@article{6087, abstract = {Cell fate specification by lateral inhibition typically involves contact signaling through the Delta-Notch signaling pathway. However, whether this is the only signaling mode mediating lateral inhibition remains unclear. Here we show that in zebrafish oogenesis, a group of cells within the granulosa cell layer at the oocyte animal pole acquire elevated levels of the transcriptional coactivator TAZ in their nuclei. One of these cells, the future micropyle precursor cell (MPC), accumulates increasingly high levels of nuclear TAZ and grows faster than its surrounding cells, mechanically compressing those cells, which ultimately lose TAZ from their nuclei. Strikingly, relieving neighbor-cell compression by MPC ablation or aspiration restores nuclear TAZ accumulation in neighboring cells, eventually leading to MPC re-specification from these cells. Conversely, MPC specification is defective in taz−/− follicles. These findings uncover a novel mode of lateral inhibition in cell fate specification based on mechanical signals controlling TAZ activity.}, author = {Xia, Peng and Gütl, Daniel J and Zheden, Vanessa and Heisenberg, Carl-Philipp J}, journal = {Cell}, number = {6}, pages = {1379--1392.e14}, publisher = {Elsevier}, title = {{Lateral inhibition in cell specification mediated by mechanical signals modulating TAZ activity}}, doi = {10.1016/j.cell.2019.01.019}, volume = {176}, year = {2019}, } @misc{9806, abstract = {1. Hosts can alter their strategy towards pathogens during their lifetime, i.e., they can show phenotypic plasticity in immunity or life history. Immune priming is one such example, where a previous encounter with a pathogen confers enhanced protection upon secondary challenge, resulting in reduced pathogen load (i.e. resistance) and improved host survival. However, an initial encounter might also enhance tolerance, particularly to less virulent opportunistic pathogens that establish persistent infections. In this scenario, individuals are better able to reduce the negative fitness consequences that result from a high pathogen load. Finally, previous exposure may also lead to life history adjustments, such as terminal investment into reproduction. 2. Using different Drosophila melanogaster host genotypes and two bacterial pathogens, Lactococcus lactis and Pseudomonas entomophila, we tested if previous exposure results in resistance or tolerance and whether it modifies immune gene expression during an acute-phase infection (one day post-challenge). We then asked if previous pathogen exposure affects chronic-phase pathogen persistence and longer-term survival (28 days post-challenge). 3. We predicted that previous exposure would increase host resistance to an early stage bacterial infection while it might come at a cost to host fecundity tolerance. We reasoned that resistance would be due in part to stronger immune gene expression after challenge. We expected that previous exposure would improve long-term survival, that it would reduce infection persistence, and we expected to find genetic variation in these responses. 4. We found that previous exposure to P. entomophila weakened host resistance to a second infection independent of genotype and had no effect on immune gene expression. Fecundity tolerance showed genotypic variation but was not influenced by previous exposure. However, L. lactis persisted as a chronic infection, whereas survivors cleared the more pathogenic P. entomophila infection. 5. To our knowledge, this is the first study that addresses host tolerance to bacteria in relation to previous exposure, taking a multi-faceted approach to address the topic. Our results suggest that previous exposure comes with transient costs to resistance during the early stage of infection in this host-pathogen system and that infection persistence may be bacterium-specific.}, author = {Kutzer, Megan and Kurtz, Joachim and Armitage, Sophie A.O.}, publisher = {Dryad}, title = {{Data from: A multi-faceted approach testing the effects of previous bacterial exposure on resistance and tolerance}}, doi = {10.5061/dryad.9kj41f0}, year = {2019}, } @article{6086, abstract = {We show that linear analytic cocycles where all Lyapunov exponents are negative infinite are nilpotent. For such one-frequency cocycles we show that they can be analytically conjugated to an upper triangular cocycle or a Jordan normal form. As a consequence, an arbitrarily small analytic perturbation leads to distinct Lyapunov exponents. Moreover, in the one-frequency case where the th Lyapunov exponent is finite and the st negative infinite, we obtain a simple criterion for domination in which case there is a splitting into a nilpotent part and an invertible part.}, author = {Sadel, Christian and Xu, Disheng}, journal = {Ergodic Theory and Dynamical Systems}, number = {4}, pages = {1082--1098}, publisher = {Cambridge University Press}, title = {{Singular analytic linear cocycles with negative infinite Lyapunov exponents}}, doi = {10.1017/etds.2017.52}, volume = {39}, year = {2019}, } @article{6102, abstract = {Light is a union of electric and magnetic fields, and nowhere is the complex relationship between these fields more evident than in the near fields of nanophotonic structures. There, complicated electric and magnetic fields varying over subwavelength scales are generally present, which results in photonic phenomena such as extraordinary optical momentum, superchiral fields, and a complex spatial evolution of optical singularities. An understanding of such phenomena requires nanoscale measurements of the complete optical field vector. Although the sensitivity of near- field scanning optical microscopy to the complete electromagnetic field was recently demonstrated, a separation of different components required a priori knowledge of the sample. Here, we introduce a robust algorithm that can disentangle all six electric and magnetic field components from a single near-field measurement without any numerical modeling of the structure. As examples, we unravel the fields of two prototypical nanophotonic structures: a photonic crystal waveguide and a plasmonic nanowire. These results pave the way for new studies of complex photonic phenomena at the nanoscale and for the design of structures that optimize their optical behavior.}, author = {Le Feber, B. and Sipe, J. E. and Wulf, Matthias and Kuipers, L. and Rotenberg, N.}, issn = {20477538}, journal = {Light: Science and Applications}, number = {1}, publisher = {Springer Nature}, title = {{A full vectorial mapping of nanophotonic light fields}}, doi = {10.1038/s41377-019-0124-3}, volume = {8}, year = {2019}, } @article{6104, abstract = {Abiotic stress poses constant challenges for plant survival and is a serious problem for global agricultural productivity. On a molecular level, stress conditions result in elevation of reactive oxygen species (ROS) production causing oxidative stress associated with oxidation of proteins and nucleic acids as well as impairment of membrane functions. Adaptation of root growth to ROS accumulation is facilitated through modification of auxin and cytokinin hormone homeostasis. Here, we report that in Arabidopsis root meristem, ROS-induced changes of auxin levels correspond to decreased abundance of PIN auxin efflux carriers at the plasma membrane (PM). Specifically, increase in H2O2 levels affects PIN2 endocytic recycling. We show that the PIN2 intracellular trafficking during adaptation to oxidative stress requires the function of the ADP-ribosylation factor (ARF)-guanine-nucleotide exchange factor (GEF) BEN1, an actin-associated regulator of the trafficking from the PM to early endosomes and, presumably, indirectly, trafficking to the vacuoles. We propose that H2O2 levels affect the actin dynamics thus modulating ARF-GEF-dependent trafficking of PIN2. This mechanism provides a way how root growth acclimates to stress and adapts to a changing environment.}, author = {Zwiewka, Marta and Bielach, Agnieszka and Tamizhselvan, Prashanth and Madhavan, Sharmila and Ryad, Eman Elrefaay and Tan, Shutang and Hrtyan, Mónika and Dobrev, Petre and Vanková, Radomira and Friml, Jiří and Tognetti, Vanesa B.}, issn = {1471-9053}, journal = {Plant and Cell Physiology}, number = {2}, pages = {255--273}, publisher = {Oxford University Press}, title = {{Root adaptation to H2O2-induced oxidative stress by ARF-GEF BEN1- and cytoskeleton-mediated PIN2 trafficking}}, doi = {10.1093/pcp/pcz001}, volume = {60}, year = {2019}, } @article{6191, abstract = {The formation of self-organized patterns is key to the morphogenesis of multicellular organisms, although a comprehensive theory of biological pattern formation is still lacking. Here, we propose a minimal model combining tissue mechanics with morphogen turnover and transport to explore routes to patterning. Our active description couples morphogen reaction and diffusion, which impact cell differentiation and tissue mechanics, to a two-phase poroelastic rheology, where one tissue phase consists of a poroelastic cell network and the other one of a permeating extracellular fluid, which provides a feedback by actively transporting morphogens. While this model encompasses previous theories approximating tissues to inert monophasic media, such as Turing’s reaction–diffusion model, it overcomes some of their key limitations permitting pattern formation via any two-species biochemical kinetics due to mechanically induced cross-diffusion flows. Moreover, we describe a qualitatively different advection-driven Keller–Segel instability which allows for the formation of patterns with a single morphogen and whose fundamental mode pattern robustly scales with tissue size. We discuss the potential relevance of these findings for tissue morphogenesis.}, author = {Recho, Pierre and Hallou, Adrien and Hannezo, Edouard B}, issn = {10916490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {12}, pages = {5344--5349}, publisher = {National Academy of Sciences}, title = {{Theory of mechanochemical patterning in biphasic biological tissues}}, doi = {10.1073/pnas.1813255116}, volume = {116}, year = {2019}, } @article{6190, abstract = {Increased levels of the chemokine CCL2 in cancer patients are associated with poor prognosis. Experimental evidence suggests that CCL2 correlates with inflammatory monocyte recruitment and induction of vascular activation, but the functionality remains open. Here, we show that endothelial Ccr2 facilitates pulmonary metastasis using an endothelial-specific Ccr2-deficient mouse model (Ccr2ecKO). Similar levels of circulating monocytes and equal leukocyte recruitment to metastatic lesions of Ccr2ecKO and Ccr2fl/fl littermates were observed. The absence of endothelial Ccr2 strongly reduced pulmonary metastasis, while the primary tumor growth was unaffected. Despite a comparable cytokine milieu in Ccr2ecKO and Ccr2fl/fl littermates the absence of vascular permeability induction was observed only in Ccr2ecKO mice. CCL2 stimulation of pulmonary endothelial cells resulted in increased phosphorylation of MLC2, endothelial cell retraction, and vascular leakiness that was blocked by an addition of a CCR2 inhibitor. These data demonstrate that endothelial CCR2 expression is required for tumor cell extravasation and pulmonary metastasis. Implications: The findings provide mechanistic insight into how CCL2–CCR2 signaling in endothelial cells promotes their activation through myosin light chain phosphorylation, resulting in endothelial retraction and enhanced tumor cell migration and metastasis.}, author = {Roblek, Marko and Protsyuk, Darya and Becker, Paul F. and Stefanescu, Cristina and Gorzelanny, Christian and Glaus Garzon, Jesus F. and Knopfova, Lucia and Heikenwalder, Mathias and Luckow, Bruno and Schneider, Stefan W. and Borsig, Lubor}, issn = {15573125}, journal = {Molecular Cancer Research}, number = {3}, pages = {783--793}, publisher = {AACR}, title = {{CCL2 is a vascular permeability factor inducing CCR2-dependent endothelial retraction during lung metastasis}}, doi = {10.1158/1541-7786.MCR-18-0530}, volume = {17}, year = {2019}, } @article{6230, abstract = {Great care is needed when interpreting claims about the genetic basis of human variation based on data from genome-wide association studies.}, author = {Barton, Nicholas H and Hermisson, Joachim and Nordborg, Magnus}, issn = {2050084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Why structure matters}}, doi = {10.7554/eLife.45380}, volume = {8}, year = {2019}, } @article{6232, abstract = {The boundary behaviour of solutions of stochastic PDEs with Dirichlet boundary conditions can be surprisingly—and in a sense, arbitrarily—bad: as shown by Krylov[ SIAM J. Math. Anal.34(2003) 1167–1182], for any α>0 one can find a simple 1-dimensional constant coefficient linear equation whose solution at the boundary is not α-Hölder continuous.We obtain a positive counterpart of this: under some mild regularity assumptions on the coefficients, solutions of semilinear SPDEs on C1 domains are proved to be α-Hölder continuous up to the boundary with some α>0.}, author = {Gerencser, Mate}, issn = {00911798}, journal = {Annals of Probability}, number = {2}, pages = {804--834}, publisher = {Institute of Mathematical Statistics}, title = {{Boundary regularity of stochastic PDEs}}, doi = {10.1214/18-AOP1272}, volume = {47}, year = {2019}, } @article{6262, abstract = {Gravitropism is an adaptive response that orients plant growth parallel to the gravity vector. Asymmetric distribution of the phytohormone auxin is a necessary prerequisite to the tropic bending both in roots and shoots. During hypocotyl gravitropic response, the PIN3 auxin transporter polarizes within gravity-sensing cells to redirect intercellular auxin fluxes. First gravity-induced PIN3 polarization to the bottom cell mem- branes leads to the auxin accumulation at the lower side of the organ, initiating bending and, later, auxin feedback-mediated repolarization restores symmetric auxin distribution to terminate bending. Here, we per- formed a forward genetic screen to identify regulators of both PIN3 polarization events during gravitropic response. We searched for mutants with defective PIN3 polarizations based on easy-to-score morphological outputs of decreased or increased gravity-induced hypocotyl bending. We identified the number of hypocotyl reduced bending (hrb) and hypocotyl hyperbending (hhb) mutants, revealing that reduced bending corre- lated typically with defective gravity-induced PIN3 relocation whereas all analyzed hhb mutants showed defects in the second, auxin-mediated PIN3 relocation. Next-generation sequencing-aided mutation map- ping identified several candidate genes, including SCARECROW and ACTIN2, revealing roles of endodermis specification and actin cytoskeleton in the respective gravity- and auxin-induced PIN polarization events. The hypocotyl gravitropism screen thus promises to provide novel insights into mechanisms underlying cell polarity and plant adaptive development.}, author = {Rakusová, Hana and Han, Huibin and Valošek, Petr and Friml, Jiří}, issn = {1365-313x}, journal = {The Plant Journal}, number = {6}, pages = {1048--1059}, publisher = {Wiley}, title = {{Genetic screen for factors mediating PIN polarization in gravistimulated Arabidopsis thaliana hypocotyls}}, doi = {10.1111/tpj.14301}, volume = {98}, year = {2019}, } @article{6297, abstract = {Cell-cell and cell-glycocalyx interactions under flow are important for the behaviour of circulating cells in blood and lymphatic vessels. However, such interactions are not well understood due in part to a lack of tools to study them in defined environments. Here, we develop a versatile in vitro platform for the study of cell-glycocalyx interactions in well-defined physical and chemical settings under flow. Our approach is demonstrated with the interaction between hyaluronan (HA, a key component of the endothelial glycocalyx) and its cell receptor CD44. We generate HA brushes in situ within a microfluidic device, and demonstrate the tuning of their physical (thickness and softness) and chemical (density of CD44 binding sites) properties using characterisation with reflection interference contrast microscopy (RICM) and application of polymer theory. We highlight the interactions of HA brushes with CD44-displaying beads and cells under flow. Observations of CD44+ beads on a HA brush with RICM enabled the 3-dimensional trajectories to be generated, and revealed interactions in the form of stop and go phases with reduced rolling velocity and reduced distance between the bead and the HA brush, compared to uncoated beads. Combined RICM and bright-field microscopy of CD44+ AKR1 T-lymphocytes revealed complementary information about the dynamics of cell rolling and cell morphology, and highlighted the formation of tethers and slings, as they interacted with a HA brush under flow. This platform can readily incorporate more complex models of the glycocalyx, and should permit the study of how mechanical and biochemical factors are orchestrated to enable highly selective blood cell-vessel wall interactions under flow.}, author = {Davies, Heather S. and Baranova, Natalia S. and El Amri, Nouha and Coche-Guérente, Liliane and Verdier, Claude and Bureau, Lionel and Richter, Ralf P. and Débarre, Delphine}, issn = {0945-053X}, journal = {Matrix Biology}, pages = {47--59}, publisher = {Elsevier}, title = {{An integrated assay to probe endothelial glycocalyx-blood cell interactions under flow in mechanically and biochemically well-defined environments}}, doi = {10.1016/j.matbio.2018.12.002}, volume = {78-79}, year = {2019}, } @article{6310, abstract = {An asymptotic formula is established for the number of rational points of bounded anticanonical height which lie on a certain Zariskiopen subset of an arbitrary smooth biquadratic hypersurface in sufficiently many variables. The proof uses the Hardy–Littlewood circle method.}, author = {Browning, Timothy D and Hu, L.Q.}, issn = {10902082}, journal = {Advances in Mathematics}, pages = {920--940}, publisher = {Elsevier}, title = {{Counting rational points on biquadratic hypersurfaces}}, doi = {10.1016/j.aim.2019.04.031}, volume = {349}, year = {2019}, } @article{6261, abstract = {Nitrate regulation of root stem cell activity is auxin-dependent.}, author = {Wang, Y and Gong, Z and Friml, Jiří and Zhang, J}, issn = {1532-2548}, journal = {Plant Physiology}, number = {1}, pages = {22--25}, publisher = {ASPB}, title = {{Nitrate modulates the differentiation of root distal stem cells}}, doi = {10.1104/pp.18.01305}, volume = {180}, year = {2019}, } @article{6352, abstract = {Chronic overuse of common pharmaceuticals, e.g. acetaminophen (paracetamol), often leads to the development of acute liver failure (ALF). This study aimed to elucidate the effect of cultured mesenchymal stem cells (MSCs) proteome on the onset of liver damage and regeneration dynamics in animals with ALF induced by acetaminophen, to test the liver protective efficacy of MSCs proteome depending on the oxygen tension in cell culture, and to blueprint protein components responsible for the effect. Protein compositions prepared from MSCs cultured in mild hypoxic (5% and 10% O2) and normal (21% O2) conditions were used to treat ALF induced in mice by injection of acetaminophen. To test the effect of reduced oxygen tension in cell culture on resulting MSCs proteome content we applied a combination of high performance liquid chromatography and mass-spectrometry (LC–MS/MS) for the identification of proteins in lysates of MSCs cultured at different O2 levels. The treatment of acetaminophen-administered animals with proteins released from cultured MSCs resulted in the inhibition of inflammatory reactions in damaged liver; the area of hepatocyte necrosis being reduced in the first 24 h. Compositions obtained from MSCs cultured at lower O2 level were shown to be more potent than a composition prepared from normoxic cells. A comparative characterization of protein pattern and identification of individual components done by a cytokine assay and proteomics analysis of protein compositions revealed that even moderate hypoxia produces discrete changes in the expression of various subsets of proteins responsible for intracellular respiration and cell signaling. The application of proteins prepared from MSCs grown in vitro at reduced oxygen tension significantly accelerates healing process in damaged liver tissue. The proteomics data obtained for different preparations offer new information about the potential candidates in the MSCs protein repertoire sensitive to oxygen tension in culture medium, which can be involved in the generalized mechanisms the cells use to respond to acute liver failure.}, author = {Temnov, Andrey Alexandrovich and Rogov, Konstantin Arkadevich and Sklifas, Alla Nikolaevna and Klychnikova, Elena Valerievna and Hartl, Markus and Djinovic-Carugo, Kristina and Charnagalov, Alexej}, issn = {15734978}, journal = {Molecular Biology Reports}, publisher = {Springer}, title = {{Protective properties of the cultured stem cell proteome studied in an animal model of acetaminophen-induced acute liver failure}}, doi = {10.1007/s11033-019-04765-z}, year = {2019}, } @article{6348, abstract = {High-speed optical telecommunication is enabled by wavelength-division multiplexing, whereby hundreds of individually stabilized lasers encode information within a single-mode optical fibre. Higher bandwidths require higher total optical power, but the power sent into the fibre is limited by optical nonlinearities within the fibre, and energy consumption by the light sources starts to become a substantial cost factor1. Optical frequency combs have been suggested to remedy this problem by generating numerous discrete, equidistant laser lines within a monolithic device; however, at present their stability and coherence allow them to operate only within small parameter ranges2,3,4. Here we show that a broadband frequency comb realized through the electro-optic effect within a high-quality whispering-gallery-mode resonator can operate at low microwave and optical powers. Unlike the usual third-order Kerr nonlinear optical frequency combs, our combs rely on the second-order nonlinear effect, which is much more efficient. Our result uses a fixed microwave signal that is mixed with an optical-pump signal to generate a coherent frequency comb with a precisely determined carrier separation. The resonant enhancement enables us to work with microwave powers that are three orders of magnitude lower than those in commercially available devices. We emphasize the practical relevance of our results to high rates of data communication. To circumvent the limitations imposed by nonlinear effects in optical communication fibres, one has to solve two problems: to provide a compact and fully integrated, yet high-quality and coherent, frequency comb generator; and to calculate nonlinear signal propagation in real time5. We report a solution to the first problem.}, author = {Rueda Sanchez, Alfredo R and Sedlmeir, Florian and Kumari, Madhuri and Leuchs, Gerd and Schwefel, Harald G.L.}, issn = {14764687}, journal = {Nature}, number = {7752}, pages = {378--381}, publisher = {Springer Nature}, title = {{Resonant electro-optic frequency comb}}, doi = {10.1038/s41586-019-1110-x}, volume = {568}, year = {2019}, } @article{6338, abstract = {Hippocampal activity patterns representing movement trajectories are reactivated in immobility and sleep periods, a process associated with memory recall, consolidation, and decision making. It is thought that only fixed, behaviorally relevant patterns can be reactivated, which are stored across hippocampal synaptic connections. To test whether some generalized rules govern reactivation, we examined trajectory reactivation following non-stereotypical exploration of familiar open-field environments. We found that random trajectories of varying lengths and timescales were reactivated, resembling that of Brownian motion of particles. The animals’ behavioral trajectory did not follow Brownian diffusion demonstrating that the exact behavioral experience is not reactivated. Therefore, hippocampal circuits are able to generate random trajectories of any recently active map by following diffusion dynamics. This ability of hippocampal circuits to generate representations of all behavioral outcome combinations, experienced or not, may underlie a wide variety of hippocampal-dependent cognitive functions such as learning, generalization, and planning.}, author = {Stella, Federico and Baracskay, Peter and O'Neill, Joseph and Csicsvari, Jozsef L}, journal = {Neuron}, pages = {450--461}, publisher = {Elsevier}, title = {{Hippocampal reactivation of random trajectories resembling Brownian diffusion}}, doi = {10.1016/j.neuron.2019.01.052}, volume = {102}, year = {2019}, } @article{5878, abstract = {We consider the motion of a droplet bouncing on a vibrating bath of the same fluid in the presence of a central potential. We formulate a rotation symmetry-reduced description of this system, which allows for the straightforward application of dynamical systems theory tools. As an illustration of the utility of the symmetry reduction, we apply it to a model of the pilot-wave system with a central harmonic force. We begin our analysis by identifying local bifurcations and the onset of chaos. We then describe the emergence of chaotic regions and their merging bifurcations, which lead to the formation of a global attractor. In this final regime, the droplet’s angular momentum spontaneously changes its sign as observed in the experiments of Perrard et al.}, author = {Budanur, Nazmi B and Fleury, Marc}, issn = {1089-7682}, journal = {Chaos: An Interdisciplinary Journal of Nonlinear Science}, number = {1}, publisher = {AIP Publishing}, title = {{State space geometry of the chaotic pilot-wave hydrodynamics}}, doi = {10.1063/1.5058279}, volume = {29}, year = {2019}, } @article{6343, abstract = {Cryo-electron tomography (cryo-ET) provides unprecedented insights into the molecular constituents of biological environments. In combination with an image processing method called subtomogram averaging (STA), detailed 3D structures of biological molecules can be obtained in large, irregular macromolecular assemblies or in situ, without the need for purification. The contextual meta-information these methods also provide, such as a protein’s location within its native environment, can then be combined with functional data. This allows the derivation of a detailed view on the physiological or pathological roles of proteins from the molecular to cellular level. Despite their tremendous potential in in situ structural biology, cryo-ET and STA have been restricted by methodological limitations, such as the low obtainable resolution. Exciting progress now allows one to reach unprecedented resolutions in situ, ranging in optimal cases beyond the nanometer barrier. Here, I review current frontiers and future challenges in routinely determining high-resolution structures in in situ environments using cryo-ET and STA.}, author = {Schur, Florian KM}, issn = {0959-440X}, journal = {Current Opinion in Structural Biology}, number = {10}, pages = {1--9}, publisher = {Elsevier}, title = {{Toward high-resolution in situ structural biology with cryo-electron tomography and subtomogram averaging}}, doi = {10.1016/j.sbi.2019.03.018}, volume = {58}, year = {2019}, } @inproceedings{6428, abstract = {Safety and security are major concerns in the development of Cyber-Physical Systems (CPS). Signal temporal logic (STL) was proposedas a language to specify and monitor the correctness of CPS relativeto formalized requirements. Incorporating STL into a developmentprocess enables designers to automatically monitor and diagnosetraces, compute robustness estimates based on requirements, andperform requirement falsification, leading to productivity gains inverification and validation activities; however, in its current formSTL is agnostic to the input/output classification of signals, andthis negatively impacts the relevance of the analysis results.In this paper we propose to make the interface explicit in theSTL language by introducing input/output signal declarations. Wethen define new measures of input vacuity and output robustnessthat better reflect the nature of the system and the specification in-tent. The resulting framework, which we call interface-aware signaltemporal logic (IA-STL), aids verification and validation activities.We demonstrate the benefits of IA-STL on several CPS analysisactivities: (1) robustness-driven sensitivity analysis, (2) falsificationand (3) fault localization. We describe an implementation of our en-hancement to STL and associated notions of robustness and vacuityin a prototype extension of Breach, a MATLAB®/Simulink®toolboxfor CPS verification and validation. We explore these methodologi-cal improvements and evaluate our results on two examples fromthe automotive domain: a benchmark powertrain control systemand a hydrogen fuel cell system.}, author = {Ferrere, Thomas and Nickovic, Dejan and Donzé, Alexandre and Ito, Hisahiro and Kapinski, James}, booktitle = {Proceedings of the 2019 22nd ACM International Conference on Hybrid Systems: Computation and Control}, isbn = {9781450362825}, location = {Montreal, Canada}, pages = {57--66}, publisher = {ACM}, title = {{Interface-aware signal temporal logic}}, doi = {10.1145/3302504.3311800}, year = {2019}, } @article{6442, abstract = {This paper investigates the use of fundamental solutions for animating detailed linear water surface waves. We first propose an analytical solution for efficiently animating circular ripples in closed form. We then show how to adapt the method of fundamental solutions (MFS) to create ambient waves interacting with complex obstacles. Subsequently, we present a novel wavelet-based discretization which outperforms the state of the art MFS approach for simulating time-varying water surface waves with moving obstacles. Our results feature high-resolution spatial details, interactions with complex boundaries, and large open ocean domains. Our method compares favorably with previous work as well as known analytical solutions. We also present comparisons between our method and real world examples.}, author = {Schreck, Camille and Hafner, Christian and Wojtan, Christopher J}, journal = {ACM Transactions on Graphics}, number = {4}, publisher = {ACM}, title = {{Fundamental solutions for water wave animation}}, doi = {10.1145/3306346.3323002}, volume = {38}, year = {2019}, } @article{6413, abstract = {Phase-field methods have long been used to model the flow of immiscible fluids. Their ability to naturally capture interface topological changes is widely recognized, but their accuracy in simulating flows of real fluids in practical geometries is not established. We here quantitatively investigate the convergence of the phase-field method to the sharp-interface limit with simulations of two-phase pipe flow. We focus on core-annular flows, in which a highly viscous fluid is lubricated by a less viscous fluid, and validate our simulations with an analytic laminar solution, a formal linear stability analysis and also in the fully nonlinear regime. We demonstrate the ability of the phase-field method to accurately deal with non-rectangular geometry, strong advection, unsteady fluctuations and large viscosity contrast. We argue that phase-field methods are very promising for quantitatively studying moderately turbulent flows, especially at high concentrations of the disperse phase.}, author = {Song, Baofang and Plana, Carlos and Lopez Alonso, Jose M and Avila, Marc}, issn = {03019322}, journal = {International Journal of Multiphase Flow}, pages = {14--24}, publisher = {Elsevier}, title = {{Phase-field simulation of core-annular pipe flow}}, doi = {10.1016/j.ijmultiphaseflow.2019.04.027}, volume = {117}, year = {2019}, } @article{6419, abstract = {Characterizing the fitness landscape, a representation of fitness for a large set of genotypes, is key to understanding how genetic information is interpreted to create functional organisms. Here we determined the evolutionarily-relevant segment of the fitness landscape of His3, a gene coding for an enzyme in the histidine synthesis pathway, focusing on combinations of amino acid states found at orthologous sites of extant species. Just 15% of amino acids found in yeast His3 orthologues were always neutral while the impact on fitness of the remaining 85% depended on the genetic background. Furthermore, at 67% of sites, amino acid replacements were under sign epistasis, having both strongly positive and negative effect in different genetic backgrounds. 46% of sites were under reciprocal sign epistasis. The fitness impact of amino acid replacements was influenced by only a few genetic backgrounds but involved interaction of multiple sites, shaping a rugged fitness landscape in which many of the shortest paths between highly fit genotypes are inaccessible.}, author = {Pokusaeva, Victoria and Usmanova, Dinara R. and Putintseva, Ekaterina V. and Espinar, Lorena and Sarkisyan, Karen and Mishin, Alexander S. and Bogatyreva, Natalya S. and Ivankov, Dmitry and Akopyan, Arseniy and Avvakumov, Sergey and Povolotskaya, Inna S. and Filion, Guillaume J. and Carey, Lucas B. and Kondrashov, Fyodor}, issn = {15537404}, journal = {PLoS Genetics}, number = {4}, publisher = {Public Library of Science}, title = {{An experimental assay of the interactions of amino acids from orthologous sequences shaping a complex fitness landscape}}, doi = {10.1371/journal.pgen.1008079}, volume = {15}, year = {2019}, } @article{6412, abstract = {Polycomb group (PcG) proteins play critical roles in the epigenetic inheritance of cell fate. The Polycomb Repressive Complexes PRC1 and PRC2 catalyse distinct chromatin modifications to enforce gene silencing, but how transcriptional repression is propagated through mitotic cell divisions remains a key unresolved question. Using reversible tethering of PcG proteins to ectopic sites in mouse embryonic stem cells, here we show that PRC1 can trigger transcriptional repression and Polycomb-dependent chromatin modifications. We find that canonical PRC1 (cPRC1), but not variant PRC1, maintains gene silencing through cell division upon reversal of tethering. Propagation of gene repression is sustained by cis-acting histone modifications, PRC2-mediated H3K27me3 and cPRC1-mediated H2AK119ub1, promoting a sequence-independent feedback mechanism for PcG protein recruitment. Thus, the distinct PRC1 complexes present in vertebrates can differentially regulate epigenetic maintenance of gene silencing, potentially enabling dynamic heritable responses to complex stimuli. Our findings reveal how PcG repression is potentially inherited in vertebrates.}, author = {Moussa, Hagar F. and Bsteh, Daniel and Yelagandula, Ramesh and Pribitzer, Carina and Stecher, Karin and Bartalska, Katarina and Michetti, Luca and Wang, Jingkui and Zepeda-Martinez, Jorge A. and Elling, Ulrich and Stuckey, Jacob I. and James, Lindsey I. and Frye, Stephen V. and Bell, Oliver}, issn = {20411723}, journal = {Nature Communications}, number = {1}, publisher = {Springer Nature}, title = {{Canonical PRC1 controls sequence-independent propagation of Polycomb-mediated gene silencing}}, doi = {10.1038/s41467-019-09628-6}, volume = {10}, year = {2019}, } @article{6415, abstract = {Ant invasions are often harmful to native species communities. Their pathogens and host disease defense mechanisms may be one component of their devastating success. First, they can introduce harmful diseases to their competitors in the introduced range, to which they themselves are tolerant. Second, their supercolonial social structure of huge multi-queen nest networks means that they will harbor a broad pathogen spectrum and high pathogen load while remaining resilient, unlike the smaller, territorial colonies of the native species. Thus, it is likely that invasive ants act as a disease reservoir, promoting their competitive advantage and invasive success.}, author = {Cremer, Sylvia}, issn = {22145753}, journal = {Current Opinion in Insect Science}, pages = {63--68}, publisher = {Elsevier}, title = {{Pathogens and disease defense of invasive ants}}, doi = {10.1016/j.cois.2019.03.011}, volume = {33}, year = {2019}, } @misc{9790, author = {Pokusaeva, Victoria and Usmanova, Dinara R. and Putintseva, Ekaterina V. and Espinar, Lorena and Sarkisyan, Karen and Mishin, Alexander S. and Bogatyreva, Natalya S. and Ivankov, Dmitry and Akopyan, Arseniy and Avvakumov, Sergey and Povolotskaya, Inna S. and Filion, Guillaume J. and Carey, Lucas B. and Kondrashov, Fyodor}, publisher = {Public Library of Science}, title = {{A statistical summary of segment libraries and sequencing results}}, doi = {10.1371/journal.pgen.1008079.s011}, year = {2019}, } @misc{9797, author = {Pokusaeva, Victoria and Usmanova, Dinara R. and Putintseva, Ekaterina V. and Espinar, Lorena and Sarkisyan, Karen and Mishin, Alexander S. and Bogatyreva, Natalya S. and Ivankov, Dmitry and Akopyan, Arseniy and Povolotskaya, Inna S. and Filion, Guillaume J. and Carey, Lucas B. and Kondrashov, Fyodor}, publisher = {Public Library of Science}, title = {{A statistical summary of segment libraries and sequencing results}}, doi = {10.1371/journal.pgen.1008079.s011}, year = {2019}, } @misc{9789, author = {Pokusaeva, Victoria and Usmanova, Dinara R. and Putintseva, Ekaterina V. and Espinar, Lorena and Sarkisyan, Karen and Mishin, Alexander S. and Bogatyreva, Natalya S. and Ivankov, Dmitry and Akopyan, Arseniy and Avvakumov, Sergey and Povolotskaya, Inna S. and Filion, Guillaume J. and Carey, Lucas B. and Kondrashov, Fyodor}, publisher = {Public Library of Science}, title = {{Multiple alignment of His3 orthologues}}, doi = {10.1371/journal.pgen.1008079.s010}, year = {2019}, } @inproceedings{6462, abstract = {A controller is a device that interacts with a plant. At each time point,it reads the plant’s state and issues commands with the goal that the plant oper-ates optimally. Constructing optimal controllers is a fundamental and challengingproblem. Machine learning techniques have recently been successfully applied totrain controllers, yet they have limitations. Learned controllers are monolithic andhard to reason about. In particular, it is difficult to add features without retraining,to guarantee any level of performance, and to achieve acceptable performancewhen encountering untrained scenarios. These limitations can be addressed bydeploying quantitative run-timeshieldsthat serve as a proxy for the controller.At each time point, the shield reads the command issued by the controller andmay choose to alter it before passing it on to the plant. We show how optimalshields that interfere as little as possible while guaranteeing a desired level ofcontroller performance, can be generated systematically and automatically usingreactive synthesis. First, we abstract the plant by building a stochastic model.Second, we consider the learned controller to be a black box. Third, we mea-surecontroller performanceandshield interferenceby two quantitative run-timemeasures that are formally defined using weighted automata. Then, the problemof constructing a shield that guarantees maximal performance with minimal inter-ference is the problem of finding an optimal strategy in a stochastic2-player game“controller versus shield” played on the abstract state space of the plant with aquantitative objective obtained from combining the performance and interferencemeasures. We illustrate the effectiveness of our approach by automatically con-structing lightweight shields for learned traffic-light controllers in various roadnetworks. The shields we generate avoid liveness bugs, improve controller per-formance in untrained and changing traffic situations, and add features to learnedcontrollers, such as giving priority to emergency vehicles.}, author = {Avni, Guy and Bloem, Roderick and Chatterjee, Krishnendu and Henzinger, Thomas A and Konighofer, Bettina and Pranger, Stefan}, booktitle = {31st International Conference on Computer-Aided Verification}, isbn = {9783030255398}, issn = {0302-9743}, location = {New York, NY, United States}, pages = {630--649}, publisher = {Springer}, title = {{Run-time optimization for learned controllers through quantitative games}}, doi = {10.1007/978-3-030-25540-4_36}, volume = {11561}, year = {2019}, } @article{6477, abstract = {Thermalizing quantum systems are conventionallydescribed by statistical mechanics at equilib-rium. However, not all systems fall into this category, with many-body localization providinga generic mechanism for thermalization to fail in strongly disordered systems. Many-bodylocalized (MBL) systems remain perfect insulators at nonzero temperature, which do notthermalize and therefore cannot be describedusing statistical mechanics. This Colloquiumreviews recent theoretical and experimental advances in studies of MBL systems, focusing onthe new perspective provided by entanglement and nonequilibrium experimental probes suchas quantum quenches. Theoretically, MBL systems exhibit a new kind of robust integrability: anextensive set of quasilocal integrals of motion emerges, which provides an intuitive explanationof the breakdown of thermalization. A description based on quasilocal integrals of motion isused to predict dynamical properties of MBL systems, such as the spreading of quantumentanglement, the behavior of local observables, and the response to external dissipativeprocesses. Furthermore, MBL systems can exhibit eigenstate transitions and quantum ordersforbidden in thermodynamic equilibrium. An outline isgiven of the current theoretical under-standing of the quantum-to-classical transitionbetween many-body localized and ergodic phasesand anomalous transport in the vicinity of that transition. Experimentally, synthetic quantumsystems, which are well isolated from an external thermal reservoir, provide natural platforms forrealizing the MBL phase. Recent experiments with ultracold atoms, trapped ions, superconductingqubits, and quantum materials, in which different signatures of many-body localization have beenobserved, are reviewed. This Colloquium concludes by listing outstanding challenges andpromising future research directions.}, author = {Abanin, Dmitry A. and Altman, Ehud and Bloch, Immanuel and Serbyn, Maksym}, issn = {0034-6861}, journal = {Reviews of Modern Physics}, number = {2}, publisher = {American Physical Society}, title = {{Colloquium: Many-body localization, thermalization, and entanglement}}, doi = {10.1103/revmodphys.91.021001}, volume = {91}, year = {2019}, } @article{6466, abstract = {One of the most striking and consistent results in speciation genomics is the heterogeneous divergence observed across the genomes of closely related species. This pattern was initially attributed to different levels of gene exchange—with divergence preserved at loci generating a barrier to gene flow but homogenized at unlinked neutral loci. Although there is evidence to support this model, it is now recognized that interpreting patterns of divergence across genomes is not so straightforward. One problem is that heterogenous divergence between populations can also be generated by other processes (e.g. recurrent selective sweeps or background selection) without any involvement of differential gene flow. Thus, integrated studies that identify which loci are likely subject to divergent selection are required to shed light on the interplay between selection and gene flow during the early phases of speciation. In this issue of Molecular Ecology, Rifkin et al. (2019) confront this challenge using a pair of sister morning glory species. They wisely design their sampling to take the geographic context of individuals into account, including geographically isolated (allopatric) and co‐occurring (sympatric) populations. This enabled them to show that individuals are phenotypically less differentiated in sympatry. They also found that the loci that resist introgression are enriched for those most differentiated in allopatry and loci that exhibit signals of divergent selection. One great strength of the study is the combination of methods from population genetics and molecular evolution, including the development of a model to simultaneously infer admixture proportions and selfing rates.}, author = {Field, David and Fraisse, Christelle}, issn = {1365294X}, journal = {Molecular ecology}, number = {7}, pages = {1579--1581}, publisher = {Wiley}, title = {{Breaking down barriers in morning glories}}, doi = {10.1111/mec.15048}, volume = {28}, year = {2019}, } @article{6465, abstract = {Tight control over protein degradation is a fundamental requirement for cells to respond rapidly to various stimuli and adapt to a fluctuating environment. Here we develop a versatile, easy-to-handle library of destabilizing tags (degrons) for the precise regulation of protein expression profiles in mammalian cells by modulating target protein half-lives in a predictable manner. Using the well-established tetracycline gene-regulation system as a model, we show that the dynamics of protein expression can be tuned by fusing appropriate degron tags to gene regulators. Next, we apply this degron library to tune a synthetic pulse-generating circuit in mammalian cells. With this toolbox we establish a set of pulse generators with tailored pulse lengths and magnitudes of protein expression. This methodology will prove useful in the functional roles of essential proteins, fine-tuning of gene-expression systems, and enabling a higher complexity in the design of synthetic biological systems in mammalian cells.}, author = {Chassin, Hélène and Müller, Marius and Tigges, Marcel and Scheller, Leo and Lang, Moritz and Fussenegger, Martin}, issn = {20411723}, journal = {Nature Communications}, number = {1}, publisher = {Springer Nature}, title = {{A modular degron library for synthetic circuits in mammalian cells}}, doi = {10.1038/s41467-019-09974-5}, volume = {10}, year = {2019}, } @article{6467, abstract = {Fitness interactions between mutations can influence a population’s evolution in many different ways. While epistatic effects are difficult to measure precisely, important information is captured by the mean and variance of log fitnesses for individuals carrying different numbers of mutations. We derive predictions for these quantities from a class of simple fitness landscapes, based on models of optimizing selection on quantitative traits. We also explore extensions to the models, including modular pleiotropy, variable effect sizes, mutational bias and maladaptation of the wild type. We illustrate our approach by reanalysing a large dataset of mutant effects in a yeast snoRNA (small nucleolar RNA). Though characterized by some large epistatic effects, these data give a good overall fit to the non-epistatic null model, suggesting that epistasis might have limited influence on the evolutionary dynamics in this system. We also show how the amount of epistasis depends on both the underlying fitness landscape and the distribution of mutations, and so is expected to vary in consistent ways between new mutations, standing variation and fixed mutations.}, author = {Fraisse, Christelle and Welch, John J.}, issn = {1744957X}, journal = {Biology Letters}, number = {4}, publisher = {Royal Society of London}, title = {{The distribution of epistasis on simple fitness landscapes}}, doi = {10.1098/rsbl.2018.0881}, volume = {15}, year = {2019}, } @article{6470, abstract = {Investigating neuronal activity using genetically encoded Ca2+ indicators in behaving animals is hampered by inaccuracies in spike inference from fluorescent tracers. Here we combine two‐photon [Ca2+] imaging with cell‐attached recordings, followed by post hoc determination of the expression level of GCaMP6f, to explore how it affects the amplitude, kinetics and temporal summation of somatic [Ca2+] transients in mouse hippocampal pyramidal cells (PCs). The amplitude of unitary [Ca2+] transients (evoked by a single action potential) negatively correlates with GCaMP6f expression, but displays large variability even among PCs with similarly low expression levels. The summation of fluorescence signals is frequency‐dependent, supralinear and also shows remarkable cell‐to‐cell variability. We performed experimental data‐based simulations and found that spike inference error rates using MLspike depend strongly on unitary peak amplitudes and GCaMP6f expression levels. We provide simple methods for estimating the unitary [Ca2+] transients in individual weakly GCaMP6f‐expressing PCs, with which we achieve spike inference error rates of ∼5%. }, author = {Éltes, Tímea and Szoboszlay, Miklos and Szigeti, Margit Katalin and Nusser, Zoltan}, issn = {14697793}, journal = {Journal of Physiology}, number = {11}, pages = {2925–2947}, publisher = {Wiley}, title = {{Improved spike inference accuracy by estimating the peak amplitude of unitary [Ca2+] transients in weakly GCaMP6f-expressing hippocampal pyramidal cells}}, doi = {10.1113/JP277681}, volume = {597}, year = {2019}, } @inproceedings{6493, abstract = {We present two algorithmic approaches for synthesizing linear hybrid automata from experimental data. Unlike previous approaches, our algorithms work without a template and generate an automaton with nondeterministic guards and invariants, and with an arbitrary number and topology of modes. They thus construct a succinct model from the data and provide formal guarantees. In particular, (1) the generated automaton can reproduce the data up to a specified tolerance and (2) the automaton is tight, given the first guarantee. Our first approach encodes the synthesis problem as a logical formula in the theory of linear arithmetic, which can then be solved by an SMT solver. This approach minimizes the number of modes in the resulting model but is only feasible for limited data sets. To address scalability, we propose a second approach that does not enforce to find a minimal model. The algorithm constructs an initial automaton and then iteratively extends the automaton based on processing new data. Therefore the algorithm is well-suited for online and synthesis-in-the-loop applications. The core of the algorithm is a membership query that checks whether, within the specified tolerance, a given data set can result from the execution of a given automaton. We solve this membership problem for linear hybrid automata by repeated reachability computations. We demonstrate the effectiveness of the algorithm on synthetic data sets and on cardiac-cell measurements.}, author = {Garcia Soto, Miriam and Henzinger, Thomas A and Schilling, Christian and Zeleznik, Luka}, booktitle = {31st International Conference on Computer-Aided Verification}, isbn = {9783030255398}, issn = {0302-9743}, keywords = {Synthesis, Linear hybrid automaton, Membership}, location = {New York City, NY, USA}, pages = {297--314}, publisher = {Springer}, title = {{Membership-based synthesis of linear hybrid automata}}, doi = {10.1007/978-3-030-25540-4_16}, volume = {11561}, year = {2019}, } @misc{6485, abstract = {Traditional concurrent programming involves manipulating shared mutable state. Alternatives to this programming style are communicating sequential processes (CSP) [1] and actor [2] models, which share data via explicit communication. Rendezvous channelis the common abstraction for communication between several processes, where senders and receivers perform a rendezvous handshake as a part of their protocol (senders wait for receivers and vice versa). Additionally to this, channels support the select expression. In this work, we present the first efficient lock-free channel algorithm, and compare it against Go [3] and Kotlin [4] baseline implementations.}, author = {Koval, Nikita and Alistarh, Dan-Adrian and Elizarov, Roman}, booktitle = {Proceedings of the 24th Symposium on Principles and Practice of Parallel Programming}, isbn = {9781450362252}, location = {Washington, NY, United States}, pages = {417--418}, publisher = {ACM Press}, title = {{Lock-free channels for programming via communicating sequential processes}}, doi = {10.1145/3293883.3297000}, year = {2019}, } @article{6504, abstract = {Root gravitropism is one of the most important processes allowing plant adaptation to the land environment. Auxin plays a central role in mediating root gravitropism, but how auxin contributes to gravitational perception and the subsequent response is still unclear. Here, we showed that the local auxin maximum/gradient within the root apex, which is generated by the PIN directional auxin transporters, regulates the expression of three key starch granule synthesis genes, SS4, PGM and ADG1, which in turn influence the accumulation of starch granules that serve as a statolith perceiving gravity. Moreover, using the cvxIAA‐ccvTIR1 system, we also showed that TIR1‐mediated auxin signaling is required for starch granule formation and gravitropic response within root tips. In addition, axr3 mutants showed reduced auxin‐mediated starch granule accumulation and disruption of gravitropism within the root apex. Our results indicate that auxin‐mediated statolith production relies on the TIR1/AFB‐AXR3‐mediated auxin signaling pathway. In summary, we propose a dual role for auxin in gravitropism: the regulation of both gravity perception and response.}, author = {Zhang, Yuzhou and He, P and Ma, X and Yang, Z and Pang, C and Yu, J and Wang, G and Friml, Jiří and Xiao, G}, issn = {1469-8137}, journal = {New Phytologist}, number = {2}, pages = {761--774}, publisher = {Wiley}, title = {{Auxin-mediated statolith production for root gravitropism}}, doi = {10.1111/nph.15932}, volume = {224}, year = {2019}, } @article{6506, abstract = {How does environmental complexity affect the evolution of single genes? Here, we measured the effects of a set of Bacillus subtilis glutamate dehydrogenase mutants across 19 different environments—from phenotypically homogeneous single-cell populations in liquid media to heterogeneous biofilms, plant roots and soil populations. The effects of individual gene mutations on organismal fitness were highly reproducible in liquid cultures. However, 84% of the tested alleles showed opposing fitness effects under different growth conditions (sign environmental pleiotropy). In colony biofilms and soil samples, different alleles dominated in parallel replica experiments. Accordingly, we found that in these heterogeneous cell populations the fate of mutations was dictated by a combination of selection and drift. The latter relates to programmed prophage excisions that occurred during biofilm development. Overall, for each condition, a wide range of glutamate dehydrogenase mutations persisted and sometimes fixated as a result of the combined action of selection, pleiotropy and chance. However, over longer periods and in multiple environments, nearly all of this diversity would be lost—across all the environments and conditions that we tested, the wild type was the fittest allele.}, author = {Noda-García, Lianet and Davidi, Dan and Korenblum, Elisa and Elazar, Assaf and Putintseva, Ekaterina and Aharoni, Asaph and Tawfik, Dan S.}, issn = {2058-5276}, journal = {Nature Microbiology}, number = {7}, pages = {1221–1230}, publisher = {Springer Nature}, title = {{Chance and pleiotropy dominate genetic diversity in complex bacterial environments}}, doi = {10.1038/s41564-019-0412-y}, volume = {4}, year = {2019}, } @article{6521, abstract = {Microglia have emerged as a critical component of neurodegenerative diseases. Genetic manipulation of microglia can elucidate their functional impact in disease. In neuroscience, recombinant viruses such as lentiviruses and adeno-associated viruses (AAVs) have been successfully used to target various cell types in the brain, although effective transduction of microglia is rare. In this review, we provide a short background of lentiviruses and AAVs, and strategies for designing recombinant viral vectors. Then, we will summarize recent literature on successful microglial transductions in vitro and in vivo, and discuss the current challenges. Finally, we provide guidelines for reporting the efficiency and specificity of viral targeting in microglia, which will enable the microglial research community to assess and improve methodologies for future studies.}, author = {Maes, Margaret E and Colombo, Gloria and Schulz, Rouven and Siegert, Sandra}, issn = {0304-3940}, journal = {Neuroscience Letters}, publisher = {Elsevier}, title = {{Targeting microglia with lentivirus and AAV: Recent advances and remaining challenges}}, doi = {10.1016/j.neulet.2019.134310}, volume = {707}, year = {2019}, } @article{6513, abstract = {Adult intestinal stem cells are located at the bottom of crypts of Lieberkühn, where they express markers such as LGR5 1,2 and fuel the constant replenishment of the intestinal epithelium1. Although fetal LGR5-expressing cells can give rise to adult intestinal stem cells3,4, it remains unclear whether this population in the patterned epithelium represents unique intestinal stem-cell precursors. Here we show, using unbiased quantitative lineage-tracing approaches, biophysical modelling and intestinal transplantation, that all cells of the mouse intestinal epithelium—irrespective of their location and pattern of LGR5 expression in the fetal gut tube—contribute actively to the adult intestinal stem cell pool. Using 3D imaging, we find that during fetal development the villus undergoes gross remodelling and fission. This brings epithelial cells from the non-proliferative villus into the proliferative intervillus region, which enables them to contribute to the adult stem-cell niche. Our results demonstrate that large-scale remodelling of the intestinal wall and cell-fate specification are closely linked. Moreover, these findings provide a direct link between the observed plasticity and cellular reprogramming of differentiating cells in adult tissues following damage5,6,7,8,9, revealing that stem-cell identity is an induced rather than a hardwired property.}, author = {Guiu, Jordi and Hannezo, Edouard B and Yui, Shiro and Demharter, Samuel and Ulyanchenko, Svetlana and Maimets, Martti and Jørgensen, Anne and Perlman, Signe and Lundvall, Lene and Mamsen, Linn Salto and Larsen, Agnete and Olesen, Rasmus H. and Andersen, Claus Yding and Thuesen, Lea Langhoff and Hare, Kristine Juul and Pers, Tune H. and Khodosevich, Konstantin and Simons, Benjamin D. and Jensen, Kim B.}, issn = {14764687}, journal = {Nature}, pages = {107--111}, publisher = {Springer Nature}, title = {{Tracing the origin of adult intestinal stem cells}}, doi = {10.1038/s41586-019-1212-5}, volume = {570}, year = {2019}, } @article{6564, abstract = {Optogenetics enables the spatio-temporally precise control of cell and animal behavior. Many optogenetic tools are driven by light-controlled protein–protein interactions (PPIs) that are repurposed from natural light-sensitive domains (LSDs). Applying light-controlled PPIs to new target proteins is challenging because it is difficult to predict which of the many available LSDs, if any, will yield robust light regulation. As a consequence, fusion protein libraries need to be prepared and tested, but methods and platforms to facilitate this process are currently not available. Here, we developed a genetic engineering strategy and vector library for the rapid generation of light-controlled PPIs. The strategy permits fusing a target protein to multiple LSDs efficiently and in two orientations. The public and expandable library contains 29 vectors with blue, green or red light-responsive LSDs, many of which have been previously applied ex vivo and in vivo. We demonstrate the versatility of the approach and the necessity for sampling LSDs by generating light-activated caspase-9 (casp9) enzymes. Collectively, this work provides a new resource for optical regulation of a broad range of target proteins in cell and developmental biology.}, author = {Tichy, Alexandra-Madelaine and Gerrard, Elliot J. and Legrand, Julien M.D. and Hobbs, Robin M. and Janovjak, Harald L}, issn = {10898638}, journal = {Journal of Molecular Biology}, number = {17}, pages = {3046--3055}, publisher = {Elsevier}, title = {{Engineering strategy and vector library for the rapid generation of modular light-controlled protein–protein interactions}}, doi = {10.1016/j.jmb.2019.05.033}, volume = {431}, year = {2019}, } @article{6552, abstract = {When animals become sick, infected cells and an armada of activated immune cells attempt to eliminate the pathogen from the body. Once infectious particles have breached the body's physical barriers of the skin or gut lining, an initially local response quickly escalates into a systemic response, attracting mobile immune cells to the site of infection. These cells complement the initial, unspecific defense with a more specialized, targeted response. This can also provide long-term immune memory and protection against future infection. The cell-autonomous defenses of the infected cells are thus aided by the actions of recruited immune cells. These specialized cells are the most mobile cells in the body, constantly patrolling through the otherwise static tissue to detect incoming pathogens. Such constant immune surveillance means infections are noticed immediately and can be rapidly cleared from the body. Some immune cells also remove infected cells that have succumbed to infection. All this prevents pathogen replication and spread to healthy tissues. Although this may involve the sacrifice of some somatic tissue, this is typically replaced quickly. Particular care is, however, given to the reproductive organs, which should always remain disease free (immune privilege). }, author = {Cremer, Sylvia}, issn = {09609822}, journal = {Current Biology}, number = {11}, pages = {R458--R463}, publisher = {Elsevier}, title = {{Social immunity in insects}}, doi = {10.1016/j.cub.2019.03.035}, volume = {29}, year = {2019}, } @article{6511, abstract = {Let U and V be two independent N by N random matrices that are distributed according to Haar measure on U(N). Let Σ be a nonnegative deterministic N by N matrix. The single ring theorem [Ann. of Math. (2) 174 (2011) 1189–1217] asserts that the empirical eigenvalue distribution of the matrix X:=UΣV∗ converges weakly, in the limit of large N, to a deterministic measure which is supported on a single ring centered at the origin in ℂ. Within the bulk regime, that is, in the interior of the single ring, we establish the convergence of the empirical eigenvalue distribution on the optimal local scale of order N−1/2+ε and establish the optimal convergence rate. The same results hold true when U and V are Haar distributed on O(N).}, author = {Bao, Zhigang and Erdös, László and Schnelli, Kevin}, issn = {00911798}, journal = {Annals of Probability}, number = {3}, pages = {1270--1334}, publisher = {Institute of Mathematical Statistics}, title = {{Local single ring theorem on optimal scale}}, doi = {10.1214/18-AOP1284}, volume = {47}, year = {2019}, } @article{6559, abstract = {Branching morphogenesis is a prototypical example of complex three-dimensional organ sculpting, required in multiple developmental settings to maximize the area of exchange surfaces. It requires, in particular, the coordinated growth of different cell types together with complex patterning to lead to robust macroscopic outputs. In recent years, novel multiscale quantitative biology approaches, together with biophysical modelling, have begun to shed new light of this topic. Here, we wish to review some of these recent developments, highlighting the generic design principles that can be abstracted across different branched organs, as well as the implications for the broader fields of stem cell, developmental and systems biology.}, author = {Hannezo, Edouard B and Simons, Benjamin D.}, issn = {18790410}, journal = {Current Opinion in Cell Biology}, pages = {99--105}, publisher = {Elsevier}, title = {{Multiscale dynamics of branching morphogenesis}}, doi = {10.1016/j.ceb.2019.04.008}, volume = {60}, year = {2019}, } @article{6566, abstract = {Methodologies that involve the use of nanoparticles as “artificial atoms” to rationally build materials in a bottom-up fashion are particularly well-suited to control the matter at the nanoscale. Colloidal synthetic routes allow for an exquisite control over such “artificial atoms” in terms of size, shape, and crystal phase as well as core and surface compositions. We present here a bottom-up approach to produce Pb–Ag–K–S–Te nanocomposites, which is a highly promising system for thermoelectric energy conversion. First, we developed a high-yield and scalable colloidal synthesis route to uniform lead sulfide (PbS) nanorods, whose tips are made of silver sulfide (Ag2S). We then took advantage of the large surface-to-volume ratio to introduce a p-type dopant (K) by replacing native organic ligands with K2Te. Upon thermal consolidation, K2Te-surface modified PbS–Ag2S nanorods yield p-type doped nanocomposites with PbTe and PbS as major phases and Ag2S and Ag2Te as embedded nanoinclusions. Thermoelectric characterization of such consolidated nanosolids showed a high thermoelectric figure-of-merit of 1 at 620 K.}, author = {Ibáñez, Maria and Genç, Aziz and Hasler, Roger and Liu, Yu and Dobrozhan, Oleksandr and Nazarenko, Olga and Mata, María de la and Arbiol, Jordi and Cabot, Andreu and Kovalenko, Maksym V.}, issn = {1936-086X}, journal = {ACS Nano}, keywords = {colloidal nanoparticles, asymmetric nanoparticles, inorganic ligands, heterostructures, catalyst assisted growth, nanocomposites, thermoelectrics}, number = {6}, pages = {6572--6580}, publisher = {American Chemical Society}, title = {{Tuning transport properties in thermoelectric nanocomposites through inorganic ligands and heterostructured building blocks}}, doi = {10.1021/acsnano.9b00346}, volume = {13}, year = {2019}, } @article{6607, abstract = {Acute myeloid leukemia (AML) is a heterogeneous disease with respect to its genetic and molecular basis and to patients´ outcome. Clinical, cytogenetic, and mutational data are used to classify patients into risk groups with different survival, however, within-group heterogeneity is still an issue. Here, we used a robust likelihood-based survival modeling approach and publicly available gene expression data to identify a minimal number of genes whose combined expression values were prognostic of overall survival. The resulting gene expression signature (4-GES) consisted of 4 genes (SOCS2, IL2RA, NPDC1, PHGDH), predicted patient survival as an independent prognostic parameter in several cohorts of AML patients (total, 1272 patients), and further refined prognostication based on the European Leukemia Net classification. An oncogenic role of the top scoring gene in this signature, SOCS2, was investigated using MLL-AF9 and Flt3-ITD/NPM1c driven mouse models of AML. SOCS2 promoted leukemogenesis as well as the abundance, quiescence, and activity of AML stem cells. Overall, the 4-GES represents a highly discriminating prognostic parameter in AML, whose clinical applicability is greatly enhanced by its small number of genes. The newly established role of SOCS2 in leukemia aggressiveness and stemness raises the possibility that the signature might even be exploitable therapeutically.}, author = {Nguyen, Chi Huu and Glüxam, Tobias and Schlerka, Angela and Bauer, Katharina and Grandits, Alexander M. and Hackl, Hubert and Dovey, Oliver and Zöchbauer-Müller, Sabine and Cooper, Jonathan L. and Vassiliou, George S. and Stoiber, Dagmar and Wieser, Rotraud and Heller, Gerwin}, journal = {Scientific Reports}, number = {1}, publisher = {Nature Publishing Group}, title = {{SOCS2 is part of a highly prognostic 4-gene signature in AML and promotes disease aggressiveness}}, doi = {10.1038/s41598-019-45579-0}, volume = {9}, year = {2019}, } @article{6609, abstract = {Mechanical systems facilitate the development of a hybrid quantum technology comprising electrical, optical, atomic and acoustic degrees of freedom1, and entanglement is essential to realize quantum-enabled devices. Continuous-variable entangled fields—known as Einstein–Podolsky–Rosen (EPR) states—are spatially separated two-mode squeezed states that can be used for quantum teleportation and quantum communication2. In the optical domain, EPR states are typically generated using nondegenerate optical amplifiers3, and at microwave frequencies Josephson circuits can serve as a nonlinear medium4,5,6. An outstanding goal is to deterministically generate and distribute entangled states with a mechanical oscillator, which requires a carefully arranged balance between excitation, cooling and dissipation in an ultralow noise environment. Here we observe stationary emission of path-entangled microwave radiation from a parametrically driven 30-micrometre-long silicon nanostring oscillator, squeezing the joint field operators of two thermal modes by 3.40 decibels below the vacuum level. The motion of this micromechanical system correlates up to 50 photons per second per hertz, giving rise to a quantum discord that is robust with respect to microwave noise7. Such generalized quantum correlations of separable states are important for quantum-enhanced detection8 and provide direct evidence of the non-classical nature of the mechanical oscillator without directly measuring its state9. This noninvasive measurement scheme allows to infer information about otherwise inaccessible objects, with potential implications for sensing, open-system dynamics and fundamental tests of quantum gravity. In the future, similar on-chip devices could be used to entangle subsystems on very different energy scales, such as microwave and optical photons.}, author = {Barzanjeh, Shabir and Redchenko, Elena and Peruzzo, Matilda and Wulf, Matthias and Lewis, Dylan and Arnold, Georg M and Fink, Johannes M}, journal = {Nature}, pages = {480--483}, publisher = {Nature Publishing Group}, title = {{Stationary entangled radiation from micromechanical motion}}, doi = {10.1038/s41586-019-1320-2}, volume = {570}, year = {2019}, } @article{6596, abstract = {It is well known that many problems in image recovery, signal processing, and machine learning can be modeled as finding zeros of the sum of maximal monotone and Lipschitz continuous monotone operators. Many papers have studied forward-backward splitting methods for finding zeros of the sum of two monotone operators in Hilbert spaces. Most of the proposed splitting methods in the literature have been proposed for the sum of maximal monotone and inverse-strongly monotone operators in Hilbert spaces. In this paper, we consider splitting methods for finding zeros of the sum of maximal monotone operators and Lipschitz continuous monotone operators in Banach spaces. We obtain weak and strong convergence results for the zeros of the sum of maximal monotone and Lipschitz continuous monotone operators in Banach spaces. Many already studied problems in the literature can be considered as special cases of this paper.}, author = {Shehu, Yekini}, issn = {1420-9012}, journal = {Results in Mathematics}, number = {4}, publisher = {Springer}, title = {{Convergence results of forward-backward algorithms for sum of monotone operators in Banach spaces}}, doi = {10.1007/s00025-019-1061-4}, volume = {74}, year = {2019}, } @article{6601, abstract = {There is increasing evidence that both mechanical and biochemical signals play important roles in development and disease. The development of complex organisms, in particular, has been proposed to rely on the feedback between mechanical and biochemical patterning events. This feedback occurs at the molecular level via mechanosensation but can also arise as an emergent property of the system at the cellular and tissue level. In recent years, dynamic changes in tissue geometry, flow, rheology, and cell fate specification have emerged as key platforms of mechanochemical feedback loops in multiple processes. Here, we review recent experimental and theoretical advances in understanding how these feedbacks function in development and disease.}, author = {Hannezo, Edouard B and Heisenberg, Carl-Philipp J}, issn = {00928674}, journal = {Cell}, number = {1}, pages = {12--25}, publisher = {Elsevier}, title = {{Mechanochemical feedback loops in development and disease}}, doi = {10.1016/j.cell.2019.05.052}, volume = {178}, year = {2019}, } @article{6617, abstract = {The effective large-scale properties of materials with random heterogeneities on a small scale are typically determined by the method of representative volumes: a sample of the random material is chosen—the representative volume—and its effective properties are computed by the cell formula. Intuitively, for a fixed sample size it should be possible to increase the accuracy of the method by choosing a material sample which captures the statistical properties of the material particularly well; for example, for a composite material consisting of two constituents, one would select a representative volume in which the volume fraction of the constituents matches closely with their volume fraction in the overall material. Inspired by similar attempts in materials science, Le Bris, Legoll and Minvielle have designed a selection approach for representative volumes which performs remarkably well in numerical examples of linear materials with moderate contrast. In the present work, we provide a rigorous analysis of this selection approach for representative volumes in the context of stochastic homogenization of linear elliptic equations. In particular, we prove that the method essentially never performs worse than a random selection of the material sample and may perform much better if the selection criterion for the material samples is chosen suitably.}, author = {Fischer, Julian L}, issn = {1432-0673}, journal = {Archive for Rational Mechanics and Analysis}, number = {2}, pages = {635–726}, publisher = {Springer}, title = {{The choice of representative volumes in the approximation of effective properties of random materials}}, doi = {10.1007/s00205-019-01400-w}, volume = {234}, year = {2019}, } @article{6611, abstract = {Cell polarity is crucial for the coordinated development of all multicellular organisms. In plants, this is exemplified by the PIN-FORMED (PIN) efflux carriers of the phytohormone auxin: The polar subcellular localization of the PINs is instructive to the directional intercellular auxin transport, and thus to a plethora of auxin-regulated growth and developmental processes. Despite its importance, the regulation of PIN polar subcellular localization remains poorly understood. Here, we have employed advanced live-cell imaging techniques to study the roles of microtubules and actin microfilaments in the establishment of apical polar localization of PIN2 in the epidermis of the Arabidopsis root meristem. We report that apical PIN2 polarity requires neither intact actin microfilaments nor microtubules, suggesting that the primary spatial cue for polar PIN distribution is likely independent of cytoskeleton-guided endomembrane trafficking.}, author = {Glanc, Matous and Fendrych, Matyas and Friml, Jiří}, journal = {Biomolecules}, number = {6}, publisher = {MDPI}, title = {{PIN2 polarity establishment in arabidopsis in the absence of an intact cytoskeleton}}, doi = {10.3390/biom9060222}, volume = {9}, year = {2019}, }