@article{676, abstract = {The segregation of different cell types into distinct tissues is a fundamental process in metazoan development. Differences in cell adhesion and cortex tension are commonly thought to drive cell sorting by regulating tissue surface tension (TST). However, the role that differential TST plays in cell segregation within the developing embryo is as yet unclear. Here, we have analyzed the role of differential TST for germ layer progenitor cell segregation during zebrafish gastrulation. Contrary to previous observations that differential TST drives germ layer progenitor cell segregation in vitro, we show that germ layers display indistinguishable TST within the gastrulating embryo, arguing against differential TST driving germ layer progenitor cell segregation in vivo. We further show that the osmolarity of the interstitial fluid (IF) is an important factor that influences germ layer TST in vivo, and that lower osmolarity of the IF compared with standard cell culture medium can explain why germ layers display differential TST in culture but not in vivo. Finally, we show that directed migration of mesendoderm progenitors is required for germ layer progenitor cell segregation and germ layer formation.}, author = {Krens, Gabriel and Veldhuis, Jim and Barone, Vanessa and Capek, Daniel and Maître, Jean-Léon and Brodland, Wayne and Heisenberg, Carl-Philipp J}, issn = {0950-1991}, journal = {Development}, number = {10}, pages = {1798 -- 1806}, publisher = {Company of Biologists}, title = {{Interstitial fluid osmolarity modulates the action of differential tissue surface tension in progenitor cell segregation during gastrulation}}, doi = {10.1242/dev.144964}, volume = {144}, year = {2017}, } @article{1024, abstract = {The history of auxin and cytokinin biology including the initial discoveries by father–son duo Charles Darwin and Francis Darwin (1880), and Gottlieb Haberlandt (1919) is a beautiful demonstration of unceasing continuity of research. Novel findings are integrated into existing hypotheses and models and deepen our understanding of biological principles. At the same time new questions are triggered and hand to hand with this new methodologies are developed to address these new challenges.}, author = {Hurny, Andrej and Benková, Eva}, issn = {1064-3745}, journal = {Auxins and Cytokinins in Plant Biology}, pages = {1 -- 29}, publisher = {Springer}, title = {{Methodological advances in auxin and cytokinin biology}}, doi = {10.1007/978-1-4939-6831-2_1}, volume = {1569}, year = {2017}, } @article{696, abstract = {Mutator strains are expected to evolve when the availability and effect of beneficial mutations are high enough to counteract the disadvantage from deleterious mutations that will inevitably accumulate. As the population becomes more adapted to its environment, both availability and effect of beneficial mutations necessarily decrease and mutation rates are predicted to decrease. It has been shown that certain molecular mechanisms can lead to increased mutation rates when the organism finds itself in a stressful environment. While this may be a correlated response to other functions, it could also be an adaptive mechanism, raising mutation rates only when it is most advantageous. Here, we use a mathematical model to investigate the plausibility of the adaptive hypothesis. We show that such a mechanism can be mantained if the population is subjected to diverse stresses. By simulating various antibiotic treatment schemes, we find that combination treatments can reduce the effectiveness of second-order selection on stress-induced mutagenesis. We discuss the implications of our results to strategies of antibiotic therapy.}, author = {Lukacisinova, Marta and Novak, Sebastian and Paixao, Tiago}, issn = {1553-734X}, journal = {PLoS Computational Biology}, number = {7}, publisher = {Public Library of Science}, title = {{Stress induced mutagenesis: Stress diversity facilitates the persistence of mutator genes}}, doi = {10.1371/journal.pcbi.1005609}, volume = {13}, year = {2017}, } @article{1027, abstract = {The rising prevalence of antibiotic resistant bacteria is an increasingly serious public health challenge. To address this problem, recent work ranging from clinical studies to theoretical modeling has provided valuable insights into the mechanisms of resistance, its emergence and spread, and ways to counteract it. A deeper understanding of the underlying dynamics of resistance evolution will require a combination of experimental and theoretical expertise from different disciplines and new technology for studying evolution in the laboratory. Here, we review recent advances in the quantitative understanding of the mechanisms and evolution of antibiotic resistance. We focus on key theoretical concepts and new technology that enables well-controlled experiments. We further highlight key challenges that can be met in the near future to ultimately develop effective strategies for combating resistance.}, author = {Lukacisinova, Marta and Bollenbach, Mark Tobias}, journal = {Current Opinion in Biotechnology}, pages = {90 -- 97}, publisher = {Elsevier}, title = {{Toward a quantitative understanding of antibiotic resistance evolution}}, doi = {10.1016/j.copbio.2017.02.013}, volume = {46}, year = {2017}, } @article{1029, abstract = {RNA Polymerase II pauses and backtracks during transcription, with many consequences for gene expression and cellular physiology. Here, we show that the energy required to melt double-stranded nucleic acids in the transcription bubble predicts pausing in Saccharomyces cerevisiae far more accurately than nucleosome roadblocks do. In addition, the same energy difference also determines when the RNA polymerase backtracks instead of continuing to move forward. This data-driven model corroborates—in a genome wide and quantitative manner—previous evidence that sequence-dependent thermodynamic features of nucleic acids influence both transcriptional pausing and backtracking.}, author = {Lukacisin, Martin and Landon, Matthieu and Jajoo, Rishi}, issn = {1932-6203}, journal = {PLoS One}, number = {3}, publisher = {Public Library of Science}, title = {{Sequence-specific thermodynamic properties of nucleic acids influence both transcriptional pausing and backtracking in yeast}}, doi = {10.1371/journal.pone.0174066}, volume = {12}, year = {2017}, } @article{1028, abstract = {Optogenetics and photopharmacology provide spatiotemporally precise control over protein interactions and protein function in cells and animals. Optogenetic methods that are sensitive to green light and can be used to break protein complexes are not broadly available but would enable multichromatic experiments with previously inaccessible biological targets. Herein, we repurposed cobalamin (vitamin B12) binding domains of bacterial CarH transcription factors for green-light-induced receptor dissociation. In cultured cells, we observed oligomerization-induced cell signaling for the fibroblast growth factor receptor 1 fused to cobalamin-binding domains in the dark that was rapidly eliminated upon illumination. In zebrafish embryos expressing fusion receptors, green light endowed control over aberrant fibroblast growth factor signaling during development. Green-light-induced domain dissociation and light-inactivated receptors will critically expand the optogenetic toolbox for control of biological processes.}, author = {Kainrath, Stephanie and Stadler, Manuela and Gschaider-Reichhart, Eva and Distel, Martin and Janovjak, Harald L}, issn = {1433-7851}, journal = {Angewandte Chemie - International Edition}, number = {16}, pages = {4608--4611}, publisher = {Wiley-Blackwell}, title = {{Green-light-induced inactivation of receptor signaling using cobalamin-binding domains}}, doi = {10.1002/anie.201611998}, volume = {56}, year = {2017}, } @article{661, abstract = {During embryonic development, mechanical forces are essential for cellular rearrangements driving tissue morphogenesis. Here, we show that in the early zebrafish embryo, friction forces are generated at the interface between anterior axial mesoderm (prechordal plate, ppl) progenitors migrating towards the animal pole and neurectoderm progenitors moving in the opposite direction towards the vegetal pole of the embryo. These friction forces lead to global rearrangement of cells within the neurectoderm and determine the position of the neural anlage. Using a combination of experiments and simulations, we show that this process depends on hydrodynamic coupling between neurectoderm and ppl as a result of E-cadherin-mediated adhesion between those tissues. Our data thus establish the emergence of friction forces at the interface between moving tissues as a critical force-generating process shaping the embryo.}, author = {Smutny, Michael and Ákos, Zsuzsa and Grigolon, Silvia and Shamipour, Shayan and Ruprecht, Verena and Capek, Daniel and Behrndt, Martin and Papusheva, Ekaterina and Tada, Masazumi and Hof, Björn and Vicsek, Tamás and Salbreux, Guillaume and Heisenberg, Carl-Philipp J}, issn = {1465-7392}, journal = {Nature Cell Biology}, pages = {306 -- 317}, publisher = {Nature Publishing Group}, title = {{Friction forces position the neural anlage}}, doi = {10.1038/ncb3492}, volume = {19}, year = {2017}, } @article{735, abstract = {Cell-cell contact formation constitutes an essential step in evolution, leading to the differentiation of specialized cell types. However, remarkably little is known about whether and how the interplay between contact formation and fate specification affects development. Here, we identify a positive feedback loop between cell-cell contact duration, morphogen signaling, and mesendoderm cell-fate specification during zebrafish gastrulation. We show that long-lasting cell-cell contacts enhance the competence of prechordal plate (ppl) progenitor cells to respond to Nodal signaling, required for ppl cell-fate specification. We further show that Nodal signaling promotes ppl cell-cell contact duration, generating a positive feedback loop between ppl cell-cell contact duration and cell-fate specification. Finally, by combining mathematical modeling and experimentation, we show that this feedback determines whether anterior axial mesendoderm cells become ppl or, instead, turn into endoderm. Thus, the interdependent activities of cell-cell signaling and contact formation control fate diversification within the developing embryo.}, author = {Barone, Vanessa and Lang, Moritz and Krens, Gabriel and Pradhan, Saurabh and Shamipour, Shayan and Sako, Keisuke and Sikora, Mateusz K and Guet, Calin C and Heisenberg, Carl-Philipp J}, issn = {1534-5807}, journal = {Developmental Cell}, number = {2}, pages = {198 -- 211}, publisher = {Cell Press}, title = {{An effective feedback loop between cell-cell contact duration and morphogen signaling determines cell fate}}, doi = {10.1016/j.devcel.2017.09.014}, volume = {43}, year = {2017}, } @inproceedings{949, abstract = {The notion of treewidth of graphs has been exploited for faster algorithms for several problems arising in verification and program analysis. Moreover, various notions of balanced tree decompositions have been used for improved algorithms supporting dynamic updates and analysis of concurrent programs. In this work, we present a tool for constructing tree-decompositions of CFGs obtained from Java methods, which is implemented as an extension to the widely used Soot framework. The experimental results show that our implementation on real-world Java benchmarks is very efficient. Our tool also provides the first implementation for balancing tree-decompositions. In summary, we present the first tool support for exploiting treewidth in the static analysis problems on Java programs.}, author = {Chatterjee, Krishnendu and Goharshady, Amir and Pavlogiannis, Andreas}, editor = {D'Souza, Deepak}, issn = {0302-9743}, location = {Pune, India}, pages = {59 -- 66}, publisher = {Springer}, title = {{JTDec: A tool for tree decompositions in soot}}, doi = {10.1007/978-3-319-68167-2_4}, volume = {10482}, year = {2017}, } @inproceedings{639, abstract = {We study the problem of developing efficient approaches for proving worst-case bounds of non-deterministic recursive programs. Ranking functions are sound and complete for proving termination and worst-case bounds of non-recursive programs. First, we apply ranking functions to recursion, resulting in measure functions, and show that they provide a sound and complete approach to prove worst-case bounds of non-deterministic recursive programs. Our second contribution is the synthesis of measure functions in non-polynomial forms. We show that non-polynomial measure functions with logarithm and exponentiation can be synthesized through abstraction of logarithmic or exponentiation terms, Farkas’ Lemma, and Handelman’s Theorem using linear programming. While previous methods obtain worst-case polynomial bounds, our approach can synthesize bounds of the form O(n log n) as well as O(nr) where r is not an integer. We present experimental results to demonstrate that our approach can efficiently obtain worst-case bounds of classical recursive algorithms such as Merge-Sort, Closest-Pair, Karatsuba’s algorithm and Strassen’s algorithm.}, author = {Chatterjee, Krishnendu and Fu, Hongfei and Goharshady, Amir}, editor = {Majumdar, Rupak and Kunčak, Viktor}, isbn = {978-331963389-3}, location = {Heidelberg, Germany}, pages = {41 -- 63}, publisher = {Springer}, title = {{Non-polynomial worst case analysis of recursive programs}}, doi = {10.1007/978-3-319-63390-9_3}, volume = {10427}, year = {2017}, } @article{664, abstract = {Immune cells communicate using cytokine signals, but the quantitative rules of this communication aren't clear. In this issue of Immunity, Oyler-Yaniv et al. (2017) suggest that the distribution of a cytokine within a lymphatic organ is primarily governed by the local density of cells consuming it.}, author = {Assen, Frank P and Sixt, Michael K}, issn = {1074-7613}, journal = {Immunity}, number = {4}, pages = {519 -- 520}, publisher = {Cell Press}, title = {{The dynamic cytokine niche}}, doi = {10.1016/j.immuni.2017.04.006}, volume = {46}, year = {2017}, } @article{960, abstract = {The human cerebral cortex is the seat of our cognitive abilities and composed of an extraordinary number of neurons, organized in six distinct layers. The establishment of specific morphological and physiological features in individual neurons needs to be regulated with high precision. Impairments in the sequential developmental programs instructing corticogenesis lead to alterations in the cortical cytoarchitecture which is thought to represent the major underlying cause for several neurological disorders including neurodevelopmental and psychiatric diseases. In this review we discuss the role of cell polarity at sequential stages during cortex development. We first provide an overview of morphological cell polarity features in cortical neural stem cells and newly-born postmitotic neurons. We then synthesize a conceptual molecular and biochemical framework how cell polarity is established at the cellular level through a break in symmetry in nascent cortical projection neurons. Lastly we provide a perspective how the molecular mechanisms applying to single cells could be probed and integrated in an in vivo and tissue-wide context.}, author = {Hansen, Andi H and Düllberg, Christian F and Mieck, Christine and Loose, Martin and Hippenmeyer, Simon}, issn = {1662-5102}, journal = {Frontiers in Cellular Neuroscience}, publisher = {Frontiers Research Foundation}, title = {{Cell polarity in cerebral cortex development - cellular architecture shaped by biochemical networks}}, doi = {10.3389/fncel.2017.00176}, volume = {11}, year = {2017}, } @inproceedings{1082, abstract = {In many applications, it is desirable to extract only the relevant aspects of data. A principled way to do this is the information bottleneck (IB) method, where one seeks a code that maximises information about a relevance variable, Y, while constraining the information encoded about the original data, X. Unfortunately however, the IB method is computationally demanding when data are high-dimensional and/or non-gaussian. Here we propose an approximate variational scheme for maximising a lower bound on the IB objective, analogous to variational EM. Using this method, we derive an IB algorithm to recover features that are both relevant and sparse. Finally, we demonstrate how kernelised versions of the algorithm can be used to address a broad range of problems with non-linear relation between X and Y.}, author = {Chalk, Matthew J and Marre, Olivier and Tkacik, Gasper}, location = {Barcelona, Spain}, pages = {1965--1973}, publisher = {Neural Information Processing Systems Foundation}, title = {{Relevant sparse codes with variational information bottleneck}}, volume = {29}, year = {2016}, } @article{1083, abstract = { Cholecystokinin-expressing interneurons (CCK-INs) mediate behavior state-dependent inhibition in cortical circuits and themselves receive strong GABAergic input. However, it remains unclear to what extent GABABreceptors (GABABRs) contribute to their inhibitory control. Using immunoelectron microscopy, we found that CCK-INs in the rat hippocampus possessed high levels of dendritic GABABRs and KCTD12 auxiliary proteins, whereas postsynaptic effector Kir3 channels were present at lower levels. Consistently, whole-cell recordings revealed slow GABABR-mediated inhibitory postsynaptic currents (IPSCs) in most CCK-INs. In spite of the higher surface density of GABABRs in CCK-INs than in CA1 principal cells, the amplitudes of IPSCs were comparable, suggesting that the expression of Kir3 channels is the limiting factor for the GABABR currents in these INs. Morphological analysis showed that CCK-INs were diverse, comprising perisomatic-targeting basket cells (BCs), as well as dendrite-targeting (DT) interneurons, including a previously undescribed DT type. GABABR-mediated IPSCs in CCK-INs were large in BCs, but small in DT subtypes. In response to prolonged activation, GABABR-mediated currents displayed strong desensitization, which was absent in KCTD12-deficient mice. This study highlights that GABABRs differentially control CCK-IN subtypes, and the kinetics and desensitization of GABABR-mediated currents are modulated by KCTD12 proteins. }, author = {Booker, Sam and Althof, Daniel and Gross, Anna and Loreth, Desiree and Müller, Johanna and Unger, Andreas and Fakler, Bernd and Varro, Andrea and Watanabe, Masahiko and Gassmann, Martin and Bettler, Bernhard and Shigemoto, Ryuichi and Vida, Imre and Kulik, Ákos}, journal = {Cerebral Cortex}, number = {3}, pages = {2318 -- 2334}, publisher = {Oxford University Press}, title = {{KCTD12 auxiliary proteins modulate kinetics of GABAB receptor-mediated inhibition in Cholecystokinin-containing interneurons}}, doi = {10.1093/cercor/bhw090}, volume = {27}, year = {2016}, } @article{1088, abstract = {Cell geometry is tightly coupled to gene expression patterns within the tissue microenvironment. This perspective synthesizes evidence that the 3D organization of chromosomes is a critical intermediate for geometric control of genomic programs. Using a combination of experiments and modeling we outline approaches to decipher the mechano-genomic code that governs cellular homeostasis and reprogramming.}, author = {Uhler, Caroline and Shivashankar, G V}, journal = {BioArchitecture}, number = {4}, pages = {76 -- 84}, publisher = {Taylor & Francis}, title = {{Geometric control and modeling of genome reprogramming}}, doi = {10.1080/19490992.2016.1201620}, volume = {6}, year = {2016}, } @inproceedings{1090, abstract = { While weighted automata provide a natural framework to express quantitative properties, many basic properties like average response time cannot be expressed with weighted automata. Nested weighted automata extend weighted automata and consist of a master automaton and a set of slave automata that are invoked by the master automaton. Nested weighted automata are strictly more expressive than weighted automata (e.g., average response time can be expressed with nested weighted automata), but the basic decision questions have higher complexity (e.g., for deterministic automata, the emptiness question for nested weighted automata is PSPACE-hard, whereas the corresponding complexity for weighted automata is PTIME). We consider a natural subclass of nested weighted automata where at any point at most a bounded number k of slave automata can be active. We focus on automata whose master value function is the limit average. We show that these nested weighted automata with bounded width are strictly more expressive than weighted automata (e.g., average response time with no overlapping requests can be expressed with bound k=1, but not with non-nested weighted automata). We show that the complexity of the basic decision problems (i.e., emptiness and universality) for the subclass with k constant matches the complexity for weighted automata. Moreover, when k is part of the input given in unary we establish PSPACE-completeness.}, author = {Chatterjee, Krishnendu and Henzinger, Thomas A and Otop, Jan}, location = {Krakow; Poland}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Nested weighted limit-average automata of bounded width}}, doi = {10.4230/LIPIcs.MFCS.2016.24}, volume = {58}, year = {2016}, } @inproceedings{1093, abstract = {We introduce a general class of distances (metrics) between Markov chains, which are based on linear behaviour. This class encompasses distances given topologically (such as the total variation distance or trace distance) as well as by temporal logics or automata. We investigate which of the distances can be approximated by observing the systems, i.e. by black-box testing or simulation, and we provide both negative and positive results. }, author = {Daca, Przemyslaw and Henzinger, Thomas A and Kretinsky, Jan and Petrov, Tatjana}, location = {Quebec City; Canada}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Linear distances between Markov chains}}, doi = {10.4230/LIPIcs.CONCUR.2016.20}, volume = {59}, year = {2016}, } @inbook{1094, abstract = {Immunogold labeling of freeze-fracture replicas has recently been used for high-resolution visualization of protein localization in electron microscopy. This method has higher labeling efficiency than conventional immunogold methods for membrane molecules allowing precise quantitative measurements. However, one of the limitations of freeze-fracture replica immunolabeling is difficulty in keeping structural orientation and identifying labeled profiles in complex tissues like brain. The difficulty is partly due to fragmentation of freeze-fracture replica preparations during labeling procedures and limited morphological clues on the replica surface. To overcome these issues, we introduce here a grid-glued replica method combined with SEM observation. This method allows histological staining before dissolving the tissue and easy handling of replicas during immunogold labeling, and keeps the whole replica surface intact without fragmentation. The procedure described here is also useful for matched double-replica analysis allowing further identification of labeled profiles in corresponding P-face and E-face.}, author = {Harada, Harumi and Shigemoto, Ryuichi}, booktitle = {High-Resolution Imaging of Cellular Proteins}, issn = {1611-3349}, pages = {203 -- 216}, publisher = {Springer}, title = {{Immunogold protein localization on grid-glued freeze-fracture replicas}}, doi = {10.1007/978-1-4939-6352-2_12}, volume = {1474}, year = {2016}, } @inproceedings{1095, abstract = { The semantics of concurrent data structures is usually given by a sequential specification and a consistency condition. Linearizability is the most popular consistency condition due to its simplicity and general applicability. Nevertheless, for applications that do not require all guarantees offered by linearizability, recent research has focused on improving performance and scalability of concurrent data structures by relaxing their semantics. In this paper, we present local linearizability, a relaxed consistency condition that is applicable to container-type concurrent data structures like pools, queues, and stacks. While linearizability requires that the effect of each operation is observed by all threads at the same time, local linearizability only requires that for each thread T, the effects of its local insertion operations and the effects of those removal operations that remove values inserted by T are observed by all threads at the same time. We investigate theoretical and practical properties of local linearizability and its relationship to many existing consistency conditions. We present a generic implementation method for locally linearizable data structures that uses existing linearizable data structures as building blocks. Our implementations show performance and scalability improvements over the original building blocks and outperform the fastest existing container-type implementations. }, author = {Haas, Andreas and Henzinger, Thomas A and Holzer, Andreas and Kirsch, Christoph and Lippautz, Michael and Payer, Hannes and Sezgin, Ali and Sokolova, Ana and Veith, Helmut}, booktitle = {Leibniz International Proceedings in Informatics}, location = {Quebec City; Canada}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Local linearizability for concurrent container-type data structures}}, doi = {10.4230/LIPIcs.CONCUR.2016.6}, volume = {59}, year = {2016}, } @article{1096, author = {Schwayer, Cornelia and Sikora, Mateusz K and Slovakova, Jana and Kardos, Roland and Heisenberg, Carl-Philipp J}, journal = {Developmental Cell}, number = {6}, pages = {493 -- 506}, publisher = {Cell Press}, title = {{Actin rings of power}}, doi = {10.1016/j.devcel.2016.05.024}, volume = {37}, year = {2016}, }