TY - JOUR AB - Bow-tie or hourglass structure is a common architectural feature found in many biological systems. A bow-tie in a multi-layered structure occurs when intermediate layers have much fewer components than the input and output layers. Examples include metabolism where a handful of building blocks mediate between multiple input nutrients and multiple output biomass components, and signaling networks where information from numerous receptor types passes through a small set of signaling pathways to regulate multiple output genes. Little is known, however, about how bow-tie architectures evolve. Here, we address the evolution of bow-tie architectures using simulations of multi-layered systems evolving to fulfill a given input-output goal. We find that bow-ties spontaneously evolve when the information in the evolutionary goal can be compressed. Mathematically speaking, bow-ties evolve when the rank of the input-output matrix describing the evolutionary goal is deficient. The maximal compression possible (the rank of the goal) determines the size of the narrowest part of the network—that is the bow-tie. A further requirement is that a process is active to reduce the number of links in the network, such as product-rule mutations, otherwise a non-bow-tie solution is found in the evolutionary simulations. This offers a mechanism to understand a common architectural principle of biological systems, and a way to quantitate the effective rank of the goals under which they evolved. AU - Friedlander, Tamar AU - Mayo, Avraham AU - Tlusty, Tsvi AU - Alon, Uri ID - 1827 IS - 3 JF - PLoS Computational Biology TI - Evolution of bow-tie architectures in biology VL - 11 ER - TY - JOUR AB - Background: Indirect genetic effects (IGEs) occur when genes expressed in one individual alter the expression of traits in social partners. Previous studies focused on the evolutionary consequences and evolutionary dynamics of IGEs, using equilibrium solutions to predict phenotypes in subsequent generations. However, whether or not such steady states may be reached may depend on the dynamics of interactions themselves. Results: In our study, we focus on the dynamics of social interactions and indirect genetic effects and investigate how they modify phenotypes over time. Unlike previous IGE studies, we do not analyse evolutionary dynamics; rather we consider within-individual phenotypic changes, also referred to as phenotypic plasticity. We analyse iterative interactions, when individuals interact in a series of discontinuous events, and investigate the stability of steady state solutions and the dependence on model parameters, such as population size, strength, and the nature of interactions. We show that for interactions where a feedback loop occurs, the possible parameter space of interaction strength is fairly limited, affecting the evolutionary consequences of IGEs. We discuss the implications of our results for current IGE model predictions and their limitations. AU - Trubenova, Barbora AU - Novak, Sebastian AU - Hager, Reinmar ID - 1809 IS - 5 JF - PLoS One TI - Indirect genetic effects and the dynamics of social interactions VL - 10 ER - TY - GEN AU - Trubenova, Barbora AU - Novak, Sebastian AU - Hager, Reinmar ID - 9772 TI - Description of the agent based simulations ER - TY - GEN AU - Friedlander, Tamar AU - Mayo, Avraham E. AU - Tlusty, Tsvi AU - Alon, Uri ID - 9773 TI - Evolutionary simulation code ER - TY - JOUR AB - The tunability of topological surface states and controllable opening of the Dirac gap are of fundamental and practical interest in the field of topological materials. In the newly discovered topological crystalline insulators (TCIs), theory predicts that the Dirac node is protected by a crystalline symmetry and that the surface state electrons can acquire a mass if this symmetry is broken. Recent studies have detected signatures of a spontaneously generated Dirac gap in TCIs; however, the mechanism of mass formation remains elusive. In this work, we present scanning tunnelling microscopy (STM) measurements of the TCI Pb 1â'x Sn x Se for a wide range of alloy compositions spanning the topological and non-topological regimes. The STM topographies reveal a symmetry-breaking distortion on the surface, which imparts mass to the otherwise massless Dirac electrons-a mechanism analogous to the long sought-after Higgs mechanism in particle physics. Interestingly, the measured Dirac gap decreases on approaching the trivial phase, whereas the magnitude of the distortion remains nearly constant. Our data and calculations reveal that the penetration depth of Dirac surface states controls the magnitude of the Dirac mass. At the limit of the critical composition, the penetration depth is predicted to go to infinity, resulting in zero mass, consistent with our measurements. Finally, we discover the existence of surface states in the non-topological regime, which have the characteristics of gapped, double-branched Dirac fermions and could be exploited in realizing superconductivity in these materials. AU - Zeljkovic, Ilija AU - Okada, Yoshinori AU - Maksym Serbyn AU - Sankar, Raman AU - Walkup, Daniel AU - Zhou, Wenwen AU - Liu, Junwei AU - Chang, Guoqing AU - Wang, Yungjui AU - Hasan, Md Z AU - Chou, Fangcheng AU - Lin, Hsin AU - Bansil, Arun AU - Fu, Liang AU - Madhavan, Vidya ID - 981 IS - 3 JF - Nature Materials TI - Dirac mass generation from crystal symmetry breaking on the surfaces of topological crystalline insulators VL - 14 ER - TY - JOUR AB - We propose a new approach to probing ergodicity and its breakdown in one-dimensional quantum manybody systems based on their response to a local perturbation. We study the distribution of matrix elements of a local operator between the system's eigenstates, finding a qualitatively different behavior in the manybody localized (MBL) and ergodic phases. To characterize how strongly a local perturbation modifies the eigenstates, we introduce the parameter g(L) = (In (Vnm/δ)) which represents the disorder-averaged ratio of a typical matrix element of a local operator V to energy level spacing δ this parameter is reminiscent of the Thouless conductance in the single-particle localization. We show that the parameter g(L) decreases with system size L in the MBL phase and grows in the ergodic phase. We surmise that the delocalization transition occurs when g(L) is independent of system size, g(L)=gc ~ 1. We illustrate our approach by studying the many-body localization transition and resolving the many-body mobility edge in a disordered one-dimensional XXZ spin-1=2 chain using exact diagonalization and time-evolving block-decimation methods. Our criterion for the MBL transition gives insights into microscopic details of transition. Its direct physical consequences, in particular, logarithmically slow transport at the transition and extensive entanglement entropy of the eigenstates, are consistent with recent renormalization-group predictions. AU - Maksym Serbyn AU - Papić, Zlatko AU - Abanin, Dmitry A ID - 982 IS - 4 JF - Physical Review X TI - Criterion for many-body localization-delocalization phase transition VL - 5 ER - TY - JOUR AB - Quasiparticle excitations can compromise the performance of superconducting devices, causing high-frequency dissipation, decoherence in Josephson qubits, and braiding errors in proposed Majorana-based topological quantum computers. Quasiparticle dynamics have been studied in detail in metallic superconductors but remain relatively unexplored in semiconductor-superconductor structures, which are now being intensely pursued in the context of topological superconductivity. To this end, we use a system comprising a gate-confined semiconductor nanowire with an epitaxially grown superconductor layer, yielding an isolated, proximitized nanowire segment. We identify bound states in the semiconductor by means of bias spectroscopy, determine the characteristic temperatures and magnetic fields for quasiparticle excitations, and extract a parity lifetime (poisoning time) of the bound state in the semiconductor exceeding 10 ms. AU - Higginbotham, Andrew P AU - Albrecht, S M AU - Kiršanskas, Gediminas AU - Chang, W AU - Kuemmeth, Ferdinand AU - Krogstrup, Peter AU - Jespersen, Thomas AU - Nygård, Jesper AU - Flensberg, Karsten AU - Marcus, Charles ID - 99 IS - 12 JF - Nature Physics TI - Parity lifetime of bound states in a proximitized semiconductor nanowire VL - 11 ER - TY - JOUR AB - In this note, we consider the dynamics associated to a perturbation of an integrable Hamiltonian system in action-angle coordinates in any number of degrees of freedom and we prove the following result of ``micro-diffusion'': under generic assumptions on $ h$ and $ f$, there exists an orbit of the system for which the drift of its action variables is at least of order $ \sqrt {\varepsilon }$, after a time of order $ \sqrt {\varepsilon }^{-1}$. The assumptions, which are essentially minimal, are that there exists a resonant point for $ h$ and that the corresponding averaged perturbation is non-constant. The conclusions, although very weak when compared to usual instability phenomena, are also essentially optimal within this setting. AU - Bounemoura, Abed AU - Kaloshin, Vadim ID - 8495 IS - 4 JF - Proceedings of the American Mathematical Society SN - 0002-9939 TI - A note on micro-instability for Hamiltonian systems close to integrable VL - 144 ER - TY - JOUR AB - Proteases play important roles in many biologic processes and are key mediators of cancer, inflammation, and thrombosis. However, comprehensive and quantitative techniques to define the substrate specificity profile of proteases are lacking. The metalloprotease ADAMTS13 regulates blood coagulation by cleaving von Willebrand factor (VWF), reducing its procoagulant activity. A mutagenized substrate phage display library based on a 73-amino acid fragment of VWF was constructed, and the ADAMTS13-dependent change in library complexity was evaluated over reaction time points, using high-throughput sequencing. Reaction rate constants (kcat/KM) were calculated for nearly every possible single amino acid substitution within this fragment. This massively parallel enzyme kinetics analysis detailed the specificity of ADAMTS13 and demonstrated the critical importance of the P1-P1' substrate residues while defining exosite binding domains. These data provided empirical evidence for the propensity for epistasis within VWF and showed strong correlation to conservation across orthologs, highlighting evolutionary selective pressures for VWF. AU - Kretz, Colin A AU - Dai, Manhong AU - Soylemez, Onuralp AU - Yee, Andrew AU - Desch, Karl C AU - Siemieniak, David R AU - Tomberg, Kärt AU - Fyodor Kondrashov AU - Meng, Fan AU - Ginsburg, David B ID - 866 IS - 30 JF - PNAS TI - Massively parallel enzyme kinetics reveals the substrate recognition landscape of the metalloprotease ADAMTS13 VL - 112 ER - TY - JOUR AB - The factors that determine the tempo and mode of protein evolution continue to be a central question in molecular evolution. Traditionally, studies of protein evolution focused on the rates of amino acid substitutions. More recently, with the availability of sequence data and advanced experimental techniques, the focus of attention has shifted toward the study of evolutionary trajectories and the overall layout of protein fitness landscapes. In this review we describe the effect of epistasis on the topology of evolutionary pathways that are likely to be found in fitness landscapes and develop a simple theory to connect the number of maladapted genotypes to the topology of fitness landscapes with epistatic interactions. Finally, we review recent studies that have probed the extent of epistatic interactions and have begun to chart the fitness landscapes in protein sequence space. AU - Kondrashov, Dmitry A AU - Fyodor Kondrashov ID - 886 IS - 1 JF - Trends in Genetics TI - Topological features of rugged fitness landscapes in sequence space VL - 31 ER - TY - JOUR AB - MCM2 is a subunit of the replicative helicase machinery shown to interact with histones H3 and H4 during the replication process through its N-terminal domain. During replication, this interaction has been proposed to assist disassembly and assembly of nucleosomes on DNA. However, how this interaction participates in crosstalk with histone chaperones at the replication fork remains to be elucidated. Here, we solved the crystal structure of the ternary complex between the histone-binding domain of Mcm2 and the histones H3-H4 at 2.9 Å resolution. Histones H3 and H4 assemble as a tetramer in the crystal structure, but MCM2 interacts only with a single molecule of H3-H4. The latter interaction exploits binding surfaces that contact either DNA or H2B when H3-H4 dimers are incorporated in the nucleosome core particle. Upon binding of the ternary complex with the histone chaperone ASF1, the histone tetramer dissociates and both MCM2 and ASF1 interact simultaneously with the histones forming a 1:1:1:1 heteromeric complex. Thermodynamic analysis of the quaternary complex together with structural modeling support that ASF1 and MCM2 could form a chaperoning module for histones H3 and H4 protecting them from promiscuous interactions. This suggests an additional function for MCM2 outside its helicase function as a proper histone chaperone connected to the replication pathway. AU - Richet, Nicolas AU - Liu, Danni AU - Legrand, Pierre AU - Velours, Christophe AU - Corpet, Armelle AU - Gaubert, Albane AU - Bakail, May M AU - Moal-Raisin, Gwenaelle AU - Guerois, Raphael AU - Compper, Christel AU - Besle, Arthur AU - Guichard, Berengère AU - Almouzni, Genevieve AU - Ochsenbein, Françoise ID - 9017 IS - 3 JF - Nucleic Acids Research SN - 1362-4962 TI - Structural insight into how the human helicase subunit MCM2 may act as a histone chaperone together with ASF1 at the replication fork VL - 43 ER - TY - JOUR AB - This paper presents a numerical study of a Capillary Pumped Loop evaporator. A two-dimensional unsteady mathematical model of a flat evaporator is developed to simulate heat and mass transfer in unsaturated porous wick with phase change. The liquid-vapor phase change inside the porous wick is described by Langmuir's law. The governing equations are solved by the Finite Element Method. The results are presented then for a sintered nickel wick and methanol as a working fluid. The heat flux required to the transition from the all-liquid wick to the vapor-liquid wick is calculated. The dynamic and thermodynamic behavior of the working fluid in the capillary structure are discussed in this paper. AU - Boubaker, Riadh AU - Platel, Vincent AU - Bergès, Alexis AU - Bancelin, Mathieu AU - Hannezo, Edouard B ID - 924 JF - Applied Thermal Engineering TI - Dynamic model of heat and mass transfer in an unsaturated porous wick of capillary pumped loop VL - 76 ER - TY - JOUR AB - An essential question of morphogenesis is how patterns arise without preexisting positional information, as inspired by Turing. In the past few years, cytoskeletal flows in the cell cortex have been identified as a key mechanism of molecular patterning at the subcellular level. Theoretical and in vitro studies have suggested that biological polymers such as actomyosin gels have the property to self-organize, but the applicability of this concept in an in vivo setting remains unclear. Here, we report that the regular spacing pattern of supracellular actin rings in the Drosophila tracheal tubule is governed by a self-organizing principle. We propose a simple biophysical model where pattern formation arises from the interplay of myosin contractility and actin turnover. We validate the hypotheses of the model using photobleaching experiments and report that the formation of actin rings is contractility dependent. Moreover, genetic and pharmacological perturbations of the physical properties of the actomyosin gel modify the spacing of the pattern, as the model predicted. In addition, our model posited a role of cortical friction in stabilizing the spacing pattern of actin rings. Consistently, genetic depletion of apical extracellular matrix caused strikingly dynamic movements of actin rings, mirroring our model prediction of a transition from steady to chaotic actin patterns at low cortical friction. Our results therefore demonstrate quantitatively that a hydrodynamical instability of the actin cortex can trigger regular pattern formation and drive morphogenesis in an in vivo setting. AU - Hannezo, Edouard B AU - Dong, Bo AU - Recho, Pierre AU - Joanny, Jean AU - Hayashi, Shigeo ID - 929 IS - 28 JF - PNAS TI - Cortical instability drives periodic supracellular actin pattern formation in epithelial tubes VL - 112 ER - TY - JOUR AB - Although collective cell motion plays an important role, for example during wound healing, embryogenesis, or cancer progression, the fundamental rules governing this motion are still not well understood, in particular at high cell density. We study here the motion of human bronchial epithelial cells within a monolayer, over long times. We observe that, as the monolayer ages, the cells slow down monotonously, while the velocity correlation length first increases as the cells slow down but eventually decreases at the slowest motions. By comparing experiments, analytic model, and detailed particle-based simulations, we shed light on this biological amorphous solidification process, demonstrating that the observed dynamics can be explained as a consequence of the combined maturation and strengthening of cell-cell and cell-substrate adhesions. Surprisingly, the increase of cell surface density due to proliferation is only secondary in this process. This analysis is confirmed with two other cell types. The very general relations between the mean cell velocity and velocity correlation lengths, which apply for aggregates of self-propelled particles, as well as motile cells, can possibly be used to discriminate between various parameter changes in vivo, from noninvasive microscopy data. AU - García, Simón AU - Hannezo, Edouard B AU - Elgeti, Jens AU - Joanny, Jean AU - Silberzan, Pascal AU - Gov, Nir ID - 933 IS - 50 JF - PNAS TI - Physics of active jamming during collective cellular motion in a monolayer VL - 112 ER - TY - JOUR AB - Genomic imprinting, an inherently epigenetic phenomenon defined by parent of origin-dependent gene expression, is observed in mammals and flowering plants. Genome-scale surveys of imprinted expression and the underlying differential epigenetic marks have led to the discovery of hundreds of imprinted plant genes and confirmed DNA and histone methylation as key regulators of plant imprinting. However, the biological roles of the vast majority of imprinted plant genes are unknown, and the evolutionary forces shaping plant imprinting remain rather opaque. Here, we review the mechanisms of plant genomic imprinting and discuss theories of imprinting evolution and biological significance in light of recent findings. AU - Rodrigues, Jessica A. AU - Zilberman, Daniel ID - 9532 IS - 24 JF - Genes and Development SN - 0890-9369 TI - Evolution and function of genomic imprinting in plants VL - 29 ER - TY - JOUR AB - The size dependence of the strength of nano- and micron-sized crystals is studied using a new simulation approach in which the dynamics of the density functions of dislocations are modeled. Since any quantity of dislocations can be represented by a density, this approach can handle large systems containing large quantities of dislocations, which may handicap discrete dislocation dynamics schemes due to the excessive computation time involved. For this reason, pillar sizes spanning a large range, from the sub-micron to micron regimes, can be simulated. The simulation results reveal the power-law relationship between strength and specimen size up to a certain size, beyond which the strength varies much more slowly with size. For specimens smaller than ~4000b, their strength is found to be controlled by the dislocation depletion condition, in which the total dislocation density remains almost constant throughout the loading process. In specimens larger than ~4000b, the initial dislocation distribution is of critical importance since the presence of dislocation entanglements is found to obstruct deformation in the neighboring regions within a distance of ~2000b. This length scale suggests that the effects of dense dislocation clusters are greater in intermediate-sized specimens (e.g. 4000b and 8000b) than in larger specimens (e.g. 16 000b), according to the weakest-link concept. AU - Leung, P S S AU - Leung, H S AU - Cheng, Bingqing AU - Ngan, A H W ID - 9684 IS - 3 JF - Modelling and Simulation in Materials Science and Engineering SN - 0965-0393 TI - Size dependence of yield strength simulated by a dislocation-density function dynamics approach VL - 23 ER - TY - JOUR AB - Deposits of misfolded proteins in the human brain are associated with the development of many neurodegenerative diseases. Recent studies show that these proteins have common traits even at the monomer level. Among them, a polyglutamine region that is present in huntingtin is known to exhibit a correlation between the length of the chain and the severity as well as the earliness of the onset of Huntington disease. Here, we apply bias exchange molecular dynamics to generate structures of polyglutamine expansions of several lengths and characterize the resulting independent conformations. We compare the properties of these conformations to those of the standard proteins, as well as to other homopolymeric tracts. We find that, similar to the previously studied polyvaline chains, the set of possible transient folds is much broader than the set of known-to-date folds, although the conformations have different structures. We show that the mechanical stability is not related to any simple geometrical characteristics of the structures. We demonstrate that long polyglutamine expansions result in higher mechanical stability than the shorter ones. They also have a longer life span and are substantially more prone to form knotted structures. The knotted region has an average length of 35 residues, similar to the typical threshold for most polyglutamine-related diseases. Similarly, changes in shape and mechanical stability appear once the total length of the peptide exceeds this threshold of 35 glutamine residues. We suggest that knotted conformers may also harm the cellular machinery and thus lead to disease. AU - Gómez Sicilia, Àngel AU - Sikora, Mateusz K AU - Cieplak, Marek AU - Carrión Vázquez, Mariano ID - 1566 IS - 10 JF - PLoS Computational Biology TI - An exploration of the universe of polyglutamine structures VL - 11 ER - TY - GEN AU - Tugrul, Murat AU - Paixao, Tiago AU - Barton, Nicholas H AU - Tkačik, Gašper ID - 9712 TI - Other fitness models for comparison & for interacting TFBSs ER - TY - GEN AU - Gómez Sicilia, Àngel AU - Sikora, Mateusz K AU - Cieplak, Marek AU - Carrión Vázquez, Mariano ID - 9714 TI - An exploration of the universe of polyglutamine structures - submission to PLOS journals ER - TY - GEN AU - Trubenova, Barbora AU - Novak, Sebastian AU - Hager, Reinmar ID - 9715 TI - Mathematical inference of the results ER - TY - JOUR AB - The fitness effects of symbionts on their hosts can be context-dependent, with usually benign symbionts causing detrimental effects when their hosts are stressed, or typically parasitic symbionts providing protection towards their hosts (e.g. against pathogen infection). Here, we studied the novel association between the invasive garden ant Lasius neglectus and its fungal ectosymbiont Laboulbenia formicarum for potential costs and benefits. We tested ants with different Laboulbenia levels for their survival and immunity under resource limitation and exposure to the obligate killing entomopathogen Metarhizium brunneum. While survival of L. neglectus workers under starvation was significantly decreased with increasing Laboulbenia levels, host survival under Metarhizium exposure increased with higher levels of the ectosymbiont, suggesting a symbiont-mediated anti-pathogen protection, which seems to be driven mechanistically by both improved sanitary behaviours and an upregulated immune system. Ants with high Laboulbenia levels showed significantly longer self-grooming and elevated expression of immune genes relevant for wound repair and antifungal responses (β-1,3-glucan binding protein, Prophenoloxidase), compared with ants carrying low Laboulbenia levels. This suggests that the ectosymbiont Laboulbenia formicarum weakens its ant host by either direct resource exploitation or the costs of an upregulated behavioural and immunological response, which, however, provides a prophylactic protection upon later exposure to pathogens. AU - Konrad, Matthias AU - Grasse, Anna V AU - Tragust, Simon AU - Cremer, Sylvia ID - 1993 IS - 1799 JF - Proceedings of the Royal Society of London Series B Biological Sciences SN - 0962-8452 TI - Anti-pathogen protection versus survival costs mediated by an ectosymbiont in an ant host VL - 282 ER - TY - GEN AB - Repeated pathogen exposure is a common threat in colonies of social insects, posing selection pressures on colony members to respond with improved disease-defense performance. We here tested whether experience gained by repeated tending of low-level fungus-exposed (Metarhizium robertsii) larvae may alter the performance of sanitary brood care in the clonal ant, Platythyrea punctata. We trained ants individually over nine consecutive trials to either sham-treated or fungus-exposed larvae. We then compared the larval grooming behavior of naive and trained ants and measured how effectively they removed infectious fungal conidiospores from the fungus-exposed larvae. We found that the ants changed the duration of larval grooming in response to both, larval treatment and their level of experience: (1) sham-treated larvae received longer grooming than the fungus-exposed larvae and (2) trained ants performed less self-grooming but longer larval grooming than naive ants, which was true for both, ants trained to fungus-exposed and also to sham-treated larvae. Ants that groomed the fungus-exposed larvae for longer periods removed a higher number of fungal conidiospores from the surface of the fungus-exposed larvae. As experienced ants performed longer larval grooming, they were more effective in fungal removal, thus making them better caretakers under pathogen attack of the colony. By studying this clonal ant, we can thus conclude that even in the absence of genetic variation between colony members, differences in experience levels of brood care may affect performance of sanitary brood care in social insects. AU - Westhus, Claudia AU - Ugelvig, Line V AU - Tourdot, Edouard AU - Heinze, Jürgen AU - Doums, Claudie AU - Cremer, Sylvia ID - 9742 TI - Data from: Increased grooming after repeated brood care provides sanitary benefits in a clonal ant ER - TY - GEN AU - Chevereau, Guillaume AU - Lukacisinova, Marta AU - Batur, Tugce AU - Guvenek, Aysegul AU - Ayhan, Dilay Hazal AU - Toprak, Erdal AU - Bollenbach, Mark Tobias ID - 9765 TI - Gene ontology enrichment analysis for the most sensitive gene deletion strains for all drugs ER - TY - JOUR AB - The hydrology of high-elevation watersheds of the Hindu Kush-Himalaya region (HKH) is poorly known. The correct representation of internal states and process dynamics in glacio-hydrological models can often not be verified due to missing in situ measurements. We use a new set of detailed ground data from the upper Langtang valley in Nepal to systematically guide a state-of-the art glacio-hydrological model through a parameter assigning process with the aim to understand the hydrology of the catchment and contribution of snow and ice processes to runoff. 14 parameters are directly calculated on the basis of local data, and 13 parameters are calibrated against 5 different datasets of in situ or remote sensing data. Spatial fields of debris thickness are reconstructed through a novel approach that employs data from an Unmanned Aerial Vehicle (UAV), energy balance modeling and statistical techniques. The model is validated against measured catchment runoff (Nash–Sutcliffe efficiency 0.87) and modeled snow cover is compared to Landsat snow cover. The advanced representation of processes allowed assessing the role played by avalanching for runoff for the first time for a Himalayan catchment (5% of annual water inputs to the hydrological system are due to snow redistribution) and to quantify the hydrological significance of sub-debris ice melt (9% of annual water inputs). Snowmelt is the most important contributor to total runoff during the hydrological year 2012/2013 (representing 40% of all sources), followed by rainfall (34%) and ice melt (26%). A sensitivity analysis is used to assess the efficiency of the monitoring network and identify the timing and location of field measurements that constrain model uncertainty. The methodology to set up a glacio-hydrological model in high-elevation regions presented in this study can be regarded as a benchmark for modelers in the HKH seeking to evaluate their calibration approach, their experimental setup and thus to reduce the predictive model uncertainty. AU - Ragettli, S. AU - Pellicciotti, Francesca AU - Immerzeel, W.W. AU - Miles, E.S. AU - Petersen, L. AU - Heynen, M. AU - Shea, J.M. AU - Stumm, D. AU - Joshi, S. AU - Shrestha, A. ID - 12630 IS - 4 JF - Advances in Water Resources KW - Water Science and Technology SN - 0309-1708 TI - Unraveling the hydrology of a Himalayan catchment through integration of high resolution in situ data and remote sensing with an advanced simulation model VL - 78 ER - TY - JOUR AB - Thick debris cover on glaciers can significantly reduce ice melt. However, several studies have suggested that debris-covered glaciers in the Himalaya might have lost mass at a rate similar to debris-free glaciers. We reconstruct elevation and mass changes for the debris-covered glaciers of the upper Langtang valley, Nepalese Himalaya, using a digital elevation model (DEM) from 1974 stereo Hexagon satellite data and the 2000 SRTM (Shuttle Radar Topography Mission) DEM. Uncertainties are high in the accumulation areas, due to data gaps in the SRTM and difficulties with delineation of the glacier borders. Even with these uncertainties, we obtain thinning rates comparable to those of several other studies in the Himalaya. In particular, we obtain a total mass balance for the investigated debris-covered glaciers of the basin of –0.32 ± 0.18 m w.e. a−1. However, there are major spatial differences both between glaciers and within any single glacier, exhibiting a very distinct nonlinear mass-balance profile with elevation. Through analysis of surface velocities derived from Landsat ETM+ imagery, we show that thinning occurs in areas of low velocity and low slope. These areas are prone to a general, dynamic decay of surface features and to the development of supraglacial lakes and ice cliffs, which may be responsible for a considerable increase in overall glacier ablation. AU - Pellicciotti, Francesca AU - Stephan, Christa AU - Miles, Evan AU - Herreid, Sam AU - Immerzeel, Walter W. AU - Bolch, Tobias ID - 12628 IS - 226 JF - Journal of Glaciology KW - Earth-Surface Processes SN - 0022-1430 TI - Mass-balance changes of the debris-covered glaciers in the Langtang Himal, Nepal, from 1974 to 1999 VL - 61 ER - TY - JOUR AB - Air temperature is one of the most relevant input variables for snow and ice melt calculations. However, local meteorological conditions, complex topography, and logistical concerns in glacierized regions make the measuring and modeling of air temperature a difficult task. In this study, we investigate the spatial distribution of 2 m air temperature over mountain glaciers and propose a modification to an existing model to improve its representation. Spatially distributed meteorological data from Haut Glacier d'Arolla (Switzerland), Place (Canada), and Juncal Norte (Chile) Glaciers are used to examine approximate flow line temperatures during their respective ablation seasons. During warm conditions (off-glacier temperatures well above 0°C), observed air temperatures in the upper reaches of Place Glacier and Haut Glacier d'Arolla decrease down glacier along the approximate flow line. At Juncal Norte and Haut Glacier d'Arolla, an increase in air temperature is observed over the glacier tongue. While the temperature behavior over the upper part can be explained by the cooling effect of the glacier surface, the temperature increase over the glacier tongue may be caused by several processes induced by the surrounding warm atmosphere. In order to capture the latter effect, we add an additional term to the Greuell and Böhm (GB) thermodynamic glacier wind model. For high off-glacier temperatures, the modified GB model reduces root-mean-square error up to 32% and provides a new approach for distributing air temperature over mountain glaciers as a function of off-glacier temperatures and approximate glacier flow lines. AU - Ayala, A. AU - Pellicciotti, Francesca AU - Shea, J. M. ID - 12631 IS - 8 JF - Journal of Geophysical Research: Atmospheres KW - Space and Planetary Science KW - Earth and Planetary Sciences (miscellaneous) KW - Atmospheric Science KW - Geophysics SN - 2169-897X TI - Modeling 2 m air temperatures over mountain glaciers: Exploring the influence of katabatic cooling and external warming VL - 120 ER - TY - JOUR AB - Meteorological studies in high-mountain environments form the basis of our understanding of catchment hydrology and glacier accumulation and melt processes, yet high-altitude (>4000 m above sea level, asl) observatories are rare. This research presents meteorological data recorded between December 2012 and November 2013 at seven stations in Nepal, ranging in elevation from 3860 to 5360 m asl. Seasonal and diurnal cycles in air temperature, vapour pressure, incoming short-wave and long-wave radiation, atmospheric transmissivity, wind speed, and precipitation are compared between sites. Solar radiation strongly affects diurnal temperature and vapour pressure cycles, but local topography and valley-scale circulations alter wind speed and precipitation cycles. The observed diurnal variability in vertical temperature gradients in all seasons highlights the importance of in situ measurements for melt modelling. The monsoon signal (progressive onset and sharp end) is visible in all data-sets, and the passage of the remnants of Typhoon Phailin in mid-October 2013 provides an interesting case study on the possible effects of such storms on glaciers in the region. AU - Shea, J.M. AU - Wagnon, P. AU - Immerzeel, W.W. AU - Biron, R. AU - Brun, F. AU - Pellicciotti, Francesca ID - 12629 IS - 2 JF - International Journal of Water Resources Development KW - Water Science and Technology KW - Development SN - 0790-0627 TI - A comparative high-altitude meteorological analysis from three catchments in the Nepalese Himalaya VL - 31 ER - TY - JOUR AB - Ice cliffs have been identified as a reason for higher ablation rates on debris-covered glaciers than are implied by the insulation effects of the debris. This study aims to improve our understanding of cliff backwasting, and the role of radiative fluxes in particular. An energy-balance model is forced with new data gathered in May and October 2013 on Lirung Glacier, Nepalese Himalaya. Observations show substantial variability in melt between cliffs, between locations on any cliff and between seasons. Using a high-resolution digital elevation model we calculate longwave fluxes incident to the cliff from surrounding terrain and include the effect of local shading on shortwave radiation. This is an advance over previous studies, that made simplified assumptions on cliff geometry and radiative fluxes. Measured melt rates varied between 3.25 and 8.6 cm d−1 in May and 0.18 and 1.34 cm d−1 in October. Model results reproduce the strong variability in space and time, suggesting considerable differences in radiative fluxes over one cliff. In October the model fails to reproduce stake readings, probably due to the lack of a refreezing component. Disregarding local topography can lead to overestimation of melt at the point scale by up to ∼9%. AU - Steiner, Jakob F. AU - Pellicciotti, Francesca AU - Buri, Pascal AU - Miles, Evan S. AU - Immerzeel, Walter W. AU - Reid, Tim D. ID - 12626 IS - 229 JF - Journal of Glaciology SN - 0022-1430 TI - Modelling ice-cliff backwasting on a debris-covered glacier in the Nepalese Himalaya VL - 61 ER - TY - JOUR AB - Spatial evolution of supraglacial debris cover on mountain glaciers is a largely unmonitored and poorly understood phenomenon that directly affects glacier melt. Supraglacial debris cover for 93 glaciers in the Karakoram, northern Pakistan, was mapped from Landsat imagery acquired in 1977, 1998, 2009 and 2014. Surge-type glaciers occupy 41% of the study area and were considered separately. The time series of debris-covered surface area change shows a mean value of zero or near-zero change for both surging and non-surging glaciers. An increase in debris-covered area is often associated with negative regional mass balances. We extend this logic to suggest that the stable regional mass balances in the Karakoram explain the zero or near-zero change in debris-covered area. This coupling of trends combined with our 37 year time series of data suggests the Karakoram anomaly extends further back in time than previously known. AU - Herreid, Sam AU - Pellicciotti, Francesca AU - Ayala, Alvaro AU - Chesnokova, Anna AU - Kienholz, Christian AU - Shea, Joseph AU - Shrestha, Arun ID - 12627 IS - 227 JF - Journal of Glaciology SN - 0022-1430 TI - Satellite observations show no net change in the percentage of supraglacial debris-covered area in northern Pakistan from 1977 to 2014 VL - 61 ER - TY - JOUR AB - CCL19 and CCL21 are chemokines involved in the trafficking of immune cells, particularly within the lymphatic system, through activation of CCR7. Concurrent expression of PSGL-1 and CCR7 in naive T-cells enhances recruitment of these cells to secondary lymphoid organs by CCL19 and CCL21. Here the solution structure of CCL19 is reported. It contains a canonical chemokine domain. Chemical shift mapping shows the N-termini of PSGL-1 and CCR7 have overlapping binding sites for CCL19 and binding is competitive. Implications for the mechanism of PSGL-1's enhancement of resting T-cell recruitment are discussed. AU - Veldkamp, Christopher AU - Kiermaier, Eva AU - Gabel Eissens, Skylar AU - Gillitzer, Miranda AU - Lippner, David AU - Disilvio, Frank AU - Mueller, Casey AU - Wantuch, Paeton AU - Chaffee, Gary AU - Famiglietti, Michael AU - Zgoba, Danielle AU - Bailey, Asha AU - Bah, Yaya AU - Engebretson, Samantha AU - Graupner, David AU - Lackner, Emily AU - Larosa, Vincent AU - Medeiros, Tysha AU - Olson, Michael AU - Phillips, Andrew AU - Pyles, Harley AU - Richard, Amanda AU - Schoeller, Scott AU - Touzeau, Boris AU - Williams, Larry AU - Sixt, Michael K AU - Peterson, Francis ID - 1618 IS - 27 JF - Biochemistry TI - Solution structure of CCL19 and identification of overlapping CCR7 and PSGL-1 binding sites VL - 54 ER - TY - CONF AU - Martius, Georg S AU - Olbrich, Eckehard ID - 12881 SN - 9780262330275 T2 - Proceedings of the 13th European Conference on Artificial Life TI - Quantifying self-organizing behavior of autonomous robots ER - TY - JOUR AB - SNC1 (SUPPRESSOR OF NPR1, CONSTITUTIVE 1) is one of a suite of intracellular Arabidopsis NOD-like receptor (NLR) proteins which, upon activation, result in the induction of defense responses. However, the molecular mechanisms underlying NLR activation and the subsequent provocation of immune responses are only partially characterized. To identify negative regulators of NLR-mediated immunity, a forward genetic screen was undertaken to search for enhancers of the dwarf, autoimmune gain-of-function snc1 mutant. To avoid lethality resulting from severe dwarfism, the screen was conducted using mos4 (modifier of snc1, 4) snc1 plants, which display wild-type-like morphology and resistance. M2 progeny were screened for mutant, snc1-enhancing (muse) mutants displaying a reversion to snc1-like phenotypes. The muse9 mos4 snc1 triple mutant was found to exhibit dwarf morphology, elevated expression of the pPR2-GUS defense marker reporter gene and enhanced resistance to the oomycete pathogen Hyaloperonospora arabidopsidis Noco2. Via map-based cloning and Illumina sequencing, it was determined that the muse9 mutation is in the gene encoding the SWI/SNF chromatin remodeler SYD (SPLAYED), and was thus renamed syd-10. The syd-10 single mutant has no observable alteration from wild-type-like resistance, although the syd-4 T-DNA insertion allele displays enhanced resistance to the bacterial pathogen Pseudomonas syringae pv. maculicola ES4326. Transcription of SNC1 is increased in both syd-4 and syd-10. These data suggest that SYD plays a subtle, specific role in the regulation of SNC1 expression and SNC1-mediated immunity. SYD may work with other proteins at the chromatin level to repress SNC1 transcription; such regulation is important for fine-tuning the expression of NLR-encoding genes to prevent unpropitious autoimmunity. AU - Johnson, Kaeli C.M. AU - Xia, Shitou AU - Feng, Xiaoqi AU - Li, Xin ID - 12196 IS - 8 JF - Plant and Cell Physiology KW - Cell Biology KW - Plant Science KW - Physiology KW - General Medicine SN - 0032-0781 TI - The chromatin remodeler SPLAYED negatively regulates SNC1-mediated immunity VL - 56 ER - TY - JOUR AB - The chemical behaviour of molecules can be significantly modified by confinement to volumes comparable to the dimensions of the molecules. Although such confined spaces can be found in various nanostructured materials, such as zeolites, nanoporous organic frameworks and colloidal nanocrystal assemblies, the slow diffusion of molecules in and out of these materials has greatly hampered studying the effect of confinement on their physicochemical properties. Here, we show that this diffusion limitation can be overcome by reversibly creating and destroying confined environments by means of ultraviolet and visible light irradiation. We use colloidal nanocrystals functionalized with light-responsive ligands that readily self-assemble and trap various molecules from the surrounding bulk solution. Once trapped, these molecules can undergo chemical reactions with increased rates and with stereoselectivities significantly different from those in bulk solution. Illumination with visible light disassembles these nanoflasks, releasing the product in solution and thereby establishes a catalytic cycle. These dynamic nanoflasks can be useful for studying chemical reactivities in confined environments and for synthesizing molecules that are otherwise hard to achieve in bulk solution. AU - Zhao, Hui AU - Sen, Soumyo AU - Udayabhaskararao, T. AU - Sawczyk, Michał AU - Kučanda, Kristina AU - Manna, Debasish AU - Kundu, Pintu K. AU - Lee, Ji-Woong AU - Král, Petr AU - Klajn, Rafal ID - 13392 JF - Nature Nanotechnology KW - Electrical and Electronic Engineering KW - Condensed Matter Physics KW - General Materials Science KW - Biomedical Engineering KW - Atomic and Molecular Physics KW - and Optics KW - Bioengineering SN - 1748-3387 TI - Reversible trapping and reaction acceleration within dynamically self-assembling nanoflasks VL - 11 ER - TY - JOUR AB - The ability to guide the assembly of nanosized objects reversibly with external stimuli, in particular light, is of fundamental importance, and it contributes to the development of applications as diverse as nanofabrication and controlled drug delivery. However, all the systems described to date are based on nanoparticles (NPs) that are inherently photoresponsive, which makes their preparation cumbersome and can markedly hamper their performance. Here we describe a conceptually new methodology to assemble NPs reversibly using light that does not require the particles to be functionalized with light-responsive ligands. Our strategy is based on the use of a photoswitchable medium that responds to light in such a way that it modulates the interparticle interactions. NP assembly proceeds quantitatively and without apparent fatigue, both in solution and in gels. Exposing the gels to light in a spatially controlled manner allowed us to draw images that spontaneously disappeared after a specific period of time. AU - Kundu, Pintu K. AU - Samanta, Dipak AU - Leizrowice, Ron AU - Margulis, Baruch AU - Zhao, Hui AU - Börner, Martin AU - Udayabhaskararao, T. AU - Manna, Debasish AU - Klajn, Rafal ID - 13394 JF - Nature Chemistry KW - General Chemical Engineering KW - General Chemistry SN - 1755-4330 TI - Light-controlled self-assembly of non-photoresponsive nanoparticles VL - 7 ER - TY - JOUR AB - Precise control of the self-assembly of selected components within complex mixtures is a challenging goal whose realization is important for fabricating novel nanomaterials. Herein we show that by decorating the surfaces of metallic nanoparticles with differently substituted azobenzenes, it is possible to modulate the wavelength of light at which the self-assembly of these nanoparticles is induced. Exposing a mixture of two types of nanoparticles, each functionalized with a different azobenzene, to UV or blue light induces the selective self-assembly of only one type of nanoparticles. Irradiation with the other wavelength triggers the disassembly of the aggregates, and the simultaneous self-assembly of nanoparticles of the other type. By placing both types of azobenzenes on the same nanoparticles, we created unique materials (“frustrated” nanoparticles) whose self-assembly is induced irrespective of the wavelength of the incident light. AU - Manna, Debasish AU - Udayabhaskararao, Thumu AU - Zhao, Hui AU - Klajn, Rafal ID - 13393 IS - 42 JF - Angewandte Chemie International Edition KW - General Chemistry KW - Catalysis SN - 1433-7851 TI - Orthogonal light-induced self-assembly of nanoparticles using differently substituted azobenzenes VL - 54 ER - TY - JOUR AB - Metallic nanoparticles co-functionalised with monolayers of UV- and CO2-sensitive ligands were prepared and shown to respond to these two types of stimuli reversibly and in an orthogonal fashion. The composition of the coating could be tailored to yield nanoparticles capable of aggregating exclusively when both UV and CO2 were applied at the same time, analogously to the behaviour of an AND logic gate. AU - Lee, Ji-Woong AU - Klajn, Rafal ID - 13395 IS - 11 JF - Chemical Communications KW - Materials Chemistry KW - Metals and Alloys KW - Surfaces KW - Coatings and Films KW - General Chemistry KW - Ceramics and Composites KW - Electronic KW - Optical and Magnetic Materials KW - Catalysis SN - 1359-7345 TI - Dual-responsive nanoparticles that aggregate under the simultaneous action of light and CO2 VL - 51 ER - TY - JOUR AB - Photoswitching in densely packed azobenzene self-assembled monolayers (SAMs) is strongly affected by steric constraints and excitonic coupling between neighboring chromophores. Therefore, control of the chromophore density is essential for enhancing and manipulating the photoisomerization yield. We systematically compare two methods to achieve this goal: First, we assemble monocomponent azobenzene–alkanethiolate SAMs on gold nanoparticles of varying size. Second, we form mixed SAMs of azobenzene–alkanethiolates and “dummy” alkanethiolates on planar substrates. Both methods lead to a gradual decrease of the chromophore density and enable efficient photoswitching with low-power light sources. X-ray spectroscopy reveals that coadsorption from solution yields mixtures with tunable composition. The orientation of the chromophores with respect to the surface normal changes from a tilted to an upright position with increasing azobenzene density. For both systems, optical spectroscopy reveals a pronounced excitonic shift that increases with the chromophore density. In spite of exciting the optical transition of the monomer, the main spectral change in mixed SAMs occurs in the excitonic band. In addition, the photoisomerization yield decreases only slightly by increasing the azobenzene–alkanethiolate density, and we observed photoswitching even with minor dilutions. Unlike in solution, azobenzene in the planar SAM can be switched back almost completely by optical excitation from the cis to the original trans state within a short time scale. These observations indicate cooperativity in the photoswitching process of mixed SAMs. AU - Moldt, Thomas AU - Brete, Daniel AU - Przyrembel, Daniel AU - Das, Sanjib AU - Goldman, Joel R. AU - Kundu, Pintu K. AU - Gahl, Cornelius AU - Klajn, Rafal AU - Weinelt, Martin ID - 13396 IS - 3 JF - Langmuir KW - Electrochemistry KW - Spectroscopy KW - Surfaces and Interfaces KW - Condensed Matter Physics KW - General Materials Science SN - 0743-7463 TI - Tailoring the properties of surface-immobilized azobenzenes by monolayer dilution and surface curvature VL - 31 ER - TY - JOUR AB - Self-assembly of inorganic nanoparticles has been studied extensively for particles having different sizes and compositions. However, relatively little attention has been devoted to how the shape and surface chemistry of magnetic nanoparticles affects their self-assembly properties. Here, we undertook a combined experiment–theory study aimed at better understanding of the self-assembly of cubic magnetite (Fe3O4) particles. We demonstrated that, depending on the experimental parameters, such as the direction of the magnetic field and nanoparticle density, a variety of superstructures can be obtained, including one-dimensional filaments and helices, as well as C-shaped assemblies described here for the first time. Furthermore, we functionalized the surfaces of the magnetic nanocubes with light-sensitive ligands. Using these modified nanoparticles, we were able to achieve orthogonal control of self-assembly using a magnetic field and light. AU - Singh, Gurvinder AU - Chan, Henry AU - Udayabhaskararao, T. AU - Gelman, Elijah AU - Peddis, Davide AU - Baskin, Artem AU - Leitus, Gregory AU - Král, Petr AU - Klajn, Rafal ID - 13397 JF - Faraday Discussions KW - Physical and Theoretical Chemistry SN - 1359-6640 TI - Magnetic field-induced self-assembly of iron oxide nanocubes VL - 181 ER - TY - JOUR AU - Sun, Yugang AU - Scarabelli, Leonardo AU - Kotov, Nicholas AU - Tebbe, Moritz AU - Lin, Xiao-Min AU - Brullot, Ward AU - Isa, Lucio AU - Schurtenberger, Peter AU - Moehwald, Helmuth AU - Fedin, Igor AU - Velev, Orlin AU - Faivre, Damien AU - Sorensen, Christopher AU - Perzynski, Régine AU - Chanana, Munish AU - Li, Zhihai AU - Bresme, Fernando AU - Král, Petr AU - Firlar, Emre AU - Schiffrin, David AU - Souza Junior, Joao Batista AU - Fery, Andreas AU - Shevchenko, Elena AU - Tarhan, Ozgur AU - Alivisatos, Armand Paul AU - Disch, Sabrina AU - Klajn, Rafal AU - Ghosh, Suvojit ID - 13398 JF - Faraday Discussions KW - Physical and Theoretical Chemistry SN - 1359-6640 TI - Field-assisted self-assembly process: General discussion VL - 181 ER - TY - JOUR AB - The detection of electron motion and electronic wave-packet dynamics is one of the core goals of attosecond science. Recently, choosing the nitric oxide molecule as an example, we have introduced and demonstrated an experimental approach to measure coupled valence electronic and rotational wave packets using high-order-harmonic-generation (HHG) spectroscopy [Kraus et al., Phys. Rev. Lett. 111, 243005 (2013)]. A short outline of the theory to describe the combination of the pump and HHG probe process was published together with an extensive discussion of experimental results [Baykusheva et al., Faraday Discuss. 171, 113 (2014)]. The comparison of theory and experiment showed good agreement on a quantitative level. Here, we present the theory in detail, which is based on a generalized density-matrix approach that describes the pump process and the subsequent probing of the wave packets by a semiclassical quantitative rescattering approach. An in-depth analysis of the different Raman scattering contributions to the creation of the coupled rotational and electronic spin-orbit wave packets is made. We present results for parallel and perpendicular linear polarizations of the pump and probe laser pulses. Furthermore, an analysis of the combined rotational-electronic density matrix in terms of irreducible components is presented that facilitates interpretation of the results. AU - Zhang, Song Bin AU - Baykusheva, Denitsa Rangelova AU - Kraus, Peter M. AU - Wörner, Hans Jakob AU - Rohringer, Nina ID - 14017 IS - 2 JF - Physical Review A KW - Atomic and Molecular Physics KW - and Optics SN - 1050-2947 TI - Theoretical study of molecular electronic and rotational coherences by high-order-harmonic generation VL - 91 ER - TY - JOUR AB - All attosecond time-resolved measurements have so far relied on the use of intense near-infrared laser pulses. In particular, attosecond streaking, laser-induced electron diffraction and high-harmonic generation all make use of non-perturbative light–matter interactions. Remarkably, the effect of the strong laser field on the studied sample has often been neglected in previous studies. Here we use high-harmonic spectroscopy to measure laser-induced modifications of the electronic structure of molecules. We study high-harmonic spectra of spatially oriented CH3F and CH3Br as generic examples of polar polyatomic molecules. We accurately measure intensity ratios of even and odd-harmonic orders, and of the emission from aligned and unaligned molecules. We show that these robust observables reveal a substantial modification of the molecular electronic structure by the external laser field. Our insights offer new challenges and opportunities for a range of emerging strong-field attosecond spectroscopies. AU - Kraus, P. M. AU - Tolstikhin, O. I. AU - Baykusheva, Denitsa Rangelova AU - Rupenyan, A. AU - Schneider, J. AU - Bisgaard, C. Z. AU - Morishita, T. AU - Jensen, F. AU - Madsen, L. B. AU - Wörner, H. J. ID - 14016 JF - Nature Communications KW - General Physics and Astronomy KW - General Biochemistry KW - Genetics and Molecular Biology KW - General Chemistry KW - Multidisciplinary TI - Observation of laser-induced electronic structure in oriented polyatomic molecules VL - 6 ER - TY - JOUR AB - The ultrafast motion of electrons and holes after light-matter interaction is fundamental to a broad range of chemical and biophysical processes. We advanced high-harmonic spectroscopy to resolve spatially and temporally the migration of an electron hole immediately after ionization of iodoacetylene while simultaneously demonstrating extensive control over the process. A multidimensional approach, based on the measurement and accurate theoretical description of both even and odd harmonic orders, enabled us to reconstruct both quantum amplitudes and phases of the electronic states with a resolution of ~100 attoseconds. We separately reconstructed quasi-field-free and laser-controlled charge migration as a function of the spatial orientation of the molecule and determined the shape of the hole created by ionization. Our technique opens the prospect of laser control over electronic primary processes. AU - Kraus, P. M. AU - Mignolet, B. AU - Baykusheva, Denitsa Rangelova AU - Rupenyan, A. AU - Horný, L. AU - Penka, E. F. AU - Grassi, G. AU - Tolstikhin, O. I. AU - Schneider, J. AU - Jensen, F. AU - Madsen, L. B. AU - Bandrauk, A. D. AU - Remacle, F. AU - Wörner, H. J. ID - 14013 IS - 6262 JF - Science KW - Multidisciplinary SN - 0036-8075 TI - Measurement and laser control of attosecond charge migration in ionized iodoacetylene VL - 350 ER - TY - JOUR AB - We advance high-harmonic spectroscopy to resolve molecular charge migration in time and space and simultaneously demonstrate extensive control over the process. A multidimensional approach enables us to reconstruct both quantum amplitudes and phases with a resolution of better than 100 attoseconds and to separately reconstruct field-free and laser- driven charge migration. Our techniques make charge migration in molecules measurable on the attosecond time scale and open new avenues for laser control of electronic primary processes. AU - Kraus, P M AU - Mignolet, B AU - Baykusheva, Denitsa Rangelova AU - Rupenyan, A AU - Horný, L AU - Penka, E F AU - Tolstikhin, O I AU - Schneider, J AU - Jensen, F AU - Madsen, L B AU - Bandrauk, A D AU - Remacle, F AU - Wörner, H J ID - 14015 IS - 11 JF - Journal of Physics: Conference Series KW - General Physics and Astronomy SN - 1742-6588 TI - Attosecond charge migration and its laser control VL - 635 ER - TY - JOUR AB - We have studied a coupled electronic-nuclear wave packet in nitric oxide using time-resolved strong-field photoelectron holography and rescattering. We show that the electronic dynamics mainly appears in the holographic structures whereas nuclear motion strongly modulates the angular distribution of the rescattered photoelectrons. AU - Walt, Samuel G AU - Ram, N Bhargava AU - von Conta, Aaron AU - Baykusheva, Denitsa Rangelova AU - Atala, Marcos AU - Wörner, Hans Jakob ID - 14014 IS - 11 JF - Journal of Physics: Conference Series KW - General Physics and Astronomy SN - 1742-6588 TI - Resolving the dynamics of valence-shell electrons and nuclei through laser-induced diffraction and holography VL - 635 ER - TY - GEN AB - Parasitism creates selection for resistance mechanisms in host populations and is hypothesized to promote increased host evolvability. However, the influence of these traits on host evolution when parasites are no longer present is unclear. We used experimental evolution and whole-genome sequencing of Escherichia coli to determine the effects of past and present exposure to parasitic viruses (phages) on the spread of mutator alleles, resistance, and bacterial competitive fitness. We found that mutator alleles spread rapidly during adaptation to any of four different phage species, and this pattern was even more pronounced with multiple phages present simultaneously. However, hypermutability did not detectably accelerate adaptation in the absence of phages and recovery of fitness costs associated with resistance. Several lineages evolved phage resistance through elevated mucoidy, and during subsequent evolution in phage-free conditions they rapidly reverted to nonmucoid, phage-susceptible phenotypes. Genome sequencing revealed that this phenotypic reversion was achieved by additional genetic changes rather than by genotypic reversion of the initial resistance mutations. Insertion sequence (IS) elements played a key role in both the acquisition of resistance and adaptation in the absence of parasites; unlike single nucleotide polymorphisms, IS insertions were not more frequent in mutator lineages. Our results provide a genetic explanation for rapid reversion of mucoidy, a phenotype observed in other bacterial species including human pathogens. Moreover, this demonstrates that the types of genetic change underlying adaptation to fitness costs, and consequently the impact of evolvability mechanisms such as increased point-mutation rates, depend critically on the mechanism of resistance. AU - Wielgoss, Sébastien AU - Bergmiller, Tobias AU - Bischofberger, Anna M. AU - Hall, Alex R. ID - 9719 TI - Data from: Adaptation to parasites and costs of parasite resistance in mutator and non-mutator bacteria ER - TY - THES AB - The human ability to recognize objects in complex scenes has driven research in the computer vision field over couple of decades. This thesis focuses on the object recognition task in images. That is, given the image, we want the computer system to be able to predict the class of the object that appears in the image. A recent successful attempt to bridge semantic understanding of the image perceived by humans and by computers uses attribute-based models. Attributes are semantic properties of the objects shared across different categories, which humans and computers can decide on. To explore the attribute-based models we take a statistical machine learning approach, and address two key learning challenges in view of object recognition task: learning augmented attributes as mid-level discriminative feature representation, and learning with attributes as privileged information. Our main contributions are parametric and non-parametric models and algorithms to solve these frameworks. In the parametric approach, we explore an autoencoder model combined with the large margin nearest neighbor principle for mid-level feature learning, and linear support vector machines for learning with privileged information. In the non-parametric approach, we propose a supervised Indian Buffet Process for automatic augmentation of semantic attributes, and explore the Gaussian Processes classification framework for learning with privileged information. A thorough experimental analysis shows the effectiveness of the proposed models in both parametric and non-parametric views. AU - Sharmanska, Viktoriia ID - 1401 SN - 2663-337X TI - Learning with attributes for object recognition: Parametric and non-parametrics views ER - TY - JOUR AB - The competition for resources among cells, individuals or species is a fundamental characteristic of evolution. Biological all-pay auctions have been used to model situations where multiple individuals compete for a single resource. However, in many situations multiple resources with various values exist and single reward auctions are not applicable. We generalize the model to multiple rewards and study the evolution of strategies. In biological all-pay auctions the bid of an individual corresponds to its strategy and is equivalent to its payment in the auction. The decreasingly ordered rewards are distributed according to the decreasingly ordered bids of the participating individuals. The reproductive success of an individual is proportional to its fitness given by the sum of the rewards won minus its payments. Hence, successful bidding strategies spread in the population. We find that the results for the multiple reward case are very different from the single reward case. While the mixed strategy equilibrium in the single reward case with more than two players consists of mostly low-bidding individuals, we show that the equilibrium can convert to many high-bidding individuals and a few low-bidding individuals in the multiple reward case. Some reward values lead to a specialization among the individuals where one subpopulation competes for the rewards and the other subpopulation largely avoids costly competitions. Whether the mixed strategy equilibrium is an evolutionarily stable strategy (ESS) depends on the specific values of the rewards. AU - Reiter, Johannes AU - Kanodia, Ayush AU - Gupta, Raghav AU - Nowak, Martin AU - Chatterjee, Krishnendu ID - 1709 IS - 1812 JF - Proceedings of the Royal Society of London Series B Biological Sciences TI - Biological auctions with multiple rewards VL - 282 ER - TY - THES AB - Cancer results from an uncontrolled growth of abnormal cells. Sequentially accumulated genetic and epigenetic alterations decrease cell death and increase cell replication. We used mathematical models to quantify the effect of driver gene mutations. The recently developed targeted therapies can lead to dramatic regressions. However, in solid cancers, clinical responses are often short-lived because resistant cancer cells evolve. We estimated that approximately 50 different mutations can confer resistance to a typical targeted therapeutic agent. We find that resistant cells are likely to be present in expanded subclones before the start of the treatment. The dominant strategy to prevent the evolution of resistance is combination therapy. Our analytical results suggest that in most patients, dual therapy, but not monotherapy, can result in long-term disease control. However, long-term control can only occur if there are no possible mutations in the genome that can cause cross-resistance to both drugs. Furthermore, we showed that simultaneous therapy with two drugs is much more likely to result in long-term disease control than sequential therapy with the same drugs. To improve our understanding of the underlying subclonal evolution we reconstruct the evolutionary history of a patient's cancer from next-generation sequencing data of spatially-distinct DNA samples. Using a quantitative measure of genetic relatedness, we found that pancreatic cancers and their metastases demonstrated a higher level of relatedness than that expected for any two cells randomly taken from a normal tissue. This minimal amount of genetic divergence among advanced lesions indicates that genetic heterogeneity, when quantitatively defined, is not a fundamental feature of the natural history of untreated pancreatic cancers. Our newly developed, phylogenomic tool Treeomics finds evidence for seeding patterns of metastases and can directly be used to discover rules governing the evolution of solid malignancies to transform cancer into a more predictable disease. AU - Reiter, Johannes ID - 1400 SN - 2663-337X TI - The subclonal evolution of cancer ER - TY - JOUR AB - Motivated by recent ideas of Harman (Unif. Distrib. Theory, 2010) we develop a new concept of variation of multivariate functions on a compact Hausdorff space with respect to a collection D of subsets. We prove a general version of the Koksma-Hlawka theorem that holds for this notion of variation and discrepancy with respect to D. As special cases, we obtain Koksma-Hlawka inequalities for classical notions, such as extreme or isotropic discrepancy. For extreme discrepancy, our result coincides with the usual Koksma-Hlawka theorem. We show that the space of functions of bounded D-variation contains important discontinuous functions and is closed under natural algebraic operations. Finally, we illustrate the results on concrete integration problems from integral geometry and stereology. AU - Pausinger, Florian AU - Svane, Anne ID - 1792 IS - 6 JF - Journal of Complexity TI - A Koksma-Hlawka inequality for general discrepancy systems VL - 31 ER - TY - THES AB - This thesis is concerned with the computation and approximation of intrinsic volumes. Given a smooth body M and a certain digital approximation of it, we develop algorithms to approximate various intrinsic volumes of M using only measurements taken from its digital approximations. The crucial idea behind our novel algorithms is to link the recent theory of persistent homology to the theory of intrinsic volumes via the Crofton formula from integral geometry and, in particular, via Euler characteristic computations. Our main contributions are a multigrid convergent digital algorithm to compute the first intrinsic volume of a solid body in R^n as well as an appropriate integration pipeline to approximate integral-geometric integrals defined over the Grassmannian manifold. AU - Pausinger, Florian ID - 1399 SN - 2663-337X TI - On the approximation of intrinsic volumes ER - TY - JOUR AB - Evolution of gene regulation is crucial for our understanding of the phenotypic differences between species, populations and individuals. Sequence-specific binding of transcription factors to the regulatory regions on the DNA is a key regulatory mechanism that determines gene expression and hence heritable phenotypic variation. We use a biophysical model for directional selection on gene expression to estimate the rates of gain and loss of transcription factor binding sites (TFBS) in finite populations under both point and insertion/deletion mutations. Our results show that these rates are typically slow for a single TFBS in an isolated DNA region, unless the selection is extremely strong. These rates decrease drastically with increasing TFBS length or increasingly specific protein-DNA interactions, making the evolution of sites longer than ∼ 10 bp unlikely on typical eukaryotic speciation timescales. Similarly, evolution converges to the stationary distribution of binding sequences very slowly, making the equilibrium assumption questionable. The availability of longer regulatory sequences in which multiple binding sites can evolve simultaneously, the presence of “pre-sites” or partially decayed old sites in the initial sequence, and biophysical cooperativity between transcription factors, can all facilitate gain of TFBS and reconcile theoretical calculations with timescales inferred from comparative genomics. AU - Tugrul, Murat AU - Paixao, Tiago AU - Barton, Nicholas H AU - Tkacik, Gasper ID - 1666 IS - 11 JF - PLoS Genetics TI - Dynamics of transcription factor binding site evolution VL - 11 ER - TY - CONF AB - We extend the theory of input-output conformance with operators for merge and quotient. The former is useful when testing against multiple requirements or views. The latter can be used to generate tests for patches of an already tested system. Both operators can combine systems with different action alphabets, which is usually the case when constructing complex systems and specifications from parts, for instance different views as well as newly defined functionality of a~previous version of the system. AU - Beneš, Nikola AU - Daca, Przemyslaw AU - Henzinger, Thomas A AU - Kretinsky, Jan AU - Nickovic, Dejan ID - 1502 SN - 978-1-4503-3471-6 TI - Complete composition operators for IOCO-testing theory ER - TY - JOUR AB - We consider Markov decision processes (MDPs) which are a standard model for probabilistic systems. We focus on qualitative properties for MDPs that can express that desired behaviors of the system arise almost-surely (with probability 1) or with positive probability. We introduce a new simulation relation to capture the refinement relation of MDPs with respect to qualitative properties, and present discrete graph algorithms with quadratic complexity to compute the simulation relation. We present an automated technique for assume-guarantee style reasoning for compositional analysis of two-player games by giving a counterexample guided abstraction-refinement approach to compute our new simulation relation. We show a tight link between two-player games and MDPs, and as a consequence the results for games are lifted to MDPs with qualitative properties. We have implemented our algorithms and show that the compositional analysis leads to significant improvements. AU - Chatterjee, Krishnendu AU - Chmelik, Martin AU - Daca, Przemyslaw ID - 1501 IS - 2 JF - Formal Methods in System Design TI - CEGAR for compositional analysis of qualitative properties in Markov decision processes VL - 47 ER - TY - JOUR AB - Interprocedural analysis is at the heart of numerous applications in programming languages, such as alias analysis, constant propagation, etc. Recursive state machines (RSMs) are standard models for interprocedural analysis. We consider a general framework with RSMs where the transitions are labeled from a semiring, and path properties are algebraic with semiring operations. RSMs with algebraic path properties can model interprocedural dataflow analysis problems, the shortest path problem, the most probable path problem, etc. The traditional algorithms for interprocedural analysis focus on path properties where the starting point is fixed as the entry point of a specific method. In this work, we consider possible multiple queries as required in many applications such as in alias analysis. The study of multiple queries allows us to bring in a very important algorithmic distinction between the resource usage of the one-time preprocessing vs for each individual query. The second aspect that we consider is that the control flow graphs for most programs have constant treewidth. Our main contributions are simple and implementable algorithms that supportmultiple queries for algebraic path properties for RSMs that have constant treewidth. Our theoretical results show that our algorithms have small additional one-time preprocessing, but can answer subsequent queries significantly faster as compared to the current best-known solutions for several important problems, such as interprocedural reachability and shortest path. We provide a prototype implementation for interprocedural reachability and intraprocedural shortest path that gives a significant speed-up on several benchmarks. AU - Chatterjee, Krishnendu AU - Ibsen-Jensen, Rasmus AU - Pavlogiannis, Andreas AU - Goyal, Prateesh ID - 1602 IS - 1 JF - ACM SIGPLAN Notices TI - Faster algorithms for algebraic path properties in recursive state machines with constant treewidth VL - 50 ER - TY - JOUR AB - We consider the quantitative analysis problem for interprocedural control-flow graphs (ICFGs). The input consists of an ICFG, a positive weight function that assigns every transition a positive integer-valued number, and a labelling of the transitions (events) as good, bad, and neutral events. The weight function assigns to each transition a numerical value that represents ameasure of how good or bad an event is. The quantitative analysis problem asks whether there is a run of the ICFG where the ratio of the sum of the numerical weights of good events versus the sum of weights of bad events in the long-run is at least a given threshold (or equivalently, to compute the maximal ratio among all valid paths in the ICFG). The quantitative analysis problem for ICFGs can be solved in polynomial time, and we present an efficient and practical algorithm for the problem. We show that several problems relevant for static program analysis, such as estimating the worst-case execution time of a program or the average energy consumption of a mobile application, can be modeled in our framework. We have implemented our algorithm as a tool in the Java Soot framework. We demonstrate the effectiveness of our approach with two case studies. First, we show that our framework provides a sound approach (no false positives) for the analysis of inefficiently-used containers. Second, we show that our approach can also be used for static profiling of programs which reasons about methods that are frequently invoked. Our experimental results show that our tool scales to relatively large benchmarks, and discovers relevant and useful information that can be used to optimize performance of the programs. AU - Chatterjee, Krishnendu AU - Pavlogiannis, Andreas AU - Velner, Yaron ID - 1604 IS - 1 JF - Proceedings of the 42nd Annual ACM SIGPLAN-SIGACT SN - 978-1-4503-3300-9 TI - Quantitative interprocedural analysis VL - 50 ER - TY - CONF AB - We consider the core algorithmic problems related to verification of systems with respect to three classical quantitative properties, namely, the mean-payoff property, the ratio property, and the minimum initial credit for energy property. The algorithmic problem given a graph and a quantitative property asks to compute the optimal value (the infimum value over all traces) from every node of the graph. We consider graphs with constant treewidth, and it is well-known that the control-flow graphs of most programs have constant treewidth. Let n denote the number of nodes of a graph, m the number of edges (for constant treewidth graphs m=O(n)) and W the largest absolute value of the weights. Our main theoretical results are as follows. First, for constant treewidth graphs we present an algorithm that approximates the mean-payoff value within a multiplicative factor of ϵ in time O(n⋅log(n/ϵ)) and linear space, as compared to the classical algorithms that require quadratic time. Second, for the ratio property we present an algorithm that for constant treewidth graphs works in time O(n⋅log(|a⋅b|))=O(n⋅log(n⋅W)), when the output is ab, as compared to the previously best known algorithm with running time O(n2⋅log(n⋅W)). Third, for the minimum initial credit problem we show that (i) for general graphs the problem can be solved in O(n2⋅m) time and the associated decision problem can be solved in O(n⋅m) time, improving the previous known O(n3⋅m⋅log(n⋅W)) and O(n2⋅m) bounds, respectively; and (ii) for constant treewidth graphs we present an algorithm that requires O(n⋅logn) time, improving the previous known O(n4⋅log(n⋅W)) bound. We have implemented some of our algorithms and show that they present a significant speedup on standard benchmarks. AU - Chatterjee, Krishnendu AU - Ibsen-Jensen, Rasmus AU - Pavlogiannis, Andreas ID - 1607 TI - Faster algorithms for quantitative verification in constant treewidth graphs VL - 9206 ER - TY - CONF AB - We present a flexible framework for the automated competitive analysis of on-line scheduling algorithms for firm-deadline real-time tasks based on multi-objective graphs: Given a task set and an on-line scheduling algorithm specified as a labeled transition system, along with some optional safety, liveness, and/or limit-average constraints for the adversary, we automatically compute the competitive ratio of the algorithm w.r.t. A clairvoyant scheduler. We demonstrate the flexibility and power of our approach by comparing the competitive ratio of several on-line algorithms, including Dover, that have been proposed in the past, for various task sets. Our experimental results reveal that none of these algorithms is universally optimal, in the sense that there are task sets where other schedulers provide better performance. Our framework is hence a very useful design tool for selecting optimal algorithms for a given application. AU - Chatterjee, Krishnendu AU - Pavlogiannis, Andreas AU - Kößler, Alexander AU - Schmid, Ulrich ID - 1714 IS - January T2 - Real-Time Systems Symposium TI - A framework for automated competitive analysis of on-line scheduling of firm-deadline tasks VL - 2015 ER - TY - CONF AB - We present a method for simulating brittle fracture under the assumptions of quasi-static linear elastic fracture mechanics (LEFM). Using the boundary element method (BEM) and Lagrangian crack-fronts, we produce highly detailed fracture surfaces. The computational cost of the BEM is alleviated by using a low-resolution mesh and interpolating the resulting stress intensity factors when propagating the high-resolution crack-front. Our system produces physics-based fracture surfaces with high spatial and temporal resolution, taking spatial variation of material toughness and/or strength into account. It also allows for crack initiation to be handled separately from crack propagation, which is not only more reasonable from a physics perspective, but can also be used to control the simulation. Separating the resolution of the crack-front from the resolution of the computational mesh increases the efficiency and therefore the amount of visual detail on the resulting fracture surfaces. The BEM also allows us to re-use previously computed blocks of the system matrix. AU - Hahn, David AU - Wojtan, Christopher J ID - 1633 IS - 4 TI - High-resolution brittle fracture simulation with boundary elements VL - 34 ER - TY - JOUR AB - 3D amoeboid cell migration is central to many developmental and disease-related processes such as cancer metastasis. Here, we identify a unique prototypic amoeboid cell migration mode in early zebrafish embryos, termed stable-bleb migration. Stable-bleb cells display an invariant polarized balloon-like shape with exceptional migration speed and persistence. Progenitor cells can be reversibly transformed into stable-bleb cells irrespective of their primary fate and motile characteristics by increasing myosin II activity through biochemical or mechanical stimuli. Using a combination of theory and experiments, we show that, in stable-bleb cells, cortical contractility fluctuations trigger a stochastic switch into amoeboid motility, and a positive feedback between cortical flows and gradients in contractility maintains stable-bleb cell polarization. We further show that rearward cortical flows drive stable-bleb cell migration in various adhesive and non-adhesive environments, unraveling a highly versatile amoeboid migration phenotype. AU - Ruprecht, Verena AU - Wieser, Stefan AU - Callan Jones, Andrew AU - Smutny, Michael AU - Morita, Hitoshi AU - Sako, Keisuke AU - Barone, Vanessa AU - Ritsch Marte, Monika AU - Sixt, Michael K AU - Voituriez, Raphaël AU - Heisenberg, Carl-Philipp J ID - 1537 IS - 4 JF - Cell TI - Cortical contractility triggers a stochastic switch to fast amoeboid cell motility VL - 160 ER - TY - JOUR AB - Auxin participates in a multitude of developmental processes, as well as responses to environmental cues. Compared with other plant hormones, auxin exhibits a unique property, as it undergoes directional, cell-to-cell transport facilitated by plasma membrane-localized transport proteins. Among them, a prominent role has been ascribed to the PIN family of auxin efflux facilitators. PIN proteins direct polar auxin transport on account of their asymmetric subcellular localizations. In this review, we provide an overview of the multiple developmental roles of PIN proteins, including the atypical endoplasmic reticulum-localized members of the family, and look at the family from an evolutionary perspective. Next, we cover the cell biological and molecular aspects of PIN function, in particular the establishment of their polar subcellular localization. Hormonal and environmental inputs into the regulation of PIN action are summarized as well. AU - Adamowski, Maciek AU - Friml, Jirí ID - 1591 IS - 1 JF - Plant Cell TI - PIN-dependent auxin transport: Action, regulation, and evolution VL - 27 ER - TY - JOUR AB - We consider real symmetric and complex Hermitian random matrices with the additional symmetry hxy = hN-y,N-x. The matrix elements are independent (up to the fourfold symmetry) and not necessarily identically distributed. This ensemble naturally arises as the Fourier transform of a Gaussian orthogonal ensemble. Italso occurs as the flip matrix model - an approximation of the two-dimensional Anderson model at small disorder. We show that the density of states converges to the Wigner semicircle law despite the new symmetry type. We also prove the local version of the semicircle law on the optimal scale. AU - Alt, Johannes ID - 1677 IS - 10 JF - Journal of Mathematical Physics TI - The local semicircle law for random matrices with a fourfold symmetry VL - 56 ER - TY - JOUR AB - High-throughput live-cell screens are intricate elements of systems biology studies and drug discovery pipelines. Here, we demonstrate an optogenetics-assisted method that avoids the need for chemical activators and reporters, reduces the number of operational steps and increases information content in a cell-based small-molecule screen against human protein kinases, including an orphan receptor tyrosine kinase. This blueprint for all-optical screening can be adapted to many drug targets and cellular processes. AU - Inglés Prieto, Álvaro AU - Gschaider-Reichhart, Eva AU - Muellner, Markus AU - Nowak, Matthias AU - Nijman, Sebastian AU - Grusch, Michael AU - Janovjak, Harald L ID - 1678 IS - 12 JF - Nature Chemical Biology TI - Light-assisted small-molecule screening against protein kinases VL - 11 ER - TY - JOUR AB - Gene expression is controlled primarily by interactions between transcription factor proteins (TFs) and the regulatory DNA sequence, a process that can be captured well by thermodynamic models of regulation. These models, however, neglect regulatory crosstalk: the possibility that noncognate TFs could initiate transcription, with potentially disastrous effects for the cell. Here, we estimate the importance of crosstalk, suggest that its avoidance strongly constrains equilibrium models of TF binding, and propose an alternative nonequilibrium scheme that implements kinetic proofreading to suppress erroneous initiation. This proposal is consistent with the observed covalent modifications of the transcriptional apparatus and predicts increased noise in gene expression as a trade-off for improved specificity. Using information theory, we quantify this trade-off to find when optimal proofreading architectures are favored over their equilibrium counterparts. Such architectures exhibit significant super-Poisson noise at low expression in steady state. AU - Cepeda Humerez, Sarah A AU - Rieckh, Georg AU - Tkacik, Gasper ID - 1576 IS - 24 JF - Physical Review Letters TI - Stochastic proofreading mechanism alleviates crosstalk in transcriptional regulation VL - 115 ER - TY - GEN AB - We study conditions under which a finite simplicial complex $K$ can be mapped to $\mathbb R^d$ without higher-multiplicity intersections. An almost $r$-embedding is a map $f: K\to \mathbb R^d$ such that the images of any $r$ pairwise disjoint simplices of $K$ do not have a common point. We show that if $r$ is not a prime power and $d\geq 2r+1$, then there is a counterexample to the topological Tverberg conjecture, i.e., there is an almost $r$-embedding of the $(d+1)(r-1)$-simplex in $\mathbb R^d$. This improves on previous constructions of counterexamples (for $d\geq 3r$) based on a series of papers by M. \"Ozaydin, M. Gromov, P. Blagojevi\'c, F. Frick, G. Ziegler, and the second and fourth present authors. The counterexamples are obtained by proving the following algebraic criterion in codimension 2: If $r\ge3$ and if $K$ is a finite $2(r-1)$-complex then there exists an almost $r$-embedding $K\to \mathbb R^{2r}$ if and only if there exists a general position PL map $f:K\to \mathbb R^{2r}$ such that the algebraic intersection number of the $f$-images of any $r$ pairwise disjoint simplices of $K$ is zero. This result can be restated in terms of cohomological obstructions or equivariant maps, and extends an analogous codimension 3 criterion by the second and fourth authors. As another application we classify ornaments $f:S^3 \sqcup S^3\sqcup S^3\to \mathbb R^5$ up to ornament concordance. It follows from work of M. Freedman, V. Krushkal and P. Teichner that the analogous criterion for $r=2$ is false. We prove a lemma on singular higher-dimensional Borromean rings, yielding an elementary proof of the counterexample. AU - Avvakumov, Sergey AU - Mabillard, Isaac AU - Skopenkov, A. AU - Wagner, Uli ID - 8183 T2 - arXiv TI - Eliminating higher-multiplicity intersections, III. Codimension 2 ER - TY - GEN AB - We study algorithmic questions for concurrent systems where the transitions are labeled from a complete, closed semiring, and path properties are algebraic with semiring operations. The algebraic path properties can model dataflow analysis problems, the shortest path problem, and many other natural problems that arise in program analysis. We consider that each component of the concurrent system is a graph with constant treewidth, a property satisfied by the controlflow graphs of most programs. We allow for multiple possible queries, which arise naturally in demand driven dataflow analysis. The study of multiple queries allows us to consider the tradeoff between the resource usage of the one-time preprocessing and for each individual query. The traditional approach constructs the product graph of all components and applies the best-known graph algorithm on the product. In this approach, even the answer to a single query requires the transitive closure (i.e., the results of all possible queries), which provides no room for tradeoff between preprocessing and query time. Our main contributions are algorithms that significantly improve the worst-case running time of the traditional approach, and provide various tradeoffs depending on the number of queries. For example, in a concurrent system of two components, the traditional approach requires hexic time in the worst case for answering one query as well as computing the transitive closure, whereas we show that with one-time preprocessing in almost cubic time, each subsequent query can be answered in at most linear time, and even the transitive closure can be computed in almost quartic time. Furthermore, we establish conditional optimality results showing that the worst-case running time of our algorithms cannot be improved without achieving major breakthroughs in graph algorithms (i.e., improving the worst-case bound for the shortest path problem in general graphs). Preliminary experimental results show that our algorithms perform favorably on several benchmarks. AU - Chatterjee, Krishnendu AU - Ibsen-Jensen, Rasmus AU - Goharshady, Amir AU - Pavlogiannis, Andreas ID - 5441 SN - 2664-1690 TI - Algorithms for algebraic path properties in concurrent systems of constant treewidth components ER - TY - GEN AB - We study algorithmic questions for concurrent systems where the transitions are labeled from a complete, closed semiring, and path properties are algebraic with semiring operations. The algebraic path properties can model dataflow analysis problems, the shortest path problem, and many other natural properties that arise in program analysis. We consider that each component of the concurrent system is a graph with constant treewidth, and it is known that the controlflow graphs of most programs have constant treewidth. We allow for multiple possible queries, which arise naturally in demand driven dataflow analysis problems (e.g., alias analysis). The study of multiple queries allows us to consider the tradeoff between the resource usage of the \emph{one-time} preprocessing and for \emph{each individual} query. The traditional approaches construct the product graph of all components and apply the best-known graph algorithm on the product. In the traditional approach, even the answer to a single query requires the transitive closure computation (i.e., the results of all possible queries), which provides no room for tradeoff between preprocessing and query time. Our main contributions are algorithms that significantly improve the worst-case running time of the traditional approach, and provide various tradeoffs depending on the number of queries. For example, in a concurrent system of two components, the traditional approach requires hexic time in the worst case for answering one query as well as computing the transitive closure, whereas we show that with one-time preprocessing in almost cubic time, each subsequent query can be answered in at most linear time, and even the transitive closure can be computed in almost quartic time. Furthermore, we establish conditional optimality results that show that the worst-case running times of our algorithms cannot be improved without achieving major breakthroughs in graph algorithms (such as improving the worst-case bounds for the shortest path problem in general graphs whose current best-known bound has not been improved in five decades). Finally, we provide a prototype implementation of our algorithms which significantly outperforms the existing algorithmic methods on several benchmarks. AU - Anonymous, 1 AU - Anonymous, 2 AU - Anonymous, 3 AU - Anonymous, 4 ID - 5442 SN - 2664-1690 TI - Algorithms for algebraic path properties in concurrent systems of constant treewidth components ER - TY - CONF AB - We consider the problem of computing the set of initial states of a dynamical system such that there exists a control strategy to ensure that the trajectories satisfy a temporal logic specification with probability 1 (almost-surely). We focus on discrete-time, stochastic linear dynamics and specifications given as formulas of the Generalized Reactivity(1) fragment of Linear Temporal Logic over linear predicates in the states of the system. We propose a solution based on iterative abstraction-refinement, and turn-based 2-player probabilistic games. While the theoretical guarantee of our algorithm after any finite number of iterations is only a partial solution, we show that if our algorithm terminates, then the result is the set of satisfying initial states. Moreover, for any (partial) solution our algorithm synthesizes witness control strategies to ensure almost-sure satisfaction of the temporal logic specification. We demonstrate our approach on an illustrative case study. AU - Svoreňová, Mária AU - Kretinsky, Jan AU - Chmelik, Martin AU - Chatterjee, Krishnendu AU - Cěrná, Ivana AU - Belta, Cǎlin ID - 1689 T2 - Proceedings of the 18th International Conference on Hybrid Systems: Computation and Control TI - Temporal logic control for stochastic linear systems using abstraction refinement of probabilistic games ER - TY - CONF AB - We present a computer-aided programming approach to concurrency. The approach allows programmers to program assuming a friendly, non-preemptive scheduler, and our synthesis procedure inserts synchronization to ensure that the final program works even with a preemptive scheduler. The correctness specification is implicit, inferred from the non-preemptive behavior. Let us consider sequences of calls that the program makes to an external interface. The specification requires that any such sequence produced under a preemptive scheduler should be included in the set of such sequences produced under a non-preemptive scheduler. The solution is based on a finitary abstraction, an algorithm for bounded language inclusion modulo an independence relation, and rules for inserting synchronization. We apply the approach to device-driver programming, where the driver threads call the software interface of the device and the API provided by the operating system. Our experiments demonstrate that our synthesis method is precise and efficient, and, since it does not require explicit specifications, is more practical than the conventional approach based on user-provided assertions. AU - Cerny, Pavol AU - Clarke, Edmund AU - Henzinger, Thomas A AU - Radhakrishna, Arjun AU - Ryzhyk, Leonid AU - Samanta, Roopsha AU - Tarrach, Thorsten ID - 1729 TI - From non-preemptive to preemptive scheduling using synchronization synthesis VL - 9207 ER - TY - CONF AB - The behaviour of gene regulatory networks (GRNs) is typically analysed using simulation-based statistical testing-like methods. In this paper, we demonstrate that we can replace this approach by a formal verification-like method that gives higher assurance and scalability. We focus on Wagner’s weighted GRN model with varying weights, which is used in evolutionary biology. In the model, weight parameters represent the gene interaction strength that may change due to genetic mutations. For a property of interest, we synthesise the constraints over the parameter space that represent the set of GRNs satisfying the property. We experimentally show that our parameter synthesis procedure computes the mutational robustness of GRNs –an important problem of interest in evolutionary biology– more efficiently than the classical simulation method. We specify the property in linear temporal logics. We employ symbolic bounded model checking and SMT solving to compute the space of GRNs that satisfy the property, which amounts to synthesizing a set of linear constraints on the weights. AU - Giacobbe, Mirco AU - Guet, Calin C AU - Gupta, Ashutosh AU - Henzinger, Thomas A AU - Paixao, Tiago AU - Petrov, Tatjana ID - 1835 TI - Model checking gene regulatory networks VL - 9035 ER - TY - JOUR AB - The Auxin Binding Protein1 (ABP1) has been identified based on its ability to bind auxin with high affinity and studied for a long time as a prime candidate for the extracellular auxin receptor responsible for mediating in particular the fast non-transcriptional auxin responses. However, the contradiction between the embryo-lethal phenotypes of the originally described Arabidopsis T-DNA insertional knock-out alleles (abp1-1 and abp1-1s) and the wild type-like phenotypes of other recently described loss-of-function alleles (abp1-c1 and abp1-TD1) questions the biological importance of ABP1 and relevance of the previous genetic studies. Here we show that there is no hidden copy of the ABP1 gene in the Arabidopsis genome but the embryo-lethal phenotypes of abp1-1 and abp1-1s alleles are very similar to the knock-out phenotypes of the neighboring gene, BELAYA SMERT (BSM). Furthermore, the allelic complementation test between bsm and abp1 alleles shows that the embryo-lethality in the abp1-1 and abp1-1s alleles is caused by the off-target disruption of the BSM locus by the T-DNA insertions. This clarifies the controversy of different phenotypes among published abp1 knock-out alleles and asks for reflections on the developmental role of ABP1. AU - Michalko, Jaroslav AU - Dravecka, Marta AU - Bollenbach, Tobias AU - Friml, Jirí ID - 1509 JF - F1000 Research TI - Embryo-lethal phenotypes in early abp1 mutants are due to disruption of the neighboring BSM gene VL - 4 ER - TY - JOUR AB - In many social situations, individuals endeavor to find the single best possible partner, but are constrained to evaluate the candidates in sequence. Examples include the search for mates, economic partnerships, or any other long-term ties where the choice to interact involves two parties. Surprisingly, however, previous theoretical work on mutual choice problems focuses on finding equilibrium solutions, while ignoring the evolutionary dynamics of decisions. Empirically, this may be of high importance, as some equilibrium solutions can never be reached unless the population undergoes radical changes and a sufficient number of individuals change their decisions simultaneously. To address this question, we apply a mutual choice sequential search problem in an evolutionary game-theoretical model that allows one to find solutions that are favored by evolution. As an example, we study the influence of sequential search on the evolutionary dynamics of cooperation. For this, we focus on the classic snowdrift game and the prisoner’s dilemma game. AU - Priklopil, Tadeas AU - Chatterjee, Krishnendu ID - 1681 IS - 4 JF - Games TI - Evolution of decisions in population games with sequentially searching individuals VL - 6 ER - TY - JOUR AB - Quantifying behaviors of robots which were generated autonomously from task-independent objective functions is an important prerequisite for objective comparisons of algorithms and movements of animals. The temporal sequence of such a behavior can be considered as a time series and hence complexity measures developed for time series are natural candidates for its quantification. The predictive information and the excess entropy are such complexity measures. They measure the amount of information the past contains about the future and thus quantify the nonrandom structure in the temporal sequence. However, when using these measures for systems with continuous states one has to deal with the fact that their values will depend on the resolution with which the systems states are observed. For deterministic systems both measures will diverge with increasing resolution. We therefore propose a new decomposition of the excess entropy in resolution dependent and resolution independent parts and discuss how they depend on the dimensionality of the dynamics, correlations and the noise level. For the practical estimation we propose to use estimates based on the correlation integral instead of the direct estimation of the mutual information based on next neighbor statistics because the latter allows less control of the scale dependencies. Using our algorithm we are able to show how autonomous learning generates behavior of increasing complexity with increasing learning duration. AU - Martius, Georg S AU - Olbrich, Eckehard ID - 1655 IS - 10 JF - Entropy TI - Quantifying emergent behavior of autonomous robots VL - 17 ER - TY - JOUR AB - Huge body of evidences demonstrated that volatile anesthetics affect the hippocampal neurogenesis and neurocognitive functions, and most of them showed impairment at anesthetic dose. Here, we investigated the effect of low dose (1.8%) sevoflurane on hippocampal neurogenesis and dentate gyrus-dependent learning. Neonatal rats at postnatal day 4 to 6 (P4-6) were treated with 1.8% sevoflurane for 6 hours. Neurogenesis was quantified by bromodeoxyuridine labeling and electrophysiology recording. Four and seven weeks after treatment, the Morris water maze and contextual-fear discrimination learning tests were performed to determine the influence on spatial learning and pattern separation. A 6-hour treatment with 1.8% sevoflurane promoted hippocampal neurogenesis and increased the survival of newborn cells and the proportion of immature granular cells in the dentate gyrus of neonatal rats. Sevoflurane-treated rats performed better during the training days of the Morris water maze test and in contextual-fear discrimination learning test. These results suggest that a subanesthetic dose of sevoflurane promotes hippocampal neurogenesis in neonatal rats and facilitates their performance in dentate gyrus-dependent learning tasks. AU - Chen, Chong AU - Wang, Chao AU - Zhao, Xuan AU - Zhou, Tao AU - Xu, Dao AU - Wang, Zhi AU - Wang, Ying ID - 1834 IS - 2 JF - ASN Neuro TI - Low-dose sevoflurane promoteshippocampal neurogenesis and facilitates the development of dentate gyrus-dependent learning in neonatal rats VL - 7 ER - TY - JOUR AB - We calculate a Ricci curvature lower bound for some classical examples of random walks, namely, a chain on a slice of the n-dimensional discrete cube (the so-called Bernoulli-Laplace model) and the random transposition shuffle of the symmetric group of permutations on n letters. AU - Erbar, Matthias AU - Maas, Jan AU - Tetali, Prasad ID - 1635 IS - 4 JF - Annales de la faculté des sciences de Toulouse TI - Discrete Ricci curvature bounds for Bernoulli-Laplace and random transposition models VL - 24 ER - TY - JOUR AB - Scaffolded DNA origami enables the fabrication of a variety of complex nanostructures that promise utility in diverse fields of application, ranging from biosensing over advanced therapeutics to metamaterials. The broad applicability of DNA origami as a material beyond the level of proof-of-concept studies critically depends, among other factors, on the availability of large amounts of pure single-stranded scaffold DNA. Here, we present a method for the efficient production of M13 bacteriophage-derived genomic DNA using high-cell-density fermentation of Escherichia coli in stirred-tank bioreactors. We achieve phage titers of up to 1.6 × 1014 plaque-forming units per mL. Downstream processing yields up to 410 mg of high-quality single-stranded DNA per one liter reaction volume, thus upgrading DNA origami-based nanotechnology from the milligram to the gram scale. AU - Kick, B AU - Praetorius, Florian M AU - Dietz, H AU - Weuster-Botz, D ID - 14303 IS - 7 JF - Nano Letters SN - 1530-6984 TI - Efficient production of single-stranded phage DNA as scaffolds for DNA origami VL - 15 ER - TY - CONF AB - For deterministic systems, a counterexample to a property can simply be an error trace, whereas counterexamples in probabilistic systems are necessarily more complex. For instance, a set of erroneous traces with a sufficient cumulative probability mass can be used. Since these are too large objects to understand and manipulate, compact representations such as subchains have been considered. In the case of probabilistic systems with non-determinism, the situation is even more complex. While a subchain for a given strategy (or scheduler, resolving non-determinism) is a straightforward choice, we take a different approach. Instead, we focus on the strategy itself, and extract the most important decisions it makes, and present its succinct representation. The key tools we employ to achieve this are (1) introducing a concept of importance of a state w.r.t. the strategy, and (2) learning using decision trees. There are three main consequent advantages of our approach. Firstly, it exploits the quantitative information on states, stressing the more important decisions. Secondly, it leads to a greater variability and degree of freedom in representing the strategies. Thirdly, the representation uses a self-explanatory data structure. In summary, our approach produces more succinct and more explainable strategies, as opposed to e.g. binary decision diagrams. Finally, our experimental results show that we can extract several rules describing the strategy even for very large systems that do not fit in memory, and based on the rules explain the erroneous behaviour. AU - Brázdil, Tomáš AU - Chatterjee, Krishnendu AU - Chmelik, Martin AU - Fellner, Andreas AU - Kretinsky, Jan ID - 1603 TI - Counterexample explanation by learning small strategies in Markov decision processes VL - 9206 ER - TY - DATA AB - This repository contains the experimental part of the CAV 2015 publication Counterexample Explanation by Learning Small Strategies in Markov Decision Processes. We extended the probabilistic model checker PRISM to represent strategies of Markov Decision Processes as Decision Trees. The archive contains a java executable version of the extended tool (prism_dectree.jar) together with a few examples of the PRISM benchmark library. To execute the program, please have a look at the README.txt, which provides instructions and further information on the archive. The archive contains scripts that (if run often enough) reproduces the data presented in the publication. AU - Fellner, Andreas ID - 5549 KW - Markov Decision Process KW - Decision Tree KW - Probabilistic Verification KW - Counterexample Explanation TI - Experimental part of CAV 2015 publication: Counterexample Explanation by Learning Small Strategies in Markov Decision Processes ER - TY - CONF AB - We show that very weak topological assumptions are enough to ensure the existence of a Helly-type theorem. More precisely, we show that for any non-negative integers b and d there exists an integer h(b,d) such that the following holds. If F is a finite family of subsets of R^d such that the ith reduced Betti number (with Z_2 coefficients in singular homology) of the intersection of any proper subfamily G of F is at most b for every non-negative integer i less or equal to (d-1)/2, then F has Helly number at most h(b,d). These topological conditions are sharp: not controlling any of these first Betti numbers allow for families with unbounded Helly number. Our proofs combine homological non-embeddability results with a Ramsey-based approach to build, given an arbitrary simplicial complex K, some well-behaved chain map from C_*(K) to C_*(R^d). Both techniques are of independent interest. AU - Goaoc, Xavier AU - Paták, Pavel AU - Patakova, Zuzana AU - Tancer, Martin AU - Wagner, Uli ID - 1512 TI - Bounding Helly numbers via Betti numbers VL - 34 ER - TY - JOUR AB - We show that a non-singular integral form of degree d is soluble non-trivially over the integers if and only if it is soluble non-trivially over the reals and the p-adic numbers, provided that the form has at least (d-\sqrt{d}/2)2^d variables. This improves on a longstanding result of Birch. AU - Browning, Timothy D AU - Prendiville, Sean ID - 271 IS - 731 JF - Journal fur die Reine und Angewandte Mathematik SN - 0075-4102 TI - Improvements in Birch's theorem on forms in many variables VL - 2017 ER - TY - CONF AB - Proofs of work (PoW) have been suggested by Dwork and Naor (Crypto’92) as protection to a shared resource. The basic idea is to ask the service requestor to dedicate some non-trivial amount of computational work to every request. The original applications included prevention of spam and protection against denial of service attacks. More recently, PoWs have been used to prevent double spending in the Bitcoin digital currency system. In this work, we put forward an alternative concept for PoWs - so-called proofs of space (PoS), where a service requestor must dedicate a significant amount of disk space as opposed to computation. We construct secure PoS schemes in the random oracle model (with one additional mild assumption required for the proof to go through), using graphs with high “pebbling complexity” and Merkle hash-trees. We discuss some applications, including follow-up work where a decentralized digital currency scheme called Spacecoin is constructed that uses PoS (instead of wasteful PoW like in Bitcoin) to prevent double spending. The main technical contribution of this work is the construction of (directed, loop-free) graphs on N vertices with in-degree O(log logN) such that even if one places Θ(N) pebbles on the nodes of the graph, there’s a constant fraction of nodes that needs Θ(N) steps to be pebbled (where in every step one can put a pebble on a node if all its parents have a pebble). AU - Dziembowski, Stefan AU - Faust, Sebastian AU - Kolmogorov, Vladimir AU - Pietrzak, Krzysztof Z ID - 1675 SN - 0302-9743 T2 - 35th Annual Cryptology Conference TI - Proofs of space VL - 9216 ER - TY - JOUR AB - The circadian clock orchestrates global changes in transcriptional regulation on a daily basis via the bHLH-PAS transcription factor CLOCK:BMAL1. Pathways driven by other bHLH-PAS transcription factors have a homologous repressor that modulates activity on a tissue-specific basis, but none have been identified for CLOCK:BMAL1. We show here that the cancer/testis antigen PASD1 fulfills this role to suppress circadian rhythms. PASD1 is evolutionarily related to CLOCK and interacts with the CLOCK:BMAL1 complex to repress transcriptional activation. Expression of PASD1 is restricted to germline tissues in healthy individuals but can be induced in cells of somatic origin upon oncogenic transformation. Reducing PASD1 in human cancer cells significantly increases the amplitude of transcriptional oscillations to generate more robust circadian rhythms. Our results describe a function for a germline-specific protein in regulation of the circadian clock and provide a molecular link from oncogenic transformation to suppression of circadian rhythms. AU - Michael, Alicia Kathleen AU - Harvey, Stacy L. AU - Sammons, Patrick J. AU - Anderson, Amanda P. AU - Kopalle, Hema M. AU - Banham, Alison H. AU - Partch, Carrie L. ID - 15160 IS - 5 JF - Molecular Cell KW - Cell Biology KW - Molecular Biology SN - 1097-2765 TI - Cancer/Testis antigen PASD1 silences the circadian clock VL - 58 ER - TY - JOUR AB - It is widely recognized that BMAL1 is an essential subunit of the primary transcription factor that drives rhythmic circadian transcription in the nucleus. In a surprising turn, Lipton et al. now show that BMAL1 rhythmically interacts with translational machinery in the cytosol to stimulate protein synthesis in response to mTOR signaling. AU - Michael, Alicia Kathleen AU - Asimgil, Hande AU - Partch, Carrie L. ID - 15159 IS - 9 JF - Trends in Biochemical Sciences KW - Molecular Biology KW - Biochemistry SN - 0968-0004 TI - Cytosolic BMAL1 moonlights as a translation factor VL - 40 ER - TY - JOUR AB - The emergence of drug resistant pathogens is a serious public health problem. It is a long-standing goal to predict rates of resistance evolution and design optimal treatment strategies accordingly. To this end, it is crucial to reveal the underlying causes of drug-specific differences in the evolutionary dynamics leading to resistance. However, it remains largely unknown why the rates of resistance evolution via spontaneous mutations and the diversity of mutational paths vary substantially between drugs. Here we comprehensively quantify the distribution of fitness effects (DFE) of mutations, a key determinant of evolutionary dynamics, in the presence of eight antibiotics representing the main modes of action. Using precise high-throughput fitness measurements for genome-wide Escherichia coli gene deletion strains, we find that the width of the DFE varies dramatically between antibiotics and, contrary to conventional wisdom, for some drugs the DFE width is lower than in the absence of stress. We show that this previously underappreciated divergence in DFE width among antibiotics is largely caused by their distinct drug-specific dose-response characteristics. Unlike the DFE, the magnitude of the changes in tolerated drug concentration resulting from genome-wide mutations is similar for most drugs but exceptionally small for the antibiotic nitrofurantoin, i.e., mutations generally have considerably smaller resistance effects for nitrofurantoin than for other drugs. A population genetics model predicts that resistance evolution for drugs with this property is severely limited and confined to reproducible mutational paths. We tested this prediction in laboratory evolution experiments using the “morbidostat”, a device for evolving bacteria in well-controlled drug environments. Nitrofurantoin resistance indeed evolved extremely slowly via reproducible mutations—an almost paradoxical behavior since this drug causes DNA damage and increases the mutation rate. Overall, we identified novel quantitative characteristics of the evolutionary landscape that provide the conceptual foundation for predicting the dynamics of drug resistance evolution. AU - Chevereau, Guillaume AU - Dravecka, Marta AU - Batur, Tugce AU - Guvenek, Aysegul AU - Ayhan, Dilay AU - Toprak, Erdal AU - Bollenbach, Mark Tobias ID - 1619 IS - 11 JF - PLoS Biology TI - Quantifying the determinants of evolutionary dynamics leading to drug resistance VL - 13 ER - TY - JOUR AB - Protein oligomers have been implicated as toxic agents in a wide range of amyloid-related diseases. However, it has remained unsolved whether the oligomers are a necessary step in the formation of amyloid fibrils or just a dangerous byproduct. Analogously, it has not been resolved if the amyloid nucleation process is a classical one-step nucleation process or a two-step process involving prenucleation clusters. We use coarse-grained computer simulations to study the effect of nonspecific attractions between peptides on the primary nucleation process underlying amyloid fibrillization. We find that, for peptides that do not attract, the classical one-step nucleation mechanism is possible but only at nonphysiologically high peptide concentrations. At low peptide concentrations, which mimic the physiologically relevant regime, attractive interpeptide interactions are essential for fibril formation. Nucleation then inevitably takes place through a two-step mechanism involving prefibrillar oligomers. We show that oligomers not only help peptides meet each other but also, create an environment that facilitates the conversion of monomers into the β-sheet–rich form characteristic of fibrils. Nucleation typically does not proceed through the most prevalent oligomers but through an oligomer size that is only observed in rare fluctuations, which is why such aggregates might be hard to capture experimentally. Finally, we find that the nucleation of amyloid fibrils cannot be described by classical nucleation theory: in the two-step mechanism, the critical nucleus size increases with increases in both concentration and interpeptide interactions, which is in direct contrast with predictions from classical nucleation theory. AU - Šarić, Anđela AU - Chebaro, Yassmine C. AU - Knowles, Tuomas P. J. AU - Frenkel, Daan ID - 10382 IS - 50 JF - Proceedings of the National Academy of Sciences KW - multidisciplinary SN - 0027-8424 TI - Crucial role of nonspecific interactions in amyloid nucleation VL - 111 ER - TY - JOUR AB - We use numerical simulations to compute the equation of state of a suspension of spherical self-propelled nanoparticles in two and three dimensions. We study in detail the effect of excluded volume interactions and confinement as a function of the system's temperature, concentration, and strength of the propulsion. We find a striking nonmonotonic dependence of the pressure on the temperature and provide simple scaling arguments to predict and explain the occurrence of such anomalous behavior. We explicitly show how our results have important implications for the effective forces on passive components suspended in a bath of active particles. AU - Mallory, S. A. AU - Šarić, Anđela AU - Valeriani, C. AU - Cacciuto, A. ID - 10383 IS - 5 JF - Physical Review E SN - 1539-3755 TI - Anomalous thermomechanical properties of a self-propelled colloidal fluid VL - 89 ER - TY - JOUR AB - Diffraction-unlimited far-field super-resolution fluorescence (nanoscopy) methods typically rely on transiently transferring fluorophores between two states, whereby this transfer is usually laid out as a switch. However, depending on whether this is induced in a spatially controlled manner using a pattern of light (coordinate-targeted) or stochastically on a single-molecule basis, specific requirements on the fluorophores are imposed. Therefore, the fluorophores are usually utilized just for one class of methods only. In this study we demonstrate that the reversibly switchable fluorescent protein Dreiklang enables live-cell recordings in both spatially controlled and stochastic modes. We show that the Dreiklang chromophore entails three different light-induced switching mechanisms, namely a reversible photochemical one, off-switching by stimulated emission, and a reversible transfer to a long-lived dark state from the S1 state, all of which can be utilized to overcome the diffraction barrier. We also find that for the single-molecule- based stochastic GSDIM approach (ground-state depletion followed by individual molecule return), Dreiklang provides a larger number of on-off localization events as compared to its progenitor Citrine. Altogether, Dreiklang is a versatile probe for essentially all popular forms of live-cell fluorescence nanoscopy. AU - Jensen, Nickels AU - Danzl, Johann G AU - Willig, Katrin AU - Lavoie Cardinal, Flavie AU - Brakemann, Tanja AU - Hell, Stefan AU - Jakobs, Stefan ID - 1058 IS - 4 JF - ChemPhysChem TI - Coordinate-targeted and coordinate-stochastic super-resolution microscopy with the reversibly switchable fluorescent protein dreiklang VL - 15 ER - TY - JOUR AB - In the last several decades, developmental biology has clarified the molecular mechanisms of embryogenesis and organogenesis. In particular, it has demonstrated that the “tool-kit genes” essential for regulating developmental processes are not only highly conserved among species, but are also used as systems at various times and places in an organism to control distinct developmental events. Therefore, mutations in many of these tool-kit genes may cause congenital diseases involving morphological abnormalities. This link between genes and abnormal morphological phenotypes underscores the importance of understanding how cells behave and contribute to morphogenesis as a result of gene function. Recent improvements in live imaging and in quantitative analyses of cellular dynamics will advance our understanding of the cellular pathogenesis of congenital diseases associated with aberrant morphologies. In these studies, it is critical to select an appropriate model organism for the particular phenomenon of interest. AU - Hashimoto, Masakazu AU - Morita, Hitoshi AU - Ueno, Naoto ID - 10815 IS - 1 JF - Congenital Anomalies KW - Developmental Biology KW - Embryology KW - General Medicine KW - Pediatrics KW - Perinatology KW - and Child Health SN - 0914-3505 TI - Molecular and cellular mechanisms of development underlying congenital diseases VL - 54 ER - TY - BOOK AB - Auxin is an important signaling compound in plants and vital for plant development and growth. The present book, Auxin and its Role in Plant Development, provides the reader with detailed and comprehensive insight into the functioning of the molecule on the whole and specifically in plant development. In the first part, the functioning, metabolism and signaling pathways of auxin in plants are explained, the second part depicts the specific role of auxin in plant development and the third part describes the interaction and functioning of the signaling compound upon stimuli of the environment. Each chapter is written by international experts in the respective field and designed for scientists and researchers in plant biology, plant development and cell biology to summarize the recent progress in understanding the role of auxin and suggest future perspectives for auxin research. ED - Zažímalová, Eva ED - Petrášek, Jan ED - Benková, Eva ID - 10811 SN - 9783709115251 TI - Auxin and Its Role in Plant Development ER - TY - CONF AB - We revisit the parameterized model checking problem for token-passing systems and specifications in indexed CTL  ∗ \X. Emerson and Namjoshi (1995, 2003) have shown that parameterized model checking of indexed CTL  ∗ \X in uni-directional token rings can be reduced to checking rings up to some cutoff size. Clarke et al. (2004) have shown a similar result for general topologies and indexed LTL \X, provided processes cannot choose the directions for sending or receiving the token. We unify and substantially extend these results by systematically exploring fragments of indexed CTL  ∗ \X with respect to general topologies. For each fragment we establish whether a cutoff exists, and for some concrete topologies, such as rings, cliques and stars, we infer small cutoffs. Finally, we show that the problem becomes undecidable, and thus no cutoffs exist, if processes are allowed to choose the directions in which they send or from which they receive the token. AU - Aminof, Benjamin AU - Jacobs, Swen AU - Khalimov, Ayrat AU - Rubin, Sasha ID - 10884 SN - 0302-9743 T2 - Verification, Model Checking, and Abstract Interpretation TI - Parameterized model checking of token-passing systems VL - 8318 ER - TY - CHAP AB - Saddle periodic orbits are an essential and stable part of the topological skeleton of a 3D vector field. Nevertheless, there is currently no efficient algorithm to robustly extract these features. In this chapter, we present a novel technique to extract saddle periodic orbits. Exploiting the analytic properties of such an orbit, we propose a scalar measure based on the finite-time Lyapunov exponent (FTLE) that indicates its presence. Using persistent homology, we can then extract the robust cycles of this field. These cycles thereby represent the saddle periodic orbits of the given vector field. We discuss the different existing FTLE approximation schemes regarding their applicability to this specific problem and propose an adapted version of FTLE called Normalized Velocity Separation. Finally, we evaluate our method using simple analytic vector field data. AU - Kasten, Jens AU - Reininghaus, Jan AU - Reich, Wieland AU - Scheuermann, Gerik ED - Bremer, Peer-Timo ED - Hotz, Ingrid ED - Pascucci, Valerio ED - Peikert, Ronald ID - 10893 SN - 1612-3786 T2 - Topological Methods in Data Analysis and Visualization III TI - Toward the extraction of saddle periodic orbits VL - 1 ER - TY - JOUR AB - The spindle assembly checkpoint prevents separation of sister chromatids until each kinetochore is attached to the mitotic spindle. Rodriguez-Bravo et al. report that the nuclear pore complex scaffolds spindle assembly checkpoint signaling in interphase, providing a store of inhibitory signals that limits the speed of the subsequent mitosis. AU - Buchwalter, Abigail AU - HETZER, Martin W ID - 11080 IS - 5 JF - Cell KW - General Biochemistry KW - Genetics and Molecular Biology SN - 0092-8674 TI - Nuclear pores set the speed limit for mitosis VL - 156 ER - TY - JOUR AB - The nuclear pore complex (NPC) plays a critical role in gene expression by mediating import of transcription regulators into the nucleus and export of RNA transcripts to the cytoplasm. Emerging evidence suggests that in addition to mediating transport, a subset of nucleoporins (Nups) engage in transcriptional activation and elongation at genomic loci that are not associated with NPCs. The underlying mechanism and regulation of Nup mobility on and off nuclear pores remain unclear. Here we show that Nup50 is a mobile Nup with a pronounced presence both at the NPC and in the nucleoplasm that can move between these different localizations. Strikingly, the dynamic behavior of Nup50 in both locations is dependent on active transcription by RNA polymerase II and requires the N-terminal half of the protein, which contains importin α– and Nup153-binding domains. However, Nup50 dynamics are independent of importin α, Nup153, and Nup98, even though the latter two proteins also exhibit transcription-dependent mobility. Of interest, depletion of Nup50 from C2C12 myoblasts does not affect cell proliferation but inhibits differentiation into myotubes. Taken together, our results suggest a transport-independent role for Nup50 in chromatin biology that occurs away from the NPC. AU - Buchwalter, Abigail L. AU - Liang, Yun AU - HETZER, Martin W ID - 11082 IS - 16 JF - Molecular Biology of the Cell KW - Cell Biology KW - Molecular Biology SN - 1059-1524 TI - Nup50 is required for cell differentiation and exhibits transcription-dependent dynamics VL - 25 ER - TY - JOUR AB - In eukaryotic cells the nuclear genome is enclosed by the nuclear envelope (NE). In metazoans, the NE breaks down in mitosis and it has been assumed that the physical barrier separating nucleoplasm and cytoplasm remains intact during the rest of the cell cycle and cell differentiation. However, recent studies suggest that nonmitotic NE remodeling plays a critical role in development, virus infection, laminopathies, and cancer. Although the mechanisms underlying these NE restructuring events are currently being defined, one common theme is activation of protein kinase C family members in the interphase nucleus to disrupt the nuclear lamina, demonstrating the importance of the lamina in maintaining nuclear integrity. AU - Hatch, Emily AU - HETZER, Martin W ID - 11081 IS - 2 JF - Journal of Cell Biology KW - Cell Biology SN - 1540-8140 TI - Breaching the nuclear envelope in development and disease VL - 205 ER - TY - JOUR AB - Candidate galaxies at redshifts of z ∼ 10 are now being found in extremely deep surveys, probing very small areas. As a consequence, candidates are very faint, making spectroscopic confirmation practically impossible. In order to overcome such limitations, we have undertaken the CF-HiZELS survey, which is a large-area, medium-depth near-infrared narrow-band survey targeted at z = 8.8 Lyman α (Lyα) emitters (LAEs) and covering 10 deg2 in part of the SSA22 field with the Canada–France–Hawaii Telescope (CFHT). We surveyed a comoving volume of 4.7 × 106 Mpc3 to a Lyα luminosity limit of 6.3 × 1043舁erg舁s−1. We look for Lyα candidates by applying the following criteria: (i) clear emission-line source, (ii) no optical detections (ugriz from CFHTLS), (iii) no visible detection in the optical stack (ugriz > 27), (iv) visually checked reliable NBJ and J detections and (v) J − K ≤ 0. We compute photometric redshifts and remove a significant amount of dusty lower redshift line-emitters at z ∼ 1.4 or 2.2. A total of 13 Lyα candidates were found, of which two are marked as strong candidates, but the majority have very weak constraints on their spectral energy distributions. Using follow-up observations with SINFONI/VLT, we are able to exclude the most robust candidates as LAEs. We put a strong constraint on the Lyα luminosity function at z ∼ 9 and make realistic predictions for ongoing and future surveys. Our results show that surveys for the highest redshift LAEs are susceptible of multiple contaminations and that spectroscopic follow-up is absolutely necessary. AU - Matthee, Jorryt J AU - Sobral, David AU - Swinbank, A. M. AU - Smail, Ian AU - Best, P. N. AU - Kim, Jae-Woo AU - Franx, Marijn AU - Milvang-Jensen, Bo AU - Fynbo, Johan ID - 11583 IS - 3 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - galaxies: evolution KW - galaxies: high-redshift KW - cosmology: observations KW - dark ages KW - reionization KW - first stars SN - 0035-8711 TI - A 10 deg2 Lyman α survey at z=8.8 with spectroscopic follow-up: Strong constraints on the luminosity function and implications for other surveys VL - 440 ER - TY - JOUR AB - We have observed a sample of typical z ∼ 1 star-forming galaxies, selected from the HiZELS survey, with the new K-band Multi-Object Spectrograph (KMOS) near-infrared, multi-integral field unit instrument on the Very Large Telescope (VLT), in order to obtain their dynamics and metallicity gradients. The majority of our galaxies have a metallicity gradient consistent with being flat or negative (i.e. higher metallicity cores than outskirts). Intriguingly, we find a trend between metallicity gradient and specific star formation rate (sSFR), such that galaxies with a high sSFR tend to have relatively metal poor centres, a result which is strengthened when combined with data sets from the literature. This result appears to explain the discrepancies reported between different high-redshift studies and varying claims for evolution. From a galaxy evolution perspective, the trend we see would mean that a galaxy's sSFR is governed by the amount of metal-poor gas that can be funnelled into its core, triggered either by merging or through efficient accretion. In fact, merging may play a significant role as it is the starburst galaxies at all epochs, which have the more positive metallicity gradients. Our results may help to explain the origin of the fundamental metallicity relation, in which galaxies at a fixed mass are observed to have lower metallicities at higher star formation rates, especially if the metallicity is measured in an aperture encompassing only the central regions of the galaxy. Finally, we note that this study demonstrates the power of KMOS as an efficient instrument for large-scale resolved galaxy surveys. AU - Stott, John P. AU - Sobral, David AU - Swinbank, A. M. AU - Smail, Ian AU - Bower, Richard AU - Best, Philip N. AU - Sharples, Ray M. AU - Geach, James E. AU - Matthee, Jorryt J ID - 11582 IS - 3 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - galaxies: abundances KW - galaxies: evolution KW - galaxies: kinematics and dynamics SN - 0035-8711 TI - A relationship between specific star formation rate and metallicity gradient within z ∼ 1 galaxies from KMOS-HiZELS VL - 443 ER - TY - JOUR AB - We report on the magnetic properties of a hot-pressed FeSb 2 sample. We find a significant increase in the magnetic susceptibility in our sample when compared with the values previously reported for the polycrystalline sample. The pronounced Curie tail at low temperature corresponds to 0.2% of Fe 2+ impurities per mole. In the intrinsic conductivity region, the susceptibility due to free carriers shows thermally activated behavior and is consistent with the data reported for single crystal FeSb 2 . Based on our data and analysis, while the enhanced magnetic susceptibility in our sample comes mainly from a small amount of unreacted Fe, the contribution from the enhanced carrier density due to lattice and strain defects arising from the ball milling process is also significant. Existence of an unreacted Fe phase is evidenced by small coercivity values of ~100 observed at 50 and 300 K. AU - Pokharel, Mani AU - Zhao, Huaizhou AU - Modic, Kimberly A AU - Ren, Zhifeng AU - Opeil, Cyril ID - 11750 IS - 5 JF - IEEE Transactions on Magnetics SN - 0018-9464 TI - Magnetic properties of hot-pressed FeSb2 VL - 50 ER - TY - CONF AB - We study a weighted online bipartite matching problem: G(V 1, V 2, E) is a weighted bipartite graph where V 1 is known beforehand and the vertices of V 2 arrive online. The goal is to match vertices of V 2 as they arrive to vertices in V 1, so as to maximize the sum of weights of edges in the matching. If assignments to V 1 cannot be changed, no bounded competitive ratio is achievable. We study the weighted online matching problem with free disposal, where vertices in V 1 can be assigned multiple times, but only get credit for the maximum weight edge assigned to them over the course of the algorithm. For this problem, the greedy algorithm is 0.5-competitive and determining whether a better competitive ratio is achievable is a well known open problem. We identify an interesting special case where the edge weights are decomposable as the product of two factors, one corresponding to each end point of the edge. This is analogous to the well studied related machines model in the scheduling literature, although the objective functions are different. For this case of decomposable edge weights, we design a 0.5664 competitive randomized algorithm in complete bipartite graphs. We show that such instances with decomposable weights are non-trivial by establishing upper bounds of 0.618 for deterministic and 0.8 for randomized algorithms. A tight competitive ratio of 1 − 1/e ≈ 0.632 was known previously for both the 0-1 case as well as the case where edge weights depend on the offline vertices only, but for these cases, reassignments cannot change the quality of the solution. Beating 0.5 for weighted matching where reassignments are necessary has been a significant challenge. We thus give the first online algorithm with competitive ratio strictly better than 0.5 for a non-trivial case of weighted matching with free disposal. AU - Charikar, Moses AU - Henzinger, Monika H AU - Nguyễn, Huy L. ID - 11789 SN - 0302-9743 T2 - 22nd Annual European Symposium on Algorithms TI - Online bipartite matching with decomposable weights VL - 8737 ER - TY - CONF AB - Assume a seller wants to sell a digital product in a social network where a buyer’s valuation of the item has positive network externalities from her neighbors that already have the item. The goal of the seller is to maximize his revenue. Previous work on this problem [7] studies the case where clients are offered the item in sequence and have to pay personalized prices. This is highly infeasible in large scale networks such as the Facebook graph: (1) Offering items to the clients one after the other consumes a large amount of time, and (2) price-discrimination of clients could appear unfair to them and result in negative client reaction or could conflict with legal requirements. We study a setting dealing with these issues. Specifically, the item is offered in parallel to multiple clients at the same time and at the same price. This is called a round. We show that with O(logn) rounds, where n is the number of clients, a constant factor of the revenue with price discrimination can be achieved and that this is not possible with o(logn) rounds. Moreover we show that it is APX-hard to maximize the revenue and we give constant factor approximation algorithms for various further settings of limited price discrimination. AU - Cigler, Luděk AU - Dvořák, Wolfgang AU - Henzinger, Monika H AU - Starnberger, Martin ID - 11790 SN - 0302-9743 T2 - 10th International Conference of Web and Internet Economics TI - Limiting price discrimination when selling products with positive network externalities VL - 8877 ER - TY - JOUR AB - While the penetration of objects into granular media is well-studied, there is little understanding of how objects settle in gravities, geff, different from that of Earth - a scenario potentially relevant to the geomorphology of planets and asteroids and also to their exploration using man-made devices. By conducting experiments in an accelerating frame, we explore geff ranging from 0.4 g to 1.2 g. Surprisingly, we find that the rest depth is independent of geff and also that the time required for the object to come to rest scales like geff-1/2. With discrete element modeling simulations, we reproduce the experimental results and extend the range of geff to objects as small as asteroids and as large as Jupiter. Our results shed light on the initial stage of sedimentation into dry granular media across a range of celestial bodies and also have implications for the design of man-made, extraterrestrial vehicles and structures. Key Points The settling depth in granular media is independent of gravity The settling time scales like g-1/2 Layering driven by granular sedimentation should be similar. AU - Altshuler, Ernesto AU - Torres, H AU - González_Pita, A AU - Sánchez, Colina G AU - Pérez Penichet, Carlos AU - Waitukaitis, Scott R AU - Hidalgo, Rauól ID - 118 IS - 9 JF - Geophysical Research Letters TI - Settling into dry granular media in different gravities VL - 41 ER - TY - CONF AB - The decremental single-source shortest paths (SSSP) problem concerns maintaining the distances between a given source node s to every node in an n-node m-edge graph G undergoing edge deletions. While its static counterpart can be easily solved in near-linear time, this decremental problem is much more challenging even in the undirected unweighted case. In this case, the classic O(mn) total update time of Even and Shiloach (JACM 1981) has been the fastest known algorithm for three decades. With the loss of a (1 + ε)-approximation factor, the running time was recently improved to O(n 2+o(1) ) by Bernstein and Roditty (SODA 2011), and more recently to O(n 1.8+o(1) + m 1+o(1) ) by Henzinger, Krinninger, and Nanongkai (SODA 2014). In this paper, we finally bring the running time of this case down to near-linear: We give a (1 + ε)-approximation algorithm with O(m 1+o(1) ) total update time, thus obtaining near-linear time. Moreover, we obtain O(m 1+o(1) log W) time for the weighted case, where the edge weights are integers from 1 to W. The only prior work on weighted graphs in o(mn log W) time is the O(mn 0.986 log W)-time algorithm by Henzinger, Krinninger, and Nanongkai (STOC 2014) which works for the general weighted directed case. In contrast to the previous results which rely on maintaining a sparse emulator, our algorithm relies on maintaining a so-called sparse (d, ε)-hop set introduced by Cohen (JACM 2000) in the PRAM literature. A (d, ε)-hop set of a graph G = (V, E) is a set E' of weighted edges such that the distance between any pair of nodes in G can be (1 + ε)-approximated by their d-hop distance (given by a path containing at most d edges) on G'=(V, E∪E'). Our algorithm can maintain an (n o(1) , ε)-hop set of near-linear size in near-linear time under edge deletions. It is the first of its kind to the best of our knowledge. To maintain the distances on this hop set, we develop a monotone bounded-hop Even-Shiloach tree. It results from extending and combining the monotone Even-Shiloach tree of Henzinger, Krinninger, and Nanongkai (FOCS 2013) with the bounded-hop SSSP technique of Bernstein (STOC 2013). These two new tools might be of independent interest. AU - Henzinger, Monika H AU - Krinninger, Sebastian AU - Nanongkai, Danupon ID - 11855 SN - 0272-5428 T2 - 55th Annual Symposium on Foundations of Computer Science TI - Decremental single-source shortest paths on undirected graphs in near-linear total update time ER -