@article{319, abstract = {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.}, author = {Gerencser, Mate and Hairer, Martin}, issn = {14322064}, journal = {Probability Theory and Related Fields}, number = {3-4}, pages = {697–758}, publisher = {Springer}, title = {{Singular SPDEs in domains with boundaries}}, doi = {10.1007/s00440-018-0841-1}, volume = {173}, year = {2019}, } @article{429, abstract = {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.}, author = {Ajanki, Oskari H and Erdös, László and Krüger, Torben H}, issn = {14322064}, journal = {Probability Theory and Related Fields}, number = {1-2}, pages = {293–373}, publisher = {Springer}, title = {{Stability of the matrix Dyson equation and random matrices with correlations}}, doi = {10.1007/s00440-018-0835-z}, volume = {173}, year = {2019}, } @inproceedings{5947, abstract = {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.}, author = {Chatterjee, Bapi and Peri, Sathya and Sa, Muktikanta and Singhal, Nandini}, booktitle = {ACM International Conference Proceeding Series}, isbn = {978-1-4503-6094-4 }, location = {Bangalore, India}, pages = {168--177}, publisher = {ACM}, title = {{A simple and practical concurrent non-blocking unbounded graph with linearizable reachability queries}}, doi = {10.1145/3288599.3288617}, year = {2019}, } @article{5857, abstract = {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.}, author = {Fulek, Radoslav and Pach, János}, issn = {0166218X}, journal = {Discrete Applied Mathematics}, number = {4}, pages = {266--231}, publisher = {Elsevier}, title = {{Thrackles: An improved upper bound}}, doi = {10.1016/j.dam.2018.12.025}, volume = {259}, year = {2019}, } @article{5944, abstract = {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.}, author = {Corominas-Murtra, Bernat}, issn = {20751729}, journal = {Life}, number = {1}, publisher = {MDPI}, title = {{Thermodynamics of duplication thresholds in synthetic protocell systems}}, doi = {10.3390/life9010009}, volume = {9}, year = {2019}, } @article{6029, abstract = {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.}, author = {Lindner, Marco and Tresztenyak, Aliz and Fülöp, Gergö and Jahr, Wiebke and Prinz, Adrian and Prinz, Iris and Danzl, Johann G and Schütz, Gerhard J. and Sevcsik, Eva}, issn = {22962646}, journal = {Frontiers in Chemistry}, publisher = {Frontiers Media S.A.}, title = {{A fast and simple contact printing approach to generate 2D protein nanopatterns}}, doi = {10.3389/fchem.2018.00655}, volume = {6}, year = {2019}, } @article{6028, abstract = {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.}, author = {Gerencser, Mate and Hairer, Martin}, journal = {Communications on Pure and Applied Mathematics}, number = {9}, pages = {1983--2005}, publisher = {Wiley}, title = {{A solution theory for quasilinear singular SPDEs}}, doi = {10.1002/cpa.21816}, volume = {72}, year = {2019}, } @inproceedings{5948, abstract = {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.}, author = {Fu, Hongfei and Chatterjee, Krishnendu}, booktitle = {International Conference on Verification, Model Checking, and Abstract Interpretation}, location = {Cascais, Portugal}, pages = {468--490}, publisher = {Springer Nature}, title = {{Termination of nondeterministic probabilistic programs}}, doi = {10.1007/978-3-030-11245-5_22}, volume = {11388}, year = {2019}, } @article{5945, abstract = {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.}, author = {Petkova, Mariela D. and Tkacik, Gasper and Bialek, William and Wieschaus, Eric F. and Gregor, Thomas}, journal = {Cell}, number = {4}, pages = {844--855.e15}, publisher = {Cell Press}, title = {{Optimal decoding of cellular identities in a genetic network}}, doi = {10.1016/j.cell.2019.01.007}, volume = {176}, year = {2019}, } @article{5943, abstract = {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.}, author = {Klotz, Lukasz and Gumowski, Konrad and Wesfreid, José Eduardo}, journal = {Journal of Fluid Mechanics}, pages = {386--406}, publisher = {Cambridge University Press}, title = {{Experiments on a jet in a crossflow in the low-velocity-ratio regime}}, doi = {10.1017/jfm.2018.974}, volume = {863}, year = {2019}, } @inproceedings{6042, abstract = {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.}, author = {Christakis, Maria and Heizmann, Matthias and Mansur, Muhammad Numair and Schilling, Christian and Wüstholz, Valentin}, booktitle = {25th International Conference on Tools and Algorithms for the Construction and Analysis of Systems }, location = {Prague, Czech Republic}, pages = {226--243}, publisher = {Springer Nature}, title = {{Semantic fault localization and suspiciousness ranking}}, doi = {10.1007/978-3-030-17462-0_13}, volume = {11427}, year = {2019}, } @inproceedings{6035, abstract = {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.}, author = {Bogomolov, Sergiy and Forets, Marcelo and Frehse, Goran and Potomkin, Kostiantyn and Schilling, Christian}, booktitle = {Proceedings of the 22nd International Conference on Hybrid Systems: Computation and Control}, isbn = {9781450362825}, keywords = {reachability analysis, hybrid systems, lazy computation}, location = {Montreal, QC, Canada}, pages = {39--44}, publisher = {ACM}, title = {{JuliaReach: A toolbox for set-based reachability}}, doi = {10.1145/3302504.3311804}, volume = {22}, year = {2019}, } @article{6052, abstract = {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.}, author = {Truckenbrodt, Sven M and Sommer, Christoph M and Rizzoli, Silvio O and Danzl, Johann G}, journal = {Nature Protocols}, number = {3}, pages = {832–863}, publisher = {Nature Publishing Group}, title = {{A practical guide to optimization in X10 expansion microscopy}}, doi = {10.1038/s41596-018-0117-3}, volume = {14}, year = {2019}, } @article{6025, abstract = {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.}, author = {Capek, Daniel and Smutny, Michael and Tichy, Alexandra Madelaine and Morri, Maurizio and Janovjak, Harald L and Heisenberg, Carl-Philipp J}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Light-activated Frizzled7 reveals a permissive role of non-canonical wnt signaling in mesendoderm cell migration}}, doi = {10.7554/eLife.42093}, volume = {8}, year = {2019}, } @article{6022, abstract = {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.}, author = {Merrill, Richard M. and Rastas, Pasi and Martin, Simon H. and Melo Hurtado, Maria C and Barker, Sarah and Davey, John and Mcmillan, W. Owen and Jiggins, Chris D.}, journal = {PLoS Biology}, number = {2}, publisher = {Public Library of Science}, title = {{Genetic dissection of assortative mating behavior}}, doi = {10.1371/journal.pbio.2005902}, volume = {17}, year = {2019}, } @article{6023, abstract = {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.}, author = {Yoshida, Saiko and Van Der Schuren, Alja and Van Dop, Maritza and Van Galen, Luc and Saiga, Shunsuke and Adibi, Milad and Möller, Barbara and Ten Hove, Colette A. and Marhavy, Peter and Smith, Richard and Friml, Jiří and Weijers, Dolf}, journal = {Nature Plants}, number = {2}, pages = {160--166}, publisher = {Springer Nature}, title = {{A SOSEKI-based coordinate system interprets global polarity cues in arabidopsis}}, doi = {10.1038/s41477-019-0363-6}, volume = {5}, year = {2019}, } @article{6053, abstract = {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.}, author = {Kalaee, Mahmoud and Mirhosseini, Mohammad and Dieterle, Paul B. and Peruzzo, Matilda and Fink, Johannes M and Painter, Oskar}, issn = {1748-3395}, journal = {Nature Nanotechnology}, number = {4}, pages = {334–339}, publisher = {Springer Nature}, title = {{Quantum electromechanics of a hypersonic crystal}}, doi = {10.1038/s41565-019-0377-2}, volume = {14}, year = {2019}, } @article{6050, abstract = {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. }, author = {Akopyan, Arseniy and Fedorov, Roman}, journal = {Proceedings of the American Mathematical Society}, pages = {91--102}, publisher = {AMS}, title = {{Two circles and only a straightedge}}, doi = {10.1090/proc/14240}, volume = {147}, year = {2019}, } @misc{9801, author = {Merrill, Richard M. and Rastas, Pasi and Martin, Simon H. and Melo Hurtado, Maria C and Barker, Sarah and Davey, John and Mcmillan, W. Owen and Jiggins, Chris D.}, publisher = {Public Library of Science}, title = {{Raw behavioral data}}, doi = {10.1371/journal.pbio.2005902.s006}, year = {2019}, } @article{6095, abstract = {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.}, author = {Faria, Rui and Chaube, Pragya and Morales, Hernán E. and Larsson, Tomas and Lemmon, Alan R. and Lemmon, Emily M. and Rafajlović, Marina and Panova, Marina and Ravinet, Mark and Johannesson, Kerstin and Westram, Anja M and Butlin, Roger K.}, issn = {1365-294X}, journal = {Molecular Ecology}, number = {6}, pages = {1375--1393}, publisher = {Wiley}, title = {{Multiple chromosomal rearrangements in a hybrid zone between Littorina saxatilis ecotypes}}, doi = {10.1111/mec.14972}, volume = {28}, year = {2019}, } @article{6049, abstract = {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.}, author = {De Martino, Daniele}, journal = {Journal of Physics A: Mathematical and Theoretical}, number = {4}, publisher = {IOP Publishing}, title = {{Feedback-induced self-oscillations in large interacting systems subjected to phase transitions}}, doi = {10.1088/1751-8121/aaf2dd}, volume = {52}, year = {2019}, } @article{6091, abstract = {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.}, author = {Henderson, Nathan T. and Le Marchand, Sylvain J. and Hruska, Martin and Hippenmeyer, Simon and Luo, Liqun and Dalva, Matthew B.}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Ephrin-B3 controls excitatory synapse density through cell-cell competition for EphBs}}, doi = {10.7554/eLife.41563}, volume = {8}, year = {2019}, } @article{6046, abstract = {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.}, author = {Mitosch, Karin and Rieckh, Georg and Bollenbach, Mark Tobias}, journal = {Molecular systems biology}, number = {2}, publisher = {Embo Press}, title = {{Temporal order and precision of complex stress responses in individual bacteria}}, doi = {10.15252/msb.20188470}, volume = {15}, year = {2019}, } @article{6105, abstract = { 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. }, author = {Kutzer, Megan and Kurtz, Joachim and Armitage, Sophie A.O.}, issn = {13652656}, journal = {Journal of Animal Ecology}, number = {4}, pages = {566--578}, publisher = {Wiley}, title = {{A multi-faceted approach testing the effects of previous bacterial exposure on resistance and tolerance}}, doi = {10.1111/1365-2656.12953}, volume = {88}, year = {2019}, } @article{6088, abstract = {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.}, author = {Traxl, Alexander and Mairinger, Severin and Filip, Thomas and Sauberer, Michael and Stanek, Johann and Poschner, Stefan and Jäger, Walter and Zoufal, Viktoria and Novarino, Gaia and Tournier, Nicolas and Bauer, Martin and Wanek, Thomas and Langer, Oliver}, journal = {Molecular Pharmaceutics}, number = {3}, pages = {1282--1293}, publisher = {American Chemical Society}, title = {{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}}, doi = {10.1021/acs.molpharmaceut.8b01217}, volume = {16}, year = {2019}, } @article{6087, abstract = {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.}, author = {Xia, Peng and Gütl, Daniel J and Zheden, Vanessa and Heisenberg, Carl-Philipp J}, journal = {Cell}, number = {6}, pages = {1379--1392.e14}, publisher = {Elsevier}, title = {{Lateral inhibition in cell specification mediated by mechanical signals modulating TAZ activity}}, doi = {10.1016/j.cell.2019.01.019}, volume = {176}, year = {2019}, } @misc{9806, abstract = {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.}, author = {Kutzer, Megan and Kurtz, Joachim and Armitage, Sophie A.O.}, publisher = {Dryad}, title = {{Data from: A multi-faceted approach testing the effects of previous bacterial exposure on resistance and tolerance}}, doi = {10.5061/dryad.9kj41f0}, year = {2019}, } @article{6086, abstract = {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.}, author = {Sadel, Christian and Xu, Disheng}, journal = {Ergodic Theory and Dynamical Systems}, number = {4}, pages = {1082--1098}, publisher = {Cambridge University Press}, title = {{Singular analytic linear cocycles with negative infinite Lyapunov exponents}}, doi = {10.1017/etds.2017.52}, volume = {39}, year = {2019}, } @article{6102, abstract = {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.}, author = {Le Feber, B. and Sipe, J. E. and Wulf, Matthias and Kuipers, L. and Rotenberg, N.}, issn = {20477538}, journal = {Light: Science and Applications}, number = {1}, publisher = {Springer Nature}, title = {{A full vectorial mapping of nanophotonic light fields}}, doi = {10.1038/s41377-019-0124-3}, volume = {8}, year = {2019}, } @article{6104, abstract = {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.}, author = {Zwiewka, Marta and Bielach, Agnieszka and Tamizhselvan, Prashanth and Madhavan, Sharmila and Ryad, Eman Elrefaay and Tan, Shutang and Hrtyan, Mónika and Dobrev, Petre and Vanková, Radomira and Friml, Jiří and Tognetti, Vanesa B.}, issn = {1471-9053}, journal = {Plant and Cell Physiology}, number = {2}, pages = {255--273}, publisher = {Oxford University Press}, title = {{Root adaptation to H2O2-induced oxidative stress by ARF-GEF BEN1- and cytoskeleton-mediated PIN2 trafficking}}, doi = {10.1093/pcp/pcz001}, volume = {60}, year = {2019}, } @article{6191, abstract = {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.}, author = {Recho, Pierre and Hallou, Adrien and Hannezo, Edouard B}, issn = {10916490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {12}, pages = {5344--5349}, publisher = {National Academy of Sciences}, title = {{Theory of mechanochemical patterning in biphasic biological tissues}}, doi = {10.1073/pnas.1813255116}, volume = {116}, year = {2019}, } @article{6190, abstract = {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.}, author = {Roblek, Marko and Protsyuk, Darya and Becker, Paul F. and Stefanescu, Cristina and Gorzelanny, Christian and Glaus Garzon, Jesus F. and Knopfova, Lucia and Heikenwalder, Mathias and Luckow, Bruno and Schneider, Stefan W. and Borsig, Lubor}, issn = {15573125}, journal = {Molecular Cancer Research}, number = {3}, pages = {783--793}, publisher = {AACR}, title = {{CCL2 is a vascular permeability factor inducing CCR2-dependent endothelial retraction during lung metastasis}}, doi = {10.1158/1541-7786.MCR-18-0530}, volume = {17}, year = {2019}, } @article{6230, abstract = {Great care is needed when interpreting claims about the genetic basis of human variation based on data from genome-wide association studies.}, author = {Barton, Nicholas H and Hermisson, Joachim and Nordborg, Magnus}, issn = {2050084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Why structure matters}}, doi = {10.7554/eLife.45380}, volume = {8}, year = {2019}, } @article{6232, abstract = {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.}, author = {Gerencser, Mate}, issn = {00911798}, journal = {Annals of Probability}, number = {2}, pages = {804--834}, publisher = {Institute of Mathematical Statistics}, title = {{Boundary regularity of stochastic PDEs}}, doi = {10.1214/18-AOP1272}, volume = {47}, year = {2019}, } @article{6262, abstract = {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.}, author = {Rakusová, Hana and Han, Huibin and Valošek, Petr and Friml, Jiří}, issn = {1365-313x}, journal = {The Plant Journal}, number = {6}, pages = {1048--1059}, publisher = {Wiley}, title = {{Genetic screen for factors mediating PIN polarization in gravistimulated Arabidopsis thaliana hypocotyls}}, doi = {10.1111/tpj.14301}, volume = {98}, year = {2019}, } @article{6297, abstract = {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.}, author = {Davies, Heather S. and Baranova, Natalia S. and El Amri, Nouha and Coche-Guérente, Liliane and Verdier, Claude and Bureau, Lionel and Richter, Ralf P. and Débarre, Delphine}, issn = {0945-053X}, journal = {Matrix Biology}, pages = {47--59}, publisher = {Elsevier}, title = {{An integrated assay to probe endothelial glycocalyx-blood cell interactions under flow in mechanically and biochemically well-defined environments}}, doi = {10.1016/j.matbio.2018.12.002}, volume = {78-79}, year = {2019}, } @article{6310, abstract = {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.}, author = {Browning, Timothy D and Hu, L.Q.}, issn = {10902082}, journal = {Advances in Mathematics}, pages = {920--940}, publisher = {Elsevier}, title = {{Counting rational points on biquadratic hypersurfaces}}, doi = {10.1016/j.aim.2019.04.031}, volume = {349}, year = {2019}, } @article{6261, abstract = {Nitrate regulation of root stem cell activity is auxin-dependent.}, author = {Wang, Y and Gong, Z and Friml, Jiří and Zhang, J}, issn = {1532-2548}, journal = {Plant Physiology}, number = {1}, pages = {22--25}, publisher = {ASPB}, title = {{Nitrate modulates the differentiation of root distal stem cells}}, doi = {10.1104/pp.18.01305}, volume = {180}, year = {2019}, } @article{6352, abstract = {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.}, author = {Temnov, Andrey Alexandrovich and Rogov, Konstantin Arkadevich and Sklifas, Alla Nikolaevna and Klychnikova, Elena Valerievna and Hartl, Markus and Djinovic-Carugo, Kristina and Charnagalov, Alexej}, issn = {15734978}, journal = {Molecular Biology Reports}, publisher = {Springer}, title = {{Protective properties of the cultured stem cell proteome studied in an animal model of acetaminophen-induced acute liver failure}}, doi = {10.1007/s11033-019-04765-z}, year = {2019}, } @article{6348, abstract = {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.}, author = {Rueda Sanchez, Alfredo R and Sedlmeir, Florian and Kumari, Madhuri and Leuchs, Gerd and Schwefel, Harald G.L.}, issn = {14764687}, journal = {Nature}, number = {7752}, pages = {378--381}, publisher = {Springer Nature}, title = {{Resonant electro-optic frequency comb}}, doi = {10.1038/s41586-019-1110-x}, volume = {568}, year = {2019}, } @article{6338, abstract = {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.}, author = {Stella, Federico and Baracskay, Peter and O'Neill, Joseph and Csicsvari, Jozsef L}, journal = {Neuron}, pages = {450--461}, publisher = {Elsevier}, title = {{Hippocampal reactivation of random trajectories resembling Brownian diffusion}}, doi = {10.1016/j.neuron.2019.01.052}, volume = {102}, year = {2019}, } @article{5878, abstract = {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.}, author = {Budanur, Nazmi B and Fleury, Marc}, issn = {1089-7682}, journal = {Chaos: An Interdisciplinary Journal of Nonlinear Science}, number = {1}, publisher = {AIP Publishing}, title = {{State space geometry of the chaotic pilot-wave hydrodynamics}}, doi = {10.1063/1.5058279}, volume = {29}, year = {2019}, } @article{6343, abstract = {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.}, author = {Schur, Florian KM}, issn = {0959-440X}, journal = {Current Opinion in Structural Biology}, number = {10}, pages = {1--9}, publisher = {Elsevier}, title = {{Toward high-resolution in situ structural biology with cryo-electron tomography and subtomogram averaging}}, doi = {10.1016/j.sbi.2019.03.018}, volume = {58}, year = {2019}, } @inproceedings{6428, abstract = {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.}, author = {Ferrere, Thomas and Nickovic, Dejan and Donzé, Alexandre and Ito, Hisahiro and Kapinski, James}, booktitle = {Proceedings of the 2019 22nd ACM International Conference on Hybrid Systems: Computation and Control}, isbn = {9781450362825}, location = {Montreal, Canada}, pages = {57--66}, publisher = {ACM}, title = {{Interface-aware signal temporal logic}}, doi = {10.1145/3302504.3311800}, year = {2019}, } @article{6442, abstract = {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.}, author = {Schreck, Camille and Hafner, Christian and Wojtan, Christopher J}, journal = {ACM Transactions on Graphics}, number = {4}, publisher = {ACM}, title = {{Fundamental solutions for water wave animation}}, doi = {10.1145/3306346.3323002}, volume = {38}, year = {2019}, } @article{6413, abstract = {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.}, author = {Song, Baofang and Plana, Carlos and Lopez Alonso, Jose M and Avila, Marc}, issn = {03019322}, journal = {International Journal of Multiphase Flow}, pages = {14--24}, publisher = {Elsevier}, title = {{Phase-field simulation of core-annular pipe flow}}, doi = {10.1016/j.ijmultiphaseflow.2019.04.027}, volume = {117}, year = {2019}, } @article{6419, abstract = {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.}, author = {Pokusaeva, Victoria and Usmanova, Dinara R. and Putintseva, Ekaterina V. and Espinar, Lorena and Sarkisyan, Karen and Mishin, Alexander S. and Bogatyreva, Natalya S. and Ivankov, Dmitry and Akopyan, Arseniy and Avvakumov, Sergey and Povolotskaya, Inna S. and Filion, Guillaume J. and Carey, Lucas B. and Kondrashov, Fyodor}, issn = {15537404}, journal = {PLoS Genetics}, number = {4}, publisher = {Public Library of Science}, title = {{An experimental assay of the interactions of amino acids from orthologous sequences shaping a complex fitness landscape}}, doi = {10.1371/journal.pgen.1008079}, volume = {15}, year = {2019}, } @article{6412, abstract = {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.}, author = {Moussa, Hagar F. and Bsteh, Daniel and Yelagandula, Ramesh and Pribitzer, Carina and Stecher, Karin and Bartalska, Katarina and Michetti, Luca and Wang, Jingkui and Zepeda-Martinez, Jorge A. and Elling, Ulrich and Stuckey, Jacob I. and James, Lindsey I. and Frye, Stephen V. and Bell, Oliver}, issn = {20411723}, journal = {Nature Communications}, number = {1}, publisher = {Springer Nature}, title = {{Canonical PRC1 controls sequence-independent propagation of Polycomb-mediated gene silencing}}, doi = {10.1038/s41467-019-09628-6}, volume = {10}, year = {2019}, } @article{6415, abstract = {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.}, author = {Cremer, Sylvia}, issn = {22145753}, journal = {Current Opinion in Insect Science}, pages = {63--68}, publisher = {Elsevier}, title = {{Pathogens and disease defense of invasive ants}}, doi = {10.1016/j.cois.2019.03.011}, volume = {33}, year = {2019}, } @misc{9790, author = {Pokusaeva, Victoria and Usmanova, Dinara R. and Putintseva, Ekaterina V. and Espinar, Lorena and Sarkisyan, Karen and Mishin, Alexander S. and Bogatyreva, Natalya S. and Ivankov, Dmitry and Akopyan, Arseniy and Avvakumov, Sergey and Povolotskaya, Inna S. and Filion, Guillaume J. and Carey, Lucas B. and Kondrashov, Fyodor}, publisher = {Public Library of Science}, title = {{A statistical summary of segment libraries and sequencing results}}, doi = {10.1371/journal.pgen.1008079.s011}, year = {2019}, }