TY - CONF AB - In this paper, we introduce a novel method to interpret recurrent neural networks (RNNs), particularly long short-term memory networks (LSTMs) at the cellular level. We propose a systematic pipeline for interpreting individual hidden state dynamics within the network using response characterization methods. The ranked contribution of individual cells to the network's output is computed by analyzing a set of interpretable metrics of their decoupled step and sinusoidal responses. As a result, our method is able to uniquely identify neurons with insightful dynamics, quantify relationships between dynamical properties and test accuracy through ablation analysis, and interpret the impact of network capacity on a network's dynamical distribution. Finally, we demonstrate the generalizability and scalability of our method by evaluating a series of different benchmark sequential datasets. AU - Hasani, Ramin AU - Amini, Alexander AU - Lechner, Mathias AU - Naser, Felix AU - Grosu, Radu AU - Rus, Daniela ID - 6985 SN - 9781728119854 T2 - Proceedings of the International Joint Conference on Neural Networks TI - Response characterization for auditing cell dynamics in long short-term memory networks ER - TY - JOUR AB - We consider the primitive relay channel, where the source sends a message to the relay and to the destination, and the relay helps the communication by transmitting an additional message to the destination via a separate channel. Two well-known coding techniques have been introduced for this setting: decode-and-forward and compress-and-forward. In decode-and-forward, the relay completely decodes the message and sends some information to the destination; in compress-and-forward, the relay does not decode, and it sends a compressed version of the received signal to the destination using Wyner–Ziv coding. In this paper, we present a novel coding paradigm that provides an improved achievable rate for the primitive relay channel. The idea is to combine compress-and-forward and decode-and-forward via a chaining construction. We transmit over pairs of blocks: in the first block, we use compress-and-forward; and, in the second block, we use decode-and-forward. More specifically, in the first block, the relay does not decode, it compresses the received signal via Wyner–Ziv, and it sends only part of the compression to the destination. In the second block, the relay completely decodes the message, it sends some information to the destination, and it also sends the remaining part of the compression coming from the first block. By doing so, we are able to strictly outperform both compress-and-forward and decode-and-forward. Note that the proposed coding scheme can be implemented with polar codes. As such, it has the typical attractive properties of polar coding schemes, namely, quasi-linear encoding and decoding complexity, and error probability that decays at super-polynomial speed. As a running example, we take into account the special case of the erasure relay channel, and we provide a comparison between the rates achievable by our proposed scheme and the existing upper and lower bounds. AU - Mondelli, Marco AU - Hassani, S. Hamed AU - Urbanke, Rüdiger ID - 7007 IS - 10 JF - Algorithms SN - 1999-4893 TI - A new coding paradigm for the primitive relay channel VL - 12 ER - TY - CONF AB - The aim of this short note is to expound one particular issue that was discussed during the talk [10] given at the symposium ”Researches on isometries as preserver problems and related topics” at Kyoto RIMS. That is, the role of Dirac masses by describing the isometry group of various metric spaces of probability measures. This article is of survey character, and it does not contain any essentially new results.From an isometric point of view, in some cases, metric spaces of measures are similar to C(K)-type function spaces. Similarity means here that their isometries are driven by some nice transformations of the underlying space. Of course, it depends on the particular choice of the metric how nice these transformations should be. Sometimes, as we will see, being a homeomorphism is enough to generate an isometry. But sometimes we need more: the transformation must preserve the underlying distance as well. Statements claiming that isometries in questions are necessarily induced by homeomorphisms are called Banach-Stone-type results, while results asserting that the underlying transformation is necessarily an isometry are termed as isometric rigidity results.As Dirac masses can be considered as building bricks of the set of all Borel measures, a natural question arises:Is it enough to understand how an isometry acts on the set of Dirac masses? Does this action extend uniquely to all measures?In what follows, we will thoroughly investigate this question. AU - Geher, Gyorgy Pal AU - Titkos, Tamas AU - Virosztek, Daniel ID - 7035 T2 - Kyoto RIMS Kôkyûroku TI - Dirac masses and isometric rigidity VL - 2125 ER - TY - BOOK AB - Wissen Sie, was sich hinter künstlicher Intelligenz und maschinellem Lernen verbirgt? Dieses Sachbuch erklärt Ihnen leicht verständlich und ohne komplizierte Formeln die grundlegenden Methoden und Vorgehensweisen des maschinellen Lernens. Mathematisches Vorwissen ist dafür nicht nötig. Kurzweilig und informativ illustriert Lisa, die Protagonistin des Buches, diese anhand von Alltagssituationen. Ein Buch für alle, die in Diskussionen über Chancen und Risiken der aktuellen Entwicklung der künstlichen Intelligenz und des maschinellen Lernens mit Faktenwissen punkten möchten. Auch für Schülerinnen und Schüler geeignet! ED - Kersting, Kristian ED - Lampert, Christoph ED - Rothkopf, Constantin ID - 7171 SN - 978-3-658-26762-9 TI - Wie Maschinen Lernen: Künstliche Intelligenz Verständlich Erklärt ER - TY - CONF AB - The genus g(G) of a graph G is the minimum g such that G has an embedding on the orientable surface M_g of genus g. A drawing of a graph on a surface is independently even if every pair of nonadjacent edges in the drawing crosses an even number of times. The Z_2-genus of a graph G, denoted by g_0(G), is the minimum g such that G has an independently even drawing on M_g. By a result of Battle, Harary, Kodama and Youngs from 1962, the graph genus is additive over 2-connected blocks. In 2013, Schaefer and Stefankovic proved that the Z_2-genus of a graph is additive over 2-connected blocks as well, and asked whether this result can be extended to so-called 2-amalgamations, as an analogue of results by Decker, Glover, Huneke, and Stahl for the genus. We give the following partial answer. If G=G_1 cup G_2, G_1 and G_2 intersect in two vertices u and v, and G-u-v has k connected components (among which we count the edge uv if present), then |g_0(G)-(g_0(G_1)+g_0(G_2))|<=k+1. For complete bipartite graphs K_{m,n}, with n >= m >= 3, we prove that g_0(K_{m,n})/g(K_{m,n})=1-O(1/n). Similar results are proved also for the Euler Z_2-genus. We express the Z_2-genus of a graph using the minimum rank of partial symmetric matrices over Z_2; a problem that might be of independent interest. AU - Fulek, Radoslav AU - Kyncl, Jan ID - 7401 SN - 1868-8969 T2 - 35th International Symposium on Computational Geometry (SoCG 2019) TI - Z_2-Genus of graphs and minimum rank of partial symmetric matrices VL - 129 ER - TY - CHAP AB - We illustrate the ingredients of the state-of-the-art of model-based approach for the formal design and verification of cyber-physical systems. To capture the interaction between a discrete controller and its continuously evolving environment, we use the formal models of timed and hybrid automata. We explain the steps of modeling and verification in the tools Uppaal and SpaceEx using a case study based on a dual-chamber implantable pacemaker monitoring a human heart. We show how to design a model as a composition of components, how to construct models at varying levels of detail, how to establish that one model is an abstraction of another, how to specify correctness requirements using temporal logic, and how to verify that a model satisfies a logical requirement. AU - Alur, Rajeev AU - Giacobbe, Mirco AU - Henzinger, Thomas A AU - Larsen, Kim G. AU - Mikučionis, Marius ED - Steffen, Bernhard ED - Woeginger, Gerhard ID - 7453 SN - 1611-3349 T2 - Computing and Software Science TI - Continuous-time models for system design and analysis VL - 10000 ER - TY - JOUR AB - We consider an optimal control problem for an abstract nonlinear dissipative evolution equation. The differential constraint is penalized by augmenting the target functional by a nonnegative global-in-time functional which is null-minimized in the evolution equation is satisfied. Different variational settings are presented, leading to the convergence of the penalization method for gradient flows, noncyclic and semimonotone flows, doubly nonlinear evolutions, and GENERIC systems. AU - Portinale, Lorenzo AU - Stefanelli, Ulisse ID - 7550 IS - 2 JF - Advances in Mathematical Sciences and Applications SN - 1343-4373 TI - Penalization via global functionals of optimal-control problems for dissipative evolution VL - 28 ER - TY - GEN AB - There is increasing evidence that protein binding to specific sites along DNA can activate the reading out of genetic information without coming into direct physical contact with the gene. There also is evidence that these distant but interacting sites are embedded in a liquid droplet of proteins which condenses out of the surrounding solution. We argue that droplet-mediated interactions can account for crucial features of gene regulation only if the droplet is poised at a non-generic point in its phase diagram. We explore a minimal model that embodies this idea, show that this model has a natural mechanism for self-tuning, and suggest direct experimental tests. AU - Bialek, William AU - Gregor, Thomas AU - Tkačik, Gašper ID - 7552 T2 - arXiv:1912.08579 TI - Action at a distance in transcriptional regulation ER - TY - CONF AB - We present the results of a friendly competition for formal verification of continuous and hybrid systems with nonlinear continuous dynamics. The friendly competition took place as part of the workshop Applied Verification for Continuous and Hybrid Systems (ARCH) in 2019. In this year, 6 tools Ariadne, CORA, DynIbex, Flow*, Isabelle/HOL, and JuliaReach (in alphabetic order) participated. They are applied to solve reachability analysis problems on four benchmark problems, one of them with hybrid dynamics. We do not rank the tools based on the results, but show the current status and discover the potential advantages of different tools. AU - Immler, Fabian AU - Althoff, Matthias AU - Benet, Luis AU - Chapoutot, Alexandre AU - Chen, Xin AU - Forets, Marcelo AU - Geretti, Luca AU - Kochdumper, Niklas AU - Sanders, David P. AU - Schilling, Christian ID - 7576 T2 - EPiC Series in Computing TI - ARCH-COMP19 Category Report: Continuous and hybrid systems with nonlinear dynamics VL - 61 ER - TY - CONF AB - We study edge asymptotics of poissonized Plancherel-type measures on skew Young diagrams (integer partitions). These measures can be seen as generalizations of those studied by Baik--Deift--Johansson and Baik--Rains in resolving Ulam's problem on longest increasing subsequences of random permutations and the last passage percolation (corner growth) discrete versions thereof. Moreover they interpolate between said measures and the uniform measure on partitions. In the new KPZ-like 1/3 exponent edge scaling limit with logarithmic corrections, we find new probability distributions generalizing the classical Tracy--Widom GUE, GOE and GSE distributions from the theory of random matrices. AU - Betea, Dan AU - Bouttier, Jérémie AU - Nejjar, Peter AU - Vuletíc, Mirjana ID - 8175 T2 - Proceedings on the 31st International Conference on Formal Power Series and Algebraic Combinatorics TI - New edge asymptotics of skew Young diagrams via free boundaries ER - TY - CONF AB - This report presents the results of a friendly competition for formal verification of continuous and hybrid systems with linear continuous dynamics. The friendly competition took place as part of the workshop Applied Verification for Continuous and Hybrid Systems (ARCH) in 2019. In its third edition, seven tools have been applied to solve six different benchmark problems in the category for linear continuous dynamics (in alphabetical order): CORA, CORA/SX, HyDRA, Hylaa, JuliaReach, SpaceEx, and XSpeed. This report is a snapshot of the current landscape of tools and the types of benchmarks they are particularly suited for. Due to the diversity of problems, we are not ranking tools, yet the presented results provide one of the most complete assessments of tools for the safety verification of continuous and hybrid systems with linear continuous dynamics up to this date. AU - Althoff, Matthias AU - Bak, Stanley AU - Forets, Marcelo AU - Frehse, Goran AU - Kochdumper, Niklas AU - Ray, Rajarshi AU - Schilling, Christian AU - Schupp, Stefan ID - 8570 T2 - EPiC Series in Computing TI - ARCH-COMP19 Category Report: Continuous and hybrid systems with linear continuous dynamics VL - 61 ER - TY - JOUR AB - Epigenetic reprogramming is required for proper regulation of gene expression in eukaryotic organisms. In Arabidopsis, active DNA demethylation is crucial for seed viability, pollen function, and successful reproduction. The DEMETER (DME) DNA glycosylase initiates localized DNA demethylation in vegetative and central cells, so-called companion cells that are adjacent to sperm and egg gametes, respectively. In rice, the central cell genome displays local DNA hypomethylation, suggesting that active DNA demethylation also occurs in rice; however, the enzyme responsible for this process is unknown. One candidate is the rice REPRESSOR OF SILENCING 1a (ROS1a) gene, which is related to DME and is essential for rice seed viability and pollen function. Here, we report genome-wide analyses of DNA methylation in wild-type and ros1a mutant sperm and vegetative cells. We find that the rice vegetative cell genome is locally hypomethylated compared with sperm by a process that requires ROS1a activity. We show that many ROS1a target sequences in the vegetative cell are hypomethylated in the rice central cell, suggesting that ROS1a also demethylates the central cell genome. Similar to Arabidopsis, we show that sperm non-CG methylation is indirectly promoted by DNA demethylation in the vegetative cell. These results reveal that DNA glycosylase-mediated DNA demethylation processes are conserved in Arabidopsis and rice, plant species that diverged 150 million years ago. Finally, although global non-CG methylation levels of sperm and egg differ, the maternal and paternal embryo genomes show similar non-CG methylation levels, suggesting that rice gamete genomes undergo dynamic DNA methylation reprogramming after cell fusion. AU - Kim, M. Yvonne AU - Ono, Akemi AU - Scholten, Stefan AU - Kinoshita, Tetsu AU - Zilberman, Daniel AU - Okamoto, Takashi AU - Fischer, Robert L. ID - 9460 IS - 19 JF - Proceedings of the National Academy of Sciences KW - Multidisciplinary SN - 0027-8424 TI - DNA demethylation by ROS1a in rice vegetative cells promotes methylation in sperm VL - 116 ER - TY - GEN AB - More than 100 years after Grigg’s influential analysis of species’ borders, the causes of limits to species’ ranges still represent a puzzle that has never been understood with clarity. The topic has become especially important recently as many scientists have become interested in the potential for species’ ranges to shift in response to climate change—and yet nearly all of those studies fail to recognise or incorporate evolutionary genetics in a way that relates to theoretical developments. I show that range margins can be understood based on just two measurable parameters: (i) the fitness cost of dispersal—a measure of environmental heterogeneity—and (ii) the strength of genetic drift, which reduces genetic diversity. Together, these two parameters define an ‘expansion threshold’: adaptation fails when genetic drift reduces genetic diversity below that required for adaptation to a heterogeneous environment. When the key parameters drop below this expansion threshold locally, a sharp range margin forms. When they drop below this threshold throughout the species’ range, adaptation collapses everywhere, resulting in either extinction or formation of a fragmented metapopulation. Because the effects of dispersal differ fundamentally with dimension, the second parameter—the strength of genetic drift—is qualitatively different compared to a linear habitat. In two-dimensional habitats, genetic drift becomes effectively independent of selection. It decreases with ‘neighbourhood size’—the number of individuals accessible by dispersal within one generation. Moreover, in contrast to earlier predictions, which neglected evolution of genetic variance and/or stochasticity in two dimensions, dispersal into small marginal populations aids adaptation. This is because the reduction of both genetic and demographic stochasticity has a stronger effect than the cost of dispersal through increased maladaptation. The expansion threshold thus provides a novel, theoretically justified, and testable prediction for formation of the range margin and collapse of the species’ range. AU - Polechova, Jitka ID - 9839 TI - Data from: Is the sky the limit? On the expansion threshold of a species' range ER - TY - JOUR AB - Background DNA methylation of active genes, also known as gene body methylation, is found in many animal and plant genomes. Despite this, the transcriptional and developmental role of such methylation remains poorly understood. Here, we explore the dynamic range of DNA methylation in honey bee, a model organism for gene body methylation. Results Our data show that CG methylation in gene bodies globally fluctuates during honey bee development. However, these changes cause no gene expression alterations. Intriguingly, despite the global alterations, tissue-specific CG methylation patterns of complete genes or exons are rare, implying robust maintenance of genic methylation during development. Additionally, we show that CG methylation maintenance fluctuates in somatic cells, while reaching maximum fidelity in sperm cells. Finally, unlike universally present CG methylation, we discovered non-CG methylation specifically in bee heads that resembles such methylation in mammalian brain tissue. Conclusions Based on these results, we propose that gene body CG methylation can oscillate during development if it is kept to a level adequate to preserve function. Additionally, our data suggest that heightened non-CG methylation is a conserved regulator of animal nervous systems. AU - Harris, Keith D. AU - Lloyd, James P. B. AU - Domb, Katherine AU - Zilberman, Daniel AU - Zemach, Assaf ID - 9530 JF - Epigenetics and Chromatin TI - DNA methylation is maintained with high fidelity in the honey bee germline and exhibits global non-functional fluctuations during somatic development VL - 12 ER - TY - JOUR AB - Transposable elements (TEs), the movement of which can damage the genome, are epigenetically silenced in eukaryotes. Intriguingly, TEs are activated in the sperm companion cell – vegetative cell (VC) – of the flowering plant Arabidopsis thaliana. However, the extent and mechanism of this activation are unknown. Here we show that about 100 heterochromatic TEs are activated in VCs, mostly by DEMETER-catalyzed DNA demethylation. We further demonstrate that DEMETER access to some of these TEs is permitted by the natural depletion of linker histone H1 in VCs. Ectopically expressed H1 suppresses TEs in VCs by reducing DNA demethylation and via a methylation-independent mechanism. We demonstrate that H1 is required for heterochromatin condensation in plant cells and show that H1 overexpression creates heterochromatic foci in the VC progenitor cell. Taken together, our results demonstrate that the natural depletion of H1 during male gametogenesis facilitates DEMETER-directed DNA demethylation, heterochromatin relaxation, and TE activation. AU - He, Shengbo AU - Vickers, Martin AU - Zhang, Jingyi AU - Feng, Xiaoqi ID - 12192 JF - eLife KW - General Immunology and Microbiology KW - General Biochemistry KW - Genetics and Molecular Biology KW - General Medicine KW - General Neuroscience SN - 2050-084X TI - Natural depletion of histone H1 in sex cells causes DNA demethylation, heterochromatin decondensation and transposon activation VL - 8 ER - TY - JOUR AB - Meiotic crossover frequency varies within genomes, which influences genetic diversity and adaptation. In turn, genetic variation within populations can act to modify crossover frequency in cis and trans. To identify genetic variation that controls meiotic crossover frequency, we screened Arabidopsis accessions using fluorescent recombination reporters. We mapped a genetic modifier of crossover frequency in Col × Bur populations of Arabidopsis to a premature stop codon within TBP-ASSOCIATED FACTOR 4b (TAF4b), which encodes a subunit of the RNA polymerase II general transcription factor TFIID. The Arabidopsis taf4b mutation is a rare variant found in the British Isles, originating in South-West Ireland. Using genetics, genomics, and immunocytology, we demonstrate a genome-wide decrease in taf4b crossovers, with strongest reduction in the sub-telomeric regions. Using RNA sequencing (RNA-seq) from purified meiocytes, we show that TAF4b expression is meiocyte enriched, whereas its paralog TAF4 is broadly expressed. Consistent with the role of TFIID in promoting gene expression, RNA-seq of wild-type and taf4b meiocytes identified widespread transcriptional changes, including in genes that regulate the meiotic cell cycle and recombination. Therefore, TAF4b duplication is associated with acquisition of meiocyte-specific expression and promotion of germline transcription, which act directly or indirectly to elevate crossovers. This identifies a novel mode of meiotic recombination control via a general transcription factor. AU - Lawrence, Emma J. AU - Gao, Hongbo AU - Tock, Andrew J. AU - Lambing, Christophe AU - Blackwell, Alexander R. AU - Feng, Xiaoqi AU - Henderson, Ian R. ID - 12190 IS - 16 JF - Current Biology KW - General Agricultural and Biological Sciences KW - General Biochemistry KW - Genetics and Molecular Biology SN - 0960-9822 TI - Natural variation in TBP-ASSOCIATED FACTOR 4b controls meiotic crossover and germline transcription in Arabidopsis VL - 29 ER - TY - CONF AB - When can a polyomino piece of paper be folded into a unit cube? Prior work studied tree-like polyominoes, but polyominoes with holes remain an intriguing open problem. We present sufficient conditions for a polyomino with hole(s) to fold into a cube, and conditions under which cube folding is impossible. In particular, we show that all but five special simple holes guarantee foldability. AU - Aichholzer, Oswin AU - Akitaya, Hugo A AU - Cheung, Kenneth C AU - Demaine, Erik D AU - Demaine, Martin L AU - Fekete, Sandor P AU - Kleist, Linda AU - Kostitsyna, Irina AU - Löffler, Maarten AU - Masárová, Zuzana AU - Mundilova, Klara AU - Schmidt, Christiane ID - 6989 T2 - Proceedings of the 31st Canadian Conference on Computational Geometry TI - Folding polyominoes with holes into a cube ER - TY - CONF AB - In two-player games on graphs, the players move a token through a graph to produce a finite or infinite path, which determines the qualitative winner or quantitative payoff of the game. We study bidding games in which the players bid for the right to move the token. Several bidding rules were studied previously. In Richman bidding, in each round, the players simultaneously submit bids, and the higher bidder moves the token and pays the other player. Poorman bidding is similar except that the winner of the bidding pays the "bank" rather than the other player. Taxman bidding spans the spectrum between Richman and poorman bidding. They are parameterized by a constant tau in [0,1]: portion tau of the winning bid is paid to the other player, and portion 1-tau to the bank. While finite-duration (reachability) taxman games have been studied before, we present, for the first time, results on infinite-duration taxman games. It was previously shown that both Richman and poorman infinite-duration games with qualitative objectives reduce to reachability games, and we show a similar result here. Our most interesting results concern quantitative taxman games, namely mean-payoff games, where poorman and Richman bidding differ significantly. A central quantity in these games is the ratio between the two players' initial budgets. While in poorman mean-payoff games, the optimal payoff of a player depends on the initial ratio, in Richman bidding, the payoff depends only on the structure of the game. In both games the optimal payoffs can be found using (different) probabilistic connections with random-turn games in which in each turn, instead of bidding, a coin is tossed to determine which player moves. While the value with Richman bidding equals the value of a random-turn game with an un-biased coin, with poorman bidding, the bias in the coin is the initial ratio of the budgets. We give a complete classification of mean-payoff taxman games that is based on a probabilistic connection: the value of a taxman bidding game with parameter tau and initial ratio r, equals the value of a random-turn game that uses a coin with bias F(tau, r) = (r+tau * (1-r))/(1+tau). Thus, we show that Richman bidding is the exception; namely, for every tau <1, the value of the game depends on the initial ratio. Our proof technique simplifies and unifies the previous proof techniques for both Richman and poorman bidding. AU - Avni, Guy AU - Henzinger, Thomas A AU - Zikelic, Dorde ID - 6884 TI - Bidding mechanisms in graph games VL - 138 ER - TY - GEN AB - A detailed description of the two stochastic models, table of parameters, supplementary data for Figures 4 and 5, parameter dependence of the results, and an analysis on motors with different force–velocity functions (PDF) AU - Ucar, Mehmet C AU - Lipowsky, Reinhard ID - 9726 TI - Supplementary information - Collective force generation by molecular motors is determined by strain-induced unbinding ER - TY - JOUR AB - In this paper we discuss three results. The first two concern general sets of positive reach: we first characterize the reach of a closed set by means of a bound on the metric distortion between the distance measured in the ambient Euclidean space and the shortest path distance measured in the set. Secondly, we prove that the intersection of a ball with radius less than the reach with the set is geodesically convex, meaning that the shortest path between any two points in the intersection lies itself in the intersection. For our third result we focus on manifolds with positive reach and give a bound on the angle between tangent spaces at two different points in terms of the reach and the distance between the two points. AU - Boissonnat, Jean-Daniel AU - Lieutier, André AU - Wintraecken, Mathijs ID - 6671 IS - 1-2 JF - Journal of Applied and Computational Topology SN - 2367-1726 TI - The reach, metric distortion, geodesic convexity and the variation of tangent spaces VL - 3 ER - TY - JOUR AB - A representation formula for solutions of stochastic partial differential equations with Dirichlet boundary conditions is proved. The scope of our setting is wide enough to cover the general situation when the backward characteristics that appear in the usual formulation are not even defined in the Itô sense. AU - Gerencser, Mate AU - Gyöngy, István ID - 301 IS - 3 JF - Stochastic Processes and their Applications TI - A Feynman–Kac formula for stochastic Dirichlet problems VL - 129 ER - TY - JOUR AB - We consider an interacting, dilute Bose gas trapped in a harmonic potential at a positive temperature. The system is analyzed in a combination of a thermodynamic and a Gross–Pitaevskii (GP) limit where the trap frequency ω, the temperature T, and the particle number N are related by N∼ (T/ ω) 3→ ∞ while the scattering length is so small that the interaction energy per particle around the center of the trap is of the same order of magnitude as the spectral gap in the trap. We prove that the difference between the canonical free energy of the interacting gas and the one of the noninteracting system can be obtained by minimizing the GP energy functional. We also prove Bose–Einstein condensation in the following sense: The one-particle density matrix of any approximate minimizer of the canonical free energy functional is to leading order given by that of the noninteracting gas but with the free condensate wavefunction replaced by the GP minimizer. AU - Deuchert, Andreas AU - Seiringer, Robert AU - Yngvason, Jakob ID - 80 IS - 2 JF - Communications in Mathematical Physics TI - Bose–Einstein condensation in a dilute, trapped gas at positive temperature VL - 368 ER - TY - JOUR AB - Empirical data suggest that inversions in many species contain genes important for intraspecific divergence and speciation, yet mechanisms of evolution remain unclear. While genes inside an inversion are tightly linked, inversions are not static but evolve separately from the rest of the genome by new mutations, recombination within arrangements, and gene flux between arrangements. Inversion polymorphisms are maintained by different processes, for example, divergent or balancing selection, or a mix of multiple processes. Moreover, the relative roles of selection, drift, mutation, and recombination will change over the lifetime of an inversion and within its area of distribution. We believe inversions are central to the evolution of many species, but we need many more data and new models to understand the complex mechanisms involved. AU - Faria, Rui AU - Johannesson, Kerstin AU - Butlin, Roger K. AU - Westram, Anja M ID - 5911 IS - 3 JF - Trends in Ecology and Evolution SN - 01695347 TI - Evolving inversions VL - 34 ER - TY - JOUR AB - We count points over a finite field on wild character varieties,of Riemann surfaces for singularities with regular semisimple leading term. The new feature in our counting formulas is the appearance of characters of Yokonuma–Hecke algebras. Our result leads to the conjecture that the mixed Hodge polynomials of these character varieties agree with previously conjectured perverse Hodge polynomials of certain twisted parabolic Higgs moduli spaces, indicating the possibility of a P = W conjecture for a suitable wild Hitchin system. AU - Hausel, Tamas AU - Mereb, Martin AU - Wong, Michael ID - 439 IS - 10 JF - Journal of the European Mathematical Society TI - Arithmetic and representation theory of wild character varieties VL - 21 ER - TY - JOUR AB - Clinical Utility Gene Card. 1. Name of Disease (Synonyms): Pontocerebellar hypoplasia type 9 (PCH9) and spastic paraplegia-63 (SPG63). 2. OMIM# of the Disease: 615809 and 615686. 3. Name of the Analysed Genes or DNA/Chromosome Segments: AMPD2 at 1p13.3. 4. OMIM# of the Gene(s): 102771. AU - Marsh, Ashley AU - Novarino, Gaia AU - Lockhart, Paul AU - Leventer, Richard ID - 105 JF - European Journal of Human Genetics TI - CUGC for pontocerebellar hypoplasia type 9 and spastic paraplegia-63 VL - 27 ER - TY - JOUR AB - We provide an entropy formulation for porous medium-type equations with a stochastic, non-linear, spatially inhomogeneous forcing. Well-posedness and L1-contraction is obtained in the class of entropy solutions. Our scope allows for porous medium operators Δ(|u|m−1u) for all m∈(1,∞), and Hölder continuous diffusion nonlinearity with exponent 1/2. AU - Dareiotis, Konstantinos AU - Gerencser, Mate AU - Gess, Benjamin ID - 65 IS - 6 JF - Journal of Differential Equations TI - Entropy solutions for stochastic porous media equations VL - 266 ER - TY - JOUR AB - Microalgae of the genus Chlorella vulgaris are candidates for the production of lipids for biofuel production. Besides that, Chlorella vulgaris is marketed as protein and vitamin rich food additive. Its potential as a novel expression system for recombinant proteins inspired us to study its asparagine-linked oligosaccharides (N-glycans) by mass spectrometry, chromatography and gas chromatography. Oligomannosidic N-glycans with up to nine mannoses were the structures found in culture collection strains as well as several commercial products. These glycans co-eluted with plant N-glycans in the highly shape selective porous graphitic carbon chromatography. Thus, Chlorella vulgaris generates oligomannosidic N-glycans of the structural type known from land plants and animals. In fact, Man5 (Man5GlcNAc2) served as substrate for GlcNAc-transferase I and a trace of an endogenous structure with terminal GlcNAc was seen. The unusual more linear Man5 structure recently found on glycoproteins of Chlamydomonas reinhardtii occurred - if at all - in traces only. Notably, a majority of the oligomannosidic glycans was multiply O-methylated with 3-O-methyl and 3,6-di-O-methyl mannoses at the non-reducing termini. This modification has so far been neither found on plant nor vertebrate N-glycans. It’s possible immunogenicity raises concerns as to the use of C. vulgaris for production of pharmaceutical glycoproteins. AU - Mócsai, Réka AU - Figl, Rudolf AU - Troschl, Clemens AU - Strasser, Richard AU - Svehla, Elisabeth AU - Windwarder, Markus AU - Thader, Andreas AU - Altmann, Friedrich ID - 5907 IS - 1 JF - Scientific Reports TI - N-glycans of the microalga Chlorella vulgaris are of the oligomannosidic type but highly methylated VL - 9 ER - TY - JOUR AB - The interorganelle communication mediated by membrane contact sites (MCSs) is an evolutionary hallmark of eukaryotic cells. MCS connections enable the nonvesicular exchange of information between organelles and allow them to coordinate responses to changing cellular environments. In plants, the importance of MCS components in the responses to environmental stress has been widely established, but the molecular mechanisms regulating interorganelle connectivity during stress still remain opaque. In this report, we use the model plant Arabidopsis thaliana to show that ionic stress increases endoplasmic reticulum (ER)–plasma membrane (PM) connectivity by promoting the cortical expansion of synaptotagmin 1 (SYT1)-enriched ER–PM contact sites (S-EPCSs). We define differential roles for the cortical cytoskeleton in the regulation of S-EPCS dynamics and ER–PM connectivity, and we identify the accumulation of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] at the PM as a molecular signal associated with the ER–PM connectivity changes. Our study highlights the functional conservation of EPCS components and PM phosphoinositides as modulators of ER–PM connectivity in eukaryotes, and uncovers unique aspects of the spatiotemporal regulation of ER–PM connectivity in plants. AU - Lee, Eunkyoung AU - Vanneste, Steffen AU - Pérez-Sancho, Jessica AU - Benitez-Fuente, Francisco AU - Strelau, Matthew AU - Macho, Alberto P. AU - Botella, Miguel A. AU - Friml, Jiří AU - Rosado, Abel ID - 5908 IS - 4 JF - Proceedings of the National Academy of Sciences of the United States of America TI - Ionic stress enhances ER–PM connectivity via phosphoinositide-associated SYT1 contact site expansion in Arabidopsis VL - 116 ER - TY - JOUR AB - Pollinators display a remarkable diversity of foraging strategies with flowering plants, from primarily mutualistic interactions to cheating through nectar robbery. Despite numerous studies on the effect of nectar robbing on components of plant fitness, its contribution to reproductive isolation is unclear. We experimentally tested the impact of different pollinator strategies in a natural hybrid zone between two subspecies of Antirrhinum majus with alternate flower colour guides. On either side of a steep cline in flower colour between Antirrhinum majus pseudomajus (magenta) and A. m. striatum (yellow), we quantified the behaviour of all floral visitors at different time points during the flowering season. Using long-run camera surveys, we quantify the impact of nectar robbing on the number of flowers visited per inflorescence and the flower probing time. We further experimentally tested the effect of nectar robbing on female reproductive success by manipulating the intensity of robbing. While robbing increased over time the number of legitimate visitors tended to decrease concomitantly. We found that the number of flowers pollinated on a focal inflorescence decreased with the number of prior robbing events. However, in the manipulative experiment, fruit set and fruit volume did not vary significantly between low robbing and control treatments. Our findings challenge the idea that robbers have a negative impact on plant fitness through female function. This study also adds to our understanding of the components of pollinator-mediated reproductive isolation and the maintenance of Antirrhinum hybrid zones. AU - Andalo, Christophe AU - Burrus, Monique AU - Paute, Sandrine AU - Lauzeral, Christine AU - Field, David ID - 5680 IS - 1 JF - Botany Letters SN - 23818107 TI - Prevalence of legitimate pollinators and nectar robbers and the consequences for fruit set in an Antirrhinum majus hybrid zone VL - 166 ER - TY - JOUR AB - The partial representation extension problem is a recently introduced generalization of the recognition problem. A circle graph is an intersection graph of chords of a circle. We study the partial representation extension problem for circle graphs, where the input consists of a graph G and a partial representation R′ giving some predrawn chords that represent an induced subgraph of G. The question is whether one can extend R′ to a representation R of the entire graph G, that is, whether one can draw the remaining chords into a partially predrawn representation to obtain a representation of G. Our main result is an O(n3) time algorithm for partial representation extension of circle graphs, where n is the number of vertices. To show this, we describe the structure of all representations of a circle graph using split decomposition. This can be of independent interest. AU - Chaplick, Steven AU - Fulek, Radoslav AU - Klavík, Pavel ID - 5790 IS - 4 JF - Journal of Graph Theory SN - 03649024 TI - Extending partial representations of circle graphs VL - 91 ER - TY - JOUR AB - We investigate the quantum Jensen divergences from the viewpoint of joint convexity. It turns out that the set of the functions which generate jointly convex quantum Jensen divergences on positive matrices coincides with the Matrix Entropy Class which has been introduced by Chen and Tropp quite recently. AU - Virosztek, Daniel ID - 405 JF - Linear Algebra and Its Applications TI - Jointly convex quantum Jensen divergences VL - 576 ER - TY - JOUR AB - An upper bound sieve for rational points on suitable varieties isdeveloped, together with applications tocounting rational points in thin sets,to local solubility in families, and to the notion of “friable” rational pointswith respect to divisors. In the special case of quadrics, sharper estimates areobtained by developing a version of the Selberg sieve for rational points. AU - Browning, Timothy D AU - Loughran, Daniel ID - 175 IS - 8 JF - Transactions of the American Mathematical Society SN - 00029947 TI - Sieving rational points on varieties VL - 371 ER - TY - JOUR AB - We study spaces of modelled distributions with singular behaviour near the boundary of a domain that, in the context of the theory of regularity structures, allow one to give robust solution theories for singular stochastic PDEs with boundary conditions. The calculus of modelled distributions established in Hairer (Invent Math 198(2):269–504, 2014. https://doi.org/10.1007/s00222-014-0505-4) is extended to this setting. We formulate and solve fixed point problems in these spaces with a class of kernels that is sufficiently large to cover in particular the Dirichlet and Neumann heat kernels. These results are then used to provide solution theories for the KPZ equation with Dirichlet and Neumann boundary conditions and for the 2D generalised parabolic Anderson model with Dirichlet boundary conditions. In the case of the KPZ equation with Neumann boundary conditions, we show that, depending on the class of mollifiers one considers, a “boundary renormalisation” takes place. In other words, there are situations in which a certain boundary condition is applied to an approximation to the KPZ equation, but the limiting process is the Hopf–Cole solution to the KPZ equation with a different boundary condition. AU - Gerencser, Mate AU - Hairer, Martin ID - 319 IS - 3-4 JF - Probability Theory and Related Fields SN - 01788051 TI - Singular SPDEs in domains with boundaries VL - 173 ER - TY - JOUR AB - We consider real symmetric or complex hermitian random matrices with correlated entries. We prove local laws for the resolvent and universality of the local eigenvalue statistics in the bulk of the spectrum. The correlations have fast decay but are otherwise of general form. The key novelty is the detailed stability analysis of the corresponding matrix valued Dyson equation whose solution is the deterministic limit of the resolvent. AU - Ajanki, Oskari H AU - Erdös, László AU - Krüger, Torben H ID - 429 IS - 1-2 JF - Probability Theory and Related Fields SN - 01788051 TI - Stability of the matrix Dyson equation and random matrices with correlations VL - 173 ER - TY - CONF AB - Graph algorithms applied in many applications, including social networks, communication networks, VLSI design, graphics, and several others, require dynamic modifications - addition and removal of vertices and/or edges - in the graph. This paper presents a novel concurrent non-blocking algorithm to implement a dynamic unbounded directed graph in a shared-memory machine. The addition and removal operations of vertices and edges are lock-free. For a finite sized graph, the lookup operations are wait-free. Most significant component of the presented algorithm is the reachability query in a concurrent graph. The reachability queries in our algorithm are obstruction-free and thus impose minimal additional synchronization cost over other operations. We prove that each of the data structure operations are linearizable. We extensively evaluate a sample C/C++ implementation of the algorithm through a number of micro-benchmarks. The experimental results show that the proposed algorithm scales well with the number of threads and on an average provides 5 to 7x performance improvement over a concurrent graph implementation using coarse-grained locking. AU - Chatterjee, Bapi AU - Peri, Sathya AU - Sa, Muktikanta AU - Singhal, Nandini ID - 5947 SN - 978-1-4503-6094-4 T2 - ACM International Conference Proceeding Series TI - A simple and practical concurrent non-blocking unbounded graph with linearizable reachability queries ER - TY - JOUR AB - A thrackle is a graph drawn in the plane so that every pair of its edges meet exactly once: either at a common end vertex or in a proper crossing. We prove that any thrackle of n vertices has at most 1.3984n edges. Quasi-thrackles are defined similarly, except that every pair of edges that do not share a vertex are allowed to cross an odd number of times. It is also shown that the maximum number of edges of a quasi-thrackle on n vertices is [Formula presented](n−1), and that this bound is best possible for infinitely many values of n. AU - Fulek, Radoslav AU - Pach, János ID - 5857 IS - 4 JF - Discrete Applied Mathematics SN - 0166218X TI - Thrackles: An improved upper bound VL - 259 ER - TY - JOUR AB - Understanding the thermodynamics of the duplication process is a fundamental step towards a comprehensive physical theory of biological systems. However, the immense complexity of real cells obscures the fundamental tensions between energy gradients and entropic contributions that underlie duplication. The study of synthetic, feasible systems reproducing part of the key ingredients of living entities but overcoming major sources of biological complexity is of great relevance to deepen the comprehension of the fundamental thermodynamic processes underlying life and its prevalence. In this paper an abstract—yet realistic—synthetic system made of small synthetic protocell aggregates is studied in detail. A fundamental relation between free energy and entropic gradients is derived for a general, non-equilibrium scenario, setting the thermodynamic conditions for the occurrence and prevalence of duplication phenomena. This relation sets explicitly how the energy gradients invested in creating and maintaining structural—and eventually, functional—elements of the system must always compensate the entropic gradients, whose contributions come from changes in the translational, configurational, and macrostate entropies, as well as from dissipation due to irreversible transitions. Work/energy relations are also derived, defining lower bounds on the energy required for the duplication event to take place. A specific example including real ternary emulsions is provided in order to grasp the orders of magnitude involved in the problem. It is found that the minimal work invested over the system to trigger a duplication event is around ~ 10−13J , which results, in the case of duplication of all the vesicles contained in a liter of emulsion, in an amount of energy around ~ 1kJ . Without aiming to describe a truly biological process of duplication, this theoretical contribution seeks to explicitly define and identify the key actors that participate in it. AU - Corominas-Murtra, Bernat ID - 5944 IS - 1 JF - Life TI - Thermodynamics of duplication thresholds in synthetic protocell systems VL - 9 ER - TY - JOUR AB - Protein micropatterning has become an important tool for many biomedical applications as well as in academic research. Current techniques that allow to reduce the feature size of patterns below 1 μm are, however, often costly and require sophisticated equipment. We present here a straightforward and convenient method to generate highly condensed nanopatterns of proteins without the need for clean room facilities or expensive equipment. Our approach is based on nanocontact printing and allows for the fabrication of protein patterns with feature sizes of 80 nm and periodicities down to 140 nm. This was made possible by the use of the material X-poly(dimethylsiloxane) (X-PDMS) in a two-layer stamp layout for protein printing. In a proof of principle, different proteins at various scales were printed and the pattern quality was evaluated by atomic force microscopy (AFM) and super-resolution fluorescence microscopy. AU - Lindner, Marco AU - Tresztenyak, Aliz AU - Fülöp, Gergö AU - Jahr, Wiebke AU - Prinz, Adrian AU - Prinz, Iris AU - Danzl, Johann G AU - Schütz, Gerhard J. AU - Sevcsik, Eva ID - 6029 JF - Frontiers in Chemistry TI - A fast and simple contact printing approach to generate 2D protein nanopatterns VL - 6 ER - TY - JOUR AB - We give a construction allowing us to build local renormalized solutions to general quasilinear stochastic PDEs within the theory of regularity structures, thus greatly generalizing the recent results of [1, 5, 11]. Loosely speaking, our construction covers quasilinear variants of all classes of equations for which the general construction of [3, 4, 7] applies, including in particular one‐dimensional systems with KPZ‐type nonlinearities driven by space‐time white noise. In a less singular and more specific case, we furthermore show that the counterterms introduced by the renormalization procedure are given by local functionals of the solution. The main feature of our construction is that it allows exploitation of a number of existing results developed for the semilinear case, so that the number of additional arguments it requires is relatively small. AU - Gerencser, Mate AU - Hairer, Martin ID - 6028 IS - 9 JF - Communications on Pure and Applied Mathematics TI - A solution theory for quasilinear singular SPDEs VL - 72 ER - TY - CONF AB - We study the termination problem for nondeterministic probabilistic programs. We consider the bounded termination problem that asks whether the supremum of the expected termination time over all schedulers is bounded. First, we show that ranking supermartingales (RSMs) are both sound and complete for proving bounded termination over nondeterministic probabilistic programs. For nondeterministic probabilistic programs a previous result claimed that RSMs are not complete for bounded termination, whereas our result corrects the previous flaw and establishes completeness with a rigorous proof. Second, we present the first sound approach to establish lower bounds on expected termination time through RSMs. AU - Fu, Hongfei AU - Chatterjee, Krishnendu ID - 5948 T2 - International Conference on Verification, Model Checking, and Abstract Interpretation TI - Termination of nondeterministic probabilistic programs VL - 11388 ER - TY - JOUR AB - In developing organisms, spatially prescribed cell identities are thought to be determined by the expression levels of multiple genes. Quantitative tests of this idea, however, require a theoretical framework capable of exposing the rules and precision of cell specification over developmental time. We use the gap gene network in the early fly embryo as an example to show how expression levels of the four gap genes can be jointly decoded into an optimal specification of position with 1% accuracy. The decoder correctly predicts, with no free parameters, the dynamics of pair-rule expression patterns at different developmental time points and in various mutant backgrounds. Precise cellular identities are thus available at the earliest stages of development, contrasting the prevailing view of positional information being slowly refined across successive layers of the patterning network. Our results suggest that developmental enhancers closely approximate a mathematically optimal decoding strategy. AU - Petkova, Mariela D. AU - Tkacik, Gasper AU - Bialek, William AU - Wieschaus, Eric F. AU - Gregor, Thomas ID - 5945 IS - 4 JF - Cell TI - Optimal decoding of cellular identities in a genetic network VL - 176 ER - TY - JOUR AB - The hairpin instability of a jet in a crossflow (JICF) for a low jet-to-crossflow velocity ratio is investigated experimentally for a velocity ratio range of R ∈ (0.14, 0.75) and crossflow Reynolds numbers ReD ∈ (260, 640). From spectral analysis we characterize the Strouhal number and amplitude of the hairpin instability as a function of R and ReD. We demonstrate that the dynamics of the hairpins is well described by the Landau model, and, hence, that the instability occurs through Hopf bifurcation, similarly to other hydrodynamical oscillators such as wake behind different bluff bodies. Using the Landau model, we determine the precise threshold values of hairpin shedding. We also study the spatial dependence of this hydrodynamical instability, which shows a global behaviour. AU - Klotz, Lukasz AU - Gumowski, Konrad AU - Wesfreid, José Eduardo ID - 5943 JF - Journal of Fluid Mechanics TI - Experiments on a jet in a crossflow in the low-velocity-ratio regime VL - 863 ER - TY - CONF AB - Static program analyzers are increasingly effective in checking correctness properties of programs and reporting any errors found, often in the form of error traces. However, developers still spend a significant amount of time on debugging. This involves processing long error traces in an effort to localize a bug to a relatively small part of the program and to identify its cause. In this paper, we present a technique for automated fault localization that, given a program and an error trace, efficiently narrows down the cause of the error to a few statements. These statements are then ranked in terms of their suspiciousness. Our technique relies only on the semantics of the given program and does not require any test cases or user guidance. In experiments on a set of C benchmarks, we show that our technique is effective in quickly isolating the cause of error while out-performing other state-of-the-art fault-localization techniques. AU - Christakis, Maria AU - Heizmann, Matthias AU - Mansur, Muhammad Numair AU - Schilling, Christian AU - Wüstholz, Valentin ID - 6042 T2 - 25th International Conference on Tools and Algorithms for the Construction and Analysis of Systems TI - Semantic fault localization and suspiciousness ranking VL - 11427 ER - TY - CONF AB - We present JuliaReach, a toolbox for set-based reachability analysis of dynamical systems. JuliaReach consists of two main packages: Reachability, containing implementations of reachability algorithms for continuous and hybrid systems, and LazySets, a standalone library that implements state-of-the-art algorithms for calculus with convex sets. The library offers both concrete and lazy set representations, where the latter stands for the ability to delay set computations until they are needed. The choice of the programming language Julia and the accompanying documentation of our toolbox allow researchers to easily translate set-based algorithms from mathematics to software in a platform-independent way, while achieving runtime performance that is comparable to statically compiled languages. Combining lazy operations in high dimensions and explicit computations in low dimensions, JuliaReach can be applied to solve complex, large-scale problems. AU - Bogomolov, Sergiy AU - Forets, Marcelo AU - Frehse, Goran AU - Potomkin, Kostiantyn AU - Schilling, Christian ID - 6035 KW - reachability analysis KW - hybrid systems KW - lazy computation SN - 9781450362825 T2 - Proceedings of the 22nd International Conference on Hybrid Systems: Computation and Control TI - JuliaReach: A toolbox for set-based reachability VL - 22 ER - TY - JOUR AB - Expansion microscopy is a relatively new approach to super-resolution imaging that uses expandable hydrogels to isotropically increase the physical distance between fluorophores in biological samples such as cell cultures or tissue slices. The classic gel recipe results in an expansion factor of ~4×, with a resolution of 60–80 nm. We have recently developed X10 microscopy, which uses a gel that achieves an expansion factor of ~10×, with a resolution of ~25 nm. Here, we provide a step-by-step protocol for X10 expansion microscopy. A typical experiment consists of seven sequential stages: (i) immunostaining, (ii) anchoring, (iii) polymerization, (iv) homogenization, (v) expansion, (vi) imaging, and (vii) validation. The protocol presented here includes recommendations for optimization, pitfalls and their solutions, and detailed guidelines that should increase reproducibility. Although our protocol focuses on X10 expansion microscopy, we detail which of these suggestions are also applicable to classic fourfold expansion microscopy. We exemplify our protocol using primary hippocampal neurons from rats, but our approach can be used with other primary cells or cultured cell lines of interest. This protocol will enable any researcher with basic experience in immunostainings and access to an epifluorescence microscope to perform super-resolution microscopy with X10. The procedure takes 3 d and requires ~5 h of actively handling the sample for labeling and expansion, and another ~3 h for imaging and analysis. AU - Truckenbrodt, Sven M AU - Sommer, Christoph M AU - Rizzoli, Silvio O AU - Danzl, Johann G ID - 6052 IS - 3 JF - Nature Protocols TI - A practical guide to optimization in X10 expansion microscopy VL - 14 ER - TY - JOUR AB - Non-canonical Wnt signaling plays a central role for coordinated cell polarization and directed migration in metazoan development. While spatiotemporally restricted activation of non-canonical Wnt-signaling drives cell polarization in epithelial tissues, it remains unclear whether such instructive activity is also critical for directed mesenchymal cell migration. Here, we developed a light-activated version of the non-canonical Wnt receptor Frizzled 7 (Fz7) to analyze how restricted activation of non-canonical Wnt signaling affects directed anterior axial mesendoderm (prechordal plate, ppl) cell migration within the zebrafish gastrula. We found that Fz7 signaling is required for ppl cell protrusion formation and migration and that spatiotemporally restricted ectopic activation is capable of redirecting their migration. Finally, we show that uniform activation of Fz7 signaling in ppl cells fully rescues defective directed cell migration in fz7 mutant embryos. Together, our findings reveal that in contrast to the situation in epithelial cells, non-canonical Wnt signaling functions permissively rather than instructively in directed mesenchymal cell migration during gastrulation. AU - Capek, Daniel AU - Smutny, Michael AU - Tichy, Alexandra Madelaine AU - Morri, Maurizio AU - Janovjak, Harald L AU - Heisenberg, Carl-Philipp J ID - 6025 JF - eLife TI - Light-activated Frizzled7 reveals a permissive role of non-canonical wnt signaling in mesendoderm cell migration VL - 8 ER - TY - JOUR AB - The evolution of new species is made easier when traits under divergent ecological selection are also mating cues. Such ecological mating cues are now considered more common than previously thought, but we still know little about the genetic changes underlying their evolution or more generally about the genetic basis for assortative mating behaviors. Both tight physical linkage and the existence of large-effect preference loci will strengthen genetic associations between behavioral and ecological barriers, promoting the evolution of assortative mating. The warning patterns of Heliconius melpomene and H. cydno are under disruptive selection due to increased predation of nonmimetic hybrids and are used during mate recognition. We carried out a genome-wide quantitative trait locus (QTL) analysis of preference behaviors between these species and showed that divergent male preference has a simple genetic basis. We identify three QTLs that together explain a large proportion (approximately 60%) of the difference in preference behavior observed between the parental species. One of these QTLs is just 1.2 (0-4.8) centiMorgans (cM) from the major color pattern gene optix, and, individually, all three have a large effect on the preference phenotype. Genomic divergence between H. cydno and H. melpomene is high but broadly heterogenous, and admixture is reduced at the preference-optix color pattern locus but not the other preference QTLs. The simple genetic architecture we reveal will facilitate the evolution and maintenance of new species despite ongoing gene flow by coupling behavioral and ecological aspects of reproductive isolation. AU - Merrill, Richard M. AU - Rastas, Pasi AU - Martin, Simon H. AU - Melo Hurtado, Maria C AU - Barker, Sarah AU - Davey, John AU - Mcmillan, W. Owen AU - Jiggins, Chris D. ID - 6022 IS - 2 JF - PLoS Biology TI - Genetic dissection of assortative mating behavior VL - 17 ER - TY - JOUR AB - Multicellular development requires coordinated cell polarization relative to body axes, and translation to oriented cell division 1–3 . In plants, it is unknown how cell polarities are connected to organismal axes and translated to division. Here, we identify Arabidopsis SOSEKI proteins that integrate apical–basal and radial organismal axes to localize to polar cell edges. Localization does not depend on tissue context, requires cell wall integrity and is defined by a transferrable, protein-specific motif. A Domain of Unknown Function in SOSEKI proteins resembles the DIX oligomerization domain in the animal Dishevelled polarity regulator. The DIX-like domain self-interacts and is required for edge localization and for influencing division orientation, together with a second domain that defines the polar membrane domain. Our work shows that SOSEKI proteins locally interpret global polarity cues and can influence cell division orientation. Furthermore, this work reveals that, despite fundamental differences, cell polarity mechanisms in plants and animals converge on a similar protein domain. AU - Yoshida, Saiko AU - Van Der Schuren, Alja AU - Van Dop, Maritza AU - Van Galen, Luc AU - Saiga, Shunsuke AU - Adibi, Milad AU - Möller, Barbara AU - Ten Hove, Colette A. AU - Marhavy, Peter AU - Smith, Richard AU - Friml, Jiří AU - Weijers, Dolf ID - 6023 IS - 2 JF - Nature Plants TI - A SOSEKI-based coordinate system interprets global polarity cues in arabidopsis VL - 5 ER - TY - JOUR AB - Recent technical developments in the fields of quantum electromechanics and optomechanics have spawned nanoscale mechanical transducers with the sensitivity to measure mechanical displacements at the femtometre scale and the ability to convert electromagnetic signals at the single photon level. A key challenge in this field is obtaining strong coupling between motion and electromagnetic fields without adding additional decoherence. Here we present an electromechanical transducer that integrates a high-frequency (0.42 GHz) hypersonic phononic crystal with a superconducting microwave circuit. The use of a phononic bandgap crystal enables quantum-level transduction of hypersonic mechanical motion and concurrently eliminates decoherence caused by acoustic radiation. Devices with hypersonic mechanical frequencies provide a natural pathway for integration with Josephson junction quantum circuits, a leading quantum computing technology, and nanophotonic systems capable of optical networking and distributing quantum information. AU - Kalaee, Mahmoud AU - Mirhosseini, Mohammad AU - Dieterle, Paul B. AU - Peruzzo, Matilda AU - Fink, Johannes M AU - Painter, Oskar ID - 6053 IS - 4 JF - Nature Nanotechnology SN - 1748-3387 TI - Quantum electromechanics of a hypersonic crystal VL - 14 ER - TY - JOUR AB - We answer a question of David Hilbert: given two circles it is not possible in general to construct their centers using only a straightedge. On the other hand, we give infinitely many families of pairs of circles for which such construction is possible. AU - Akopyan, Arseniy AU - Fedorov, Roman ID - 6050 JF - Proceedings of the American Mathematical Society TI - Two circles and only a straightedge VL - 147 ER - TY - GEN AU - Merrill, Richard M. AU - Rastas, Pasi AU - Martin, Simon H. AU - Melo Hurtado, Maria C AU - Barker, Sarah AU - Davey, John AU - Mcmillan, W. Owen AU - Jiggins, Chris D. ID - 9801 TI - Raw behavioral data ER - TY - JOUR AB - Both classical and recent studies suggest that chromosomal inversion polymorphisms are important in adaptation and speciation. However, biases in discovery and reporting of inversions make it difficult to assess their prevalence and biological importance. Here, we use an approach based on linkage disequilibrium among markers genotyped for samples collected across a transect between contrasting habitats to detect chromosomal rearrangements de novo. We report 17 polymorphic rearrangements in a single locality for the coastal marine snail, Littorina saxatilis. Patterns of diversity in the field and of recombination in controlled crosses provide strong evidence that at least the majority of these rearrangements are inversions. Most show clinal changes in frequency between habitats, suggestive of divergent selection, but only one appears to be fixed for different arrangements in the two habitats. Consistent with widespread evidence for balancing selection on inversion polymorphisms, we argue that a combination of heterosis and divergent selection can explain the observed patterns and should be considered in other systems spanning environmental gradients. AU - Faria, Rui AU - Chaube, Pragya AU - Morales, Hernán E. AU - Larsson, Tomas AU - Lemmon, Alan R. AU - Lemmon, Emily M. AU - Rafajlović, Marina AU - Panova, Marina AU - Ravinet, Mark AU - Johannesson, Kerstin AU - Westram, Anja M AU - Butlin, Roger K. ID - 6095 IS - 6 JF - Molecular Ecology SN - 0962-1083 TI - Multiple chromosomal rearrangements in a hybrid zone between Littorina saxatilis ecotypes VL - 28 ER - TY - JOUR AB - In this article it is shown that large systems with many interacting units endowing multiple phases display self-oscillations in the presence of linear feedback between the control and order parameters, where an Andronov–Hopf bifurcation takes over the phase transition. This is simply illustrated through the mean field Landau theory whose feedback dynamics turn out to be described by the Van der Pol equation and it is then validated for the fully connected Ising model following heat bath dynamics. Despite its simplicity, this theory accounts potentially for a rich range of phenomena: here it is applied to describe in a stylized way (i) excess demand-price cycles due to strong herding in a simple agent-based market model; (ii) congestion waves in queuing networks triggered by user feedback to delays in overloaded conditions; and (iii) metabolic network oscillations resulting from cell growth control in a bistable phenotypic landscape. AU - De Martino, Daniele ID - 6049 IS - 4 JF - Journal of Physics A: Mathematical and Theoretical TI - Feedback-induced self-oscillations in large interacting systems subjected to phase transitions VL - 52 ER - TY - JOUR AB - Cortical networks are characterized by sparse connectivity, with synapses found at only a subset of axo-dendritic contacts. Yet within these networks, neurons can exhibit high connection probabilities, suggesting that cell-intrinsic factors, not proximity, determine connectivity. Here, we identify ephrin-B3 (eB3) as a factor that determines synapse density by mediating a cell-cell competition that requires ephrin-B-EphB signaling. In a microisland culture system designed to isolate cell-cell competition, we find that eB3 determines winning and losing neurons in a contest for synapses. In a Mosaic Analysis with Double Markers (MADM) genetic mouse model system in vivo the relative levels of eB3 control spine density in layer 5 and 6 neurons. MADM cortical neurons in vitro reveal that eB3 controls synapse density independently of action potential-driven activity. Our findings illustrate a new class of competitive mechanism mediated by trans-synaptic organizing proteins which control the number of synapses neurons receive relative to neighboring neurons. AU - Henderson, Nathan T. AU - Le Marchand, Sylvain J. AU - Hruska, Martin AU - Hippenmeyer, Simon AU - Luo, Liqun AU - Dalva, Matthew B. ID - 6091 JF - eLife TI - Ephrin-B3 controls excitatory synapse density through cell-cell competition for EphBs VL - 8 ER - TY - JOUR AB - Sudden stress often triggers diverse, temporally structured gene expression responses in microbes, but it is largely unknown how variable in time such responses are and if genes respond in the same temporal order in every single cell. Here, we quantified timing variability of individual promoters responding to sublethal antibiotic stress using fluorescent reporters, microfluidics, and time‐lapse microscopy. We identified lower and upper bounds that put definite constraints on timing variability, which varies strongly among promoters and conditions. Timing variability can be interpreted using results from statistical kinetics, which enable us to estimate the number of rate‐limiting molecular steps underlying different responses. We found that just a few critical steps control some responses while others rely on dozens of steps. To probe connections between different stress responses, we then tracked the temporal order and response time correlations of promoter pairs in individual cells. Our results support that, when bacteria are exposed to the antibiotic nitrofurantoin, the ensuing oxidative stress and SOS responses are part of the same causal chain of molecular events. In contrast, under trimethoprim, the acid stress response and the SOS response are part of different chains of events running in parallel. Our approach reveals fundamental constraints on gene expression timing and provides new insights into the molecular events that underlie the timing of stress responses. AU - Mitosch, Karin AU - Rieckh, Georg AU - Bollenbach, Mark Tobias ID - 6046 IS - 2 JF - Molecular systems biology TI - Temporal order and precision of complex stress responses in individual bacteria VL - 15 ER - TY - JOUR AB - Hosts can alter their strategy towards pathogens during their lifetime; that is, they can show phenotypic plasticity in immunity or life history. Immune priming is one such example, where a previous encounter with a pathogen confers enhanced protection upon secondary challenge, resulting in reduced pathogen load (i.e., resistance) and improved host survival. However, an initial encounter might also enhance tolerance, particularly to less virulent opportunistic pathogens that establish persistent infections. In this scenario, individuals are better able to reduce the negative fecundity consequences that result from a high pathogen burden. Finally, previous exposure may also lead to life‐history adjustments, such as terminal investment into reproduction. Using different Drosophila melanogaster host genotypes and two bacterial pathogens, Lactococcus lactis and Pseudomonas entomophila, we tested whether previous exposure results in resistance or tolerance and whether it modifies immune gene expression during an acute‐phase infection (one day post‐challenge). We then asked whether previous pathogen exposure affects chronic‐phase pathogen persistence and longer‐term survival (28 days post‐challenge). We predicted that previous exposure would increase host resistance to an early stage bacterial infection while it might come at a cost to host fecundity tolerance. We reasoned that resistance would be due in part to stronger immune gene expression after challenge. We expected that previous exposure would improve long‐term survival, that it would reduce infection persistence, and we expected to find genetic variation in these responses. We found that previous exposure to P. entomophila weakened host resistance to a second infection independent of genotype and had no effect on immune gene expression. Fecundity tolerance showed genotypic variation but was not influenced by previous exposure. However, L. lactis persisted as a chronic infection, whereas survivors cleared the more pathogenic P. entomophila infection. To our knowledge, this is the first study that addresses host tolerance to bacteria in relation to previous exposure, taking a multi‐faceted approach to address the topic. Our results suggest that previous exposure comes with transient costs to resistance during the early stage of infection in this host–pathogen system and that infection persistence may be bacterium‐specific. AU - Kutzer, Megan AU - Kurtz, Joachim AU - Armitage, Sophie A.O. ID - 6105 IS - 4 JF - Journal of Animal Ecology SN - 00218790 TI - A multi-faceted approach testing the effects of previous bacterial exposure on resistance and tolerance VL - 88 ER - TY - JOUR AB - P-Glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are two efflux transporters at the blood–brain barrier (BBB), which effectively restrict brain distribution of diverse drugs, such as tyrosine kinase inhibitors. There is a crucial need for pharmacological ABCB1 and ABCG2 inhibition protocols for a more effective treatment of brain diseases. In the present study, seven marketed drugs (osimertinib, erlotinib, nilotinib, imatinib, lapatinib, pazopanib, and cyclosporine A) and one nonmarketed drug (tariquidar), with known in vitro ABCB1/ABCG2 inhibitory properties, were screened for their inhibitory potency at the BBB in vivo. Positron emission tomography (PET) using the model ABCB1/ABCG2 substrate [11C]erlotinib was performed in mice. Tested inhibitors were administered as i.v. bolus injections at 30 min before the start of the PET scan, followed by a continuous i.v. infusion for the duration of the PET scan. Five of the tested drugs increased total distribution volume of [11C]erlotinib in the brain (VT,brain) compared to vehicle-treated animals (tariquidar, + 69%; erlotinib, + 19% and +23% for the 21.5 mg/kg and the 43 mg/kg dose, respectively; imatinib, + 22%; lapatinib, + 25%; and cyclosporine A, + 49%). For all drugs, increases in [11C]erlotinib brain distribution were lower than in Abcb1a/b(−/−)Abcg2(−/−) mice (+149%), which suggested that only partial ABCB1/ABCG2 inhibition was reached at the mouse BBB. The plasma concentrations of the tested drugs at the time of the PET scan were higher than clinically achievable plasma concentrations. Some of the tested drugs led to significant increases in blood radioactivity concentrations measured at the end of the PET scan (erlotinib, + 103% and +113% for the 21.5 mg/kg and the 43 mg/kg dose, respectively; imatinib, + 125%; and cyclosporine A, + 101%), which was most likely caused by decreased hepatobiliary excretion of radioactivity. Taken together, our data suggest that some marketed tyrosine kinase inhibitors may be repurposed to inhibit ABCB1 and ABCG2 at the BBB. From a clinical perspective, moderate increases in brain delivery despite the administration of high i.v. doses as well as peripheral drug–drug interactions due to transporter inhibition in clearance organs question the translatability of this concept. AU - Traxl, Alexander AU - Mairinger, Severin AU - Filip, Thomas AU - Sauberer, Michael AU - Stanek, Johann AU - Poschner, Stefan AU - Jäger, Walter AU - Zoufal, Viktoria AU - Novarino, Gaia AU - Tournier, Nicolas AU - Bauer, Martin AU - Wanek, Thomas AU - Langer, Oliver ID - 6088 IS - 3 JF - Molecular Pharmaceutics TI - Inhibition of ABCB1 and ABCG2 at the mouse blood-brain barrier with marketed drugs to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib VL - 16 ER - TY - JOUR AB - Cell fate specification by lateral inhibition typically involves contact signaling through the Delta-Notch signaling pathway. However, whether this is the only signaling mode mediating lateral inhibition remains unclear. Here we show that in zebrafish oogenesis, a group of cells within the granulosa cell layer at the oocyte animal pole acquire elevated levels of the transcriptional coactivator TAZ in their nuclei. One of these cells, the future micropyle precursor cell (MPC), accumulates increasingly high levels of nuclear TAZ and grows faster than its surrounding cells, mechanically compressing those cells, which ultimately lose TAZ from their nuclei. Strikingly, relieving neighbor-cell compression by MPC ablation or aspiration restores nuclear TAZ accumulation in neighboring cells, eventually leading to MPC re-specification from these cells. Conversely, MPC specification is defective in taz−/− follicles. These findings uncover a novel mode of lateral inhibition in cell fate specification based on mechanical signals controlling TAZ activity. AU - Xia, Peng AU - Gütl, Daniel J AU - Zheden, Vanessa AU - Heisenberg, Carl-Philipp J ID - 6087 IS - 6 JF - Cell TI - Lateral inhibition in cell specification mediated by mechanical signals modulating TAZ activity VL - 176 ER - TY - GEN AB - 1. Hosts can alter their strategy towards pathogens during their lifetime, i.e., they can show phenotypic plasticity in immunity or life history. Immune priming is one such example, where a previous encounter with a pathogen confers enhanced protection upon secondary challenge, resulting in reduced pathogen load (i.e. resistance) and improved host survival. However, an initial encounter might also enhance tolerance, particularly to less virulent opportunistic pathogens that establish persistent infections. In this scenario, individuals are better able to reduce the negative fitness consequences that result from a high pathogen load. Finally, previous exposure may also lead to life history adjustments, such as terminal investment into reproduction. 2. Using different Drosophila melanogaster host genotypes and two bacterial pathogens, Lactococcus lactis and Pseudomonas entomophila, we tested if previous exposure results in resistance or tolerance and whether it modifies immune gene expression during an acute-phase infection (one day post-challenge). We then asked if previous pathogen exposure affects chronic-phase pathogen persistence and longer-term survival (28 days post-challenge). 3. We predicted that previous exposure would increase host resistance to an early stage bacterial infection while it might come at a cost to host fecundity tolerance. We reasoned that resistance would be due in part to stronger immune gene expression after challenge. We expected that previous exposure would improve long-term survival, that it would reduce infection persistence, and we expected to find genetic variation in these responses. 4. We found that previous exposure to P. entomophila weakened host resistance to a second infection independent of genotype and had no effect on immune gene expression. Fecundity tolerance showed genotypic variation but was not influenced by previous exposure. However, L. lactis persisted as a chronic infection, whereas survivors cleared the more pathogenic P. entomophila infection. 5. To our knowledge, this is the first study that addresses host tolerance to bacteria in relation to previous exposure, taking a multi-faceted approach to address the topic. Our results suggest that previous exposure comes with transient costs to resistance during the early stage of infection in this host-pathogen system and that infection persistence may be bacterium-specific. AU - Kutzer, Megan AU - Kurtz, Joachim AU - Armitage, Sophie A.O. ID - 9806 TI - Data from: A multi-faceted approach testing the effects of previous bacterial exposure on resistance and tolerance ER - TY - JOUR AB - We show that linear analytic cocycles where all Lyapunov exponents are negative infinite are nilpotent. For such one-frequency cocycles we show that they can be analytically conjugated to an upper triangular cocycle or a Jordan normal form. As a consequence, an arbitrarily small analytic perturbation leads to distinct Lyapunov exponents. Moreover, in the one-frequency case where the th Lyapunov exponent is finite and the st negative infinite, we obtain a simple criterion for domination in which case there is a splitting into a nilpotent part and an invertible part. AU - Sadel, Christian AU - Xu, Disheng ID - 6086 IS - 4 JF - Ergodic Theory and Dynamical Systems TI - Singular analytic linear cocycles with negative infinite Lyapunov exponents VL - 39 ER - TY - JOUR AB - Light is a union of electric and magnetic fields, and nowhere is the complex relationship between these fields more evident than in the near fields of nanophotonic structures. There, complicated electric and magnetic fields varying over subwavelength scales are generally present, which results in photonic phenomena such as extraordinary optical momentum, superchiral fields, and a complex spatial evolution of optical singularities. An understanding of such phenomena requires nanoscale measurements of the complete optical field vector. Although the sensitivity of near- field scanning optical microscopy to the complete electromagnetic field was recently demonstrated, a separation of different components required a priori knowledge of the sample. Here, we introduce a robust algorithm that can disentangle all six electric and magnetic field components from a single near-field measurement without any numerical modeling of the structure. As examples, we unravel the fields of two prototypical nanophotonic structures: a photonic crystal waveguide and a plasmonic nanowire. These results pave the way for new studies of complex photonic phenomena at the nanoscale and for the design of structures that optimize their optical behavior. AU - Le Feber, B. AU - Sipe, J. E. AU - Wulf, Matthias AU - Kuipers, L. AU - Rotenberg, N. ID - 6102 IS - 1 JF - Light: Science and Applications SN - 20955545 TI - A full vectorial mapping of nanophotonic light fields VL - 8 ER - TY - JOUR AB - Abiotic stress poses constant challenges for plant survival and is a serious problem for global agricultural productivity. On a molecular level, stress conditions result in elevation of reactive oxygen species (ROS) production causing oxidative stress associated with oxidation of proteins and nucleic acids as well as impairment of membrane functions. Adaptation of root growth to ROS accumulation is facilitated through modification of auxin and cytokinin hormone homeostasis. Here, we report that in Arabidopsis root meristem, ROS-induced changes of auxin levels correspond to decreased abundance of PIN auxin efflux carriers at the plasma membrane (PM). Specifically, increase in H2O2 levels affects PIN2 endocytic recycling. We show that the PIN2 intracellular trafficking during adaptation to oxidative stress requires the function of the ADP-ribosylation factor (ARF)-guanine-nucleotide exchange factor (GEF) BEN1, an actin-associated regulator of the trafficking from the PM to early endosomes and, presumably, indirectly, trafficking to the vacuoles. We propose that H2O2 levels affect the actin dynamics thus modulating ARF-GEF-dependent trafficking of PIN2. This mechanism provides a way how root growth acclimates to stress and adapts to a changing environment. AU - Zwiewka, Marta AU - Bielach, Agnieszka AU - Tamizhselvan, Prashanth AU - Madhavan, Sharmila AU - Ryad, Eman Elrefaay AU - Tan, Shutang AU - Hrtyan, Mónika AU - Dobrev, Petre AU - Vanková, Radomira AU - Friml, Jiří AU - Tognetti, Vanesa B. ID - 6104 IS - 2 JF - Plant and Cell Physiology SN - 0032-0781 TI - Root adaptation to H2O2-induced oxidative stress by ARF-GEF BEN1- and cytoskeleton-mediated PIN2 trafficking VL - 60 ER - TY - JOUR AB - The formation of self-organized patterns is key to the morphogenesis of multicellular organisms, although a comprehensive theory of biological pattern formation is still lacking. Here, we propose a minimal model combining tissue mechanics with morphogen turnover and transport to explore routes to patterning. Our active description couples morphogen reaction and diffusion, which impact cell differentiation and tissue mechanics, to a two-phase poroelastic rheology, where one tissue phase consists of a poroelastic cell network and the other one of a permeating extracellular fluid, which provides a feedback by actively transporting morphogens. While this model encompasses previous theories approximating tissues to inert monophasic media, such as Turing’s reaction–diffusion model, it overcomes some of their key limitations permitting pattern formation via any two-species biochemical kinetics due to mechanically induced cross-diffusion flows. Moreover, we describe a qualitatively different advection-driven Keller–Segel instability which allows for the formation of patterns with a single morphogen and whose fundamental mode pattern robustly scales with tissue size. We discuss the potential relevance of these findings for tissue morphogenesis. AU - Recho, Pierre AU - Hallou, Adrien AU - Hannezo, Edouard B ID - 6191 IS - 12 JF - Proceedings of the National Academy of Sciences of the United States of America SN - 00278424 TI - Theory of mechanochemical patterning in biphasic biological tissues VL - 116 ER - TY - JOUR AB - Increased levels of the chemokine CCL2 in cancer patients are associated with poor prognosis. Experimental evidence suggests that CCL2 correlates with inflammatory monocyte recruitment and induction of vascular activation, but the functionality remains open. Here, we show that endothelial Ccr2 facilitates pulmonary metastasis using an endothelial-specific Ccr2-deficient mouse model (Ccr2ecKO). Similar levels of circulating monocytes and equal leukocyte recruitment to metastatic lesions of Ccr2ecKO and Ccr2fl/fl littermates were observed. The absence of endothelial Ccr2 strongly reduced pulmonary metastasis, while the primary tumor growth was unaffected. Despite a comparable cytokine milieu in Ccr2ecKO and Ccr2fl/fl littermates the absence of vascular permeability induction was observed only in Ccr2ecKO mice. CCL2 stimulation of pulmonary endothelial cells resulted in increased phosphorylation of MLC2, endothelial cell retraction, and vascular leakiness that was blocked by an addition of a CCR2 inhibitor. These data demonstrate that endothelial CCR2 expression is required for tumor cell extravasation and pulmonary metastasis. Implications: The findings provide mechanistic insight into how CCL2–CCR2 signaling in endothelial cells promotes their activation through myosin light chain phosphorylation, resulting in endothelial retraction and enhanced tumor cell migration and metastasis. AU - Roblek, Marko AU - Protsyuk, Darya AU - Becker, Paul F. AU - Stefanescu, Cristina AU - Gorzelanny, Christian AU - Glaus Garzon, Jesus F. AU - Knopfova, Lucia AU - Heikenwalder, Mathias AU - Luckow, Bruno AU - Schneider, Stefan W. AU - Borsig, Lubor ID - 6190 IS - 3 JF - Molecular Cancer Research SN - 15417786 TI - CCL2 is a vascular permeability factor inducing CCR2-dependent endothelial retraction during lung metastasis VL - 17 ER - TY - JOUR AB - Great care is needed when interpreting claims about the genetic basis of human variation based on data from genome-wide association studies. AU - Barton, Nicholas H AU - Hermisson, Joachim AU - Nordborg, Magnus ID - 6230 JF - eLife TI - Why structure matters VL - 8 ER - TY - JOUR AB - The boundary behaviour of solutions of stochastic PDEs with Dirichlet boundary conditions can be surprisingly—and in a sense, arbitrarily—bad: as shown by Krylov[ SIAM J. Math. Anal.34(2003) 1167–1182], for any α>0 one can find a simple 1-dimensional constant coefficient linear equation whose solution at the boundary is not α-Hölder continuous.We obtain a positive counterpart of this: under some mild regularity assumptions on the coefficients, solutions of semilinear SPDEs on C1 domains are proved to be α-Hölder continuous up to the boundary with some α>0. AU - Gerencser, Mate ID - 6232 IS - 2 JF - Annals of Probability SN - 00911798 TI - Boundary regularity of stochastic PDEs VL - 47 ER - TY - JOUR AB - Gravitropism is an adaptive response that orients plant growth parallel to the gravity vector. Asymmetric distribution of the phytohormone auxin is a necessary prerequisite to the tropic bending both in roots and shoots. During hypocotyl gravitropic response, the PIN3 auxin transporter polarizes within gravity-sensing cells to redirect intercellular auxin fluxes. First gravity-induced PIN3 polarization to the bottom cell mem- branes leads to the auxin accumulation at the lower side of the organ, initiating bending and, later, auxin feedback-mediated repolarization restores symmetric auxin distribution to terminate bending. Here, we per- formed a forward genetic screen to identify regulators of both PIN3 polarization events during gravitropic response. We searched for mutants with defective PIN3 polarizations based on easy-to-score morphological outputs of decreased or increased gravity-induced hypocotyl bending. We identified the number of hypocotyl reduced bending (hrb) and hypocotyl hyperbending (hhb) mutants, revealing that reduced bending corre- lated typically with defective gravity-induced PIN3 relocation whereas all analyzed hhb mutants showed defects in the second, auxin-mediated PIN3 relocation. Next-generation sequencing-aided mutation map- ping identified several candidate genes, including SCARECROW and ACTIN2, revealing roles of endodermis specification and actin cytoskeleton in the respective gravity- and auxin-induced PIN polarization events. The hypocotyl gravitropism screen thus promises to provide novel insights into mechanisms underlying cell polarity and plant adaptive development. AU - Rakusová, Hana AU - Han, Huibin AU - Valošek, Petr AU - Friml, Jiří ID - 6262 IS - 6 JF - The Plant Journal SN - 0960-7412 TI - Genetic screen for factors mediating PIN polarization in gravistimulated Arabidopsis thaliana hypocotyls VL - 98 ER - TY - JOUR AB - Cell-cell and cell-glycocalyx interactions under flow are important for the behaviour of circulating cells in blood and lymphatic vessels. However, such interactions are not well understood due in part to a lack of tools to study them in defined environments. Here, we develop a versatile in vitro platform for the study of cell-glycocalyx interactions in well-defined physical and chemical settings under flow. Our approach is demonstrated with the interaction between hyaluronan (HA, a key component of the endothelial glycocalyx) and its cell receptor CD44. We generate HA brushes in situ within a microfluidic device, and demonstrate the tuning of their physical (thickness and softness) and chemical (density of CD44 binding sites) properties using characterisation with reflection interference contrast microscopy (RICM) and application of polymer theory. We highlight the interactions of HA brushes with CD44-displaying beads and cells under flow. Observations of CD44+ beads on a HA brush with RICM enabled the 3-dimensional trajectories to be generated, and revealed interactions in the form of stop and go phases with reduced rolling velocity and reduced distance between the bead and the HA brush, compared to uncoated beads. Combined RICM and bright-field microscopy of CD44+ AKR1 T-lymphocytes revealed complementary information about the dynamics of cell rolling and cell morphology, and highlighted the formation of tethers and slings, as they interacted with a HA brush under flow. This platform can readily incorporate more complex models of the glycocalyx, and should permit the study of how mechanical and biochemical factors are orchestrated to enable highly selective blood cell-vessel wall interactions under flow. AU - Davies, Heather S. AU - Baranova, Natalia S. AU - El Amri, Nouha AU - Coche-Guérente, Liliane AU - Verdier, Claude AU - Bureau, Lionel AU - Richter, Ralf P. AU - Débarre, Delphine ID - 6297 JF - Matrix Biology SN - 0945-053X TI - An integrated assay to probe endothelial glycocalyx-blood cell interactions under flow in mechanically and biochemically well-defined environments VL - 78-79 ER - TY - JOUR AB - An asymptotic formula is established for the number of rational points of bounded anticanonical height which lie on a certain Zariskiopen subset of an arbitrary smooth biquadratic hypersurface in sufficiently many variables. The proof uses the Hardy–Littlewood circle method. AU - Browning, Timothy D AU - Hu, L.Q. ID - 6310 JF - Advances in Mathematics SN - 00018708 TI - Counting rational points on biquadratic hypersurfaces VL - 349 ER - TY - JOUR AB - Nitrate regulation of root stem cell activity is auxin-dependent. AU - Wang, Y AU - Gong, Z AU - Friml, Jiří AU - Zhang, J ID - 6261 IS - 1 JF - Plant Physiology SN - 0032-0889 TI - Nitrate modulates the differentiation of root distal stem cells VL - 180 ER - TY - JOUR AB - Chronic overuse of common pharmaceuticals, e.g. acetaminophen (paracetamol), often leads to the development of acute liver failure (ALF). This study aimed to elucidate the effect of cultured mesenchymal stem cells (MSCs) proteome on the onset of liver damage and regeneration dynamics in animals with ALF induced by acetaminophen, to test the liver protective efficacy of MSCs proteome depending on the oxygen tension in cell culture, and to blueprint protein components responsible for the effect. Protein compositions prepared from MSCs cultured in mild hypoxic (5% and 10% O2) and normal (21% O2) conditions were used to treat ALF induced in mice by injection of acetaminophen. To test the effect of reduced oxygen tension in cell culture on resulting MSCs proteome content we applied a combination of high performance liquid chromatography and mass-spectrometry (LC–MS/MS) for the identification of proteins in lysates of MSCs cultured at different O2 levels. The treatment of acetaminophen-administered animals with proteins released from cultured MSCs resulted in the inhibition of inflammatory reactions in damaged liver; the area of hepatocyte necrosis being reduced in the first 24 h. Compositions obtained from MSCs cultured at lower O2 level were shown to be more potent than a composition prepared from normoxic cells. A comparative characterization of protein pattern and identification of individual components done by a cytokine assay and proteomics analysis of protein compositions revealed that even moderate hypoxia produces discrete changes in the expression of various subsets of proteins responsible for intracellular respiration and cell signaling. The application of proteins prepared from MSCs grown in vitro at reduced oxygen tension significantly accelerates healing process in damaged liver tissue. The proteomics data obtained for different preparations offer new information about the potential candidates in the MSCs protein repertoire sensitive to oxygen tension in culture medium, which can be involved in the generalized mechanisms the cells use to respond to acute liver failure. AU - Temnov, Andrey Alexandrovich AU - Rogov, Konstantin Arkadevich AU - Sklifas, Alla Nikolaevna AU - Klychnikova, Elena Valerievna AU - Hartl, Markus AU - Djinovic-Carugo, Kristina AU - Charnagalov, Alexej ID - 6352 JF - Molecular Biology Reports SN - 03014851 TI - Protective properties of the cultured stem cell proteome studied in an animal model of acetaminophen-induced acute liver failure ER - TY - JOUR AB - High-speed optical telecommunication is enabled by wavelength-division multiplexing, whereby hundreds of individually stabilized lasers encode information within a single-mode optical fibre. Higher bandwidths require higher total optical power, but the power sent into the fibre is limited by optical nonlinearities within the fibre, and energy consumption by the light sources starts to become a substantial cost factor1. Optical frequency combs have been suggested to remedy this problem by generating numerous discrete, equidistant laser lines within a monolithic device; however, at present their stability and coherence allow them to operate only within small parameter ranges2,3,4. Here we show that a broadband frequency comb realized through the electro-optic effect within a high-quality whispering-gallery-mode resonator can operate at low microwave and optical powers. Unlike the usual third-order Kerr nonlinear optical frequency combs, our combs rely on the second-order nonlinear effect, which is much more efficient. Our result uses a fixed microwave signal that is mixed with an optical-pump signal to generate a coherent frequency comb with a precisely determined carrier separation. The resonant enhancement enables us to work with microwave powers that are three orders of magnitude lower than those in commercially available devices. We emphasize the practical relevance of our results to high rates of data communication. To circumvent the limitations imposed by nonlinear effects in optical communication fibres, one has to solve two problems: to provide a compact and fully integrated, yet high-quality and coherent, frequency comb generator; and to calculate nonlinear signal propagation in real time5. We report a solution to the first problem. AU - Rueda Sanchez, Alfredo R AU - Sedlmeir, Florian AU - Kumari, Madhuri AU - Leuchs, Gerd AU - Schwefel, Harald G.L. ID - 6348 IS - 7752 JF - Nature SN - 00280836 TI - Resonant electro-optic frequency comb VL - 568 ER - TY - JOUR AB - Hippocampal activity patterns representing movement trajectories are reactivated in immobility and sleep periods, a process associated with memory recall, consolidation, and decision making. It is thought that only fixed, behaviorally relevant patterns can be reactivated, which are stored across hippocampal synaptic connections. To test whether some generalized rules govern reactivation, we examined trajectory reactivation following non-stereotypical exploration of familiar open-field environments. We found that random trajectories of varying lengths and timescales were reactivated, resembling that of Brownian motion of particles. The animals’ behavioral trajectory did not follow Brownian diffusion demonstrating that the exact behavioral experience is not reactivated. Therefore, hippocampal circuits are able to generate random trajectories of any recently active map by following diffusion dynamics. This ability of hippocampal circuits to generate representations of all behavioral outcome combinations, experienced or not, may underlie a wide variety of hippocampal-dependent cognitive functions such as learning, generalization, and planning. AU - Stella, Federico AU - Baracskay, Peter AU - O'Neill, Joseph AU - Csicsvari, Jozsef L ID - 6338 JF - Neuron TI - Hippocampal reactivation of random trajectories resembling Brownian diffusion VL - 102 ER - TY - JOUR AB - We consider the motion of a droplet bouncing on a vibrating bath of the same fluid in the presence of a central potential. We formulate a rotation symmetry-reduced description of this system, which allows for the straightforward application of dynamical systems theory tools. As an illustration of the utility of the symmetry reduction, we apply it to a model of the pilot-wave system with a central harmonic force. We begin our analysis by identifying local bifurcations and the onset of chaos. We then describe the emergence of chaotic regions and their merging bifurcations, which lead to the formation of a global attractor. In this final regime, the droplet’s angular momentum spontaneously changes its sign as observed in the experiments of Perrard et al. AU - Budanur, Nazmi B AU - Fleury, Marc ID - 5878 IS - 1 JF - Chaos: An Interdisciplinary Journal of Nonlinear Science SN - 1054-1500 TI - State space geometry of the chaotic pilot-wave hydrodynamics VL - 29 ER - TY - JOUR AB - Cryo-electron tomography (cryo-ET) provides unprecedented insights into the molecular constituents of biological environments. In combination with an image processing method called subtomogram averaging (STA), detailed 3D structures of biological molecules can be obtained in large, irregular macromolecular assemblies or in situ, without the need for purification. The contextual meta-information these methods also provide, such as a protein’s location within its native environment, can then be combined with functional data. This allows the derivation of a detailed view on the physiological or pathological roles of proteins from the molecular to cellular level. Despite their tremendous potential in in situ structural biology, cryo-ET and STA have been restricted by methodological limitations, such as the low obtainable resolution. Exciting progress now allows one to reach unprecedented resolutions in situ, ranging in optimal cases beyond the nanometer barrier. Here, I review current frontiers and future challenges in routinely determining high-resolution structures in in situ environments using cryo-ET and STA. AU - Schur, Florian KM ID - 6343 IS - 10 JF - Current Opinion in Structural Biology SN - 0959-440X TI - Toward high-resolution in situ structural biology with cryo-electron tomography and subtomogram averaging VL - 58 ER - TY - CONF AB - Safety and security are major concerns in the development of Cyber-Physical Systems (CPS). Signal temporal logic (STL) was proposedas a language to specify and monitor the correctness of CPS relativeto formalized requirements. Incorporating STL into a developmentprocess enables designers to automatically monitor and diagnosetraces, compute robustness estimates based on requirements, andperform requirement falsification, leading to productivity gains inverification and validation activities; however, in its current formSTL is agnostic to the input/output classification of signals, andthis negatively impacts the relevance of the analysis results.In this paper we propose to make the interface explicit in theSTL language by introducing input/output signal declarations. Wethen define new measures of input vacuity and output robustnessthat better reflect the nature of the system and the specification in-tent. The resulting framework, which we call interface-aware signaltemporal logic (IA-STL), aids verification and validation activities.We demonstrate the benefits of IA-STL on several CPS analysisactivities: (1) robustness-driven sensitivity analysis, (2) falsificationand (3) fault localization. We describe an implementation of our en-hancement to STL and associated notions of robustness and vacuityin a prototype extension of Breach, a MATLAB®/Simulink®toolboxfor CPS verification and validation. We explore these methodologi-cal improvements and evaluate our results on two examples fromthe automotive domain: a benchmark powertrain control systemand a hydrogen fuel cell system. AU - Ferrere, Thomas AU - Nickovic, Dejan AU - Donzé, Alexandre AU - Ito, Hisahiro AU - Kapinski, James ID - 6428 SN - 9781450362825 T2 - Proceedings of the 2019 22nd ACM International Conference on Hybrid Systems: Computation and Control TI - Interface-aware signal temporal logic ER - TY - JOUR AB - This paper investigates the use of fundamental solutions for animating detailed linear water surface waves. We first propose an analytical solution for efficiently animating circular ripples in closed form. We then show how to adapt the method of fundamental solutions (MFS) to create ambient waves interacting with complex obstacles. Subsequently, we present a novel wavelet-based discretization which outperforms the state of the art MFS approach for simulating time-varying water surface waves with moving obstacles. Our results feature high-resolution spatial details, interactions with complex boundaries, and large open ocean domains. Our method compares favorably with previous work as well as known analytical solutions. We also present comparisons between our method and real world examples. AU - Schreck, Camille AU - Hafner, Christian AU - Wojtan, Christopher J ID - 6442 IS - 4 JF - ACM Transactions on Graphics TI - Fundamental solutions for water wave animation VL - 38 ER - TY - JOUR AB - Phase-field methods have long been used to model the flow of immiscible fluids. Their ability to naturally capture interface topological changes is widely recognized, but their accuracy in simulating flows of real fluids in practical geometries is not established. We here quantitatively investigate the convergence of the phase-field method to the sharp-interface limit with simulations of two-phase pipe flow. We focus on core-annular flows, in which a highly viscous fluid is lubricated by a less viscous fluid, and validate our simulations with an analytic laminar solution, a formal linear stability analysis and also in the fully nonlinear regime. We demonstrate the ability of the phase-field method to accurately deal with non-rectangular geometry, strong advection, unsteady fluctuations and large viscosity contrast. We argue that phase-field methods are very promising for quantitatively studying moderately turbulent flows, especially at high concentrations of the disperse phase. AU - Song, Baofang AU - Plana, Carlos AU - Lopez Alonso, Jose M AU - Avila, Marc ID - 6413 JF - International Journal of Multiphase Flow SN - 03019322 TI - Phase-field simulation of core-annular pipe flow VL - 117 ER - TY - JOUR AB - Characterizing the fitness landscape, a representation of fitness for a large set of genotypes, is key to understanding how genetic information is interpreted to create functional organisms. Here we determined the evolutionarily-relevant segment of the fitness landscape of His3, a gene coding for an enzyme in the histidine synthesis pathway, focusing on combinations of amino acid states found at orthologous sites of extant species. Just 15% of amino acids found in yeast His3 orthologues were always neutral while the impact on fitness of the remaining 85% depended on the genetic background. Furthermore, at 67% of sites, amino acid replacements were under sign epistasis, having both strongly positive and negative effect in different genetic backgrounds. 46% of sites were under reciprocal sign epistasis. The fitness impact of amino acid replacements was influenced by only a few genetic backgrounds but involved interaction of multiple sites, shaping a rugged fitness landscape in which many of the shortest paths between highly fit genotypes are inaccessible. AU - Pokusaeva, Victoria AU - Usmanova, Dinara R. AU - Putintseva, Ekaterina V. AU - Espinar, Lorena AU - Sarkisyan, Karen AU - Mishin, Alexander S. AU - Bogatyreva, Natalya S. AU - Ivankov, Dmitry AU - Akopyan, Arseniy AU - Avvakumov, Sergey AU - Povolotskaya, Inna S. AU - Filion, Guillaume J. AU - Carey, Lucas B. AU - Kondrashov, Fyodor ID - 6419 IS - 4 JF - PLoS Genetics TI - An experimental assay of the interactions of amino acids from orthologous sequences shaping a complex fitness landscape VL - 15 ER - TY - JOUR AB - Polycomb group (PcG) proteins play critical roles in the epigenetic inheritance of cell fate. The Polycomb Repressive Complexes PRC1 and PRC2 catalyse distinct chromatin modifications to enforce gene silencing, but how transcriptional repression is propagated through mitotic cell divisions remains a key unresolved question. Using reversible tethering of PcG proteins to ectopic sites in mouse embryonic stem cells, here we show that PRC1 can trigger transcriptional repression and Polycomb-dependent chromatin modifications. We find that canonical PRC1 (cPRC1), but not variant PRC1, maintains gene silencing through cell division upon reversal of tethering. Propagation of gene repression is sustained by cis-acting histone modifications, PRC2-mediated H3K27me3 and cPRC1-mediated H2AK119ub1, promoting a sequence-independent feedback mechanism for PcG protein recruitment. Thus, the distinct PRC1 complexes present in vertebrates can differentially regulate epigenetic maintenance of gene silencing, potentially enabling dynamic heritable responses to complex stimuli. Our findings reveal how PcG repression is potentially inherited in vertebrates. AU - Moussa, Hagar F. AU - Bsteh, Daniel AU - Yelagandula, Ramesh AU - Pribitzer, Carina AU - Stecher, Karin AU - Bartalska, Katarina AU - Michetti, Luca AU - Wang, Jingkui AU - Zepeda-Martinez, Jorge A. AU - Elling, Ulrich AU - Stuckey, Jacob I. AU - James, Lindsey I. AU - Frye, Stephen V. AU - Bell, Oliver ID - 6412 IS - 1 JF - Nature Communications TI - Canonical PRC1 controls sequence-independent propagation of Polycomb-mediated gene silencing VL - 10 ER - TY - JOUR AB - Ant invasions are often harmful to native species communities. Their pathogens and host disease defense mechanisms may be one component of their devastating success. First, they can introduce harmful diseases to their competitors in the introduced range, to which they themselves are tolerant. Second, their supercolonial social structure of huge multi-queen nest networks means that they will harbor a broad pathogen spectrum and high pathogen load while remaining resilient, unlike the smaller, territorial colonies of the native species. Thus, it is likely that invasive ants act as a disease reservoir, promoting their competitive advantage and invasive success. AU - Cremer, Sylvia ID - 6415 JF - Current Opinion in Insect Science SN - 22145745 TI - Pathogens and disease defense of invasive ants VL - 33 ER - TY - GEN AU - Pokusaeva, Victoria AU - Usmanova, Dinara R. AU - Putintseva, Ekaterina V. AU - Espinar, Lorena AU - Sarkisyan, Karen AU - Mishin, Alexander S. AU - Bogatyreva, Natalya S. AU - Ivankov, Dmitry AU - Akopyan, Arseniy AU - Avvakumov, Sergey AU - Povolotskaya, Inna S. AU - Filion, Guillaume J. AU - Carey, Lucas B. AU - Kondrashov, Fyodor ID - 9790 TI - A statistical summary of segment libraries and sequencing results ER - TY - GEN AU - Pokusaeva, Victoria AU - Usmanova, Dinara R. AU - Putintseva, Ekaterina V. AU - Espinar, Lorena AU - Sarkisyan, Karen AU - Mishin, Alexander S. AU - Bogatyreva, Natalya S. AU - Ivankov, Dmitry AU - Akopyan, Arseniy AU - Povolotskaya, Inna S. AU - Filion, Guillaume J. AU - Carey, Lucas B. AU - Kondrashov, Fyodor ID - 9797 TI - A statistical summary of segment libraries and sequencing results ER - TY - GEN AU - Pokusaeva, Victoria AU - Usmanova, Dinara R. AU - Putintseva, Ekaterina V. AU - Espinar, Lorena AU - Sarkisyan, Karen AU - Mishin, Alexander S. AU - Bogatyreva, Natalya S. AU - Ivankov, Dmitry AU - Akopyan, Arseniy AU - Avvakumov, Sergey AU - Povolotskaya, Inna S. AU - Filion, Guillaume J. AU - Carey, Lucas B. AU - Kondrashov, Fyodor ID - 9789 TI - Multiple alignment of His3 orthologues ER - TY - CONF AB - A controller is a device that interacts with a plant. At each time point,it reads the plant’s state and issues commands with the goal that the plant oper-ates optimally. Constructing optimal controllers is a fundamental and challengingproblem. Machine learning techniques have recently been successfully applied totrain controllers, yet they have limitations. Learned controllers are monolithic andhard to reason about. In particular, it is difficult to add features without retraining,to guarantee any level of performance, and to achieve acceptable performancewhen encountering untrained scenarios. These limitations can be addressed bydeploying quantitative run-timeshieldsthat serve as a proxy for the controller.At each time point, the shield reads the command issued by the controller andmay choose to alter it before passing it on to the plant. We show how optimalshields that interfere as little as possible while guaranteeing a desired level ofcontroller performance, can be generated systematically and automatically usingreactive synthesis. First, we abstract the plant by building a stochastic model.Second, we consider the learned controller to be a black box. Third, we mea-surecontroller performanceandshield interferenceby two quantitative run-timemeasures that are formally defined using weighted automata. Then, the problemof constructing a shield that guarantees maximal performance with minimal inter-ference is the problem of finding an optimal strategy in a stochastic2-player game“controller versus shield” played on the abstract state space of the plant with aquantitative objective obtained from combining the performance and interferencemeasures. We illustrate the effectiveness of our approach by automatically con-structing lightweight shields for learned traffic-light controllers in various roadnetworks. The shields we generate avoid liveness bugs, improve controller per-formance in untrained and changing traffic situations, and add features to learnedcontrollers, such as giving priority to emergency vehicles. AU - Avni, Guy AU - Bloem, Roderick AU - Chatterjee, Krishnendu AU - Henzinger, Thomas A AU - Konighofer, Bettina AU - Pranger, Stefan ID - 6462 SN - 0302-9743 T2 - 31st International Conference on Computer-Aided Verification TI - Run-time optimization for learned controllers through quantitative games VL - 11561 ER - TY - JOUR AB - Thermalizing quantum systems are conventionallydescribed by statistical mechanics at equilib-rium. However, not all systems fall into this category, with many-body localization providinga generic mechanism for thermalization to fail in strongly disordered systems. Many-bodylocalized (MBL) systems remain perfect insulators at nonzero temperature, which do notthermalize and therefore cannot be describedusing statistical mechanics. This Colloquiumreviews recent theoretical and experimental advances in studies of MBL systems, focusing onthe new perspective provided by entanglement and nonequilibrium experimental probes suchas quantum quenches. Theoretically, MBL systems exhibit a new kind of robust integrability: anextensive set of quasilocal integrals of motion emerges, which provides an intuitive explanationof the breakdown of thermalization. A description based on quasilocal integrals of motion isused to predict dynamical properties of MBL systems, such as the spreading of quantumentanglement, the behavior of local observables, and the response to external dissipativeprocesses. Furthermore, MBL systems can exhibit eigenstate transitions and quantum ordersforbidden in thermodynamic equilibrium. An outline isgiven of the current theoretical under-standing of the quantum-to-classical transitionbetween many-body localized and ergodic phasesand anomalous transport in the vicinity of that transition. Experimentally, synthetic quantumsystems, which are well isolated from an external thermal reservoir, provide natural platforms forrealizing the MBL phase. Recent experiments with ultracold atoms, trapped ions, superconductingqubits, and quantum materials, in which different signatures of many-body localization have beenobserved, are reviewed. This Colloquium concludes by listing outstanding challenges andpromising future research directions. AU - Abanin, Dmitry A. AU - Altman, Ehud AU - Bloch, Immanuel AU - Serbyn, Maksym ID - 6477 IS - 2 JF - Reviews of Modern Physics SN - 1539-0756 TI - Colloquium: Many-body localization, thermalization, and entanglement VL - 91 ER - TY - JOUR AB - One of the most striking and consistent results in speciation genomics is the heterogeneous divergence observed across the genomes of closely related species. This pattern was initially attributed to different levels of gene exchange—with divergence preserved at loci generating a barrier to gene flow but homogenized at unlinked neutral loci. Although there is evidence to support this model, it is now recognized that interpreting patterns of divergence across genomes is not so straightforward. One problem is that heterogenous divergence between populations can also be generated by other processes (e.g. recurrent selective sweeps or background selection) without any involvement of differential gene flow. Thus, integrated studies that identify which loci are likely subject to divergent selection are required to shed light on the interplay between selection and gene flow during the early phases of speciation. In this issue of Molecular Ecology, Rifkin et al. (2019) confront this challenge using a pair of sister morning glory species. They wisely design their sampling to take the geographic context of individuals into account, including geographically isolated (allopatric) and co‐occurring (sympatric) populations. This enabled them to show that individuals are phenotypically less differentiated in sympatry. They also found that the loci that resist introgression are enriched for those most differentiated in allopatry and loci that exhibit signals of divergent selection. One great strength of the study is the combination of methods from population genetics and molecular evolution, including the development of a model to simultaneously infer admixture proportions and selfing rates. AU - Field, David AU - Fraisse, Christelle ID - 6466 IS - 7 JF - Molecular ecology TI - Breaking down barriers in morning glories VL - 28 ER - TY - JOUR AB - Tight control over protein degradation is a fundamental requirement for cells to respond rapidly to various stimuli and adapt to a fluctuating environment. Here we develop a versatile, easy-to-handle library of destabilizing tags (degrons) for the precise regulation of protein expression profiles in mammalian cells by modulating target protein half-lives in a predictable manner. Using the well-established tetracycline gene-regulation system as a model, we show that the dynamics of protein expression can be tuned by fusing appropriate degron tags to gene regulators. Next, we apply this degron library to tune a synthetic pulse-generating circuit in mammalian cells. With this toolbox we establish a set of pulse generators with tailored pulse lengths and magnitudes of protein expression. This methodology will prove useful in the functional roles of essential proteins, fine-tuning of gene-expression systems, and enabling a higher complexity in the design of synthetic biological systems in mammalian cells. AU - Chassin, Hélène AU - Müller, Marius AU - Tigges, Marcel AU - Scheller, Leo AU - Lang, Moritz AU - Fussenegger, Martin ID - 6465 IS - 1 JF - Nature Communications TI - A modular degron library for synthetic circuits in mammalian cells VL - 10 ER - TY - JOUR AB - Fitness interactions between mutations can influence a population’s evolution in many different ways. While epistatic effects are difficult to measure precisely, important information is captured by the mean and variance of log fitnesses for individuals carrying different numbers of mutations. We derive predictions for these quantities from a class of simple fitness landscapes, based on models of optimizing selection on quantitative traits. We also explore extensions to the models, including modular pleiotropy, variable effect sizes, mutational bias and maladaptation of the wild type. We illustrate our approach by reanalysing a large dataset of mutant effects in a yeast snoRNA (small nucleolar RNA). Though characterized by some large epistatic effects, these data give a good overall fit to the non-epistatic null model, suggesting that epistasis might have limited influence on the evolutionary dynamics in this system. We also show how the amount of epistasis depends on both the underlying fitness landscape and the distribution of mutations, and so is expected to vary in consistent ways between new mutations, standing variation and fixed mutations. AU - Fraisse, Christelle AU - Welch, John J. ID - 6467 IS - 4 JF - Biology Letters SN - 17449561 TI - The distribution of epistasis on simple fitness landscapes VL - 15 ER - TY - JOUR AB - Investigating neuronal activity using genetically encoded Ca2+ indicators in behaving animals is hampered by inaccuracies in spike inference from fluorescent tracers. Here we combine two‐photon [Ca2+] imaging with cell‐attached recordings, followed by post hoc determination of the expression level of GCaMP6f, to explore how it affects the amplitude, kinetics and temporal summation of somatic [Ca2+] transients in mouse hippocampal pyramidal cells (PCs). The amplitude of unitary [Ca2+] transients (evoked by a single action potential) negatively correlates with GCaMP6f expression, but displays large variability even among PCs with similarly low expression levels. The summation of fluorescence signals is frequency‐dependent, supralinear and also shows remarkable cell‐to‐cell variability. We performed experimental data‐based simulations and found that spike inference error rates using MLspike depend strongly on unitary peak amplitudes and GCaMP6f expression levels. We provide simple methods for estimating the unitary [Ca2+] transients in individual weakly GCaMP6f‐expressing PCs, with which we achieve spike inference error rates of ∼5%. AU - Éltes, Tímea AU - Szoboszlay, Miklos AU - Szigeti, Margit Katalin AU - Nusser, Zoltan ID - 6470 IS - 11 JF - Journal of Physiology SN - 00223751 TI - Improved spike inference accuracy by estimating the peak amplitude of unitary [Ca2+] transients in weakly GCaMP6f-expressing hippocampal pyramidal cells VL - 597 ER - TY - CONF AB - We present two algorithmic approaches for synthesizing linear hybrid automata from experimental data. Unlike previous approaches, our algorithms work without a template and generate an automaton with nondeterministic guards and invariants, and with an arbitrary number and topology of modes. They thus construct a succinct model from the data and provide formal guarantees. In particular, (1) the generated automaton can reproduce the data up to a specified tolerance and (2) the automaton is tight, given the first guarantee. Our first approach encodes the synthesis problem as a logical formula in the theory of linear arithmetic, which can then be solved by an SMT solver. This approach minimizes the number of modes in the resulting model but is only feasible for limited data sets. To address scalability, we propose a second approach that does not enforce to find a minimal model. The algorithm constructs an initial automaton and then iteratively extends the automaton based on processing new data. Therefore the algorithm is well-suited for online and synthesis-in-the-loop applications. The core of the algorithm is a membership query that checks whether, within the specified tolerance, a given data set can result from the execution of a given automaton. We solve this membership problem for linear hybrid automata by repeated reachability computations. We demonstrate the effectiveness of the algorithm on synthetic data sets and on cardiac-cell measurements. AU - Garcia Soto, Miriam AU - Henzinger, Thomas A AU - Schilling, Christian AU - Zeleznik, Luka ID - 6493 KW - Synthesis KW - Linear hybrid automaton KW - Membership SN - 0302-9743 T2 - 31st International Conference on Computer-Aided Verification TI - Membership-based synthesis of linear hybrid automata VL - 11561 ER - TY - GEN AB - Traditional concurrent programming involves manipulating shared mutable state. Alternatives to this programming style are communicating sequential processes (CSP) [1] and actor [2] models, which share data via explicit communication. Rendezvous channelis the common abstraction for communication between several processes, where senders and receivers perform a rendezvous handshake as a part of their protocol (senders wait for receivers and vice versa). Additionally to this, channels support the select expression. In this work, we present the first efficient lock-free channel algorithm, and compare it against Go [3] and Kotlin [4] baseline implementations. AU - Koval, Nikita AU - Alistarh, Dan-Adrian AU - Elizarov, Roman ID - 6485 SN - 9781450362252 T2 - Proceedings of the 24th Symposium on Principles and Practice of Parallel Programming TI - Lock-free channels for programming via communicating sequential processes ER - TY - JOUR AB - Root gravitropism is one of the most important processes allowing plant adaptation to the land environment. Auxin plays a central role in mediating root gravitropism, but how auxin contributes to gravitational perception and the subsequent response is still unclear. Here, we showed that the local auxin maximum/gradient within the root apex, which is generated by the PIN directional auxin transporters, regulates the expression of three key starch granule synthesis genes, SS4, PGM and ADG1, which in turn influence the accumulation of starch granules that serve as a statolith perceiving gravity. Moreover, using the cvxIAA‐ccvTIR1 system, we also showed that TIR1‐mediated auxin signaling is required for starch granule formation and gravitropic response within root tips. In addition, axr3 mutants showed reduced auxin‐mediated starch granule accumulation and disruption of gravitropism within the root apex. Our results indicate that auxin‐mediated statolith production relies on the TIR1/AFB‐AXR3‐mediated auxin signaling pathway. In summary, we propose a dual role for auxin in gravitropism: the regulation of both gravity perception and response. AU - Zhang, Yuzhou AU - He, P AU - Ma, X AU - Yang, Z AU - Pang, C AU - Yu, J AU - Wang, G AU - Friml, Jiří AU - Xiao, G ID - 6504 IS - 2 JF - New Phytologist SN - 0028-646x TI - Auxin-mediated statolith production for root gravitropism VL - 224 ER - TY - JOUR AB - How does environmental complexity affect the evolution of single genes? Here, we measured the effects of a set of Bacillus subtilis glutamate dehydrogenase mutants across 19 different environments—from phenotypically homogeneous single-cell populations in liquid media to heterogeneous biofilms, plant roots and soil populations. The effects of individual gene mutations on organismal fitness were highly reproducible in liquid cultures. However, 84% of the tested alleles showed opposing fitness effects under different growth conditions (sign environmental pleiotropy). In colony biofilms and soil samples, different alleles dominated in parallel replica experiments. Accordingly, we found that in these heterogeneous cell populations the fate of mutations was dictated by a combination of selection and drift. The latter relates to programmed prophage excisions that occurred during biofilm development. Overall, for each condition, a wide range of glutamate dehydrogenase mutations persisted and sometimes fixated as a result of the combined action of selection, pleiotropy and chance. However, over longer periods and in multiple environments, nearly all of this diversity would be lost—across all the environments and conditions that we tested, the wild type was the fittest allele. AU - Noda-García, Lianet AU - Davidi, Dan AU - Korenblum, Elisa AU - Elazar, Assaf AU - Putintseva, Ekaterina AU - Aharoni, Asaph AU - Tawfik, Dan S. ID - 6506 IS - 7 JF - Nature Microbiology SN - 2058-5276 TI - Chance and pleiotropy dominate genetic diversity in complex bacterial environments VL - 4 ER - TY - JOUR AB - Microglia have emerged as a critical component of neurodegenerative diseases. Genetic manipulation of microglia can elucidate their functional impact in disease. In neuroscience, recombinant viruses such as lentiviruses and adeno-associated viruses (AAVs) have been successfully used to target various cell types in the brain, although effective transduction of microglia is rare. In this review, we provide a short background of lentiviruses and AAVs, and strategies for designing recombinant viral vectors. Then, we will summarize recent literature on successful microglial transductions in vitro and in vivo, and discuss the current challenges. Finally, we provide guidelines for reporting the efficiency and specificity of viral targeting in microglia, which will enable the microglial research community to assess and improve methodologies for future studies. AU - Maes, Margaret E AU - Colombo, Gloria AU - Schulz, Rouven AU - Siegert, Sandra ID - 6521 JF - Neuroscience Letters SN - 0304-3940 TI - Targeting microglia with lentivirus and AAV: Recent advances and remaining challenges VL - 707 ER - TY - JOUR AB - Adult intestinal stem cells are located at the bottom of crypts of Lieberkühn, where they express markers such as LGR5 1,2 and fuel the constant replenishment of the intestinal epithelium1. Although fetal LGR5-expressing cells can give rise to adult intestinal stem cells3,4, it remains unclear whether this population in the patterned epithelium represents unique intestinal stem-cell precursors. Here we show, using unbiased quantitative lineage-tracing approaches, biophysical modelling and intestinal transplantation, that all cells of the mouse intestinal epithelium—irrespective of their location and pattern of LGR5 expression in the fetal gut tube—contribute actively to the adult intestinal stem cell pool. Using 3D imaging, we find that during fetal development the villus undergoes gross remodelling and fission. This brings epithelial cells from the non-proliferative villus into the proliferative intervillus region, which enables them to contribute to the adult stem-cell niche. Our results demonstrate that large-scale remodelling of the intestinal wall and cell-fate specification are closely linked. Moreover, these findings provide a direct link between the observed plasticity and cellular reprogramming of differentiating cells in adult tissues following damage5,6,7,8,9, revealing that stem-cell identity is an induced rather than a hardwired property. AU - Guiu, Jordi AU - Hannezo, Edouard B AU - Yui, Shiro AU - Demharter, Samuel AU - Ulyanchenko, Svetlana AU - Maimets, Martti AU - Jørgensen, Anne AU - Perlman, Signe AU - Lundvall, Lene AU - Mamsen, Linn Salto AU - Larsen, Agnete AU - Olesen, Rasmus H. AU - Andersen, Claus Yding AU - Thuesen, Lea Langhoff AU - Hare, Kristine Juul AU - Pers, Tune H. AU - Khodosevich, Konstantin AU - Simons, Benjamin D. AU - Jensen, Kim B. ID - 6513 JF - Nature SN - 00280836 TI - Tracing the origin of adult intestinal stem cells VL - 570 ER - TY - JOUR AB - Optogenetics enables the spatio-temporally precise control of cell and animal behavior. Many optogenetic tools are driven by light-controlled protein–protein interactions (PPIs) that are repurposed from natural light-sensitive domains (LSDs). Applying light-controlled PPIs to new target proteins is challenging because it is difficult to predict which of the many available LSDs, if any, will yield robust light regulation. As a consequence, fusion protein libraries need to be prepared and tested, but methods and platforms to facilitate this process are currently not available. Here, we developed a genetic engineering strategy and vector library for the rapid generation of light-controlled PPIs. The strategy permits fusing a target protein to multiple LSDs efficiently and in two orientations. The public and expandable library contains 29 vectors with blue, green or red light-responsive LSDs, many of which have been previously applied ex vivo and in vivo. We demonstrate the versatility of the approach and the necessity for sampling LSDs by generating light-activated caspase-9 (casp9) enzymes. Collectively, this work provides a new resource for optical regulation of a broad range of target proteins in cell and developmental biology. AU - Tichy, Alexandra-Madelaine AU - Gerrard, Elliot J. AU - Legrand, Julien M.D. AU - Hobbs, Robin M. AU - Janovjak, Harald L ID - 6564 IS - 17 JF - Journal of Molecular Biology SN - 00222836 TI - Engineering strategy and vector library for the rapid generation of modular light-controlled protein–protein interactions VL - 431 ER - TY - JOUR AB - When animals become sick, infected cells and an armada of activated immune cells attempt to eliminate the pathogen from the body. Once infectious particles have breached the body's physical barriers of the skin or gut lining, an initially local response quickly escalates into a systemic response, attracting mobile immune cells to the site of infection. These cells complement the initial, unspecific defense with a more specialized, targeted response. This can also provide long-term immune memory and protection against future infection. The cell-autonomous defenses of the infected cells are thus aided by the actions of recruited immune cells. These specialized cells are the most mobile cells in the body, constantly patrolling through the otherwise static tissue to detect incoming pathogens. Such constant immune surveillance means infections are noticed immediately and can be rapidly cleared from the body. Some immune cells also remove infected cells that have succumbed to infection. All this prevents pathogen replication and spread to healthy tissues. Although this may involve the sacrifice of some somatic tissue, this is typically replaced quickly. Particular care is, however, given to the reproductive organs, which should always remain disease free (immune privilege). AU - Cremer, Sylvia ID - 6552 IS - 11 JF - Current Biology SN - 09609822 TI - Social immunity in insects VL - 29 ER - TY - JOUR AB - Let U and V be two independent N by N random matrices that are distributed according to Haar measure on U(N). Let Σ be a nonnegative deterministic N by N matrix. The single ring theorem [Ann. of Math. (2) 174 (2011) 1189–1217] asserts that the empirical eigenvalue distribution of the matrix X:=UΣV∗ converges weakly, in the limit of large N, to a deterministic measure which is supported on a single ring centered at the origin in ℂ. Within the bulk regime, that is, in the interior of the single ring, we establish the convergence of the empirical eigenvalue distribution on the optimal local scale of order N−1/2+ε and establish the optimal convergence rate. The same results hold true when U and V are Haar distributed on O(N). AU - Bao, Zhigang AU - Erdös, László AU - Schnelli, Kevin ID - 6511 IS - 3 JF - Annals of Probability SN - 00911798 TI - Local single ring theorem on optimal scale VL - 47 ER - TY - JOUR AB - Branching morphogenesis is a prototypical example of complex three-dimensional organ sculpting, required in multiple developmental settings to maximize the area of exchange surfaces. It requires, in particular, the coordinated growth of different cell types together with complex patterning to lead to robust macroscopic outputs. In recent years, novel multiscale quantitative biology approaches, together with biophysical modelling, have begun to shed new light of this topic. Here, we wish to review some of these recent developments, highlighting the generic design principles that can be abstracted across different branched organs, as well as the implications for the broader fields of stem cell, developmental and systems biology. AU - Hannezo, Edouard B AU - Simons, Benjamin D. ID - 6559 JF - Current Opinion in Cell Biology SN - 09550674 TI - Multiscale dynamics of branching morphogenesis VL - 60 ER -