TY - JOUR AB - 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. AU - Martins, Rui AU - Maier, Julia AU - Gorki, Anna AU - Huber, Kilian AU - Sharif, Omar AU - Starkl, Philipp AU - Saluzzo, Simona AU - Quattrone, Federica AU - Gawish, Riem AU - Lakovits, Karin AU - Aichinger, Michael AU - Radic Sarikas, Branka AU - Lardeau, Charles AU - Hladik, Anastasiya AU - Korosec, Ana AU - Brown, Markus AU - Vaahtomeri, Kari AU - Duggan, Michelle AU - Kerjaschki, Dontscho AU - Esterbauer, Harald AU - Colinge, Jacques AU - Eisenbarth, Stephanie AU - Decker, Thomas AU - Bennett, Keiryn AU - Kubicek, Stefan AU - Sixt, Michael K AU - Superti Furga, Giulio AU - Knapp, Sylvia ID - 1142 IS - 12 JF - Nature Immunology TI - Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions VL - 17 ER - TY - JOUR AB - 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. AU - Łazarz, Radosław AU - Idzik, Michał AU - Gądek, Konrad AU - Gajda-Zagorska, Ewa P ID - 1141 IS - 1 JF - Journal of Computational Science TI - Hierarchic genetic strategy with maturing as a generic tool for multiobjective optimization VL - 17 ER - TY - JOUR AB - 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. AU - Nam, Phan AU - Rougerie, Nicolas AU - Seiringer, Robert ID - 1143 IS - 2 JF - Analysis and PDE TI - Ground states of large bosonic systems: The gross Pitaevskii limit revisited VL - 9 ER - TY - JOUR AB - 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 AU - Nodzyński, Tomasz AU - Vanneste, Steffen AU - Zwiewka, Marta AU - Pernisová, Markéta AU - Hejátko, Jan AU - Friml, Jirí ID - 1145 IS - 11 JF - Molecular Plant TI - Enquiry into the topology of plasma membrane localized PIN auxin transport components VL - 9 ER - TY - JOUR AB - 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. AU - Balla, Jozef AU - Medved'Ová, Zuzana AU - Kalousek, Petr AU - Matiješčuková, Natálie AU - Friml, Jirí AU - Reinöhl, Vilém AU - Procházka, Stanislav ID - 1147 JF - Scientific Reports TI - Auxin flow mediated competition between axillary buds to restore apical dominance VL - 6 ER - TY - JOUR AB - 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. AU - Miyaji, Tomoyuki AU - Pilarczyk, Pawel AU - Gameiro, Marcio AU - Kokubu, Hiroshi AU - Mischaikow, Konstantin ID - 1149 JF - Applied Numerical Mathematics TI - A study of rigorous ODE integrators for multi scale set oriented computations VL - 107 ER - TY - JOUR AB - 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. AU - Renkawitz, Jörg AU - Sixt, Michael K ID - 1150 IS - 5 JF - Developmental Cell TI - A Radical Break Restraining Neutrophil Migration VL - 38 ER - TY - JOUR AB - 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. AU - Simonini, Sara AU - Deb, Joyita AU - Moubayidin, Laila AU - Stephenson, Pauline AU - Valluru, Manoj AU - Freire Rios, Alejandra AU - Sorefan, Karim AU - Weijers, Dolf AU - Friml, Jirí AU - Östergaard, Lars ID - 1151 IS - 20 JF - Genes and Development TI - A noncanonical auxin sensing mechanism is required for organ morphogenesis in arabidopsis VL - 30 ER - TY - JOUR AB - 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. AU - Žádníková, Petra AU - Wabnik, Krzysztof T AU - Abuzeineh, Anas AU - Gallemí, Marçal AU - Van Der Straeten, Dominique AU - Smith, Richard AU - Inze, Dirk AU - Friml, Jirí AU - Prusinkiewicz, Przemysław AU - Benková, Eva ID - 1153 IS - 10 JF - Plant Cell TI - A model of differential growth guided apical hook formation in plants VL - 28 ER - TY - JOUR AB - Cellular locomotion is a central hallmark of eukaryotic life. It is governed by cell-extrinsic molecular factors, which can either emerge in the soluble phase or as immobilized, often adhesive ligands. To encode for direction, every cue must be present as a spatial or temporal gradient. Here, we developed a microfluidic chamber that allows measurement of cell migration in combined response to surface immobilized and soluble molecular gradients. As a proof of principle we study the response of dendritic cells to their major guidance cues, chemokines. The majority of data on chemokine gradient sensing is based on in vitro studies employing soluble gradients. Despite evidence suggesting that in vivo chemokines are often immobilized to sugar residues, limited information is available how cells respond to immobilized chemokines. We tracked migration of dendritic cells towards immobilized gradients of the chemokine CCL21 and varying superimposed soluble gradients of CCL19. Differential migratory patterns illustrate the potential of our setup to quantitatively study the competitive response to both types of gradients. Beyond chemokines our approach is broadly applicable to alternative systems of chemo- and haptotaxis such as cells migrating along gradients of adhesion receptor ligands vs. any soluble cue. AU - Schwarz, Jan AU - Bierbaum, Veronika AU - Merrin, Jack AU - Frank, Tino AU - Hauschild, Robert AU - Bollenbach, Mark Tobias AU - Tay, Savaş AU - Sixt, Michael K AU - Mehling, Matthias ID - 1154 JF - Scientific Reports TI - A microfluidic device for measuring cell migration towards substrate bound and soluble chemokine gradients VL - 6 ER -