TY - JOUR
AB - An optical lattice model developed that is similar to the Bose-Hubbard model to describe the transition between Bose-Einstein condensation (BEC) and a Mott insulator state was analyzed. It was found that the system was a hard core lattice gas at half of the maximum density and the optical lattice was modeled by a periodic potential of strength λ. It was also observed that the interparticle interaction was essential for this transition that occurred even in the ground state. The results show that all the essential features could be proved rigorously such as the existence of BEC for small λ and its suppression for a large λ.
AU - Aizenman, Michael
AU - Lieb, Élliott H
AU - Robert Seiringer
AU - Solovej, Jan P
AU - Yngvason, Jakob
ID - 2360
IS - 2
JF - Physical Review A - Atomic, Molecular, and Optical Physics
TI - Bose-Einstein quantum phase transition in an optical lattice model
VL - 70
ER -
TY - CHAP
AU - Lovász, László
AU - Vesztergombi, Katalin
AU - Uli Wagner
AU - Welzl, Emo
ED - Pach, János
ID - 2417
T2 - Towards a Theory of Geometric Graphs
TI - Convex quadrilaterals and k-sets
VL - 342
ER -
TY - JOUR
AB - It is widely believed that the inflammatory events mediated by microglial activation contribute to several neurodegenerative processes. Alzheimer's disease, for example, is characterized by an accumulation of β-amyloid protein (Aβ) in neuritic plaques that are infiltrated by reactive microglia and astrocytes. Although Aβ and its fragment 25-35 exert a direct toxic effect on neurons, they also activate microglia. Microglial activation is accompanied by morphological changes, cell proliferation, and release of various cytokines and growth factors. A number of scientific reports suggest that the increased proliferation of microglial cells is dependent on ionic membrane currents and in particular on chloride conductances. An unusual chloride ion channel known to be associated with macrophage activation is the chloride intracellular channel-1 (CLIC1). Here we show that Aβ stimulation of neonatal rat microglia specifically leads to the increase in CLIC1 protein and to the functional expression of CLIC1 chloride conductance, both barely detectable on the plasma membrane of quiescent cells. CLIC1 protein expression in microglia increases after 24 hr of incubation with Aβ, simultaneously with the production of reactive nitrogen intermediates and of tumor necrosis factor-α (TNF-α). We demonstrate that reducing CLIC1 chloride conductance by a specific blocker [IAA-94 (R(+)-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5yl)-oxy] acetic acid)] prevents neuronal apoptosis in neurons cocultured with Aβ-treated microglia. Furthermore, we show that small interfering RNAs used to knock down CLIC1 expression prevent TNF-α release induced by Aβ stimulation. These results provide a direct link between Aβ-induced microglial activation and CLIC1 functional expression.
AU - Gaia Novarino
AU - Fabrizi, Cinzia
AU - Tonini, Raffaella
AU - Denti, Michela A
AU - Malchiodi, Albedi F
AU - Lauro, Giuliana M
AU - Sacchetti, Benedetto
AU - Paradisi, Silvia
AU - Ferroni, Arnaldo
AU - Curmi, Paul M G
AU - Breit, Samuel N
AU - Mazzanti, Michele
ID - 2308
IS - 23
JF - Journal of Neuroscience
TI - Involvement of the intracellular ion channel CLIC1 in microglia-mediated β-amyloid-induced neurotoxicity
VL - 24
ER -
TY - JOUR
AB - A finite set N ⊂ Rd is a weak ε-net for an n-point set X ⊂ Rd (with respect to convex sets) if N intersects every convex set K with |K ∩ X| ≥ εn. We give an alternative, and arguably simpler, proof of the fact, first shown by Chazelle et al., that every point set X in Rd admits a weak ε-net of cardinality O(ε-dpolylog(1/ε)). Moreover, for a number of special point sets (e.g., for points on the moment curve), our method gives substantially better bounds. The construction yields an algorithm to construct such weak ε-nets in time O(n ln(1/ε)).
AU - Matoušek, Jiří
AU - Uli Wagner
ID - 2425
IS - 2
JF - Discrete & Computational Geometry
TI - New constructions of weak ε-nets
VL - 32
ER -
TY - JOUR
AB - We introduce the adaptive neighborhood graph as a data structure for modeling a smooth manifold M embedded in some Euclidean space ℝ d. We assume that M is known to us only through a finite sample P ⊂ M, as is often the case in applications. The adaptive neighborhood graph is a geometric graph on P. Its complexity is at most min{2O(k)n, n2}, where n = P and k = dim M, as opposed to the n[d/2] complexity of the Delaunay triangulation, which is often used to model manifolds. We prove that we can correctly infer the connected components and the dimension of M from the adaptive neighborhood graph provided a certain standard sampling condition is fulfilled. The running time of the dimension detection algorithm is d20(k7 log k) for each connected component of M. If the dimension is considered constant, this is a constant-time operation, and the adaptive neighborhood graph is of linear size. Moreover, the exponential dependence of the constants is only on the intrinsic dimension k, not on the ambient dimension d. This is of particular interest if the co-dimension is high, i.e., if k is much smaller than d, as is the case in many applications. The adaptive neighborhood graph also allows us to approximate the geodesic distances between the points in P.
AU - Giesen, Joachim
AU - Uli Wagner
ID - 2426
IS - 2
JF - Discrete & Computational Geometry
TI - Shape dimension and intrinsic metric from samples of manifolds
VL - 32
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 - 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 - Vesicular glutamate transporter type 3 (VGLUT3) containing neuronal elements were characterized using antibodies to VGLUT3 and molecular cell markers. All VGLUT3-positive somata were immunoreactive for CCK, and very rarely, also for calbindin; none was positive for parvalbumin, calretinin, VIP or somatostatin. In the CA1 area, 26.8 ± 0.7% of CCK-positive interneuron somata were VGLUT3-positive, a nonoverlapping 22.8 ± 1.9% were calbindin-positive, 10.7 ± 2.5% VIP-positive and the rest were only CCK-positive. The patterns of coexpression were similar in the CA3 area, the dentate gyrus and the isocortex. Immunoreactivity for VGLUT3 was undetectable in pyramidal and dentate granule cells. Boutons colabelled for VGLUT3, CCK and GAD were most abundant in the cellular layers of the hippocampus and in layers II-III of the isocortex. Large VGLUT3-labelled boutons at the border of strata radiatum and lacunosum-moleculare in the CA1 area were negative for GAD, but were labelled for vesicular monoamine transporter type 2, plasmalemmal serotonin transporter or serotonin. No colocalization was found in terminals between VGLUT3 and parvalbumin, vesicular acetylcholine transporter and group III (mGluR7a,b; mGluR8a,b) metabotropic glutamate receptors. In stratum radiatum and the isocortex, VGLUT3-positive but GAD-negative boutons heavily innervated the soma and proximal dendrites of some VGLUT3- or calbindin-positive interneurons. The results suggest that boutons coexpressing VGLUT3, CCK and GAD originate from CCK-positive basket cells, which are VIP-immunonegative. Other VGLUT3-positive boutons immunopositive for serotonergic markers but negative for GAD probably originate from the median raphe nucleus and innervate select interneurons. The presumed amino acid substrate of VGLUT3 may act on presynaptic kainate or group II metabotropic glutamate receptors.
AU - Somogyi, Jozsef
AU - Baude, Agnès
AU - Omori, Yuko
AU - Shimizu, Hidemi
AU - El-Mestikawy, Salah
AU - Fukaya, Masahiro
AU - Ryuichi Shigemoto
AU - Watanabe, Masahiko
AU - Somogyi, Péter
ID - 2639
IS - 3
JF - European Journal of Neuroscience
TI - GABAergic basket cells expressing cholecystokinin contain vesicular glutamate transporter type 3 (VGLUT3) in their synaptic terminals in hippocampus and isocortex of the rat
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 - JOUR
AB - In the hippocampal CA1 region, metabotropic glutamate subtype 1 (mGluR1) receptors have been implicated in a variety of physiological responses to glutamate, which include modulation of synaptic transmission and plasticity, as well as neuronal excitability and synchronization. The mGluR1α isoform is characteristically expressed only by nonprincipal cells, and it is particularly enriched in somatostatin (SS -containing interneurons in stratum oriens-alveus. Anatomical and physiological data have indicated the presence of mGluR1α in several distinct classes of interneurons with their somata located also in strata pyramidale, radiatum, and lacunosum moleculare. Each different interneuron subtype, as defined by functionally relevant criteria, including input/output characteristics and expression of selective molecular markers, subserves distinct functions in local hippocampal circuits. We have investigated which of the different CA1 interneuron classes express mGluR1α by immunofluorescent labeling, combining antibodies to mGluR1α, calcium-binding proteins, and neuropeptides, and by intracellular labeling in vitro. Several types of interneuron that are immunopositive for mGluR1α each targeted different domains of pyramidal cells and included (1) O-LM interneurons, found to coexpress both SS and parvalbumin (PV); (2) interneurons with target selectivity for other interneurons, expressing vasoactive intestinal polypeptide (VIP) and/or the calcium-binding protein calretinin; (3) procholecystokinin-immunopositive interneurons probably non-basket and dendrite-targeting; and (4) an as-yet unidentified SS-immunoreactive but PV-immunonegative interneuron class, possibly corresponding to oriensbistratified cells. Estimation of the relative proportion of mGluR1α-positive interneurons showed 43%, 46%, and 30% co-labeling with SS, VIP, or PV, respectively. The identification of the specific subclasses of CA1 interneurons expressing mGluR1α provides the network basis for assessing the contribution of this receptor to the excitability of the hippocampus.
AU - Ferraguti, Francesco
AU - Cobden, Philip M
AU - Pollard, Marie
AU - Cope, David W
AU - Ryuichi Shigemoto
AU - Watanabe, Masahiko
AU - Somogyi, Péter
ID - 2642
IS - 2
JF - Hippocampus
TI - Immunolocalization of metabotropic glutamate receptor 1α (mGluR1α) in distinct classes of interneuron in the CA1 region of the rat hippocampus
VL - 14
ER -
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 - 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 - 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 - 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 - GEN
AU - Sauer, Michael
AU - Friml, Jirí
ID - 2461
IS - 23
T2 - Development
TI - The Matryoshka dolls of plant polarity
VL - 131
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 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 - 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 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - CHAP
AU - Herbert Edelsbrunner
ID - 3574
T2 - Handbook of Discrete and Computational Geometry
TI - Biological applications of computational topology
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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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(Δz̄) =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(Δz̄); (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(Δz̄)=inline image=1 (2F) kVA(k) and (V*A) = (1 –F)inline imagek(2F)k-1VA(k) With dominance (and even without epistasis), var(Δz̄)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 - GEN
AU - Nicholas Barton
ID - 3616
IS - 15
T2 - Current Biology
TI - Speciation: Why, how, where and when?
VL - 14
ER -