TY - CONF AB - Fault-localization is considered to be a very tedious and time-consuming activity in the design of complex Cyber-Physical Systems (CPS). This laborious task essentially requires expert knowledge of the system in order to discover the cause of the fault. In this context, we propose a new procedure that AIDS designers in debugging Simulink/Stateflow hybrid system models, guided by Signal Temporal Logic (STL) specifications. The proposed method relies on three main ingredients: (1) a monitoring and a trace diagnostics procedure that checks whether a tested behavior satisfies or violates an STL specification, localizes time segments and interfaces variables contributing to the property violations; (2) a slicing procedure that maps these observable behavior segments to the internal states and transitions of the Simulink model; and (3) a spectrum-based fault-localization method that combines the previous analysis from multiple tests to identify the internal states and/or transitions that are the most likely to explain the fault. We demonstrate the applicability of our approach on two Simulink models from the automotive and the avionics domain. AU - Bartocci, Ezio AU - Ferrere, Thomas AU - Manjunath, Niveditha AU - Nickovic, Dejan ID - 183 TI - Localizing faults in simulink/stateflow models with STL ER - TY - JOUR AB - We consider large random matrices X with centered, independent entries which have comparable but not necessarily identical variances. Girko's circular law asserts that the spectrum is supported in a disk and in case of identical variances, the limiting density is uniform. In this special case, the local circular law by Bourgade et. al. [11,12] shows that the empirical density converges even locally on scales slightly above the typical eigenvalue spacing. In the general case, the limiting density is typically inhomogeneous and it is obtained via solving a system of deterministic equations. Our main result is the local inhomogeneous circular law in the bulk spectrum on the optimal scale for a general variance profile of the entries of X. AU - Alt, Johannes AU - Erdös, László AU - Krüger, Torben H ID - 566 IS - 1 JF - Annals Applied Probability TI - Local inhomogeneous circular law VL - 28 ER - TY - JOUR AB - The goal of this article is to introduce the reader to the theory of intrinsic geometry of convex surfaces. We illustrate the power of the tools by proving a theorem on convex surfaces containing an arbitrarily long closed simple geodesic. Let us remind ourselves that a curve in a surface is called geodesic if every sufficiently short arc of the curve is length minimizing; if, in addition, it has no self-intersections, we call it simple geodesic. A tetrahedron with equal opposite edges is called isosceles. The axiomatic method of Alexandrov geometry allows us to work with the metrics of convex surfaces directly, without approximating it first by a smooth or polyhedral metric. Such approximations destroy the closed geodesics on the surface; therefore it is difficult (if at all possible) to apply approximations in the proof of our theorem. On the other hand, a proof in the smooth or polyhedral case usually admits a translation into Alexandrov’s language; such translation makes the result more general. In fact, our proof resembles a translation of the proof given by Protasov. Note that the main theorem implies in particular that a smooth convex surface does not have arbitrarily long simple closed geodesics. However we do not know a proof of this corollary that is essentially simpler than the one presented below. AU - Akopyan, Arseniy AU - Petrunin, Anton ID - 106 IS - 3 JF - Mathematical Intelligencer TI - Long geodesics on convex surfaces VL - 40 ER - TY - GEN AU - Chaudhry, Waqas AU - Pleska, Maros AU - Shah, Nilang AU - Weiss, Howard AU - Mccall, Ingrid AU - Meyer, Justin AU - Gupta, Animesh AU - Guet, Calin C AU - Levin, Bruce ID - 9810 TI - Numerical data used in figures ER - TY - JOUR AB - Lymphatic endothelial cells (LECs) release extracellular chemokines to guide the migration of dendritic cells. In this study, we report that LECs also release basolateral exosome-rich endothelial vesicles (EEVs) that are secreted in greater numbers in the presence of inflammatory cytokines and accumulate in the perivascular stroma of small lymphatic vessels in human chronic inflammatory diseases. Proteomic analyses of EEV fractions identified > 1,700 cargo proteins and revealed a dominant motility-promoting protein signature. In vitro and ex vivo EEV fractions augmented cellular protrusion formation in a CX3CL1/fractalkine-dependent fashion and enhanced the directional migratory response of human dendritic cells along guidance cues. We conclude that perilymphatic LEC exosomes enhance exploratory behavior and thus promote directional migration of CX3CR1-expressing cells in complex tissue environments. AU - Brown, Markus AU - Johnson, Louise AU - Leone, Dario AU - Májek, Peter AU - Vaahtomeri, Kari AU - Senfter, Daniel AU - Bukosza, Nora AU - Schachner, Helga AU - Asfour, Gabriele AU - Langer, Brigitte AU - Hauschild, Robert AU - Parapatics, Katja AU - Hong, Young AU - Bennett, Keiryn AU - Kain, Renate AU - Detmar, Michael AU - Sixt, Michael K AU - Jackson, David AU - Kerjaschki, Dontscho ID - 275 IS - 6 JF - Journal of Cell Biology TI - Lymphatic exosomes promote dendritic cell migration along guidance cues VL - 217 ER - TY - JOUR AB - The angiosperm seed is composed of three genetically distinct tissues: the diploid embryo that originates from the fertilized egg cell, the triploid endosperm that is produced from the fertilized central cell, and the maternal sporophytic integuments that develop into the seed coat1. At the onset of embryo development in Arabidopsis thaliana, the zygote divides asymmetrically, producing a small apical embryonic cell and a larger basal cell that connects the embryo to the maternal tissue2. The coordinated and synchronous development of the embryo and the surrounding integuments, and the alignment of their growth axes, suggest communication between maternal tissues and the embryo. In contrast to animals, however, where a network of maternal factors that direct embryo patterning have been identified3,4, only a few maternal mutations have been described to affect embryo development in plants5–7. Early embryo patterning in Arabidopsis requires accumulation of the phytohormone auxin in the apical cell by directed transport from the suspensor8–10. However, the origin of this auxin has remained obscure. Here we investigate the source of auxin for early embryogenesis and provide evidence that the mother plant coordinates seed development by supplying auxin to the early embryo from the integuments of the ovule. We show that auxin response increases in ovules after fertilization, due to upregulated auxin biosynthesis in the integuments, and this maternally produced auxin is required for correct embryo development. AU - Robert, Hélène AU - Park, Chulmin AU - Gutièrrez, Carla AU - Wójcikowska, Barbara AU - Pěnčík, Aleš AU - Novák, Ondřej AU - Chen, Junyi AU - Grunewald, Wim AU - Dresselhaus, Thomas AU - Friml, Jirí AU - Laux, Thomas ID - 158 IS - 8 JF - Nature Plants TI - Maternal auxin supply contributes to early embryo patterning in Arabidopsis VL - 4 ER - TY - JOUR AB - Complex I has an essential role in ATP production by coupling electron transfer from NADH to quinone with translocation of protons across the inner mitochondrial membrane. Isolated complex I deficiency is a frequent cause of mitochondrial inherited diseases. Complex I has also been implicated in cancer, ageing, and neurodegenerative conditions. Until recently, the understanding of complex I deficiency on the molecular level was limited due to the lack of high-resolution structures of the enzyme. However, due to developments in single particle cryo-electron microscopy (cryo-EM), recent studies have reported nearly atomic resolution maps and models of mitochondrial complex I. These structures significantly add to our understanding of complex I mechanism and assembly. The disease-causing mutations are discussed here in their structural context. AU - Fiedorczuk, Karol AU - Sazanov, Leonid A ID - 152 IS - 10 JF - Trends in Cell Biology TI - Mammalian mitochondrial complex I structure and disease causing mutations VL - 28 ER - TY - CONF AB - A model of computation that is widely used in the formal analysis of reactive systems is symbolic algorithms. In this model the access to the input graph is restricted to consist of symbolic operations, which are expensive in comparison to the standard RAM operations. We give lower bounds on the number of symbolic operations for basic graph problems such as the computation of the strongly connected components and of the approximate diameter as well as for fundamental problems in model checking such as safety, liveness, and coliveness. Our lower bounds are linear in the number of vertices of the graph, even for constant-diameter graphs. For none of these problems lower bounds on the number of symbolic operations were known before. The lower bounds show an interesting separation of these problems from the reachability problem, which can be solved with O(D) symbolic operations, where D is the diameter of the graph. Additionally we present an approximation algorithm for the graph diameter which requires Õ(n/D) symbolic steps to achieve a (1 +ϵ)-approximation for any constant > 0. This compares to O(n/D) symbolic steps for the (naive) exact algorithm and O(D) symbolic steps for a 2-approximation. Finally we also give a refined analysis of the strongly connected components algorithms of [15], showing that it uses an optimal number of symbolic steps that is proportional to the sum of the diameters of the strongly connected components. AU - Chatterjee, Krishnendu AU - Dvorák, Wolfgang AU - Henzinger, Monika H AU - Loitzenbauer, Veronika ID - 310 TI - Lower bounds for symbolic computation on graphs: Strongly connected components, liveness, safety, and diameter ER - TY - JOUR AB - There has been significant interest recently in using complex quantum systems to create effective nonreciprocal dynamics. Proposals have been put forward for the realization of artificial magnetic fields for photons and phonons; experimental progress is fast making these proposals a reality. Much work has concentrated on the use of such systems for controlling the flow of signals, e.g., to create isolators or directional amplifiers for optical signals. In this Letter, we build on this work but move in a different direction. We develop the theory of and discuss a potential realization for the controllable flow of thermal noise in quantum systems. We demonstrate theoretically that the unidirectional flow of thermal noise is possible within quantum cascaded systems. Viewing an optomechanical platform as a cascaded system we show here that one can ultimately control the direction of the flow of thermal noise. By appropriately engineering the mechanical resonator, which acts as an artificial reservoir, the flow of thermal noise can be constrained to a desired direction, yielding a thermal rectifier. The proposed quantum thermal noise rectifier could potentially be used to develop devices such as a thermal modulator, a thermal router, and a thermal amplifier for nanoelectronic devices and superconducting circuits. AU - Barzanjeh, Shabir AU - Aquilina, Matteo AU - Xuereb, André ID - 436 IS - 6 JF - Physical Review Letters TI - Manipulating the flow of thermal noise in quantum devices VL - 120 ER - TY - JOUR AB - Spatial patterns are ubiquitous on the subcellular, cellular and tissue level, and can be studied using imaging techniques such as light and fluorescence microscopy. Imaging data provide quantitative information about biological systems; however, mechanisms causing spatial patterning often remain elusive. In recent years, spatio-temporal mathematical modelling has helped to overcome this problem. Yet, outliers and structured noise limit modelling of whole imaging data, and models often consider spatial summary statistics. Here, we introduce an integrated data-driven modelling approach that can cope with measurement artefacts and whole imaging data. Our approach combines mechanistic models of the biological processes with robust statistical models of the measurement process. The parameters of the integrated model are calibrated using a maximum-likelihood approach. We used this integrated modelling approach to study in vivo gradients of the chemokine (C-C motif) ligand 21 (CCL21). CCL21 gradients guide dendritic cells and are important in the adaptive immune response. Using artificial data, we verified that the integrated modelling approach provides reliable parameter estimates in the presence of measurement noise and that bias and variance of these estimates are reduced compared to conventional approaches. The application to experimental data allowed the parametrization and subsequent refinement of the model using additional mechanisms. Among other results, model-based hypothesis testing predicted lymphatic vessel-dependent concentration of heparan sulfate, the binding partner of CCL21. The selected model provided an accurate description of the experimental data and was partially validated using published data. Our findings demonstrate that integrated statistical modelling of whole imaging data is computationally feasible and can provide novel biological insights. AU - Hross, Sabrina AU - Theis, Fabian J. AU - Sixt, Michael K AU - Hasenauer, Jan ID - 5858 IS - 149 JF - Journal of the Royal Society Interface SN - 17425689 TI - Mechanistic description of spatial processes using integrative modelling of noise-corrupted imaging data VL - 15 ER - TY - JOUR AB - We report quantitative evidence of mixing-layer elastic instability in a viscoelastic fluid flow between two widely spaced obstacles hindering a channel flow at Re 1 and Wi 1. Two mixing layers with nonuniform shear velocity profiles are formed in the region between the obstacles. The mixing-layer instability arises in the vicinity of an inflection point on the shear velocity profile with a steep variation in the elastic stress. The instability results in an intermittent appearance of small vortices in the mixing layers and an amplification of spatiotemporal averaged vorticity in the elastic turbulence regime. The latter is characterized through scaling of friction factor with Wi and both pressure and velocity spectra. Furthermore, the observations reported provide improved understanding of the stability of the mixing layer in a viscoelastic fluid at large elasticity, i.e., Wi 1 and Re 1 and oppose the current view of suppression of vorticity solely by polymer additives. AU - Varshney, Atul AU - Steinberg, Victor ID - 16 IS - 10 JF - Physical Review Fluids TI - Mixing layer instability and vorticity amplification in a creeping viscoelastic flow VL - 3 ER - TY - JOUR AB - The initial amount of pathogens required to start an infection within a susceptible host is called the infective dose and is known to vary to a large extent between different pathogen species. We investigate the hypothesis that the differences in infective doses are explained by the mode of action in the underlying mechanism of pathogenesis: Pathogens with locally acting mechanisms tend to have smaller infective doses than pathogens with distantly acting mechanisms. While empirical evidence tends to support the hypothesis, a formal theoretical explanation has been lacking. We give simple analytical models to gain insight into this phenomenon and also investigate a stochastic, spatially explicit, mechanistic within-host model for toxin-dependent bacterial infections. The model shows that pathogens secreting locally acting toxins have smaller infective doses than pathogens secreting diffusive toxins, as hypothesized. While local pathogenetic mechanisms require smaller infective doses, pathogens with distantly acting toxins tend to spread faster and may cause more damage to the host. The proposed model can serve as a basis for the spatially explicit analysis of various virulence factors also in the context of other problems in infection dynamics. AU - Rybicki, Joel AU - Kisdi, Eva AU - Anttila, Jani ID - 43 IS - 42 JF - PNAS TI - Model of bacterial toxin-dependent pathogenesis explains infective dose VL - 115 ER - TY - JOUR AB - We propose a new method for fabricating digital objects through reusable silicone molds. Molds are generated by casting liquid silicone into custom 3D printed containers called metamolds. Metamolds automatically define the cuts that are needed to extract the cast object from the silicone mold. The shape of metamolds is designed through a novel segmentation technique, which takes into account both geometric and topological constraints involved in the process of mold casting. Our technique is simple, does not require changing the shape or topology of the input objects, and only requires off-the- shelf materials and technologies. We successfully tested our method on a set of challenging examples with complex shapes and rich geometric detail. © 2018 Association for Computing Machinery. AU - Alderighi, Thomas AU - Malomo, Luigi AU - Giorgi, Daniela AU - Pietroni, Nico AU - Bickel, Bernd AU - Cignoni, Paolo ID - 13 IS - 4 JF - ACM Trans. Graph. TI - Metamolds: Computational design of silicone molds VL - 37 ER - TY - JOUR AB - Fluorescent sensors are an essential part of the experimental toolbox of the life sciences, where they are used ubiquitously to visualize intra- and extracellular signaling. In the brain, optical neurotransmitter sensors can shed light on temporal and spatial aspects of signal transmission by directly observing, for instance, neurotransmitter release and spread. Here we report the development and application of the first optical sensor for the amino acid glycine, which is both an inhibitory neurotransmitter and a co-agonist of the N-methyl-d-aspartate receptors (NMDARs) involved in synaptic plasticity. Computational design of a glycine-specific binding protein allowed us to produce the optical glycine FRET sensor (GlyFS), which can be used with single and two-photon excitation fluorescence microscopy. We took advantage of this newly developed sensor to test predictions about the uneven spatial distribution of glycine in extracellular space and to demonstrate that extracellular glycine levels are controlled by plasticity-inducing stimuli. AU - Zhang, William AU - Herde, Michel AU - Mitchell, Joshua AU - Whitfield, Jason AU - Wulff, Andreas AU - Vongsouthi, Vanessa AU - Sanchez Romero, Inmaculada AU - Gulakova, Polina AU - Minge, Daniel AU - Breithausen, Björn AU - Schoch, Susanne AU - Janovjak, Harald L AU - Jackson, Colin AU - Henneberger, Christian ID - 137 IS - 9 JF - Nature Chemical Biology TI - Monitoring hippocampal glycine with the computationally designed optical sensor GlyFS VL - 14 ER - TY - CHAP AB - Cells migrating in multicellular organisms steadily traverse complex three-dimensional (3D) environments. To decipher the underlying cell biology, current experimental setups either use simplified 2D, tissue-mimetic 3D (e.g., collagen matrices) or in vivo environments. While only in vivo experiments are truly physiological, they do not allow for precise manipulation of environmental parameters. 2D in vitro experiments do allow mechanical and chemical manipulations, but increasing evidence demonstrates substantial differences of migratory mechanisms in 2D and 3D. Here, we describe simple, robust, and versatile “pillar forests” to investigate cell migration in complex but fully controllable 3D environments. Pillar forests are polydimethylsiloxane-based setups, in which two closely adjacent surfaces are interconnected by arrays of micrometer-sized pillars. Changing the pillar shape, size, height and the inter-pillar distance precisely manipulates microenvironmental parameters (e.g., pore sizes, micro-geometry, micro-topology), while being easily combined with chemotactic cues, surface coatings, diverse cell types and advanced imaging techniques. Thus, pillar forests combine the advantages of 2D cell migration assays with the precise definition of 3D environmental parameters. AU - Renkawitz, Jörg AU - Reversat, Anne AU - Leithner, Alexander F AU - Merrin, Jack AU - Sixt, Michael K ID - 153 SN - 0091679X T2 - Methods in Cell Biology TI - Micro-engineered “pillar forests” to study cell migration in complex but controlled 3D environments VL - 147 ER - TY - JOUR AB - During epithelial tissue development, repair, and homeostasis, adherens junctions (AJs) ensure intercellular adhesion and tissue integrity while allowing for cell and tissue dynamics. Mechanical forces play critical roles in AJs’ composition and dynamics. Recent findings highlight that beyond a well-established role in reinforcing cell-cell adhesion, AJ mechanosensitivity promotes junctional remodeling and polarization, thereby regulating critical processes such as cell intercalation, division, and collective migration. Here, we provide an integrated view of mechanosensing mechanisms that regulate cell-cell contact composition, geometry, and integrity under tension and highlight pivotal roles for mechanosensitive AJ remodeling in preserving epithelial integrity and sustaining tissue dynamics. AU - Nunes Pinheiro, Diana C AU - Bellaïche, Yohanns ID - 54 IS - 1 JF - Developmental Cell TI - Mechanical force-driven adherents junction remodeling and epithelial dynamics VL - 47 ER - TY - JOUR AB - Directed migration of cells relies on their ability to sense directional guidance cues and to interact with pericellular structures in order to transduce contractile cytoskeletal- into mechanical forces. These biomechanical processes depend highly on microenvironmental factors such as exposure to 2D surfaces or 3D matrices. In vivo, the majority of cells are exposed to 3D environments. Data on 3D cell migration are mostly derived from intravital microscopy or collagen-based in vitro assays. Both approaches offer only limited controlla-bility of experimental conditions. Here, we developed an automated microfluidic system that allows positioning of cells in 3D microenvironments containing highly controlled diffusion-based chemokine gradients. Tracking migration in such gradients was feasible in real time at the single cell level. Moreover, the setup allowed on-chip immunocytochemistry and thus linking of functional with phenotypical properties in individual cells. Spatially defined retrieval of cells from the device allows down-stream off-chip analysis. Using dendritic cells as a model, our setup specifically allowed us for the first time to quantitate key migration characteristics of cells exposed to identical gradients of the chemokine CCL19 yet placed on 2D vs in 3D environments. Migration properties between 2D and 3D migration were distinct. Morphological features of cells migrating in an in vitro 3D environment were similar to those of cells migrating in animal tissues, but different from cells migrating on a surface. Our system thus offers a highly controllable in vitro-mimic of a 3D environment that cells traffic in vivo. AU - Frick, Corina AU - Dettinger, Philip AU - Renkawitz, Jörg AU - Jauch, Annaïse AU - Berger, Christoph AU - Recher, Mike AU - Schroeder, Timm AU - Mehling, Matthias ID - 276 IS - 6 JF - PLoS One TI - Nano-scale microfluidics to study 3D chemotaxis at the single cell level VL - 13 ER - TY - JOUR AB - Light represents the principal signal driving circadian clock entrainment. However, how light influences the evolution of the clock remains poorly understood. The cavefish Phreatichthys andruzzii represents a fascinating model to explore how evolution under extreme aphotic conditions shapes the circadian clock, since in this species the clock is unresponsive to light. We have previously demonstrated that loss-of-function mutations targeting non-visual opsins contribute in part to this blind clock phenotype. Here, we have compared orthologs of two core clock genes that play a key role in photic entrainment, cry1a and per2, in both zebrafish and P. andruzzii. We encountered aberrantly spliced variants for the P. andruzzii per2 transcript. The most abundant transcript encodes a truncated protein lacking the C-terminal Cry binding domain and incorporating an intronic, transposon-derived coding sequence. We demonstrate that the transposon insertion leads to a predominantly cytoplasmic localization of the cavefish Per2 protein in contrast to the zebrafish ortholog which is distributed in both the nucleus and cytoplasm. Thus, it seems that during evolution in complete darkness, the photic entrainment pathway of the circadian clock has been subject to mutation at multiple levels, extending from opsin photoreceptors to nuclear effectors. AU - Ceinos, Rosa Maria AU - Frigato, Elena AU - Pagano, Cristina AU - Frohlich, Nadine AU - Negrini, Pietro AU - Cavallari, Nicola AU - Vallone, Daniela AU - Fuselli, Silvia AU - Bertolucci, Cristiano AU - Foulkes, Nicholas S ID - 283 IS - 1 JF - Scientific Reports TI - Mutations in blind cavefish target the light regulated circadian clock gene period 2 VL - 8 ER - TY - CONF AB - We solve the offline monitoring problem for timed propositional temporal logic (TPTL), interpreted over dense-time Boolean signals. The variant of TPTL we consider extends linear temporal logic (LTL) with clock variables and reset quantifiers, providing a mechanism to specify real-time constraints. We first describe a general monitoring algorithm based on an exhaustive computation of the set of satisfying clock assignments as a finite union of zones. We then propose a specialized monitoring algorithm for the one-variable case using a partition of the time domain based on the notion of region equivalence, whose complexity is linear in the length of the signal, thereby generalizing a known result regarding the monitoring of metric temporal logic (MTL). The region and zone representations of time constraints are known from timed automata verification and can also be used in the discrete-time case. Our prototype implementation appears to outperform previous discrete-time implementations of TPTL monitoring, AU - Elgyütt, Adrian AU - Ferrere, Thomas AU - Henzinger, Thomas A ID - 81 TI - Monitoring temporal logic with clock variables VL - 11022 ER - TY - JOUR AB - Consider a fully-connected synchronous distributed system consisting of n nodes, where up to f nodes may be faulty and every node starts in an arbitrary initial state. In the synchronous C-counting problem, all nodes need to eventually agree on a counter that is increased by one modulo C in each round for given C>1. In the self-stabilising firing squad problem, the task is to eventually guarantee that all non-faulty nodes have simultaneous responses to external inputs: if a subset of the correct nodes receive an external “go” signal as input, then all correct nodes should agree on a round (in the not-too-distant future) in which to jointly output a “fire” signal. Moreover, no node should generate a “fire” signal without some correct node having previously received a “go” signal as input. We present a framework reducing both tasks to binary consensus at very small cost. For example, we obtain a deterministic algorithm for self-stabilising Byzantine firing squads with optimal resilience f<n/3, asymptotically optimal stabilisation and response time O(f), and message size O(log f). As our framework does not restrict the type of consensus routines used, we also obtain efficient randomised solutions. AU - Lenzen, Christoph AU - Rybicki, Joel ID - 76 JF - Distributed Computing TI - Near-optimal self-stabilising counting and firing squads ER -