@article{275, abstract = {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.}, author = {Brown, Markus and Johnson, Louise and Leone, Dario and Májek, Peter and Vaahtomeri, Kari and Senfter, Daniel and Bukosza, Nora and Schachner, Helga and Asfour, Gabriele and Langer, Brigitte and Hauschild, Robert and Parapatics, Katja and Hong, Young and Bennett, Keiryn and Kain, Renate and Detmar, Michael and Sixt, Michael K and Jackson, David and Kerjaschki, Dontscho}, journal = {Journal of Cell Biology}, number = {6}, pages = {2205 -- 2221}, publisher = {Rockefeller University Press}, title = {{Lymphatic exosomes promote dendritic cell migration along guidance cues}}, doi = {10.1083/jcb.201612051}, volume = {217}, year = {2018}, } @article{158, abstract = {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.}, author = {Robert, Hélène and Park, Chulmin and Gutièrrez, Carla and Wójcikowska, Barbara and Pěnčík, Aleš and Novák, Ondřej and Chen, Junyi and Grunewald, Wim and Dresselhaus, Thomas and Friml, Jirí and Laux, Thomas}, journal = {Nature Plants}, number = {8}, pages = {548 -- 553}, publisher = {Nature Publishing Group}, title = {{Maternal auxin supply contributes to early embryo patterning in Arabidopsis}}, doi = {10.1038/s41477-018-0204-z}, volume = {4}, year = {2018}, } @article{152, abstract = {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.}, author = {Fiedorczuk, Karol and Sazanov, Leonid A}, journal = {Trends in Cell Biology}, number = {10}, pages = {835 -- 867}, publisher = {Elsevier}, title = {{Mammalian mitochondrial complex I structure and disease causing mutations}}, doi = {10.1016/j.tcb.2018.06.006}, volume = {28}, year = {2018}, } @inproceedings{310, abstract = {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.}, author = {Chatterjee, Krishnendu and Dvorák, Wolfgang and Henzinger, Monika H and Loitzenbauer, Veronika}, location = {New Orleans, Louisiana, United States}, pages = {2341 -- 2356}, publisher = {ACM}, title = {{Lower bounds for symbolic computation on graphs: Strongly connected components, liveness, safety, and diameter}}, doi = {10.1137/1.9781611975031.151}, year = {2018}, } @article{436, abstract = {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.}, author = {Barzanjeh, Shabir and Aquilina, Matteo and Xuereb, André}, journal = {Physical Review Letters}, number = {6}, publisher = {American Physical Society}, title = {{Manipulating the flow of thermal noise in quantum devices}}, doi = {10.1103/PhysRevLett.120.060601}, volume = {120}, year = {2018}, } @article{5858, abstract = {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.}, author = {Hross, Sabrina and Theis, Fabian J. and Sixt, Michael K and Hasenauer, Jan}, issn = {17425689}, journal = {Journal of the Royal Society Interface}, number = {149}, publisher = {Royal Society Publishing}, title = {{Mechanistic description of spatial processes using integrative modelling of noise-corrupted imaging data}}, doi = {10.1098/rsif.2018.0600}, volume = {15}, year = {2018}, } @article{16, abstract = {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.}, author = {Varshney, Atul and Steinberg, Victor}, journal = {Physical Review Fluids}, number = {10}, publisher = {American Physical Society}, title = {{Mixing layer instability and vorticity amplification in a creeping viscoelastic flow}}, doi = {10.1103/PhysRevFluids.3.103303}, volume = {3}, year = {2018}, } @article{43, abstract = {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.}, author = {Rybicki, Joel and Kisdi, Eva and Anttila, Jani}, journal = {PNAS}, number = {42}, pages = {10690 -- 10695}, publisher = {National Academy of Sciences}, title = {{Model of bacterial toxin-dependent pathogenesis explains infective dose}}, doi = {10.1073/pnas.1721061115}, volume = {115}, year = {2018}, } @article{13, abstract = {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.}, author = {Alderighi, Thomas and Malomo, Luigi and Giorgi, Daniela and Pietroni, Nico and Bickel, Bernd and Cignoni, Paolo}, journal = {ACM Trans. Graph.}, number = {4}, publisher = {ACM}, title = {{Metamolds: Computational design of silicone molds}}, doi = {10.1145/3197517.3201381}, volume = {37}, year = {2018}, } @article{137, abstract = {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.}, author = {Zhang, William and Herde, Michel and Mitchell, Joshua and Whitfield, Jason and Wulff, Andreas and Vongsouthi, Vanessa and Sanchez Romero, Inmaculada and Gulakova, Polina and Minge, Daniel and Breithausen, Björn and Schoch, Susanne and Janovjak, Harald L and Jackson, Colin and Henneberger, Christian}, journal = {Nature Chemical Biology}, number = {9}, pages = {861 -- 869}, publisher = {Nature Publishing Group}, title = {{Monitoring hippocampal glycine with the computationally designed optical sensor GlyFS}}, doi = {10.1038/s41589-018-0108-2}, volume = {14}, year = {2018}, }