@phdthesis{1129, abstract = {Directed cell migration is a hallmark feature, present in almost all multi-cellular organisms. Despite its importance, basic questions regarding force transduction or directional sensing are still heavily investigated. Directed migration of cells guided by immobilized guidance cues - haptotaxis - occurs in key-processes, such as embryonic development and immunity (Middleton et al., 1997; Nguyen et al., 2000; Thiery, 1984; Weber et al., 2013). Immobilized guidance cues comprise adhesive ligands, such as collagen and fibronectin (Barczyk et al., 2009), or chemokines - the main guidance cues for migratory leukocytes (Middleton et al., 1997; Weber et al., 2013). While adhesive ligands serve as attachment sites guiding cell migration (Carter, 1965), chemokines instruct haptotactic migration by inducing adhesion to adhesive ligands and directional guidance (Rot and Andrian, 2004; Schumann et al., 2010). Quantitative analysis of the cellular response to immobilized guidance cues requires in vitro assays that foster cell migration, offer accurate control of the immobilized cues on a subcellular scale and in the ideal case closely reproduce in vivo conditions. The exploration of haptotactic cell migration through design and employment of such assays represents the main focus of this work. Dendritic cells (DCs) are leukocytes, which after encountering danger signals such as pathogens in peripheral organs instruct naïve T-cells and consequently the adaptive immune response in the lymph node (Mellman and Steinman, 2001). To reach the lymph node from the periphery, DCs follow haptotactic gradients of the chemokine CCL21 towards lymphatic vessels (Weber et al., 2013). Questions about how DCs interpret haptotactic CCL21 gradients have not yet been addressed. The main reason for this is the lack of an assay that offers diverse haptotactic environments, hence allowing the study of DC migration as a response to different signals of immobilized guidance cue. In this work, we developed an in vitro assay that enables us to quantitatively assess DC haptotaxis, by combining precisely controllable chemokine photo-patterning with physically confining migration conditions. With this tool at hand, we studied the influence of CCL21 gradient properties and concentration on DC haptotaxis. We found that haptotactic gradient sensing depends on the absolute CCL21 concentration in combination with the local steepness of the gradient. Our analysis suggests that the directionality of migrating DCs is governed by the signal-to-noise ratio of CCL21 binding to its receptor CCR7. Moreover, the haptotactic CCL21 gradient formed in vivo provides an optimal shape for DCs to recognize haptotactic guidance cue. By reconstitution of the CCL21 gradient in vitro we were also able to study the influence of CCR7 signal termination on DC haptotaxis. To this end, we used DCs lacking the G-protein coupled receptor kinase GRK6, which is responsible for CCL21 induced CCR7 receptor phosphorylation and desensitization (Zidar et al., 2009). We found that CCR7 desensitization by GRK6 is crucial for maintenance of haptotactic CCL21 gradient sensing in vitro and confirm those observations in vivo. In the context of the organism, immobilized haptotactic guidance cues often coincide and compete with soluble chemotactic guidance cues. During wound healing, fibroblasts are exposed and influenced by adhesive cues and soluble factors at the same time (Wu et al., 2012; Wynn, 2008). Similarly, migrating DCs are exposed to both, soluble chemokines (CCL19 and truncated CCL21) inducing chemotactic behavior as well as the immobilized CCL21. To quantitatively assess these complex coinciding immobilized and soluble guidance cues, we implemented our chemokine photo-patterning technique in a microfluidic system allowing for chemotactic gradient generation. To validate the assay, we observed DC migration in competing CCL19/CCL21 environments. Adhesiveness guided haptotaxis has been studied intensively over the last century. However, quantitative studies leading to conceptual models are largely missing, again due to the lack of a precisely controllable in vitro assay. A requirement for such an in vitro assay is that it must prevent any uncontrolled cell adhesion. This can be accomplished by stable passivation of the surface. In addition, controlled adhesion must be sustainable, quantifiable and dose dependent in order to create homogenous gradients. Therefore, we developed a novel covalent photo-patterning technique satisfying all these needs. In combination with a sustainable poly-vinyl alcohol (PVA) surface coating we were able to generate gradients of adhesive cue to direct cell migration. This approach allowed us to characterize the haptotactic migratory behavior of zebrafish keratocytes in vitro. Furthermore, defined patterns of adhesive cue allowed us to control for cell shape and growth on a subcellular scale.}, author = {Schwarz, Jan}, issn = {2663-337X}, pages = {178}, publisher = {Institute of Science and Technology Austria}, title = {{Quantitative analysis of haptotactic cell migration}}, year = {2016}, } @phdthesis{1130, abstract = {In this thesis we present a computer-aided programming approach to concurrency. Our approach helps the programmer by automatically fixing concurrency-related bugs, i.e. bugs that occur when the program is executed using an aggressive preemptive scheduler, but not when using a non-preemptive (cooperative) scheduler. Bugs are program behaviours that are incorrect w.r.t. a specification. We consider both user-provided explicit specifications in the form of assertion statements in the code as well as an implicit specification. The implicit specification is inferred from the non-preemptive behaviour. Let us consider sequences of calls that the program makes to an external interface. The implicit specification requires that any such sequence produced under a preemptive scheduler should be included in the set of sequences produced under a non-preemptive scheduler. We consider several semantics-preserving fixes that go beyond atomic sections typically explored in the synchronisation synthesis literature. Our synthesis is able to place locks, barriers and wait-signal statements and last, but not least reorder independent statements. The latter may be useful if a thread is released to early, e.g., before some initialisation is completed. We guarantee that our synthesis does not introduce deadlocks and that the synchronisation inserted is optimal w.r.t. a given objective function. We dub our solution trace-based synchronisation synthesis and it is loosely based on counterexample-guided inductive synthesis (CEGIS). The synthesis works by discovering a trace that is incorrect w.r.t. the specification and identifying ordering constraints crucial to trigger the specification violation. Synchronisation may be placed immediately (greedy approach) or delayed until all incorrect traces are found (non-greedy approach). For the non-greedy approach we construct a set of global constraints over synchronisation placements. Each model of the global constraints set corresponds to a correctness-ensuring synchronisation placement. The placement that is optimal w.r.t. the given objective function is chosen as the synchronisation solution. We evaluate our approach on a number of realistic (albeit simplified) Linux device-driver benchmarks. The benchmarks are versions of the drivers with known concurrency-related bugs. For the experiments with an explicit specification we added assertions that would detect the bugs in the experiments. Device drivers lend themselves to implicit specification, where the device and the operating system are the external interfaces. Our experiments demonstrate that our synthesis method is precise and efficient. We implemented objective functions for coarse-grained and fine-grained locking and observed that different synchronisation placements are produced for our experiments, favouring e.g. a minimal number of synchronisation operations or maximum concurrency.}, author = {Tarrach, Thorsten}, issn = {2663-337X}, pages = {151}, publisher = {Institute of Science and Technology Austria}, title = {{Automatic synthesis of synchronisation primitives for concurrent programs}}, doi = {10.15479/at:ista:1130}, year = {2016}, } @phdthesis{1131, abstract = {Evolution of gene regulation is important for phenotypic evolution and diversity. Sequence-specific binding of regulatory proteins is one of the key regulatory mechanisms determining gene expression. Although there has been intense interest in evolution of regulatory binding sites in the last decades, a theoretical understanding is far from being complete. In this thesis, I aim at a better understanding of the evolution of transcriptional regulatory binding sequences by using biophysical and population genetic models. In the first part of the thesis, I discuss how to formulate the evolutionary dynamics of binding se- quences in a single isolated binding site and in promoter/enhancer regions. I develop a theoretical framework bridging between a thermodynamical model for transcription and a mutation-selection-drift model for monomorphic populations. I mainly address the typical evolutionary rates, and how they de- pend on biophysical parameters (e.g. binding length and specificity) and population genetic parameters (e.g. population size and selection strength). In the second part of the thesis, I analyse empirical data for a better evolutionary and biophysical understanding of sequence-specific binding of bacterial RNA polymerase. First, I infer selection on regulatory and non-regulatory binding sites of RNA polymerase in the E. coli K12 genome. Second, I infer the chemical potential of RNA polymerase, an important but unknown physical parameter defining the threshold energy for strong binding. Furthermore, I try to understand the relation between the lac promoter sequence diversity and the LacZ activity variation among 20 bacterial isolates by constructing a simple but biophysically motivated gene expression model. Lastly, I lay out a statistical framework to predict adaptive point mutations in de novo promoter evolution in a selection experiment.}, author = {Tugrul, Murat}, issn = {2663-337X}, pages = {89}, publisher = {Institute of Science and Technology Austria}, title = {{Evolution of transcriptional regulatory sequences}}, year = {2016}, } @inproceedings{1134, abstract = {Hybrid systems have both continuous and discrete dynamics and are useful for modeling a variety of control systems, from air traffic control protocols to robotic maneuvers and beyond. Recently, numerous powerful and scalable tools for analyzing hybrid systems have emerged. Several of these tools implement automated formal methods for mathematically proving a system meets a specification. This tutorial session will present three recent hybrid systems tools: C2E2, HyST, and TuLiP. C2E2 is a simulated-based verification tool for hybrid systems, and uses validated numerical solvers and bloating of simulation traces to verify systems meet specifications. HyST is a hybrid systems model transformation and translation tool, and uses a canonical intermediate representation to support most of the recent verification tools, as well as automated sound abstractions that simplify verification of a given hybrid system. TuLiP is a controller synthesis tool for hybrid systems, where given a temporal logic specification to be satisfied for a system (plant) model, TuLiP will find a controller that meets a given specification. © 2016 IEEE.}, author = {Duggirala, Parasara and Fan, Chuchu and Potok, Matthew and Qi, Bolun and Mitra, Sayan and Viswanathan, Mahesh and Bak, Stanley and Bogomolov, Sergiy and Johnson, Taylor and Nguyen, Luan and Schilling, Christian and Sogokon, Andrew and Tran, Hoang and Xiang, Weiming}, booktitle = {2016 IEEE Conference on Control Applications}, location = {Buenos Aires, Argentina }, publisher = {IEEE}, title = {{Tutorial: Software tools for hybrid systems verification transformation and synthesis C2E2 HyST and TuLiP}}, doi = {10.1109/CCA.2016.7587948}, year = {2016}, } @inproceedings{1135, abstract = {Time-triggered (TT) switched networks are a deterministic communication infrastructure used by real-time distributed embedded systems. These networks rely on the notion of globally discretized time (i.e. time slots) and a static TT schedule that prescribes which message is sent through which link at every time slot, such that all messages reach their destination before a global timeout. These schedules are generated offline, assuming a static network with fault-free links, and entrusting all error-handling functions to the end user. Assuming the network is static is an over-optimistic view, and indeed links tend to fail in practice. We study synthesis of TT schedules on a network in which links fail over time and we assume the switches run a very simple error-recovery protocol once they detect a crashed link. We address the problem of finding a pk; qresistant schedule; namely, one that, assuming the switches run a fixed error-recovery protocol, guarantees that the number of messages that arrive at their destination by the timeout is at least no matter what sequence of at most k links fail. Thus, we maintain the simplicity of the switches while giving a guarantee on the number of messages that meet the timeout. We show how a pk; q-resistant schedule can be obtained using a CEGAR-like approach: find a schedule, decide whether it is pk; q-resistant, and if it is not, use the witnessing fault sequence to generate a constraint that is added to the program. The newly added constraint disallows the schedule to be regenerated in a future iteration while also eliminating several other schedules that are not pk; q-resistant. We illustrate the applicability of our approach using an SMT-based implementation. © 2016 ACM.}, author = {Avni, Guy and Guha, Shibashis and Rodríguez Navas, Guillermo}, booktitle = {Proceedings of the 13th International Conference on Embedded Software }, location = {Pittsburgh, PA, USA}, publisher = {ACM}, title = {{Synthesizing time triggered schedules for switched networks with faulty links}}, doi = {10.1145/2968478.2968499}, year = {2016}, } @inproceedings{1136, abstract = {We propose an interactive sculpting system for seamlessly editing pre-computed animations of liquid, without the need for any resimulation. The input is a sequence of meshes without correspondences representing the liquid surface over time. Our method enables the efficient selection of consistent space-time parts of this animation, such as moving waves or droplets, which we call space-time features. Once selected, a feature can be copied, edited, or duplicated and then pasted back anywhere in space and time in the same or in another liquid animation sequence. Our method circumvents tedious user interactions by automatically computing the spatial and temporal ranges of the selected feature. We also provide space-time shape editing tools for non-uniform scaling, rotation, trajectory changes, and temporal editing to locally speed up or slow down motion. Using our tools, the user can edit and progressively refine any input simulation result, possibly using a library of precomputed space-time features extracted from other animations. In contrast to the trial-and-error loop usually required to edit animation results through the tuning of indirect simulation parameters, our method gives the user full control over the edited space-time behaviors. © 2016 Copyright held by the owner/author(s).}, author = {Manteaux, Pierre and Vimont, Ulysse and Wojtan, Christopher J and Rohmer, Damien and Cani, Marie}, booktitle = {Proceedings of the 9th International Conference on Motion in Games }, location = {San Francisco, CA, USA}, publisher = {ACM}, title = {{Space-time sculpting of liquid animation}}, doi = {10.1145/2994258.2994261}, year = {2016}, } @article{1137, abstract = {RASGRP1 is an important guanine nucleotide exchange factor and activator of the RAS-MAPK pathway following T cell antigen receptor (TCR) signaling. The consequences of RASGRP1 mutations in humans are unknown. In a patient with recurrent bacterial and viral infections, born to healthy consanguineous parents, we used homozygosity mapping and exome sequencing to identify a biallelic stop-gain variant in RASGRP1. This variant segregated perfectly with the disease and has not been reported in genetic databases. RASGRP1 deficiency was associated in T cells and B cells with decreased phosphorylation of the extracellular-signal-regulated serine kinase ERK, which was restored following expression of wild-type RASGRP1. RASGRP1 deficiency also resulted in defective proliferation, activation and motility of T cells and B cells. RASGRP1-deficient natural killer (NK) cells exhibited impaired cytotoxicity with defective granule convergence and actin accumulation. Interaction proteomics identified the dynein light chain DYNLL1 as interacting with RASGRP1, which links RASGRP1 to cytoskeletal dynamics. RASGRP1-deficient cells showed decreased activation of the GTPase RhoA. Treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects of RASGRP1-deficient lymphocytes.}, author = {Salzer, Elisabeth and Çaǧdaş, Deniz and Hons, Miroslav and Mace, Emily and Garncarz, Wojciech and Petronczki, Oezlem and Platzer, René and Pfajfer, Laurène and Bilic, Ivan and Ban, Sol and Willmann, Katharina and Mukherjee, Malini and Supper, Verena and Hsu, Hsiangting and Banerjee, Pinaki and Sinha, Papiya and Mcclanahan, Fabienne and Zlabinger, Gerhard and Pickl, Winfried and Gribben, John and Stockinger, Hannes and Bennett, Keiryn and Huppa, Johannes and Dupré, Loï̈C and Sanal, Özden and Jäger, Ulrich and Sixt, Michael K and Tezcan, Ilhan and Orange, Jordan and Boztug, Kaan}, journal = {Nature Immunology}, number = {12}, pages = {1352 -- 1360}, publisher = {Nature Publishing Group}, title = {{RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics}}, doi = {10.1038/ni.3575}, volume = {17}, year = {2016}, } @inproceedings{1138, abstract = {Automata with monitor counters, where the transitions do not depend on counter values, and nested weighted automata are two expressive automata-theoretic frameworks for quantitative properties. For a well-studied and wide class of quantitative functions, we establish that automata with monitor counters and nested weighted automata are equivalent. We study for the first time such quantitative automata under probabilistic semantics. We show that several problems that are undecidable for the classical questions of emptiness and universality become decidable under the probabilistic semantics. We present a complete picture of decidability for such automata, and even an almost-complete picture of computational complexity, for the probabilistic questions we consider. © 2016 ACM.}, author = {Chatterjee, Krishnendu and Henzinger, Thomas A and Otop, Jan}, booktitle = {Proceedings of the 31st Annual ACM/IEEE Symposium}, location = {New York, NY, USA}, pages = {76 -- 85}, publisher = {IEEE}, title = {{Quantitative automata under probabilistic semantics}}, doi = {10.1145/2933575.2933588}, year = {2016}, } @article{1139, abstract = {Microtubules switch stochastically between phases of growth and shrinkage. The molecular mechanism responsible for the end of a growth phase, an event called catastrophe, is still not understood. The probability for a catastrophe to occur increases with microtubule age, putting constraints on the possible molecular mechanism of catastrophe induction. Here we used microfluidics-Assisted fast tubulin washout experiments to induce microtubule depolymerization in a controlled manner at different times after the start of growth. We found that aging can also be observed in this assay, providing valuable new constraints against which theoretical models of catastrophe induction can be tested. We found that the data can be quantitatively well explained by a simple kinetic threshold model that assumes an age-dependent broadening of the protective cap at the microtubule end as a result of an evolving tapered end structure; this leads to a decrease of the cap density and its stability. This analysis suggests an intuitive picture of the role of morphological changes of the protective cap for the age dependence of microtubule stability.}, author = {Düllberg, Christian F and Cade, Nicholas and Surrey, Thomas}, journal = {Molecular Biology and Evolution}, number = {22}, pages = {3563 -- 3573}, publisher = {Oxford University Press}, title = {{Microtubule aging probed by microfluidics assisted tubulin washout}}, doi = {10.1091/mbc.E16-07-0548}, volume = {27}, year = {2016}, } @inproceedings{1140, abstract = {Given a model of a system and an objective, the model-checking question asks whether the model satisfies the objective. We study polynomial-time problems in two classical models, graphs and Markov Decision Processes (MDPs), with respect to several fundamental -regular objectives, e.g., Rabin and Streett objectives. For many of these problems the best-known upper bounds are quadratic or cubic, yet no super-linear lower bounds are known. In this work our contributions are two-fold: First, we present several improved algorithms, and second, we present the first conditional super-linear lower bounds based on widely believed assumptions about the complexity of CNF-SAT and combinatorial Boolean matrix multiplication. A separation result for two models with respect to an objective means a conditional lower bound for one model that is strictly higher than the existing upper bound for the other model, and similarly for two objectives with respect to a model. Our results establish the following separation results: (1) A separation of models (graphs and MDPs) for disjunctive queries of reachability and Büchi objectives. (2) Two kinds of separations of objectives, both for graphs and MDPs, namely, (2a) the separation of dual objectives such as Streett/Rabin objectives, and (2b) the separation of conjunction and disjunction of multiple objectives of the same type such as safety, Büchi, and coBüchi. In summary, our results establish the first model and objective separation results for graphs and MDPs for various classical -regular objectives. Quite strikingly, we establish conditional lower bounds for the disjunction of objectives that are strictly higher than the existing upper bounds for the conjunction of the same objectives. © 2016 ACM.}, author = {Chatterjee, Krishnendu and Dvoák, Wolfgang and Henzinger, Monika H and Loitzenbauer, Veronika}, booktitle = {Proceedings of the 31st Annual ACM/IEEE Symposium on Logic in Computer Science}, location = {New York, NY, USA}, pages = {197 -- 206}, publisher = {IEEE}, title = {{Model and objective separation with conditional lower bounds: disjunction is harder than conjunction}}, doi = {10.1145/2933575.2935304}, year = {2016}, } @article{1141, abstract = {In this paper we introduce the Multiobjective Optimization Hierarchic Genetic Strategy with maturing (MO-mHGS), a meta-algorithm that performs evolutionary optimization in a hierarchy of populations. The maturing mechanism improves growth and reduces redundancy. The performance of MO-mHGS with selected state-of-the-art multiobjective evolutionary algorithms as internal algorithms is analysed on benchmark problems and their modifications for which single fitness evaluation time depends on the solution accuracy. We compare the proposed algorithm with the Island Model Genetic Algorithm as well as with single-deme methods, and discuss the impact of internal algorithms on the MO-mHGS meta-algorithm. © 2016 Elsevier B.V.}, author = {Łazarz, Radosław and Idzik, Michał and Gądek, Konrad and Gajda-Zagorska, Ewa P}, journal = {Journal of Computational Science}, number = {1}, pages = {249 -- 260}, publisher = {Elsevier}, title = {{Hierarchic genetic strategy with maturing as a generic tool for multiobjective optimization}}, doi = {10.1016/j.jocs.2016.03.004}, volume = {17}, year = {2016}, } @article{1142, abstract = {Hemolysis drives susceptibility to bacterial infections and predicts poor outcome from sepsis. These detrimental effects are commonly considered to be a consequence of heme-iron serving as a nutrient for bacteria. We employed a Gram-negative sepsis model and found that elevated heme levels impaired the control of bacterial proliferation independently of heme-iron acquisition by pathogens. Heme strongly inhibited phagocytosis and the migration of human and mouse phagocytes by disrupting actin cytoskeletal dynamics via activation of the GTP-binding Rho family protein Cdc42 by the guanine nucleotide exchange factor DOCK8. A chemical screening approach revealed that quinine effectively prevented heme effects on the cytoskeleton, restored phagocytosis and improved survival in sepsis. These mechanistic insights provide potential therapeutic targets for patients with sepsis or hemolytic disorders.}, author = {Martins, Rui and Maier, Julia and Gorki, Anna and Huber, Kilian and Sharif, Omar and Starkl, Philipp and Saluzzo, Simona and Quattrone, Federica and Gawish, Riem and Lakovits, Karin and Aichinger, Michael and Radic Sarikas, Branka and Lardeau, Charles and Hladik, Anastasiya and Korosec, Ana and Brown, Markus and Vaahtomeri, Kari and Duggan, Michelle and Kerjaschki, Dontscho and Esterbauer, Harald and Colinge, Jacques and Eisenbarth, Stephanie and Decker, Thomas and Bennett, Keiryn and Kubicek, Stefan and Sixt, Michael K and Superti Furga, Giulio and Knapp, Sylvia}, journal = {Nature Immunology}, number = {12}, pages = {1361 -- 1372}, publisher = {Nature Publishing Group}, title = {{Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions}}, doi = {10.1038/ni.3590}, volume = {17}, year = {2016}, } @article{1143, abstract = {We study the ground state of a dilute Bose gas in a scaling limit where the Gross-Pitaevskii functional emerges. This is a repulsive nonlinear Schrödinger functional whose quartic term is proportional to the scattering length of the interparticle interaction potential. We propose a new derivation of this limit problem, with a method that bypasses some of the technical difficulties that previous derivations had to face. The new method is based on a combination of Dyson\'s lemma, the quantum de Finetti theorem and a second moment estimate for ground states of the effective Dyson Hamiltonian. It applies equally well to the case where magnetic fields or rotation are present.}, author = {Nam, Phan and Rougerie, Nicolas and Seiringer, Robert}, journal = {Analysis and PDE}, number = {2}, pages = {459 -- 485}, publisher = {Mathematical Sciences Publishers}, title = {{Ground states of large bosonic systems: The gross Pitaevskii limit revisited}}, doi = {10.2140/apde.2016.9.459}, volume = {9}, year = {2016}, } @article{1145, abstract = {Auxin directs plant ontogenesis via differential accumulation within tissues depending largely on the activity of PIN proteins that mediate auxin efflux from cells and its directional cell-to-cell transport. Regardless of the developmental importance of PINs, the structure of these transporters is poorly characterized. Here, we present experimental data concerning protein topology of plasma membrane-localized PINs. Utilizing approaches based on pH-dependent quenching of fluorescent reporters combined with immunolocalization techniques, we mapped the membrane topology of PINs and further cross-validated our results using available topology modeling software. We delineated the topology of PIN1 with two transmembrane (TM) bundles of five α-helices linked by a large intracellular loop and a C-terminus positioned outside the cytoplasm. Using constraints derived from our experimental data, we also provide an updated position of helical regions generating a verisimilitude model of PIN1. Since the canonical long PINs show a high degree of conservation in TM domains and auxin transport capacity has been demonstrated for Arabidopsis representatives of this group, this empirically enhanced topological model of PIN1 will be an important starting point for further studies on PIN structure–function relationships. In addition, we have established protocols that can be used to probe the topology of other plasma membrane proteins in plants. © 2016 The Authors}, author = {Nodzyński, Tomasz and Vanneste, Steffen and Zwiewka, Marta and Pernisová, Markéta and Hejátko, Jan and Friml, Jirí}, journal = {Molecular Plant}, number = {11}, pages = {1504 -- 1519}, publisher = {Cell Press}, title = {{Enquiry into the topology of plasma membrane localized PIN auxin transport components}}, doi = {10.1016/j.molp.2016.08.010}, volume = {9}, year = {2016}, } @article{1147, abstract = {Apical dominance is one of the fundamental developmental phenomena in plant biology, which determines the overall architecture of aerial plant parts. Here we show apex decapitation activated competition for dominance in adjacent upper and lower axillary buds. A two-nodal-bud pea (Pisum sativum L.) was used as a model system to monitor and assess auxin flow, auxin transport channels, and dormancy and initiation status of axillary buds. Auxin flow was manipulated by lateral stem wounds or chemically by auxin efflux inhibitors 2,3,5-triiodobenzoic acid (TIBA), 1-N-naphtylphtalamic acid (NPA), or protein synthesis inhibitor cycloheximide (CHX) treatments, which served to interfere with axillary bud competition. Redirecting auxin flow to different points influenced which bud formed the outgrowing and dominant shoot. The obtained results proved that competition between upper and lower axillary buds as secondary auxin sources is based on the same auxin canalization principle that operates between the shoot apex and axillary bud. © The Author(s) 2016.}, author = {Balla, Jozef and Medved'Ová, Zuzana and Kalousek, Petr and Matiješčuková, Natálie and Friml, Jirí and Reinöhl, Vilém and Procházka, Stanislav}, journal = {Scientific Reports}, publisher = {Nature Publishing Group}, title = {{Auxin flow mediated competition between axillary buds to restore apical dominance}}, doi = {10.1038/srep35955}, volume = {6}, year = {2016}, } @article{1148, abstract = {Continuous-time Markov chain (CTMC) models have become a central tool for understanding the dynamics of complex reaction networks and the importance of stochasticity in the underlying biochemical processes. When such models are employed to answer questions in applications, in order to ensure that the model provides a sufficiently accurate representation of the real system, it is of vital importance that the model parameters are inferred from real measured data. This, however, is often a formidable task and all of the existing methods fail in one case or the other, usually because the underlying CTMC model is high-dimensional and computationally difficult to analyze. The parameter inference methods that tend to scale best in the dimension of the CTMC are based on so-called moment closure approximations. However, there exists a large number of different moment closure approximations and it is typically hard to say a priori which of the approximations is the most suitable for the inference procedure. Here, we propose a moment-based parameter inference method that automatically chooses the most appropriate moment closure method. Accordingly, contrary to existing methods, the user is not required to be experienced in moment closure techniques. In addition to that, our method adaptively changes the approximation during the parameter inference to ensure that always the best approximation is used, even in cases where different approximations are best in different regions of the parameter space. © 2016 Elsevier Ireland Ltd}, author = {Schilling, Christian and Bogomolov, Sergiy and Henzinger, Thomas A and Podelski, Andreas and Ruess, Jakob}, journal = {Biosystems}, pages = {15 -- 25}, publisher = {Elsevier}, title = {{Adaptive moment closure for parameter inference of biochemical reaction networks}}, doi = {10.1016/j.biosystems.2016.07.005}, volume = {149}, year = {2016}, } @article{1149, abstract = {We study the usefulness of two most prominent publicly available rigorous ODE integrators: one provided by the CAPD group (capd.ii.uj.edu.pl), the other based on the COSY Infinity project (cosyinfinity.org). Both integrators are capable of handling entire sets of initial conditions and provide tight rigorous outer enclosures of the images under a time-T map. We conduct extensive benchmark computations using the well-known Lorenz system, and compare the computation time against the final accuracy achieved. We also discuss the effect of a few technical parameters, such as the order of the numerical integration method, the value of T, and the phase space resolution. We conclude that COSY may provide more precise results due to its ability of avoiding the variable dependency problem. However, the overall cost of computations conducted using CAPD is typically lower, especially when intervals of parameters are involved. Moreover, access to COSY is limited (registration required) and the rigorous ODE integrators are not publicly available, while CAPD is an open source free software project. Therefore, we recommend the latter integrator for this kind of computations. Nevertheless, proper choice of the various integration parameters turns out to be of even greater importance than the choice of the integrator itself. © 2016 IMACS. Published by Elsevier B.V. All rights reserved.}, author = {Miyaji, Tomoyuki and Pilarczyk, Pawel and Gameiro, Marcio and Kokubu, Hiroshi and Mischaikow, Konstantin}, journal = {Applied Numerical Mathematics}, pages = {34 -- 47}, publisher = {Elsevier}, title = {{A study of rigorous ODE integrators for multi scale set oriented computations}}, doi = {10.1016/j.apnum.2016.04.005}, volume = {107}, year = {2016}, } @article{1150, abstract = {When neutrophils infiltrate a site of inflammation, they have to stop at the right place to exert their effector function. In this issue of Developmental Cell, Wang et al. (2016) show that neutrophils sense reactive oxygen species via the TRPM2 channel to arrest migration at their target site. © 2016 Elsevier Inc.}, author = {Renkawitz, Jörg and Sixt, Michael K}, journal = {Developmental Cell}, number = {5}, pages = {448 -- 450}, publisher = {Cell Press}, title = {{A Radical Break Restraining Neutrophil Migration}}, doi = {10.1016/j.devcel.2016.08.017}, volume = {38}, year = {2016}, } @article{1151, abstract = {Tissue patterning in multicellular organisms is the output of precise spatio–temporal regulation of gene expression coupled with changes in hormone dynamics. In plants, the hormone auxin regulates growth and development at every stage of a plant’s life cycle. Auxin signaling occurs through binding of the auxin molecule to a TIR1/AFB F-box ubiquitin ligase, allowing interaction with Aux/IAA transcriptional repressor proteins. These are subsequently ubiquitinated and degraded via the 26S proteasome, leading to derepression of auxin response factors (ARFs). How auxin is able to elicit such a diverse range of developmental responses through a single signaling module has not yet been resolved. Here we present an alternative auxin-sensing mechanism in which the ARF ARF3/ETTIN controls gene expression through interactions with process-specific transcription factors. This noncanonical hormonesensing mechanism exhibits strong preference for the naturally occurring auxin indole 3-acetic acid (IAA) and is important for coordinating growth and patterning in diverse developmental contexts such as gynoecium morphogenesis, lateral root emergence, ovule development, and primary branch formation. Disrupting this IAA-sensing ability induces morphological aberrations with consequences for plant fitness. Therefore, our findings introduce a novel transcription factor-based mechanism of hormone perception in plants. © 2016 Simonini et al.}, author = {Simonini, Sara and Deb, Joyita and Moubayidin, Laila and Stephenson, Pauline and Valluru, Manoj and Freire Rios, Alejandra and Sorefan, Karim and Weijers, Dolf and Friml, Jirí and Östergaard, Lars}, journal = {Genes and Development}, number = {20}, pages = {2286 -- 2296}, publisher = {Cold Spring Harbor Laboratory Press}, title = {{A noncanonical auxin sensing mechanism is required for organ morphogenesis in arabidopsis}}, doi = {10.1101/gad.285361.116}, volume = {30}, year = {2016}, } @article{1153, abstract = {Differential cell growth enables flexible organ bending in the presence of environmental signals such as light or gravity. A prominent example of the developmental processes based on differential cell growth is the formation of the apical hook that protects the fragile shoot apical meristem when it breaks through the soil during germination. Here, we combined in silico and in vivo approaches to identify a minimal mechanism producing auxin gradient-guided differential growth during the establishment of the apical hook in the model plant Arabidopsis thaliana. Computer simulation models based on experimental data demonstrate that asymmetric expression of the PIN-FORMED auxin efflux carrier at the concave (inner) versus convex (outer) side of the hook suffices to establish an auxin maximum in the epidermis at the concave side of the apical hook. Furthermore, we propose a mechanism that translates this maximum into differential growth, and thus curvature, of the apical hook. Through a combination of experimental and in silico computational approaches, we have identified the individual contributions of differential cell elongation and proliferation to defining the apical hook and reveal the role of auxin-ethylene crosstalk in balancing these two processes. © 2016 American Society of Plant Biologists. All rights reserved.}, author = {Žádníková, Petra and Wabnik, Krzysztof T and Abuzeineh, Anas and Gallemí, Marçal and Van Der Straeten, Dominique and Smith, Richard and Inze, Dirk and Friml, Jirí and Prusinkiewicz, Przemysław and Benková, Eva}, journal = {Plant Cell}, number = {10}, pages = {2464 -- 2477}, publisher = {American Society of Plant Biologists}, title = {{A model of differential growth guided apical hook formation in plants}}, doi = {10.1105/tpc.15.00569}, volume = {28}, year = {2016}, }