) based on the Euclidean distance metric produces convex Voronoi regions. In this paper, we first show that this metric produces a persistent VD on the 2D digital plane, as it comprises digitally convex Voronoi regions and hence correctly approximates the corresponding VD on the 2D real plane. Next, we show that on a 3D digital plane D, the Euclidean metric spanning over its voxel set does not guarantee a digital VD which is persistent with the real-space VD. As a solution, we introduce a novel concept of functional-plane-convexity, which is ensured by the Euclidean metric spanning over the pedal set of D. Necessary proofs and some visual result have been provided to adjudge the merit and usefulness of the proposed concept. AU - Biswas, Ranita AU - Bhowmick, Partha ID - 5803 SN - 0302-9743 T2 - Combinatorial image analysis TI - Construction of persistent Voronoi diagram on 3D digital plane VL - 10256 ER - TY - CONF AB - Tunneling of a particle through a potential barrier remains one of the most remarkable quantum phenomena. Owing to advances in laser technology, electric fields comparable to those electrons experience in atoms are readily generated and open opportunities to dynamically investigate the process of electron tunneling through the potential barrier formed by the superposition of both laser and atomic fields. Attosecond-time and angstrom-space resolution of the strong laser-field technique allow to address fundamental questions related to tunneling, which are still open and debated: Which time is spent under the barrier and what momentum is picked up by the particle in the meantime? In this combined experimental and theoretical study we demonstrate that for strong-field ionization the leading quantum mechanical Wigner treatment for the time resolved description of tunneling is valid. We achieve a high sensitivity on the tunneling barrier and unambiguously isolate its effects by performing a differential study of two systems with almost identical tunneling geometry. Moreover, working with a low frequency laser, we essentially limit the non-adiabaticity of the process as a major source of uncertainty. The agreement between experiment and theory implies two substantial corrections with respect to the widely employed quasiclassical treatment: In addition to a non-vanishing longitudinal momentum along the laser field-direction we provide clear evidence for a non-zero tunneling time delay. This addresses also the fundamental question how the transition occurs from the tunnel barrier to free space classical evolution of the ejected electron. AU - Camus, Nicolas AU - Yakaboylu, Enderalp AU - Fechner, Lutz AU - Klaiber, Michael AU - Laux, Martin AU - Mi, Yonghao AU - Hatsagortsyan, Karen AU - Pfeifer, Thomas AU - Keitel, Cristoph AU - Moshammer, Robert ID - 313 IS - 1 SN - 17426588 TI - Experimental evidence for Wigner's tunneling time VL - 999 ER - TY - JOUR AB - The first hundred attoseconds of the electron dynamics during strong field tunneling ionization are investigated. We quantify theoretically how the electron’s classical trajectories in the continuum emerge from the tunneling process and test the results with those achieved in parallel from attoclock measurements. An especially high sensitivity on the tunneling barrier is accomplished here by comparing the momentum distributions of two atomic species of slightly deviating atomic potentials (argon and krypton) being ionized under absolutely identical conditions with near-infrared laser pulses (1300 nm). The agreement between experiment and theory provides clear evidence for a nonzero tunneling time delay and a nonvanishing longitudinal momentum of the electron at the “tunnel exit.” AU - Camus, Nicolas AU - Yakaboylu, Enderalp AU - Fechner, Lutz AU - Klaiber, Michael AU - Laux, Martin AU - Mi, Yonghao AU - Hatsagortsyan, Karen Z. AU - Pfeifer, Thomas AU - Keitel, Christoph H. AU - Moshammer, Robert ID - 6013 IS - 2 JF - Physical Review Letters SN - 0031-9007 TI - Experimental evidence for quantum tunneling time VL - 119 ER -