TY - JOUR AB - Bradykinin (BK), a component of the kallikrein-kininogen-kinin system exerts multiple effects via B1 and B2 receptor activation. In the cardiovascular system, bradykinin has cardioprotective and vasodilator properties. We investigated the effect of BK on cardiac-projecting neurons of nucleus ambiguus, a key site for the parasympathetic cardiac regulation. BK produced a dose-dependent increase in cytosolic Ca2+ concentration. Pretreatment with HOE140, a B2 receptor antagonist, but not with R715, a B1 receptor antagonist, abolished the response to BK. A selective B2 receptor agonist, but not a B1 receptor agonist, elicited an increase in cytosolic Ca2+ similarly to BK. Inhibition of N-type voltage-gated Ca2+ channels with ω-conotoxin GVIA had no effect on the Ca2+ signal produced by BK, while pretreatment with ω-conotoxin MVIIC, a blocker of P/Q-type of Ca2+ channels, significantly diminished the effect of BK. Pretreatment with xestospongin C and 2-aminoethoxydiphenyl borate, antagonists of inositol 1,4,5-trisphosphate receptors, abolished the response to BK. Inhibition of ryanodine receptors reduced the BK-induced Ca2+ increase, while disruption of lysosomal Ca2+ stores with bafilomycin A1 did not affect the response. BK produced a dose-dependent depolarization of nucleus ambiguus neurons, which was prevented by the B2 receptor antagonist. In vivo studies indicate that microinjection of BK into nucleus ambiguus elicited bradycardia in conscious rats via B2 receptors. In summary, in cardiac vagal neurons of nucleus ambiguus, BK activates B2 receptors promoting Ca2+ influx and Ca2+ release from endoplasmic reticulum, and membrane depolarization; these effects are translated in vivo by bradycardia. AU - Brǎiloiu, Eugen AU - Mcguire, Matthew AU - Shuler, Shadaria AU - Deliu, Elena AU - Barr, Jeffrey AU - Abood, Mary AU - Brailoiu, Gabriela ID - 747 JF - Neuroscience SN - 03064522 TI - Modulation of cardiac vagal tone by bradykinin acting on nucleus ambiguus VL - 365 ER - TY - JOUR AB - This special issue of the Journal on Formal Methods in System Design is dedicated to Prof. Helmut Veith, who unexpectedly passed away in March 2016. Helmut Veith was a brilliant researcher, inspiring collaborator, passionate mentor, generous friend, and valued member of the formal methods community. Helmut was not only known for his numerous and influential contributions in the field of automated verification (most prominently his work on Counterexample-Guided Abstraction Refinement [1,2]), but also for his untiring and passionate efforts for the logic community: he co-organized the Vienna Summer of Logic (an event comprising twelve conferences and numerous workshops which attracted thousands of researchers from all over the world), he initiated the Vienna Center for Logic and Algorithms (which promotes international collaboration on logic and algorithms and organizes outreach events such as the LogicLounge), and he coordinated the Doctoral Program on Logical Methods in Computer Science at TU Wien (currently educating more than 40 doctoral students) and a National Research Network on Rigorous Systems Engineering (uniting fifteen researchers in Austria to address the challenge of building reliable and safe computer systems). With his enthusiasm and commitment, Helmut completely reshaped the Austrian research landscape in the field of logic and verification in his few years as a full professor at TU Wien. AU - Gottlob, Georg AU - Henzinger, Thomas A AU - Weißenbacher, Georg ID - 743 IS - 2 JF - Formal Methods in System Design TI - Preface of the special issue in memoriam Helmut Veith VL - 51 ER - TY - THES AB - Cell-cell contact formation constitutes the first step in the emergence of multicellularity in evolution, thereby allowing the differentiation of specialized cell types. In metazoan development, cell-cell contact formation is thought to influence cell fate specification, and cell fate specification has been implicated in cell-cell contact formation. However, remarkably little is yet known about whether and how the interaction and feedback between cell-cell contact formation and cell fate specification affect development. Here we identify a positive feedback loop between cell-cell contact duration, morphogen signaling and mesendoderm cell fate specification during zebrafish gastrulation. We show that long lasting cell-cell contacts enhance the competence of prechordal plate (ppl) progenitor cells to respond to Nodal signaling, required for proper ppl cell fate specification. We further show that Nodal signalling romotes ppl cell-cell contact duration, thereby generating an effective positive feedback loop between ppl cell-cell contact duration and cell fate specification. Finally, by using a combination of theoretical modeling and experimentation, we show that this feedback loop determines whether anterior axial mesendoderm cells become ppl progenitors or, instead, turn into endoderm progenitors. Our findings reveal that the gene regulatory networks leading to cell fate diversification within the developing embryo are controlled by the interdependent activities of cell-cell signaling and contact formation. AU - Barone, Vanessa ID - 961 SN - 2663-337X TI - Cell adhesion and cell fate: An effective feedback loop during zebrafish gastrulation ER - TY - JOUR AB - Social insect societies are long-standing models for understanding social behaviour and evolution. Unlike other advanced biological societies (such as the multicellular body), the component parts of social insect societies can be easily deconstructed and manipulated. Recent methodological and theoretical innovations have exploited this trait to address an expanded range of biological questions. We illustrate the broadening range of biological insight coming from social insect biology with four examples. These new frontiers promote open-minded, interdisciplinary exploration of one of the richest and most complex of biological phenomena: sociality. AU - Kennedy, Patrick AU - Baron, Gemma AU - Qiu, Bitao AU - Freitak, Dalial AU - Helantera, Heikki AU - Hunt, Edmund AU - Manfredini, Fabio AU - O'Shea Wheller, Thomas AU - Patalano, Solenn AU - Pull, Christopher AU - Sasaki, Takao AU - Taylor, Daisy AU - Wyatt, Christopher AU - Sumner, Seirian ID - 734 IS - 11 JF - Trends in Ecology and Evolution SN - 01695347 TI - Deconstructing superorganisms and societies to address big questions in biology VL - 32 ER - TY - THES AB - Contagious diseases must transmit from infectious to susceptible hosts in order to reproduce. Whilst vectored pathogens can rely on intermediaries to find new hosts for them, many infectious pathogens require close contact or direct interaction between hosts for transmission. Hence, this means that conspecifics are often the main source of infection for most animals and so, in theory, animals should avoid conspecifics to reduce their risk of infection. Of course, in reality animals must interact with one another, as a bare minimum, to mate. However, being social provides many additional benefits and group living has become a taxonomically diverse and widespread trait. How then do social animals overcome the issue of increased disease? Over the last few decades, the social insects (ants, termites and some bees and wasps) have become a model system for studying disease in social animals. On paper, a social insect colony should be particularly susceptible to disease, given that they often contain thousands of potential hosts that are closely related and frequently interact, as well as exhibiting stable environmental conditions that encourage microbial growth. Yet, disease outbreaks appear to be rare and attempts to eradicate pest species using pathogens have failed time and again. Evolutionary biologists investigating this observation have discovered that the reduced disease susceptibility in social insects is, in part, due to collectively performed disease defences of the workers. These defences act like a “social immune system” for the colony, resulting in a per capita decrease in disease, termed social immunity. Our understanding of social immunity, and its importance in relation to the immunological defences of each insect, continues to grow, but there remain many open questions. In this thesis I have studied disease defence in garden ants. In the first data chapter, I use the invasive garden ant, Lasius neglectus, to investigate how colonies mitigate lethal infections and prevent them from spreading systemically. I find that ants have evolved ‘destructive disinfection’ – a behaviour that uses endogenously produced acidic poison to kill diseased brood and to prevent the pathogen from replicating. In the second experimental chapter, I continue to study the use of poison in invasive garden ant colonies, finding that it is sprayed prophylactically within the nest. However, this spraying has negative effects on developing pupae when they have had their cocoons artificially removed. Hence, I suggest that acidic nest sanitation may be maintaining larval cocoon spinning in this species. In the next experimental chapter, I investigated how colony founding black garden ant queens (Lasius niger) prevent disease when a co-foundress dies. I show that ant queens prophylactically perform undertaking behaviours, similar to those performed by the workers in mature nests. When a co-foundress was infected, these undertaking behaviours improved the survival of the healthy queen. In the final data chapter, I explored how immunocompetence (measured as antifungal activity) changes as incipient black garden ant colonies grow and mature, from the solitary queen phase to colonies with several hundred workers. Queen and worker antifungal activity varied throughout this time period, but despite social immunity, did not decrease as colonies matured. In addition to the above data chapters, this thesis includes two co-authored reviews. In the first, we examine the state of the art in the field of social immunity and how it might develop in the future. In the second, we identify several challenges and open questions in the study of disease defence in animals. We highlight how social insects offer a unique model to tackle some of these problems, as disease defence can be studied from the cell to the society. AU - Pull, Christopher ID - 819 SN - 2663-337X TI - Disease defence in garden ants ER - TY - JOUR AB - Background: Social insects form densely crowded societies in environments with high pathogen loads, but have evolved collective defences that mitigate the impact of disease. However, colony-founding queens lack this protection and suffer high rates of mortality. The impact of pathogens may be exacerbated in species where queens found colonies together, as healthy individuals may contract pathogens from infectious co-founders. Therefore, we tested whether ant queens avoid founding colonies with pathogen-exposed conspecifics and how they might limit disease transmission from infectious individuals. Results: Using Lasius Niger queens and a naturally infecting fungal pathogen Metarhizium brunneum, we observed that queens were equally likely to found colonies with another pathogen-exposed or sham-treated queen. However, when one queen died, the surviving individual performed biting, burial and removal of the corpse. These undertaking behaviours were performed prophylactically, i.e. targeted equally towards non-infected and infected corpses, as well as carried out before infected corpses became infectious. Biting and burial reduced the risk of the queens contracting and dying from disease from an infectious corpse of a dead co-foundress. Conclusions: We show that co-founding ant queens express undertaking behaviours that, in mature colonies, are performed exclusively by workers. Such infection avoidance behaviours act before the queens can contract the disease and will therefore improve the overall chance of colony founding success in ant queens. AU - Pull, Christopher AU - Cremer, Sylvia ID - 732 IS - 1 JF - BMC Evolutionary Biology SN - 14712148 TI - Co-founding ant queens prevent disease by performing prophylactic undertaking behaviour VL - 17 ER - TY - JOUR AB - The morphogenesis of branched organs remains a subject of abiding interest. Although much is known about the underlying signaling pathways, it remains unclear how macroscopic features of branched organs, including their size, network topology, and spatial patterning, are encoded. Here, we show that, in mouse mammary gland, kidney, and human prostate, these features can be explained quantitatively within a single unifying framework of branching and annihilating random walks. Based on quantitative analyses of large-scale organ reconstructions and proliferation kinetics measurements, we propose that morphogenesis follows from the proliferative activity of equipotent tips that stochastically branch and randomly explore their environment but compete neutrally for space, becoming proliferatively inactive when in proximity with neighboring ducts. These results show that complex branched epithelial structures develop as a self-organized process, reliant upon a strikingly simple but generic rule, without recourse to a rigid and deterministic sequence of genetically programmed events. AU - Hannezo, Edouard B AU - Scheele, Colinda AU - Moad, Mohammad AU - Drogo, Nicholas AU - Heer, Rakesh AU - Sampogna, Rosemary AU - Van Rheenen, Jacco AU - Simons, Benjamin ID - 726 IS - 1 JF - Cell SN - 00928674 TI - A unifying theory of branching morphogenesis VL - 171 ER - TY - JOUR AB - Actin filaments polymerizing against membranes power endocytosis, vesicular traffic, and cell motility. In vitro reconstitution studies suggest that the structure and the dynamics of actin networks respond to mechanical forces. We demonstrate that lamellipodial actin of migrating cells responds to mechanical load when membrane tension is modulated. In a steady state, migrating cell filaments assume the canonical dendritic geometry, defined by Arp2/3-generated 70° branch points. Increased tension triggers a dense network with a broadened range of angles, whereas decreased tension causes a shift to a sparse configuration dominated by filaments growing perpendicularly to the plasma membrane. We show that these responses emerge from the geometry of branched actin: when load per filament decreases, elongation speed increases and perpendicular filaments gradually outcompete others because they polymerize the shortest distance to the membrane, where they are protected from capping. This network-intrinsic geometrical adaptation mechanism tunes protrusive force in response to mechanical load. AU - Mueller, Jan AU - Szep, Gregory AU - Nemethova, Maria AU - De Vries, Ingrid AU - Lieber, Arnon AU - Winkler, Christoph AU - Kruse, Karsten AU - Small, John AU - Schmeiser, Christian AU - Keren, Kinneret AU - Hauschild, Robert AU - Sixt, Michael K ID - 727 IS - 1 JF - Cell SN - 00928674 TI - Load adaptation of lamellipodial actin networks VL - 171 ER - TY - JOUR AB - Neural responses are highly structured, with population activity restricted to a small subset of the astronomical range of possible activity patterns. Characterizing these statistical regularities is important for understanding circuit computation, but challenging in practice. Here we review recent approaches based on the maximum entropy principle used for quantifying collective behavior in neural activity. We highlight recent models that capture population-level statistics of neural data, yielding insights into the organization of the neural code and its biological substrate. Furthermore, the MaxEnt framework provides a general recipe for constructing surrogate ensembles that preserve aspects of the data, but are otherwise maximally unstructured. This idea can be used to generate a hierarchy of controls against which rigorous statistical tests are possible. AU - Savin, Cristina AU - Tkacik, Gasper ID - 730 JF - Current Opinion in Neurobiology SN - 09594388 TI - Maximum entropy models as a tool for building precise neural controls VL - 46 ER - TY - JOUR AB - During animal development, cell-fate-specific changes in gene expression can modify the material properties of a tissue and drive tissue morphogenesis. While mechanistic insights into the genetic control of tissue-shaping events are beginning to emerge, how tissue morphogenesis and mechanics can reciprocally impact cell-fate specification remains relatively unexplored. Here we review recent findings reporting how multicellular morphogenetic events and their underlying mechanical forces can feed back into gene regulatory pathways to specify cell fate. We further discuss emerging techniques that allow for the direct measurement and manipulation of mechanical signals in vivo, offering unprecedented access to study mechanotransduction during development. Examination of the mechanical control of cell fate during tissue morphogenesis will pave the way to an integrated understanding of the design principles that underlie robust tissue patterning in embryonic development. AU - Chan, Chii AU - Heisenberg, Carl-Philipp J AU - Hiiragi, Takashi ID - 728 IS - 18 JF - Current Biology SN - 09609822 TI - Coordination of morphogenesis and cell fate specification in development VL - 27 ER - TY - JOUR AB - The cellular mechanisms allowing tissues to efficiently regenerate are not fully understood. In this issue of Developmental Cell, Cao et al. (2017)) discover that during zebrafish heart regeneration, epicardial cells at the leading edge of regenerating tissue undergo endoreplication, possibly due to increased tissue tension, thereby boosting their regenerative capacity. AU - Spiro, Zoltan P AU - Heisenberg, Carl-Philipp J ID - 729 IS - 6 JF - Developmental Cell SN - 15345807 TI - Regeneration tensed up polyploidy takes the lead VL - 42 ER - TY - JOUR AB - In this work maximum entropy distributions in the space of steady states of metabolic networks are considered upon constraining the first and second moments of the growth rate. Coexistence of fast and slow phenotypes, with bimodal flux distributions, emerges upon considering control on the average growth (optimization) and its fluctuations (heterogeneity). This is applied to the carbon catabolic core of Escherichia coli where it quantifies the metabolic activity of slow growing phenotypes and it provides a quantitative map with metabolic fluxes, opening the possibility to detect coexistence from flux data. A preliminary analysis on data for E. coli cultures in standard conditions shows degeneracy for the inferred parameters that extend in the coexistence region. AU - De Martino, Daniele ID - 548 IS - 6 JF - Physical Review E SN - 2470-0045 TI - Maximum entropy modeling of metabolic networks by constraining growth-rate moments predicts coexistence of phenotypes VL - 96 ER - TY - JOUR AB - We present a numerical study of wavy supercritical cylindrical Couette flow between counter-rotating cylinders in which the wavy pattern propagates either prograde with the inner cylinder or retrograde opposite the rotation of the inner cylinder. The wave propagation reversals from prograde to retrograde and vice versa occur at distinct values of the inner cylinder Reynolds number when the associated frequency of the wavy instability vanishes. The reversal occurs for both twofold and threefold symmetric wavy vortices. Moreover, the wave propagation reversal only occurs for sufficiently strong counter-rotation. The flow pattern reversal appears to be intrinsic in the system as either periodic boundary conditions or fixed end wall boundary conditions for different system sizes always result in the wave propagation reversal. We present a detailed bifurcation sequence and parameter space diagram with respect to retrograde behavior of wavy flows. The retrograde propagation of the instability occurs when the inner Reynolds number is about two times the outer Reynolds number. The mechanism for the retrograde propagation is associated with the inviscidly unstable region near the inner cylinder and the direction of the global average azimuthal velocity. Flow dynamics, spatio-temporal behavior, global mean angular velocity, and torque of the flow with the wavy pattern are explored. AU - Altmeyer, Sebastian AU - Lueptow, Richard ID - 673 IS - 5 JF - Physical Review E SN - 2470-0045 TI - Wave propagation reversal for wavy vortices in wide gap counter rotating cylindrical Couette flow VL - 95 ER - TY - JOUR AB - We consider last passage percolation (LPP) models with exponentially distributed random variables, which are linked to the totally asymmetric simple exclusion process (TASEP). The competition interface for LPP was introduced and studied in Ferrari and Pimentel (2005a) for cases where the corresponding exclusion process had a rarefaction fan. Here we consider situations with a shock and determine the law of the fluctuations of the competition interface around its deter- ministic law of large number position. We also study the multipoint distribution of the LPP around the shock, extending our one-point result of Ferrari and Nejjar (2015). AU - Ferrari, Patrik AU - Nejjar, Peter ID - 447 JF - Revista Latino-Americana de Probabilidade e Estatística TI - Fluctuations of the competition interface in presence of shocks VL - 9 ER - TY - JOUR AB - PURPOSE. Gene therapy of retinal ganglion cells (RGCs) has promise as a powerful therapeutic for the rescue and regeneration of these cells after optic nerve damage. However, early after damage, RGCs undergo atrophic changes, including gene silencing. It is not known if these changes will deleteriously affect transduction and transgene expression, or if the therapeutic protein can influence reactivation of the endogenous genome. METHODS. Double-transgenic mice carrying a Rosa26-(LoxP)-tdTomato reporter, and a mutant allele for the proapoptotic Bax gene were reared. The Bax mutant blocks apoptosis, but RGCs still exhibit nuclear atrophy and gene silencing. At times ranging from 1 hour to 4 weeks after optic nerve crush (ONC), eyes received an intravitreal injection of AAV2 virus carrying the Cre recombinase. Successful transduction was monitored by expression of the tdTomato reporter. Immunostaining was used to localize tdTomato expression in select cell types. RESULTS. Successful transduction of RGCs was achieved at all time points after ONC using AAV2 expressing Cre from the phosphoglycerate kinase (Pgk) promoter, but not the CMV promoter. ONC promoted an increase in the transduction of cell types in the inner nuclear layer, including Müller cells and rod bipolar neurons. There was minimal evidence of transduction of amacrine cells and astrocytes in the inner retina or optic nerve. CONCLUSIONS. Damaged RGCs can be transduced and at least some endogenous genes can be subsequently activated. Optic nerve damage may change retinal architecture to allow greater penetration of an AAV2 virus to transduce several additional cell types in the inner nuclear layer. AU - Nickells, Robert AU - Schmitt, Heather AU - Maes, Margaret E AU - Schlamp, Cassandra ID - 557 IS - 14 JF - Investigative Ophthalmology and Visual Science SN - 01460404 TI - AAV2 mediated transduction of the mouse retina after optic nerve injury VL - 58 ER - TY - JOUR AB - Recently it was shown that molecules rotating in superfluid helium can be described in terms of the angulon quasiparticles (Phys. Rev. Lett. 118, 095301 (2017)). Here we demonstrate that in the experimentally realized regime the angulon can be seen as a point charge on a 2-sphere interacting with a gauge field of a non-abelian magnetic monopole. Unlike in several other settings, the gauge fields of the angulon problem emerge in the real coordinate space, as opposed to the momentum space or some effective parameter space. Furthermore, we find a topological transition associated with making the monopole abelian, which takes place in the vicinity of the previously reported angulon instabilities. These results pave the way for studying topological phenomena in experiments on molecules trapped in superfluid helium nanodroplets, as well as on other realizations of orbital impurity problems. AU - Yakaboylu, Enderalp AU - Deuchert, Andreas AU - Lemeshko, Mikhail ID - 997 IS - 23 JF - Physical Review Letters SN - 0031-9007 TI - Emergence of non-abelian magnetic monopoles in a quantum impurity problem VL - 119 ER - TY - CONF AB - We develop a probabilistic technique for colorizing grayscale natural images. In light of the intrinsic uncertainty of this task, the proposed probabilistic framework has numerous desirable properties. In particular, our model is able to produce multiple plausible and vivid colorizations for a given grayscale image and is one of the first colorization models to provide a proper stochastic sampling scheme. Moreover, our training procedure is supported by a rigorous theoretical framework that does not require any ad hoc heuristics and allows for efficient modeling and learning of the joint pixel color distribution.We demonstrate strong quantitative and qualitative experimental results on the CIFAR-10 dataset and the challenging ILSVRC 2012 dataset. AU - Royer, Amélie AU - Kolesnikov, Alexander AU - Lampert, Christoph ID - 911 TI - Probabilistic image colorization ER - TY - JOUR AB - Aim: The present study was to compare the effects of nicotinic acid and nicotinamide on the plasma methyl donors, choline and betaine. Methods: Thirty adult subjects were randomly divided into three groups of equal size, and orally received purified water (C group), nicotinic acid (300 mg, NA group) or nicotinamide (300 mg, NM group). Plasma nicotinamide, N 1-methylnicotinamide, homocysteine, betaine and choline levels before and 1.5-h and 3-h post-dosing, plasma normetanephrine and metanephrine concentrations at 3-h post-dosing, and the urinary excretion of N 1-methyl-2-pyridone-5-carboxamide during the test period were examined. Results: The level of 3-h plasma nicotinamide, N 1-methylnicotinamide, homocysteine, the urinary excretion of N 1-methyl-2-pyridone-5-carboxamide and pulse pressure (PP) in the NM group was 221%, 3972%, 61%, 1728% and 21.2% higher than that of the control group (P < 0.01, except homocysteine and PP P < 0.05), while the 3-h plasma betaine, normetanephrine and metanephrine level in the NM group was 24.4%, 9.4% and 11.7% lower (P < 0.05, except betaine P < 0.01), without significant difference in choline levels. Similar but less pronounced changes were observed in the NA group, with a lower level of 3-h plasma N 1-methylnicotinamide (1.90 ± 0.20 μmol/l vs. 3.62 ± 0.27 μmol/l, P < 0.01) and homocysteine (12.85 ± 1.39 μmol/l vs. 18.08 ± 1.02 μmol/l, P < 0.05) but a higher level of betaine (27.44 ± 0.71 μmol/l vs. 23.52 ± 0.61 μmol/l, P < 0.05) than that of the NM group. Conclusion: The degradation of nicotinamide consumes more betaine than that of nicotinic acid at identical doses. This difference should be taken into consideration in niacin fortification. © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. AU - Sun, Wuping AU - Zhai, Ming-Zhu AU - Li, Da AU - Zhou, Yiming AU - Chen, Nana AU - Guo, Ming AU - Zhou, Shisheng ID - 1146 IS - 4 JF - Clinical Nutrition SN - 0261-5614 TI - Comparison of the effects of nicotinic acid and nicotinamide degradation on plasma betaine and choline levels VL - 36 ER - TY - CHAP AB - The advent of high-throughput technologies and the concurrent advances in information sciences have led to a data revolution in biology. This revolution is most significant in molecular biology, with an increase in the number and scale of the “omics” projects over the last decade. Genomics projects, for example, have produced impressive advances in our knowledge of the information concealed into genomes, from the many genes that encode for the proteins that are responsible for most if not all cellular functions, to the noncoding regions that are now known to provide regulatory functions. Proteomics initiatives help to decipher the role of post-translation modifications on the protein structures and provide maps of protein-protein interactions, while functional genomics is the field that attempts to make use of the data produced by these projects to understand protein functions. The biggest challenge today is to assimilate the wealth of information provided by these initiatives into a conceptual framework that will help us decipher life. For example, the current views of the relationship between protein structure and function remain fragmented. We know of their sequences, more and more about their structures, we have information on their biological activities, but we have difficulties connecting this dotted line into an informed whole. We lack the experimental and computational tools for directly studying protein structure, function, and dynamics at the molecular and supra-molecular levels. In this chapter, we review some of the current developments in building the computational tools that are needed, focusing on the role that geometry and topology play in these efforts. One of our goals is to raise the general awareness about the importance of geometric methods in elucidating the mysterious foundations of our very existence. Another goal is the broadening of what we consider a geometric algorithm. There is plenty of valuable no-man’s-land between combinatorial and numerical algorithms, and it seems opportune to explore this land with a computational-geometric frame of mind. AU - Edelsbrunner, Herbert AU - Koehl, Patrice ED - Toth, Csaba ED - O'Rourke, Joseph ED - Goodman, Jacob ID - 84 T2 - Handbook of Discrete and Computational Geometry, Third Edition TI - Computational topology for structural molecular biology ER - TY - JOUR AB - Beige adipocytes are a new type of recruitable brownish adipocytes, with highly mitochondrial membrane uncoupling protein 1 expression and thermogenesis. Beige adipocytes were found among white adipocytes, especially in subcutaneous white adipose tissue (sWAT). Therefore, beige adipocytes may be involved in the regulation of energy metabolism and fat deposition. Transient receptor potential melastatin 8 (TRPM8), a Ca2+-permeable non-selective cation channel, plays vital roles in the regulation of various cellular functions. It has been reported that TRPM8 activation enhanced the thermogenic function of brown adiposytes. However, the involvement of TRPM8 in the thermogenic function of WAT remains unexplored. Our data revealed that TRPM8 was expressed in mouse white adipocytes at mRNA, protein and functional levels. The mRNA expression of Trpm8 was significantly increased in the differentiated white adipocytes than pre-adipocytes. Moreover, activation of TRPM8 by menthol enhanced the expression of thermogenic genes in cultured white aidpocytes. And menthol-induced increases of the thermogenic genes in white adipocytes was inhibited by either KT5720 (a protein kinase A inhibitor) or BAPTA-AM. In addition, high fat diet (HFD)-induced obesity in mice was significantly recovered by co-treatment with menthol. Dietary menthol enhanced WAT "browning" and improved glucose metabolism in HFD-induced obesity mice as well. Therefore, we concluded that TRPM8 might be involved in WAT "browning" by increasing the expression levels of genes related to thermogenesis and energy metabolism. And dietary menthol could be a novel approach for combating human obesity and related metabolic diseases. AU - Jiang, Changyu AU - Zhai, Ming-Zhu AU - Yan, Dong AU - Li, Da AU - Li, Chen AU - Zhang, Yonghong AU - Xiao, Lizu AU - Xiong, Donglin AU - Deng, Qiwen AU - Sun, Wuping ID - 627 IS - 43 JF - Oncotarget SN - 1949-2553 TI - Dietary menthol-induced TRPM8 activation enhances WAT “browning” and ameliorates diet-induced obesity VL - 8 ER - TY - JOUR AB - A nonlinear system possesses an invariance with respect to a set of transformations if its output dynamics remain invariant when transforming the input, and adjusting the initial condition accordingly. Most research has focused on invariances with respect to time-independent pointwise transformations like translational-invariance (u(t) -> u(t) + p, p in R) or scale-invariance (u(t) -> pu(t), p in R>0). In this article, we introduce the concept of s0-invariances with respect to continuous input transformations exponentially growing/decaying over time. We show that s0-invariant systems not only encompass linear time-invariant (LTI) systems with transfer functions having an irreducible zero at s0 in R, but also that the input/output relationship of nonlinear s0-invariant systems possesses properties well known from their linear counterparts. Furthermore, we extend the concept of s0-invariances to second- and higher-order s0-invariances, corresponding to invariances with respect to transformations of the time-derivatives of the input, and encompassing LTI systems with zeros of multiplicity two or higher. Finally, we show that nth-order 0-invariant systems realize – under mild conditions – nth-order nonlinear differential operators: when excited by an input of a characteristic functional form, the system’s output converges to a constant value only depending on the nth (nonlinear) derivative of the input. AU - Lang, Moritz AU - Sontag, Eduardo ID - 1007 JF - Automatica SN - 0005-1098 TI - Zeros of nonlinear systems with input invariances VL - 81C ER - TY - CONF AB - In this work we study the learnability of stochastic processes with respect to the conditional risk, i.e. the existence of a learning algorithm that improves its next-step performance with the amount of observed data. We introduce a notion of pairwise discrepancy between conditional distributions at different times steps and show how certain properties of these discrepancies can be used to construct a successful learning algorithm. Our main results are two theorems that establish criteria for learnability for many classes of stochastic processes, including all special cases studied previously in the literature. AU - Zimin, Alexander AU - Lampert, Christoph ID - 1108 TI - Learning theory for conditional risk minimization VL - 54 ER - TY - JOUR AB - We study the lengths of curves passing through a fixed number of points on the boundary of a convex shape in the plane. We show that, for any convex shape K, there exist four points on the boundary of K such that the length of any curve passing through these points is at least half of the perimeter of K. It is also shown that the same statement does not remain valid with the additional constraint that the points are extreme points of K. Moreover, the factor &#xbd; cannot be achieved with any fixed number of extreme points. We conclude the paper with a few other inequalities related to the perimeter of a convex shape. AU - Akopyan, Arseniy AU - Vysotsky, Vladislav ID - 909 IS - 7 JF - The American Mathematical Monthly SN - 00029890 TI - On the lengths of curves passing through boundary points of a planar convex shape VL - 124 ER - TY - CONF AB - Parallel implementations of stochastic gradient descent (SGD) have received significant research attention, thanks to its excellent scalability properties. A fundamental barrier when parallelizing SGD is the high bandwidth cost of communicating gradient updates between nodes; consequently, several lossy compresion heuristics have been proposed, by which nodes only communicate quantized gradients. Although effective in practice, these heuristics do not always converge. In this paper, we propose Quantized SGD (QSGD), a family of compression schemes with convergence guarantees and good practical performance. QSGD allows the user to smoothly trade off communication bandwidth and convergence time: nodes can adjust the number of bits sent per iteration, at the cost of possibly higher variance. We show that this trade-off is inherent, in the sense that improving it past some threshold would violate information-theoretic lower bounds. QSGD guarantees convergence for convex and non-convex objectives, under asynchrony, and can be extended to stochastic variance-reduced techniques. When applied to training deep neural networks for image classification and automated speech recognition, QSGD leads to significant reductions in end-to-end training time. For instance, on 16GPUs, we can train the ResNet-152 network to full accuracy on ImageNet 1.8 × faster than the full-precision variant. AU - Alistarh, Dan-Adrian AU - Grubic, Demjan AU - Li, Jerry AU - Tomioka, Ryota AU - Vojnović, Milan ID - 431 SN - 10495258 TI - QSGD: Communication-efficient SGD via gradient quantization and encoding VL - 2017 ER - TY - CONF AB - Model checking is usually based on a comprehensive traversal of the state space. Causality-based model checking is a radically different approach that instead analyzes the cause-effect relationships in a program. We give an overview on a new class of model checking algorithms that capture the causal relationships in a special data structure called concurrent traces. Concurrent traces identify key events in an execution history and link them through their cause-effect relationships. The model checker builds a tableau of concurrent traces, where the case splits represent different causal explanations of a hypothetical error. Causality-based model checking has been implemented in the ARCTOR tool, and applied to previously intractable multi-threaded benchmarks. AU - Finkbeiner, Bernd AU - Kupriyanov, Andrey ID - 549 SN - 2075-2180 T2 - Electronic Proceedings in Theoretical Computer Science TI - Causality-based model checking VL - 259 ER - TY - CONF AB - In multi-task learning, a learner is given a collection of prediction tasks and needs to solve all of them. In contrast to previous work, which required that annotated training data must be available for all tasks, we consider a new setting, in which for some tasks, potentially most of them, only unlabeled training data is provided. Consequently, to solve all tasks, information must be transferred between tasks with labels and tasks without labels. Focusing on an instance-based transfer method we analyze two variants of this setting: when the set of labeled tasks is fixed, and when it can be actively selected by the learner. We state and prove a generalization bound that covers both scenarios and derive from it an algorithm for making the choice of labeled tasks (in the active case) and for transferring information between the tasks in a principled way. We also illustrate the effectiveness of the algorithm on synthetic and real data. AU - Pentina, Anastasia AU - Lampert, Christoph ID - 999 SN - 9781510855144 TI - Multi-task learning with labeled and unlabeled tasks VL - 70 ER - TY - CONF AB - We present results on nonlinear electro-optical conversion of microwave radiation into the optical telecommunication band with more than 0.1% photon number conversion efficiency with MHz bandwidth, in a crystalline whispering gallery mode resonator AU - Rueda Sanchez, Alfredo R AU - Sedlmeir, Florian AU - Collodo, Michele AU - Vogl, Ulrich AU - Stiller, Birgit AU - Schunk, Gerhard AU - Strekalov, Dmitry AU - Marquardt, Christoph AU - Fink, Johannes M AU - Painter, Oskar AU - Leuchs, Gerd AU - Schwefel, Harald ID - 485 SN - 978-155752820-9 T2 - Optics InfoBase Conference Papers TI - Single sideband microwave to optical photon conversion-an-electro-optic-realization VL - F54 ER - TY - JOUR AB - The social insects bees, wasps, ants, and termites are species-rich, occur in many habitats, and often constitute a large part of the biomass. Many are also invasive, including species of termites, the red imported fire ant, and the Argentine ant. While invasive social insects have been a problem in Southern Europe for some time, Central Europa was free of invasive ant species until recently because most ants are adapted to warmer climates. Only in the 1990s, did Lasius neglectus, a close relative of the common black garden ant, arrive in Germany. First described in 1990 based on individuals collected in Budapest, the species has since been detected for example in France, Germany, Spain, England, and Kyrgyzstan. The species is spread with soil during construction work or plantings, and L. neglectus therefore is often found in parks and botanical gardens. Another invasive ant now spreading in southern Germany is Formica fuscocinerea, which occurs along rivers, including in the sandy floodplains of the river Isar. As is typical of pioneer species, F. fuscocinerea quickly becomes extremely abundant and therefore causes problems for example on playgrounds in Munich. All invasive ant species are characterized by cooperation across nests, leading to strongly interconnected, very large super-colonies. The resulting dominance results in the extinction of native ant species as well as other arthropod species and thus in the reduction of biodiversity. AU - Cremer, Sylvia ID - 459 JF - Rundgespräche Forum Ökologie SN - 2366-2875 TI - Invasive Ameisen in Europa: Wie sie sich ausbreiten und die heimische Fauna verändern VL - 46 ER - TY - CONF AB - Recently there has been significant interest in training machine-learning models at low precision: by reducing precision, one can reduce computation and communication by one order of magnitude. We examine training at reduced precision, both from a theoretical and practical perspective, and ask: is it possible to train models at end-to-end low precision with provable guarantees? Can this lead to consistent order-of-magnitude speedups? We mainly focus on linear models, and the answer is yes for linear models. We develop a simple framework called ZipML based on one simple but novel strategy called double sampling. Our ZipML framework is able to execute training at low precision with no bias, guaranteeing convergence, whereas naive quanti- zation would introduce significant bias. We val- idate our framework across a range of applica- tions, and show that it enables an FPGA proto- type that is up to 6.5 × faster than an implemen- tation using full 32-bit precision. We further de- velop a variance-optimal stochastic quantization strategy and show that it can make a significant difference in a variety of settings. When applied to linear models together with double sampling, we save up to another 1.7 × in data movement compared with uniform quantization. When training deep networks with quantized models, we achieve higher accuracy than the state-of-the- art XNOR-Net. AU - Zhang, Hantian AU - Li, Jerry AU - Kara, Kaan AU - Alistarh, Dan-Adrian AU - Liu, Ji AU - Zhang, Ce ID - 432 SN - 978-151085514-4 T2 - Proceedings of Machine Learning Research TI - ZipML: Training linear models with end-to-end low precision, and a little bit of deep learning VL - 70 ER - TY - CONF AB - We consider the problem of estimating the partition function Z(β)=∑xexp(−β(H(x)) of a Gibbs distribution with a Hamilton H(⋅), or more precisely the logarithm of the ratio q=lnZ(0)/Z(β). It has been recently shown how to approximate q with high probability assuming the existence of an oracle that produces samples from the Gibbs distribution for a given parameter value in [0,β]. The current best known approach due to Huber [9] uses O(qlnn⋅[lnq+lnlnn+ε−2]) oracle calls on average where ε is the desired accuracy of approximation and H(⋅) is assumed to lie in {0}∪[1,n]. We improve the complexity to O(qlnn⋅ε−2) oracle calls. We also show that the same complexity can be achieved if exact oracles are replaced with approximate sampling oracles that are within O(ε2qlnn) variation distance from exact oracles. Finally, we prove a lower bound of Ω(q⋅ε−2) oracle calls under a natural model of computation. AU - Kolmogorov, Vladimir ID - 274 T2 - Proceedings of the 31st Conference On Learning Theory TI - A faster approximation algorithm for the Gibbs partition function VL - 75 ER - TY - JOUR AB - Immune specificity is the degree to which a host’s immune system discriminates among various pathogens or antigenic variants. Vertebrate immune memory is highly specific due to antibody responses. On the other hand, some invertebrates show immune priming, i.e. improved survival after secondary exposure to a previously encountered pathogen. Until now, specificity of priming has only been demonstrated via the septic infection route or when live pathogens were used for priming. Therefore, we tested for specificity in the oral priming route in the red flour beetle, Tribolium castaneum. For priming, we used pathogen-free supernatants derived from three different strains of the entomopathogen, Bacillus thuringiensis, which express different Cry toxin variants known for their toxicity against this beetle. Subsequent exposure to the infective spores showed that oral priming was specific for two naturally occurring strains, while a third engineered strain did not induce any priming effect. Our data demonstrate that oral immune priming with a non-infectious bacterial agent can be specific, but the priming effect is not universal across all bacterial strains. AU - Futo, Momir AU - Sell, Marie AU - Kutzer, Megan AU - Kurtz, Joachim ID - 558 IS - 12 JF - Biology Letters SN - 1744-9561 TI - Specificity of oral immune priming in the red flour beetle Tribolium castaneum VL - 13 ER - TY - JOUR AB - DNA methylation regulates eukaryotic gene expression and is extensively reprogrammed during animal development. However, whether developmental methylation reprogramming during the sporophytic life cycle of flowering plants regulates genes is presently unknown. Here we report a distinctive gene-targeted RNA-directed DNA methylation (RdDM) activity in the Arabidopsis thaliana male sexual lineage that regulates gene expression in meiocytes. Loss of sexual-lineage-specific RdDM causes mis-splicing of the MPS1 gene (also known as PRD2), thereby disrupting meiosis. Our results establish a regulatory paradigm in which de novo methylation creates a cell-lineage-specific epigenetic signature that controls gene expression and contributes to cellular function in flowering plants. AU - Walker, James AU - Gao, Hongbo AU - Zhang, Jingyi AU - Aldridge, Billy AU - Vickers, Martin AU - Higgins, James D. AU - Feng, Xiaoqi ID - 12193 IS - 1 JF - Nature Genetics KW - Genetics SN - 1061-4036 TI - Sexual-lineage-specific DNA methylation regulates meiosis in Arabidopsis VL - 50 ER - TY - CONF AB - Termination is one of the basic liveness properties, and we study the termination problem for probabilistic programs with real-valued variables. Previous works focused on the qualitative problem that asks whether an input program terminates with probability~1 (almost-sure termination). A powerful approach for this qualitative problem is the notion of ranking supermartingales with respect to a given set of invariants. The quantitative problem (probabilistic termination) asks for bounds on the termination probability. A fundamental and conceptual drawback of the existing approaches to address probabilistic termination is that even though the supermartingales consider the probabilistic behavior of the programs, the invariants are obtained completely ignoring the probabilistic aspect. In this work we address the probabilistic termination problem for linear-arithmetic probabilistic programs with nondeterminism. We define the notion of {\em stochastic invariants}, which are constraints along with a probability bound that the constraints hold. We introduce a concept of {\em repulsing supermartingales}. First, we show that repulsing supermartingales can be used to obtain bounds on the probability of the stochastic invariants. Second, we show the effectiveness of repulsing supermartingales in the following three ways: (1)~With a combination of ranking and repulsing supermartingales we can compute lower bounds on the probability of termination; (2)~repulsing supermartingales provide witnesses for refutation of almost-sure termination; and (3)~with a combination of ranking and repulsing supermartingales we can establish persistence properties of probabilistic programs. We also present results on related computational problems and an experimental evaluation of our approach on academic examples. AU - Chatterjee, Krishnendu AU - Novotny, Petr AU - Zikelic, Djordje ID - 1194 IS - 1 SN - 07308566 TI - Stochastic invariants for probabilistic termination VL - 52 ER - TY - CHAP AB - Development of vascular tissue is a remarkable example of intercellular communication and coordinated development involving hormonal signaling and tissue polarity. Thus far, studies on vascular patterning and regeneration have been conducted mainly in trees—woody plants—with a well-developed layer of vascular cambium and secondary tissues. Trees are difficult to use as genetic models, i.e., due to long generation time, unstable environmental conditions, and lack of available mutants and transgenic lines. Therefore, the use of the main genetic model plant Arabidopsis thaliana (L.) Heynh., with a wealth of available marker and transgenic lines, provides a unique opportunity to address molecular mechanism of vascular tissue formation and regeneration. With specific treatments, the tiny weed Arabidopsis can serve as a model to understand the growth of mighty trees and interconnect a tree physiology with molecular genetics and cell biology of Arabidopsis. AU - Mazur, Ewa AU - Friml, Jirí ED - Jurić, Snježana ID - 545 T2 - Plant Engineering TI - Vascular tissue development and regeneration in the model plant arabidopsis ER - TY - JOUR AB - The mammalian cerebral cortex is responsible for higher cognitive functions such as perception, consciousness, and acquiring and processing information. The neocortex is organized into six distinct laminae, each composed of a rich diversity of cell types which assemble into highly complex cortical circuits. Radial glia progenitors (RGPs) are responsible for producing all neocortical neurons and certain glia lineages. Here, we discuss recent discoveries emerging from clonal lineage analysis at the single RGP cell level that provide us with an inaugural quantitative framework of RGP lineage progression. We further discuss the importance of the relative contribution of intrinsic gene functions and non-cell-autonomous or community effects in regulating RGP proliferation behavior and lineage progression. AU - Beattie, Robert J AU - Hippenmeyer, Simon ID - 621 IS - 24 JF - FEBS letters SN - 00145793 TI - Mechanisms of radial glia progenitor cell lineage progression VL - 591 ER - TY - DATA AB - This data was collected as part of the study [1]. It consists of preprocessed multi-electrode array recording from 160 salamander retinal ganglion cells responding to 297 repeats of a 19 s natural movie. The data is available in two formats: (1) a .mat file containing an array with dimensions “number of repeats” x “number of neurons” x “time in a repeat”; (2) a zipped .txt file containing the same data represented as an array with dimensions “number of neurons” x “number of samples”, where the number of samples is equal to the product of the number of repeats and timebins within a repeat. The time dimension is divided into 20 ms time windows, and the array is binary indicating whether a given cell elicited at least one spike in a given time window during a particular repeat. See the reference below for details regarding collection and preprocessing: [1] Tkačik G, Marre O, Amodei D, Schneidman E, Bialek W, Berry MJ II. Searching for Collective Behavior in a Large Network of Sensory Neurons. PLoS Comput Biol. 2014;10(1):e1003408. AU - Marre, Olivier AU - Tkacik, Gasper AU - Amodei, Dario AU - Schneidman, Elad AU - Bialek, William AU - Berry, Michael ID - 5562 KW - multi-electrode recording KW - retinal ganglion cells TI - Multi-electrode array recording from salamander retinal ganglion cells ER - TY - DATA AB - Graph matching problems as described in "Active Graph Matching for Automatic Joint Segmentation and Annotation of C. Elegans." by Kainmueller, Dagmar and Jug, Florian and Rother, Carsten and Myers, Gene, MICCAI 2014. Problems are in OpenGM2 hdf5 format (see http://hciweb2.iwr.uni-heidelberg.de/opengm/) and a custom text format used by the feature matching solver described in "Feature Correspondence via Graph Matching: Models and Global Optimization." by Lorenzo Torresani, Vladimir Kolmogorov and Carsten Rother, ECCV 2008, code at http://pub.ist.ac.at/~vnk/software/GraphMatching-v1.02.src.zip. AU - Kainmueller, Dagmar AU - Jug, Florian AU - Rother, Carsten AU - Meyers, Gene ID - 5561 KW - graph matching KW - feature matching KW - QAP KW - MAP-inference TI - Graph matching problems for annotating C. Elegans ER - TY - DATA AB - MATLAB code and processed datasets available for reproducing the results in: Lukačišin, M.*, Landon, M.*, Jajoo, R*. (2016) Sequence-Specific Thermodynamic Properties of Nucleic Acids Influence Both Transcriptional Pausing and Backtracking in Yeast. *equal contributions AU - Lukacisin, Martin ID - 5563 TI - MATLAB analysis code for 'Sequence-Specific Thermodynamic Properties of Nucleic Acids Influence Both Transcriptional Pausing and Backtracking in Yeast' ER - TY - THES AB - This thesis describes a brittle fracture simulation method for visual effects applications. Building upon a symmetric Galerkin boundary element method, we first compute stress intensity factors following the theory of linear elastic fracture mechanics. We then use these stress intensities to simulate the motion of a propagating crack front at a significantly higher resolution than the overall deformation of the breaking object. Allowing for spatial variations of the material's toughness during crack propagation produces visually realistic, highly-detailed fracture surfaces. Furthermore, we introduce approximations for stress intensities and crack opening displacements, resulting in both practical speed-up and theoretically superior runtime complexity compared to previous methods. While we choose a quasi-static approach to fracture mechanics, ignoring dynamic deformations, we also couple our fracture simulation framework to a standard rigid-body dynamics solver, enabling visual effects artists to simulate both large scale motion, as well as fracturing due to collision forces in a combined system. As fractures inside of an object grow, their geometry must be represented both in the coarse boundary element mesh, as well as at the desired fine output resolution. Using a boundary element method, we avoid complicated volumetric meshing operations. Instead we describe a simple set of surface meshing operations that allow us to progressively add cracks to the mesh of an object and still re-use all previously computed entries of the linear boundary element system matrix. On the high resolution level, we opt for an implicit surface representation. We then describe how to capture fracture surfaces during crack propagation, as well as separate the individual fragments resulting from the fracture process, based on this implicit representation. We show results obtained with our method, either solving the full boundary element system in every time step, or alternatively using our fast approximations. These results demonstrate that both of these methods perform well in basic test cases and produce realistic fracture surfaces. Furthermore we show that our fast approximations substantially out-perform the standard approach in more demanding scenarios. Finally, these two methods naturally combine, using the full solution while the problem size is manageably small and switching to the fast approximations later on. The resulting hybrid method gives the user a direct way to choose between speed and accuracy of the simulation. AU - Hahn, David ID - 839 SN - 2663-337X TI - Brittle fracture simulation with boundary elements for computer graphics ER - TY - JOUR AB - Moths and butterflies (Lepidoptera) usually have a pair of differentiated WZ sex chromosomes. However, in most lineages outside of the division Ditrysia, as well as in the sister order Trichoptera, females lack a W chromosome. The W is therefore thought to have been acquired secondarily. Here we compare the genomes of three Lepidoptera species (one Dytrisia and two non-Dytrisia) to test three models accounting for the origin of the W: (1) a Z-autosome fusion; (2) a sex chromosome turnover; and (3) a non-canonical mechanism (e.g., through the recruitment of a B chromosome). We show that the gene content of the Z is highly conserved across Lepidoptera (rejecting a sex chromosome turnover) and that very few genes moved onto the Z in the common ancestor of the Ditrysia (arguing against a Z-autosome fusion). Our comparative genomics analysis therefore supports the secondary acquisition of the Lepidoptera W by a non-canonical mechanism, and it confirms the extreme stability of well-differentiated sex chromosomes. AU - Fraisse, Christelle AU - Picard, Marion A AU - Vicoso, Beatriz ID - 614 IS - 1 JF - Nature Communications SN - 20411723 TI - The deep conservation of the Lepidoptera Z chromosome suggests a non canonical origin of the W VL - 8 ER - TY - DATA AB - Compressed Fastq files with whole-genome sequencing data of IS-wt strain D and clones from four evolved populations (A11, C08, C10, D08). Information on this data collection is available in the Methods Section of the primary publication. AU - Steinrück, Magdalena AU - Guet, Calin C ID - 5564 TI - Fastq files for "Complex chromosomal neighborhood effects determine the adaptive potential of a gene under selection" ER - TY - DATA AB - Includes source codes, test cases, and example data used in the thesis Brittle Fracture Simulation with Boundary Elements for Computer Graphics. Also includes pre-built binaries of the HyENA library, but not sources - please contact the HyENA authors to obtain these sources if required (https://mech.tugraz.at/hyena) AU - Hahn, David ID - 5568 KW - Boundary elements KW - brittle fracture KW - computer graphics KW - fracture simulation TI - Source codes: Brittle fracture simulation with boundary elements for computer graphics ER - TY - DATA AB - The de novo genome assemblies generated for this study, and the associated metadata. AU - Fraisse, Christelle ID - 7163 TI - Supplementary Files for "The deep conservation of the Lepidoptera Z chromosome suggests a non canonical origin of the W" ER - TY - DATA AB - Immunological synapse DC-Tcells AU - Leithner, Alexander F ID - 5567 KW - Immunological synapse TI - Immunological synapse DC-Tcells ER - TY - DATA AB - This repository contains the data collected for the manuscript "Biased partitioning of the multi-drug efflux pump AcrAB-TolC underlies long-lived phenotypic heterogeneity". The data is compressed into a single archive. Within the archive, different folders correspond to figures of the main text and the SI of the related publication. Data is saved as plain text, with each folder containing a separate readme file describing the format. Typically, the data is from fluorescence microscopy measurements of single cells growing in a microfluidic "mother machine" device, and consists of relevant values (primarily arbitrary unit or normalized fluorescence measurements, and division times / growth rates) after raw microscopy images have been processed, segmented, and their features extracted, as described in the methods section of the related publication. AU - Bergmiller, Tobias AU - Andersson, Anna M AU - Tomasek, Kathrin AU - Balleza, Enrique AU - Kiviet, Daniel AU - Hauschild, Robert AU - Tkacik, Gasper AU - Guet, Calin C ID - 5560 KW - single cell microscopy KW - mother machine microfluidic device KW - AcrAB-TolC pump KW - multi-drug efflux KW - Escherichia coli TI - Biased partitioning of the multi-drug efflux pump AcrAB-TolC underlies long-lived phenotypic heterogeneity ER - TY - JOUR AB - The molecular mechanisms underlying phenotypic variation in isogenic bacterial populations remain poorly understood.We report that AcrAB-TolC, the main multidrug efflux pump of Escherichia coli, exhibits a strong partitioning bias for old cell poles by a segregation mechanism that is mediated by ternary AcrAB-TolC complex formation. Mother cells inheriting old poles are phenotypically distinct and display increased drug efflux activity relative to daughters. Consequently, we find systematic and long-lived growth differences between mother and daughter cells in the presence of subinhibitory drug concentrations. A simple model for biased partitioning predicts a population structure of long-lived and highly heterogeneous phenotypes. This straightforward mechanism of generating sustained growth rate differences at subinhibitory antibiotic concentrations has implications for understanding the emergence of multidrug resistance in bacteria. AU - Bergmiller, Tobias AU - Andersson, Anna M AU - Tomasek, Kathrin AU - Balleza, Enrique AU - Kiviet, Daniel AU - Hauschild, Robert AU - Tkacik, Gasper AU - Guet, Calin C ID - 665 IS - 6335 JF - Science SN - 00368075 TI - Biased partitioning of the multidrug efflux pump AcrAB TolC underlies long lived phenotypic heterogeneity VL - 356 ER - TY - DATA AB - This folder contains all the data used in each of the main figures of "The genomic characterization of the t-haplotype, a mouse meiotic driver, highlights its complex history and specialized biology" (Kelemen, R., Vicoso, B.), as well as in the supplementary figures. AU - Vicoso, Beatriz ID - 5571 TI - Data for "The genomic characterization of the t-haplotype, a mouse meiotic driver, highlights its complex history and specialized biology" ER - TY - DATA AB - Strong amplifiers of natural selection AU - Pavlogiannis, Andreas AU - Tkadlec, Josef AU - Chatterjee, Krishnendu AU - Nowak , Martin ID - 5559 KW - natural selection TI - Strong amplifiers of natural selection ER - TY - DATA AB - Code described in the Supplementary Methods of "The genomic characterization of the t-haplotype, a mouse meiotic driver, highlights its complex history and specialized biology" (Kelemen, R., Vicoso, B.) AU - Vicoso, Beatriz ID - 5572 TI - Code for "The genomic characterization of the t-haplotype, a mouse meiotic driver, highlights its complex history and specialized biology" ER - TY - JOUR AB - Roots navigate through soil integrating environmental signals to orient their growth. The Arabidopsis root is a widely used model for developmental, physiological and cell biological studies. Live imaging greatly aids these efforts, but the horizontal sample position and continuous root tip displacement present significant difficulties. Here, we develop a confocal microscope setup for vertical sample mounting and integrated directional illumination. We present TipTracker – a custom software for automatic tracking of diverse moving objects usable on various microscope setups. Combined, this enables observation of root tips growing along the natural gravity vector over prolonged periods of time, as well as the ability to induce rapid gravity or light stimulation. We also track migrating cells in the developing zebrafish embryo, demonstrating the utility of this system in the acquisition of high-resolution data sets of dynamic samples. We provide detailed descriptions of the tools enabling the easy implementation on other microscopes. AU - Von Wangenheim, Daniel AU - Hauschild, Robert AU - Fendrych, Matyas AU - Barone, Vanessa AU - Benková, Eva AU - Friml, Jirí ID - 946 JF - eLife TI - Live tracking of moving samples in confocal microscopy for vertically grown roots VL - 6 ER - TY - JOUR AB - One of the key questions in understanding plant development is how single cells behave in a larger context of the tissue. Therefore, it requires the observation of the whole organ with a high spatial- as well as temporal resolution over prolonged periods of time, which may cause photo-toxic effects. This protocol shows a plant sample preparation method for light-sheet microscopy, which is characterized by mounting the plant vertically on the surface of a gel. The plant is mounted in such a way that the roots are submerged in a liquid medium while the leaves remain in the air. In order to ensure photosynthetic activity of the plant, a custom-made lighting system illuminates the leaves. To keep the roots in darkness the water surface is covered with sheets of black plastic foil. This method allows long-term imaging of plant organ development in standardized conditions. AU - Von Wangenheim, Daniel AU - Hauschild, Robert AU - Friml, Jirí ID - 1078 IS - 119 JF - Journal of visualized experiments JoVE TI - Light sheet fluorescence microscopy of plant roots growing on the surface of a gel VL - 2017 ER - TY - DATA AB - One of the key questions in understanding plant development is how single cells behave in a larger context of the tissue. Therefore, it requires the observation of the whole organ with a high spatial- as well as temporal resolution over prolonged periods of time, which may cause photo-toxic effects. This protocol shows a plant sample preparation method for light-sheet microscopy, which is characterized by mounting the plant vertically on the surface of a gel. The plant is mounted in such a way that the roots are submerged in a liquid medium while the leaves remain in the air. In order to ensure photosynthetic activity of the plant, a custom-made lighting system illuminates the leaves. To keep the roots in darkness the water surface is covered with sheets of black plastic foil. This method allows long-term imaging of plant organ development in standardized conditions. The Video is licensed under a CC BY NC ND license. AU - Von Wangenheim, Daniel AU - Hauschild, Robert AU - Friml, Jirí ID - 5565 TI - Light Sheet Fluorescence microscopy of plant roots growing on the surface of a gel ER - TY - CHAP AB - We show that very weak topological assumptions are enough to ensure the existence of a Helly-type theorem. More precisely, we show that for any non-negative integers b and d there exists an integer h(b, d) such that the following holds. If F is a finite family of subsets of Rd such that βi(∩G)≤b for any G⊊F and every 0 ≤ i ≤ [d/2]-1 then F has Helly number at most h(b, d). Here βi denotes the reduced Z2-Betti numbers (with singular homology). These topological conditions are sharp: not controlling any of these [d/2] first Betti numbers allow for families with unbounded Helly number. Our proofs combine homological non-embeddability results with a Ramsey-based approach to build, given an arbitrary simplicial complex K, some well-behaved chain map C*(K)→C*(Rd). AU - Goaoc, Xavier AU - Paták, Pavel AU - Patakova, Zuzana AU - Tancer, Martin AU - Wagner, Uli ED - Loebl, Martin ED - Nešetřil, Jaroslav ED - Thomas, Robin ID - 424 SN - 978-331944479-6 T2 - A Journey through Discrete Mathematics: A Tribute to Jiri Matousek TI - Bounding helly numbers via betti numbers ER - TY - JOUR AB - We investigate transient behaviors induced by magnetic fields on the dynamics of the flow of a ferrofluid in the gap between two concentric, independently rotating cylinders. Without applying any magnetic fields, we uncover emergence of flow states constituted by a combination of a localized spiral state (SPIl) in the top and bottom of the annulus and different multi-cell flow states (SPI2v, SPI3v) with toroidally closed vortices in the interior of the bulk (SPIl+2v = SPIl + SPI2v and SPIl+3v = SPIl + SPI3v). However, when a magnetic field is presented, we observe the transient behaviors between multi-cell states passing through two critical thresholds in a strength of an axial (transverse) magnetic field. Before the first critical threshold of a magnetic field strength, multi-stable states with different number of cells could be observed. After the first critical threshold, we find the transient behavior between the three- and two-cell flow states. For more strength of magnetic field or after the second critical threshold, we discover that multi-cell states are disappeared and a localized spiral state remains to be stimulated. The studied transient behavior could be understood by the investigation of various quantities including a modal kinetic energy, a mode amplitude of the radial velocity, wavenumber, angular momentum, and torque. In addition, the emergence of new flow states and the transient behavior between their states in ferrofluidic flows indicate that richer and potentially controllable dynamics through magnetic fields could be possible in ferrofluic flow. AU - Altmeyer, Sebastian AU - Do, Younghae AU - Ryu, Soorok ID - 463 IS - 11 JF - Chaos SN - 10541500 TI - Transient behavior between multi-cell flow states in ferrofluidic Taylor-Couette flow VL - 27 ER - TY - JOUR AB - Iodine (I 2 ) molecules embedded in He nanodroplets are aligned by a 160 ps long laser pulse. The highest degree of alignment, occurring at the peak of the pulse and quantified by ⟨cos 2 θ 2D ⟩ , is measured as a function of the laser intensity. The results are well described by ⟨cos 2 θ 2D ⟩ calculated for a gas of isolated molecules each with an effective rotational constant of 0.6 times the gas-phase value, and at a temperature of 0.4 K. Theoretical analysis using the angulon quasiparticle to describe rotating molecules in superfluid helium rationalizes why the alignment mechanism is similar to that of isolated molecules with an effective rotational constant. A major advantage of molecules in He droplets is that their 0.4 K temperature leads to stronger alignment than what can generally be achieved for gas phase molecules -- here demonstrated by a direct comparison of the droplet results to measurements on a ∼ 1 K supersonic beam of isolated molecules. This point is further illustrated for more complex system by measurements on 1,4-diiodobenzene and 1,4-dibromobenzene. For all three molecular species studied the highest values of ⟨cos 2 θ 2D ⟩ achieved in He droplets exceed 0.96. AU - Shepperson, Benjamin AU - Chatterley, Adam AU - Søndergaard, Anders AU - Christiansen, Lars AU - Lemeshko, Mikhail AU - Stapelfeldt, Henrik ID - 996 IS - 1 JF - The Journal of Chemical Physics SN - 00219606 TI - Strongly aligned molecules inside helium droplets in the near-adiabatic regime VL - 147 ER - TY - JOUR AB - We consider a many-body system of fermionic atoms interacting via a local pair potential and subject to an external potential within the framework of Bardeen-Cooper-Schrieffer (BCS) theory. We measure the free energy of the whole sample with respect to the free energy of a reference state which allows us to define a BCS functional with boundary conditions at infinity. Our main result is a lower bound for this energy functional in terms of expressions that typically appear in Ginzburg-Landau functionals. AU - Deuchert, Andreas ID - 912 IS - 8 JF - Journal of Mathematical Physics SN - 00222488 TI - A lower bound for the BCS functional with boundary conditions at infinity VL - 58 ER - TY - JOUR AB - RNA Polymerase II pauses and backtracks during transcription, with many consequences for gene expression and cellular physiology. Here, we show that the energy required to melt double-stranded nucleic acids in the transcription bubble predicts pausing in Saccharomyces cerevisiae far more accurately than nucleosome roadblocks do. In addition, the same energy difference also determines when the RNA polymerase backtracks instead of continuing to move forward. This data-driven model corroborates—in a genome wide and quantitative manner—previous evidence that sequence-dependent thermodynamic features of nucleic acids influence both transcriptional pausing and backtracking. AU - Lukacisin, Martin AU - Landon, Matthieu AU - Jajoo, Rishi ID - 1029 IS - 3 JF - PLoS One SN - 19326203 TI - Sequence-specific thermodynamic properties of nucleic acids influence both transcriptional pausing and backtracking in yeast VL - 12 ER - TY - JOUR AB - Immune cells communicate using cytokine signals, but the quantitative rules of this communication aren't clear. In this issue of Immunity, Oyler-Yaniv et al. (2017) suggest that the distribution of a cytokine within a lymphatic organ is primarily governed by the local density of cells consuming it. AU - Assen, Frank P AU - Sixt, Michael K ID - 664 IS - 4 JF - Immunity SN - 10747613 TI - The dynamic cytokine niche VL - 46 ER - TY - JOUR AB - Left-right asymmetry is a fundamental feature of higher-order brain structure; however, the molecular basis of brain asymmetry remains unclear. We recently identified structural and functional asymmetries in mouse hippocampal circuitry that result from the asymmetrical distribution of two distinct populations of pyramidal cell synapses that differ in the density of the NMDA receptor subunit GluRε2 (also known as NR2B, GRIN2B or GluN2B). By examining the synaptic distribution of ε2 subunits, we previously found that β2-microglobulin-deficient mice, which lack cell surface expression of the vast majority of major histocompatibility complex class I (MHCI) proteins, do not exhibit circuit asymmetry. In the present study, we conducted electrophysiological and anatomical analyses on the hippocampal circuitry of mice with a knockout of the paired immunoglobulin-like receptor B (PirB), an MHCI receptor. As in β2-microglobulin-deficient mice, the PirB-deficient hippocampus lacked circuit asymmetries. This finding that MHCI loss-of-function mice and PirB knockout mice have identical phenotypes suggests that MHCI signals that produce hippocampal asymmetries are transduced through PirB. Our results provide evidence for a critical role of the MHCI/PirB signaling system in the generation of asymmetries in hippocampal circuitry. AU - Ukai, Hikari AU - Kawahara, Aiko AU - Hirayama, Keiko AU - Case, Matthew J AU - Aino, Shotaro AU - Miyabe, Masahiro AU - Wakita, Ken AU - Oogi, Ryohei AU - Kasayuki, Michiyo AU - Kawashima, Shihomi AU - Sugimoto, Shunichi AU - Chikamatsu, Kanako AU - Nitta, Noritaka AU - Koga, Tsuneyuki AU - Shigemoto, Ryuichi AU - Takai, Toshiyuki AU - Ito, Isao ID - 682 IS - 6 JF - PLoS One SN - 19326203 TI - PirB regulates asymmetries in hippocampal circuitry VL - 12 ER - TY - JOUR AB - Optogenetics and photopharmacology provide spatiotemporally precise control over protein interactions and protein function in cells and animals. Optogenetic methods that are sensitive to green light and can be used to break protein complexes are not broadly available but would enable multichromatic experiments with previously inaccessible biological targets. Herein, we repurposed cobalamin (vitamin B12) binding domains of bacterial CarH transcription factors for green-light-induced receptor dissociation. In cultured cells, we observed oligomerization-induced cell signaling for the fibroblast growth factor receptor 1 fused to cobalamin-binding domains in the dark that was rapidly eliminated upon illumination. In zebrafish embryos expressing fusion receptors, green light endowed control over aberrant fibroblast growth factor signaling during development. Green-light-induced domain dissociation and light-inactivated receptors will critically expand the optogenetic toolbox for control of biological processes. AU - Kainrath, Stephanie AU - Stadler, Manuela AU - Gschaider-Reichhart, Eva AU - Distel, Martin AU - Janovjak, Harald L ID - 1028 IS - 16 JF - Angewandte Chemie - International Edition SN - 14337851 TI - Green-light-induced inactivation of receptor signaling using cobalamin-binding domains VL - 56 ER - TY - JOUR AB - The history of auxin and cytokinin biology including the initial discoveries by father–son duo Charles Darwin and Francis Darwin (1880), and Gottlieb Haberlandt (1919) is a beautiful demonstration of unceasing continuity of research. Novel findings are integrated into existing hypotheses and models and deepen our understanding of biological principles. At the same time new questions are triggered and hand to hand with this new methodologies are developed to address these new challenges. AU - Hurny, Andrej AU - Benková, Eva ID - 1024 JF - Auxins and Cytokinins in Plant Biology SN - 10643745 TI - Methodological advances in auxin and cytokinin biology VL - 1569 ER - TY - JOUR AB - Protective responses against pathogens require a rapid mobilization of resting neutrophils and the timely removal of activated ones. Neutrophils are exceptionally short-lived leukocytes, yet it remains unclear whether the lifespan of pathogen-engaged neutrophils is regulated differently from that in the circulating steady-state pool. Here, we have found that under homeostatic conditions, the mRNA-destabilizing protein tristetraprolin (TTP) regulates apoptosis and the numbers of activated infiltrating murine neutrophils but not neutrophil cellularity. Activated TTP-deficient neutrophils exhibited decreased apoptosis and enhanced accumulation at the infection site. In the context of myeloid-specific deletion of Ttp, the potentiation of neutrophil deployment protected mice against lethal soft tissue infection with Streptococcus pyogenes and prevented bacterial dissemination. Neutrophil transcriptome analysis revealed that decreased apoptosis of TTP-deficient neutrophils was specifically associated with elevated expression of myeloid cell leukemia 1 (Mcl1) but not other antiapoptotic B cell leukemia/ lymphoma 2 (Bcl2) family members. Higher Mcl1 expression resulted from stabilization of Mcl1 mRNA in the absence of TTP. The low apoptosis rate of infiltrating TTP-deficient neutrophils was comparable to that of transgenic Mcl1-overexpressing neutrophils. Our study demonstrates that posttranscriptional gene regulation by TTP schedules the termination of the antimicrobial engagement of neutrophils. The balancing role of TTP comes at the cost of an increased risk of bacterial infections. AU - Ebner, Florian AU - Sedlyarov, Vitaly AU - Tasciyan, Saren AU - Ivin, Masa AU - Kratochvill, Franz AU - Gratz, Nina AU - Kenner, Lukas AU - Villunger, Andreas AU - Sixt, Michael K AU - Kovarik, Pavel ID - 679 IS - 6 JF - The Journal of Clinical Investigation SN - 00219738 TI - The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection VL - 127 ER - TY - JOUR AB - The segregation of different cell types into distinct tissues is a fundamental process in metazoan development. Differences in cell adhesion and cortex tension are commonly thought to drive cell sorting by regulating tissue surface tension (TST). However, the role that differential TST plays in cell segregation within the developing embryo is as yet unclear. Here, we have analyzed the role of differential TST for germ layer progenitor cell segregation during zebrafish gastrulation. Contrary to previous observations that differential TST drives germ layer progenitor cell segregation in vitro, we show that germ layers display indistinguishable TST within the gastrulating embryo, arguing against differential TST driving germ layer progenitor cell segregation in vivo. We further show that the osmolarity of the interstitial fluid (IF) is an important factor that influences germ layer TST in vivo, and that lower osmolarity of the IF compared with standard cell culture medium can explain why germ layers display differential TST in culture but not in vivo. Finally, we show that directed migration of mesendoderm progenitors is required for germ layer progenitor cell segregation and germ layer formation. AU - Krens, Gabriel AU - Veldhuis, Jim AU - Barone, Vanessa AU - Capek, Daniel AU - Maître, Jean-Léon AU - Brodland, Wayne AU - Heisenberg, Carl-Philipp J ID - 676 IS - 10 JF - Development SN - 09501991 TI - Interstitial fluid osmolarity modulates the action of differential tissue surface tension in progenitor cell segregation during gastrulation VL - 144 ER - TY - JOUR AB - How the organization of genes on a chromosome shapes adaptation is essential for understanding evolutionary paths. Here, we investigate how adaptation to rapidly increasing levels of antibiotic depends on the chromosomal neighborhood of a drug-resistance gene inserted at different positions of the Escherichia coli chromosome. Using a dual-fluorescence reporter that allows us to distinguish gene amplifications from other up-mutations, we track in real-time adaptive changes in expression of the drug-resistance gene. We find that the relative contribution of several mutation types differs systematically between loci due to properties of neighboring genes: essentiality, expression, orientation, termination, and presence of duplicates. These properties determine rate and fitness effects of gene amplification, deletions, and mutations compromising transcriptional termination. Thus, the adaptive potential of a gene under selection is a system-property with a complex genetic basis that is specific for each chromosomal locus, and it can be inferred from detailed functional and genomic data. AU - Steinrück, Magdalena AU - Guet, Calin C ID - 704 JF - eLife SN - 2050084X TI - Complex chromosomal neighborhood effects determine the adaptive potential of a gene under selection VL - 6 ER - TY - JOUR AB - Mutator strains are expected to evolve when the availability and effect of beneficial mutations are high enough to counteract the disadvantage from deleterious mutations that will inevitably accumulate. As the population becomes more adapted to its environment, both availability and effect of beneficial mutations necessarily decrease and mutation rates are predicted to decrease. It has been shown that certain molecular mechanisms can lead to increased mutation rates when the organism finds itself in a stressful environment. While this may be a correlated response to other functions, it could also be an adaptive mechanism, raising mutation rates only when it is most advantageous. Here, we use a mathematical model to investigate the plausibility of the adaptive hypothesis. We show that such a mechanism can be mantained if the population is subjected to diverse stresses. By simulating various antibiotic treatment schemes, we find that combination treatments can reduce the effectiveness of second-order selection on stress-induced mutagenesis. We discuss the implications of our results to strategies of antibiotic therapy. AU - Lukacisinova, Marta AU - Novak, Sebastian AU - Paixao, Tiago ID - 696 IS - 7 JF - PLoS Computational Biology SN - 1553734X TI - Stress induced mutagenesis: Stress diversity facilitates the persistence of mutator genes VL - 13 ER - TY - JOUR AB - The rising prevalence of antibiotic resistant bacteria is an increasingly serious public health challenge. To address this problem, recent work ranging from clinical studies to theoretical modeling has provided valuable insights into the mechanisms of resistance, its emergence and spread, and ways to counteract it. A deeper understanding of the underlying dynamics of resistance evolution will require a combination of experimental and theoretical expertise from different disciplines and new technology for studying evolution in the laboratory. Here, we review recent advances in the quantitative understanding of the mechanisms and evolution of antibiotic resistance. We focus on key theoretical concepts and new technology that enables well-controlled experiments. We further highlight key challenges that can be met in the near future to ultimately develop effective strategies for combating resistance. AU - Lukacisinova, Marta AU - Bollenbach, Mark Tobias ID - 1027 JF - Current Opinion in Biotechnology TI - Toward a quantitative understanding of antibiotic resistance evolution VL - 46 ER - TY - CONF AB - We study the problem of developing efficient approaches for proving worst-case bounds of non-deterministic recursive programs. Ranking functions are sound and complete for proving termination and worst-case bounds of non-recursive programs. First, we apply ranking functions to recursion, resulting in measure functions, and show that they provide a sound and complete approach to prove worst-case bounds of non-deterministic recursive programs. Our second contribution is the synthesis of measure functions in non-polynomial forms. We show that non-polynomial measure functions with logarithm and exponentiation can be synthesized through abstraction of logarithmic or exponentiation terms, Farkas’ Lemma, and Handelman’s Theorem using linear programming. While previous methods obtain worst-case polynomial bounds, our approach can synthesize bounds of the form O(n log n) as well as O(nr) where r is not an integer. We present experimental results to demonstrate that our approach can efficiently obtain worst-case bounds of classical recursive algorithms such as Merge-Sort, Closest-Pair, Karatsuba’s algorithm and Strassen’s algorithm. AU - Chatterjee, Krishnendu AU - Fu, Hongfei AU - Goharshady, Amir ED - Majumdar, Rupak ED - Kunčak, Viktor ID - 639 SN - 978-331963389-3 TI - Non-polynomial worst case analysis of recursive programs VL - 10427 ER - TY - CONF AB - The notion of treewidth of graphs has been exploited for faster algorithms for several problems arising in verification and program analysis. Moreover, various notions of balanced tree decompositions have been used for improved algorithms supporting dynamic updates and analysis of concurrent programs. In this work, we present a tool for constructing tree-decompositions of CFGs obtained from Java methods, which is implemented as an extension to the widely used Soot framework. The experimental results show that our implementation on real-world Java benchmarks is very efficient. Our tool also provides the first implementation for balancing tree-decompositions. In summary, we present the first tool support for exploiting treewidth in the static analysis problems on Java programs. AU - Chatterjee, Krishnendu AU - Goharshady, Amir AU - Pavlogiannis, Andreas ED - D'Souza, Deepak ID - 949 SN - 03029743 TI - JTDec: A tool for tree decompositions in soot VL - 10482 ER - TY - JOUR AB - During embryonic development, mechanical forces are essential for cellular rearrangements driving tissue morphogenesis. Here, we show that in the early zebrafish embryo, friction forces are generated at the interface between anterior axial mesoderm (prechordal plate, ppl) progenitors migrating towards the animal pole and neurectoderm progenitors moving in the opposite direction towards the vegetal pole of the embryo. These friction forces lead to global rearrangement of cells within the neurectoderm and determine the position of the neural anlage. Using a combination of experiments and simulations, we show that this process depends on hydrodynamic coupling between neurectoderm and ppl as a result of E-cadherin-mediated adhesion between those tissues. Our data thus establish the emergence of friction forces at the interface between moving tissues as a critical force-generating process shaping the embryo. AU - Smutny, Michael AU - Ákos, Zsuzsa AU - Grigolon, Silvia AU - Shamipour, Shayan AU - Ruprecht, Verena AU - Capek, Daniel AU - Behrndt, Martin AU - Papusheva, Ekaterina AU - Tada, Masazumi AU - Hof, Björn AU - Vicsek, Tamás AU - Salbreux, Guillaume AU - Heisenberg, Carl-Philipp J ID - 661 JF - Nature Cell Biology SN - 14657392 TI - Friction forces position the neural anlage VL - 19 ER - TY - JOUR AB - Cell-cell contact formation constitutes an essential step in evolution, leading to the differentiation of specialized cell types. However, remarkably little is known about whether and how the interplay between contact formation and fate specification affects development. Here, we identify a positive feedback loop between cell-cell contact duration, morphogen signaling, and mesendoderm cell-fate specification during zebrafish gastrulation. We show that long-lasting cell-cell contacts enhance the competence of prechordal plate (ppl) progenitor cells to respond to Nodal signaling, required for ppl cell-fate specification. We further show that Nodal signaling promotes ppl cell-cell contact duration, generating a positive feedback loop between ppl cell-cell contact duration and cell-fate specification. Finally, by combining mathematical modeling and experimentation, we show that this feedback determines whether anterior axial mesendoderm cells become ppl or, instead, turn into endoderm. Thus, the interdependent activities of cell-cell signaling and contact formation control fate diversification within the developing embryo. AU - Barone, Vanessa AU - Lang, Moritz AU - Krens, Gabriel AU - Pradhan, Saurabh AU - Shamipour, Shayan AU - Sako, Keisuke AU - Sikora, Mateusz K AU - Guet, Calin C AU - Heisenberg, Carl-Philipp J ID - 735 IS - 2 JF - Developmental Cell SN - 15345807 TI - An effective feedback loop between cell-cell contact duration and morphogen signaling determines cell fate VL - 43 ER - TY - JOUR AB - The human cerebral cortex is the seat of our cognitive abilities and composed of an extraordinary number of neurons, organized in six distinct layers. The establishment of specific morphological and physiological features in individual neurons needs to be regulated with high precision. Impairments in the sequential developmental programs instructing corticogenesis lead to alterations in the cortical cytoarchitecture which is thought to represent the major underlying cause for several neurological disorders including neurodevelopmental and psychiatric diseases. In this review we discuss the role of cell polarity at sequential stages during cortex development. We first provide an overview of morphological cell polarity features in cortical neural stem cells and newly-born postmitotic neurons. We then synthesize a conceptual molecular and biochemical framework how cell polarity is established at the cellular level through a break in symmetry in nascent cortical projection neurons. Lastly we provide a perspective how the molecular mechanisms applying to single cells could be probed and integrated in an in vivo and tissue-wide context. AU - Hansen, Andi H AU - Düllberg, Christian F AU - Mieck, Christine AU - Loose, Martin AU - Hippenmeyer, Simon ID - 960 JF - Frontiers in Cellular Neuroscience SN - 16625102 TI - Cell polarity in cerebral cortex development - cellular architecture shaped by biochemical networks VL - 11 ER - TY - JOUR AB - Feedback loops in biological networks, among others, enable differentiation and cell cycle progression, and increase robustness in signal transduction. In natural networks, feedback loops are often complex and intertwined, making it challenging to identify which loops are mainly responsible for an observed behavior. However, minimal synthetic replicas could allow for such identification. Here, we engineered a synthetic permease-inducer-repressor system in Saccharomyces cerevisiae to analyze if a transport-mediated positive feedback loop could be a core mechanism for the switch-like behavior in the regulation of metabolic gene networks such as the S. cerevisiae GAL system or the Escherichia coli lac operon. We characterized the synthetic circuit using deterministic and stochastic mathematical models. Similar to its natural counterparts, our synthetic system shows bistable and hysteretic behavior, and the inducer concentration range for bistability as well as the switching rates between the two stable states depend on the repressor concentration. Our results indicate that a generic permease–inducer–repressor circuit with a single feedback loop is sufficient to explain the experimentally observed bistable behavior of the natural systems. We anticipate that the approach of reimplementing natural systems with orthogonal parts to identify crucial network components is applicable to other natural systems such as signaling pathways. AU - Gnügge, Robert AU - Dharmarajan, Lekshmi AU - Lang, Moritz AU - Stelling, Jörg ID - 1008 IS - 10 JF - ACS Synthetic Biology TI - An orthogonal permease–inducer–repressor feedback loop shows bistability VL - 5 ER - TY - CONF AB - Games on graphs provide the appropriate framework to study several central problems in computer science, such as verification and synthesis of reactive systems. One of the most basic objectives for games on graphs is the liveness (or Büchi) objective that given a target set of vertices requires that some vertex in the target set is visited infinitely often. We study generalized Büchi objectives (i.e., conjunction of liveness objectives), and implications between two generalized Büchi objectives (known as GR(1) objectives), that arise in numerous applications in computer-aided verification. We present improved algorithms and conditional super-linear lower bounds based on widely believed assumptions about the complexity of (A1) combinatorial Boolean matrix multiplication and (A2) CNF-SAT. We consider graph games with n vertices, m edges, and generalized Büchi objectives with k conjunctions. First, we present an algorithm with running time O(k*n^2), improving the previously known O(k*n*m) and O(k^2*n^2) worst-case bounds. Our algorithm is optimal for dense graphs under (A1). Second, we show that the basic algorithm for the problem is optimal for sparse graphs when the target sets have constant size under (A2). Finally, we consider GR(1) objectives, with k_1 conjunctions in the antecedent and k_2 conjunctions in the consequent, and present an O(k_1 k_2 n^{2.5})-time algorithm, improving the previously known O(k_1*k_2*n*m)-time algorithm for m > n^{1.5}. AU - Chatterjee, Krishnendu AU - Dvorák, Wolfgang AU - Henzinger, Monika H AU - Loitzenbauer, Veronika ID - 1068 TI - Conditionally optimal algorithms for generalized Büchi Games VL - 58 ER - TY - CONF AB - The Continuous Skolem Problem asks whether a real-valued function satisfying a linear differen- tial equation has a zero in a given interval of real numbers. This is a fundamental reachability problem for continuous linear dynamical systems, such as linear hybrid automata and continuous- time Markov chains. Decidability of the problem is currently open – indeed decidability is open even for the sub-problem in which a zero is sought in a bounded interval. In this paper we show decidability of the bounded problem subject to Schanuel’s Conjecture, a unifying conjecture in transcendental number theory. We furthermore analyse the unbounded problem in terms of the frequencies of the differential equation, that is, the imaginary parts of the characteristic roots. We show that the unbounded problem can be reduced to the bounded problem if there is at most one rationally linearly independent frequency, or if there are two rationally linearly independent frequencies and all characteristic roots are simple. We complete the picture by showing that de- cidability of the unbounded problem in the case of two (or more) rationally linearly independent frequencies would entail a major new effectiveness result in Diophantine approximation, namely computability of the Diophantine-approximation types of all real algebraic numbers. AU - Chonev, Ventsislav K AU - Ouaknine, Joël AU - Worrell, James ID - 1069 TI - On the skolem problem for continuous linear dynamical systems VL - 55 ER - TY - CONF AB - We present a logic that extends CTL (Computation Tree Logic) with operators that express synchronization properties. A property is synchronized in a system if it holds in all paths of a certain length. The new logic is obtained by using the same path quantifiers and temporal operators as in CTL, but allowing a different order of the quantifiers. This small syntactic variation induces a logic that can express non-regular properties for which known extensions of MSO with equality of path length are undecidable. We show that our variant of CTL is decidable and that the model-checking problem is in Delta_3^P = P^{NP^NP}, and is DP-hard. We analogously consider quantifier exchange in extensions of CTL, and we present operators defined using basic operators of CTL* that express the occurrence of infinitely many synchronization points. We show that the model-checking problem remains in Delta_3^P. The distinguishing power of CTL and of our new logic coincide if the Next operator is allowed in the logics, thus the classical bisimulation quotient can be used for state-space reduction before model checking. AU - Chatterjee, Krishnendu AU - Doyen, Laurent ID - 1070 TI - Computation tree logic for synchronization properties VL - 55 ER - TY - JOUR AB - The asymmetric localization of proteins in the plasma membrane domains of eukaryotic cells is a fundamental manifestation of cell polarity that is central to multicellular organization and developmental patterning. In plants, the mechanisms underlying the polar localization of cargo proteins are still largely unknown and appear to be fundamentally distinct from those operating in mammals. Here, we present a systematic, quantitative comparative analysis of the polar delivery and subcellular localization of proteins that characterize distinct polar plasma membrane domains in plant cells. The combination of microscopic analyses and computational modeling revealed a mechanistic framework common to diverse polar cargos and underlying the establishment and maintenance of apical, basal, and lateral polar domains in plant cells. This mechanism depends on the polar secretion, constitutive endocytic recycling, and restricted lateral diffusion of cargos within the plasma membrane. Moreover, our observations suggest that polar cargo distribution involves the individual protein potential to form clusters within the plasma membrane and interact with the extracellular matrix. Our observations provide insights into the shared cellular mechanisms of polar cargo delivery and polarity maintenance in plant cells. AU - Łangowski, Łukasz AU - Wabnik, Krzysztof T AU - Li, Hongjiang AU - Vanneste, Steffen AU - Naramoto, Satoshi AU - Tanaka, Hirokazu AU - Friml, Jirí ID - 1081 JF - Cell Discovery TI - Cellular mechanisms for cargo delivery and polarity maintenance at different polar domains in plant cells VL - 2 ER - TY - CONF AB - In many applications, it is desirable to extract only the relevant aspects of data. A principled way to do this is the information bottleneck (IB) method, where one seeks a code that maximises information about a relevance variable, Y, while constraining the information encoded about the original data, X. Unfortunately however, the IB method is computationally demanding when data are high-dimensional and/or non-gaussian. Here we propose an approximate variational scheme for maximising a lower bound on the IB objective, analogous to variational EM. Using this method, we derive an IB algorithm to recover features that are both relevant and sparse. Finally, we demonstrate how kernelised versions of the algorithm can be used to address a broad range of problems with non-linear relation between X and Y. AU - Chalk, Matthew J AU - Marre, Olivier AU - Tkacik, Gasper ID - 1082 TI - Relevant sparse codes with variational information bottleneck VL - 29 ER - TY - JOUR AB - Cholecystokinin-expressing interneurons (CCK-INs) mediate behavior state-dependent inhibition in cortical circuits and themselves receive strong GABAergic input. However, it remains unclear to what extent GABABreceptors (GABABRs) contribute to their inhibitory control. Using immunoelectron microscopy, we found that CCK-INs in the rat hippocampus possessed high levels of dendritic GABABRs and KCTD12 auxiliary proteins, whereas postsynaptic effector Kir3 channels were present at lower levels. Consistently, whole-cell recordings revealed slow GABABR-mediated inhibitory postsynaptic currents (IPSCs) in most CCK-INs. In spite of the higher surface density of GABABRs in CCK-INs than in CA1 principal cells, the amplitudes of IPSCs were comparable, suggesting that the expression of Kir3 channels is the limiting factor for the GABABR currents in these INs. Morphological analysis showed that CCK-INs were diverse, comprising perisomatic-targeting basket cells (BCs), as well as dendrite-targeting (DT) interneurons, including a previously undescribed DT type. GABABR-mediated IPSCs in CCK-INs were large in BCs, but small in DT subtypes. In response to prolonged activation, GABABR-mediated currents displayed strong desensitization, which was absent in KCTD12-deficient mice. This study highlights that GABABRs differentially control CCK-IN subtypes, and the kinetics and desensitization of GABABR-mediated currents are modulated by KCTD12 proteins. AU - Booker, Sam AU - Althof, Daniel AU - Gross, Anna AU - Loreth, Desiree AU - Müller, Johanna AU - Unger, Andreas AU - Fakler, Bernd AU - Varro, Andrea AU - Watanabe, Masahiko AU - Gassmann, Martin AU - Bettler, Bernhard AU - Shigemoto, Ryuichi AU - Vida, Imre AU - Kulik, Ákos ID - 1083 IS - 3 JF - Cerebral Cortex TI - KCTD12 auxiliary proteins modulate kinetics of GABAB receptor-mediated inhibition in Cholecystokinin-containing interneurons VL - 27 ER - TY - CONF AB - While weighted automata provide a natural framework to express quantitative properties, many basic properties like average response time cannot be expressed with weighted automata. Nested weighted automata extend weighted automata and consist of a master automaton and a set of slave automata that are invoked by the master automaton. Nested weighted automata are strictly more expressive than weighted automata (e.g., average response time can be expressed with nested weighted automata), but the basic decision questions have higher complexity (e.g., for deterministic automata, the emptiness question for nested weighted automata is PSPACE-hard, whereas the corresponding complexity for weighted automata is PTIME). We consider a natural subclass of nested weighted automata where at any point at most a bounded number k of slave automata can be active. We focus on automata whose master value function is the limit average. We show that these nested weighted automata with bounded width are strictly more expressive than weighted automata (e.g., average response time with no overlapping requests can be expressed with bound k=1, but not with non-nested weighted automata). We show that the complexity of the basic decision problems (i.e., emptiness and universality) for the subclass with k constant matches the complexity for weighted automata. Moreover, when k is part of the input given in unary we establish PSPACE-completeness. AU - Chatterjee, Krishnendu AU - Henzinger, Thomas A AU - Otop, Jan ID - 1090 TI - Nested weighted limit-average automata of bounded width VL - 58 ER - TY - CONF AB - The semantics of concurrent data structures is usually given by a sequential specification and a consistency condition. Linearizability is the most popular consistency condition due to its simplicity and general applicability. Nevertheless, for applications that do not require all guarantees offered by linearizability, recent research has focused on improving performance and scalability of concurrent data structures by relaxing their semantics. In this paper, we present local linearizability, a relaxed consistency condition that is applicable to container-type concurrent data structures like pools, queues, and stacks. While linearizability requires that the effect of each operation is observed by all threads at the same time, local linearizability only requires that for each thread T, the effects of its local insertion operations and the effects of those removal operations that remove values inserted by T are observed by all threads at the same time. We investigate theoretical and practical properties of local linearizability and its relationship to many existing consistency conditions. We present a generic implementation method for locally linearizable data structures that uses existing linearizable data structures as building blocks. Our implementations show performance and scalability improvements over the original building blocks and outperform the fastest existing container-type implementations. AU - Haas, Andreas AU - Henzinger, Thomas A AU - Holzer, Andreas AU - Kirsch, Christoph AU - Lippautz, Michael AU - Payer, Hannes AU - Sezgin, Ali AU - Sokolova, Ana AU - Veith, Helmut ID - 1095 T2 - Leibniz International Proceedings in Informatics TI - Local linearizability for concurrent container-type data structures VL - 59 ER - TY - CONF AB - We present an interactive system for computational design, optimization, and fabrication of multicopters. Our computational approach allows non-experts to design, explore, and evaluate a wide range of different multicopters. We provide users with an intuitive interface for assembling a multicopter from a collection of components (e.g., propellers, motors, and carbon fiber rods). Our algorithm interactively optimizes shape and controller parameters of the current design to ensure its proper operation. In addition, we allow incorporating a variety of other metrics (such as payload, battery usage, size, and cost) into the design process and exploring tradeoffs between them. We show the efficacy of our method and system by designing, optimizing, fabricating, and operating multicopters with complex geometries and propeller configurations. We also demonstrate the ability of our optimization algorithm to improve the multicopter performance under different metrics. AU - Du, Tao AU - Schulz, Adriana AU - Zhu, Bo AU - Bickel, Bernd AU - Matusik, Wojciech ID - 1097 IS - 6 TI - Computational multicopter design VL - 35 ER - TY - CONF AB - Better understanding of the potential benefits of information transfer and representation learning is an important step towards the goal of building intelligent systems that are able to persist in the world and learn over time. In this work, we consider a setting where the learner encounters a stream of tasks but is able to retain only limited information from each encountered task, such as a learned predictor. In contrast to most previous works analyzing this scenario, we do not make any distributional assumptions on the task generating process. Instead, we formulate a complexity measure that captures the diversity of the observed tasks. We provide a lifelong learning algorithm with error guarantees for every observed task (rather than on average). We show sample complexity reductions in comparison to solving every task in isolation in terms of our task complexity measure. Further, our algorithmic framework can naturally be viewed as learning a representation from encountered tasks with a neural network. AU - Pentina, Anastasia AU - Urner, Ruth ID - 1098 TI - Lifelong learning with weighted majority votes VL - 29 ER - TY - CONF AB - We present FlexMolds, a novel computational approach to automatically design flexible, reusable molds that, once 3D printed, allow us to physically fabricate, by means of liquid casting, multiple copies of complex shapes with rich surface details and complex topology. The approach to design such flexible molds is based on a greedy bottom-up search of possible cuts over an object, evaluating for each possible cut the feasibility of the resulting mold. We use a dynamic simulation approach to evaluate candidate molds, providing a heuristic to generate forces that are able to open, detach, and remove a complex mold from the object it surrounds. We have tested the approach with a number of objects with nontrivial shapes and topologies. AU - Malomo, Luigi AU - Pietroni, Nico AU - Bickel, Bernd AU - Cignoni, Paolo ID - 1099 IS - 6 TI - FlexMolds: Automatic design of flexible shells for molding VL - 35 ER - TY - CONF AB - Weakly-supervised object localization methods tend to fail for object classes that consistently co-occur with the same background elements, e.g. trains on tracks. We propose a method to overcome these failures by adding a very small amount of model-specific additional annotation. The main idea is to cluster a deep network\'s mid-level representations and assign object or distractor labels to each cluster. Experiments show substantially improved localization results on the challenging ILSVC2014 dataset for bounding box detection and the PASCAL VOC2012 dataset for semantic segmentation. AU - Kolesnikov, Alexander AU - Lampert, Christoph ID - 1102 T2 - Proceedings of the British Machine Vision Conference 2016 TI - Improving weakly-supervised object localization by micro-annotation VL - 2016-September ER - TY - CONF AB - We propose two parallel state-space-exploration algorithms for hybrid automaton (HA), with the goal of enhancing performance on multi-core shared-memory systems. The first uses the parallel, breadth-first-search algorithm (PBFS) of the SPIN model checker, when traversing the discrete modes of the HA, and enhances it with a parallel exploration of the continuous states within each mode. We show that this simple-minded extension of PBFS does not provide the desired load balancing in many HA benchmarks. The second algorithm is a task-parallel BFS algorithm (TP-BFS), which uses a cheap precomputation of the cost associated with the post operations (both continuous and discrete) in order to improve load balancing. We illustrate the TP-BFS and the cost precomputation of the post operators on a support-function-based algorithm for state-space exploration. The performance comparison of the two algorithms shows that, in general, TP-BFS provides a better utilization/load-balancing of the CPU. Both algorithms are implemented in the model checker XSpeed. Our experiments show a maximum speed-up of more than 2000 χ on a navigation benchmark, with respect to SpaceEx LGG scenario. In order to make the comparison fair, we employed an equal number of post operations in both tools. To the best of our knowledge, this paper represents the first attempt to provide parallel, reachability-analysis algorithms for HA. AU - Gurung, Amit AU - Deka, Arup AU - Bartocci, Ezio AU - Bogomolov, Sergiy AU - Grosu, Radu AU - Ray, Rajarshi ID - 1103 TI - Parallel reachability analysis for hybrid systems ER - TY - CONF AB - Jointly characterizing neural responses in terms of several external variables promises novel insights into circuit function, but remains computationally prohibitive in practice. Here we use gaussian process (GP) priors and exploit recent advances in fast GP inference and learning based on Kronecker methods, to efficiently estimate multidimensional nonlinear tuning functions. Our estimator require considerably less data than traditional methods and further provides principled uncertainty estimates. We apply these tools to hippocampal recordings during open field exploration and use them to characterize the joint dependence of CA1 responses on the position of the animal and several other variables, including the animal\'s speed, direction of motion, and network oscillations.Our results provide an unprecedentedly detailed quantification of the tuning of hippocampal neurons. The model\'s generality suggests that our approach can be used to estimate neural response properties in other brain regions. AU - Savin, Cristina AU - Tkacik, Gasper ID - 1105 TI - Estimating nonlinear neural response functions using GP priors and Kronecker methods VL - 29 ER - TY - CONF AB - We present a coherent microwave to telecom signal converter based on the electro-optical effect using a crystalline WGM-resonator coupled to a 3D microwave cavity, achieving high photon conversion efficiency of 0.1% with MHz bandwidth. AU - Rueda, Alfredo AU - Sedlmeir, Florian AU - Collodo, Michele AU - Vogl, Ulrich AU - Stiller, Birgit AU - Schunk, Georg AU - Strekalov, Dimitry AU - Marquardt, Christoph AU - Fink, Johannes M AU - Painter, Oskar AU - Leuchs, Gerd AU - Schwefel, Harald ID - 1115 TI - Efficient single sideband microwave to optical conversion using a LiNbO₃ WGM-resonator ER - TY - CONF AB - Time-triggered (TT) switched networks are a deterministic communication infrastructure used by real-time distributed embedded systems. These networks rely on the notion of globally discretized time (i.e. time slots) and a static TT schedule that prescribes which message is sent through which link at every time slot, such that all messages reach their destination before a global timeout. These schedules are generated offline, assuming a static network with fault-free links, and entrusting all error-handling functions to the end user. Assuming the network is static is an over-optimistic view, and indeed links tend to fail in practice. We study synthesis of TT schedules on a network in which links fail over time and we assume the switches run a very simple error-recovery protocol once they detect a crashed link. We address the problem of finding a pk; qresistant schedule; namely, one that, assuming the switches run a fixed error-recovery protocol, guarantees that the number of messages that arrive at their destination by the timeout is at least no matter what sequence of at most k links fail. Thus, we maintain the simplicity of the switches while giving a guarantee on the number of messages that meet the timeout. We show how a pk; q-resistant schedule can be obtained using a CEGAR-like approach: find a schedule, decide whether it is pk; q-resistant, and if it is not, use the witnessing fault sequence to generate a constraint that is added to the program. The newly added constraint disallows the schedule to be regenerated in a future iteration while also eliminating several other schedules that are not pk; q-resistant. We illustrate the applicability of our approach using an SMT-based implementation. © 2016 ACM. AU - Avni, Guy AU - Guha, Shibashis AU - Rodríguez Navas, Guillermo ID - 1135 T2 - Proceedings of the 13th International Conference on Embedded Software TI - Synthesizing time triggered schedules for switched networks with faulty links ER - TY - CONF AB - Hybrid systems have both continuous and discrete dynamics and are useful for modeling a variety of control systems, from air traffic control protocols to robotic maneuvers and beyond. Recently, numerous powerful and scalable tools for analyzing hybrid systems have emerged. Several of these tools implement automated formal methods for mathematically proving a system meets a specification. This tutorial session will present three recent hybrid systems tools: C2E2, HyST, and TuLiP. C2E2 is a simulated-based verification tool for hybrid systems, and uses validated numerical solvers and bloating of simulation traces to verify systems meet specifications. HyST is a hybrid systems model transformation and translation tool, and uses a canonical intermediate representation to support most of the recent verification tools, as well as automated sound abstractions that simplify verification of a given hybrid system. TuLiP is a controller synthesis tool for hybrid systems, where given a temporal logic specification to be satisfied for a system (plant) model, TuLiP will find a controller that meets a given specification. © 2016 IEEE. AU - Duggirala, Parasara AU - Fan, Chuchu AU - Potok, Matthew AU - Qi, Bolun AU - Mitra, Sayan AU - Viswanathan, Mahesh AU - Bak, Stanley AU - Bogomolov, Sergiy AU - Johnson, Taylor AU - Nguyen, Luan AU - Schilling, Christian AU - Sogokon, Andrew AU - Tran, Hoang AU - Xiang, Weiming ID - 1134 T2 - 2016 IEEE Conference on Control Applications TI - Tutorial: Software tools for hybrid systems verification transformation and synthesis C2E2 HyST and TuLiP ER - TY - CONF AB - We propose an interactive sculpting system for seamlessly editing pre-computed animations of liquid, without the need for any resimulation. The input is a sequence of meshes without correspondences representing the liquid surface over time. Our method enables the efficient selection of consistent space-time parts of this animation, such as moving waves or droplets, which we call space-time features. Once selected, a feature can be copied, edited, or duplicated and then pasted back anywhere in space and time in the same or in another liquid animation sequence. Our method circumvents tedious user interactions by automatically computing the spatial and temporal ranges of the selected feature. We also provide space-time shape editing tools for non-uniform scaling, rotation, trajectory changes, and temporal editing to locally speed up or slow down motion. Using our tools, the user can edit and progressively refine any input simulation result, possibly using a library of precomputed space-time features extracted from other animations. In contrast to the trial-and-error loop usually required to edit animation results through the tuning of indirect simulation parameters, our method gives the user full control over the edited space-time behaviors. © 2016 Copyright held by the owner/author(s). AU - Manteaux, Pierre AU - Vimont, Ulysse AU - Wojtan, Christopher J AU - Rohmer, Damien AU - Cani, Marie ID - 1136 T2 - Proceedings of the 9th International Conference on Motion in Games TI - Space-time sculpting of liquid animation ER - TY - JOUR AB - RASGRP1 is an important guanine nucleotide exchange factor and activator of the RAS-MAPK pathway following T cell antigen receptor (TCR) signaling. The consequences of RASGRP1 mutations in humans are unknown. In a patient with recurrent bacterial and viral infections, born to healthy consanguineous parents, we used homozygosity mapping and exome sequencing to identify a biallelic stop-gain variant in RASGRP1. This variant segregated perfectly with the disease and has not been reported in genetic databases. RASGRP1 deficiency was associated in T cells and B cells with decreased phosphorylation of the extracellular-signal-regulated serine kinase ERK, which was restored following expression of wild-type RASGRP1. RASGRP1 deficiency also resulted in defective proliferation, activation and motility of T cells and B cells. RASGRP1-deficient natural killer (NK) cells exhibited impaired cytotoxicity with defective granule convergence and actin accumulation. Interaction proteomics identified the dynein light chain DYNLL1 as interacting with RASGRP1, which links RASGRP1 to cytoskeletal dynamics. RASGRP1-deficient cells showed decreased activation of the GTPase RhoA. Treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects of RASGRP1-deficient lymphocytes. AU - Salzer, Elisabeth AU - Çaǧdaş, Deniz AU - Hons, Miroslav AU - Mace, Emily AU - Garncarz, Wojciech AU - Petronczki, Oezlem AU - Platzer, René AU - Pfajfer, Laurène AU - Bilic, Ivan AU - Ban, Sol AU - Willmann, Katharina AU - Mukherjee, Malini AU - Supper, Verena AU - Hsu, Hsiangting AU - Banerjee, Pinaki AU - Sinha, Papiya AU - Mcclanahan, Fabienne AU - Zlabinger, Gerhard AU - Pickl, Winfried AU - Gribben, John AU - Stockinger, Hannes AU - Bennett, Keiryn AU - Huppa, Johannes AU - Dupré, Loï̈C AU - Sanal, Özden AU - Jäger, Ulrich AU - Sixt, Michael K AU - Tezcan, Ilhan AU - Orange, Jordan AU - Boztug, Kaan ID - 1137 IS - 12 JF - Nature Immunology TI - RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics VL - 17 ER - TY - CONF AB - Automata with monitor counters, where the transitions do not depend on counter values, and nested weighted automata are two expressive automata-theoretic frameworks for quantitative properties. For a well-studied and wide class of quantitative functions, we establish that automata with monitor counters and nested weighted automata are equivalent. We study for the first time such quantitative automata under probabilistic semantics. We show that several problems that are undecidable for the classical questions of emptiness and universality become decidable under the probabilistic semantics. We present a complete picture of decidability for such automata, and even an almost-complete picture of computational complexity, for the probabilistic questions we consider. © 2016 ACM. AU - Chatterjee, Krishnendu AU - Henzinger, Thomas A AU - Otop, Jan ID - 1138 T2 - Proceedings of the 31st Annual ACM/IEEE Symposium TI - Quantitative automata under probabilistic semantics ER - TY - CONF AB - Given a model of a system and an objective, the model-checking question asks whether the model satisfies the objective. We study polynomial-time problems in two classical models, graphs and Markov Decision Processes (MDPs), with respect to several fundamental -regular objectives, e.g., Rabin and Streett objectives. For many of these problems the best-known upper bounds are quadratic or cubic, yet no super-linear lower bounds are known. In this work our contributions are two-fold: First, we present several improved algorithms, and second, we present the first conditional super-linear lower bounds based on widely believed assumptions about the complexity of CNF-SAT and combinatorial Boolean matrix multiplication. A separation result for two models with respect to an objective means a conditional lower bound for one model that is strictly higher than the existing upper bound for the other model, and similarly for two objectives with respect to a model. Our results establish the following separation results: (1) A separation of models (graphs and MDPs) for disjunctive queries of reachability and Büchi objectives. (2) Two kinds of separations of objectives, both for graphs and MDPs, namely, (2a) the separation of dual objectives such as Streett/Rabin objectives, and (2b) the separation of conjunction and disjunction of multiple objectives of the same type such as safety, Büchi, and coBüchi. In summary, our results establish the first model and objective separation results for graphs and MDPs for various classical -regular objectives. Quite strikingly, we establish conditional lower bounds for the disjunction of objectives that are strictly higher than the existing upper bounds for the conjunction of the same objectives. © 2016 ACM. AU - Chatterjee, Krishnendu AU - Dvoák, Wolfgang AU - Henzinger, Monika H AU - Loitzenbauer, Veronika ID - 1140 T2 - Proceedings of the 31st Annual ACM/IEEE Symposium on Logic in Computer Science TI - Model and objective separation with conditional lower bounds: disjunction is harder than conjunction ER - TY - JOUR AB - Hemolysis drives susceptibility to bacterial infections and predicts poor outcome from sepsis. These detrimental effects are commonly considered to be a consequence of heme-iron serving as a nutrient for bacteria. We employed a Gram-negative sepsis model and found that elevated heme levels impaired the control of bacterial proliferation independently of heme-iron acquisition by pathogens. Heme strongly inhibited phagocytosis and the migration of human and mouse phagocytes by disrupting actin cytoskeletal dynamics via activation of the GTP-binding Rho family protein Cdc42 by the guanine nucleotide exchange factor DOCK8. A chemical screening approach revealed that quinine effectively prevented heme effects on the cytoskeleton, restored phagocytosis and improved survival in sepsis. These mechanistic insights provide potential therapeutic targets for patients with sepsis or hemolytic disorders. AU - Martins, Rui AU - Maier, Julia AU - Gorki, Anna AU - Huber, Kilian AU - Sharif, Omar AU - Starkl, Philipp AU - Saluzzo, Simona AU - Quattrone, Federica AU - Gawish, Riem AU - Lakovits, Karin AU - Aichinger, Michael AU - Radic Sarikas, Branka AU - Lardeau, Charles AU - Hladik, Anastasiya AU - Korosec, Ana AU - Brown, Markus AU - Vaahtomeri, Kari AU - Duggan, Michelle AU - Kerjaschki, Dontscho AU - Esterbauer, Harald AU - Colinge, Jacques AU - Eisenbarth, Stephanie AU - Decker, Thomas AU - Bennett, Keiryn AU - Kubicek, Stefan AU - Sixt, Michael K AU - Superti Furga, Giulio AU - Knapp, Sylvia ID - 1142 IS - 12 JF - Nature Immunology TI - Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions VL - 17 ER - TY - JOUR AB - In this paper we introduce the Multiobjective Optimization Hierarchic Genetic Strategy with maturing (MO-mHGS), a meta-algorithm that performs evolutionary optimization in a hierarchy of populations. The maturing mechanism improves growth and reduces redundancy. The performance of MO-mHGS with selected state-of-the-art multiobjective evolutionary algorithms as internal algorithms is analysed on benchmark problems and their modifications for which single fitness evaluation time depends on the solution accuracy. We compare the proposed algorithm with the Island Model Genetic Algorithm as well as with single-deme methods, and discuss the impact of internal algorithms on the MO-mHGS meta-algorithm. © 2016 Elsevier B.V. AU - Łazarz, Radosław AU - Idzik, Michał AU - Gądek, Konrad AU - Gajda-Zagorska, Ewa P ID - 1141 IS - 1 JF - Journal of Computational Science TI - Hierarchic genetic strategy with maturing as a generic tool for multiobjective optimization VL - 17 ER - TY - JOUR AB - We study the ground state of a dilute Bose gas in a scaling limit where the Gross-Pitaevskii functional emerges. This is a repulsive nonlinear Schrödinger functional whose quartic term is proportional to the scattering length of the interparticle interaction potential. We propose a new derivation of this limit problem, with a method that bypasses some of the technical difficulties that previous derivations had to face. The new method is based on a combination of Dyson\'s lemma, the quantum de Finetti theorem and a second moment estimate for ground states of the effective Dyson Hamiltonian. It applies equally well to the case where magnetic fields or rotation are present. AU - Nam, Phan AU - Rougerie, Nicolas AU - Seiringer, Robert ID - 1143 IS - 2 JF - Analysis and PDE TI - Ground states of large bosonic systems: The gross Pitaevskii limit revisited VL - 9 ER - TY - JOUR AB - Auxin directs plant ontogenesis via differential accumulation within tissues depending largely on the activity of PIN proteins that mediate auxin efflux from cells and its directional cell-to-cell transport. Regardless of the developmental importance of PINs, the structure of these transporters is poorly characterized. Here, we present experimental data concerning protein topology of plasma membrane-localized PINs. Utilizing approaches based on pH-dependent quenching of fluorescent reporters combined with immunolocalization techniques, we mapped the membrane topology of PINs and further cross-validated our results using available topology modeling software. We delineated the topology of PIN1 with two transmembrane (TM) bundles of five α-helices linked by a large intracellular loop and a C-terminus positioned outside the cytoplasm. Using constraints derived from our experimental data, we also provide an updated position of helical regions generating a verisimilitude model of PIN1. Since the canonical long PINs show a high degree of conservation in TM domains and auxin transport capacity has been demonstrated for Arabidopsis representatives of this group, this empirically enhanced topological model of PIN1 will be an important starting point for further studies on PIN structure–function relationships. In addition, we have established protocols that can be used to probe the topology of other plasma membrane proteins in plants. © 2016 The Authors AU - Nodzyński, Tomasz AU - Vanneste, Steffen AU - Zwiewka, Marta AU - Pernisová, Markéta AU - Hejátko, Jan AU - Friml, Jirí ID - 1145 IS - 11 JF - Molecular Plant TI - Enquiry into the topology of plasma membrane localized PIN auxin transport components VL - 9 ER - TY - JOUR AB - Apical dominance is one of the fundamental developmental phenomena in plant biology, which determines the overall architecture of aerial plant parts. Here we show apex decapitation activated competition for dominance in adjacent upper and lower axillary buds. A two-nodal-bud pea (Pisum sativum L.) was used as a model system to monitor and assess auxin flow, auxin transport channels, and dormancy and initiation status of axillary buds. Auxin flow was manipulated by lateral stem wounds or chemically by auxin efflux inhibitors 2,3,5-triiodobenzoic acid (TIBA), 1-N-naphtylphtalamic acid (NPA), or protein synthesis inhibitor cycloheximide (CHX) treatments, which served to interfere with axillary bud competition. Redirecting auxin flow to different points influenced which bud formed the outgrowing and dominant shoot. The obtained results proved that competition between upper and lower axillary buds as secondary auxin sources is based on the same auxin canalization principle that operates between the shoot apex and axillary bud. © The Author(s) 2016. AU - Balla, Jozef AU - Medved'Ová, Zuzana AU - Kalousek, Petr AU - Matiješčuková, Natálie AU - Friml, Jirí AU - Reinöhl, Vilém AU - Procházka, Stanislav ID - 1147 JF - Scientific Reports TI - Auxin flow mediated competition between axillary buds to restore apical dominance VL - 6 ER - TY - JOUR AB - We study the usefulness of two most prominent publicly available rigorous ODE integrators: one provided by the CAPD group (capd.ii.uj.edu.pl), the other based on the COSY Infinity project (cosyinfinity.org). Both integrators are capable of handling entire sets of initial conditions and provide tight rigorous outer enclosures of the images under a time-T map. We conduct extensive benchmark computations using the well-known Lorenz system, and compare the computation time against the final accuracy achieved. We also discuss the effect of a few technical parameters, such as the order of the numerical integration method, the value of T, and the phase space resolution. We conclude that COSY may provide more precise results due to its ability of avoiding the variable dependency problem. However, the overall cost of computations conducted using CAPD is typically lower, especially when intervals of parameters are involved. Moreover, access to COSY is limited (registration required) and the rigorous ODE integrators are not publicly available, while CAPD is an open source free software project. Therefore, we recommend the latter integrator for this kind of computations. Nevertheless, proper choice of the various integration parameters turns out to be of even greater importance than the choice of the integrator itself. © 2016 IMACS. Published by Elsevier B.V. All rights reserved. AU - Miyaji, Tomoyuki AU - Pilarczyk, Pawel AU - Gameiro, Marcio AU - Kokubu, Hiroshi AU - Mischaikow, Konstantin ID - 1149 JF - Applied Numerical Mathematics TI - A study of rigorous ODE integrators for multi scale set oriented computations VL - 107 ER - TY - JOUR AB - When neutrophils infiltrate a site of inflammation, they have to stop at the right place to exert their effector function. In this issue of Developmental Cell, Wang et al. (2016) show that neutrophils sense reactive oxygen species via the TRPM2 channel to arrest migration at their target site. © 2016 Elsevier Inc. AU - Renkawitz, Jörg AU - Sixt, Michael K ID - 1150 IS - 5 JF - Developmental Cell TI - A Radical Break Restraining Neutrophil Migration VL - 38 ER -