TY - JOUR AB - Metabotropic γ-aminobutyric acid receptors (GABAB) are involved in pre- and postsynaptic inhibitory effects upon auditory neurons and have been implicated in different aspects of acoustic information processing. To understand better the mechanisms by which GABAB receptors mediate their inhibitory effects, we used pre-embedding immunocytochemical techniques combined with quantification of immunogold particles to reveal the precise subcellular distribution of the GABAB1 subunit in the rat dorsal cochlear nucleus. At the light microscopic level, GABAB1 was detected in all divisions of the cochlear complex. The most intense immunoreactivity for GABAB1 was found in the dorsal cochlear nucleus, whereas immunoreactivity in the anteroventral and posteroventral cochlear nuclei was very low. In the dorsal cochlear nucleus, a punctate labeling was observed in the superficial (molecular and fusiform cell) layers. At the electron microscopic level, GABAB1 was found at both post- and presynaptic locations. Postsynaptically, GABAB1 was localized mainly in the dendritic spines of presumed fusiform cells. Quantitative immunogold immunocytochemistry revealed that the highest concentration of GABA B1 in the plasma membrane was in dendritic spines, followed by dendritic shafts and somata. Thus, the most intense immunoreactivity for GABAB1 was observed in dendritic spines with a high density of immunogold particles at extrasynaptic sites, peaking around 300 nm from glutamatergic synapses. This is in contrast to GABAergic synapses, in which GABAB1 was only occasionally found. Presynaptically, receptor immunoreactivity was detected primarily in axospinous endings, probably from granule cells, in both the active zone and extrasynaptic sites. The localization of GABAB1 relative to synaptic sites in the DCN suggests a role for the receptor in the regulation of dendritic excitability and excitatory inputs. AU - Luján, Rafael AU - Ryuichi Shigemoto AU - Kulik, Ákos AU - Juíz, José M ID - 2643 IS - 1 JF - Journal of Comparative Neurology TI - Localization of the GABAB receptor 1a/b subunit relative to glutamatergic synapses in the dorsal cochlear nucleus of the rat VL - 475 ER - TY - JOUR AB - Among various types of low- and high-threshold calcium channels, the high voltage-activated P/Q-type channel is the most abundant in the cerebellum. These P/Q-type channels are involved in the regulation of neurotransmitter release and in the integration of dendritic inputs. We used an antibody specific for the α1A subunit of the P/Q-type channel in quantitative pre-embedding immunogold labelling combined with three-dimensional reconstruction to reveal the subcellular distribution of pre- and postsynaptic P/Q-type channels in the rat cerebellum. At the light microscopic level, immunoreactivity for the α1A protein was prevalent in the molecular layer, whereas immunostaining was moderate in the somata of Purkinje cells and weak in the granule cell layer. At the electron microscopic level, the most intense Immunoreactivity for the α1A subunit was found in the presynaptic active zone of parallel fibre varicosities. The dendritic spines of Purkinje cells were also strongly labelled with the highest density of immunoparticles detected within 180 nm from the edge of the asymmetrical parallel fibre-Purkinje cell synapses. By contrast, the immunolabelling was sparse in climbing fibre varicosities and axon terminals of GABAergic cells, and weak and diffuse in dendritic shafts of Purkinje cells. The association of the α1A subunit with the glutamatergic parallel fibre-Purkinje cell synapses suggests that presynaptic channels have a major role in the mediation of excitatory neurotransmission, whereas postsynaptic channels are likely to be involved in depolarization-induced generation of local calcium transients in Purkinje cells. AU - Kulik, Ákos AU - Nakadate, Kazuhiko AU - Hagiwara, Akari AU - Fukazawa, Yugo AU - Luján, Rafael AU - Saito, Hiromitsu AU - Suzuki, Noboru AU - Futatsugi, Akira AU - Mikoshiba, Katsuhiko AU - Frotscher, Michael AU - Ryuichi Shigemoto ID - 2638 IS - 8 JF - European Journal of Neuroscience TI - Immunocytochemical localization of the α1A subunit of the P/Q-type calcium channel in the rat cerebellum VL - 19 ER - TY - JOUR AB - Hyperpolarization-activated cation currents (Ih) contribute to various physiological properties and functions in the brain, including neuronal pacemaker activity, setting of resting membrane potential, and dendritic integration of synaptic input. Four subunits of the Hyperpolarization-activated and Cyclic-Nucleotide-gated nonselective cation channels (HCN1-4), which generate Ih, have been cloned recently. To better understand the functional diversity of Ih in the brain, we examined precise immunohistochemical localization of four HCNs in the rat brain. Immunoreactivity for HCN1 showed predominantly cortical distribution, being intense in the neocortex, hippocampus, superior colliculus, and cerebellum, whereas those for HCN3 and HCN4 exhibited subcortical distribution mainly concentrated in the hypothalamus and thalamus, respectively. Immunoreactivity for HCN2 had a widespread distribution throughout the brain. Double immunofluorescence revealed colocalization of immunoreactivity for HCN1 and HCN2 in distal dendrites of pyramidal cells in the hippocampus and neocortex. At the electron microscopic level, immunogold particles for HCN1 and HCN2 had similar distribution patterns along plasma membrane of dendritic shafts in layer I of the neocortex and stratum lacunosum moleculare of the hippocampal CA1 area, suggesting that these subunits could form heteromeric channels. Our results further indicate that HCNs are localized not only in somato-dendritic compartments but also in axonal compartments of neurons. Immunoreactivity for HCNs often occurred in preterminal rather than terminal portions of axons and in specific populations of myelinated axons. We also found HCN2-immunopositive oligodendrocytes including perineuronal oligodendrocytes throughout the brain. These results support previous electrophysiological findings and further suggest unexpected roles of Ih channels in the brain. AU - Notomi, Takuya AU - Ryuichi Shigemoto ID - 2640 IS - 3 JF - Journal of Comparative Neurology TI - Immunohistochemical localization of Ih channel subunits, HCN1-4, in the rat brain VL - 471 ER - TY - JOUR AB - The Na+-K+ pump current (Ip) and the h-current (Ih) flowing through hyperpolarization-activated channels (h-channels) participate in generating the resting potential. These two currents are thought to be produced independently. We show here bidirectional interactions between Na+-K+ pumps and h-channels in mesencephalic trigeminal neurons. Activation of Ih leads to the generation of two types of ouabain-sensitive Ip with temporal profiles similar to those of instantaneous and slow components of I h, presumably reflecting Na+ transients in a restricted cellular space. Moreover, the Ip activated by instantaneous I h can facilitate the subsequent activation of slow Ih. Such counteractive and cooperative interactions were also disclosed by replacing extracellular Na+ with Li+, which is permeant through h-channels but does not stimulate the Na+-K+ pump as strongly as Na+ ions. These observations indicate that the interactions are bidirectional and mediated by Na+ ions. Also after substitution of extracellular Na+ with Li+, the tail Ih was reduced markedly despite an enhancement of Ih itself, attributable to a negative shift of the reversal potential for I h presumably caused by intracellular accumulation of Li+ ions. This suggests the presence of a microdomain where the interactions can take place. Thus, the bidirectional interactions between Na+-K + pumps and h-channels are likely to be mediated by Na+ microdomain. Consistent with these findings, hyperpolarization-activated and cyclic nucleotide-modulated subunits (HCN1/2) and the Na+-K + pump α3 isoform were colocalized in plasma membrane of mesencephalic trigeminal neurons having numerous spines. AU - Kang, Youngnam AU - Notomi, Takuya AU - Saito, Mitsuru AU - Zhang, Wei AU - Ryuichi Shigemoto ID - 2641 IS - 14 JF - Journal of Neuroscience TI - Bidirectional interactions between H-channels and Na+-K + pumps in mesencephalic trigeminal neurons VL - 24 ER - TY - GEN AU - Momiyama, Akiko AU - Ryuichi Shigemoto ID - 2636 IS - 3 Suppl T2 - Tanpakushitsu kakusan koso Protein nucleic acid enzyme TI - Function and distribution of glutamate receptors in the central synapses VL - 49 ER - TY - JOUR AB - The globus pallidus (GP) is a critical component of the basal ganglia circuitry controlling motor behavior. Dysregulation of GP activity has been implicated in a number of psychomotor disorders, including Parkinson's disease (PD), in which a cardinal feature of the pathophysiology is an alteration in the pattern and synchrony of discharge in GP neurons. Yet the determinants of this activity in GP neurons are poorly understood. To help fill this gap, electrophysiological, molecular, and computational approaches were used to identify and characterize GABAergic GP neurons in tissue slices from rodents. In vitro, GABAergic GP neurons generate a regular, autonomous, single-spike pacemaker activity. Hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels make an important contribution to this process: their blockade with ZD7288 significantly slowed discharge rate and decreased its regularity. HCN currents evoked by somatic voltage clamp had fast and slow components. Single-cell RT-PCR and immunohistochemical approaches revealed robust expression of HCN2 subunits as well as significant levels of HCN1 subunits in GABAergic GP neurons. Transient activation of striatal GABAergic input to GP neurons led to a resetting of rhythmic discharge that was dependent on HCN currents. Simulations suggested that the ability of transient striatal GABAergic input to reset pacemaking was dependent on dendritic HCN2/HCN1 channels. Together, these studies show that HCN channels in GABAergic GP neurons are key determinants of the regularity and rate of pacemaking as well as striatal resetting of this activity, implicating HCN channels in the emergence of synchrony in PD. AU - Chan, Savio AU - Ryuichi Shigemoto AU - Mercer, Jeff N AU - Surmeier, James D ID - 2645 IS - 44 JF - Journal of Neuroscience TI - HCN2 and HCN1 channels govern the regularity of autonomous pacemaking and synaptic resetting in globus pallidus neurons VL - 24 ER - TY - JOUR AB - The release of GABA in synapses is modulated by presynaptic metabotropic glutamate receptors (mGluRs). We tested whether GABA release to identified hippocampal neurons is influenced by group III mGluR activation using the agonist L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) on inhibitory postsynaptic currents (IPSCs) evoked in CA1 interneurons and pyramidal cells. In interneurons, characterized with biocytin and immunolabelling for somatostatin, evoked IPSCs were depressed by 50 μM L-AP4 (activating mGluR4 and 8) to 68±6% of control, but they were rarely depressed in pyramidal cells (96±4% of control). At 300-500 μM concentration (activating mGluR4, 7 and 8), L-AP4 depressed IPSCs in both interneurons (to 70±6%) and pyramidal cells (to 67±4%). The change in trial-to-trial variability and in paired-pulse depression indicated a presynaptic action. In interneurons, the degree of IPSC depression was variable (to 9-87%), and a third of IPSCs were not affected by L-AP4. The L-AP4-evoked IPSC depression was blocked by LY341495. The depression of IPSCs was similar in O-LM cells and other interneurons. The lack of cell-type selectivity and the similar efficacy of different concentrations of L-AP4 suggest that several group III mGluRs are involved in the depression of IPSCs. Electron microscopic immunocytochemistry confirmed that mGluR4, mGluR7a and mGluR8a occur in the presynaptic active zone of GABAergic terminals on interneurons, but not on those innervating pyramidal cells. The high variability of L-AP4-evoked IPSC suppression is in line with the selective expression of presynaptic mGluRs by several distinct types of GABAergic neuron innervating each interneuron type. AU - Kogo, Naoki AU - Dalezios, Yannis AU - Capogna,Marco AU - Ferraguti, Francesco AU - Ryuichi Shigemoto AU - Somogyi, Péter ID - 2644 IS - 10 JF - European Journal of Neuroscience TI - Depression of GABAergic input to identified hippocampal neurons by group III metabotropic glutamate receptors in the rat VL - 19 ER - TY - JOUR AB - Metabotropic γ-aminobutyric acid receptors (GABAB) play modulatory roles in central synaptic transmission and are involved in controlling neuronal migration during development. We used immunohistochemical methods to elucidate the expression pattern as well as the cellular and the precise subcellular localization of the GABAB1a/b and GABAB2 subunits in the rat hippocampus during prenatal and postnatal development. At the light microscopic level, both GABABB1a/b and GABAB2 were expressed in the hippocampal primordium from embryonic day E14. During postnatal development, immunoreactivity for GABAB1a/b and GABAB2 was distributed mainly in pyramidal cells, with discrete GABABB1a/b-immunopositive cell bodies of interneurons present throughout the hippocampus. Using double immunofluorescence, we demonstrated that during the second week of postnatal development, GABAB1a/b but not GABAB2 was expressed in glial cells throughout the hippocampal formation. At the electron microscopic level, GABAB1a/b and GABAB2 showed a similar distribution pattern during postnatal development. Thus, at all ages the two receptor subunits were located postsynaptically in dendritic spines and shafts at extrasynaptic and perisynaptic sites in both pyramidal and nonpyramidal cells. We further demonstrated that the two subunits were localized presynaptically along the extrasynaptic plasma membrane of axon terminals and along the presynaptic active zone in both asymmetrical and, to a lesser extent, symmetrical synapses. These results suggest that GABAB receptors are widely expressed in the hippocampus throughout development and that GABABB1a/b and GABAB2 form both pre- and postsynaptic receptors. AU - López-Bendito, Guillermina AU - Ryuichi Shigemoto AU - Kulik, Ákos AU - Vida, Imre AU - Fairén, Alfonso AU - Luján, Rafael ID - 2646 IS - 7 JF - Hippocampus TI - Distribution of metabotropic GABA receptor subunits GABAB1a/b and GABAB2 in the rat hippocampus during prenatal and postnatal development VL - 14 ER - TY - JOUR AB - The Pauli operator describes the energy of a nonrelativistic quantum particle with spin in a magnetic field and an external potential. Bounds on the sum of the negative eigenvalues are called magnetic Lieb-Thirring (MLT) inequalities. The purpose of this paper is twofold. First, we prove a new MLT inequality in a simple way. Second, we give a short summary of our recent proof of a more refined MLT inequality(8) and we explain the differences between the two results and methods. The main feature of both estimates, compared to earlier results, is that in the large field regime they grow with the optimal (first) power of the strength of the magnetic field. As a byproduct of the method, we also obtain optimal upper bounds on the pointwise density of zero energy eigenfunctions of the Dirac operator. AU - László Erdös AU - Solovej, Jan P ID - 2706 IS - 1-4 JF - Journal of Statistical Physics TI - Magnetic Lieb-Thirring inequalities with optimal dependence on the field strength VL - 116 ER - TY - JOUR AB - We give a nonrigorous derivation of the nonlinear Boltzmann equation from the Schrödinger evolution of interacting fermions. The argument is based mainly on the assumption that a quasifree initial state satisfies a property called restricted quasifreeness in the weak coupling limit at any later time. By definition, a state is called restricted quasifree if the four-point and the eight-point functions of the state factorize in the same manner as in a quasifree state. AU - László Erdös AU - Salmhofer, Manfred AU - Yau, Horng-Tzer ID - 2707 IS - 1-4 JF - Journal of Statistical Physics TI - On the quantum Boltzmann equation VL - 116 ER - TY - JOUR AB - The Pauli operator describes the energy of a nonrelativistic quantum particle with spin 1/2 in a magnetic field and an external potential. A new Lieb-Thirring type inequality on the sum of the negative eigenvalues is presented. The main feature compared to earlier results is that in the large field regime the present estimate grows with the optimal (first) power of the strength of the magnetic field. As a byproduct of the method, we also obtain an optimal upper bound on the pointwise density of zero energy eigenfunctions of the Dirac operator. The main technical tools are: (i) a new localization scheme for the square of the resolvent of a general class of second order elliptic operators; (ii) a geometric construction of a Dirac operator with a constant magnetic field that approximates the original Dirac operator in a tubular neighborhood of a fixed field line. The errors may depend on the regularity of the magnetic field but they are uniform in the field strength. AU - László Erdös AU - Solovej, Jan P ID - 2741 IS - 4 JF - Annales Henri Poincare TI - Uniform Lieb-Thirring inequality for the three-dimensional Pauli operator with a strong non-homogeneous magnetic field VL - 5 ER - TY - JOUR AB - We consider a system of N weakly interacting fermions with a real analytic pair interaction. We prove that for a general class of initial data there exists a fixed time T such that the difference between the one particle density matrix of this system and the solution of the nonlinear Hartree equation is of order N−1 for any time t⩽T. AU - Elgart, Alexander AU - László Erdös AU - Schlein, Benjamin AU - Yau, Horng-Tzer ID - 2742 IS - 10 JF - Journal de Mathématiques Pures et Appliquées TI - Nonlinear Hartree equation as the mean field limit of weakly coupled fermions VL - 83 ER - TY - JOUR AB - The results of experimental and numerical investigations of the onset of oscillatory convection in a sidewall heated rectangular cavity of molten gallium are reported. Detailed comparisons are made between experimental observations and calculations from numerical simulations of a three-dimensional Boussinesq model. The onset of time-dependence takes place through supercritical Hopf bifurcations and the loci of critical points in the (Gr, Pr)-plane are qualitatively similar with excellent agreement between the frequencies of the oscillatory motion. This provides a severe test of the control of the experiment since the mode of oscillation is extremely sensitive to imperfections. Detailed numerical investigations reveal that there are a pair of Hopf bifurcations which exist on two asymmetric states which themselves arise at a subcritical pitchfork from the symmetric state. There is no evidence for this in the experiment and this qualitative difference is attributed to non-Boussinesq perturbations which increase with Gr. However, the antisymmetric spatial structure of the oscillatory state is robust and is present in both the experiment and the numerical model. Moreover, the detailed analysis of the numerical results reveals the origins of the oscillatory instability. AU - Björn Hof AU - Juel, Anne AU - Zhao, Li AU - Henry, Daniel AU - Ben Hadid, Hamda AU - Mullin, Tom P ID - 2787 JF - Journal of Fluid Mechanics TI - On the onset of oscillatory convection in molten gallium VL - 515 ER - TY - JOUR AB - Transition to turbulence in pipe flow is one of the most fundamental and longest- standing problems in fluid dynamics. Stability theory suggests that the flow remains laminar for all flow rates, but in practice pipe flow becomes turbulent even at moderate speeds. This transition drastically affects the transport efficiency of mass, momentum, and heat. On the basis of the recent discovery of unstable traveling waves in computational studies of the Navier-Stokes equations and ideas from dynamical systems theory, a model for the transition process has been suggested. We report experimental observation of these traveling waves in pipe flow, confirming the proposed transition scenario and suggesting that the dynamics associated with these unstable states may indeed capture the nature of fluid turbulence. AU - Björn Hof AU - van Doorne, Casimir W AU - Westerweel, Jerry AU - Nieuwstadt, Frans T AU - Faisst, Holger AU - Eckhardt, Bruno AU - Wedin, Håkan AU - Kersweli, Richard R AU - Waleffe, Fabian ID - 2786 IS - 5690 JF - Science TI - Experimental observation of nonlinear traveling waves in turbulent pipe flow VL - 305 ER - TY - JOUR AB - The packaging of the genomic DNA into chromatin in the cell nucleus requires machineries that facilitate DNA-dependent processes such as transcription in the presence of repressive chromatin structures. Using co-immunoprecipitation we have identified in Arabidopsis thaliana cells the FAcilitates Chromatin Transcription (FACT) complex, consisting of the 120-kDa Spt16 and the 71-kDa SSRP1 proteins. Indirect immunofluorecence analyses revealed that both FACT subunits co-localize to nuclei of the majority of cell types in embryos, shoots and roots, whereas FACT is not present in terminally differentiated cells such as mature trichoblasts or cells of the root cap. In the nucleus, Spt16 and SSRP1 are found in the cytologically defined euchromatin of interphase cells independent of the status of DNA replication, but the proteins are not associated with heterochromatic chromocentres and condensed mitotic chromosomes. FACT can be detected by chromatin immunoprecipitation over the entire transcribed region (5′-UTR, coding sequence, 3′-UTR) of actively transcribed genes, whereas it does not occur at transcriptionally inactive heterochromatic regions and intergenic regions. FACT localizes to inducible genes only after induction of transcription, and the association of the complex with the genes correlates with the level of transcription. Collectively, these results indicate that FACT assists transcription elongation through plant chromatin. AU - Duroux, Meg AU - Houben, Andreas AU - Růžička, Kamil AU - Jirí Friml AU - Grasser, Klaus D ID - 2998 IS - 5 JF - Plant Journal TI - The chromatin remodelling complex FACT associates with actively transcribed regions of the Arabidopsis genome VL - 40 ER - TY - JOUR AB - Polar transport-dependent local accumulation of auxin provides positional cues for multiple plant patterning processes. This directional auxin flow depends on the polar subcellular localization of the PIN auxin efflux regulators. Overexpression of the PINOID protein kinase induces a basal-to-apical shift in PIN localization, resulting in the loss of auxin gradients and strong defects in embryo and seedling roots. Conversely, pid loss of function induces an apical-to-basal shift in PIN1 polar targeting at the inflorescence apex, accompanied by defective organogenesis. Our results show that a PINOID-dependent binary switch controls PIN polarity and mediates changes in auxin flow to create local gradients for patterning processes. AU - Jirí Friml AU - Yang, Xiong AU - Michniewicz, Marta AU - Weijers, Dolf AU - Quint, Ab AU - Tietz, Olaf AU - Benjamins, René AU - Ouwerkerk, Pieter B AU - Ljung, Karin AU - Sandberg, Göran AU - Hooykaas, Paul J AU - Palme, Klaus AU - Offringa, Remko ID - 2997 IS - 5697 JF - Science TI - A PINOID-dependent binary switch in apical-basal PIN polar targeting directs auxin efflux VL - 306 ER - TY - JOUR AB - Embryogenesis of flowering plants establishes a basic body plan with apical-basal, radial and bilateral patterns from the single-celled zygote. Arabidopsis embryogenesis exhibits a nearly invariant cell division pattern and therefore is an ideal system for studies of early plant development. However, plant embryos are difficult to access for experimental manipulation, as they develop deeply inside maternal tissues. Here we present a method for the culture of zygotic Arabidopsis embryos in vitro. The technique omits excision of the embryo by culturing the entire ovule, thus greatly facilitating the time and effort involved. It enables external manipulation of embryo development and culture from the earliest developmental stages up to maturity. Administration of various chemical treatments as well as the use of different molecular markers is demonstrated together with standard techniques for visualizing gene expression and protein localization in in vitro cultivated embryos. The presented set of techniques allows for so far unavailable molecular physiology approaches in the study of early plant development. AU - Sauer, Michael AU - Jirí Friml ID - 2999 IS - 5 JF - Plant Journal TI - In vitro culture of Arabidopsis embryos within their ovules VL - 40 ER - TY - CONF AB - A new technique for proving the adaptive indistinguishability of two systems, each composed of some component systems, is presented, using only the fact that corresponding component systems are non-adaptively indistinguishable. The main tool is the definition of a special monotone condition for a random system F, relative to another random system G, whose probability of occurring for a given distinguisher D is closely related to the distinguishing advantage ε of D for F and G, namely it is lower and upper bounded by ε and (1+ln1), respectively. A concrete instantiation of this result shows that the cascade of two random permutations (with the second one inverted) is indistinguishable from a uniform random permutation by adaptive distinguishers which may query the system from both sides, assuming the components’ security only against non-adaptive one-sided distinguishers. As applications we provide some results in various fields as almost k-wise independent probability spaces, decorrelation theory and computational indistinguishability (i.e., pseudo-randomness). AU - Maurer, Ueli M AU - Krzysztof Pietrzak ID - 3208 TI - Composition of random systems: When two weak make one strong VL - 2951 ER - TY - CHAP AU - Ulrich, Florian AU - Heisenberg, Carl-Philipp J ED - Korzh, Vladimir ED - Gong, Zhiyuan ID - 3587 T2 - Fish development and genetics : the zebrafish and medaka models TI - Gastrulation in zebrafish VL - 2 ER - TY - JOUR AB - The coalescent process can describe the effects of selection at linked loci only if selection is so strong that genotype frequencies evolve deterministically. Here, we develop methods proposed by Kaplan, Darden, and Hudson to find the effects of weak selection. We show that the overall effect is given by an extension to Price's equation: the change in properties such as moments of coalescence times is equal to the covariance between those properties and the fitness of the sample of genes. The distribution of coalescence times differs substantially between allelic classes, even in the absence of selection. However, the average coalescence time between randomly chosen genes is insensitive to the current allele frequency and is affected significantly by purifying selection only if deleterious mutations are common and selection is strong (i.e., the product of population size and selection coefficient, Ns > 3). Balancing selection increases mean coalescence times, but the effect becomes large only when mutation rates between allelic classes are low and when selection is extremely strong. Our analysis supports previous simulations that show that selection has surprisingly little effect on genealogies. Moreover, small fluctuations in allele frequency due to random drift can greatly reduce any such effects. This will make it difficult to detect the action of selection from neutral variation alone. AU - Nicholas Barton AU - Etheridge, Alison M ID - 3617 IS - 2 JF - Genetics TI - The effect of selection on genealogies VL - 166 ER - TY - GEN AU - Nicholas Barton ID - 3616 IS - 15 T2 - Current Biology TI - Speciation: Why, how, where and when? VL - 14 ER - TY - CONF AB - Capturing images of documents using handheld digital cameras has a variety of applications in academia, research, knowledge management, retail, and office settings. The ultimate goal of such systems is to achieve image quality comparable to that currently achieved with flatbed scanners even for curved, warped, or curled pages. This can be achieved by high-accuracy 3D modeling of the page surface, followed by a "flattening" of the surface. A number of previous systems have either assumed only perspective distortions, or used techniques like structured lighting, shading, or side-imaging for obtaining 3D shape. This paper describes a system for handheld camera-based document capture using general purpose stereo vision methods followed by a new document dewarping technique. Examples of shape modeling and dewarping of book images is shown. AU - Ulges, Adrian AU - Christoph Lampert AU - Breuel,Thomas M ID - 3688 TI - Document capture using stereo vision ER - TY - JOUR AB - Voltage-gated potassium (Kv) channels control action potential repolarization, interspike membrane potential, and action potential frequency in excitable cells. It is thought that the combinatorial association between distinct alpha and beta subunits determines whether Kv channels function as non-inactivating delayed rectifiers or as rapidly inactivating A-type channels. We show that membrane lipids can convert A-type channels into delayed rectifiers and vice versa. Phosphoinositides remove N-type inactivation from A-type channels by immobilizing the inactivation domains. Conversely, arachidonic acid and its amide anandamide endow delayed rectifiers with rapid voltage-dependent inactivation. The bidirectional control of Kv channel gating by lipids may provide a mechanism for the dynamic regulation of electrical signaling in the nervous system. AU - Oliver, Dominik AU - Lien, Cheng-Chang AU - Soom, Malle AU - Baukrowitz, Thomas AU - Peter Jonas AU - Fakler, Bernd ID - 3810 IS - 5668 JF - Science TI - Functional conversion between A-type and delayed rectifier K+ channels by membrane lipids VL - 304 ER - TY - CONF AB - We study infinite stochastic games played by n-players on a finite graph with goals given by sets of infinite traces. The games are stochastic (each player simultaneously and independently chooses an action at each round, and the next state is determined by a probability distribution depending on the current state and the chosen actions), infinite (the game continues for an infinite number of rounds), nonzero sum (the players' goals are not necessarily conflicting), and undiscounted. We show that if each player has a reachability objective, that is, if the goal for each player i is to visit some subset R-i of the states, then there exists an epsilon-Nash equilibrium in memoryless strategies, for every epsilon > 0. However, exact Nash equilibria need not exist. We study the complexity of finding such Nash equilibria, and show that the payoff of some epsilon-Nash equilibrium in memoryless strategies can be epsilon-approximated in NP. We study the important subclass of n-player turn-based probabilistic games, where at each state at most one player has a nontrivial choice of moves. For turn-based probabilistic games, we show the existence of epsilon-Nash equilibria in pure strategies for games where the objective of player i is a Borel set B-i of infinite traces. However, exact Nash equilibria may not exist. For the special case of omega-regular objectives, we show exact Nash equilibria exist, and can be computed in NP when the omega-regular objectives are expressed as parity objectives. AU - Krishnendu Chatterjee AU - Majumdar, Ritankar S AU - Jurdziński, Marcin ID - 3894 TI - On Nash equilibria in stochastic games VL - 3210 ER - TY - CONF AB - In 2-player non-zero-sum games, Nash equilibria capture the options for rational behavior if each player attempts to maximize her payoff. In contrast to classical game theory, we consider lexicographic objectives: first, each player tries to maximize her own payoff, and then, the player tries to minimize the opponent's payoff. Such objectives arise naturally in the verification of systems with multiple components. There, instead of proving that each component satisfies its specification no matter how the other components behave, it often suffices to prove that each component satisfies its specification provided that the other components satisfy their specifications. We say that a Nash equilibrium is secure if it is an equilibrium with respect to the lexicographic objectives of both players. We prove that in graph games with Borel objectives, which include the games that arise in verification, there may be several Nash equilibria, but there is always a unique maximal payoff profile of secure equilibria. We show how this equilibrium can be computed in the case of omega-regular objectives, and we characterize the memory requirements of strategies that achieve the equilibrium. AU - Krishnendu Chatterjee AU - Thomas Henzinger AU - Jurdziński, Marcin ID - 3895 TI - Games with secure equilibria ER - TY - JOUR AB - Hyaluronan is an unsulfated glycosaminoglycan (GAG) that is ubiquitously expressed in the extracellular matrix (ECM) of all vertebrates, where hyaluronan rich matrices constitute a particular permissive environment for the development of complex biological structures and also for tumor progression. Because of its conserved structure and ubiquitous expression, antibodies for its histochemical detection cannot be produced. We have engineered a fusion protein, neurocan-GFP, and expressed it as a secreted molecule in mammalian cells. Neurocan-GFP fusion protein specifically binds to hyaluronan and directly visualizes hyaluronan on tissue sections, revealing a very detailed picture of hyaluronan distribution. The fluorescent fusion protein can be used in combination with antibodies and nuclear markers for double or triple staining. In addition, it is suitable to visualize hyaluronan on living cells by time-lapse video microscopy. The successful production and application of the neurocan-GFP fusion protein opens up new perspectives for using GFP fusion proteins as detection tools in histological and cytological studies complementing conventional antibody and biotin/avidin techniques. AU - Zhang, Hui AU - Baader, Stephan L AU - Michael Sixt AU - Kappler, Joachim AU - Rauch, Uwe ID - 3931 IS - 7 JF - Journal of Histochemistry and Cytochemistry TI - Neurocan-GFP fusion protein: a new approach to detect hyaluronan on tissue sections and living cells VL - 52 ER - TY - JOUR AB - The Nef protein of human and simian immunodeficiency virus (HIV/SIV) is believed to interfere with T cell activation signals by forming a signaling complex at the plasma membrane. Composition and function of the complex are not fully understood. Here we report that Nef recruits the Polycomb Group (PcG) protein Eed, so far known as a nuclear factor and repressor of transcription, to the membrane of cells. The Nef-induced translocation of Eed led to a potent stimulation of Tat-dependent HIV transcription, implying that Eed removal from the nucleus is required for optimal Tat function. Similar to Nef action, activation of integrin receptors recruited Eed to the plasma membrane, also leading to enhanced Tat/Nef-mediated transcription. Our results suggest a link between membrane-associated activation processes and transcriptional derepression and demonstrate how HIV exploits this mechanism. AU - Witte, Vanessa AU - Laffert, Bernd AU - Rosorius, Olaf AU - Lischka, Peter AU - Blume, Katja AU - Galler, Gunther AU - Stilper, Andrea AU - Willbold, Dieter AU - D'Aloja, Paola AU - Michael Sixt AU - Kolanus, Johanna AU - Ott, Melanie AU - Kolanus, Waldemar AU - Schuler, Gerold AU - Baur, Andreas S ID - 3929 IS - 2 JF - Molecular Cell TI - HIV-1 Nef mimics an integrin receptor signal that recruits the polycomb group protein Eed to the plasma membrane VL - 13 ER - TY - JOUR AB - The writhing number measures the global geometry of a closed space curve or knot. We show that this measure is related to the average winding number of its Gauss map. Using this relationship, we give an algorithm for computing the writhing number for a polygonal knot with n edges in time roughly proportional to n(1.6). We also implement a different, simple algorithm and provide experimental evidence for its practical efficiency. AU - Agarwal, Pankaj K AU - Herbert Edelsbrunner AU - Wang, Yusu ID - 3990 IS - 1 JF - Discrete & Computational Geometry TI - Computing the writhing number of a polygonal knot VL - 32 ER - TY - JOUR AB - Developing cells acquire positional information by reading the graded distribution of morphogens. In Drosophila, the Dpp morphogen forms a long-range concentration gradient by spreading from a restricted source in the developing wing. It has been assumed that Dpp spreads by extracellular diffusion. Under this assumption, the main role of endocytosis in gradient formation is to downregulate receptors at the cell surface. These surface receptors bind to the ligand and thereby interfere with its long-range movement. Recent experiments indicate that Dpp spreading is mediated by Dynamin-dependent endocytosis in the target tissue, suggesting that extracellular diffusion alone cannot account for Dpp dispersal. Here, we perform a theoretical study of a model for morphogen spreading based on extracellular diffusion, which takes into account receptor binding and trafficking. We compare profiles of ligand and surface receptors obtained in this model with experimental data. To this end, we monitored directly the pool of surface receptors and extracellular Dpp with specific antibodies. We conclude that current models considering pure extracellular diffusion cannot explain the observed role of endocytosis during Dpp long-range movement. AU - Kruse, Karsten AU - Pantazis, Periklis AU - Bollenbach, Mark Tobias AU - Julicher, Frank AU - Gonzalez Gaitan, Marcos ID - 4224 IS - 19 JF - Development TI - Dpp gradient formation by dynamin-dependent endocytosis: receptor trafficking and the diffusion model VL - 131 ER - TY - CHAP AU - Harold Vladar AU - Cipriani, Roberto AU - Scharifker, Benjamin AU - Bubis, Jose ED - Seckbach,J. ED - Chela-Flores,J. ED - Owen,T. ED - Raulin,F. ID - 4239 T2 - Life in the Universe From the Miller Experiment to the Search for Life on Other Worlds TI - A Mechanism for the Prebiotic Emergence of Proteins VL - 7 ER - TY - JOUR AB - We consider a single genetic locus which carries two alleles, labelled P and Q. This locus experiences selection and mutation. It is linked to a second neutral locus with recombination rate r. If r = 0, this reduces to the study of a single selected locus. Assuming a Moran model for the population dynamics, we pass to a diffusion approximation and, assuming that the allele frequencies at the selected locus have reached stationarity, establish the joint generating function for the genealogy of a sample from the population and the frequency of the P allele. In essence this is the joint generating function for a coalescent and the random background in which it evolves. We use this to characterize, for the diffusion approximation, the probability of identity in state at the neutral locus of a sample of two individuals (whose type at the selected locus is known) as solutions to a system of ordinary differential equations. The only subtlety is to find the boundary conditions for this system. Finally, numerical examples are presented that illustrate the accuracy and predictions of the diffusion approximation. In particular, a comparison is made between this approach and one in which the frequencies at the selected locus are estimated by their value in the absence of fluctuations and a classical structured coalescent model is used. AU - Nicholas Barton AU - Etheridge, Alison M AU - Sturm, Anja K ID - 4253 IS - 2 JF - Annals of Applied Probability TI - Coalescence in a Random Background VL - 14 ER - TY - GEN AB - Assembly of neuronal circuits is controlled by the sequential acquisition of neuronal subpopulation-specific identities at progressive developmental steps. Whereas neuronal features involved in initial phases of differentiation are already established at cell-cycle exit, recent findings, based mainly on work in the peripheral nervous system, suggest that the timely integration of signals encountered en route to targets and from the target region itself is essential to control late steps in connectivity. As neurons project towards their targets they require target-derived signals to establish mature axonal projections and acquire neuronal traits such as the expression of distinct combinations of neurotransmitters. Recent evidence presented in this review shows that this principle, of a signaling interplay between target-derived signals and neuronal cell bodies, is often mediated through transcriptional events and is evolutionarily conserved. AU - Simon Hippenmeyer AU - Kramer, Ina AU - Arber, Silvia ID - 3142 IS - 8 T2 - Trends in Neurosciences TI - Control of neuronal phenotype: What targets tell the cell bodies VL - 27 ER - TY - JOUR AB - Minimum cut/maximum flow algorithms on graphs have emerged as an increasingly useful tool for exactor approximate energy minimization in low-level vision. The combinatorial optimization literature provides many min-cut/max-flow algorithms with different polynomial time complexity. Their practical efficiency, however, has to date been studied mainly outside the scope of computer vision. The goal of this paper is to provide an experimental comparison of the efficiency of min-cut/max flow algorithms for applications in vision. We compare the running times of several standard algorithms, as well as a new algorithm that we have recently developed. The algorithms we study include both Goldberg-Tarjan style "push -relabel" methods and algorithms based on Ford-Fulkerson style "augmenting paths." We benchmark these algorithms on a number of typical graphs in the contexts of image restoration, stereo, and segmentation. In many cases, our new algorithm works several times faster than any of the other methods, making near real-time performance possible. An implementation of our max-flow/min-cut algorithm is available upon request for research purposes. AU - Boykov, Yuri AU - Vladimir Kolmogorov ID - 3178 IS - 9 JF - IEEE Transactions on Pattern Analysis and Machine Intelligence TI - An experimental comparison of min-cut/max-flow algorithms for energy minimization in vision VL - 26 ER - TY - JOUR AB - In the last few years, several new algorithms based on graph cuts have been developed to solve energy minimization problems in computer vision. Each of these techniques constructs a graph such that the minimum cut on the graph also minimizes the energy. Yet, because these graph constructions are complex and highly specific to a particular energy function, graph cuts have seen limited application to date. In this paper, we give a characterization of the energy functions that can be minimized by graph cuts. Our results are restricted to functions of binary variables. However, our work generalizes many previous constructions and is easily applicable to vision problems that involve large numbers of labels, such as stereo, motion, image restoration, and scene reconstruction. We give a precise characterization of what energy functions can be minimized using graph cuts, among the energy functions that can be written as a sum of terms containing three or fewer binary variables. We also provide a general-purpose construction to minimize such an energy function. Finally, we give a necessary condition for any energy function of binary variables to be minimized by graph cuts. Researchers who are considering the use of graph cuts to optimize a particular energy function can use our results to determine if this is possible and then follow our construction to create the appropriate graph. A software implementation is freely available. AU - Vladimir Kolmogorov AU - Zabih, Ramin ID - 3173 IS - 2 JF - IEEE Transactions on Pattern Analysis and Machine Intelligence TI - What energy functions can be minimized via graph cuts? VL - 26 ER - TY - JOUR AB - The simultaneous multiple volume (SMV) approach in navigator-gated MRI allows the use of the whole motion range or the entire scan time for the reconstruction of final images by simultaneously acquiring different image volumes at different motion states. The motion tolerance range for each volume is kept small, thus SMV substantially increases the scan efficiency of navigator methods while maintaining the effectiveness of motion suppression. This article reports a general implementation of the SMV approach using a multiprocessor scheduling algorithm. Each motion state is regarded as a processor and each volume is regarded as a job. An efficient scheduling that completes all jobs in minimal time is maintained even when the motion pattern changes. Initial experiments demonstrated that SMV significantly increased the scan efficiency of navigatorgated MRI. AU - Vladimir Kolmogorov AU - Nguyen, Thành D AU - Nuval, Anthony AU - Spincemaille, Pascal AU - Prince, Martin R AU - Zabih, Ramin AU - Wang, Yusu ID - 3172 IS - 2 JF - Magnetic Resonance in Medicine TI - Multiprocessor scheduling implementation of the simultaneous multiple volume SMV navigator method VL - 52 ER - TY - CONF AB - Feature space clustering is a popular approach to image segmentation, in which a feature vector of local properties (such as intensity, texture or motion) is computed at each pixel. The feature space is then clustered, and each pixel is labeled with the cluster that contains its feature vector. A major limitation of this approach is that feature space clusters generally lack spatial coherence (i.e., they do not correspond to a compact grouping of pixels). In this paper, we propose a segmentation algorithm that operates simultaneously in feature space and in image space. We define an energy function over both a set of clusters and a labeling of pixels with clusters. In our framework, a pixel is labeled with a single cluster (rather than, for example, a distribution over clusters). Our energy function penalizes clusters that are a poor fit to the data in feature space, and also penalizes clusters whose pixels lack spatial coherence. The energy function can be efficiently minimized using graph cuts. Our algorithm can incorporate both parametric and non-parametric clustering methods. It can be applied to many optimization-based clustering methods, including k-means and k-medians, and can handle models which are very close in feature space. Preliminary results are presented on segmenting real and synthetic images, using both parametric and non-parametric clustering. AU - Zabih, Ramin AU - Vladimir Kolmogorov ID - 3177 TI - Spatially coherent clustering using graph cuts VL - 2 ER - TY - CONF AB - The problem of efficient, interactive foreground/background segmentation in still images is of great practical importance in image editing. Classical image segmentation tools use either texture (colour) information, e.g. Magic Wand, or edge (contrast) information, e.g. Intelligent Scissors. Recently, an approach based on optimization by graph-cut has been developed which successfully combines both types of information. In this paper we extend the graph-cut approach in three respects. First, we have developed a more powerful, iterative version of the optimisation. Secondly, the power of the iterative algorithm is used to simplify substantially the user interaction needed for a given quality of result. Thirdly, a robust algorithm for "border matting" has been developed to estimate simultaneously the alpha-matte around an object boundary and the colours of foreground pixels. We show that for moderately difficult examples the proposed method outperforms competitive tools. AU - Rother, Carsten AU - Vladimir Kolmogorov AU - Blake, Andrew ID - 3179 IS - 3 TI - "GrabCut" - Interactive foreground extraction using iterated graph cuts VL - 23 ER - TY - JOUR AB - Single-molecule force-spectroscopy was employed to unfold and refold single sodium-proton antiporters (NhaA) of Escherichia coli from membrane patches. Although transmembrane α-helices and extracellular polypeptide loops exhibited sufficient stability to individually establish potential barriers against unfolding, two helices predominantly unfolded pairwise, thereby acting as one structural unit. Many of the potential barriers were detected unfolding NhaA either from the C-terminal or the N-terminal end. It was found that some molecular interactions stabilizing secondary structural elements were directional, while others were not. Additionally, some interactions appeared to occur between the secondary structural elements. After unfolding ten of the 12 helices, the extracted polypeptide was allowed to refold back into the membrane. After five seconds, the refolded polypeptide established all secondary structure elements of the native protein. One helical pair showed a characteristic spring like “snap in” into its folded conformation, while the refolding process of other helices was not detected in particular. Additionally, individual helices required characteristic periods of time to fold. Correlating these results with the primary structure of NhaA allowed us to obtain the first insights into how potential barriers establish and determine the folding kinetics of the secondary structure elements. AU - Kedrov, Alexej AU - Ziegler, Christine AU - Harald Janovjak AU - Kühlbrandt, Werner AU - Mueller, Daniel J ID - 3420 IS - 5 JF - Journal of Molecular Biology TI - Controlled unfolding and refolding of a single sodium/proton antiporter using atomic force microscopy VL - 340 ER - TY - JOUR AB - The folding and stability of transmembrane proteins is a fundamental and unsolved biological problem. Here, single bacteriorhodopsin molecules were mechanically unfolded from native purple membranes using atomic force microscopy and force spectroscopy. The energy landscape of individual transmembrane α helices and polypeptide loops was mapped by monitoring the pulling speed dependence of the unfolding forces and applying Monte Carlo simulations. Single helices formed independently stable units stabilized by a single potential barrier. Mechanical unfolding of the helices was triggered by 3.9–7.7 Å extension, while natural unfolding rates were of the order of 10−3 s−1. Besides acting as individually stable units, helices associated pairwise, establishing a collective potential barrier. The unfolding pathways of individual proteins reflect distinct pulling speed-dependent unfolding routes in their energy landscapes. These observations support the two-stage model of membrane protein folding in which α helices insert into the membrane as stable units and then assemble into the functional protein. AU - Harald Janovjak AU - Struckmeier, Jens AU - Hubain, Maurice AU - Kessler, Max AU - Kedrov, Alexej AU - Mueller, Daniel J ID - 3419 IS - 5 JF - Structure TI - Probing the energy landscape of the membrane protein bacteriorhodopsin VL - 12 ER - TY - CHAP AB - The Jacobi set of two Morse functions defined on a common - manifold is the set of critical points of the restrictions of one func- tion to the level sets of the other function. Equivalently, it is the set of points where the gradients of the functions are parallel. For a generic pair of Morse functions, the Jacobi set is a smoothly embed- ded 1-manifold. We give a polynomial-time algorithm that com- putes the piecewise linear analog of the Jacobi set for functions specified at the vertices of a triangulation, and we generalize all results to more than two but at most Morse functions. AU - Herbert Edelsbrunner AU - Harer, John ID - 3575 T2 - Foundations of Computational Mathematics TI - Jacobi sets of multiple Morse functions VL - 312 ER - TY - CHAP AU - Herbert Edelsbrunner ID - 3574 T2 - Handbook of Discrete and Computational Geometry TI - Biological applications of computational topology ER - TY - GEN AB - Genome sizes vary enormously. This variation in DNA content correlates with effective population size, suggesting that deleterious additions to the genome can accumulate in small populations. On this view, the increased complexity of biological functions associated with large genomes partly reflects evolutionary degeneration. AU - Charlesworth, Brian AU - Nicholas Barton ID - 3595 IS - 6 T2 - Current Biology TI - Genome size: Does bigger mean worse? VL - 14 ER - TY - JOUR AB - We analyze the changes in the mean and variance components of a quantitative trait caused by changes in allele frequencies, concentrating on the effects of genetic drift. We use a general representation of epistasis and dominance that allows an arbitrary relation between genotype and phenotype for any number of diallelic loci. We assume initial and final Hardy-Weinberg and linkage equilibrium in our analyses of drift-induced changes. Random drift generates transient linkage disequilibria that cause correlations between allele frequency fluctuations at different loci. However, we show that these have negligible effects, at least for interactions among small numbers of loci. Our analyses are based on diffusion approximations that summarize the effects of drift in terms of F, the inbreeding coefficient, interpreted as the expected proportional decrease in heterozygosity at each locus. For haploids, the variance of the trait mean after a population bottleneck is var(Δ&#x007a;̄) =inline imagewhere n is the number of loci contributing to the trait variance, VA(1)=VA is the additive genetic variance, and VA(k) is the kth-order additive epistatic variance. The expected additive genetic variance after the bottleneck, denoted (V*A), is closely related to var(Δ&#x007a;̄); (V*A) (1 –F)inline imageThus, epistasis inflates the expected additive variance above VA(1 –F), the expectation under additivity. For haploids (and diploids without dominance), the expected value of every variance component is inflated by the existence of higher order interactions (e.g., third-order epistasis inflates (V*AA)). This is not true in general with diploidy, because dominance alone can reduce (V*A) below VA(1 –F) (e.g., when dominant alleles are rare). Without dominance, diploidy produces simple expressions: var(Δ&#x007a;̄)=inline image=1 (2F) kVA(k) and (V*A) = (1 –F)inline imagek(2F)k-1VA(k) With dominance (and even without epistasis), var(Δ&#x007a;̄)and (V*A) no longer depend solely on the variance components in the base population. For small F, the expected additive variance simplifies to (V*A)(1 –F) VA+ 4FVAA+2FVD+2FCAD, where CAD is a sum of two terms describing covariances between additive effects and dominance and additive × dominance interactions. Whether population bottlenecks lead to expected increases in additive variance depends primarily on the ratio of nonadditive to additive genetic variance in the base population, but dominance precludes simple predictions based solely on variance components. We illustrate these results using a model in which genotypic values are drawn at random, allowing extreme and erratic epistatic interactions. Although our analyses clarify the conditions under which drift is expected to increase VA, we question the evolutionary importance of such increases. AU - Nicholas Barton AU - Turelli, Michael ID - 3614 IS - 10 JF - Evolution; International Journal of Organic Evolution TI - Effects of allele frequency changes on variance components under a general model of epistasis VL - 58 ER - TY - JOUR AB - We investigate three alternative selection-based scenarios proposed to maintain polygenic variation: pleiotropic balancing selection, G x E interactions (with spatial or temporal variation in allelic effects), and sex-dependent allelic effects. Each analysis assumes an additive polygenic trait with n diallelic loci under stabilizing selection. We allow loci to have different effects and consider equilibria at which the population mean departs from the stabilizing-selection optimum. Under weak selection, each model produces essentially identical, approximate allele-frequency dynamics. Variation is maintained under pleiotropic balancing selection only at loci for which the strength of balancing selection exceeds the effective strength of stabilizing selection. In addition, for all models, polymorphism requires that the population mean be close enough to the optimum that directional selection does not overwhelm balancing selection. This balance allows many simultaneously stable equilibria, and we explore their properties numerically. Both spatial and temporal G x E can maintain variation at loci for which the coefficient of variation (across environments) of the effect of a substitution exceeds a critical value greater than one. The critical value depends on the correlation between substitution effects at different loci. For large positive correlations (e.g., ρ2ij > 3/4), even extreme fluctuations in allelic effects cannot maintain variation. Surprisingly, this constraint on correlations implies that sex-dependent allelic effects cannot maintain polygenic variation. We present numerical results that support our analytical approximations and discuss our results in connection to relevant data and alternative variance-maintaining mechanisms. AU - Turelli, Michael AU - Nicholas Barton ID - 3615 IS - 2 JF - Genetics TI - Polygenic variation maintained by balancing selection: pleiotropy, sex-dependent allelic effects and GxE interactions VL - 166 ER - TY - JOUR AB - The time course of Mg(2+) block and unblock of NMDA receptors (NMDARs) determines the extent they are activated by depolarization. Here, we directly measure the rate of NMDAR channel opening in response to depolarizations at different times after brief (1 ms) and sustained (4.6 s) applications of glutamate to nucleated patches from neocortical pyramidal neurons. The kinetics of Mg(2+) unblock were found to be non-instantaneous and complex, consisting of a prominent fast component (time constant approximately 100 micros) and slower components (time constants 4 and approximately 300 ms), the relative amplitudes of which depended on the timing of the depolarizing pulse. Fitting a kinetic model to these data indicated that Mg(2+) not only blocks the NMDAR channel, but reduces both the open probability and affinity for glutamate, while enhancing desensitization. These effects slow the rate of NMDAR channel opening in response to depolarization in a time-dependent manner such that the slower components of Mg(2+) unblock are enhanced during depolarizations at later times after glutamate application. One physiological consequence of this is that brief depolarizations occurring earlier in time after glutamate application are better able to open NMDAR channels. This finding has important implications for spike-timing-dependent synaptic plasticity (STDP), where the precise (millisecond) timing of action potentials relative to synaptic inputs determines the magnitude and sign of changes in synaptic strength. Indeed, we find that STDP timing curves of NMDAR channel activation elicited by realistic dendritic action potential waveforms are narrower than expected assuming instantaneous Mg(2+) unblock, indicating that slow Mg(2+) unblock of NMDAR channels makes the STDP timing window more precise. AU - Kampa, Bjorn M AU - Clements, John AU - Peter Jonas AU - Stuart, Greg J ID - 3807 IS - Pt 2 JF - Journal of Physiology TI - Kinetics of Mg(2+) unblock of NMDA receptors: implications for spike-timing dependent synaptic plasticity VL - 556 ER - TY - JOUR AB - Neural stem cells in various regions of the vertebrate brain continuously generate neurons throughout life. In the mammalian hippocampus, a region important for spatial and episodic memory, thousands of new granule cells are produced per day, with the exact number depending on environmental conditions and physical exercise. The survival of these neurons is improved by learning and conversely learning may be promoted by neurogenesis. Although it has been suggested that newly generated neurons may have specific properties to facilitate learning, the cellular and synaptic mechanisms of plasticity in these neurons are largely unknown. Here we show that young granule cells in the adult hippocampus differ substantially from mature granule cells in both active and passive membrane properties. In young neurons, T-type Ca2+ channels can generate isolated Ca2+ spikes and boost fast Na+ action potentials, contributing to the induction of synaptic plasticity. Associative long-term potentiation can be induced more easily in young neurons than in mature neurons under identical conditions. Thus, newly generated neurons express unique mechanisms to facilitate synaptic plasticity, which may be important for the formation of new memories. AU - Schmidt-Hieber, Christoph AU - Peter Jonas AU - Bischofberger, Josef ID - 3809 IS - 6988 JF - Nature TI - Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus VL - 429 ER - TY - JOUR AB - The operation of neuronal networks crucially depends on a fast time course of signaling in inhibitory interneurons. Synapses that excite interneurons generate fast currents, owing to the expression of glutamate receptors of specific subunit composition. Interneurons generate brief action potentials in response to transient synaptic activation and discharge repetitively at very high frequencies during sustained stimulation. The ability to generate short-duration action potentials at high frequencies depends on the expression of specific voltage-gated K+ channels. Factors facilitating fast action potential initiation following synaptic excitation include depolarized interneuron resting potential, subthreshold conductances and active dendrites. Finally, GABA release at interneuron output synapses is rapid and highly synchronized, leading to a faster inhibition in postsynaptic interneurons than in principal cells. Thus, the expression of distinct transmitter receptors and voltage-gated ion channels ensures that interneurons operate with high speed and temporal precision. AU - Peter Jonas AU - Bischofberger, Josef AU - Fricker, Desdemona AU - Miles, Richard ID - 3805 IS - 1 JF - Trends in Neurosciences TI - Interneuron Diversity series: Fast in, fast out--temporal and spatial signal processing in hippocampal interneurons VL - 27 ER - TY - JOUR AB - Wingless (ergatoid) males of the tramp ant Cardiocondyla minutior attack and kill their young ergatoid rivals and thus attempt to monopolize mating with female sexuals reared in the colony. Because of the different strength of local mate competition in colonies with one or several reproductive queens, we expected the production of new ergatoid males to vary with queen number. Sex ratios were mostly female-biased, but in contrast to the sympatric species C. obscurior (Cremer and Heinze, 2002) neither the percentage of ergatoid males nor of female sexuals among the first 20 sexuals produced varied considerably with queen number. As in C. obscurior, experimental colony fragmentation led to the production of winged males, whereas in unfragmented control colonies only ergatoid males eclosed. AU - Heinze, Jürgen AU - Böttcher, A. AU - Cremer, Sylvia ID - 3918 IS - 3 JF - Insectes Sociaux TI - Production of winged and wingless males in the ant, Cardiocondyla minutior VL - 51 ER - TY - CONF AB - We give an algorithm that locally improves the fit between two proteins modeled as space-filling diagrams. The algorithm defines the fit in purely geometric terms and improves by applying a rigid motion to one of the two proteins. Our implementation of the algorithm takes between three and ten seconds and converges with high likelihood to the correct docked configuration, provided it starts at a position away from the correct one by at most 18 degrees of rotation and at most 3.0Angstrom of translation. The speed and convergence radius make this an attractive algorithm to use in combination with a coarse sampling of the six-dimensional space of rigid motions. AU - Choi, Vicky AU - Agarwal, Pankaj K AU - Herbert Edelsbrunner AU - Rudolph, Johannes ID - 3988 TI - Local search heuristic for rigid protein docking VL - 3240 ER - TY - JOUR AB - The motion of a biomolecule greatly depends on the engulfing solution, which is mostly water. Instead of representing individual water molecules, it is desirable to develop implicit solvent models that nevertheless accurately represent the contribution of the solvent interaction to the motion. In such models, hydrophobicity is expressed as a weighted sum of atomic surface areas. The derivatives of these weighted areas contribute to the force that drives the motion. In this paper we give formulas for the weighted and unweighted area derivatives of a molecule modeled as a space-filling diagram made up of balls in motion. Other than the radii and the centers of the balls, the formulas are given in terms of the sizes of circular arcs of the boundary and edges of the power diagram. We also give inclusion-exclusion formulas for these sizes. AU - Bryant, Robert AU - Herbert Edelsbrunner AU - Koehl, Patrice AU - Levitt, Michael ID - 3986 IS - 3 JF - Discrete & Computational Geometry TI - The area derivative of a space-filling diagram VL - 32 ER - TY - JOUR AB - We combine topological and geometric methods to construct a multiresolution representation for a function over a two-dimensional domain. In a preprocessing stage, we create the Morse-Smale complex of the function and progressively simplify its topology by cancelling pairs of critical points. Based on a simple notion of dependency among these cancellations, we construct a hierarchical data structure supporting traversal and reconstruction operations similarly to traditional geometry-based representations. We use this data structure to extract topologically valid approximations that satisfy error bounds provided at runtime. AU - Bremer, Peer-Timo AU - Herbert Edelsbrunner AU - Hamann, Bernd AU - Pascucci, Valerio ID - 3984 IS - 4 JF - IEEE Transactions on Visualization and Computer Graphics TI - A topological hierarchy for functions on triangulated surfaces VL - 10 ER - TY - JOUR AB - We consider scientific data sets that describe density functions over three-dimensional geometric domains. Such data sets are often large and coarsened representations are needed for visualization and analysis. Assuming a tetrahedral mesh representation, we construct such representations with a simplification algorithm that combines three goals: the approximation of the function, the preservation of the mesh topology, and the improvement of the mesh quality. The third goal is achieved with a novel extension of the well-known quadric error metric. We perform a number of computational experiments to understand the effect of mesh quality improvement on the density map approximation. In addition, we study the effect of geometric simplification on the topological features of the function by monitoring its critical points. AU - Natarajan, Vijay AU - Herbert Edelsbrunner ID - 3987 IS - 5 JF - IEEE Transactions on Visualization and Computer Graphics TI - Simplification of three-dimensional density maps VL - 10 ER - TY - JOUR AB - Given a Morse function f over a 2-manifold with or without boundary, the Reeb graph is obtained by contracting the connected components of the level sets to points. We prove tight upper and lower bounds on the number of loops in the Reeb graph that depend on the genus, the number of boundary components, and whether or not the 2-manifold is orientable. We also give an algorithm that constructs the Reeb graph in time O(n log n), where n is the number of edges in the triangulation used to represent the 2-manifold and the Morse function. AU - Cole-McLaughlin, Kree AU - Herbert Edelsbrunner AU - Harer, John AU - Natarajan, Vijay AU - Pascucci, Valerio ID - 3985 IS - 2 JF - Discrete & Computational Geometry TI - Loops in Reeb graphs of 2-manifolds VL - 32 ER - TY - CONF AB - We introduce local and global comparison measures for a collection of k less than or equal to d real-valued smooth functions on a common d-dimensional Riemannian manifold. For k = d = 2 we relate the measures to the set of critical points of one function restricted to the level sets of the other. The definition of the measures extends to piecewise linear functions for which they ace easy to compute. The computation of the measures forms the centerpiece of a software tool which we use to study scientific datasets. AU - Herbert Edelsbrunner AU - Harer, John AU - Natarajan, Vijay AU - Pascucci, Valerio ID - 3989 TI - Local and global comparison of continuous functions ER - TY - JOUR AB - During vertebrate gastrulation, a relatively limited number of blastodermal cells undergoes a stereotypical set of cellular movements that leads to formation of the three germ layers: ectoderm, mesoderm and endoderm. Gastrulation, therefore, provides a unique developmental system in which to study cell movements in vivo in a fairly simple cellular context. Recent advances have been made in elucidating the cellular and molecular mechanisms that underlie cell movements during zebrafish gastrulation. These findings can be compared with observations made in other model systems to identify potential general mechanisms of cell migration during development. AU - Montero, Juan AU - Heisenberg, Carl-Philipp J ID - 4172 IS - 11 JF - Trends in Cell Biology TI - Gastrulation dynamics: cells move into focus VL - 14 ER - TY - JOUR AB - The dynamical basis of tumoral growth has been controversial. Many models have been proposed to explain cancer development. The descriptions employ exponential, potential, logistic or Gompertzian growth laws. Some of these models are concerned with the interaction between cancer and the immunological, system. Among other properties, these models are concerned with the microscopic behavior of tumors and the emergence of cancer. We propose a modification of a previous model by Stepanova, which describes the specific immunological response against cancer. The modification consists of the substitution of a Gompertian law for the exponential rate used for tumoral growth. This modification is motivated by the numerous works confirming that Gompertz's equation correctly describes solid tumor growth. The modified model predicts that near zero, tumors always tend to grow. Immunological contraposition never suffices to induce a complete regression of the tumor. Instead, a stable microscopic equilibrium between cancer and immunological activity can be attained. In other words, our model predicts that the theory of immune surveillance is plausible. A macroscopic equilibrium in which the system develops cancer is also possible. In this case, immunological activity is depleted. This is consistent with the phenomena of cancer tolerance. Both equilibrium points can coexist or can exist without the other. In all cases the fixed point at zero tumor size is unstable. Since immunity cannot induce a complete tumor regression, a therapy is required. We include constant-dose therapies and show that they are insufficient. Final levels of immunocompetent cells and tumoral cells are finite, thus post-treatment regrowth of the tumor is certain. We also evaluate late-intensification therapies which are successful. They induce an asymptotic regression to zero tumor size. Immune response is also suppressed by the therapy, and thus plays a negligible role in the remission. We conclude that treatment evaluation should be successful without taking into account immunological effects. (C) 2003 Elsevier Ltd. All rights reserved. AU - de Vladar, Harold AU - González, J. ID - 4238 IS - 3 JF - Journal of Theoretical Biology TI - Dynamic response of cancer under the influence of immunological activity and therapy VL - 227 ER - TY - CHAP AU - Harold Vladar AU - Cipriani, Roberto AU - Scharifker, Benjamin AU - Bubis, Jose ED - Hanslmeier,A. ED - Kempe,S. ED - Seckbach,J. ID - 4230 T2 - Life in the Universe From the Miller Experiment to the Search for Life on Other Worlds TI - A mechanism for the prebiotic emergence of proteins ER - TY - THES AU - de Vladar, Harold ID - 4236 TI - Métodos no lineales y sus aplicaciones en dinámicas aleatorias de poblaciones celulares ER - TY - CONF AU - Maler, Oded AU - Dejan Nickovic ID - 4372 TI - Monitoring Temporal Properties of Continuous Signals ER - TY - THES AB - The enormous cost and ubiquity of software errors necessitates the need for techniques and tools that can precisely analyze large systems and prove that they meet given specifications, or if they don't, return counterexample behaviors showing how the system fails. Recent advances in model checking, decision procedures, program analysis and type systems, and a shift of focus to partial specifications common to several systems (e.g., memory safety and race freedom) have resulted in several practical verification methods. However, these methods are either precise or they are scalable, depending on whether they track the values of variables or only a fixed small set of dataflow facts (e.g., types), and are usually insufficient for precisely verifying large programs. We describe a new technique called Lazy Abstraction (LA) which achieves both precision and scalability by localizing the use of precise information. LA automatically builds, explores and refines a single abstract model of the program in a way that different parts of the model exhibit different degrees of precision, namely just enough to verify the desired property. The algorithm automatically mines the information required by partitioning mechanical proofs of unsatisfiability of spurious counterexamples into Craig Interpolants. For multithreaded systems, we give a new technique based on analyzing the behavior of a single thread executing in a context which is an abstraction of the other (arbitrarily many) threads. We define novel context models and show how to automatically infer them and analyze the full system (thread + context) using LA. LA is implemented in BLAST. We have run BLAST on Windows and Linux Device Drivers to verify API conformance properties, and have used it to find (or guarantee the absence of) data races in multithreaded Networked Embedded Systems (NESC) applications. BLAST is able to prove the absence of races in several cases where earlier methods, which depend on lock-based synchronization, fail. AU - Jhala, Ranjit ID - 4424 TI - Program verification by lazy abstraction ER - TY - CONF AB - We present a type system for E code, which is an assembly language that manages the release, interaction, and termination of real-time tasks. E code specifies a deadline for each task, and the type system ensures that the deadlines are path-insensitive. We show that typed E programs allow, for given worst-case execution times of tasks, a simple schedulability analysis. Moreover, the real-time programming language Giotto can be compiled into typed E~code. This shows that typed E~code identifies an easily schedulable yet expressive class of real-time programs. We have extended the Giotto compiler to generate typed E code, and enabled the run-time system for E code to perform a type and schedulability check before executing the code. AU - Thomas Henzinger AU - Kirsch, Christoph M ID - 4445 TI - A typed assembly language for real-time programs ER - TY - CONF AB - The success of model checking for large programs depends crucially on the ability to efficiently construct parsimonious abstractions. A predicate abstraction is parsimonious if at each control location, it specifies only relationships between current values of variables, and only those which are required for proving correctness. Previous methods for automatically refining predicate abstractions until sufficient precision is obtained do not systematically construct parsimonious abstractions: predicates usually contain symbolic variables, and are added heuristically and often uniformly to many or all control locations at once. We use Craig interpolation to efficiently construct, from a given abstract error trace which cannot be concretized, a parsominous abstraction that removes the trace. At each location of the trace, we infer the relevant predicates as an interpolant between the two formulas that define the past and the future segment of the trace. Each interpolant is a relationship between current values of program variables, and is relevant only at that particular program location. It can be found by a linear scan of the proof of infeasibility of the trace.We develop our method for programs with arithmetic and pointer expressions, and call-by-value function calls. For function calls, Craig interpolation offers a systematic way of generating relevant predicates that contain only the local variables of the function and the values of the formal parameters when the function was called. We have extended our model checker Blast with predicate discovery by Craig interpolation, and applied it successfully to C programs with more than 130,000 lines of code, which was not possible with approaches that build less parsimonious abstractions. AU - Thomas Henzinger AU - Jhala, Ranjit AU - Majumdar, Ritankar S AU - McMillan, Kenneth L ID - 4458 TI - Abstractions from proofs ER - TY - CHAP AB - One of the central axioms of extreme programming is the disciplined use of regression testing during stepwise software development. Due to recent progress in software model checking, it has become possible to supplement this process with automatic checks for behavioral safety properties of programs, such as conformance with locking idioms and other programming protocols and patterns. For efficiency reasons, all checks must be incremental, i.e., they must reuse partial results from previous checks in order to avoid all unnecessary repetition of expensive verification tasks. We show that the lazy-abstraction algorithm, and its implementation in Blast, can be extended to support the fully automatic and incremental checking of temporal safety properties during software development. AU - Thomas Henzinger AU - Jhala, Ranjit AU - Majumdar, Ritankar S AU - Sanvido, Marco A ID - 4461 T2 - Verification: Theory and Practice TI - Extreme model checking VL - 2772 ER - TY - CONF AB - Software model checking has been successful for sequential programs, where predicate abstraction offers suitable models, and counterexample-guided abstraction refinement permits the automatic inference of models. When checking concurrent programs, we need to abstract threads as well as the contexts in which they execute. Stateless context models, such as predicates on global variables, prove insufficient for showing the absence of race conditions in many examples. We therefore use richer context models, which combine (1) predicates for abstracting data state, (2) control flow quotients for abstracting control state, and (3) counters for abstracting an unbounded number of threads. We infer suitable context models automatically by a combination of counterexample-guided abstraction refinement, bisimulation minimization, circular assume-guarantee reasoning, and parametric reasoning about an unbounded number of threads. This algorithm, called CIRC, has been implemented in BLAST and succeeds in checking many examples of NESC code for data races. In particular, BLAST proves the absence of races in several cases where previous race checkers give false positives. AU - Thomas Henzinger AU - Jhala, Ranjit AU - Majumdar, Ritankar S ID - 4459 TI - Race checking by context inference ER - TY - CONF AB - We present a new high-level programming language, called xGiotto, for programming applications with hard real-time constraints. Like its predecessor, xGiotto is based on the LET (logical execution time) assumption: the programmer specifies when the outputs of a task become available, and the compiler checks if the specification can be implemented on a given platform. However, while the predecessor language xGiotto was purely time-triggered, xGiotto accommodates also asynchronous events. Indeed, through a mechanism called event scoping, events are the main structuring principle of the new language. The xGiotto compiler and run-time system implement event scoping through a tree-based event filter. The compiler also checks programs for determinism (absence of race conditions). AU - Ghosal, Arkadeb AU - Thomas Henzinger AU - Kirsch, Christoph M AU - Sanvido, Marco A ID - 4525 TI - Event-driven programming with logical execution times VL - 2993 ER - TY - CONF AB - Strategies in repeated games can be classified as to whether or not they use memory and/or randomization. We consider Markov decision processes and 2-player graph games, both of the deterministic and probabilistic varieties. We characterize when memory and/or randomization are required for winning with respect to various classes of w-regular objectives, noting particularly when the use of memory can be traded for the use of randomization. In particular, we show that Markov decision processes allow randomized memoryless optimal strategies for all M?ller objectives. Furthermore, we show that 2-player probabilistic graph games allow randomized memoryless strategies for winning with probability 1 those M?ller objectives which are upward-closed. Upward-closure means that if a set α of infinitely repeating vertices is winning, then all supersets of α are also winning. AU - Krishnendu Chatterjee AU - de Alfaro, Luca AU - Thomas Henzinger ID - 4555 TI - Trading memory for randomness ER - TY - CONF AB - We study perfect-information stochastic parity games. These are two-player nonterminating games which are played on a graph with turn-based probabilistic transitions. A play results in an infinite path and the conflicting goals of the two players are ω-regular path properties, formalized as parity winning conditions. The qualitative solution of such a game amounts to computing the set of vertices from which a player has a strategy to win with probability 1 (or with positive probability). The quantitative solution amounts to computing the value of the game in every vertex, i.e., the highest probability with which a player can guarantee satisfaction of his own objective in a play that starts from the vertex.For the important special case of one-player stochastic parity games (parity Markov decision processes) we give polynomial-time algorithms both for the qualitative and the quantitative solution. The running time of the qualitative solution is O(d · m3/2) for graphs with m edges and d priorities. The quantitative solution is based on a linear-programming formulation.For the two-player case, we establish the existence of optimal pure memoryless strategies. This has several important ramifications. First, it implies that the values of the games are rational. This is in contrast to the concurrent stochastic parity games of de Alfaro et al.; there, values are in general algebraic numbers, optimal strategies do not exist, and ε-optimal strategies have to be mixed and with infinite memory. Second, the existence of optimal pure memoryless strategies together with the polynomial-time solution forone-player case implies that the quantitative two-player stochastic parity game problem is in NP ∩ co-NP. This generalizes a result of Condon for stochastic games with reachability objectives. It also constitutes an exponential improvement over the best previous algorithm, which is based on a doubly exponential procedure of de Alfaro and Majumdar for concurrent stochastic parity games and provides only ε-approximations of the values. AU - Krishnendu Chatterjee AU - Jurdziński, Marcin AU - Thomas Henzinger ID - 4558 TI - Quantitative stochastic parity games ER - TY - JOUR AB - We study the problem of determining stack boundedness and the exact maximum stack size for three classes of interrupt-driven programs. Interrupt-driven programs are used in many real-time applications that require responsive interrupt handling. In order to ensure responsiveness, programmers often enable interrupt processing in the body of lower-priority interrupt handlers. In such programs a programming error can allow interrupt handlers to be interrupted in a cyclic fashion to lead to an unbounded stack, causing the system to crash. For a restricted class of interrupt-driven programs, we show that there is a polynomial-time procedure to check stack boundedness, while determining the exact maximum stack size is PSPACE-complete. For a larger class of programs, the two problems are both PSPACE-complete, and for the largest class of programs we consider, the two problems are PSPACE-hard and can be solved in exponential time. While the complexities are high, our algorithms are exponential only in the number of handlers, and polynomial in the size of the program. AU - Krishnendu Chatterjee AU - Ma, Di AU - Majumdar, Ritankar S AU - Zhao, Tian AU - Thomas Henzinger AU - Palsberg, Jens ID - 4556 IS - 2 JF - Information and Computation TI - Stack size analysis for interrupt-driven programs VL - 194 ER - TY - CONF AB - BLAST is an automatic verification tool for checking temporal safety properties of C programs. Blast is based on lazy predicate abstraction driven by interpolation-based predicate discovery. In this paper, we present the Blast specification language. The language specifies program properties at two levels of precision. At the lower level, monitor automata are used to specify temporal safety properties of program executions (traces). At the higher level, relational reachability queries over program locations are used to combine lower-level trace properties. The two-level specification language can be used to break down a verification task into several independent calls of the model-checking engine. In this way, each call to the model checker may have to analyze only part of the program, or part of the specification, and may thus succeed in a reduction of the number of predicates needed for the analysis. In addition, the two-level specification language provides a means for structuring and maintaining specifications. AU - Beyer, Dirk AU - Chlipala, Adam J AU - Thomas Henzinger AU - Jhala, Ranjit AU - Majumdar, Ritankar S ID - 4578 TI - The BLAST query language for software verification VL - 3148 ER - TY - CONF AB - While model checking has been successful in uncovering subtle bugs in code, its adoption in software engineering practice has been hampered by the absence of a simple interface to the programmer in an integrated development environment. We describe an integration of the software model checker BLAST into the Eclipse development environment. We provide a verification interface for practical solutions for some typical program analysis problems - assertion checking, reachability analysis, dead code analysis, and test generation - directly on the source code. The analysis is completely automatic, and assumes no knowledge of model checking or formal notation. Moreover, the interface supports incremental program verification to support incremental design and evolution of code. AU - Beyer, Dirk AU - Thomas Henzinger AU - Jhala, Ranjit AU - Majumdar, Ritankar S ID - 4577 TI - An eclipse plug-in for model checking ER - TY - CONF AB - We have extended the software model checker BLAST to automatically generate test suites that guarantee full coverage with respect to a given predicate. More precisely, given a C program and a target predicate p, BLAST determines the set L of program locations which program execution can reach with p true, and automatically generates a set of test vectors that exhibit the truth of p at all locations in L. We have used BLAST to generate test suites and to detect dead code in C programs with up to 30 K lines of code. The analysis and test vector generation is fully automatic (no user intervention) and exact (no false positives). AU - Beyer, Dirk AU - Chlipala, Adam J AU - Thomas Henzinger AU - Jhala, Ranjit AU - Majumdar, Ritankar S ID - 4581 TI - Generating tests from counterexamples ER - TY - CONF AB - Temporal logic is two-valued: a property is either true or false. When applied to the analysis of stochastic systems, or systems with imprecise formal models, temporal logic is therefore fragile: even small changes in the model can lead to opposite truth values for a specification. We present a generalization of the branching-time logic Ctl which achieves robustness with respect to model perturbations by giving a quantitative interpretation to predicates and logical operators, and by discounting the importance of events according to how late they occur. In every state, the value of a formula is a real number in the interval [0,1], where 1 corresponds to truth and 0 to falsehood. The boolean operators and and or are replaced by min and max, the path quantifiers ∃ and ∀ determine sup and inf over all paths from a given state, and the temporal operators and □ specify sup and inf over a given path; a new operator averages all values along a path. Furthermore, all path operators are discounted by a parameter that can be chosen to give more weight to states that are closer to the beginning of the path. We interpret the resulting logic Dctl over transition systems, Markov chains, and Markov decision processes. We present two semantics for Dctl: a path semantics, inspired by the standard interpretation of state and path formulas in CTL, and a fixpoint semantics, inspired by the μ-calculus evaluation of CTL formulas. We show that, while these semantics coincide for CTL, they differ for Dctl, and we provide model-checking algorithms for both semantics. AU - de Alfaro, Luca AU - Faella, Marco AU - Thomas Henzinger AU - Majumdar, Ritankar S AU - Stoelinga, Mariëlle ID - 4629 TI - Model checking discounted temporal properties VL - 2988 ER - TY - JOUR AB - The genome of the nematode Caenorhabditis elegans encodes seven soluble guanylate cyclases (sGCs) [1]. In mammals, sGCs function as α/β heterodimers activated by gaseous ligands binding to a haem prosthetic group 2, 3. The principal activator is nitric oxide, which acts through sGCs to regulate diverse cellular events. In C. elegans the function of sGCs is mysterious: the worm genome does not appear to encode nitric oxide synthase, and all C. elegans sGC subunits are more closely related to mammalian β than α subunits [1]. Here, we show that two of the seven C. elegans sGCs, GCY-35 and GCY-36, promote aggregation behavior. gcy-35 and gcy-36 are expressed in a small number of neurons. These include the body cavity neurons AQR, PQR, and URX, which are directly exposed to the blood equivalent of C. elegans and regulate aggregation behavior [4]. We show that GCY-35 and GCY-36 act as α-like and β-like sGC subunits and that their function in the URX sensory neurons is sufficient for strong nematode aggregation. Neither GCY-35 nor GCY-36 is absolutely required for C. elegans to aggregate. Instead, these molecules may transduce one of several pathways that induce C. elegans to aggregate or may modulate aggregation by responding to cues in C. elegans body fluid. AU - Cheung, Benny H.H AU - Arellano-Carbajal, Fausto AU - Rybicki, Irene AU - de Bono, Mario ID - 6155 IS - 12 JF - Current Biology SN - 0960-9822 TI - Soluble guanylate cyclases act in neurons exposed to the body fluid to promote C. elegans aggregation behavior VL - 14 ER - TY - JOUR AB - Fundamental and phenomenological models for cells, stacks, and complete systems of PEFC and SOFC are reviewed and their predictive power is assessed by comparing model simulations against experiments. Computationally efficient models suited for engineering design include the (1+1) dimensionality approach, which decouples the membrane in-plane and through-plane processes, and the volume-averaged-method (VAM) that considers only the lumped effect of pre-selected system components. The former model was shown to capture the measured lateral current density inhomogeneities in a PEFC and the latter was used for the optimization of commercial SOFC systems. State Space Modeling (SSM) was used to identify the main reaction pathways in SOFC and, in conjunction with the implementation of geometrically well-defined electrodes, has opened a new direction for the understanding of electrochemical reactions. Furthermore, SSM has advanced the understanding of the COpoisoning-induced anode impedance in PEFC. Detailed numerical models such as the Lattice Boltzmann (LB) method for transport in porous media and the full 3-D Computational Fluid Dynamics (CFD) Navier-Stokes simulations are addressed. These models contain all components of the relevant physics and they can improve the understanding of the related phenomena, a necessary condition for the development of both appropriate simplified models as well as reliable technologies. Within the LB framework, a technique for the characterization and computer-reconstruction of the porous electrode structure was developed using advanced pattern recognition algorithms. In CFD modeling, 3-D simulations were used to investigate SOFC with internal methane steam reforming and have exemplified the significance of porous and novel fractal channel distributors for the fuel and oxidant delivery, as well as for the cooling of PEFC. As importantly, the novel concept has been put forth of functionally designed, fractal-shaped fuel cells, showing promise of significant performance improvements over the conventional rectangular shaped units. Thermo-economic modeling for the optimization of PEFC is finally addressed. AU - Mantzaras, John AU - Freunberger, Stefan Alexander AU - Büchi, Felix N. AU - Roos, Markus AU - Brandstätter, Wilhelm AU - Prestat, Michel AU - Gauckler, Ludwig J. AU - Andreaus, Bernhard AU - Hajbolouri, Faegheh AU - Senn, Stephan M. AU - Poulikakos, Dimos AU - Chaniotis, Andreas K. AU - Larrain, Diego AU - Autissier, Nordahl AU - Maréchal, François ID - 7334 IS - 12 JF - CHIMIA International Journal for Chemistry SN - 0009-4293 TI - Fuel cell modeling and simulations VL - 58 ER - TY - JOUR AB - The analysis of the complete H2/air polymer electrolyte fuel cell system shows that process air humidification is one of the biggest obstacles for a high performance portable system in the kW range. Therefore, a new concept, with passive process air humidification integrated into the stack, has been developed. Humidification in each cell makes the process independent from the number of cells and the operation mode, thus making the concept fully scalable. Without external humidification the system is simpler, smaller, and cheaper. The humidification of the process air is achieved by transfer of product water from the exhaust air, through part of the membrane, to the dry intake air. Tests have shown that cells using the concept of internal humidification and operated with dry air at 70 ° have almost the same performance as when operated with external humidification. A 42‐cell stack with this internal humidification concept was built and integrated into a portable 1 kW power generator system. AU - Santis, M. AU - Schmid, D. AU - Ruge, M. AU - Freunberger, Stefan Alexander AU - Büchi, F.N. ID - 7333 IS - 3 JF - Fuel Cells SN - 1615-6846 TI - Modular stack-internal air humidification concept-verification in a 1 kW stack VL - 4 ER - TY - JOUR AB - We present a method for prediction of functional sites in a set of aligned protein sequences. The method selects sites which are both well conserved and clustered together in space, as inferred from the 3D structures of proteins included in the alignment. We tested the method using 86 alignments from the NCBI CDD database, where the sites of experimentally determined ligand and/or macromolecular interactions are annotated. In agreement with earlier investigations, we found that functional site predictions are most successful when overall background sequence conservation is low, such that sites under evolutionary constraint become apparent. In addition, we found that averaging of conservation values across spatially clustered sites improves predictions under certain conditions: that is, when overall conservation is relatively high and when the site in question involves a large macromolecular binding interface. Under these conditions it is better to look for clusters of conserved sites than to look for particular conserved sites. AU - Panchenko, Anna R AU - Fyodor Kondrashov AU - Bryant, Stephen H ID - 864 IS - 4 JF - Protein Science TI - Prediction of functional sites by analysis of sequence and structure conservation VL - 13 ER - TY - JOUR AB - Only a fraction of eukaryotic genes affect the phenotype drastically. We compared 18 parameters in 1273 human morbid genes, known to cause diseases, and in the remaining 16 580 unambiguous human genes. Morbid genes evolve more slowly, have wider phylogenetic distributions, are more similar to essential genes of Drosophila melanogaster, code for longer proteins containing more alanine and glycine and less histidine, lysine and methionine, possess larger numbers of longer introns with more accurate splicing signals and have higher and broader expressions. These differences make it possible to classify as non-morbid 34% of human genes with unknown morbidity, when only 5% of known morbid genes are incorrectly classified as non-morbid. This classification can help to identify disease-causing genes among multiple candidates. AU - Fyodor Kondrashov AU - Ogurtsov, Aleksey Yu AU - Kondrashov, Alexey S ID - 870 IS - 5 JF - Nucleic Acids Research TI - Bioinformatical assay of human gene morbidity VL - 32 ER - TY - JOUR AB - The dominance of wild-type alleles and the concomitant recessivity of deleterious mutant alleles might have evolved by natural selection or could be a by-product of the molecular and physiological mechanisms of gene action. We compared the properties of human haplosufficient genes, whose wild-type alleles are dominant over loss-of-function alleles, with haploinsufficient (recessive wild-type) genes, which produce an abnormal phenotype when heterozygous for a loss-of-function allele. The fraction of haplosufficient genes is the highest among the genes that encode enzymes, which is best compatible with the physiological theory. Haploinsufficient genes, on average, have more paralogs than haplosufficient genes, supporting the idea that gene dosage could be important for the initial fixation of duplications. Thus, haplo(in)sufficiency of a gene and its propensity for duplication might have a common evolutionary basis. AU - Fyodor Kondrashov AU - Koonin, Eugene V ID - 875 IS - 7 JF - Trends in Genetics TI - A common framework for understanding the origin of genetic dominance and evolutionary fates of gene duplications VL - 20 ER - TY - JOUR AB - The function of protein and RNA molecules depends on complex epistatic interactions between sites. Therefore, the deleterious effect of a mutation can be suppressed by a compensatory second-site substitution. In relating a list of 86 pathogenic mutations in human IRNAs encoded by mitochondrial genes to the sequences of their mammalian orthologs, we noted that 52 pathogenic mutations were present in normal tRNAs of one or several nonhuman mammals. We found at least five mechanisms of compensation for 32 pathogenic mutations that destroyed a Watson-Crick pair in one of the four tRNA stems: restoration of the affected Watson-Crick interaction (25 cases), strengthening of another pair (4 cases), creation of a new pair (8 cases), changes of multiple interactions in the affected stem (11 cases) and changes involving the interaction between the loop and stem structures (3 cases). A pathogenic mutation and its compensating substitution are fixed in a lineage in rapid succession, and often a compensatory interaction evolves convergently in different clades. At least 10%, and perhaps as many as 50%, of all nucleotide substitutions in evolving mammalian (RNAs participate in such interactions, indicating that the evolution of tRNAs proceeds along highly epistatic fitness ridges. AU - Kern, Andrew D AU - Fyodor Kondrashov ID - 889 IS - 11 JF - Nature Genetics TI - Mechanisms and convergence of compensatory evolution in mammalian mitochondrial tRNAs VL - 36 ER - TY - JOUR AB - In a number of organisms, transgenes containing transcribed inverted repeats (IRs) that produce hairpin RNA can trigger RNA-mediated silencing, which is associated with 21-24 nucleotide small interfering RNAs (siRNAs). In plants, IR-driven RNA silencing also causes extensive cytosine methylation of homologous DNA in both the transgene "trigger" and any other homologous DNA sequences--"targets". Endogenous genomic sequences, including transposable elements and repeated elements, are also subject to RNA-mediated silencing. The RNA silencing gene ARGONAUTE4 (AGO4) is required for maintenance of DNA methylation at several endogenous loci and for the establishment of methylation at the FWA gene. Here, we show that mutation of AGO4 substantially reduces the maintenance of DNA methylation triggered by IR transgenes, but AGO4 loss-of-function does not block the initiation of DNA methylation by IRs. AGO4 primarily affects non-CG methylation of the target sequences, while the IR trigger sequences lose methylation in all sequence contexts. Finally, we find that AGO4 and the DRM methyltransferase genes are required for maintenance of siRNAs at a subset of endogenous sequences, but AGO4 is not required for the accumulation of IR-induced siRNAs or a number of endogenous siRNAs, suggesting that AGO4 may function downstream of siRNA production. AU - Zilberman, Daniel AU - Cao, Xiaofeng AU - Johansen, Lisa K. AU - Xie, Zhixin AU - Carrington, James C. AU - Jacobsen, Steven E. ID - 9493 IS - 13 JF - Current Biology SN - 0960-9822 TI - Role of Arabidopsis ARGONAUTE4 in RNA-directed DNA methylation triggered by inverted repeats VL - 14 ER - TY - JOUR AB - Multicellular eukaryotes produce small RNA molecules (approximately 21–24 nucleotides) of two general types, microRNA (miRNA) and short interfering RNA (siRNA). They collectively function as sequence-specific guides to silence or regulate genes, transposons, and viruses and to modify chromatin and genome structure. Formation or activity of small RNAs requires factors belonging to gene families that encode DICER (or DICER-LIKE [DCL]) and ARGONAUTE proteins and, in the case of some siRNAs, RNA-dependent RNA polymerase (RDR) proteins. Unlike many animals, plants encode multiple DCL and RDR proteins. Using a series of insertion mutants of Arabidopsis thaliana, unique functions for three DCL proteins in miRNA (DCL1), endogenous siRNA (DCL3), and viral siRNA (DCL2) biogenesis were identified. One RDR protein (RDR2) was required for all endogenous siRNAs analyzed. The loss of endogenous siRNA in dcl3 and rdr2 mutants was associated with loss of heterochromatic marks and increased transcript accumulation at some loci. Defects in siRNA-generation activity in response to turnip crinkle virus in dcl2 mutant plants correlated with increased virus susceptibility. We conclude that proliferation and diversification of DCL and RDR genes during evolution of plants contributed to specialization of small RNA-directed pathways for development, chromatin structure, and defense. AU - Xie, Zhixin AU - Johansen, Lisa K. AU - Gustafson, Adam M. AU - Kasschau, Kristin D. AU - Lellis, Andrew D. AU - Zilberman, Daniel AU - Jacobsen, Steven E. AU - Carrington, James C. ID - 9517 IS - 5 JF - PLoS Biology SN - 1544-9173 TI - Genetic and functional diversification of small RNA pathways in plants VL - 2 ER - TY - JOUR AB - Recent progress in understanding the silencing of transposable elements in the model plant Arabidopsis has revealed an interplay between DNA methylation, histone methylation and small interfering RNAs. DNA and histone methylation are not always sufficient to maintain silencing, and RNA-based reinforcement can be needed to maintain as well as initiate it. AU - Zilberman, Daniel AU - Henikoff, Steven ID - 9511 IS - 12 JF - Genome Biology SN - 1474-760X TI - Silencing of transposons in plant genomes: kick them when they're down VL - 5 ER - TY - JOUR AB - We consider the evolution of a connected set on the plane carried by a space periodic incompressible stochastic flow. While for almost every realization of the stochastic flow at time t most of the particles are at a distance of order equation image away from the origin, there is a measure zero set of points that escape to infinity at the linear rate. We study the set of points visited by the original set by time t and show that such a set, when scaled down by the factor of t, has a limiting nonrandom shape. AU - Dolgopyat, Dmitry AU - Kaloshin, Vadim AU - Koralov, Leonid ID - 8517 IS - 9 JF - Communications on Pure and Applied Mathematics KW - Applied Mathematics KW - General Mathematics SN - 0010-3640 TI - A limit shape theorem for periodic stochastic dispersion VL - 57 ER - TY - JOUR AU - Koralov, Leonid AU - Kaloshin, Vadim AU - Dolgopyat, Dmitry ID - 8518 IS - 1A JF - The Annals of Probability SN - 0091-1798 TI - Sample path properties of the stochastic flows VL - 32 ER - TY - JOUR AB - New alleles become fixed owing to random drift of nearly neutral mutations or to positive selection of substantially advantageous mutations. After decades of debate, the fraction of fixations driven by selection remains uncertain. Within 9,390 genes, we analysed 28,196 codons at which rat and mouse differ from each other at two nucleotide sites and 1,982 codons with three differences. At codons where rat-mouse divergence involved two non-synonymous substitutions, both of them occurred in the same lineage, either rat or mouse, in 64% of cases; however, independent substitutions would occur in the same lineage with a probability of only 50%. All three non-synonymous substitutions occurred in the same lineage for 46% of codons, instead of the 25% expected. Furthermore, comparison of 12 pairs of prokaryotic genomes also shows clumping of multiple non-synonymous substitutions in the same lineage. This pattern cannot be explained by correlated mutation or episodes of relaxed negative selection, but instead indicates that positive selection acts at many sites of rapid, successive amino acid replacement. AU - Bazykin, Georgii A AU - Fyodor Kondrashov AU - Ogurtsov, Aleksey Yu AU - Sunyaev, Shamil R AU - Kondrashov, Alexey S ID - 898 IS - 6991 JF - Nature TI - Positive selection at sites of multiple amino acid replacements since rat-mouse divergence VL - 429 ER - TY - JOUR AB - We compare the functional spectrum of protein evolution in two separate animal lineages with respect to two hypotheses: (1) rates of divergence are distributed similarly among functional classes within both lineages, indicating that selective pressure on the proteome is largely independent of organismic-level biological requirements; and (2) rates of divergence are distributed differently among functional classes within each lineage, indicating species-specific selective regimes impact genome-wide substitutional patterns. Integrating comparative genome sequence with data from tissue-specific expressed-sequence-tag (EST) libraries and detailed database annotations, we find a functional genomic signature of rapid evolution and selective constraint shared between mammalian and nematode lineages despite their extensive morphological and ecological differences and distant common ancestry. In both phyla, we find evidence of accelerated evolution among components of molecular systems involved in coevolutionary change. In mammals, lineage-specific fast evolving genes include those involved in reproduction, immunity, and possibly, maternal-fetal conflict. Likelihood ratio tests provide evidence for positive selection in these rapidly evolving functional categories in mammals. In contrast, slowly evolving genes, in terms of amino acid or insertion/deletion (indel) change, in both phyla are involved in core molecular processes such as transcription, translation, and protein transport. Thus, strong purifying selection appears to act on the same core cellular processes in both mammalian and nematode lineages, whereas positive and/or relaxed selection acts on different biological processes in each lineage. AU - Castillo-Davis, Cristian I AU - Fyodor Kondrashov AU - Hartl, Daniel L AU - Kulathinal, Rob J ID - 902 IS - 5 JF - Genome Research TI - The functional genomic distribution of protein divergence in two animal phyla: Coevolution, genomic conflict, and constraint VL - 14 ER - TY - JOUR AU - Chan, Simon W.-L. AU - Zilberman, Daniel AU - Xie, Zhixin AU - Johansen, Lisa K. AU - Carrington, James C. AU - Jacobsen, Steven E. ID - 9454 IS - 5662 JF - Science KW - Multidisciplinary SN - 0036-8075 TI - RNA silencing genes control de novo DNA methylation VL - 303 ER - TY - JOUR AB - Geranylgeranyl diphosphate synthase (GGPPS, EC: 2.5.1.29) catalyzes the biosynthesis of geranylgeranyl diphosphate (GGPP), which is a key precursor for ginkgolide biosynthesis. Here we reported for the first time the cloning of a new full-length cDNA encoding GGPPS from the living fossil plant Ginkgo biloba. The full-length cDNA encoding G. biloba GGPPS (designated as GbGGPPS) was 1657bp long and contained a 1176bp open reading frame encoding a 391 amino acid protein. Comparative analysis showed that GbGGPPS possessed a 79 amino acid transit peptide at its N-terminal, which directed GbGGPPS to target to the plastids. Bioinformatic analysis revealed that GbGGPPS was a member of polyprenyltransferases with two highly conserved aspartate-rich motifs like other plant GGPPSs. Phylogenetic tree analysis indicated that plant GGPPSs could be classified into two groups, angiosperm and gymnosperm GGPPSs, while GbGGPPS had closer relationship with gymnosperm plant GGPPSs. AU - Liao, Zhihua AU - Chen, Min AU - Gong, Yifu AU - Guo, Liang AU - Tan, Qiumin AU - Feng, Xiaoqi AU - Sun, Xiaofen AU - Tan, Feng AU - Tang, Kexuan ID - 12203 IS - 2 JF - DNA Sequence KW - Endocrinology KW - Genetics KW - Molecular Biology KW - Biochemistry SN - 1042-5179 TI - A new geranylgeranyl Diphosphate synthase gene from Ginkgo biloba, which intermediates the biosynthesis of the key precursor for ginkgolides VL - 15 ER - TY - JOUR AB - Micropatterning of surfaces with several chemicals at different spatial locations usually requires multiple stamping and registration steps. Here, we describe an experimental method based on reaction–diffusion phenomena that allows for simultaneous micropatterning of a substrate with several coloured chemicals. In this method, called wet stamping (WETS), aqueous solutions of two or more inorganic salts are delivered onto a film of dry, ionically doped gelatin from an agarose stamp patterned in bas relief. Once in conformal contact, these salts diffuse into the gelatin, where they react to give deeply coloured precipitates. Separation of colours in the plane of the surface is the consequence of the differences in the diffusion coefficients, the solubility products, and the amounts of different salts delivered from the stamp, and is faithfully reproduced by a theoretical model based on a system of reaction–diffusion partial differential equations. The multicolour micropatterns are useful as non-binary optical elements, and could potentially form the basis of new applications in microseparations and in controlled delivery. AU - Klajn, Rafal AU - Fialkowski, Marcin AU - Bensemann, Igor T. AU - Bitner, Agnieszka AU - Campbell, C. J. AU - Bishop, Kyle AU - Smoukov, Stoyan AU - Grzybowski, Bartosz A. ID - 13435 JF - Nature Materials KW - Mechanical Engineering KW - Mechanics of Materials KW - Condensed Matter Physics KW - General Materials Science KW - General Chemistry SN - 1476-1122 TI - Multicolour micropatterning of thin films of dry gels VL - 3 ER - TY - JOUR AB - Thin films of ionically doped gelatin have been color-patterned with submicrometer precision using the wet-stamping technique. Inorganic salts are delivered onto the gelatin surface from an agarose stamp, and diffuse into the gelatine layer, producting deeply colored precipitates. Reaction fronts originating from different features of the stamp cease within < 1 μm of each other, leaving sharp, transparent regions in between. AU - Campbell, C. J. AU - Fialkowski, M. AU - Klajn, Rafal AU - Bensemann, I. T. AU - Grzybowski, B. A. ID - 13434 IS - 21 JF - Advanced Materials KW - Mechanical Engineering KW - Mechanics of Materials KW - General Materials Science SN - 0935-9648 TI - Color micro- and nanopatterning with counter-propagating reaction-diffusion fronts VL - 16 ER - TY - JOUR AB - The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance. AU - Brunet, Anne AU - Sweeney, Lora Beatrice Jaeger AU - Sturgill, J Fitzhugh AU - Chua, Katrin AU - Greer, Paul AU - Lin, Yingxi AU - Tran, Hien AU - Ross, Sarah AU - Mostoslavsky, Raul AU - Cohen, Haim AU - Hu, Linda AU - Chen, Hwei-Ling AU - Jedrychowski, Mark AU - Gygi, Steven AU - Sinclair, David AU - Alt, Frederick AU - Greenberg, Michael ID - 7706 IS - 5666 JF - Science SN - 0036-8075 TI - Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase VL - 303 ER -