TY - JOUR
AB - We compare the functional spectrum of protein evolution in two separate animal lineages with respect to two hypotheses: (1) rates of divergence are distributed similarly among functional classes within both lineages, indicating that selective pressure on the proteome is largely independent of organismic-level biological requirements; and (2) rates of divergence are distributed differently among functional classes within each lineage, indicating species-specific selective regimes impact genome-wide substitutional patterns. Integrating comparative genome sequence with data from tissue-specific expressed-sequence-tag (EST) libraries and detailed database annotations, we find a functional genomic signature of rapid evolution and selective constraint shared between mammalian and nematode lineages despite their extensive morphological and ecological differences and distant common ancestry. In both phyla, we find evidence of accelerated evolution among components of molecular systems involved in coevolutionary change. In mammals, lineage-specific fast evolving genes include those involved in reproduction, immunity, and possibly, maternal-fetal conflict. Likelihood ratio tests provide evidence for positive selection in these rapidly evolving functional categories in mammals. In contrast, slowly evolving genes, in terms of amino acid or insertion/deletion (indel) change, in both phyla are involved in core molecular processes such as transcription, translation, and protein transport. Thus, strong purifying selection appears to act on the same core cellular processes in both mammalian and nematode lineages, whereas positive and/or relaxed selection acts on different biological processes in each lineage.
AU - Castillo-Davis, Cristian I
AU - Fyodor Kondrashov
AU - Hartl, Daniel L
AU - Kulathinal, Rob J
ID - 902
IS - 5
JF - Genome Research
TI - The functional genomic distribution of protein divergence in two animal phyla: Coevolution, genomic conflict, and constraint
VL - 14
ER -
TY - JOUR
AB - The operation of neuronal networks crucially depends on a fast time course of signaling in inhibitory interneurons. Synapses that excite interneurons generate fast currents, owing to the expression of glutamate receptors of specific subunit composition. Interneurons generate brief action potentials in response to transient synaptic activation and discharge repetitively at very high frequencies during sustained stimulation. The ability to generate short-duration action potentials at high frequencies depends on the expression of specific voltage-gated K+ channels. Factors facilitating fast action potential initiation following synaptic excitation include depolarized interneuron resting potential, subthreshold conductances and active dendrites. Finally, GABA release at interneuron output synapses is rapid and highly synchronized, leading to a faster inhibition in postsynaptic interneurons than in principal cells. Thus, the expression of distinct transmitter receptors and voltage-gated ion channels ensures that interneurons operate with high speed and temporal precision.
AU - Peter Jonas
AU - Bischofberger, Josef
AU - Fricker, Desdemona
AU - Miles, Richard
ID - 3805
IS - 1
JF - Trends in Neurosciences
TI - Interneuron Diversity series: Fast in, fast out--temporal and spatial signal processing in hippocampal interneurons
VL - 27
ER -
TY - JOUR
AB - The time course of Mg(2+) block and unblock of NMDA receptors (NMDARs) determines the extent they are activated by depolarization. Here, we directly measure the rate of NMDAR channel opening in response to depolarizations at different times after brief (1 ms) and sustained (4.6 s) applications of glutamate to nucleated patches from neocortical pyramidal neurons. The kinetics of Mg(2+) unblock were found to be non-instantaneous and complex, consisting of a prominent fast component (time constant approximately 100 micros) and slower components (time constants 4 and approximately 300 ms), the relative amplitudes of which depended on the timing of the depolarizing pulse. Fitting a kinetic model to these data indicated that Mg(2+) not only blocks the NMDAR channel, but reduces both the open probability and affinity for glutamate, while enhancing desensitization. These effects slow the rate of NMDAR channel opening in response to depolarization in a time-dependent manner such that the slower components of Mg(2+) unblock are enhanced during depolarizations at later times after glutamate application. One physiological consequence of this is that brief depolarizations occurring earlier in time after glutamate application are better able to open NMDAR channels. This finding has important implications for spike-timing-dependent synaptic plasticity (STDP), where the precise (millisecond) timing of action potentials relative to synaptic inputs determines the magnitude and sign of changes in synaptic strength. Indeed, we find that STDP timing curves of NMDAR channel activation elicited by realistic dendritic action potential waveforms are narrower than expected assuming instantaneous Mg(2+) unblock, indicating that slow Mg(2+) unblock of NMDAR channels makes the STDP timing window more precise.
AU - Kampa, Bjorn M
AU - Clements, John
AU - Peter Jonas
AU - Stuart, Greg J
ID - 3807
IS - Pt 2
JF - Journal of Physiology
TI - Kinetics of Mg(2+) unblock of NMDA receptors: implications for spike-timing dependent synaptic plasticity
VL - 556
ER -
TY - JOUR
AB - Neural stem cells in various regions of the vertebrate brain continuously generate neurons throughout life. In the mammalian hippocampus, a region important for spatial and episodic memory, thousands of new granule cells are produced per day, with the exact number depending on environmental conditions and physical exercise. The survival of these neurons is improved by learning and conversely learning may be promoted by neurogenesis. Although it has been suggested that newly generated neurons may have specific properties to facilitate learning, the cellular and synaptic mechanisms of plasticity in these neurons are largely unknown. Here we show that young granule cells in the adult hippocampus differ substantially from mature granule cells in both active and passive membrane properties. In young neurons, T-type Ca2+ channels can generate isolated Ca2+ spikes and boost fast Na+ action potentials, contributing to the induction of synaptic plasticity. Associative long-term potentiation can be induced more easily in young neurons than in mature neurons under identical conditions. Thus, newly generated neurons express unique mechanisms to facilitate synaptic plasticity, which may be important for the formation of new memories.
AU - Schmidt-Hieber, Christoph
AU - Peter Jonas
AU - Bischofberger, Josef
ID - 3809
IS - 6988
JF - Nature
TI - Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus
VL - 429
ER -
TY - JOUR
AB - Voltage-gated potassium (Kv) channels control action potential repolarization, interspike membrane potential, and action potential frequency in excitable cells. It is thought that the combinatorial association between distinct alpha and beta subunits determines whether Kv channels function as non-inactivating delayed rectifiers or as rapidly inactivating A-type channels. We show that membrane lipids can convert A-type channels into delayed rectifiers and vice versa. Phosphoinositides remove N-type inactivation from A-type channels by immobilizing the inactivation domains. Conversely, arachidonic acid and its amide anandamide endow delayed rectifiers with rapid voltage-dependent inactivation. The bidirectional control of Kv channel gating by lipids may provide a mechanism for the dynamic regulation of electrical signaling in the nervous system.
AU - Oliver, Dominik
AU - Lien, Cheng-Chang
AU - Soom, Malle
AU - Baukrowitz, Thomas
AU - Peter Jonas
AU - Fakler, Bernd
ID - 3810
IS - 5668
JF - Science
TI - Functional conversion between A-type and delayed rectifier K+ channels by membrane lipids
VL - 304
ER -
TY - CONF
AB - We study infinite stochastic games played by n-players on a finite graph with goals given by sets of infinite traces. The games are stochastic (each player simultaneously and independently chooses an action at each round, and the next state is determined by a probability distribution depending on the current state and the chosen actions), infinite (the game continues for an infinite number of rounds), nonzero sum (the players' goals are not necessarily conflicting), and undiscounted. We show that if each player has a reachability objective, that is, if the goal for each player i is to visit some subset R-i of the states, then there exists an epsilon-Nash equilibrium in memoryless strategies, for every epsilon > 0. However, exact Nash equilibria need not exist. We study the complexity of finding such Nash equilibria, and show that the payoff of some epsilon-Nash equilibrium in memoryless strategies can be epsilon-approximated in NP. We study the important subclass of n-player turn-based probabilistic games, where at each state at most one player has a nontrivial choice of moves. For turn-based probabilistic games, we show the existence of epsilon-Nash equilibria in pure strategies for games where the objective of player i is a Borel set B-i of infinite traces. However, exact Nash equilibria may not exist. For the special case of omega-regular objectives, we show exact Nash equilibria exist, and can be computed in NP when the omega-regular objectives are expressed as parity objectives.
AU - Krishnendu Chatterjee
AU - Majumdar, Ritankar S
AU - Jurdziński, Marcin
ID - 3894
TI - On Nash equilibria in stochastic games
VL - 3210
ER -
TY - CONF
AB - In 2-player non-zero-sum games, Nash equilibria capture the options for rational behavior if each player attempts to maximize her payoff. In contrast to classical game theory, we consider lexicographic objectives: first, each player tries to maximize her own payoff, and then, the player tries to minimize the opponent's payoff. Such objectives arise naturally in the verification of systems with multiple components. There, instead of proving that each component satisfies its specification no matter how the other components behave, it often suffices to prove that each component satisfies its specification provided that the other components satisfy their specifications. We say that a Nash equilibrium is secure if it is an equilibrium with respect to the lexicographic objectives of both players. We prove that in graph games with Borel objectives, which include the games that arise in verification, there may be several Nash equilibria, but there is always a unique maximal payoff profile of secure equilibria. We show how this equilibrium can be computed in the case of omega-regular objectives, and we characterize the memory requirements of strategies that achieve the equilibrium.
AU - Krishnendu Chatterjee
AU - Thomas Henzinger
AU - Jurdziński, Marcin
ID - 3895
TI - Games with secure equilibria
ER -
TY - JOUR
AB - Wingless (ergatoid) males of the tramp ant Cardiocondyla minutior attack and kill their young ergatoid rivals and thus attempt to monopolize mating with female sexuals reared in the colony. Because of the different strength of local mate competition in colonies with one or several reproductive queens, we expected the production of new ergatoid males to vary with queen number. Sex ratios were mostly female-biased, but in contrast to the sympatric species C. obscurior (Cremer and Heinze, 2002) neither the percentage of ergatoid males nor of female sexuals among the first 20 sexuals produced varied considerably with queen number. As in C. obscurior, experimental colony fragmentation led to the production of winged males, whereas in unfragmented control colonies only ergatoid males eclosed.
AU - Heinze, Jürgen
AU - Böttcher, A.
AU - Cremer, Sylvia
ID - 3918
IS - 3
JF - Insectes Sociaux
TI - Production of winged and wingless males in the ant, Cardiocondyla minutior
VL - 51
ER -
TY - JOUR
AB - The Nef protein of human and simian immunodeficiency virus (HIV/SIV) is believed to interfere with T cell activation signals by forming a signaling complex at the plasma membrane. Composition and function of the complex are not fully understood. Here we report that Nef recruits the Polycomb Group (PcG) protein Eed, so far known as a nuclear factor and repressor of transcription, to the membrane of cells. The Nef-induced translocation of Eed led to a potent stimulation of Tat-dependent HIV transcription, implying that Eed removal from the nucleus is required for optimal Tat function. Similar to Nef action, activation of integrin receptors recruited Eed to the plasma membrane, also leading to enhanced Tat/Nef-mediated transcription. Our results suggest a link between membrane-associated activation processes and transcriptional derepression and demonstrate how HIV exploits this mechanism.
AU - Witte, Vanessa
AU - Laffert, Bernd
AU - Rosorius, Olaf
AU - Lischka, Peter
AU - Blume, Katja
AU - Galler, Gunther
AU - Stilper, Andrea
AU - Willbold, Dieter
AU - D'Aloja, Paola
AU - Michael Sixt
AU - Kolanus, Johanna
AU - Ott, Melanie
AU - Kolanus, Waldemar
AU - Schuler, Gerold
AU - Baur, Andreas S
ID - 3929
IS - 2
JF - Molecular Cell
TI - HIV-1 Nef mimics an integrin receptor signal that recruits the polycomb group protein Eed to the plasma membrane
VL - 13
ER -
TY - JOUR
AB - Hyaluronan is an unsulfated glycosaminoglycan (GAG) that is ubiquitously expressed in the extracellular matrix (ECM) of all vertebrates, where hyaluronan rich matrices constitute a particular permissive environment for the development of complex biological structures and also for tumor progression. Because of its conserved structure and ubiquitous expression, antibodies for its histochemical detection cannot be produced. We have engineered a fusion protein, neurocan-GFP, and expressed it as a secreted molecule in mammalian cells. Neurocan-GFP fusion protein specifically binds to hyaluronan and directly visualizes hyaluronan on tissue sections, revealing a very detailed picture of hyaluronan distribution. The fluorescent fusion protein can be used in combination with antibodies and nuclear markers for double or triple staining. In addition, it is suitable to visualize hyaluronan on living cells by time-lapse video microscopy. The successful production and application of the neurocan-GFP fusion protein opens up new perspectives for using GFP fusion proteins as detection tools in histological and cytological studies complementing conventional antibody and biotin/avidin techniques.
AU - Zhang, Hui
AU - Baader, Stephan L
AU - Michael Sixt
AU - Kappler, Joachim
AU - Rauch, Uwe
ID - 3931
IS - 7
JF - Journal of Histochemistry and Cytochemistry
TI - Neurocan-GFP fusion protein: a new approach to detect hyaluronan on tissue sections and living cells
VL - 52
ER -
TY - JOUR
AB - We combine topological and geometric methods to construct a multiresolution representation for a function over a two-dimensional domain. In a preprocessing stage, we create the Morse-Smale complex of the function and progressively simplify its topology by cancelling pairs of critical points. Based on a simple notion of dependency among these cancellations, we construct a hierarchical data structure supporting traversal and reconstruction operations similarly to traditional geometry-based representations. We use this data structure to extract topologically valid approximations that satisfy error bounds provided at runtime.
AU - Bremer, Peer-Timo
AU - Herbert Edelsbrunner
AU - Hamann, Bernd
AU - Pascucci, Valerio
ID - 3984
IS - 4
JF - IEEE Transactions on Visualization and Computer Graphics
TI - A topological hierarchy for functions on triangulated surfaces
VL - 10
ER -
TY - JOUR
AB - Given a Morse function f over a 2-manifold with or without boundary, the Reeb graph is obtained by contracting the connected components of the level sets to points. We prove tight upper and lower bounds on the number of loops in the Reeb graph that depend on the genus, the number of boundary components, and whether or not the 2-manifold is orientable. We also give an algorithm that constructs the Reeb graph in time O(n log n), where n is the number of edges in the triangulation used to represent the 2-manifold and the Morse function.
AU - Cole-McLaughlin, Kree
AU - Herbert Edelsbrunner
AU - Harer, John
AU - Natarajan, Vijay
AU - Pascucci, Valerio
ID - 3985
IS - 2
JF - Discrete & Computational Geometry
TI - Loops in Reeb graphs of 2-manifolds
VL - 32
ER -
TY - JOUR
AB - The motion of a biomolecule greatly depends on the engulfing solution, which is mostly water. Instead of representing individual water molecules, it is desirable to develop implicit solvent models that nevertheless accurately represent the contribution of the solvent interaction to the motion. In such models, hydrophobicity is expressed as a weighted sum of atomic surface areas. The derivatives of these weighted areas contribute to the force that drives the motion. In this paper we give formulas for the weighted and unweighted area derivatives of a molecule modeled as a space-filling diagram made up of balls in motion. Other than the radii and the centers of the balls, the formulas are given in terms of the sizes of circular arcs of the boundary and edges of the power diagram. We also give inclusion-exclusion formulas for these sizes.
AU - Bryant, Robert
AU - Herbert Edelsbrunner
AU - Koehl, Patrice
AU - Levitt, Michael
ID - 3986
IS - 3
JF - Discrete & Computational Geometry
TI - The area derivative of a space-filling diagram
VL - 32
ER -
TY - JOUR
AB - We consider scientific data sets that describe density functions over three-dimensional geometric domains. Such data sets are often large and coarsened representations are needed for visualization and analysis. Assuming a tetrahedral mesh representation, we construct such representations with a simplification algorithm that combines three goals: the approximation of the function, the preservation of the mesh topology, and the improvement of the mesh quality. The third goal is achieved with a novel extension of the well-known quadric error metric. We perform a number of computational experiments to understand the effect of mesh quality improvement on the density map approximation. In addition, we study the effect of geometric simplification on the topological features of the function by monitoring its critical points.
AU - Natarajan, Vijay
AU - Herbert Edelsbrunner
ID - 3987
IS - 5
JF - IEEE Transactions on Visualization and Computer Graphics
TI - Simplification of three-dimensional density maps
VL - 10
ER -
TY - CONF
AB - We give an algorithm that locally improves the fit between two proteins modeled as space-filling diagrams. The algorithm defines the fit in purely geometric terms and improves by applying a rigid motion to one of the two proteins. Our implementation of the algorithm takes between three and ten seconds and converges with high likelihood to the correct docked configuration, provided it starts at a position away from the correct one by at most 18 degrees of rotation and at most 3.0Angstrom of translation. The speed and convergence radius make this an attractive algorithm to use in combination with a coarse sampling of the six-dimensional space of rigid motions.
AU - Choi, Vicky
AU - Agarwal, Pankaj K
AU - Herbert Edelsbrunner
AU - Rudolph, Johannes
ID - 3988
TI - Local search heuristic for rigid protein docking
VL - 3240
ER -
TY - CONF
AB - We introduce local and global comparison measures for a collection of k less than or equal to d real-valued smooth functions on a common d-dimensional Riemannian manifold. For k = d = 2 we relate the measures to the set of critical points of one function restricted to the level sets of the other. The definition of the measures extends to piecewise linear functions for which they ace easy to compute. The computation of the measures forms the centerpiece of a software tool which we use to study scientific datasets.
AU - Herbert Edelsbrunner
AU - Harer, John
AU - Natarajan, Vijay
AU - Pascucci, Valerio
ID - 3989
TI - Local and global comparison of continuous functions
ER -
TY - JOUR
AB - The writhing number measures the global geometry of a closed space curve or knot. We show that this measure is related to the average winding number of its Gauss map. Using this relationship, we give an algorithm for computing the writhing number for a polygonal knot with n edges in time roughly proportional to n(1.6). We also implement a different, simple algorithm and provide experimental evidence for its practical efficiency.
AU - Agarwal, Pankaj K
AU - Herbert Edelsbrunner
AU - Wang, Yusu
ID - 3990
IS - 1
JF - Discrete & Computational Geometry
TI - Computing the writhing number of a polygonal knot
VL - 32
ER -
TY - JOUR
AB - During vertebrate gastrulation, a relatively limited number of blastodermal cells undergoes a stereotypical set of cellular movements that leads to formation of the three germ layers: ectoderm, mesoderm and endoderm. Gastrulation, therefore, provides a unique developmental system in which to study cell movements in vivo in a fairly simple cellular context. Recent advances have been made in elucidating the cellular and molecular mechanisms that underlie cell movements during zebrafish gastrulation. These findings can be compared with observations made in other model systems to identify potential general mechanisms of cell migration during development.
AU - Montero, Juan
AU - Heisenberg, Carl-Philipp J
ID - 4172
IS - 11
JF - Trends in Cell Biology
TI - Gastrulation dynamics: cells move into focus
VL - 14
ER -
TY - JOUR
AB - Developing cells acquire positional information by reading the graded distribution of morphogens. In Drosophila, the Dpp morphogen forms a long-range concentration gradient by spreading from a restricted source in the developing wing. It has been assumed that Dpp spreads by extracellular diffusion. Under this assumption, the main role of endocytosis in gradient formation is to downregulate receptors at the cell surface. These surface receptors bind to the ligand and thereby interfere with its long-range movement. Recent experiments indicate that Dpp spreading is mediated by Dynamin-dependent endocytosis in the target tissue, suggesting that extracellular diffusion alone cannot account for Dpp dispersal. Here, we perform a theoretical study of a model for morphogen spreading based on extracellular diffusion, which takes into account receptor binding and trafficking. We compare profiles of ligand and surface receptors obtained in this model with experimental data. To this end, we monitored directly the pool of surface receptors and extracellular Dpp with specific antibodies. We conclude that current models considering pure extracellular diffusion cannot explain the observed role of endocytosis during Dpp long-range movement.
AU - Kruse, Karsten
AU - Pantazis, Periklis
AU - Bollenbach, Mark Tobias
AU - Julicher, Frank
AU - Gonzalez Gaitan, Marcos
ID - 4224
IS - 19
JF - Development
TI - Dpp gradient formation by dynamin-dependent endocytosis: receptor trafficking and the diffusion model
VL - 131
ER -
TY - CHAP
AU - Harold Vladar
AU - Cipriani, Roberto
AU - Scharifker, Benjamin
AU - Bubis, Jose
ED - Hanslmeier,A.
ED - Kempe,S.
ED - Seckbach,J.
ID - 4230
T2 - Life in the Universe From the Miller Experiment to the Search for Life on Other Worlds
TI - A mechanism for the prebiotic emergence of proteins
ER -