TY - JOUR AB - Combining antibiotics is a promising strategy for increasing treatment efficacy and for controlling resistance evolution. When drugs are combined, their effects on cells may be amplified or weakened, that is the drugs may show synergistic or antagonistic interactions. Recent work revealed the underlying mechanisms of such drug interactions by elucidating the drugs'; joint effects on cell physiology. Moreover, new treatment strategies that use drug combinations to exploit evolutionary tradeoffs were shown to affect the rate of resistance evolution in predictable ways. High throughput studies have further identified drug candidates based on their interactions with established antibiotics and general principles that enable the prediction of drug interactions were suggested. Overall, the conceptual and technical foundation for the rational design of potent drug combinations is rapidly developing. AU - Bollenbach, Mark Tobias ID - 1810 JF - Current Opinion in Microbiology TI - Antimicrobial interactions: Mechanisms and implications for drug discovery and resistance evolution VL - 27 ER - TY - JOUR AB - We investigate the occurrence of rotons in a quadrupolar Bose–Einstein condensate confined to two dimensions. Depending on the particle density, the ratio of the contact and quadrupole–quadrupole interactions, and the alignment of the quadrupole moments with respect to the confinement plane, the dispersion relation features two or four point-like roton minima or one ring-shaped minimum. We map out the entire parameter space of the roton behavior and identify the instability regions. We propose to observe the exotic rotons by monitoring the characteristic density wave dynamics resulting from a short local perturbation, and discuss the possibilities to detect the predicted effects in state-of-the-art experiments with ultracold homonuclear molecules. AU - Lahrz, Martin AU - Lemeshko, Mikhail AU - Mathey, Ludwig ID - 1812 IS - 4 JF - New Journal of Physics TI - Exotic roton excitations in quadrupolar Bose–Einstein condensates VL - 17 ER - TY - JOUR AB - Atomic form factors are widely used for the characterization of targets and specimens, from crystallography to biology. By using recent mathematical results, here we derive an analytical expression for the atomic form factor within the independent particle model constructed from nonrelativistic screened hydrogenic wave functions. The range of validity of this analytical expression is checked by comparing the analytically obtained form factors with the ones obtained within the Hartee-Fock method. As an example, we apply our analytical expression for the atomic form factor to evaluate the differential cross section for Rayleigh scattering off neutral atoms. AU - Safari, Laleh AU - Santos, José AU - Amaro, Pedro AU - Jänkälä, Kari AU - Fratini, Filippo ID - 1811 IS - 5 JF - Journal of Mathematical Physics TI - Analytical evaluation of atomic form factors: Application to Rayleigh scattering VL - 56 ER - TY - JOUR AB - We develop a microscopic theory describing a quantum impurity whose rotational degree of freedom is coupled to a many-particle bath. We approach the problem by introducing the concept of an “angulon”—a quantum rotor dressed by a quantum field—and reveal its quasiparticle properties using a combination of variational and diagrammatic techniques. Our theory predicts renormalization of the impurity rotational structure, such as that observed in experiments with molecules in superfluid helium droplets, in terms of a rotational Lamb shift induced by the many-particle environment. Furthermore, we discover a rich many-body-induced fine structure, emerging in rotational spectra due to a redistribution of angular momentum within the quantum many-body system. AU - Schmidt, Richard AU - Lemeshko, Mikhail ID - 1813 IS - 20 JF - Physical Review Letters TI - Rotation of quantum impurities in the presence of a many-body environment VL - 114 ER - TY - JOUR AU - Gupta, Ashutosh AU - Henzinger, Thomas A ID - 1808 IS - 2 JF - ACM Transactions on Modeling and Computer Simulation TI - Guest editors' introduction to special issue on computational methods in systems biology VL - 25 ER - TY - JOUR AB - Vertebrates have a unique 3D body shape in which correct tissue and organ shape and alignment are essential for function. For example, vision requires the lens to be centred in the eye cup which must in turn be correctly positioned in the head. Tissue morphogenesis depends on force generation, force transmission through the tissue, and response of tissues and extracellular matrix to force. Although a century ago D'Arcy Thompson postulated that terrestrial animal body shapes are conditioned by gravity, there has been no animal model directly demonstrating how the aforementioned mechano-morphogenetic processes are coordinated to generate a body shape that withstands gravity. Here we report a unique medaka fish (Oryzias latipes) mutant, hirame (hir), which is sensitive to deformation by gravity. hir embryos display a markedly flattened body caused by mutation of YAP, a nuclear executor of Hippo signalling that regulates organ size. We show that actomyosin-mediated tissue tension is reduced in hir embryos, leading to tissue flattening and tissue misalignment, both of which contribute to body flattening. By analysing YAP function in 3D spheroids of human cells, we identify the Rho GTPase activating protein ARHGAP18 as an effector of YAP in controlling tissue tension. Together, these findings reveal a previously unrecognised function of YAP in regulating tissue shape and alignment required for proper 3D body shape. Understanding this morphogenetic function of YAP could facilitate the use of embryonic stem cells to generate complex organs requiring correct alignment of multiple tissues. AU - Porazinski, Sean AU - Wang, Huijia AU - Asaoka, Yoichi AU - Behrndt, Martin AU - Miyamoto, Tatsuo AU - Morita, Hitoshi AU - Hata, Shoji AU - Sasaki, Takashi AU - Krens, Gabriel AU - Osada, Yumi AU - Asaka, Satoshi AU - Momoi, Akihiro AU - Linton, Sarah AU - Miesfeld, Joel AU - Link, Brian AU - Senga, Takeshi AU - Castillo Morales, Atahualpa AU - Urrutia, Araxi AU - Shimizu, Nobuyoshi AU - Nagase, Hideaki AU - Matsuura, Shinya AU - Bagby, Stefan AU - Kondoh, Hisato AU - Nishina, Hiroshi AU - Heisenberg, Carl-Philipp J AU - Furutani Seiki, Makoto ID - 1817 IS - 7551 JF - Nature TI - YAP is essential for tissue tension to ensure vertebrate 3D body shape VL - 521 ER - TY - CONF AB - We consider partially observable Markov decision processes (POMDPs) with a set of target states and every transition is associated with an integer cost. The optimization objec- tive we study asks to minimize the expected total cost till the target set is reached, while ensuring that the target set is reached almost-surely (with probability 1). We show that for integer costs approximating the optimal cost is undecidable. For positive costs, our results are as follows: (i) we establish matching lower and upper bounds for the optimal cost and the bound is double exponential; (ii) we show that the problem of approximating the optimal cost is decidable and present ap- proximation algorithms developing on the existing algorithms for POMDPs with finite-horizon objectives. While the worst- case running time of our algorithm is double exponential, we present efficient stopping criteria for the algorithm and show experimentally that it performs well in many examples. AU - Chatterjee, Krishnendu AU - Chmelik, Martin AU - Gupta, Raghav AU - Kanodia, Ayush ID - 1820 T2 - Proceedings of the Twenty-Ninth AAAI Conference on Artificial Intelligence TI - Optimal cost almost-sure reachability in POMDPs VL - 5 ER - TY - JOUR AB - We present an efficient wavefront tracking algorithm for animating bodies of water that interact with their environment. Our contributions include: a novel wavefront tracking technique that enables dispersion, refraction, reflection, and diffraction in the same simulation; a unique multivalued function interpolation method that enables our simulations to elegantly sidestep the Nyquist limit; a dispersion approximation for efficiently amplifying the number of simulated waves by several orders of magnitude; and additional extensions that allow for time-dependent effects and interactive artistic editing of the resulting animation. Our contributions combine to give us multitudes more wave details than similar algorithms, while maintaining high frame rates and allowing close camera zooms. AU - Jeschke, Stefan AU - Wojtan, Christopher J ID - 1814 IS - 3 JF - ACM Transactions on Graphics TI - Water wave animation via wavefront parameter interpolation VL - 34 ER - TY - JOUR AB - Why do species not adapt to ever-wider ranges of conditions, gradually expanding their ecological niche and geographic range? Gene flow across environments has two conflicting effects: although it increases genetic variation, which is a prerequisite for adaptation, gene flow may swamp adaptation to local conditions. In 1956, Haldane proposed that, when the environment varies across space, "swamping" by gene flow creates a positive feedback between low population size and maladaptation, leading to a sharp range margin. However, current deterministic theory shows that, when variance can evolve, there is no such limit. Using simple analytical tools and simulations, we show that genetic drift can generate a sharp margin to a species' range, by reducing genetic variance below the level needed for adaptation to spatially variable conditions. Aided by separation of ecological and evolutionary timescales, the identified effective dimensionless parameters reveal a simple threshold that predicts when adaptation at the range margin fails. Two observable parameters determine the threshold: (i) the effective environmental gradient, which can be measured by the loss of fitness due to dispersal to a different environment; and (ii) the efficacy of selection relative to genetic drift. The theory predicts sharp range margins even in the absence of abrupt changes in the environment. Furthermore, it implies that gradual worsening of conditions across a species' habitat may lead to a sudden range fragmentation, when adaptation to a wide span of conditions within a single species becomes impossible. AU - Polechova, Jitka AU - Barton, Nicholas H ID - 1818 IS - 20 JF - PNAS TI - Limits to adaptation along environmental gradients VL - 112 ER - TY - JOUR AB - The sessile life style of plants creates the need to deal with an often adverse environment, in which water availability can change on a daily basis, challenging the cellular physiology and integrity. Changes in osmotic conditions disrupt the equilibrium of the plasma membrane: hypoosmotic conditions increase and hyperosmotic environment decrease the cell volume. Here, we show that short-term extracellular osmotic treatments are closely followed by a shift in the balance between endocytosis and exocytosis in root meristem cells. Acute hyperosmotic treatments (ionic and nonionic) enhance clathrin-mediated endocytosis simultaneously attenuating exocytosis, whereas hypoosmotic treatments have the opposite effects. In addition to clathrin recruitment to the plasma membrane, components of early endocytic trafficking are essential during hyperosmotic stress responses. Consequently, growth of seedlings defective in elements of clathrin or early endocytic machinery is more sensitive to hyperosmotic treatments. We also found that the endocytotic response to a change of osmotic status in the environment is dominant over the presumably evolutionary more recent regulatory effect of plant hormones, such as auxin. These results imply that osmotic perturbation influences the balance between endocytosis and exocytosis acting through clathrin-mediated endocytosis. We propose that tension on the plasma membrane determines the addition or removal of membranes at the cell surface, thus preserving cell integrity. AU - Zwiewka, Marta AU - Nodzyński, Tomasz AU - Robert, Stéphanie AU - Vanneste, Steffen AU - Friml, Jiřĺ ID - 1819 IS - 8 JF - Molecular Plant TI - Osmotic stress modulates the balance between exocytosis and clathrin mediated endocytosis in Arabidopsis thaliana VL - 8 ER - TY - JOUR AB - Abstract Drug combinations are increasingly important in disease treatments, for combating drug resistance, and for elucidating fundamental relationships in cell physiology. When drugs are combined, their individual effects on cells may be amplified or weakened. Such drug interactions are crucial for treatment efficacy, but their underlying mechanisms remain largely unknown. To uncover the causes of drug interactions, we developed a systematic approach based on precise quantification of the individual and joint effects of antibiotics on growth of genome-wide Escherichia coli gene deletion strains. We found that drug interactions between antibiotics representing the main modes of action are highly robust to genetic perturbation. This robustness is encapsulated in a general principle of bacterial growth, which enables the quantitative prediction of mutant growth rates under drug combinations. Rare violations of this principle exposed recurring cellular functions controlling drug interactions. In particular, we found that polysaccharide and ATP synthesis control multiple drug interactions with previously unexplained mechanisms, and small molecule adjuvants targeting these functions synthetically reshape drug interactions in predictable ways. These results provide a new conceptual framework for the design of multidrug combinations and suggest that there are universal mechanisms at the heart of most drug interactions. Synopsis A general principle of bacterial growth enables the prediction of mutant growth rates under drug combinations. Rare violations of this principle expose cellular functions that control drug interactions and can be targeted by small molecules to alter drug interactions in predictable ways. Drug interactions between antibiotics are highly robust to genetic perturbations. A general principle of bacterial growth enables the prediction of mutant growth rates under drug combinations. Rare violations of this principle expose cellular functions that control drug interactions. Diverse drug interactions are controlled by recurring cellular functions, including LPS synthesis and ATP synthesis. A general principle of bacterial growth enables the prediction of mutant growth rates under drug combinations. Rare violations of this principle expose cellular functions that control drug interactions and can be targeted by small molecules to alter drug interactions in predictable ways. AU - Chevereau, Guillaume AU - Bollenbach, Mark Tobias ID - 1823 IS - 4 JF - Molecular Systems Biology TI - Systematic discovery of drug interaction mechanisms VL - 11 ER - TY - JOUR AB - Condensation phenomena arise through a collective behaviour of particles. They are observed in both classical and quantum systems, ranging from the formation of traffic jams in mass transport models to the macroscopic occupation of the energetic ground state in ultra-cold bosonic gases (Bose-Einstein condensation). Recently, it has been shown that a driven and dissipative system of bosons may form multiple condensates. Which states become the condensates has, however, remained elusive thus far. The dynamics of this condensation are described by coupled birth-death processes, which also occur in evolutionary game theory. Here we apply concepts from evolutionary game theory to explain the formation of multiple condensates in such driven-dissipative bosonic systems. We show that the vanishing of relative entropy production determines their selection. The condensation proceeds exponentially fast, but the system never comes to rest. Instead, the occupation numbers of condensates may oscillate, as we demonstrate for a rock-paper-scissors game of condensates. AU - Knebel, Johannes AU - Weber, Markus AU - Krüger, Torben H AU - Frey, Erwin ID - 1824 JF - Nature Communications TI - Evolutionary games of condensates in coupled birth-death processes VL - 6 ER - TY - JOUR AB - This paper introduces a theme issue presenting the latest developments in research on the impacts of sociality on health and fitness. The articles that follow cover research on societies ranging from insects to humans. Variation in measures of fitness (i.e. survival and reproduction) has been linked to various aspects of sociality in humans and animals alike, and variability in individual health and condition has been recognized as a key mediator of these relationships. Viewed from a broad evolutionary perspective, the evolutionary transitions from a solitary lifestyle to group living have resulted in several new health-related costs and benefits of sociality. Social transmission of parasites within groups represents a major cost of group living, but some behavioural mechanisms, such as grooming, have evolved repeatedly to reduce this cost. Group living also has created novel costs in terms of altered susceptibility to infectious and non-infectious disease as a result of the unavoidable physiological consequences of social competition and integration, which are partly alleviated by social buffering in some vertebrates. Here, we define the relevant aspects of sociality, summarize their health-related costs and benefits, and discuss possible fitness measures in different study systems. Given the pervasive effects of social factors on health and fitness, we propose a synthesis of existing conceptual approaches in disease ecology, ecological immunology and behavioural neurosciences by adding sociality as a key factor, with the goal to generate a broader framework for organismal integration of health-related research. AU - Kappeler, Peter AU - Cremer, Sylvia AU - Nunn, Charles ID - 1831 IS - 1669 JF - Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences TI - Sociality and health: Impacts of sociality on disease susceptibility and transmission in animal and human societies VL - 370 ER - TY - JOUR AB - We construct a non-linear Markov process connected with a biological model of a bacterial genome recombination. The description of invariant measures of this process gives us the solution of one problem in elementary probability theory. AU - Akopyan, Arseniy AU - Pirogov, Sergey AU - Rybko, Aleksandr ID - 1828 IS - 1 JF - Journal of Statistical Physics TI - Invariant measures of genetic recombination process VL - 160 ER - TY - CONF AB - In the standard framework for worst-case execution time (WCET) analysis of programs, the main data structure is a single instance of integer linear programming (ILP) that represents the whole program. The instance of this NP-hard problem must be solved to find an estimate forWCET, and it must be refined if the estimate is not tight.We propose a new framework for WCET analysis, based on abstract segment trees (ASTs) as the main data structure. The ASTs have two advantages. First, they allow computing WCET by solving a number of independent small ILP instances. Second, ASTs store more expressive constraints, thus enabling a more efficient and precise refinement procedure. In order to realize our framework algorithmically, we develop an algorithm for WCET estimation on ASTs, and we develop an interpolation-based counterexample-guided refinement scheme for ASTs. Furthermore, we extend our framework to obtain parametric estimates of WCET. We experimentally evaluate our approach on a set of examples from WCET benchmark suites and linear-algebra packages. We show that our analysis, with comparable effort, provides WCET estimates that in many cases significantly improve those computed by existing tools. AU - Cerny, Pavol AU - Henzinger, Thomas A AU - Kovács, Laura AU - Radhakrishna, Arjun AU - Zwirchmayr, Jakob ID - 1836 TI - Segment abstraction for worst-case execution time analysis VL - 9032 ER - TY - CONF AB - Synthesis of program parts is particularly useful for concurrent systems. However, most approaches do not support common design tasks, like modifying a single process without having to re-synthesize or verify the whole system. Assume-guarantee synthesis (AGS) provides robustness against modifications of system parts, but thus far has been limited to the perfect information setting. This means that local variables cannot be hidden from other processes, which renders synthesis results cumbersome or even impossible to realize.We resolve this shortcoming by defining AGS under partial information. We analyze the complexity and decidability in different settings, showing that the problem has a high worstcase complexity and is undecidable in many interesting cases. Based on these observations, we present a pragmatic algorithm based on bounded synthesis, and demonstrate its practical applicability on several examples. AU - Bloem, Roderick AU - Chatterjee, Krishnendu AU - Jacobs, Swen AU - Könighofer, Robert ID - 1838 TI - Assume-guarantee synthesis for concurrent reactive programs with partial information VL - 9035 ER - TY - CONF AB - We present MultiGain, a tool to synthesize strategies for Markov decision processes (MDPs) with multiple mean-payoff objectives. Our models are described in PRISM, and our tool uses the existing interface and simulator of PRISM. Our tool extends PRISM by adding novel algorithms for multiple mean-payoff objectives, and also provides features such as (i) generating strategies and exploring them for simulation, and checking them with respect to other properties; and (ii) generating an approximate Pareto curve for two mean-payoff objectives. In addition, we present a new practical algorithm for the analysis of MDPs with multiple mean-payoff objectives under memoryless strategies. AU - Brázdil, Tomáš AU - Chatterjee, Krishnendu AU - Forejt, Vojtěch AU - Kučera, Antonín ID - 1839 TI - Multigain: A controller synthesis tool for MDPs with multiple mean-payoff objectives VL - 9035 ER - TY - JOUR AB - Transition to turbulence in straight pipes occurs in spite of the linear stability of the laminar Hagen-Poiseuille flow if both the amplitude of flow perturbations and the Reynolds number Re exceed a minimum threshold (subcritical transition). As the pipe curvature increases, centrifugal effects become important, modifying the basic flow as well as the most unstable linear modes. If the curvature (tube-to-coiling diameter d/D) is sufficiently large, a Hopf bifurcation (supercritical instability) is encountered before turbulence can be excited (subcritical instability). We trace the instability thresholds in the Re - d/D parameter space in the range 0.01 ≤ d/D\ ≤ 0.1 by means of laser-Doppler velocimetry and determine the point where the subcritical and supercritical instabilities meet. Two different experimental set-ups are used: a closed system where the pipe forms an axisymmetric torus and an open system employing a helical pipe. Implications for the measurement of friction factors in curved pipes are discussed. AU - Kühnen, Jakob AU - Braunshier, P AU - Schwegel, M AU - Kuhlmann, Hendrik AU - Hof, Björn ID - 1837 IS - 5 JF - Journal of Fluid Mechanics TI - Subcritical versus supercritical transition to turbulence in curved pipes VL - 770 ER - TY - JOUR AB - The ability to escape apoptosis is a hallmark of cancer-initiating cells and a key factor of resistance to oncolytic therapy. Here, we identify FAM96A as a ubiquitous, evolutionarily conserved apoptosome-activating protein and investigate its potential pro-apoptotic tumor suppressor function in gastrointestinal stromal tumors (GISTs). Interaction between FAM96A and apoptotic peptidase activating factor 1 (APAF1) was identified in yeast two-hybrid screen and further studied by deletion mutants, glutathione-S-transferase pull-down, co-immunoprecipitation and immunofluorescence. Effects of FAM96A overexpression and knock-down on apoptosis sensitivity were examined in cancer cells and zebrafish embryos. Expression of FAM96A in GISTs and histogenetically related cells including interstitial cells of Cajal (ICCs), “fibroblast-like cells” (FLCs) and ICC stem cells (ICC-SCs) was investigated by Northern blotting, reverse transcription—polymerase chain reaction, immunohistochemistry and Western immunoblotting. Tumorigenicity of GIST cells and transformed murine ICC-SCs stably transduced to re-express FAM96A was studied by xeno- and allografting into immunocompromised mice. FAM96A was found to bind APAF1 and to enhance the induction of mitochondrial apoptosis. FAM96A protein or mRNA was dramatically reduced or lost in 106 of 108 GIST samples representing three independent patient cohorts. Whereas ICCs, ICC-SCs and FLCs, the presumed normal counterparts of GIST, were found to robustly express FAM96A protein and mRNA, FAM96A expression was much reduced in tumorigenic ICC-SCs. Re-expression of FAM96A in GIST cells and transformed ICC-SCs increased apoptosis sensitivity and diminished tumorigenicity. Our data suggest FAM96A is a novel pro-apoptotic tumor suppressor that is lost during GIST tumorigenesis. AU - Schwamb, Bettina AU - Pick, Robert AU - Fernández, Sara AU - Völp, Kirsten AU - Heering, Jan AU - Dötsch, Volker AU - Bösser, Susanne AU - Jung, Jennifer AU - Beinoravičiute Kellner, Rasa AU - Wesely, Josephine AU - Zörnig, Inka AU - Hammerschmidt, Matthias AU - Nowak, Matthias AU - Penzel, Roland AU - Zatloukal, Kurt AU - Joos, Stefan AU - Rieker, Ralf AU - Agaimy, Abbas AU - Söder, Stephan AU - Reid Lombardo, Kmarie AU - Kendrick, Michael AU - Bardsley, Michael AU - Hayashi, Yujiro AU - Asuzu, David AU - Syed, Sabriya AU - Ördög, Tamás AU - Zörnig, Martin ID - 1848 IS - 6 JF - International Journal of Cancer TI - FAM96A is a novel pro-apoptotic tumor suppressor in gastrointestinal stromal tumors VL - 137 ER - TY - JOUR AB - Modal transition systems (MTS) is a well-studied specification formalism of reactive systems supporting a step-wise refinement methodology. Despite its many advantages, the formalism as well as its currently known extensions are incapable of expressing some practically needed aspects in the refinement process like exclusive, conditional and persistent choices. We introduce a new model called parametric modal transition systems (PMTS) together with a general modal refinement notion that overcomes many of the limitations. We investigate the computational complexity of modal and thorough refinement checking on PMTS and its subclasses and provide a direct encoding of the modal refinement problem into quantified Boolean formulae, allowing us to employ state-of-the-art QBF solvers for modal refinement checking. The experiments we report on show that the feasibility of refinement checking is more influenced by the degree of nondeterminism rather than by the syntactic restrictions on the types of formulae allowed in the description of the PMTS. AU - Beneš, Nikola AU - Kretinsky, Jan AU - Larsen, Kim AU - Möller, Mikael AU - Sickert, Salomon AU - Srba, Jiří ID - 1846 IS - 2-3 JF - Acta Informatica TI - Refinement checking on parametric modal transition systems VL - 52 ER -