TY - JOUR AU - Browning, Timothy D ID - 207 IS - 3 JF - Mathematical Proceedings of the Cambridge Philosophical Society TI - Sums of four biquadrates VL - 134 ER - TY - JOUR AB - For any ε > 0 and any diagonal quadratic form Q ∈ ℤ[x 1, x 2, x 3, x 4] with a square-free discriminant of modulus Δ Q ≠ 0, we establish the uniform estimate ≪ε B 3/2+ε + B 2+ε/Δ Q 1/6 for the number of rational points of height at most B lying in the projective surface Q = 0. AU - Timothy Browning ID - 208 IS - 1 JF - Quarterly Journal of Mathematics TI - Counting rational points on diagonal quadratic surfaces VL - 54 ER - TY - CONF AU - Lieb, Élliott H AU - Robert Seiringer ED - Karpeshina, Yulia ED - Weikard, Rudi ED - Zeng, Yanni ID - 2337 TI - Bose-Einstein condensation of dilute gases in traps VL - 327 ER - TY - JOUR AB - The classic Poincaré inequality bounds the L q-norm of a function f in a bounded domain Ω ⊂ ℝ n in terms of some L p-norm of its gradient in Ω. We generalize this in two ways: In the first generalization we remove a set Τ from Ω and concentrate our attention on Λ = Ω \ Τ. This new domain might not even be connected and hence no Poincaré inequality can generally hold for it, or if it does hold it might have a very bad constant. This is so even if the volume of Τ is arbitrarily small. A Poincaré inequality does hold, however, if one makes the additional assumption that f has a finite L p gradient norm on the whole of Ω, not just on Λ. The important point is that the Poincaré inequality thus obtained bounds the L q-norm of f in terms of the L p gradient norm on Λ (not Ω) plus an additional term that goes to zero as the volume of Τ goes to zero. This error term depends on Τ only through its volume. Apart from this additive error term, the constant in the inequality remains that of the 'nice' domain Ω. In the second generalization we are given a vector field A and replace ∇ by ∇ + iA(x) (geometrically, a connection on a U(1) bundle). Unlike the A = 0 case, the infimum of ∥(∇ + iA)f∥ p over all f with a given ∥f∥ q is in general not zero. This permits an improvement of the inequality by the addition of a term whose sharp value we derive. We describe some open problems that arise from these generalizations. AU - Lieb, Élliott H AU - Robert Seiringer AU - Yngvason, Jakob ID - 2357 IS - 3 JF - Annals of Mathematics TI - Poincaré inequalities in punctured domains VL - 158 ER - TY - JOUR AB - We investigate the ground state properties of a gas of interacting particles confined in an external potential in three dimensions and subject to rotation around an axis of symmetry. We consider the Gross-Pitaevskii (GP) limit of a dilute gas. Analysing both the absolute and the bosonic ground states of the system, we show, in particular, their different behaviour for a certain range of parameters. This parameter range is determined by the question whether the rotational symmetry in the minimizer of the GP functional is broken or not. For the absolute ground state, we prove that in the GP limit a modified GP functional depending on density matrices correctly describes the energy and reduced density matrices, independent of symmetry breaking. For the bosonic ground state this holds true if and only if the symmetry is unbroken. AU - Robert Seiringer ID - 2354 IS - 37 JF - Journal of Physics A: Mathematical and Theoretical TI - Ground state asymptotics of a dilute, rotating gas VL - 36 ER - TY - JOUR AB - A study was conducted on the one-dimensional (1D) bosons in three-dimensional (3D) traps. A rigorous analysis was carried out on the parameter regions in which various types of 1D or 3D behavior occurred in the ground state. The four parameter regions include density, transverse, longitudinal dimensions and scattering length. AU - Lieb, Élliott H AU - Robert Seiringer AU - Yngvason, Jakob ID - 2358 IS - 15 JF - Physical Review Letters TI - One-dimensional Bosons in three-dimensional traps VL - 91 ER - TY - THES AU - Uli Wagner ID - 2414 TI - On k-Sets and Their Applications ER - TY - CONF AB - We introduce the adaptive neighborhood graph as a data structure for modeling a smooth manifold M embedded in some (potentially very high-dimensional) Euclidean space ℝd. We assume that M is known to us only through a finite sample P ⊂ M, as it 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 show that we can provably correctly infer the connectivity of M 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 d2O(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 - 2424 TI - Shape dimension and intrinsic metric from samples of manifolds with high co-dimension ER - TY - CONF 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. [7], that every point set X in Rd admits a weak ε-net of cardinality O(ε-d polylog(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)). We also prove, by a different method, a near-linear upper bound for points uniformly distributed on the (d - 1)-dimensional sphere. AU - Matoušek, Jiří AU - Uli Wagner ID - 2423 TI - New constructions of weak epsilon-nets ER - TY - CONF AB - We prove a lower bound of 0.3288(4 n) for the rectilinear crossing number cr̄(Kn) of a complete graph on n vertices, or in other words, for the minimum number of convex quadrilaterals in any set of n points in general position in the Euclidean plane. As we see it, the main contribution of this paper is not so much the concrete numerical improvement over earlier bounds, as the novel method of proof, which is not based on bounding cr̄(Kn) for some small n. AU - Uli Wagner ID - 2422 TI - On the rectilinear crossing number of complete graphs ER - TY - JOUR AB - Patients with Hodgkin's disease can develop paraneoplastic cerebellar ataxia because of the generation of autoantibodies against mGluR1 (mGluR1-Abs). Yet, the pathophysiological mechanisms underlying their motor coordination deficits remain to be elucidated. Here, we show that application of IgG purified from the patients' serum to cerebellar slices of mice acutely reduces the basal activity of Purkinje cells, whereas application to the flocculus of mice in vivo evokes acute disturbances in the performance of their compensatory eye movements. In addition, the mGluR1-Abs block induction of long-term depression in cultured mouse Purkinje cells, whereas the cerebellar motor learning behavior of the patients is affected in that they show impaired adaptation of their saccadic eye movements. Finally, postmortem analysis of the cerebellum of a paraneoplastic cerebellar ataxia patient showed that the number of Purkinje cells was significantly reduced by approximately two thirds compared with three controls. We conclude that autoantibodies against mGluR1 can cause cerebellar motor coordination deficits caused by a combination of rapid effects on both acute and plastic responses of Purkinje cells and chronic degenerative effects. AU - Coesmans, Michiel P AU - Sillevis-Smitt, Peter A AU - Linden, David J AU - Ryuichi Shigemoto AU - Hirano, Tomoo AU - Yamakawa, Yoshinori AU - Van Alphen, Adriaan M AU - Luo, Chongde AU - Van Der Geest, Jos N AU - Kros, Johan M AU - Gaillard, Carlo A AU - Frens, Maarten A AU - De Zeeuw, Chris I ID - 2623 IS - 3 JF - Annals of Neurology TI - Mechanisms underlying cerebellar motor deficits due to mGluR1-autoantibodies VL - 53 ER - TY - JOUR AB - Metabotropic glutamate receptor 1 (mGluR1) plays a crucial role in synaptic plasticity and motor learning in the cerebellum. We have studied activity-dependent changes in mGluR1 function in mouse cultured Purkinje neurons. Depolarizing stimulation potentiated Ca2+ and current responses to an mGluR1 agonist for several hours in the cultured Purkinje neurons. It also blocked internalization of mGluR1 and increased the number of mGluR1s on the cell membrane. We found that depolarization simultaneously increased transcription of Homer1a in Purkinje neurons. Homer1a inhibited internalization and increased cell-surface expression of mGluR1 when coexpressed in human embryonic kidney (HEK)-293 cells. Depolarization-induced Homer1a expression in Purkinje neurons was blocked by a mitogen-activated protein kinase (MAPK) inhibitor. Changes in internalization and mGluR1-mediated Ca2+ response were also blocked by inhibition of MAPK activity, suggesting that localization and activity of mGluR1 were regulated in the same signalling pathway as Homer1a expression. It is thus suggested that depolarization of the Purkinje neuron leads to the increment in mGluR1 responsiveness through MAPK activity and induction of Homer1a expression, which increases active mGluR1 on the cell surface by blocking internalization of mGluR1. AU - Minami, Itsunari AU - Kengaku, Mineko AU - Smitt, Sillevis P AU - Ryuichi Shigemoto AU - Hirano, Tomoo ID - 2625 IS - 5 JF - European Journal of Neuroscience TI - Long-term potentiation of mGluR1 activity by depolarization-induced Homer1a in mouse cerebellar Purkinje neurons VL - 17 ER - TY - JOUR AB - The expression pattern of metabotropic glutamate receptor Iα (mGluR1α) was immunohistochemically investigated in substantia nigra dopaminergic neurons of the macaque monkey. In normal monkeys, mGluR1α immunoreactivity was weakly observed in the dorsal tier of the substantia nigra pars compacta (SNc-d) where calbindin-D28k-containing dopaminergic neurons invulnerable to parkinsonian degeneration are specifically located. On the other hand, mGluR1α was strongly expressed in the ventral tier of the substantia nigra pars cornpacta (SNc-v). In monkeys treated with the parkinsonism-inducing drug, I-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), mGluR1α expression was decreased in dopaminergic neurons in the SNc-v that were spared its toxic action. These results suggest that mGluR1α expression may be involved at least partly in the vulnerability of dopaminergic neurons to parkinsonian insults. AU - Kaneda, Katsuyuki AU - Imanishi, Michiko AU - Nambu, Atsushi AU - Ryuichi Shigemoto AU - Takada, Masahiko ID - 2626 IS - 7 JF - Neuroreport TI - Differential expression patterns of mGluR1α in monkey nigral dopamine neurons VL - 14 ER - TY - JOUR AB - Despite its implications for higher order functions of the brain, little is currently known about the molecular basis of left-right asymmetry of the brain. Here we report that synaptic distribution of N-methyl-D-aspartate (NMDA) receptor GluRε2 (NR2B) subunits in the adult mouse hippocampus is asymmetrical between the left and right and between the apical and basal dendrites of single neurons. These asymmetrical allocations of ε2 subunits differentiate the properties of NMDA receptors and synaptic plasticity between the left and right hippocampus. These results provide a molecular basis for the structural and functional asymmetry of the mature brain. AU - Kawakami, Ryosuke AU - Shinohara, Yoshiaki AU - Kato, Yuichiro AU - Sugiyama, Hiroyuki AU - Ryuichi Shigemoto AU - Ito, Isao ID - 2627 IS - 5621 JF - Science TI - Asymmetrical allocation of NMDA receptor ε2 subunits in hippocampal circuitry VL - 300 ER - TY - JOUR AB - The release of neurotransmitters is modulated by presynaptic metabotropic glutamate receptors (mGluRs), which show a highly selective expression and subcellular location in glutamatergic terminals in the hippocampus. Using immunocytochemistry, we investigated whether one of the receptors, mGluR7, whose level of expression is governed by the postsynaptic target, was present in GABAergic terminals and whether such terminals targeted particular cells. A total of 165 interneuron dendritic profiles receiving 466 synapses (82% mGluR7a-positive) were analysed. The presynaptic active zones of most GAD-(77%) or GABA-positive (94%) synaptic boutons on interneurons innervated by mGluR7a-enriched glutamatergic terminals (mGluR7a-decorated) were immunopositive for mGluR7a. GABAergic terminals on pyramidal cells and most other interneurons in str. oriens were mGluR7a-immunonegative. The mGluR7a-decorated cells were mostly somatostatin- and mGluR1α-immunopositive neurons in str. oriens and the alveus. Their GABAergic input mainly originated from VIP-positive terminals, 90% of which expressed high levels of mGluR7a in the presynaptic active zone. Parvalbumin-positive synaptic terminals were rare on mGluR7a-decorated cells, but on these neurons 73% of them were mGluR7a-immunopositive. Some type II synapses innervating interneurons were immunopositive for mGluR7b, as were some type I synapses. Because not all target cells of VIP-positive neurons are known it has not been possible to determine whether mGluR7 is expressed in a target-cell-specific manner in the terminals of single GABAergic cells. The activation of mGluR7 may decrease GABA release to mGluR7-decorated cells at times of high pyramidal cell activity, which elevates extracellular glutamate levels. Alternatively, the presynaptic receptor may be activated by as yet unidentified endogenous ligands released by the GABAergic terminals or the postsynaptic dendrites. AU - Somogyi, Péter AU - Dalezios, Yannis AU - Luján, Rafael AU - Roberts, John D AU - Watanabe, Masahiko AU - Ryuichi Shigemoto ID - 2629 IS - 12 JF - European Journal of Neuroscience TI - High level of mGluR7 in the presynaptic active zones of select populations of GABAergic terminals innervating interneurons in the rat hippocampus VL - 17 ER - TY - JOUR AB - We aimed to estimate the number of AMPA receptors (AMPARs) bound by the quantal transmitter packet, their single-channel conductance and their density in the postsynaptic membrane at cerebellar Purkinje cell synapses. The synaptic and extrasynaptic AMPARs were examined in Purkinje cells in 2- to 4-day-old rats, when they receive synaptic inputs solely from climbing fibres (CFs). Evoked CF EPSCs and whole-cell AMPA currents displayed roughly linear current-voltage relationships, consistent with the presence of GluR2 subunits in synaptic and extrasynaptic AMPARs. The mean quantal size, estimated from the miniature EPSCs (MEPSCs), was ∼300 pS. Peak-scaled non-stationary fluctuation analysis of spontaneous EPSCs and MEPSCs gave a weighted-mean synaptic channel conductance of ∼5 pS (∼7 pS when corrected for filtering). By applying non-stationary fluctuation analysis to extrasynaptic currents activated by brief glutamate pulses (5 mM), we also obtained a small single-channel conductance estimate for extrasynaptic AMPARs (∼11 pS). This approach allowed us to obtain a maximum open probability (Po,max) value for the extrasynaptic receptors (Po,max = 0.72). Directly resolved extrasynaptic channel openings in the continued presence of glutamate exhibited clear multiple-conductance levels. The mean area of the postsynaptic density (PSD) of these synapses was 0.074 μm2, measured by reconstructing electron-microscopic (EM) serial sections. Postembedding immunogold labelling by anti-GluR2/3 antibody revealed that AMPARs are localised in PSDs. From these data and by simulating error factors, we estimate that at least 66 AMPARs are bound by a quantal transmitter packet at CF-Purkinje cell synapses, and the receptors are packed at a minimum density of ∼900 μm-2 in the postsynaptic membrane. AU - Momiyama, Akiko AU - Silver, Rachel A AU - Häusser, Michael A AU - Notomi, Takuya AU - Wu, Yue AU - Ryuichi Shigemoto AU - Cull-Candy, Stuart G ID - 2628 IS - 1 JF - Journal of Physiology TI - The density of AMPA receptors activated by a transmitter quantum at the climbing fibre - Purkinje cell synapse in immature rats VL - 549 ER - TY - JOUR AB - Cyclic ADP-ribose (cADP-ribose) is a putative second messenger or modulator. However, the role of cADP-ribose in the downstream signals of the metabotropic glutamate receptors (mGluRs) is unclear. Here, we show that glutamate stimulates ADP-ribosyl cyclase activity in rat or mouse crude membranes of retina via group III mGluRs or in superior cervical ganglion via group I mGluRs. The retina of mGluR6-deficient mice showed no increase in the ADP-ribosyl cyclase level in response to glutamate. GTP enhanced the initial rate of basal and glutamate-stimulated cyclase activity. GTP-γ-S also stimulated basal activity. To determine whether the coupling mode of mGluRs to ADP-ribosyl cyclase is a feature common to individual cloned mGluRs, we expressed each mGluR subtype in NG108-15 neuroblastoma x glioma hybrid cells. The glutamate-induced stimulation of the cyclase occurs preferentially in NG108-15 cells over-expressing mGluRs1, 3, 5, and 6. Cells expressing mGluR2 or mGluRs4 and 7 exhibit inhibition or no coupling, respectively. Glutamate-induced activation or inhibition of the cyclase activity was eliminated after pre-treatment with cholera or pertussis toxin, respectively. Thus, the subtype-specific coupling of mGluRs to ADP-ribosyl cyclase via G proteins suggests that some glutamate-evoked neuronal functions are mediated by cADP-ribose. AU - Higashida, Haruhiro AU - Zhang, Jia-Sheng AU - Mochida, Sumiko AU - Chen, Xiao-Liang AU - Shin, Yeonsook AU - Noda, Mami AU - Hossain, Kazi Z AU - Hoshi, Naoto AU - Hashii, Minako AU - Ryuichi Shigemoto AU - Nakanishi, Shigetada AU - Fukuda, Yutaka AU - Yokoyama, Shigeru ID - 2631 IS - 5 JF - Journal of Neurochemistry TI - Subtype-specific coupling with ADP-ribosyl cyclase of metabotropic glutamate receptors in retina, cervical superior ganglion and NG108-15 cells VL - 85 ER - TY - JOUR AB - The modulation of calcium channels by metabotropic glutamate receptors (mGluRs) is a key event in the fine-tuning of neurotransmitter release. Here we report that, in cerebrocortical nerve terminals of adult rats, the inhibition of glutamate release is mediated by mGluR7. In this preparation, the major component of glutamate release is supported by P/Q-type Ca2+ channels (72.7%). However, mGluR7 selectively reduced the release component that is associated with N-type Ca2+ channels (29.9%). Inhibition of P/Q channels by mGluR7 is not masked by the higher efficiency of these channels in driving glutamate release when compared with N-type channels. Thus, activation of mGluR7 failed to reduce the release associated with P/Q channels when the extracellular calcium concentration, ([Ca2+]o), was reduced from 1.3 to 0.5 mM. Through Ca2+ imaging, we show that Ca2+ channels are distributed in a heterogeneous manner in individual nerve terminals. Indeed, in this preparation, nerve terminals were observed that contain N-type (31.1%; conotoxin GVIA-sensitive) or P/Q-type (64.3%; agatoxin IVA-sensitive) channels or that were insensitive to these two toxins (4.6%). Interestingly, the great majority of the responses to L-AP4 (95.4%) were observed in nerve terminals containing N-type channels. This specific co-localization of mGluR7 and N-type Ca2+-channels could explain the failure of the receptor to inhibit the P/Q channel-associated release component and also reveal the existence of specific targeting mechanisms to localize the two proteins in the same nerve terminal subset. AU - Millán, Carmelo AU - Castro, Enrique G AU - Torres, Magdalena AU - Ryuichi Shigemoto AU - Sánchez-Prieto, José ID - 2633 IS - 26 JF - Journal of Biological Chemistry TI - Co-expression of metabotropic glutamate receptor 7 and N-type Ca2+ channels in single cerebrocortical nerve terminals of adult rats VL - 278 ER - TY - JOUR AB - In many brain regions, hyperpolarization-activated cationic currents (Ih) are involved in the generation of rhythmic activities, but the role of Ih in olfactory oscillations remains unclear. Knowledge of the cellular and subcellular distributions of hyperpolarization-activated and cyclic nucleotide-gated channel (HCN) subunits is necessary for understanding the role of Ih in olfactory network activities. Using light microscopic immunocytochemistry, we demonstrate strong HCN1 labelling of the glomerular layer and moderate staining of granule cell, internal and external plexiform layers of the rat main olfactory bulb. In the glomerular layer, among many unlabelled neurons, two distinct subpopulations of juxtaglomerular cells are labelled. Approximately 10% of the juxtaglomerular cells strongly express HCN1. These small diameter cells are immunoreactive for GABA and comprise a subpopulation of periglomerular cells. An additional subset of juxtaglomerular cells (≈ 1%) expresses low levels of HCN1. They are large in diameter, GABA immunonegative but immunopositive for vesicular glutamate transporter 2, characterizing them as external tufted cells. Quantitative immunogold localization revealed that the somatic plasma membranes of periglomerular cells contain approximately four times more HCN1 labelling than those of external tufted cells. Unlike in cortical pyramidal cells, immunogold density for HCN1 does not significantly differ in somatic and dendritic plasma membranes of external tufted cells, indicating that post-synaptic potentials arriving at proximal and distal dendrites are modulated by the same density of I h. Our results demonstrate a cell type-dependent expression of HCN1 in the olfactory bulb and predict a differential contribution of distinct juxtaglomerular cell types to network oscillations. AU - Holderith, Noémi B AU - Ryuichi Shigemoto AU - Nusser, Zoltán ID - 2632 IS - 2 JF - European Journal of Neuroscience TI - Cell type-dependent expression of HCN1 in the main olfactory bulb VL - 18 ER - TY - JOUR AB - Metabotropic GABAB receptors mediate slow inhibitory effects presynaptically and postsynaptically. Using preembedding immunohistochemical methods combined with quantitative analysis of GABAB receptor subunit immunoreactivity, this study provides a detailed description of the cellular and subcellular localization of GABAB1a/b and GABA B2 in the rat hippocampus. At the light microscopic level, an overlapping distribution of GABAB1a/b and GABAB2 was revealed in the dendritic layers of the hippocampus. In addition, expression of the GABAB1a/b subunit was found in somata of CA1 pyramidal cells and of a subset of GABAergic interneurons. At the electron microscopic level, immunoreactivity for both subunits was observed on presynaptic and, more abundantly, on postsynaptic elements. Presynaptically, subunits were mainly detected in the extrasynaptic membrane and occasionally over the presynaptic membrane specialization of putative glutamatergic and, to a lesser extent, GABAergic axon terminals. Postsynaptically, the majority of GABAB receptor subunits were localized to the extrasynaptic plasma membrane of spines and dendritic shafts of principal cells and shafts of interneuron dendrites. Quantitative analysis revealed enrichment of GABAB1a/b around putative glutamatergic synapses on spines and an even distribution on dendritic shafts of pyramidal cells contacted by GABAergic boutons. The association of GABAB receptors with glutamatergic synapses at both presynaptic and postsynaptic sides indicates their intimate involvement in the modulation of glutamatergic neurotransmission. The dominant extrasynaptic localization of GABAB receptor subunits suggests that their activation is dependent on spillover of GABA requiring simultaneous activity of populations of GABAergic cells as it occurs during population oscillations or epileptic seizures. AU - Kulik, Ákos AU - Vida, Imre AU - Luján, Rafael AU - Haas, Carola A AU - López-Bendito, Guillermina AU - Ryuichi Shigemoto AU - Frotscher, Michael ID - 2635 IS - 35 JF - Journal of Neuroscience TI - Subcellular Localization of Metabotropic GABAB Receptor Subunits GABAB1a/b and GABAB2 in the Rat Hippocampus VL - 23 ER - TY - JOUR AB - To better understand the role of neurotransmitter receptors in neuronal differentiation and maturation a detailed knowledge of their identity, location and function in the plasma membrane of specific neuronal populations during development is required. Combining pre-embedding immunocytochemistry with cell tracking in embryonic brain slice cultures we show that virtually all neurons (∼98%) migrating through the lower intermediate zone (LIZ) on their way from the medial ganglionic eminence to the cerebral cortex, express GABA BR1. Blockade of GABABRs with a specific antagonist, CGP52432, resulted in a concentration-dependent accumulation of these tangentially migrating neurons in the ventricular/subventricular zones (VZ/SVZ) of the cortex and fewer cells were observed in the cortical plate/marginal zone (CP/MZ) and LIZ. Moreover, they had significantly shorter leading processes compared with similar migrating cells in control slices. Electrophysiological recording in LIZ and CP cells revealed no direct effect of either CGP52432 or the GABABR agonist, baclofen, on resting membrane properties suggesting that the effect of CGP52432 on migration might be mediated through a metabotropic action or the regulation of release of factors controlling migration. These results suggest that GABABRs have an important modulatory role in the migration of cortical interneurons. AU - López-Bendito, Guillermina AU - Luján, Rafael AU - Ryuichi Shigemoto AU - Ganter, Paul AU - Paulsen, Ole AU - Molnár, Zoltán ID - 2634 IS - 9 JF - Cerebral Cortex TI - Blockade of GABAB receptors alters the tangential migration of cortical neurons VL - 13 ER - TY - JOUR AB - Taste-metabotropic glutamate receptor 4 (taste-mGluR4) and the heteromers of T1R1 and T1R3 are candidate receptors involved in the sense of umami (monosodium glutamate) taste. Although the expression of group III mGluRs (taste-mGluR4) has been demonstrated in taste tissues, no mention has been made of the expression of group I mGluRs (mGluR1 and mGluR5) in taste tissues. We examined the expression of mGluR1 and mGluR5 in rat gustatory tissues by using reverse transcription-polymerase chain reaction (RT-PCR), in situ hybridization, immunohistochemistry and immunoelectron microscopy. RT-PCR assay showed that mGluR1α and mGluR1β mRNAs were expressed in circumvallate papillae, but mGluR5 mRNA was not expressed. The positive signals of mGluR1 mRNA were detected only in circumvallate taste buds by in situ hybridization analysis. In cryosections of fungiform, foliate and circumvallate papillae, the antibody against mGluRla gave intense labeling on the taste hairs in all taste pores examined. In the developing taste buds, the positive signals of mGluR1α in taste hairs gradually increased with the increase in number of taste bud cells. These results show that, in addition to taste-mGluR4 and the heteromer of T1R1 and T1R3, mGluR1α may function as a receptor for glutamate (umami) taste sensation. AU - Toyono, Takashi AU - Seta, Yuji AU - Kataoka, Shinji AU - Kawano, Shintaro AU - Ryuichi Shigemoto AU - Toyoshima, Kuniaki ID - 2630 IS - 1 JF - Cell and Tissue Research TI - Expression of metabotropic glutamate receptor group I in rat gustatory papillae VL - 313 ER - TY - JOUR AB - While the cholinergic depletion in Alzheimer's disease (AD) has been known for some time, a definitive involvement of other neurotransmitter systems has been somewhat more elusive. Our study demonstrates a clear involvement of both glutamatergic and, to a lesser extent, GABAergic neurons in an early onset transgenic mouse model of AD-like amyloid pathology. Immunohistochemical staining and subsequent quantification has revealed a statistically significant increased density of glutamatergic and GABAergic presynaptic boutons in both the plaque free and plaque adjacent cortical neuropile areas of transgenic mice as compared to non-transgenic controls. Furthermore, amyloid plaque size was shown to have a statistically significant effect on the relative area occupied by dystrophic glutamatergic neurites in the peri-plaque neuropile. These findings support our hypothesis that the amyloid pathology progresses in a time and neurotransmitter specific manner, first in the cholinergic system which appears to be most vulnerable, followed by the glutamatergic presynaptic boutons and finally the somewhat more resilient GABAergic terminals. AU - Bell, Karen F AU - De Kort, G J AU - Steggerda, S AU - Ryuichi Shigemoto AU - Ribeiro-da-Silva, Alfredo AU - Cuello, Augusto C ID - 2637 IS - 2 JF - Neuroscience Letters TI - Structural involvement of the glutamatergic presynaptic boutons in a transgenic mouse model expressing early onset amyloid pathology VL - 353 ER - TY - JOUR AB - We report the results of an experimental study of magnetohydrodynamic damping of sidewall convection in a rectangular enclosure filled with gallium. In particular we investigate the suppression of convection when a steady magnetic field is applied separately in each of the three principal directions of the flow. The strongest damping of the steady flow is found for a vertical magnetic field, which is in agreement with theory. However, we observe that the application of a field transverse to the flow provides greater damping than a longitudinal one, which seems to contradict available theory. We provide a possible resolution of this apparent dichotomy in terms of the length scale of the experiment. AU - Björn Hof AU - Juel, Anne AU - Mullin, Tom P ID - 2784 JF - Journal of Fluid Mechanics TI - Magnetohydrodynamic damping of convective flows in molten gallium VL - 482 ER - TY - JOUR AB - Experimental evidence for the scaling of the finite amplitude of perturbation theory required to promote transition in Poiseuille flow was found. The exponent is -1 and was uncovered using considerable care in the design and execution of the experiment. Interestingly, this exponent was also found in experiments on transition in boundary layers. AU - Björn Hof AU - Juel, Anne AU - Mullin, Tom P ID - 2785 IS - 24 JF - Physical Review Letters TI - Scaling of the turbulence transition threshold in a pipe VL - 91 ER - TY - JOUR AB - Plant growth is marked by its adaptability to continuous changes in environment. A regulated, differential distribution of auxin underlies many adaptation processes including organogenesis, meristem patterning and tropisms. In executing its multiple roles, auxin displays some characteristics of both a hormone and a morphogen. Studies on auxin transport, as well as tracing the intracellular movement of its molecular components, have suggested a possible scenario to explain how growth plasticity is conferred at the cellular and molecular level. The plant perceives stimuli and changes the subcellular position of auxin-transport components accordingly. These changes modulate auxin fluxes, and the newly established auxin distribution triggers the corresponding developmental response. AU - Friml, Jirí ID - 2990 IS - 1 JF - Current Opinion in Plant Biology TI - Auxin transport - Shaping the plant VL - 6 ER - TY - JOUR AB - Plants have many polarized cell types, but relatively little is known about the mechanisms that establish polarity. The orc mutant was identified originally by defects in root patterning, and positional cloning revealed that the affected gene encodes STEROL METHYLTRANSFERASE1, which is required for the appropriate synthesis and composition of major membrane sterols. smt1orc mutants displayed several conspicuous cell polarity defects. Columella root cap cells revealed perturbed polar positioning of different organelles, and in the smt1orc root epidermis, polar initiation of root hairs was more randomized. Polar auxin transport and expression of the auxin reporter DR5-β-glucuronidase were aberrant in smt1orc. Patterning defects in smt1orc resembled those observed in mutants of the PIN gene family of putative auxin efflux transporters. Consistently, the membrane localization of the PIN1 and PIN3 proteins was disturbed in smt1orc, whereas polar positioning of the influx carrier AUX1 appeared normal. Our results suggest that balanced sterol composition is a major requirement for cell polarity and auxin efflux in Arabidopsis. AU - Willemsen, Viola AU - Jirí Friml AU - Grebe, Markus AU - Van Den Toorn, Albert AU - Palme, Klaus AU - Scheres, Ben ID - 2992 IS - 3 JF - Plant Cell TI - Cell polarity and PIN protein positioning in Arabidopsis require STEROL METHYLTRANSFERASE1 function VL - 15 ER - TY - JOUR AB - Plants, compared to animals, exhibit an amazing adaptability and plasticity in their development. This is largely dependent on the ability of plants to form new organs, such as lateral roots, leaves, and flowers during postembryonic development. Organ primordia develop from founder cell populations into organs by coordinated cell division and differentiation. Here, we show that organ formation in Arabidopsis involves dynamic gradients of the signaling molecule auxin with maxima at the primordia tips. These gradients are mediated by cellular efflux requiring asymmetrically localized PIN proteins, which represent a functionally redundant network for auxin distribution in both aerial and underground organs. PIN1 polar localization undergoes a dynamic rearrangement, which correlates with establishment of auxin gradients and primordium development. Our results suggest that PIN-dependent, local auxin gradients represent a common module for formation of all plant organs, regardless of their mature morphology or developmental origin. AU - Eva Benková AU - Michniewicz, Marta AU - Sauer, Michael AU - Teichmann, Thomas AU - Seifertová, Daniela AU - Jürgens, Gerd AU - Jirí Friml ID - 2996 IS - 5 JF - Cell TI - Local, efflux-dependent auxin gradients as a common module for plant organ formation VL - 115 ER - TY - JOUR AB - Axis formation occurs in plants, as in animals, during early embryogenesis. However, the underlying mechanism is not known. Here we show that the first manifestation of the apical-basal axis in plants, the asymmetric division of the zygote, produces a basal cell that transports and an apical cell that responds to the signalling molecule auxin. This apical-basal auxin activity gradient triggers the specification of apical embryo structures and is actively maintained by a novel component of auxin efflux, PIN7, which is located apically in the basal cell. Later, the developmentally regulated reversal of PIN7 and onset of PIN1 polar localization reorganize the auxin gradient for specification of the basal root pole. An analysis of pin quadruple mutants identifies PIN-dependent transport as an essential part of the mechanism for embryo axis formation. Our results indicate how the establishment of cell polarity, polar auxin efflux and local auxin response result in apical-basal axis formation of the embryo, and thus determine the axiality of the adult plant. AU - Jirí Friml AU - Vieten, Anne AU - Sauer, Michael AU - Weijers, Dolf AU - Schwarz, Heinz AU - Hamann, Thorsten AU - Offringa, Remko AU - Jürgens, Gerd ID - 2995 IS - 6963 JF - Nature TI - Efflux dependent auxin gradients establish the apical basal axis of Arabidopsis VL - 426 ER - TY - JOUR AB - The regular arrangement of leaves around a plant's stem, called phyllotaxis, has for centuries attracted the attention of philosophers, mathematicians and natural scientists; however, to date, studies of phyllotaxis have been largely theoretical. Leaves and flowers are formed from the shoot apical meristem, triggered by the plant hormone auxin. Auxin is transported through plant tissues by specific cellular influx and efflux carrier proteins. Here we show that proteins involved in auxin transport regulate phyllotaxis. Our data indicate that auxin is transported upwards into the meristem through the epidermis and the outermost meristem cell layer. Existing leaf primordia act as sinks, redistributing auxin and creating its heterogeneous distribution in the meristem. Auxin accumulation occurs only at certain minimal distances from existing primordia, defining the position of future primordia. This model for phyllotaxis accounts for its reiterative nature, as well as its regularity and stability. AU - Reinhardt, Didier AU - Pesce, Eva-Rachele AU - Stieger, Pia AU - Mandel, Therese AU - Baltensperger, Kurt AU - Bennett, Malcolm AU - Traas, Jan AU - Jirí Friml AU - Kuhlemeier, Cris ID - 2994 IS - 6964 JF - Nature TI - Regulation of phyllotaxis by polar auxin transport VL - 426 ER - TY - JOUR AB - Plant biology is currently experiencing a growing demand for easy and reliable mRNA and protein localisation techniques. Here, we present novel whole mount in situ hybridisation and immunolocalisation protocols, suitable to localise mRNAs and proteins in Arabidopsis seedlings. We demonstrate that these methods can be used in different organs of Arabidopsis seedlings as well as in other plant species. In order to achieve better reproducibility and higher throughput, we modified these protocols for automation to be performed by a liquid handling robot. In addition, we show that other procedures such as reporter enzyme assays and tissue clearing can be similarly automated. We present examples of application of our protocols including mRNA localisation and proteins and epitope tag (co)localisations which demonstrate that these methods provide reliable and versatile tools for expression, localisation and anatomical studies in plants. AU - Jirí Friml AU - Eva Benková AU - Mayer, Ulrike AU - Palme, Klaus AU - Muster, Gerhard ID - 2993 IS - 1 JF - Plant Journal TI - Automated whole mount localisation techniques for plant seedlings VL - 34 ER - TY - JOUR AB - Biosynthesis of most peptide hormones and neuropeptides requires proteolytic excision of the active peptide from inactive proprotein precursors, an activity carried out by subtilisin-like proprotein convertases (SPCs) in constitutive or regulated secretory pathways. The Drosophila amontillado (amon) gene encodes a homolog of the mammalian PC2 protein, an SPC that functions in the regulated secretory pathway in neuroendocrine tissues. We have identified amon mutants by isolating ethylmethanesulfonate (EMS)-induced lethal and visible mutations that define two complementation groups in the amon interval at 97D1 of the third chromosome. DNA sequencing identified the amon complementation group and the DNA sequence change for each of the nine amon alleles isolated. amon mutants display partial embryonic lethality, are defective in larval growth, and arrest during the first to second instar larval molt. Mutant larvae can be rescued by heat-shock-induced expression of the amon protein. Rescued larvae arrest at the subsequent larval molt, suggesting that amon is also required for the second to third instar larval molt. Our data indicate that the amon proprotein convertase is required during embryogenesis and larval development in Drosophila and support the hypothesis that AMON acts to proteolytically process peptide hormones that regulate hatching, larval growth, and larval ecdysis. AU - Rayburn, Lowell Y AU - Gooding, Holly C AU - Choksi, Semil P AU - Maloney, Dhea AU - Kidd, Ambrose R AU - Daria Siekhaus AU - Bender, Michael ID - 3151 IS - 1 JF - Genetics TI - Amontillado, the Drosophila homolog of the prohormone processing protease PC2, is required during embryogenesis and early larval development VL - 163 ER - TY - JOUR AB - Tripartite G-protein-coupled receptors (GPCRs) represent one of the largest groups of signal transducers, transmitting signals from hormones, neuropeptides, odorants, food and light. Ligand-bound receptors catalyse GDP/GTP exchange on the G-protein α-subunit (Gα), leading to α-GTP separation from the βγ subunits and pathway activation. Activating mutations in the receptors or G proteins underlie many human diseases, including some cancers, dwarfism and premature puberty. Regulators of G-protein signalling (RGS proteins) are known to modulate the level and duration of ligand-induced signalling by accelerating the intrinsic GTPase activity of the Gα subunit, and thus reformation of the inactive GDP-bound Gα. Here we find that even in the absence of receptor, mutation of the RGS family member Sst2 (refs 6-9) permits spontaneous activation of the G-protein-coupled mating pathway in Saccharomyces cerevisiae at levels normally seen only in the presence of ligand. Our work demonstrates the occurence of spontaneous tripartite G-protein signalling in vivo and identifies a requirement for RGS proteins in preventing such receptor-independent activation. AU - Daria Siekhaus AU - Drubin, David G ID - 3150 IS - 3 JF - Nature Cell Biology TI - Spontaneous receptor-independent heterotrimeric G-protein signalling in an RGS mutant VL - 5 ER - TY - JOUR AB - We show that the fixed alphabet shortest common supersequence (SCS) and the fixed alphabet longest common subsequence (LCS) problems parameterized in the number of strings are W[1]-hard. Unless W[1]=FPT, this rules out the existence of algorithms with time complexity of O(f(k)nα) for those problems. Here n is the size of the problem instance, α is constant, k is the number of strings and f is any function of k. The fixed alphabet version of the LCS problem is of particular interest considering the importance of sequence comparison (e.g. multiple sequence alignment) in the fixed length alphabet world of DNA and protein sequences. AU - Krzysztof Pietrzak ID - 3209 IS - 4 JF - Journal of Computer and System Sciences TI - On the parameterized complexity of the fixed alphabet shortest common supersequence and longest common subsequence problems VL - 67 ER - TY - CONF AB - Luby and Rackoff showed how to construct a (super-)pseudo-random permutation {0,1}2n→ {0,1}2n from some number r of pseudo-random functions {0,1}n → {0,1}n. Their construction, motivated by DES, consists of a cascade of r Feistel permutations. A Feistel permutation 1for a pseudo-random function f is defined as (L, R) → (R,L ⊕ f (R)), where L and R are the left and right part of the input and ⊕ denotes bitwise XOR or, in this paper, any other group operation on {0,1}n. The only non-trivial step of the security proof consists of proving that the cascade of r Feistel permutations with independent uniform random functions {0,1}n → {0,1}n, denoted Ψ2nr is indistinguishable from a uniform random permutation {0,1}2n → {0,1}2n by any computationally unbounded adaptive distinguisher making at most O(2cn) combined chosen plaintext/ciphertext queries for any c < α, where a is a security parameter. Luby and Rackoff proved α = 1/2 for r = 4. A natural problem, proposed by Pieprzyk is to improve on α for larger r. The best known result, α = 3/4 for r = 6, is due to Patarin. In this paper we prove a = 1 -O(1/r), i.e., the trivial upper bound α = 1 can be approached. The proof uses some new techniques that can be of independent interest. AU - Maurer, Ueli M AU - Krzysztof Pietrzak ID - 3210 TI - The security of many round Luby Rackoff pseudo random permutations VL - 2656 ER - TY - CONF AU - Bollenbach, Mark Tobias AU - Strother, T. AU - Bauer, Wolfgang ID - 3425 TI - 3D supernova collapse calculations VL - 166 ER - TY - CHAP AU - Peter Jonas AU - Unsicker, Klaus ED - Schmidt, R. F. ID - 3458 T2 - Lehrbuch Vorklinik TI - Molekulare und zelluläre Grundlagen des Nervensystems. VL - B ER - TY - JOUR AB - Genetic engineering of the mouse brain allows investigators to address novel hypotheses in vivo. Because of the paucity of information on the network patterns of the mouse hippocampus, we investigated the electrical patterns in the behaving animal using multisite silicon probes and wire tetrodes. Theta (6-9 Hz) and gamma (40-100 Hz) oscillations were present during exploration and rapid eye movement sleep. Gamma power and theta power were comodulated and gamma power varied as a function of the theta cycle. Pyramidal cells and putative interneurons were phase-locked to theta oscillations. During immobility, consummatory behaviors and slow-wave sleep, sharp waves were present in cornu ammonis region CA1 of the hippocampus stratum radiatum associated with 140-200-Hz “ripples” in the pyramidal cell layer and population burst of CA1 neurons. In the hilus, large-amplitude “dentate spikes” occurred in association with increased discharge of hilar neurons. The amplitude of field patterns was larger in the mouse than in the rat, likely reflecting the higher neuron density in a smaller brain. We suggest that the main hippocampal network patterns are mediated by similar pathways and mechanisms in mouse and rat. AU - Buzsáki, György AU - Buhl, Derek L AU - Harris, Kenneth D AU - Jozsef Csicsvari AU - Czéh, Boldizsár AU - Morozov, Alexei ID - 3536 IS - 1 JF - Neuroscience TI - Hippocampal network patterns of activity in the mouse VL - 116 ER - TY - CONF AB - We define the Morse-Smale complex of a Morse function over a 3-manifold as the overlay of the descending and as- cending manifolds of all critical points. In the generic case, its 3-dimensional cells are shaped like crystals and are sepa- rated by quadrangular faces. In this paper, we give a combi- natorial algorithm for constructing such complexes for piece- wise linear data. AU - Herbert Edelsbrunner AU - Harer, John AU - Natarajan, Vijay AU - Pascucci, Valerio ID - 3556 TI - Morse-Smale complexes for piecewise linear 3-manifolds ER - TY - CHAP AB - Given a finite point set in R, the surface reconstruction problem asks for a surface that passes through many but not necessarily all points. We describe an unambigu- ous definition of such a surface in geometric and topological terms, and sketch a fast algorithm for constructing it. Our solution overcomes past limitations to special point distributions and heuristic design decisions. AU - Herbert Edelsbrunner ID - 3573 T2 - Discrete & Computational Geometry TI - Surface reconstruction by wrapping finite sets in space ER - TY - JOUR AB - We develop fast algorithms for computing the linking number of a simplicial complex within a filtration.We give experimental results in applying our work toward the detection of non-trivial tangling in biomolecules, modeled as alpha complexes. AU - Edelsbrunner, Herbert AU - Zomorodian, Afra ID - 3584 IS - 2 JF - Homology, Homotopy and Applications TI - Computing linking numbers of a filtration VL - 5 ER - TY - JOUR AB - Stable hybrid zones in which ecologically divergent taxa give rise to a range of recombinants are natural laboratories in which the genetic basis of adaptation and reproductive isolation can be unraveled. One such hybrid zone is formed by the fire-bellied toads Bombina bombina and B. variegata (Anura: Discoglossidae). Adaptations to permanent and ephemeral breeding habitats, respectively, have shaped numerous phenotypic differences between the taxa. All of these are, in principle, candidates for a genetic dissection via QTL mapping. We present here a linkage map of 28 codominant and 10 dominant markers in the Bombina genome. In an F2 cross, markers that were mainly microsatellites, SSCPs or allozymes were mapped to 20 linkage groups. Among the 40 isolated CA microsatellites, we noted a preponderance of compound and frequently interleaved CA-TA repeats as well as a striking polarity at the 5′ end of the repeats. AU - Nürnberger, Beate AU - Hofman, Sebastian AU - Förg-Brey, Bqruni AU - Praetzel, Gabriele AU - Maclean, Alan W AU - Szymura, Jacek M AU - Abbott, Catherine M AU - Nicholas Barton ID - 3620 IS - 2 JF - Heredity TI - A linkage map for the hybridising toads Bombina bombina and B. variegata (Anura: Discoglossidae) VL - 91 ER - TY - JOUR AB - What is the chance that some part of a stretch of genome will survive? In a population of constant size, and with no selection, the probability of survival of some part of a stretch of map length y<1 approaches View the MathML source for View the MathML source. Thus, the whole genome is certain to be lost, but the rate of loss is extremely slow. This solution extends to give the whole distribution of surviving block sizes as a function of time. We show that the expected number of blocks at time t is 1+yt and give expressions for the moments of the number of blocks and the total amount of genome that survives for a given time. The solution is based on a branching process and assumes complete interference between crossovers, so that each descendant carries only a single block of ancestral material. We consider cases where most individuals carry multiple blocks, either because there are multiple crossovers in a long genetic map, or because enough time has passed that most individuals in the population are related to each other. For species such as ours, which have a long genetic map, the genome of any individual which leaves descendants (∼80% of the population for a Poisson offspring number with mean two) is likely to persist for an extremely long time, in the form of a few short blocks of genome. AU - Baird, Stuart J AU - Nicholas Barton AU - Etheridge, Alison M ID - 3619 IS - 4 JF - Theoretical Population Biology TI - The distribution of surviving blocks of an ancestral genome VL - 64 ER - TY - JOUR AB - There are several analyses in evolutionary ecology which assume that a family of offspring has come from only two parents. Here, we present a simple test for detecting when a batch involves two or more subfamilies. It is based on the fact that the mixing of families generates associations amongst unlinked marker loci. We also present simulations illustrating the power of our method for varying numbers of loci, alleles per locus and genotyped individuals. AU - Vines, Timothy H AU - Nicholas Barton ID - 3618 IS - 7 JF - Molecular Ecology TI - A new approach to detecting mixed families VL - 12 ER - TY - JOUR AB - We use the lac operon in Escherichia coli as a prototype system to illustrate the current state, applicability, and limitations of modeling the dynamics of cellular networks. We integrate three different levels of description (molecular, cellular, and that of cell population) into a single model, which seems to capture many experimental aspects of the system. AU - Vilar,Jose M AU - Calin Guet AU - Leibler, Stanislas ID - 3752 IS - 3 JF - Journal of Cell Biology TI - Modeling network dynamics: the lac operon, a case study VL - 161 ER - TY - JOUR AU - Bauer, Wolfgang AU - Kleine Berkenbusch, Marco AU - Bollenbach, Mark Tobias ID - 3797 IS - 4 JF - Revista Mexicana De Fisica TI - Breaking atomic nuclei into little pieces: evidence for a phase transition VL - 49 ER - TY - CONF AB - Many verification, planning, and control problems can be modeled as games played on state-transition graphs by one or two players whose conflicting goals are to form a path in the graph. The focus here is on simple stochastic parity games, that is, two-player games with turn-based probabilistic transitions and omega-regular objectives formalized as parity (Rabin chain) winning conditions. An efficient translation from simple stochastic parity games to nonstochastic parity games is given. As many algorithms are known for solving the latter, the translation yields efficient algorithms for computing the states of a simple stochastic parity game from which a player can win with probability 1. An important special case of simple stochastic parity games are the Markov decision processes with Buchi objectives. For this special case a first provably subquadratic algorithm is given for computing the states from which the single player has a strategy to achieve a Buchi objective with probability 1. For game graphs with m edges the algorithm works in time O(mrootm). Interestingly, a similar technique sheds light on the question of the computational complexity of solving simple Buchi games and yields the first provably subquadratic algorithm, with a running time of O(n(2)/log n) for game graphs with n vertices and O(n) edges. AU - Krishnendu Chatterjee AU - Jurdziński, Marcin AU - Thomas Henzinger ID - 3897 TI - Simple stochastic parity games VL - 2803 ER - TY - CONF 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 axe 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 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. AU - Krishnendu Chatterjee AU - Ma, Di AU - Majumdar, Ritankar S AU - Zhao, Tian AU - Thomas Henzinger AU - Palsberg, Jens ID - 3898 TI - Stack size analysis for interrupt-driven programs VL - 2694 ER - TY - JOUR AB - We present algorithms for constructing a hierarchy of increasingly coarse Morse-Smale complexes that decompose a piecewise linear 2-manifold. While these complexes are defined only in the smooth category, we extend the construction to the piecewise linearcategory by ensuring structural integrity and simulating differentiability. We then simplify Morse-Smale complexes by canceling pairs of critical points in order of increasing persistence. AU - Herbert Edelsbrunner AU - Harer, John AU - Zomorodian, Afra ID - 3993 IS - 1 JF - Discrete & Computational Geometry TI - Hierarchical Morse-Smale complexes for piecewise linear 2-manifolds VL - 30 ER - TY - JOUR AB - The body defined by a finite collection of disks is a subset of the plane bounded by a tangent continuous curve, which we call the skin. We give analytic formulas for the area, the perimeter, the area derivative, and the perimeter derivative of the body. Given the filtrations of the Delaunay triangulation and the Voronoi diagram of the disks, all formulas can be evaluated in time proportional to the number of disks. AU - Cheng, Ho-Lun AU - Herbert Edelsbrunner ID - 3994 IS - 2 JF - Computational Geometry: Theory and Applications TI - Area, perimeter and derivatives of a skin curve VL - 26 ER - TY - GEN AB - Significant advances have been made during the past few years in our understanding of how the spinal monosynaptic reflex develops. Transcription factors in the Neurogenin, Runt, ETS, and LIM families control sequential steps of the specification of various subtypes of dorsal root ganglia sensory neurons. The initiation of muscle spindle differentiation requires neuregulin 1, derived from Ia afferent sensory neurons, and signaling through ErbB receptors in intrafusal muscle fibers. Several retrograde signals from the periphery are important for the establishment of late connectivity in the reflex circuit. Finally, neurotrophin 3 released from muscle spindles regulates the strength of sensory-motor connections within the spinal cord postnatally. AU - Chen, Hsiao Huei AU - Simon Hippenmeyer AU - Arber, Silvia AU - Frank, Eric ID - 3139 IS - 1 T2 - Current Opinion in Neurobiology TI - Development of the monosynaptic stretch reflex circuit VL - 13 ER - TY - CONF AB - Reconstructing a 3-D scene from more than one camera is a classical problem in computer vision. One of the major sources of difficulty is the fact that not all scene elements are visible from all cameras. In the last few years, two promising approaches have been developed 11,12 that formulate the scene reconstruction problem in terms of energy minimization, and minimize the energy using graph cuts. These energy minimization approaches treat the input images symmetrically, handle visibility constraints correctly, and allow spatial smoothness to be enforced. However, these algorithm propose different problem formulations, and handle a limited class of smoothness terms. One algorithm 11 uses a problem formulation that is restricted to two-camera stereo, and imposes smoothness between a pair of cameras. The other algorithm 12 can handle an arbitrary number of cameras, but imposes smoothness only with respect to a single camera. In this paper we give a more general energy minimization formulation for the problem, which allows a larger class of spatial smoothness constraints. We show that our formulation includes both of the previous approaches as special cases, as well as permitting new energy functions. Experimental results on real data with ground truth are also included. AU - Vladimir Kolmogorov AU - Zabih, Ramin AU - Gortler, Steven ID - 3171 TI - Generalized multi camera scene reconstruction using graph cuts VL - 2683 ER - TY - CONF AB - We address visual correspondence problems without assuming that scene points have similar intensities in different views. This situation is common, usually due to non-lambertian scenes or to differences between cameras. We use maximization of mutual information, a powerful technique for registering images that requires no a priori model of the relationship between scene intensities in different views. However, it has proven difficult to use mutual information to compute dense visual correspondence. Comparing fixed-size windows via mutual information suffers from the well-known problems of fixed windows, namely poor performance at discontinuities and in low-texture regions. In this paper, we show how to compute visual correspondence using mutual information without suffering from these problems. Using 'a simple approximation, mutual information can be incorporated into the standard energy minimization framework used in early vision. The energy can then be efficiently minimized using graph cuts, which preserve discontinuities and handle low-texture regions. The resulting algorithm combines the accurate disparity maps that come from graph cuts with the tolerance for intensity changes that comes from mutual information. AU - Kim, Junhwan AU - Vladimir Kolmogorov AU - Zabih, Ramin ID - 3174 TI - Visual correspondence using energy minimization and mutual information VL - 2 ER - TY - CONF AB - Geodesic active contours and graph cuts are two standard image segmentation techniques. We introduce a new segmentation method combining some of their benefits. Our main intuition is that any cut on a graph embedded in some continuous space can be interpreted as a contour (in 2D) or a surface (in 3D). We show how to build a grid graph and set its edge weights so that the cost of cuts is arbitrarily close to the length (area) of the corresponding contours (surfaces) for any anisotropic Riemannian metric. There are two interesting consequences of this technical result. First, graph cut algorithms can be used to find globally minimum geodesic contours (minimal surfaces in 3D) under arbitrary Riemannian metric for a given set of boundary conditions. Second, we show how to minimize metrication artifacts in existing graph-cut based methods in vision. Theoretically speaking, our work provides an interesting link between several branches of mathematics -differential geometry, integral geometry, and combinatorial optimization. The main technical problem is solved using Cauchy-Crofton formula from integral geometry. AU - Boykov, Yuri AU - Vladimir Kolmogorov ID - 3170 TI - Computing geodesics and minimal surfaces via graph cuts VL - 1 ER - TY - JOUR AB - Neurons can produce action potentials with high temporal precision(1). A fundamental issue is whether, and how, this capability is used in information processing. According to the `cell assembly' hypothesis, transient synchrony of anatomically distributed groups of neurons underlies processing of both external sensory input and internal cognitive mechanisms(2-4). Accordingly, neuron populations should be arranged into groups whose synchrony exceeds that predicted by common modulation by sensory input. Here we find that the spike times of hippocampal pyramidal cells can be predicted more accurately by using the spike times of simultaneously recorded neurons in addition to the animals location in space. This improvement remained when the spatial prediction was refined with a spatially dependent theta phase modulation(5-8). The time window in which spike times are best predicted from simultaneous peer activity is 10-30 ms, suggesting that cell assemblies are synchronized at this timescale. Because this temporal window matches the membrane time constant of pyramidal neurons(9), the period of the hippocampal gamma oscillation(10) and the time window for synaptic plasticity(11), we propose that cooperative activity at this timescale is optimal for information transmission and storage in cortical circuits. AU - Harris, Kenneth D AU - Jozsef Csicsvari AU - Hirase, Hajima AU - Dragoi, George AU - Buzsáki, György ID - 3526 IS - 6948 JF - Nature TI - Organization of cell assemblies in the hippocampus VL - 424 ER - TY - JOUR AB - Parallel recording of neuronal activity in the behaving animal is a prerequisite for our understanding of neuronal representation and storage of information. Here we describe the development of micro-machined silicon microelectrode arrays for unit and local field recordings. The two-dimensional probes with 96 or 64 recording sites provided high-density recording of unit and field activity with minimal tissue displacement or damage. The on-chip active circuit eliminated movement and other artifacts and greatly reduced the weight of the headgear. The precise geometry of the recording tips allowed for the estimation of the spatial location of the recorded neurons and for high-resolution estimation of extracellular current source density. Action potentials could be simultaneously recorded from the soma and dendrites of the same neurons. Silicon technology is a promising approach for high-density, high-resolution sampling of neuronal activity in both basic research and prosthetic devices. AU - Jozsef Csicsvari AU - Henze, Darrell A AU - Jamieson, Brian G AU - Harris, Kenneth D AU - Sirota, Anton M AU - Bartho, Peter AU - Wise, Kensall D AU - Buzsáki, György ID - 3529 IS - 2 JF - Journal of Neurophysiology TI - Massively parallel recording of unit and local field potentials with silicon-based electrodes VL - 90 ER - TY - JOUR AB - Gamma frequency oscillations (30-100 Hz) have been suggested to underlie various cognitive and motor functions. Here, we examine the generation of gamma oscillation currents in the hippocampus, using two-dimensional, 96-site silicon probes. Two gamma generators were identified, one in the dentate gyrus and another in the CA3-CA1 regions. The coupling strength between the two oscillators varied during both theta and nontheta states. Both pyramidal cells and interneurons were phase-locked to gamma waves. Anatomical connectivity, rather than physical distance, determined the coupling strength of the oscillating neurons. CA3 pyramidal neurons discharged CA3 and CA1 interneurons at latencies indicative of monosynaptic connections. Intrahippocampal gamma oscillation emerges in the CA3 recurrent system, which entrains the CA1 region via its interneurons. AU - Jozsef Csicsvari AU - Jamieson, Brian G AU - Wise, Kensall D AU - Buzsáki, György ID - 3528 IS - 2 JF - Neuron TI - Mechanisms of gamma oscillations in the hippocampus of the behaving rat VL - 37 ER - TY - JOUR AB - Both neocortical and hippocampal networks organize the firing patterns of their neurons by prominent oscillations during sleep, but the functional role of these rhythms is not well understood. Here, we show a robust correlation of neuronal discharges between the somatosensory cortex and hippocampus on both slow and fine time scales in the mouse and rat. Neuronal bursts in deep cortical layers, associated with sleep spindles and delta waves/slow rhythm, effectively triggered hippocampal discharges related to fast (ripple) oscillations. We hypothesize that oscillation-mediated temporal links coordinate specific information transfer between neocortical and hippocampal cell assemblies. Such a neocortical-hippocampal interplay may be important for memory consolidation. AU - Sirota, Anton M AU - Jozsef Csicsvari AU - Buhl, Derek L AU - Buzsáki, György ID - 3543 IS - 4 JF - PNAS TI - Communication between neocortex and hippocampus during sleep in rodents VL - 100 ER - TY - JOUR AB - Temporal logics such as Computation Tree Logic (CTL) and Linear Temporal Logic (LTL) have become popular for specifying temporal properties over a wide variety of planning and verification problems. In this paper we work towards building a generalized framework for automated reasoning based on temporal logics. We present a powerful extension of CTL with first-order quantification over the set of reachable states for reasoning about extremal properties of weighted labeled transition systems in general. The proposed logic, which we call Weighted Quantified Computation Tree Logic (WQCTL), captures the essential elements common to the domain of planning and verification problems and can thereby be used as an effective specification language in both domains. We show that in spite of the rich, expressive power of the logic, we are able to evaluate WQCTL formulas in time polynomial in the size of the state space times the length of the formula. Wepresent experimental results on the WQCTL verifier. AU - Krishnendu Chatterjee AU - Dasgupta, Pallab AU - Chakrabarti, Partha P ID - 3593 IS - 2 JF - Journal of Automated Reasoning TI - A branching time temporal framework for quantitative reasoning VL - 30 ER - TY - THES AU - Christoph Lampert ID - 3678 T2 - Bonner Mathematische Schriften TI - The Neumann operator in strictly pseudoconvex domains with weighted Bergman metric VL - 356 ER - TY - JOUR AB - The combination of high-resolution atomic force microscopy (AFM) imaging and single-molecule force-spectroscopy was employed to unfold single bacteriorhodopsins (BR) from native purple membrane patches at various physiologically relevant temperatures. The unfolding spectra reveal detailed insight into the stability of individual structural elements of BR against mechanical unfolding. Intermittent states in the unfolding process are associated with the stepwise unfolding of alpha-helices, whereas other states are associated with the unfolding of polypeptide loops connecting the alpha-helices. It was found that the unfolding forces of the secondary structures considerably decreased upon increasing the temperature from 8 to 52°C. Associated with this effect, the probability of individual unfolding pathways of BR was significantly influenced by the temperature. At lower temperatures, transmembrane alpha-helices and extracellular polypeptide loops exhibited sufficient stability to individually establish potential barriers against unfolding, whereas they predominantly unfolded collectively at elevated temperatures. This suggests that increasing the temperature decreases the mechanical stability of secondary structural elements and changes molecular interactions between secondary structures, thereby forcing them to act as grouped structures. AU - Harald Janovjak AU - Kessler, Max AU - Oesterhelt, Dieter AU - Gaub, Hermann AU - Mueller, Daniel J ID - 3725 IS - 19 JF - EMBO Journal TI - Unfolding pathways of native bacteriorhodopsin depend on temperature VL - 22 ER - TY - JOUR AB - Kv3 channels are thought to be essential for the fast-spiking (FS) phenotype in GABAergic interneurons, but how these channels confer the ability to generate action potentials (APs) at high frequency is unknown. To address this question, we developed a fast dynamic-clamp system (approximately 50 kHz) that allowed us to add a Kv3 model conductance to CA1 oriens alveus (OA) interneurons in hippocampal slices. Selective pharmacological block of Kv3 channels by 0.3 mm 4-aminopyridine or 1 mm tetraethylammonium ions led to a marked broadening of APs during trains of short stimuli and a reduction in AP frequency during 1 sec stimuli. The addition of artificial Kv3 conductance restored the original AP pattern. Subtraction of Kv3 conductance by dynamic clamp mimicked the effects of the blockers. Application of artificial Kv3 conductance also led to FS in OA interneurons after complete K+ channel block and even induced FS in hippocampal pyramidal neurons in the absence of blockers. Adding artificial Kv3 conductance with altered deactivation kinetics revealed a nonmonotonic relationship between mean AP frequency and deactivation rate, with a maximum slightly above the original value. Insertion of artificial Kv3 conductance with either lowered activation threshold or inactivation also led to a reduction in the mean AP frequency. However, the mechanisms were distinct. Shifting the activation threshold induced adaptation, whereas adding inactivation caused frequency-dependent AP broadening. In conclusion, Kv3 channels are necessary for the FS phenotype of OA interneurons, and several of their gating properties appear to be optimized for high-frequency repetitive activity. AU - Lien, Cheng-Chang AU - Peter Jonas ID - 3804 IS - 6 JF - Journal of Neuroscience TI - Kv3 potassium conductance is necessary and kinetically optimized for high-frequency action potential generation in hippocampal interneurons VL - 23 ER - TY - JOUR AB - To probe exocytosis at a cortical glutamatergic synapse, we made capacitance measurements in whole-cell recorded hippocampal mossy fiber terminals. Evaluation of different methods by using a morphology-based equivalent electrical model revealed that quantitative capacitance measurements are possible in this presynaptic structure. Voltage pulses leading to presynaptic Ca2+ inflow evoked large capacitance signals that showed saturation with increasing pulse duration. The mean peak capacitance increase was 100 fF, corresponding to a pool of approximately 1,400 releasable vesicles. Thus hippocampal mossy fiber synapses have a vesicular "maxipool." Large pool size and rapid vesicle recycling may underlie the uniquely large extent of activity-dependent plasticity in this synapse. AU - Hallermann, Stefan AU - Pawlu, Christian AU - Peter Jonas AU - Heckmann, Manfred ID - 3806 IS - 15 JF - PNAS TI - A large pool of releasable vesicles in a cortical glutamatergic synapse VL - 100 ER - TY - JOUR AB - Unlike most social insects, many Cardiocondyla ant species have two male morphs: wingless (ergatoid) males, who remain in the natal nest, and winged males who disperse but, strangely, before leaving may also mate within the nest. Whereas ergatoid males are highly intolerant of each other and fight among themselves, they tend to tolerate their winged counterparts. This is despite the fact that these winged males, like ergatoid males, represent mating competition. Why should ergatoid males tolerate their winged rivals? We developed a mathematical model to address this question. Our model focuses on a number of factors likely toinfluence whether ergatoid males are tolerant of winged males: ergatoid male–winged male relatedness, number of virgin queens, number of winged males, and the number of ejaculates a winged male has (winged males are sperm limited, whereas ergatoid males have lifelong spermatogenesis). Surprisingly, we found that increasing the number of virgin queens favors a kill strategy, whereas an increase in the other factors favors a let-live strategy; these predictions appear true for C. obscurior and for a number of other Cardiocondyla species. Two further aspects, unequal insemination success and multiple mating in queens, were also incorporated into the model and predictions made about their effects on toleration of winged males. The model is applicable more generally in species that have dimorphic males, such as some other ants, bees, and fig wasps. AU - Anderson, Carl AU - Cremer, Sylvia AU - Heinze, Jürgen ID - 3921 IS - 1 JF - Behavioral Ecology TI - Live and let die: Why fighter males of the ant Cardiocondyla kill each other but tolerate their winged rivals VL - 14 ER - TY - JOUR AB - Dispersal is advantageous, but, at the same time, it implies high costs and risks. Due to these counteracting selection pressures, many species evolved dispersal polymorphisms, which, in ants, are typically restricted to the female sex (queens). Male polymorphism is presently only known from a few genera, such as Cardiocondyla, in which winged dispersing males coexist with wingless fighter males that mate exclusively inside their maternal nests. We studied the developmental mechanisms underlying these alternative male morphs and found that, first, male dimorphism is not genetically determined, but is induced by environmental conditions (decreasing temperature and density). Second, male morph is not yet fixed at the egg stage, but it differentiates during larval development. This flexible developmental pattern of male morphs allows Cardiocondyla ant colonies to react quickly to changes in their environment. Under good conditions, they invest exclusively in philopatric wingless males. But, when environmental conditions turn bad, colonies start to produce winged dispersal males, even though these males require a many times higher investment by the colony than their much smaller wingless counterparts. Cardiocondyla ants share this potential of optimal resource allocation with other colonial animals and some seed dimorphic plants. AU - Cremer, Sylvia AU - Heinze, Jürgen ID - 3922 IS - 3 JF - Current Biology TI - Stress grows wings: Environmental induction of winged dispersal males in Cardiocondyla ants VL - 13 ER - TY - JOUR AB - Male dimorphism is not genetically determined, but is induced by environmental conditions particularly decreasing temperature and density. AU - Cremer, Sylvia AU - Heinze, Jürgen ID - 3917 IS - 15 JF - Blick in die Wissenschaft TI - Zwischen Hochzeitsflug und Brudermord: reproduktive Taktiken bei Ameisenmännchen VL - 12 ER - TY - THES AB - Methods for the formal specification and verification of systems are indispensible for the development of complex yet correct systems. In formal verification, the designer describes the system in a modeling language with a well-defined semantics, and this system description is analyzed against a set of correctness requirements. Model checking is an algorithmic technique to check that a system description indeed satisfies correctness requirements given as logical specifications. While successful in hardware verification, the potential for model checking for software and embedded systems has not yet been realized. This is because traditional model checking focuses on systems modeled as finite state-transition graphs. While a natural model for hardware (especially synchronous hardware), state-transition graphs often do not capture software and embedded systems at an appropriate level of granularity. This dissertation considers two orthogonal extensions to finite state-transition graphs making model checking techniques applicable to both a wider class of systems and a wider class of properties. The first direction is an extension to infinite-state structures finitely represented using constraints and operations on constraints. Infinite state arises when we wish to model variables with unbounded range (e.g., integers), or data structures, or real time. We provide a uniform framework of symbolic region algebras to study model checking of infinite-state systems. We also provide sufficient language-independent termination conditions for symbolic model checking algorithms on infinite state systems. The second direction supplements verification with game theoretic reasoning. Games are natural models for interactions between components. We study game theoretic behavior with winning conditions given by temporal logic objectives both in the deterministic and in the probabilistic context. For deterministic games, we provide an extremal model characterization of fixpoint algorithms that link solutions of verification problems to solutions for games. For probabilistic games we study fixpoint characterization of winning probabilities for games with omega-regular winning objectives, and construct (epsilon-)optimal winning strategies. AU - Majumdar, Ritankar ID - 4416 TI - Symbolic algorithms for verification and control ER - TY - THES AB - Giotto provides a time-triggered programmer’s model for the implementation of embedded control systems with hard real-time constraints. Giotto’s precise semantics and predictabil- ity make it suitable for safety-critical applications. Giotto is based around the idea that time-triggered task invocation together with time-triggered mode switching can form a useful programming model for real-time systems. To substantiate this claim, we describe the use of Giotto to refactor the software of a small, autonomous helicopter. The ease with which Giotto expresses the existing software provides evidence that Giotto is an appropriate programming language for control systems. Since Giotto is a real-time programming language, ensuring that Giotto programs meet their deadlines is crucial. To study precedence-constrained Giotto scheduling, we first examine single-mode, single-processor scheduling. We extend to an infinite, periodic setting the classical problem of meeting deadlines for a set of tasks with release times, deadlines, precedence constraints, and preemption. We then develop an algorithm for scheduling Giotto programs on a single processor by representing Giotto programs as instances of the extended scheduling problem. Next, we study multi-mode, single-processor Giotto scheduling. This problem is different from classical scheduling problems, since in our precedence-constrained approach, the deadlines of tasks may vary depending on the mode switching behavior of the program. We present conditional scheduling models which capture this varying-deadline behavior. We develop polynomial-time algorithms for some conditional scheduling models, and prove oth- ers to be computationally hard. We show how to represent multi-mode Giotto programs as instances of the model, resulting in an algorithm for scheduling multi-mode Giotto programs on a single processor. Finally, we show that the problem of scheduling Giotto programs for multiple net- worked processors is strongly NP-hard. AU - Horowitz, Benjamin ID - 4425 TI - Giotto: A time-triggered language for embedded programming ER - TY - JOUR AB - We study the free expansion of a pancake-shaped Bose-condensed gas, which is initially trapped under harmonic confinement and containing a vortex at its centre. In the case of a radial expansion holding the axial confinement fixed we consider various models for the interactions, depending on the thickness of the condensate relative to the value of the scattering length. We are thus able to evaluate different scattering regimes ranging from quasi-three-dimensional (Q3D) to strictly two-dimensional (2D). We find that as the system goes from Q3D to 2D the expansion rate of the condensate increases whereas that of the vortex core decreases. In the Q3D scattering regime we also examine a fully free expansion in 3D and find oscillatory behaviour for the vortex core radius: an initial fast expansion of the vortex core is followed by a slowing down. Such a nonuniform expansion rate of the vortex core implies that the timing of its observation should be chosen appropriately. AU - Onur Hosten AU - Vignolo, Patrizia AU - Minguzzi, Anna AU - Tanatar, Bilal AU - Tosi, Mario P ID - 576 IS - 12 JF - Journal of Physics B: Atomic, Molecular and Optical Physics TI - Free expansion of two-dimensional condensates with a vortex VL - 36 ER - TY - JOUR AB - Social and solitary feeding in natural Caenorhabditis elegans isolates are associated with two alleles of the orphan G-protein-coupled receptor (GPCR) NPR-1: social feeders contain NPR-1 215F, whereas solitary feeders contain NPR-1 215V. Here we identify FMRFamide-related neuropeptides (FaRPs) encoded by the flp-18 and flp-21 genes as NPR-1 ligands and show that these peptides can differentially activate the NPR-1 215F and NPR-1 215V receptors. Multicopy overexpression of flp-21 transformed wild social animals into solitary feeders. Conversely, a flp-21 deletion partially phenocopied the npr-1(null) phenotype, which is consistent with NPR-1 activation by FLP-21 in vivo but also implicates other ligands for NPR-1. Phylogenetic studies indicate that the dominant npr-1 215V allele likely arose from an ancestral npr-1 215F gene in C. elegans. Our data suggest a model in which solitary feeding evolved in an ancestral social strain of C. elegans by a gain-of-function mutation that modified the response of NPR-1 to FLP-18 and FLP-21 ligands. AU - Rogers, Candida AU - Reale, Vincenzina AU - Kim, Kyuhyung AU - Chatwin, Heather AU - Li, Chris AU - Evans, Peter AU - de Bono, Mario ID - 6156 IS - 11 JF - Nature Neuroscience SN - 1097-6256 TI - Inhibition of Caenorhabditis elegans social feeding by FMRFamide-related peptide activation of NPR-1 VL - 6 ER - TY - JOUR AB - In many animal species individuals aggregate to live in groups. A range of experimental approaches in different animals, including studies of social feeding in nematodes, maternal behavior in rats and sheep, and pair-bonding in voles, are providing insights into the neural bases for these behaviors. These studies are delineating multiple neural circuits and gene networks in the brain that interact in ways that are as yet poorly understood to coordinate social behavior. AU - de Bono, Mario ID - 6157 IS - 1 JF - Journal of Neurobiology SN - 0022-3034 TI - Molecular approaches to aggregation behavior and social attachment VL - 54 ER - TY - JOUR AB - The accumulation of genome-wide information on single nucleotide polymorphisms in humans provides an unprecedented opportunity to detect the evolutionary forces responsible for heterogeneity of the level of genetic variability across loci. Previous studies have shown that history of recombination events has produced long haplotype blocks in the human genome, which contribute to this heterogeneity. Other factors, however, such as natural selection or the heterogeneity of mutation rates across loci, may also lead to heterogeneity of genetic variability. We compared synonymous and non-synonymous variability within human genes with their divergence from murine orthologs. We separately analyzed the non-synonymous variants predicted to damage protein structure or function and the variants predicted to be functionally benign. The predictions were based on comparative sequence analysis and, in some cases, on the analysis of protein structure. A strong correlation between non-synonymous, benign variability and non-synonymous human-mouse divergence suggests that selection played an important role in shaping the pattern of variability in coding regions of human genes. However, the lack of correlation between deleterious variability and evolutionary divergence shows that a substantial proportion of the observed non-synonymous single-nucleotide polymorphisms reduces fitness and never reaches fixation. Evolutionary and medical implications of the impact of selection on human polymorphisms are discussed. AU - Sunyaev, Shamil R AU - Fyodor Kondrashov AU - Bork, Peer AU - Ramensky, Vasily ID - 847 IS - 24 JF - Human Molecular Genetics TI - Impact of selection, mutation rate and genetic drift on human genetic variation VL - 12 ER - TY - JOUR AB - Alternative splicing is thought to be a major source of functional diversity in animal proteins. We analyzed the evolutionary conservation of proteins encoded by alternatively spliced genes and predicted the ancestral state for 73 cases of alternative splicing (25 insertions and 48 deletions). The amino acid sequences of most of the inserts in proteins produced by alternative splicing are as conserved as the surrounding sequences. Thus, alternative splicing often creates novel isoforms by the insertion of new, functional protein sequences that probably originated from noncoding sequences of introns. AU - Fyodor Kondrashov AU - Koonin, Eugene V ID - 876 IS - 3 JF - Trends in Genetics TI - Evolution of alternative splicing: Deletions, insertions and origin of functional parts of proteins from intron sequences VL - 19 ER - TY - JOUR AB - RNA interference is a conserved process in which double-stranded RNA is processed into 21–25 nucleotide siRNAs that trigger posttranscriptional gene silencing. In addition, plants display a phenomenon termed RNA-directed DNA methylation (RdDM) in which DNA with sequence identity to silenced RNA is de novo methylated at its cytosine residues. This methylation is not only at canonical CpG sites but also at cytosines in CpNpG and asymmetric sequence contexts. In this report, we study the role of the DRM and CMT3 DNA methyltransferase genes in the initiation and maintenance of RdDM. Neither drm nor cmt3 mutants affected the maintenance of preestablished RNA-directed CpG methylation. However, drm mutants showed a nearly complete loss of asymmetric methylation and a partial loss of CpNpG methylation. The remaining asymmetric and CpNpG methylation was dependent on the activity of CMT3, showing that DRM and CMT3 act redundantly to maintain non-CpG methylation. These DNA methyltransferases appear to act downstream of siRNAs, since drm1 drm2 cmt3 triple mutants show a lack of non-CpG methylation but elevated levels of siRNAs. Finally, we demonstrate that DRM activity is required for the initial establishment of RdDM in all sequence contexts including CpG, CpNpG, and asymmetric sites. AU - Cao, Xiaofeng AU - Aufsatz, Werner AU - Zilberman, Daniel AU - Mette, M.Florian AU - Huang, Michael S. AU - Matzke, Marjori AU - Jacobsen, Steven E. ID - 9495 IS - 24 JF - Current Biology SN - 0960-9822 TI - Role of the DRM and CMT3 methyltransferases in RNA-directed DNA methylation VL - 13 ER - TY - JOUR AU - Kaloshin, Vadim ID - 8519 IS - 3 JF - Inventiones mathematicae KW - General Mathematics SN - 0020-9910 TI - The existential Hilbert 16-th problem and an estimate for cyclicity of elementary polycycles VL - 151 ER - TY - JOUR AB - Proteins of the ARGONAUTE family are important in diverse posttranscriptional RNA-mediated gene-silencing systems as well as in transcriptional gene silencing in Drosophila and fission yeast and in programmed DNA elimination in Tetrahymena. We cloned ARGONAUTE4 (AGO4) from a screen for mutants that suppress silencing of the Arabidopsis SUPERMAN(SUP) gene. The ago4-1 mutant reactivated silentSUP alleles and decreased CpNpG and asymmetric DNA methylation as well as histone H3 lysine-9 methylation. In addition,ago4-1 blocked histone and DNA methylation and the accumulation of 25-nucleotide small interfering RNAs (siRNAs) that correspond to the retroelement AtSN1. These results suggest that AGO4 and long siRNAs direct chromatin modifications, including histone methylation and non-CpG DNA methylation. AU - Zilberman, Daniel AU - Cao, Xiaofeng AU - Jacobsen, Steven E. ID - 9455 IS - 5607 JF - Science KW - Multidisciplinary SN - 0036-8075 TI - ARGONAUTE4 control of locus-specific siRNA accumulation and DNA and histone methylation VL - 299 ER - TY - CONF AB - Discounting the future means that the value, today, of a unit payoffis 1 if the payoffo ccurs today, a if it occurs tomorrow, a 2 if it occurs the day after tomorrow, and so on, for some real-valued discount factor 0 < a < 1. Discounting (or inflation) is a key paradigm in economics and has been studied in Markov decision processes as well as game theory. We submit that discounting also has a natural place in systems engineering: for nonterminating systems, a potential bug in the far-away future is less troubling than a potential bug today. We therefore develop a systems theory with discounting. Our theory includes several basic elements: discounted versions of system properties that correspond to the ω-regular properties, fixpoint-based algorithms for checking discounted properties, and a quantitative notion of bisimilarity for capturing the difference between two states with respect to discounted properties. We present the theory in a general form that applies to probabilistic systems as well as multicomponent systems (games), but it readily specializes to classical transition systems. We show that discounting, besides its natural practical appeal, has also several mathematical benefits. First, the resulting theory is robust, in that small perturbations of a system can cause only small changes in the properties of the system. Second, the theory is computational, in that the values of discounted properties, as well as the discounted bisimilarity distance between states, can be computed to any desired degree of precision. AU - De Alfaro, Luca AU - Henzinger, Thomas A AU - Majumdar, Ritankar ID - 4628 SN - 9783540404934 T2 - Proceedings of the 30th International Colloquium on Automata, Languages and Programming TI - Discounting the future in systems theory VL - 2719 ER - TY - JOUR AB - Cross-metathesis reactions of α,β-unsaturated sulfones and sulfoxides in the presence of molybdenum and ruthenium pre-catalysts were tested. A selective metahesis reaction was achieved between functionalized terminal olefins and vinyl sulfones by using the ‘second generation’ ruthenium catalysts 1c–h while the highly active Schrock catalyst 1b was found to be functional group incompatible with vinyl sulfones. The cross-metathesis products were isolated in good yields with an excellent (E)-selectivity. Both the molybdenum and ruthenium-based complexes were, however, incompatible with α,β- and β,γ-unsaturated sulfoxides. AU - Michrowska, Anna AU - Bieniek, Michał AU - Kim, Mikhail AU - Klajn, Rafal AU - Grela, Karol ID - 13436 IS - 25 JF - Tetrahedron KW - Organic Chemistry KW - Drug Discovery KW - Biochemistry SN - 0040-4020 TI - Cross-metathesis reaction of vinyl sulfones and sulfoxides VL - 59 ER - TY - CONF AB - We present a formalism for specifying component interfaces that expose component requirements on limited resources. The formalism permits an algorithmic check if two or more components, when put together, exceed the available resources. Moreover, the formalism can be used to compute the quantity of resources necessary for satisfying the requirements of a collection of components. The formalism can be instantiated in several ways. For example, several components may draw power from the same source. Then, the formalism supports compatibility checks such as: can two components, when put together, achieve their tasks without ever exceeding the available amount of peak power? or, can they achieve their tasks by using no more than the initially available amount of energy (i.e., power accumulated over time)? The corresponding quantitative questions that our algorithms answer are the following: what is the amount of peak power needed for two components to be put together? what is the corresponding amount of initial energy? To solve these questions, we model interfaces with resource requirements as games with quantitative objectives. The games are played on state spaces where each state is labeled by a number (representing, e.g., power consumption), and a play produces an infinite path of labels. The objective may be, for example, to minimize the largest label that occurs during a play. We illustrate our approach by modeling compatibility questions for the components of robot control software, and of wireless sensor networks. AU - Chakrabarti, Arindam AU - De Alfaro, Luca AU - Henzinger, Thomas A AU - Stoelinga, Mariëlle ID - 4561 SN - 9783540202233 T2 - Third International Conference on Embedded Software TI - Resource interfaces VL - 2855 ER - TY - CONF AB - We consider concurrent two-person games played in real time, in which the players decide both which action to play, and when to play it. Such timed games differ from untimed games in two essential ways. First, players can take each other by surprise, because actions are played with delays that cannot be anticipated by the opponent. Second, a player should not be able to win the game by preventing time from diverging. We present a model of timed games that preserves the element of surprise and accounts for time divergence in a way that treats both players symmetrically and applies to all ω-regular winning conditions. We prove that the ability to take each other by surprise adds extra power to the players. For the case that the games are specified in the style of timed automata, we provide symbolic algorithms for their solution with respect to all ω-regular winning conditions. We also show that for these timed games, memory strategies are more powerful than memoryless strategies already in the case of reachability objectives. AU - De Alfaro, Luca AU - Faella, Marco AU - Henzinger, Thomas A AU - Majumdar, Ritankar AU - Stoelinga, Mariëlle ID - 4630 SN - 9783540407539 T2 - Proceedings of the 14th International Conference on Concurrency Theory TI - The element of surprise in timed games VL - 2761 ER - TY - JOUR AB - Giotto is a high-level programming language for time-triggered control applications. The authors begin with a conceptual overview of its methodology, discuss the Giotto helicopter project, and summarize available Giotto implementations. AU - Henzinger, Thomas A AU - Kirsch, Christoph AU - Sanvido, Marco AU - Pree, Wolfgang ID - 4468 IS - 1 JF - IEEE Control Systems Magazine SN - 1066-033X TI - From control models to real-time code using Giotto VL - 23 ER - TY - CHAP AB - Giotto is a principled, tool-supported design methodology for implementing embedded control systems on platforms of possibly distributed sensors, actuators, CPUs, and networks. Giotto is based on the principle that time-triggered task invocations plus time-triggered mode switches can form the abstract essence of programming real-time control systems. Giotto consists of a programming language with a formal semantics, and a retargetable compiler and runtime library. Giotto supports the automation of control system design by strictly separating platform-independent functionality and timing concerns from platform-dependent scheduling and communication issues. The time-triggered predictability of Giotto makes it particularly suitable for safety-critical applications with hard real-time constraints. We illustrate the platform independence and time-triggered execution of Giotto by coordinating a heterogeneous flock of Intel x86 robots and Lego Mindstorms robots. AU - Henzinger, Thomas A AU - Horowitz, Benjamin AU - Kirsch, Christoph ID - 4465 SN - 9780471234364 T2 - Software-Enabled Control: Information Technology for Dynamical Systems TI - Embedded control systems development with Giotto ER - TY - CONF AB - One source of complexity in the μ-calculus is its ability to specify an unbounded number of switches between universal (AX) and existential (EX) branching modes. We therefore study the problems of satisfiability, validity, model checking, and implication for the universal and existential fragments of the μ-calculus, in which only one branching mode is allowed. The universal fragment is rich enough to express most specifications of interest, and therefore improved algorithms are of practical importance. We show that while the satisfiability and validity problems become indeed simpler for the existential and universal fragments, this is, unfortunately, not the case for model checking and implication. We also show the corresponding results for the alternationfree fragment of the μ-calculus, where no alternations between least and greatest fixed points are allowed. Our results imply that efforts to find a polynomial-time model-checking algorithm for the μ-calculus can be replaced by efforts to find such an algorithm for the universal or existential fragment. AU - Henzinger, Thomas A AU - Kupferman, Orna AU - Majumdar, Ritankar ID - 4466 SN - 9783540008989 T2 - Proceedings of the 9th International Conference on Tools and Algorithms for the Construction and Analysis of Systems TI - On the universal and existential fragments of the mu-calculus VL - 2619 ER - TY - CONF AB - BLAST (the Berkeley Lazy Abstraction Software verification Tool) is a verification system for checking safety properties of C programs using automatic property-driven construction and model checking of software abstractions. Blast implements an abstract-model check-refine loop to check for reachability of a specified label in the program. The abstract model is built on the fly using predicate abstraction. This model is then checked for reachability. If there is no (abstract) path to the specified error label, Blast reports that the system is safe and produces a succinct proof. Otherwise, it checks if the path is feasible using symbolic execution of the program. If the path is feasible, Blast outputs the path as an error trace, otherwise, it uses the infeasibility of the path to refine the abstract model. Blast short-circuits the loop from abstraction to verification to refinement, integrating the three steps tightly through “lazy abstraction” [5]. This integration can offer significant advantages in performance by avoiding the repetition of work from one iteration of the loop to the next. AU - Henzinger, Thomas A AU - Jhala, Ranjit AU - Majumdar, Ritankar AU - Sutre, Grégoire ID - 4467 SN - 9783540401179 T2 - Proceedings of the 10th International SPIN Workshop TI - Software verification with BLAST VL - 2648 ER - TY - CONF AB - We present an algorithm called TAR (“Thread-modular Abstraction Refinement”) for model checking safety properties of concurrent software. The TAR algorithm uses thread-modular assume-guarantee reasoning to overcome the exponential complexity in the control state of multithreaded programs. Thread modularity means that TAR explores the state space of one thread at a time, making assumptions about how the environment can interfere. The TAR algorithm uses counterexample-guided predicate-abstraction refinement to overcome the usually infinite complexity in the data state of C programs. A successive approximation scheme automatically infers the necessary precision on data variables as well as suitable environment assumptions. The scheme is novel in that transition relations are approximated from above, while at the same time environment assumptions are approximated from below. In our software verification tool BLAST we have implemented a fully automatic race checker for multithreaded C programs which is based on the TAR algorithm. This tool has verified a wide variety of commonly used locking idioms, including locking schemes that are not amenable to existing dynamic and static race checkers such as ERASER or WARLOCK. AU - Henzinger, Thomas A AU - Jhala, Ranjit AU - Majumdar, Ritankar AU - Qadeer, Shaz ID - 4463 SN - 9783540405245 T2 - Proceedings of the 15th International Conference on Computer Aided Verification TI - Thread-modular abstraction refinement VL - 2725 ER - TY - CONF AB - A major hurdle in the algorithmic verification and control of systems is the need to find suitable abstract models, which omit enough details to overcome the state-explosion problem, but retain enough details to exhibit satisfaction or controllability with respect to the specification. The paradigm of counterexample-guided abstraction refinement suggests a fully automatic way of finding suitable abstract models: one starts with a coarse abstraction, attempts to verify or control the abstract model, and if this attempt fails and the abstract counterexample does not correspond to a concrete counterexample, then one uses the spurious counterexample to guide the refinement of the abstract model. We present a counterexample-guided refinement algorithm for solving ω-regular control objectives. The main difficulty is that in control, unlike in verification, counterexamples are strategies in a game between system and controller. In the case that the controller has no choices, our scheme subsumes known counterexample-guided refinement algorithms for the verification of ω-regular specifications. Our algorithm is useful in all situations where ω-regular games need to be solved, such as supervisory control, sequential and program synthesis, and modular verification. The algorithm is fully symbolic, and therefore applicable also to infinite-state systems. AU - Henzinger, Thomas A AU - Jhala, Ranjit AU - Majumdar, Ritankar ID - 4462 SN - 9783540404934 T2 - Proceedings of the 30th International Colloquium on Automata, Languages and Programming TI - Counterexample-guided control VL - 2719 ER - TY - CONF AB - We introduce the paradigm of schedule-carrying code (SCC). A hard real-time program can be executed on a given platform only if there exists a feasible schedule for the real-time tasks of the program. Traditionally, a scheduler determines the existence of a feasible schedule according to some scheduling strategy. With SCC, a compiler proves the existence of a feasible schedule by generating executable code that is attached to the program and represents its schedule. An SCC executable is a real-time program that carries its schedule as code, which is produced once and can be revalidated and executed with each use. We evaluate SCC both in theory and practice. In theory, we give two scenarios, of nonpreemptive and distributed scheduling for Giotto programs, where the generation of a feasible schedule is hard, while the validation of scheduling instructions that are attached to the programs is easy. In practice, we implement SCC and show that explicit scheduling instructions can reduce the scheduling overhead up to 35% and can provide an efficient, flexible, and verifiable means for compiling Giotto programs on complex architectures, such as the TTA. AU - Henzinger, Thomas A AU - Kirsch, Christoph AU - Matic, Slobodan ID - 4464 SN - 9783540202233 T2 - Proceedings of the 3rd International Conference on Embedded Software TI - Schedule-carrying code VL - 2855 ER - TY - JOUR AB - Symbolic model checking, which enables the automatic verification of large systems, proceeds by calculating expressions that represent state sets. Traditionally, symbolic model-checking tools are based on back- ward state traversal; their basic operation is the function pre, which, given a set of states, returns the set of all predecessor states. This is because specifiers usually employ formalisms with future-time modalities, which are naturally evaluated by iterating applications of pre. It has been shown experimentally that symbolic model checking can perform significantly better if it is based, instead, on forward state traversal; in this case, the basic operation is the function post, which, given a set of states, returns the set of all successor states. This is because forward state traversal can ensure that only parts of the state space that are reachable from an initial state and relevant for the satisfaction or violation of the specification are explored; that is, errors can be detected as soon as possible. In this paper, we investigate which specifications can be checked by symbolic forward state traversal. We formulate the problems of symbolic backward and forward model checking by means of two μ-calculi. The pre-μ calculus is based on the pre operation, and the post-μ calculus is based on the post operation. These two μ-calculi induce query logics, which augment fixpoint expressions with a boolean emptiness query. Using query logics, we are able to relate and compare the symbolic backward and forward approaches. In particular, we prove that all ω-regular (linear-time) specifications can be expressed as post-μ queries, and therefore checked using symbolic forward state traversal. On the other hand, we show that there are simple branching-time specifications that cannot be checked in this way. AU - Henzinger, Thomas A AU - Kupferman, Orna AU - Qadeer, Shaz ID - 4460 IS - 3 JF - Formal Methods in System Design SN - 0925-9856 TI - From pre-historic to post-modern symbolic model checking VL - 23 ER - TY - JOUR AB - Giotto provides an abstract programmer's model for the implementation of embedded control systems with hard real-time constraints. A typical control application consists of periodic software tasks together with a mode-switching logic for enabling and disabling tasks. Giotto specifies time-triggered sensor readings, task invocations, actuator updates, and mode switches independent of any implementation platform. Giotto can be annotated with platform constraints such as task-to-host mappings, and task and communication schedules. The annotations are directives for the Giotto compiler, but they do not alter the functionality and timing of a Giotto program. By separating the platform-independent from the platform-dependent concerns, Giotto enables a great deal of flexibility in choosing control platforms as well as a great deal of automation in the validation and synthesis of control software. The time-triggered nature of Giotto achieves timing predictability, which makes Giotto particularly suitable for safety-critical applications. AU - Henzinger, Thomas A AU - Horowitz, Benjamin AU - Kirsch, Christoph ID - 4469 IS - 1 JF - Proceedings of the IEEE SN - 0018-9219 TI - Giotto: A time-triggered language for embedded programming VL - 91 ER - TY - JOUR AB - Mosaic hybrid zones arise when ecologically differentiated taxa hybridize across a network of habitat patches. Frequent interbreeding across a small-scale patchwork can erode species differences that might have been preserved in a clinal hybrid zone. In particular, the rapid breakdown of neutral divergence sets an upper limit to the time for which differences at marker loci can persist. We present here a case study of a mosaic hybrid zone between the fire-bellied toads Bombina bombina and B. variegata (Anura: Discoglossidae) near Apahida in Romania. In our 20 × 20 km study area, we detected no evidence of a clinal transition but found a strong association between aquatic habitat and mean allele frequencies at four molecular markers. In particular, pure populations of B. bombina in ponds appear to cause massive introgression into the surrounding B. variegata gene pool found in temporary aquatic sites. Nevertheless, the genetic structure of these hybrid populations was remarkably similar to those of a previously studied transect near Pescenica (Croatia), which had both clinal and mosaic features: estimates of heterozygote deficit and linkage disequilibrium in each country are similar. In Apahida, the observed strong linkage disequilibria should stem from an imperfect habitat preference that guides most (but not all) adults into the habitats to which they are adapted. In the absence of a clinal structure, the inferred migration rate between habitats implies that associations between selected loci and neutral markers should break down rapidly. Although plausible selection strengths can maintain differentiation at those loci adapting the toads to either permanent or temporary breeding sites, the divergence at neutral markers must be transient. The hybrid zone may be approaching a state in which the gene pools are homogenized at all but the selected loci, not dissimilar from an early stage of sympatric divergence. AU - Vines, Timothy AU - Kohler, S C AU - Thiel, M AU - Ghira, Ioan AU - Sands, T R AU - Maccallum, Catriona AU - Barton, Nicholas H AU - Nürnberger, Beate ID - 4338 IS - 8 JF - Evolution SN - 0014-3820 TI - On the maintenance of reproductive isolation in a mosaic hybrid zone between the toads Bombina bombina and B. variegata VL - 57 ER - TY - JOUR AB - The phylogeny of Crocodylia offers an unusual twist on the usual molecules versus morphology story. The true gharial (Gavialis gangeticus) and the false gharial (Tomistoma schlegelii), as their common names imply, have appeared in all cladistic morphological analyses as distantly related species, convergent upon a similar morphology. In contrast, all previous molecular studies have shown them to be sister taxa. We present the first phylogenetic study of Crocodylia using a nuclear gene. We cloned and sequenced the c-myc proto-oncogene from Alligator mississippiensis to facilitate primer design and then sequenced an 1,100-base pair fragment that includes both coding and noncoding regions and informative indels for one species in each extant crocodylian genus and six avian outgroups. Phylogenetic analyses using parsimony, maximum likelihood, and Bayesian inference all strongly agreed on the same tree, which is identical to the tree found in previous molecular analyses: Gavialis and Tomistoma are sister taxa and together are the sister group of Crocodylidae. Kishino-Hasegawa tests rejected the morphological tree in favor of the molecular tree. We excluded long-branch attraction and variation in base composition among taxa as explanations for this topology. To explore the causes of discrepancy between molecular and morphological estimates of crocodylian phylogeny, we examined puzzling features of the morphological data using a priori partitions of the data based on anatomical regions and investigated the effects of different coding schemes for two obvious morphological similarities of the two gharials. AU - Harshman, John AU - Huddleston, Christopher AU - Bollback, Jonathan P AU - Parsons, Thomas AU - Braun, Michael ID - 4350 IS - 3 JF - Systematic Biology SN - 0039-7989 TI - True and false gharials: A nuclear gene phylogeny of crocodylia VL - 52 ER - TY - JOUR AB - Many questions in evolutionary biology are best addressed by comparing traits in different species. Often such studies involve mapping characters on phylogenetic trees. Mapping characters on trees allows the nature, number, and timing of the transformations to be identified. The parsimony method is the only method available for mapping morphological characters on phylogenies. Although the parsimony method often makes reasonable reconstructions of the history of a character, it has a number of limitations. These limitations include the inability to consider more than a single change along a branch on a tree and the uncoupling of evolutionary time from amount of character change. We extended a method described by Nielsen (2002, Syst. Biol. 51:729-739) to the mapping of morphological characters under continuous-time Markov models and demonstrate here the utility of the method for mapping characters on trees and for identifying character correlation. AU - Huelsenbeck, John AU - Nielsen, Rasmus AU - Bollback, Jonathan P ID - 4348 IS - 2 JF - Systematic Biology SN - 0039-7989 TI - Stochastic mapping of morphological characters VL - 52 ER - TY - JOUR AB - Chromosomal rearrangements can promote reproductive isolation by reducing recombination along a large section of the genome. We model the effects of the genetic barrier to gene flow caused by a chromosomal rearrangement on the rate of accumulation of postzygotic isolation genes in parapatry. We find that, if reproductive isolation is produced by the accumulation in parapatry of sets of alleles compatible within but incompatible across species, chromosomal rearrangements are far more likely to favor it than classical genetic barriers without chromosomal changes. New evidence of the role of chromosomal rearrangements in parapatric speciation suggests that postzygotic isolation is often due to the accumulation of such incompatibilities. The model makes testable qualitative predictions about the genetic signature of speciation. AU - Navarro, Arcadio AU - Barton, Nicholas H ID - 4254 IS - 3 JF - Evolution; International Journal of Organic Evolution SN - 0014-3820 TI - Accumulating postzygotic isolation genes in parapatry: a new twist on chromosomal speciation VL - 57 ER - TY - JOUR AB - Variation within a species may be structured both geographically and by genetic background. We review the effects of such structuring on neutral variants, using a framework based on the coalescent process. Short-term effects of sex differences and age structure can be averaged out using fast timescale approximations, allowing a simple general treatment of effective population size and migration. We consider the effects of geographic structure on variation within and between local populations, first in general terms, and then for specific migration models. We discuss the close parallels between geographic structure and stable types of genetic structure caused by selection, including balancing selection and background selection. The effects of departures from stability, such as selective sweeps and population bottlenecks, are also described. Methods for distinguishing population history from the effects of ongoing gene flow are discussed. We relate the theoretical results to observed patterns of variation in natural populations. AU - Charlesworth, Brian AU - Charlesworth, Deborah AU - Barton, Nicholas H ID - 4257 JF - Annual Review of Ecology and Systematics SN - 1543-592X TI - The effects of genetic and geographic structure on neutral variation VL - 34 ER - TY - JOUR AB - Artificial Life models may shed new light on the long-standing challenge for evolutionary biology of explaining the origins of complex organs. Real progress on this issue, however, requires Artificial Life researchers to take seriously the tools and insights from population genetics. AU - Barton, Nicholas H AU - Zuidema, Willem ID - 4256 IS - 16 JF - Current Biology SN - 0960-9822 TI - The erratic path towards complexity VL - 13 ER - TY - JOUR AB - Humans and their closest evolutionary relatives, the chimpanzees, differ in ∼1.24% of their genomic DNA sequences. The fraction of these changes accumulated during the speciation processes that have separated the two lineages may be of special relevance in understanding the basis of their differences. We analyzed human and chimpanzee sequence data to search for the patterns of divergence and polymorphism predicted by a theoretical model of speciation. According to the model, positively selected changes should accumulate in chromosomes that present fixed structural differences, such as inversions, between the two species. Protein evolution was more than 2.2 times faster in chromosomes that had undergone structural rearrangements compared with colinear chromosomes. Also, nucleotide variability is slightly lower in rearranged chromosomes. These patterns of divergence and polymorphism may be, at least in part, the molecular footprint of speciation events in the human and chimpanzee lineages. AU - Navarro, Arcadio AU - Barton, Nicholas H ID - 4255 IS - 5617 JF - Science SN - 0036-8075 TI - Chromosomal speciation and molecular divergence -- Accelerated evolution in rearranged chromosomes VL - 300 ER - TY - JOUR AB - During vertebrate gastrulation, highly coordinated cellular rearrangements lead to the formation of the three germ layers, ectoderm, mesoderm and endoderm. In zebrafish, silberblick (slb)/wnt11 regulates normal gastrulation movements by activating a signalling pathway similar to the Frizzled-signalling pathway, which establishes epithelial planar cell polarity (PCP) in Drosophila. However, the cellular mechanisms by which slb/wnt11 functions during zebrafish gastrulation are still unclear. Using high-resolution two-photon confocal imaging followed by computer-assisted reconstruction and motion analysis, we have analysed the movement and morphology of individual cells in three dimensions during the course of gastrulation. We show that in slb-mutant embryos, hypoblast cells within the forming germ ring have slower, less directed migratory movements at the onset of gastrulation. These aberrant cell movements are accompanied by defects in the orientation of cellular processes along the individual movement directions of these cells. We conclude that slb/wnt11-mediated orientation of cellular processes plays a role in facilitating and stabilising movements of hypoblast cells in the germ ring, thereby pointing at a novel function of the slb/wnt11 signalling pathway for the regulation of migratory cell movements at early stages of gastrulation. AU - Ulrich, Florian AU - Concha, Miguel AU - Heid, Paul AU - Voss, Ed AU - Witzel, Sabine AU - Roehl, Henry AU - Tada, Masazumi AU - Wilson, Stephen AU - Adams, Richard AU - Soll, David AU - Heisenberg, Carl-Philipp J ID - 4146 IS - 22 JF - Development SN - 1011-6370 TI - Slb/Wnt11 controls hypoblast cell migration and morphogenesis at the onset of zebrafish gastrulation VL - 130 ER - TY - JOUR AB - Background: During vertebrate gastrulation, cell polarization and migration are core components in the cellular rearrangements that lead to the formation of the three germ layers, ectoderm, mesoderm, and endoderm. Previous studies have implicated the Wnt/planar cell polarity (PCP) signaling pathway in controlling cell morphology and movement during gastrulation. However, cell polarization and directed cell migration are reduced but not completely abolished in the absence of Wnt/PCP signals; this observation indicates that other signaling pathways must be involved. Results: We show that Phosphoinositide 3-Kinases (PI3Ks) are required at the onset of zebrafish gastrulation in mesendodermal cells for process formation and cell polarization. Platelet Derived Growth Factor (PDGF) functions upstream of PI3K, while Protein Kinase B (PKB), a downstream effector of PI3K activity, localizes to the leading edge of migrating mesendodermal cells. In the absence of PI3K activity, PKB localization and cell polarization are strongly reduced in mesendodermal cells and are followed by slower but still highly coordinated and directed movements of these cells. Conclusions: We have identified a novel role of a signaling pathway comprised of PDGF, PI3K, and PKB in the control of morphogenetic cell movements during gastrulation. Furthermore, our findings provide insight into the relationship between cell polarization and directed cell migration at the onset of zebrafish gastrulation. AU - Montero, Juan AU - Kilian, Beate AU - Chan, Joanne AU - Bayliss, Peter AU - Heisenberg, Carl-Philipp J ID - 4169 IS - 15 JF - Current Biology SN - 0960-9822 TI - Phosphoinositide 3-kinase is required for process outgrowth and cell polarization of gastrulating mesendodermal cells VL - 13 ER - TY - JOUR AB - Wnt genes play important roles in regulating patterning and morphogenesis during vertebrate gastrulation. In zebrafish, slb/wnt11 is required for convergence and extension movements, but not cell fate specification during gastrulation. To determine if other Wnt genes functionally interact with slb/wnt11, we analysed the role of ppt/wnt5 during zebrafish gastrulation. ppt/wnt5 is maternally provided and zygotically expressed at all stages during gastrulation. The analysis of ppt mutant embryos reveals that Ppt/Wnt5 regulates cell elongation and convergent extension movements in posterior regions of the gastrula, while its function in more anterior regions is largely redundant to that of Slb/Wnt11. Frizzled-2 functions downstream of ppt/wnt5, indicating that it might act as a receptor for Ppt/Wnt5 in this process. The characterisation of the role of Ppt/Wnt5 provides insight into the functional diversity of Wnt genes in regulating vertebrate gastrulation movements. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. AU - Kilian, Beate AU - Mansukoski, Hannu AU - Barbosa, Filipa AU - Ulrich, Florian AU - Tada, Masazumi AU - Heisenberg, Carl-Philipp J ID - 4185 IS - 4 JF - Mechanisms of Development SN - 0925-4773 TI - The role of Ppt/Wnt5 in regulating cell shape and movement during zebrafish gastrulation VL - 120 ER - TY - JOUR AB - Computing the volume occupied by individual atoms in macromolecular structures has been the subject of research for several decades. This interest has grown in the recent years, because weighted volumes are widely used in implicit solvent models. Applications of the latter in molecular mechanics simulations require that the derivatives of these weighted volumes be known. In this article, we give a formula for the volume derivative of a molecule modeled as a space-filling diagram made up of balls in motion. The formula is given in terms of the weights, radii, and distances between the centers as well as the sizes of the facets of the power diagram restricted to the space-filling diagram. Special attention is given to the detection and treatment of singularities as well as discontinuities of the derivative. AU - Edelsbrunner, Herbert AU - Koehl, Patrice ID - 3992 IS - 5 JF - PNAS SN - 0027-8424 TI - The weighted-volume derivative of a space-filling diagram VL - 100 ER -