TY - JOUR
AU - Timothy Browning
AU - Heath-Brown, Roger
ID - 209
IS - 3
JF - Inventiones Mathematicae
TI - Equal sums of three powers
VL - 157
ER -
TY - JOUR
AB - It is widely believed that the inflammatory events mediated by microglial activation contribute to several neurodegenerative processes. Alzheimer's disease, for example, is characterized by an accumulation of β-amyloid protein (Aβ) in neuritic plaques that are infiltrated by reactive microglia and astrocytes. Although Aβ and its fragment 25-35 exert a direct toxic effect on neurons, they also activate microglia. Microglial activation is accompanied by morphological changes, cell proliferation, and release of various cytokines and growth factors. A number of scientific reports suggest that the increased proliferation of microglial cells is dependent on ionic membrane currents and in particular on chloride conductances. An unusual chloride ion channel known to be associated with macrophage activation is the chloride intracellular channel-1 (CLIC1). Here we show that Aβ stimulation of neonatal rat microglia specifically leads to the increase in CLIC1 protein and to the functional expression of CLIC1 chloride conductance, both barely detectable on the plasma membrane of quiescent cells. CLIC1 protein expression in microglia increases after 24 hr of incubation with Aβ, simultaneously with the production of reactive nitrogen intermediates and of tumor necrosis factor-α (TNF-α). We demonstrate that reducing CLIC1 chloride conductance by a specific blocker [IAA-94 (R(+)-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5yl)-oxy] acetic acid)] prevents neuronal apoptosis in neurons cocultured with Aβ-treated microglia. Furthermore, we show that small interfering RNAs used to knock down CLIC1 expression prevent TNF-α release induced by Aβ stimulation. These results provide a direct link between Aβ-induced microglial activation and CLIC1 functional expression.
AU - Gaia Novarino
AU - Fabrizi, Cinzia
AU - Tonini, Raffaella
AU - Denti, Michela A
AU - Malchiodi, Albedi F
AU - Lauro, Giuliana M
AU - Sacchetti, Benedetto
AU - Paradisi, Silvia
AU - Ferroni, Arnaldo
AU - Curmi, Paul M G
AU - Breit, Samuel N
AU - Mazzanti, Michele
ID - 2308
IS - 23
JF - Journal of Neuroscience
TI - Involvement of the intracellular ion channel CLIC1 in microglia-mediated β-amyloid-induced neurotoxicity
VL - 24
ER -
TY - JOUR
AB - The BMV conjecture for traces, which states that Tr exp(A - λB) is the Laplace transform of a positive measure, is shown to be equivalent to two other statements: (i) The polynomial λ → Tr(A + λB) p has only non-negative coefficients for all A, B ≥ 0, p ∈ ℕ and (ii) λ → Tr(A + λB)-p is the Laplace transform of a positive measure for A, B ≥ 0, p > 0.
AU - Lieb, Élliott H
AU - Robert Seiringer
ID - 2355
IS - 1-2
JF - Journal of Statistical Physics
TI - Equivalent forms of the Bessis-Moussa-Villani conjecture
VL - 115
ER -
TY - JOUR
AB - Recent experimental and theoretical work has shown that there are conditions in which a trapped, low-density Bose gas behaves like the one-dimensional delta-function Bose gas solved years ago by Lieb and Liniger. This is an intrinsically quantum-mechanical phenomenon because it is not necessary to have a trap width that is the size of an atom - as might have been supposed - but it suffices merely to have a trap width such that the energy gap for motion in the transverse direction is large compared to the energy associated with the motion along the trap. Up to now the theoretical arguments have been based on variational - perturbative ideas or numerical investigations. In contrast, this paper gives a rigorous proof of the one-dimensional behavior as far as the ground state energy and particle density are concerned. There are four parameters involved: the particle number, N, transverse and longitudinal dimensions of the trap, r and L, and the scattering length a of the interaction potential. Our main result is that if r/L → 0 and N → ∞ the ground state energy and density can be obtained by minimizing a one-dimensional density functional involving the Lieb-Liniger energy density with coupling constant ∼ a/r 2. This density functional simplifies in various limiting cases and we identify five asymptotic parameter regions altogether. Three of these, corresponding to the weak coupling regime, can also be obtained as limits of a three-dimensional Gross-Pitaevskii theory. We also show that Bose-Einstein condensation in the ground state persists in a part of this regime. In the strong coupling regime the longitudinal motion of the particles is strongly correlated. The Gross-Pitaevskii description is not valid in this regime and new mathematical methods come into play.
AU - Lieb, Élliott H
AU - Robert Seiringer
AU - Yngvason, Jakob
ID - 2356
IS - 2
JF - Communications in Mathematical Physics
TI - One-dimensional behavior of dilute, trapped Bose gases
VL - 244
ER -
TY - JOUR
AB - An optical lattice model developed that is similar to the Bose-Hubbard model to describe the transition between Bose-Einstein condensation (BEC) and a Mott insulator state was analyzed. It was found that the system was a hard core lattice gas at half of the maximum density and the optical lattice was modeled by a periodic potential of strength λ. It was also observed that the interparticle interaction was essential for this transition that occurred even in the ground state. The results show that all the essential features could be proved rigorously such as the existence of BEC for small λ and its suppression for a large λ.
AU - Aizenman, Michael
AU - Lieb, Élliott H
AU - Robert Seiringer
AU - Solovej, Jan P
AU - Yngvason, Jakob
ID - 2360
IS - 2
JF - Physical Review A - Atomic, Molecular, and Optical Physics
TI - Bose-Einstein quantum phase transition in an optical lattice model
VL - 70
ER -
TY - CHAP
AU - Lovász, László
AU - Vesztergombi, Katalin
AU - Uli Wagner
AU - Welzl, Emo
ED - Pach, János
ID - 2417
T2 - Towards a Theory of Geometric Graphs
TI - Convex quadrilaterals and k-sets
VL - 342
ER -
TY - JOUR
AB - A finite set N ⊂ Rd is a weak ε-net for an n-point set X ⊂ Rd (with respect to convex sets) if N intersects every convex set K with |K ∩ X| ≥ εn. We give an alternative, and arguably simpler, proof of the fact, first shown by Chazelle et al., that every point set X in Rd admits a weak ε-net of cardinality O(ε-dpolylog(1/ε)). Moreover, for a number of special point sets (e.g., for points on the moment curve), our method gives substantially better bounds. The construction yields an algorithm to construct such weak ε-nets in time O(n ln(1/ε)).
AU - Matoušek, Jiří
AU - Uli Wagner
ID - 2425
IS - 2
JF - Discrete & Computational Geometry
TI - New constructions of weak ε-nets
VL - 32
ER -
TY - JOUR
AB - We introduce the adaptive neighborhood graph as a data structure for modeling a smooth manifold M embedded in some Euclidean space ℝ d. We assume that M is known to us only through a finite sample P ⊂ M, as is often the case in applications. The adaptive neighborhood graph is a geometric graph on P. Its complexity is at most min{2O(k)n, n2}, where n = P and k = dim M, as opposed to the n[d/2] complexity of the Delaunay triangulation, which is often used to model manifolds. We prove that we can correctly infer the connected components and the dimension of M from the adaptive neighborhood graph provided a certain standard sampling condition is fulfilled. The running time of the dimension detection algorithm is d20(k7 log k) for each connected component of M. If the dimension is considered constant, this is a constant-time operation, and the adaptive neighborhood graph is of linear size. Moreover, the exponential dependence of the constants is only on the intrinsic dimension k, not on the ambient dimension d. This is of particular interest if the co-dimension is high, i.e., if k is much smaller than d, as is the case in many applications. The adaptive neighborhood graph also allows us to approximate the geodesic distances between the points in P.
AU - Giesen, Joachim
AU - Uli Wagner
ID - 2426
IS - 2
JF - Discrete & Computational Geometry
TI - Shape dimension and intrinsic metric from samples of manifolds
VL - 32
ER -
TY - GEN
AU - Sauer, Michael
AU - Friml, Jirí
ID - 2461
IS - 23
T2 - Development
TI - The Matryoshka dolls of plant polarity
VL - 131
ER -
TY - JOUR
AB - The analysis of the complete H2/air polymer electrolyte fuel cell system shows that process air humidification is one of the biggest obstacles for a high performance portable system in the kW range. Therefore, a new concept, with passive process air humidification integrated into the stack, has been developed. Humidification in each cell makes the process independent from the number of cells and the operation mode, thus making the concept fully scalable. Without external humidification the system is simpler, smaller, and cheaper. The humidification of the process air is achieved by transfer of product water from the exhaust air, through part of the membrane, to the dry intake air. Tests have shown that cells using the concept of internal humidification and operated with dry air at 70 ° have almost the same performance as when operated with external humidification. A 42‐cell stack with this internal humidification concept was built and integrated into a portable 1 kW power generator system.
AU - Santis, M.
AU - Schmid, D.
AU - Ruge, M.
AU - Freunberger, Stefan Alexander
AU - Büchi, F.N.
ID - 7333
IS - 3
JF - Fuel Cells
SN - 1615-6846
TI - Modular stack-internal air humidification concept-verification in a 1 kW stack
VL - 4
ER -
TY - JOUR
AB - Fundamental and phenomenological models for cells, stacks, and complete systems of PEFC and SOFC are reviewed and their predictive power is assessed by comparing model simulations against experiments. Computationally efficient models suited for engineering design include the (1+1) dimensionality approach, which decouples the membrane in-plane and through-plane processes, and the volume-averaged-method (VAM) that considers only the lumped effect of pre-selected system components. The former model was shown to capture the measured lateral current density inhomogeneities in a PEFC and the latter was used for the optimization of commercial SOFC systems. State Space Modeling (SSM) was used to identify the main reaction pathways in SOFC and, in conjunction with the implementation of geometrically well-defined electrodes, has opened a new direction for the understanding of electrochemical reactions. Furthermore, SSM has advanced the understanding of the COpoisoning-induced anode impedance in PEFC. Detailed numerical models such as the Lattice Boltzmann (LB) method for transport in porous media and the full 3-D Computational Fluid Dynamics (CFD) Navier-Stokes simulations are addressed. These models contain all components of the relevant physics and they can improve the understanding of the related phenomena, a necessary condition for the development of both appropriate simplified models as well as reliable technologies. Within the LB framework, a technique for the characterization and computer-reconstruction of the porous electrode structure was developed using advanced pattern recognition algorithms. In CFD modeling, 3-D simulations were used to investigate SOFC with internal methane steam reforming and have exemplified the significance of porous and novel fractal channel distributors for the fuel and oxidant delivery, as well as for the cooling of PEFC. As importantly, the novel concept has been put forth of functionally designed, fractal-shaped fuel cells, showing promise of significant performance improvements over the conventional rectangular shaped units. Thermo-economic modeling for the optimization of PEFC is finally addressed.
AU - Mantzaras, John
AU - Freunberger, Stefan Alexander
AU - Büchi, Felix N.
AU - Roos, Markus
AU - Brandstätter, Wilhelm
AU - Prestat, Michel
AU - Gauckler, Ludwig J.
AU - Andreaus, Bernhard
AU - Hajbolouri, Faegheh
AU - Senn, Stephan M.
AU - Poulikakos, Dimos
AU - Chaniotis, Andreas K.
AU - Larrain, Diego
AU - Autissier, Nordahl
AU - Maréchal, François
ID - 7334
IS - 12
JF - CHIMIA International Journal for Chemistry
SN - 0009-4293
TI - Fuel cell modeling and simulations
VL - 58
ER -
TY - JOUR
AB - The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.
AU - Brunet, Anne
AU - Sweeney, Lora Beatrice Jaeger
AU - Sturgill, J Fitzhugh
AU - Chua, Katrin
AU - Greer, Paul
AU - Lin, Yingxi
AU - Tran, Hien
AU - Ross, Sarah
AU - Mostoslavsky, Raul
AU - Cohen, Haim
AU - Hu, Linda
AU - Chen, Hwei-Ling
AU - Jedrychowski, Mark
AU - Gygi, Steven
AU - Sinclair, David
AU - Alt, Frederick
AU - Greenberg, Michael
ID - 7706
IS - 5666
JF - Science
SN - 0036-8075
TI - Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase
VL - 303
ER -
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 - CHAP
AU - Harold Vladar
AU - Cipriani, Roberto
AU - Scharifker, Benjamin
AU - Bubis, Jose
ED - Hanslmeier,A.
ED - Kempe,S.
ED - Seckbach,J.
ID - 4230
T2 - Life in the Universe From the Miller Experiment to the Search for Life on Other Worlds
TI - A mechanism for the prebiotic emergence of proteins
ER -
TY - CHAP
AU - Harold Vladar
AU - Cipriani, Roberto
AU - Scharifker, Benjamin
AU - Bubis, Jose
ED - Seckbach,J.
ED - Chela-Flores,J.
ED - Owen,T.
ED - Raulin,F.
ID - 4239
T2 - Life in the Universe From the Miller Experiment to the Search for Life on Other Worlds
TI - A Mechanism for the Prebiotic Emergence of Proteins
VL - 7
ER -
TY - JOUR
AB - We consider a single genetic locus which carries two alleles, labelled P and Q. This locus experiences selection and mutation. It is linked to a second neutral locus with recombination rate r. If r = 0, this reduces to the study of a single selected locus. Assuming a Moran model for the population dynamics, we pass to a diffusion approximation and, assuming that the allele frequencies at the selected locus have reached stationarity, establish the joint generating function for the genealogy of a sample from the population and the frequency of the P allele. In essence this is the joint generating function for a coalescent and the random background in which it evolves. We use this to characterize, for the diffusion approximation, the probability of identity in state at the neutral locus of a sample of two individuals (whose type at the selected locus is known) as solutions to a system of ordinary differential equations. The only subtlety is to find the boundary conditions for this system. Finally, numerical examples are presented that illustrate the accuracy and predictions of the diffusion approximation. In particular, a comparison is made between this approach and one in which the frequencies at the selected locus are estimated by their value in the absence of fluctuations and a classical structured coalescent model is used.
AU - Nicholas Barton
AU - Etheridge, Alison M
AU - Sturm, Anja K
ID - 4253
IS - 2
JF - Annals of Applied Probability
TI - Coalescence in a Random Background
VL - 14
ER -
TY - CONF
AU - Maler, Oded
AU - Dejan Nickovic
ID - 4372
TI - Monitoring Temporal Properties of Continuous Signals
ER -
TY - CONF
AB - We present a type system for E code, which is an assembly language that manages the release, interaction, and termination of real-time tasks. E code specifies a deadline for each task, and the type system ensures that the deadlines are path-insensitive. We show that typed E programs allow, for given worst-case execution times of tasks, a simple schedulability analysis. Moreover, the real-time programming language Giotto can be compiled into typed E~code. This shows that typed E~code identifies an easily schedulable yet expressive class of real-time programs. We have extended the Giotto compiler to generate typed E code, and enabled the run-time system for E code to perform a type and schedulability check before executing the code.
AU - Thomas Henzinger
AU - Kirsch, Christoph M
ID - 4445
TI - A typed assembly language for real-time programs
ER -
TY - CONF
AB - The success of model checking for large programs depends crucially on the ability to efficiently construct parsimonious abstractions. A predicate abstraction is parsimonious if at each control location, it specifies only relationships between current values of variables, and only those which are required for proving correctness. Previous methods for automatically refining predicate abstractions until sufficient precision is obtained do not systematically construct parsimonious abstractions: predicates usually contain symbolic variables, and are added heuristically and often uniformly to many or all control locations at once. We use Craig interpolation to efficiently construct, from a given abstract error trace which cannot be concretized, a parsominous abstraction that removes the trace. At each location of the trace, we infer the relevant predicates as an interpolant between the two formulas that define the past and the future segment of the trace. Each interpolant is a relationship between current values of program variables, and is relevant only at that particular program location. It can be found by a linear scan of the proof of infeasibility of the trace.We develop our method for programs with arithmetic and pointer expressions, and call-by-value function calls. For function calls, Craig interpolation offers a systematic way of generating relevant predicates that contain only the local variables of the function and the values of the formal parameters when the function was called. We have extended our model checker Blast with predicate discovery by Craig interpolation, and applied it successfully to C programs with more than 130,000 lines of code, which was not possible with approaches that build less parsimonious abstractions.
AU - Thomas Henzinger
AU - Jhala, Ranjit
AU - Majumdar, Ritankar S
AU - McMillan, Kenneth L
ID - 4458
TI - Abstractions from proofs
ER -
TY - CONF
AB - Software model checking has been successful for sequential programs, where predicate abstraction offers suitable models, and counterexample-guided abstraction refinement permits the automatic inference of models. When checking concurrent programs, we need to abstract threads as well as the contexts in which they execute. Stateless context models, such as predicates on global variables, prove insufficient for showing the absence of race conditions in many examples. We therefore use richer context models, which combine (1) predicates for abstracting data state, (2) control flow quotients for abstracting control state, and (3) counters for abstracting an unbounded number of threads. We infer suitable context models automatically by a combination of counterexample-guided abstraction refinement, bisimulation minimization, circular assume-guarantee reasoning, and parametric reasoning about an unbounded number of threads. This algorithm, called CIRC, has been implemented in BLAST and succeeds in checking many examples of NESC code for data races. In particular, BLAST proves the absence of races in several cases where previous race checkers give false positives.
AU - Thomas Henzinger
AU - Jhala, Ranjit
AU - Majumdar, Ritankar S
ID - 4459
TI - Race checking by context inference
ER -
TY - CHAP
AB - One of the central axioms of extreme programming is the disciplined use of regression testing during stepwise software development. Due to recent progress in software model checking, it has become possible to supplement this process with automatic checks for behavioral safety properties of programs, such as conformance with locking idioms and other programming protocols and patterns. For efficiency reasons, all checks must be incremental, i.e., they must reuse partial results from previous checks in order to avoid all unnecessary repetition of expensive verification tasks. We show that the lazy-abstraction algorithm, and its implementation in Blast, can be extended to support the fully automatic and incremental checking of temporal safety properties during software development.
AU - Thomas Henzinger
AU - Jhala, Ranjit
AU - Majumdar, Ritankar S
AU - Sanvido, Marco A
ID - 4461
T2 - Verification: Theory and Practice
TI - Extreme model checking
VL - 2772
ER -
TY - CONF
AB - We present a new high-level programming language, called xGiotto, for programming applications with hard real-time constraints. Like its predecessor, xGiotto is based on the LET (logical execution time) assumption: the programmer specifies when the outputs of a task become available, and the compiler checks if the specification can be implemented on a given platform. However, while the predecessor language xGiotto was purely time-triggered, xGiotto accommodates also asynchronous events. Indeed, through a mechanism called event scoping, events are the main structuring principle of the new language. The xGiotto compiler and run-time system implement event scoping through a tree-based event filter. The compiler also checks programs for determinism (absence of race conditions).
AU - Ghosal, Arkadeb
AU - Thomas Henzinger
AU - Kirsch, Christoph M
AU - Sanvido, Marco A
ID - 4525
TI - Event-driven programming with logical execution times
VL - 2993
ER -
TY - CONF
AB - Strategies in repeated games can be classified as to whether or not they use memory and/or randomization. We consider Markov decision processes and 2-player graph games, both of the deterministic and probabilistic varieties. We characterize when memory and/or randomization are required for winning with respect to various classes of w-regular objectives, noting particularly when the use of memory can be traded for the use of randomization. In particular, we show that Markov decision processes allow randomized memoryless optimal strategies for all M?ller objectives. Furthermore, we show that 2-player probabilistic graph games allow randomized memoryless strategies for winning with probability 1 those M?ller objectives which are upward-closed. Upward-closure means that if a set α of infinitely repeating vertices is winning, then all supersets of α are also winning.
AU - Krishnendu Chatterjee
AU - de Alfaro, Luca
AU - Thomas Henzinger
ID - 4555
TI - Trading memory for randomness
ER -
TY - JOUR
AB - We study the problem of determining stack boundedness and the exact maximum stack size for three classes of interrupt-driven programs. Interrupt-driven programs are used in many real-time applications that require responsive interrupt handling. In order to ensure responsiveness, programmers often enable interrupt processing in the body of lower-priority interrupt handlers. In such programs a programming error can allow interrupt handlers to be interrupted in a cyclic fashion to lead to an unbounded stack, causing the system to crash. For a restricted class of interrupt-driven programs, we show that there is a polynomial-time procedure to check stack boundedness, while determining the exact maximum stack size is PSPACE-complete. For a larger class of programs, the two problems are both PSPACE-complete, and for the largest class of programs we consider, the two problems are PSPACE-hard and can be solved in exponential time. While the complexities are high, our algorithms are exponential only in the number of handlers, and polynomial in the size of the program.
AU - Krishnendu Chatterjee
AU - Ma, Di
AU - Majumdar, Ritankar S
AU - Zhao, Tian
AU - Thomas Henzinger
AU - Palsberg, Jens
ID - 4556
IS - 2
JF - Information and Computation
TI - Stack size analysis for interrupt-driven programs
VL - 194
ER -
TY - CONF
AB - We study perfect-information stochastic parity games. These are two-player nonterminating games which are played on a graph with turn-based probabilistic transitions. A play results in an infinite path and the conflicting goals of the two players are ω-regular path properties, formalized as parity winning conditions. The qualitative solution of such a game amounts to computing the set of vertices from which a player has a strategy to win with probability 1 (or with positive probability). The quantitative solution amounts to computing the value of the game in every vertex, i.e., the highest probability with which a player can guarantee satisfaction of his own objective in a play that starts from the vertex.For the important special case of one-player stochastic parity games (parity Markov decision processes) we give polynomial-time algorithms both for the qualitative and the quantitative solution. The running time of the qualitative solution is O(d · m3/2) for graphs with m edges and d priorities. The quantitative solution is based on a linear-programming formulation.For the two-player case, we establish the existence of optimal pure memoryless strategies. This has several important ramifications. First, it implies that the values of the games are rational. This is in contrast to the concurrent stochastic parity games of de Alfaro et al.; there, values are in general algebraic numbers, optimal strategies do not exist, and ε-optimal strategies have to be mixed and with infinite memory. Second, the existence of optimal pure memoryless strategies together with the polynomial-time solution forone-player case implies that the quantitative two-player stochastic parity game problem is in NP ∩ co-NP. This generalizes a result of Condon for stochastic games with reachability objectives. It also constitutes an exponential improvement over the best previous algorithm, which is based on a doubly exponential procedure of de Alfaro and Majumdar for concurrent stochastic parity games and provides only ε-approximations of the values.
AU - Krishnendu Chatterjee
AU - Jurdziński, Marcin
AU - Thomas Henzinger
ID - 4558
TI - Quantitative stochastic parity games
ER -
TY - CONF
AB - While model checking has been successful in uncovering subtle bugs in code, its adoption in software engineering practice has been hampered by the absence of a simple interface to the programmer in an integrated development environment. We describe an integration of the software model checker BLAST into the Eclipse development environment. We provide a verification interface for practical solutions for some typical program analysis problems - assertion checking, reachability analysis, dead code analysis, and test generation - directly on the source code. The analysis is completely automatic, and assumes no knowledge of model checking or formal notation. Moreover, the interface supports incremental program verification to support incremental design and evolution of code.
AU - Beyer, Dirk
AU - Thomas Henzinger
AU - Jhala, Ranjit
AU - Majumdar, Ritankar S
ID - 4577
TI - An eclipse plug-in for model checking
ER -
TY - CONF
AB - BLAST is an automatic verification tool for checking temporal safety properties of C programs. Blast is based on lazy predicate abstraction driven by interpolation-based predicate discovery. In this paper, we present the Blast specification language. The language specifies program properties at two levels of precision. At the lower level, monitor automata are used to specify temporal safety properties of program executions (traces). At the higher level, relational reachability queries over program locations are used to combine lower-level trace properties. The two-level specification language can be used to break down a verification task into several independent calls of the model-checking engine. In this way, each call to the model checker may have to analyze only part of the program, or part of the specification, and may thus succeed in a reduction of the number of predicates needed for the analysis. In addition, the two-level specification language provides a means for structuring and maintaining specifications.
AU - Beyer, Dirk
AU - Chlipala, Adam J
AU - Thomas Henzinger
AU - Jhala, Ranjit
AU - Majumdar, Ritankar S
ID - 4578
TI - The BLAST query language for software verification
VL - 3148
ER -
TY - CONF
AB - We have extended the software model checker BLAST to automatically generate test suites that guarantee full coverage with respect to a given predicate. More precisely, given a C program and a target predicate p, BLAST determines the set L of program locations which program execution can reach with p true, and automatically generates a set of test vectors that exhibit the truth of p at all locations in L. We have used BLAST to generate test suites and to detect dead code in C programs with up to 30 K lines of code. The analysis and test vector generation is fully automatic (no user intervention) and exact (no false positives).
AU - Beyer, Dirk
AU - Chlipala, Adam J
AU - Thomas Henzinger
AU - Jhala, Ranjit
AU - Majumdar, Ritankar S
ID - 4581
TI - Generating tests from counterexamples
ER -
TY - CONF
AB - Temporal logic is two-valued: a property is either true or false. When applied to the analysis of stochastic systems, or systems with imprecise formal models, temporal logic is therefore fragile: even small changes in the model can lead to opposite truth values for a specification. We present a generalization of the branching-time logic Ctl which achieves robustness with respect to model perturbations by giving a quantitative interpretation to predicates and logical operators, and by discounting the importance of events according to how late they occur. In every state, the value of a formula is a real number in the interval [0,1], where 1 corresponds to truth and 0 to falsehood. The boolean operators and and or are replaced by min and max, the path quantifiers ∃ and ∀ determine sup and inf over all paths from a given state, and the temporal operators and □ specify sup and inf over a given path; a new operator averages all values along a path. Furthermore, all path operators are discounted by a parameter that can be chosen to give more weight to states that are closer to the beginning of the path. We interpret the resulting logic Dctl over transition systems, Markov chains, and Markov decision processes. We present two semantics for Dctl: a path semantics, inspired by the standard interpretation of state and path formulas in CTL, and a fixpoint semantics, inspired by the μ-calculus evaluation of CTL formulas. We show that, while these semantics coincide for CTL, they differ for Dctl, and we provide model-checking algorithms for both semantics.
AU - de Alfaro, Luca
AU - Faella, Marco
AU - Thomas Henzinger
AU - Majumdar, Ritankar S
AU - Stoelinga, Mariëlle
ID - 4629
TI - Model checking discounted temporal properties
VL - 2988
ER -
TY - JOUR
AB - The genome of the nematode Caenorhabditis elegans encodes seven soluble guanylate cyclases (sGCs) [1]. In mammals, sGCs function as α/β heterodimers activated by gaseous ligands binding to a haem prosthetic group 2, 3. The principal activator is nitric oxide, which acts through sGCs to regulate diverse cellular events. In C. elegans the function of sGCs is mysterious: the worm genome does not appear to encode nitric oxide synthase, and all C. elegans sGC subunits are more closely related to mammalian β than α subunits [1]. Here, we show that two of the seven C. elegans sGCs, GCY-35 and GCY-36, promote aggregation behavior. gcy-35 and gcy-36 are expressed in a small number of neurons. These include the body cavity neurons AQR, PQR, and URX, which are directly exposed to the blood equivalent of C. elegans and regulate aggregation behavior [4]. We show that GCY-35 and GCY-36 act as α-like and β-like sGC subunits and that their function in the URX sensory neurons is sufficient for strong nematode aggregation. Neither GCY-35 nor GCY-36 is absolutely required for C. elegans to aggregate. Instead, these molecules may transduce one of several pathways that induce C. elegans to aggregate or may modulate aggregation by responding to cues in C. elegans body fluid.
AU - Cheung, Benny H.H
AU - Arellano-Carbajal, Fausto
AU - Rybicki, Irene
AU - de Bono, Mario
ID - 6155
IS - 12
JF - Current Biology
SN - 0960-9822
TI - Soluble guanylate cyclases act in neurons exposed to the body fluid to promote C. elegans aggregation behavior
VL - 14
ER -
TY - GEN
AU - Momiyama, Akiko
AU - Ryuichi Shigemoto
ID - 2636
IS - 3 Suppl
T2 - Tanpakushitsu kakusan koso Protein nucleic acid enzyme
TI - Function and distribution of glutamate receptors in the central synapses
VL - 49
ER -
TY - JOUR
AB - Among various types of low- and high-threshold calcium channels, the high voltage-activated P/Q-type channel is the most abundant in the cerebellum. These P/Q-type channels are involved in the regulation of neurotransmitter release and in the integration of dendritic inputs. We used an antibody specific for the α1A subunit of the P/Q-type channel in quantitative pre-embedding immunogold labelling combined with three-dimensional reconstruction to reveal the subcellular distribution of pre- and postsynaptic P/Q-type channels in the rat cerebellum. At the light microscopic level, immunoreactivity for the α1A protein was prevalent in the molecular layer, whereas immunostaining was moderate in the somata of Purkinje cells and weak in the granule cell layer. At the electron microscopic level, the most intense Immunoreactivity for the α1A subunit was found in the presynaptic active zone of parallel fibre varicosities. The dendritic spines of Purkinje cells were also strongly labelled with the highest density of immunoparticles detected within 180 nm from the edge of the asymmetrical parallel fibre-Purkinje cell synapses. By contrast, the immunolabelling was sparse in climbing fibre varicosities and axon terminals of GABAergic cells, and weak and diffuse in dendritic shafts of Purkinje cells. The association of the α1A subunit with the glutamatergic parallel fibre-Purkinje cell synapses suggests that presynaptic channels have a major role in the mediation of excitatory neurotransmission, whereas postsynaptic channels are likely to be involved in depolarization-induced generation of local calcium transients in Purkinje cells.
AU - Kulik, Ákos
AU - Nakadate, Kazuhiko
AU - Hagiwara, Akari
AU - Fukazawa, Yugo
AU - Luján, Rafael
AU - Saito, Hiromitsu
AU - Suzuki, Noboru
AU - Futatsugi, Akira
AU - Mikoshiba, Katsuhiko
AU - Frotscher, Michael
AU - Ryuichi Shigemoto
ID - 2638
IS - 8
JF - European Journal of Neuroscience
TI - Immunocytochemical localization of the α1A subunit of the P/Q-type calcium channel in the rat cerebellum
VL - 19
ER -
TY - JOUR
AB - Vesicular glutamate transporter type 3 (VGLUT3) containing neuronal elements were characterized using antibodies to VGLUT3 and molecular cell markers. All VGLUT3-positive somata were immunoreactive for CCK, and very rarely, also for calbindin; none was positive for parvalbumin, calretinin, VIP or somatostatin. In the CA1 area, 26.8 ± 0.7% of CCK-positive interneuron somata were VGLUT3-positive, a nonoverlapping 22.8 ± 1.9% were calbindin-positive, 10.7 ± 2.5% VIP-positive and the rest were only CCK-positive. The patterns of coexpression were similar in the CA3 area, the dentate gyrus and the isocortex. Immunoreactivity for VGLUT3 was undetectable in pyramidal and dentate granule cells. Boutons colabelled for VGLUT3, CCK and GAD were most abundant in the cellular layers of the hippocampus and in layers II-III of the isocortex. Large VGLUT3-labelled boutons at the border of strata radiatum and lacunosum-moleculare in the CA1 area were negative for GAD, but were labelled for vesicular monoamine transporter type 2, plasmalemmal serotonin transporter or serotonin. No colocalization was found in terminals between VGLUT3 and parvalbumin, vesicular acetylcholine transporter and group III (mGluR7a,b; mGluR8a,b) metabotropic glutamate receptors. In stratum radiatum and the isocortex, VGLUT3-positive but GAD-negative boutons heavily innervated the soma and proximal dendrites of some VGLUT3- or calbindin-positive interneurons. The results suggest that boutons coexpressing VGLUT3, CCK and GAD originate from CCK-positive basket cells, which are VIP-immunonegative. Other VGLUT3-positive boutons immunopositive for serotonergic markers but negative for GAD probably originate from the median raphe nucleus and innervate select interneurons. The presumed amino acid substrate of VGLUT3 may act on presynaptic kainate or group II metabotropic glutamate receptors.
AU - Somogyi, Jozsef
AU - Baude, Agnès
AU - Omori, Yuko
AU - Shimizu, Hidemi
AU - El-Mestikawy, Salah
AU - Fukaya, Masahiro
AU - Ryuichi Shigemoto
AU - Watanabe, Masahiko
AU - Somogyi, Péter
ID - 2639
IS - 3
JF - European Journal of Neuroscience
TI - GABAergic basket cells expressing cholecystokinin contain vesicular glutamate transporter type 3 (VGLUT3) in their synaptic terminals in hippocampus and isocortex of the rat
VL - 19
ER -
TY - JOUR
AB - Hyperpolarization-activated cation currents (Ih) contribute to various physiological properties and functions in the brain, including neuronal pacemaker activity, setting of resting membrane potential, and dendritic integration of synaptic input. Four subunits of the Hyperpolarization-activated and Cyclic-Nucleotide-gated nonselective cation channels (HCN1-4), which generate Ih, have been cloned recently. To better understand the functional diversity of Ih in the brain, we examined precise immunohistochemical localization of four HCNs in the rat brain. Immunoreactivity for HCN1 showed predominantly cortical distribution, being intense in the neocortex, hippocampus, superior colliculus, and cerebellum, whereas those for HCN3 and HCN4 exhibited subcortical distribution mainly concentrated in the hypothalamus and thalamus, respectively. Immunoreactivity for HCN2 had a widespread distribution throughout the brain. Double immunofluorescence revealed colocalization of immunoreactivity for HCN1 and HCN2 in distal dendrites of pyramidal cells in the hippocampus and neocortex. At the electron microscopic level, immunogold particles for HCN1 and HCN2 had similar distribution patterns along plasma membrane of dendritic shafts in layer I of the neocortex and stratum lacunosum moleculare of the hippocampal CA1 area, suggesting that these subunits could form heteromeric channels. Our results further indicate that HCNs are localized not only in somato-dendritic compartments but also in axonal compartments of neurons. Immunoreactivity for HCNs often occurred in preterminal rather than terminal portions of axons and in specific populations of myelinated axons. We also found HCN2-immunopositive oligodendrocytes including perineuronal oligodendrocytes throughout the brain. These results support previous electrophysiological findings and further suggest unexpected roles of Ih channels in the brain.
AU - Notomi, Takuya
AU - Ryuichi Shigemoto
ID - 2640
IS - 3
JF - Journal of Comparative Neurology
TI - Immunohistochemical localization of Ih channel subunits, HCN1-4, in the rat brain
VL - 471
ER -
TY - JOUR
AB - The Na+-K+ pump current (Ip) and the h-current (Ih) flowing through hyperpolarization-activated channels (h-channels) participate in generating the resting potential. These two currents are thought to be produced independently. We show here bidirectional interactions between Na+-K+ pumps and h-channels in mesencephalic trigeminal neurons. Activation of Ih leads to the generation of two types of ouabain-sensitive Ip with temporal profiles similar to those of instantaneous and slow components of I h, presumably reflecting Na+ transients in a restricted cellular space. Moreover, the Ip activated by instantaneous I h can facilitate the subsequent activation of slow Ih. Such counteractive and cooperative interactions were also disclosed by replacing extracellular Na+ with Li+, which is permeant through h-channels but does not stimulate the Na+-K+ pump as strongly as Na+ ions. These observations indicate that the interactions are bidirectional and mediated by Na+ ions. Also after substitution of extracellular Na+ with Li+, the tail Ih was reduced markedly despite an enhancement of Ih itself, attributable to a negative shift of the reversal potential for I h presumably caused by intracellular accumulation of Li+ ions. This suggests the presence of a microdomain where the interactions can take place. Thus, the bidirectional interactions between Na+-K + pumps and h-channels are likely to be mediated by Na+ microdomain. Consistent with these findings, hyperpolarization-activated and cyclic nucleotide-modulated subunits (HCN1/2) and the Na+-K + pump α3 isoform were colocalized in plasma membrane of mesencephalic trigeminal neurons having numerous spines.
AU - Kang, Youngnam
AU - Notomi, Takuya
AU - Saito, Mitsuru
AU - Zhang, Wei
AU - Ryuichi Shigemoto
ID - 2641
IS - 14
JF - Journal of Neuroscience
TI - Bidirectional interactions between H-channels and Na+-K + pumps in mesencephalic trigeminal neurons
VL - 24
ER -
TY - JOUR
AB - In the hippocampal CA1 region, metabotropic glutamate subtype 1 (mGluR1) receptors have been implicated in a variety of physiological responses to glutamate, which include modulation of synaptic transmission and plasticity, as well as neuronal excitability and synchronization. The mGluR1α isoform is characteristically expressed only by nonprincipal cells, and it is particularly enriched in somatostatin (SS -containing interneurons in stratum oriens-alveus. Anatomical and physiological data have indicated the presence of mGluR1α in several distinct classes of interneurons with their somata located also in strata pyramidale, radiatum, and lacunosum moleculare. Each different interneuron subtype, as defined by functionally relevant criteria, including input/output characteristics and expression of selective molecular markers, subserves distinct functions in local hippocampal circuits. We have investigated which of the different CA1 interneuron classes express mGluR1α by immunofluorescent labeling, combining antibodies to mGluR1α, calcium-binding proteins, and neuropeptides, and by intracellular labeling in vitro. Several types of interneuron that are immunopositive for mGluR1α each targeted different domains of pyramidal cells and included (1) O-LM interneurons, found to coexpress both SS and parvalbumin (PV); (2) interneurons with target selectivity for other interneurons, expressing vasoactive intestinal polypeptide (VIP) and/or the calcium-binding protein calretinin; (3) procholecystokinin-immunopositive interneurons probably non-basket and dendrite-targeting; and (4) an as-yet unidentified SS-immunoreactive but PV-immunonegative interneuron class, possibly corresponding to oriensbistratified cells. Estimation of the relative proportion of mGluR1α-positive interneurons showed 43%, 46%, and 30% co-labeling with SS, VIP, or PV, respectively. The identification of the specific subclasses of CA1 interneurons expressing mGluR1α provides the network basis for assessing the contribution of this receptor to the excitability of the hippocampus.
AU - Ferraguti, Francesco
AU - Cobden, Philip M
AU - Pollard, Marie
AU - Cope, David W
AU - Ryuichi Shigemoto
AU - Watanabe, Masahiko
AU - Somogyi, Péter
ID - 2642
IS - 2
JF - Hippocampus
TI - Immunolocalization of metabotropic glutamate receptor 1α (mGluR1α) in distinct classes of interneuron in the CA1 region of the rat hippocampus
VL - 14
ER -
TY - JOUR
AB - Metabotropic γ-aminobutyric acid receptors (GABAB) are involved in pre- and postsynaptic inhibitory effects upon auditory neurons and have been implicated in different aspects of acoustic information processing. To understand better the mechanisms by which GABAB receptors mediate their inhibitory effects, we used pre-embedding immunocytochemical techniques combined with quantification of immunogold particles to reveal the precise subcellular distribution of the GABAB1 subunit in the rat dorsal cochlear nucleus. At the light microscopic level, GABAB1 was detected in all divisions of the cochlear complex. The most intense immunoreactivity for GABAB1 was found in the dorsal cochlear nucleus, whereas immunoreactivity in the anteroventral and posteroventral cochlear nuclei was very low. In the dorsal cochlear nucleus, a punctate labeling was observed in the superficial (molecular and fusiform cell) layers. At the electron microscopic level, GABAB1 was found at both post- and presynaptic locations. Postsynaptically, GABAB1 was localized mainly in the dendritic spines of presumed fusiform cells. Quantitative immunogold immunocytochemistry revealed that the highest concentration of GABA B1 in the plasma membrane was in dendritic spines, followed by dendritic shafts and somata. Thus, the most intense immunoreactivity for GABAB1 was observed in dendritic spines with a high density of immunogold particles at extrasynaptic sites, peaking around 300 nm from glutamatergic synapses. This is in contrast to GABAergic synapses, in which GABAB1 was only occasionally found. Presynaptically, receptor immunoreactivity was detected primarily in axospinous endings, probably from granule cells, in both the active zone and extrasynaptic sites. The localization of GABAB1 relative to synaptic sites in the DCN suggests a role for the receptor in the regulation of dendritic excitability and excitatory inputs.
AU - Luján, Rafael
AU - Ryuichi Shigemoto
AU - Kulik, Ákos
AU - Juíz, José M
ID - 2643
IS - 1
JF - Journal of Comparative Neurology
TI - Localization of the GABAB receptor 1a/b subunit relative to glutamatergic synapses in the dorsal cochlear nucleus of the rat
VL - 475
ER -
TY - JOUR
AB - The release of GABA in synapses is modulated by presynaptic metabotropic glutamate receptors (mGluRs). We tested whether GABA release to identified hippocampal neurons is influenced by group III mGluR activation using the agonist L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) on inhibitory postsynaptic currents (IPSCs) evoked in CA1 interneurons and pyramidal cells. In interneurons, characterized with biocytin and immunolabelling for somatostatin, evoked IPSCs were depressed by 50 μM L-AP4 (activating mGluR4 and 8) to 68±6% of control, but they were rarely depressed in pyramidal cells (96±4% of control). At 300-500 μM concentration (activating mGluR4, 7 and 8), L-AP4 depressed IPSCs in both interneurons (to 70±6%) and pyramidal cells (to 67±4%). The change in trial-to-trial variability and in paired-pulse depression indicated a presynaptic action. In interneurons, the degree of IPSC depression was variable (to 9-87%), and a third of IPSCs were not affected by L-AP4. The L-AP4-evoked IPSC depression was blocked by LY341495. The depression of IPSCs was similar in O-LM cells and other interneurons. The lack of cell-type selectivity and the similar efficacy of different concentrations of L-AP4 suggest that several group III mGluRs are involved in the depression of IPSCs. Electron microscopic immunocytochemistry confirmed that mGluR4, mGluR7a and mGluR8a occur in the presynaptic active zone of GABAergic terminals on interneurons, but not on those innervating pyramidal cells. The high variability of L-AP4-evoked IPSC suppression is in line with the selective expression of presynaptic mGluRs by several distinct types of GABAergic neuron innervating each interneuron type.
AU - Kogo, Naoki
AU - Dalezios, Yannis
AU - Capogna,Marco
AU - Ferraguti, Francesco
AU - Ryuichi Shigemoto
AU - Somogyi, Péter
ID - 2644
IS - 10
JF - European Journal of Neuroscience
TI - Depression of GABAergic input to identified hippocampal neurons by group III metabotropic glutamate receptors in the rat
VL - 19
ER -
TY - JOUR
AB - The globus pallidus (GP) is a critical component of the basal ganglia circuitry controlling motor behavior. Dysregulation of GP activity has been implicated in a number of psychomotor disorders, including Parkinson's disease (PD), in which a cardinal feature of the pathophysiology is an alteration in the pattern and synchrony of discharge in GP neurons. Yet the determinants of this activity in GP neurons are poorly understood. To help fill this gap, electrophysiological, molecular, and computational approaches were used to identify and characterize GABAergic GP neurons in tissue slices from rodents. In vitro, GABAergic GP neurons generate a regular, autonomous, single-spike pacemaker activity. Hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels make an important contribution to this process: their blockade with ZD7288 significantly slowed discharge rate and decreased its regularity. HCN currents evoked by somatic voltage clamp had fast and slow components. Single-cell RT-PCR and immunohistochemical approaches revealed robust expression of HCN2 subunits as well as significant levels of HCN1 subunits in GABAergic GP neurons. Transient activation of striatal GABAergic input to GP neurons led to a resetting of rhythmic discharge that was dependent on HCN currents. Simulations suggested that the ability of transient striatal GABAergic input to reset pacemaking was dependent on dendritic HCN2/HCN1 channels. Together, these studies show that HCN channels in GABAergic GP neurons are key determinants of the regularity and rate of pacemaking as well as striatal resetting of this activity, implicating HCN channels in the emergence of synchrony in PD.
AU - Chan, Savio
AU - Ryuichi Shigemoto
AU - Mercer, Jeff N
AU - Surmeier, James D
ID - 2645
IS - 44
JF - Journal of Neuroscience
TI - HCN2 and HCN1 channels govern the regularity of autonomous pacemaking and synaptic resetting in globus pallidus neurons
VL - 24
ER -
TY - JOUR
AB - Metabotropic γ-aminobutyric acid receptors (GABAB) play modulatory roles in central synaptic transmission and are involved in controlling neuronal migration during development. We used immunohistochemical methods to elucidate the expression pattern as well as the cellular and the precise subcellular localization of the GABAB1a/b and GABAB2 subunits in the rat hippocampus during prenatal and postnatal development. At the light microscopic level, both GABABB1a/b and GABAB2 were expressed in the hippocampal primordium from embryonic day E14. During postnatal development, immunoreactivity for GABAB1a/b and GABAB2 was distributed mainly in pyramidal cells, with discrete GABABB1a/b-immunopositive cell bodies of interneurons present throughout the hippocampus. Using double immunofluorescence, we demonstrated that during the second week of postnatal development, GABAB1a/b but not GABAB2 was expressed in glial cells throughout the hippocampal formation. At the electron microscopic level, GABAB1a/b and GABAB2 showed a similar distribution pattern during postnatal development. Thus, at all ages the two receptor subunits were located postsynaptically in dendritic spines and shafts at extrasynaptic and perisynaptic sites in both pyramidal and nonpyramidal cells. We further demonstrated that the two subunits were localized presynaptically along the extrasynaptic plasma membrane of axon terminals and along the presynaptic active zone in both asymmetrical and, to a lesser extent, symmetrical synapses. These results suggest that GABAB receptors are widely expressed in the hippocampus throughout development and that GABABB1a/b and GABAB2 form both pre- and postsynaptic receptors.
AU - López-Bendito, Guillermina
AU - Ryuichi Shigemoto
AU - Kulik, Ákos
AU - Vida, Imre
AU - Fairén, Alfonso
AU - Luján, Rafael
ID - 2646
IS - 7
JF - Hippocampus
TI - Distribution of metabotropic GABA receptor subunits GABAB1a/b and GABAB2 in the rat hippocampus during prenatal and postnatal development
VL - 14
ER -
TY - JOUR
AB - The Pauli operator describes the energy of a nonrelativistic quantum particle with spin in a magnetic field and an external potential. Bounds on the sum of the negative eigenvalues are called magnetic Lieb-Thirring (MLT) inequalities. The purpose of this paper is twofold. First, we prove a new MLT inequality in a simple way. Second, we give a short summary of our recent proof of a more refined MLT inequality(8) and we explain the differences between the two results and methods. The main feature of both estimates, compared to earlier results, is that in the large field regime they grow with the optimal (first) power of the strength of the magnetic field. As a byproduct of the method, we also obtain optimal upper bounds on the pointwise density of zero energy eigenfunctions of the Dirac operator.
AU - László Erdös
AU - Solovej, Jan P
ID - 2706
IS - 1-4
JF - Journal of Statistical Physics
TI - Magnetic Lieb-Thirring inequalities with optimal dependence on the field strength
VL - 116
ER -
TY - JOUR
AB - We give a nonrigorous derivation of the nonlinear Boltzmann equation from the Schrödinger evolution of interacting fermions. The argument is based mainly on the assumption that a quasifree initial state satisfies a property called restricted quasifreeness in the weak coupling limit at any later time. By definition, a state is called restricted quasifree if the four-point and the eight-point functions of the state factorize in the same manner as in a quasifree state.
AU - László Erdös
AU - Salmhofer, Manfred
AU - Yau, Horng-Tzer
ID - 2707
IS - 1-4
JF - Journal of Statistical Physics
TI - On the quantum Boltzmann equation
VL - 116
ER -
TY - JOUR
AB - The Pauli operator describes the energy of a nonrelativistic quantum particle with spin 1/2 in a magnetic field and an external potential. A new Lieb-Thirring type inequality on the sum of the negative eigenvalues is presented. The main feature compared to earlier results is that in the large field regime the present estimate grows with the optimal (first) power of the strength of the magnetic field. As a byproduct of the method, we also obtain an optimal upper bound on the pointwise density of zero energy eigenfunctions of the Dirac operator. The main technical tools are: (i) a new localization scheme for the square of the resolvent of a general class of second order elliptic operators; (ii) a geometric construction of a Dirac operator with a constant magnetic field that approximates the original Dirac operator in a tubular neighborhood of a fixed field line. The errors may depend on the regularity of the magnetic field but they are uniform in the field strength.
AU - László Erdös
AU - Solovej, Jan P
ID - 2741
IS - 4
JF - Annales Henri Poincare
TI - Uniform Lieb-Thirring inequality for the three-dimensional Pauli operator with a strong non-homogeneous magnetic field
VL - 5
ER -
TY - JOUR
AB - We consider a system of N weakly interacting fermions with a real analytic pair interaction. We prove that for a general class of initial data there exists a fixed time T such that the difference between the one particle density matrix of this system and the solution of the nonlinear Hartree equation is of order N−1 for any time t⩽T.
AU - Elgart, Alexander
AU - László Erdös
AU - Schlein, Benjamin
AU - Yau, Horng-Tzer
ID - 2742
IS - 10
JF - Journal de Mathématiques Pures et Appliquées
TI - Nonlinear Hartree equation as the mean field limit of weakly coupled fermions
VL - 83
ER -
TY - JOUR
AB - Transition to turbulence in pipe flow is one of the most fundamental and longest- standing problems in fluid dynamics. Stability theory suggests that the flow remains laminar for all flow rates, but in practice pipe flow becomes turbulent even at moderate speeds. This transition drastically affects the transport efficiency of mass, momentum, and heat. On the basis of the recent discovery of unstable traveling waves in computational studies of the Navier-Stokes equations and ideas from dynamical systems theory, a model for the transition process has been suggested. We report experimental observation of these traveling waves in pipe flow, confirming the proposed transition scenario and suggesting that the dynamics associated with these unstable states may indeed capture the nature of fluid turbulence.
AU - Björn Hof
AU - van Doorne, Casimir W
AU - Westerweel, Jerry
AU - Nieuwstadt, Frans T
AU - Faisst, Holger
AU - Eckhardt, Bruno
AU - Wedin, Håkan
AU - Kersweli, Richard R
AU - Waleffe, Fabian
ID - 2786
IS - 5690
JF - Science
TI - Experimental observation of nonlinear traveling waves in turbulent pipe flow
VL - 305
ER -
TY - JOUR
AB - The results of experimental and numerical investigations of the onset of oscillatory convection in a sidewall heated rectangular cavity of molten gallium are reported. Detailed comparisons are made between experimental observations and calculations from numerical simulations of a three-dimensional Boussinesq model. The onset of time-dependence takes place through supercritical Hopf bifurcations and the loci of critical points in the (Gr, Pr)-plane are qualitatively similar with excellent agreement between the frequencies of the oscillatory motion. This provides a severe test of the control of the experiment since the mode of oscillation is extremely sensitive to imperfections. Detailed numerical investigations reveal that there are a pair of Hopf bifurcations which exist on two asymmetric states which themselves arise at a subcritical pitchfork from the symmetric state. There is no evidence for this in the experiment and this qualitative difference is attributed to non-Boussinesq perturbations which increase with Gr. However, the antisymmetric spatial structure of the oscillatory state is robust and is present in both the experiment and the numerical model. Moreover, the detailed analysis of the numerical results reveals the origins of the oscillatory instability.
AU - Björn Hof
AU - Juel, Anne
AU - Zhao, Li
AU - Henry, Daniel
AU - Ben Hadid, Hamda
AU - Mullin, Tom P
ID - 2787
JF - Journal of Fluid Mechanics
TI - On the onset of oscillatory convection in molten gallium
VL - 515
ER -
TY - JOUR
AB - Polar transport-dependent local accumulation of auxin provides positional cues for multiple plant patterning processes. This directional auxin flow depends on the polar subcellular localization of the PIN auxin efflux regulators. Overexpression of the PINOID protein kinase induces a basal-to-apical shift in PIN localization, resulting in the loss of auxin gradients and strong defects in embryo and seedling roots. Conversely, pid loss of function induces an apical-to-basal shift in PIN1 polar targeting at the inflorescence apex, accompanied by defective organogenesis. Our results show that a PINOID-dependent binary switch controls PIN polarity and mediates changes in auxin flow to create local gradients for patterning processes.
AU - Jirí Friml
AU - Yang, Xiong
AU - Michniewicz, Marta
AU - Weijers, Dolf
AU - Quint, Ab
AU - Tietz, Olaf
AU - Benjamins, René
AU - Ouwerkerk, Pieter B
AU - Ljung, Karin
AU - Sandberg, Göran
AU - Hooykaas, Paul J
AU - Palme, Klaus
AU - Offringa, Remko
ID - 2997
IS - 5697
JF - Science
TI - A PINOID-dependent binary switch in apical-basal PIN polar targeting directs auxin efflux
VL - 306
ER -
TY - JOUR
AB - The packaging of the genomic DNA into chromatin in the cell nucleus requires machineries that facilitate DNA-dependent processes such as transcription in the presence of repressive chromatin structures. Using co-immunoprecipitation we have identified in Arabidopsis thaliana cells the FAcilitates Chromatin Transcription (FACT) complex, consisting of the 120-kDa Spt16 and the 71-kDa SSRP1 proteins. Indirect immunofluorecence analyses revealed that both FACT subunits co-localize to nuclei of the majority of cell types in embryos, shoots and roots, whereas FACT is not present in terminally differentiated cells such as mature trichoblasts or cells of the root cap. In the nucleus, Spt16 and SSRP1 are found in the cytologically defined euchromatin of interphase cells independent of the status of DNA replication, but the proteins are not associated with heterochromatic chromocentres and condensed mitotic chromosomes. FACT can be detected by chromatin immunoprecipitation over the entire transcribed region (5′-UTR, coding sequence, 3′-UTR) of actively transcribed genes, whereas it does not occur at transcriptionally inactive heterochromatic regions and intergenic regions. FACT localizes to inducible genes only after induction of transcription, and the association of the complex with the genes correlates with the level of transcription. Collectively, these results indicate that FACT assists transcription elongation through plant chromatin.
AU - Duroux, Meg
AU - Houben, Andreas
AU - Růžička, Kamil
AU - Jirí Friml
AU - Grasser, Klaus D
ID - 2998
IS - 5
JF - Plant Journal
TI - The chromatin remodelling complex FACT associates with actively transcribed regions of the Arabidopsis genome
VL - 40
ER -
TY - JOUR
AB - Embryogenesis of flowering plants establishes a basic body plan with apical-basal, radial and bilateral patterns from the single-celled zygote. Arabidopsis embryogenesis exhibits a nearly invariant cell division pattern and therefore is an ideal system for studies of early plant development. However, plant embryos are difficult to access for experimental manipulation, as they develop deeply inside maternal tissues. Here we present a method for the culture of zygotic Arabidopsis embryos in vitro. The technique omits excision of the embryo by culturing the entire ovule, thus greatly facilitating the time and effort involved. It enables external manipulation of embryo development and culture from the earliest developmental stages up to maturity. Administration of various chemical treatments as well as the use of different molecular markers is demonstrated together with standard techniques for visualizing gene expression and protein localization in in vitro cultivated embryos. The presented set of techniques allows for so far unavailable molecular physiology approaches in the study of early plant development.
AU - Sauer, Michael
AU - Jirí Friml
ID - 2999
IS - 5
JF - Plant Journal
TI - In vitro culture of Arabidopsis embryos within their ovules
VL - 40
ER -
TY - GEN
AB - Assembly of neuronal circuits is controlled by the sequential acquisition of neuronal subpopulation-specific identities at progressive developmental steps. Whereas neuronal features involved in initial phases of differentiation are already established at cell-cycle exit, recent findings, based mainly on work in the peripheral nervous system, suggest that the timely integration of signals encountered en route to targets and from the target region itself is essential to control late steps in connectivity. As neurons project towards their targets they require target-derived signals to establish mature axonal projections and acquire neuronal traits such as the expression of distinct combinations of neurotransmitters. Recent evidence presented in this review shows that this principle, of a signaling interplay between target-derived signals and neuronal cell bodies, is often mediated through transcriptional events and is evolutionarily conserved.
AU - Simon Hippenmeyer
AU - Kramer, Ina
AU - Arber, Silvia
ID - 3142
IS - 8
T2 - Trends in Neurosciences
TI - Control of neuronal phenotype: What targets tell the cell bodies
VL - 27
ER -
TY - JOUR
AB - The mechanism coupling electron transfer and proton pumping in respiratory complex I (NADH-ubiquinone oxidoreductase) has not been established, but it has been suggested that it involves conformational changes. Here, the influence of substrates on the conformation of purified complex I from Escherichia coli was studied by cross-linking and electron microscopy. When a zero-length cross-linking reagent was used, the presence of NAD(P)H, in contrast to that of NAD+, prevented the formation of cross-links between the hydrophilic subunits of the complex, including NuoB, NuoI, and NuoCD. Comparisons using different cross-linkers suggested that NuoB, which is likely to coordinate the key iron-sulfur cluster N2, is the most mobile subunit. The presence of NAD(P)H led also to enhanced proteolysis of subunit NuoG. These data indicate that upon NAD(P)H binding, the peripheral arm of the complex adopts a more open conformation, with increased distances between subunits. Single particle analysis showed the nature of this conformational change. The enzyme retains its L-shape in the presence of NADH, but exhibits a significantly more open or expanded structure both in the peripheral arm and, unexpectedly, in the membrane domain also.
AU - Mamedova, Aygun A
AU - Holt, Peter J
AU - Carroll, Joe D
AU - Leonid Sazanov
ID - 1963
IS - 22
JF - Journal of Biological Chemistry
TI - Substrate-induced conformational change in bacterial complex I
VL - 279
ER -
TY - JOUR
AB - We present a method for prediction of functional sites in a set of aligned protein sequences. The method selects sites which are both well conserved and clustered together in space, as inferred from the 3D structures of proteins included in the alignment. We tested the method using 86 alignments from the NCBI CDD database, where the sites of experimentally determined ligand and/or macromolecular interactions are annotated. In agreement with earlier investigations, we found that functional site predictions are most successful when overall background sequence conservation is low, such that sites under evolutionary constraint become apparent. In addition, we found that averaging of conservation values across spatially clustered sites improves predictions under certain conditions: that is, when overall conservation is relatively high and when the site in question involves a large macromolecular binding interface. Under these conditions it is better to look for clusters of conserved sites than to look for particular conserved sites.
AU - Panchenko, Anna R
AU - Fyodor Kondrashov
AU - Bryant, Stephen H
ID - 864
IS - 4
JF - Protein Science
TI - Prediction of functional sites by analysis of sequence and structure conservation
VL - 13
ER -
TY - JOUR
AB - Only a fraction of eukaryotic genes affect the phenotype drastically. We compared 18 parameters in 1273 human morbid genes, known to cause diseases, and in the remaining 16 580 unambiguous human genes. Morbid genes evolve more slowly, have wider phylogenetic distributions, are more similar to essential genes of Drosophila melanogaster, code for longer proteins containing more alanine and glycine and less histidine, lysine and methionine, possess larger numbers of longer introns with more accurate splicing signals and have higher and broader expressions. These differences make it possible to classify as non-morbid 34% of human genes with unknown morbidity, when only 5% of known morbid genes are incorrectly classified as non-morbid. This classification can help to identify disease-causing genes among multiple candidates.
AU - Fyodor Kondrashov
AU - Ogurtsov, Aleksey Yu
AU - Kondrashov, Alexey S
ID - 870
IS - 5
JF - Nucleic Acids Research
TI - Bioinformatical assay of human gene morbidity
VL - 32
ER -
TY - JOUR
AB - The dominance of wild-type alleles and the concomitant recessivity of deleterious mutant alleles might have evolved by natural selection or could be a by-product of the molecular and physiological mechanisms of gene action. We compared the properties of human haplosufficient genes, whose wild-type alleles are dominant over loss-of-function alleles, with haploinsufficient (recessive wild-type) genes, which produce an abnormal phenotype when heterozygous for a loss-of-function allele. The fraction of haplosufficient genes is the highest among the genes that encode enzymes, which is best compatible with the physiological theory. Haploinsufficient genes, on average, have more paralogs than haplosufficient genes, supporting the idea that gene dosage could be important for the initial fixation of duplications. Thus, haplo(in)sufficiency of a gene and its propensity for duplication might have a common evolutionary basis.
AU - Fyodor Kondrashov
AU - Koonin, Eugene V
ID - 875
IS - 7
JF - Trends in Genetics
TI - A common framework for understanding the origin of genetic dominance and evolutionary fates of gene duplications
VL - 20
ER -
TY - JOUR
AB - The function of protein and RNA molecules depends on complex epistatic interactions between sites. Therefore, the deleterious effect of a mutation can be suppressed by a compensatory second-site substitution. In relating a list of 86 pathogenic mutations in human IRNAs encoded by mitochondrial genes to the sequences of their mammalian orthologs, we noted that 52 pathogenic mutations were present in normal tRNAs of one or several nonhuman mammals. We found at least five mechanisms of compensation for 32 pathogenic mutations that destroyed a Watson-Crick pair in one of the four tRNA stems: restoration of the affected Watson-Crick interaction (25 cases), strengthening of another pair (4 cases), creation of a new pair (8 cases), changes of multiple interactions in the affected stem (11 cases) and changes involving the interaction between the loop and stem structures (3 cases). A pathogenic mutation and its compensating substitution are fixed in a lineage in rapid succession, and often a compensatory interaction evolves convergently in different clades. At least 10%, and perhaps as many as 50%, of all nucleotide substitutions in evolving mammalian (RNAs participate in such interactions, indicating that the evolution of tRNAs proceeds along highly epistatic fitness ridges.
AU - Kern, Andrew D
AU - Fyodor Kondrashov
ID - 889
IS - 11
JF - Nature Genetics
TI - Mechanisms and convergence of compensatory evolution in mammalian mitochondrial tRNAs
VL - 36
ER -
TY - JOUR
AB - New alleles become fixed owing to random drift of nearly neutral mutations or to positive selection of substantially advantageous mutations. After decades of debate, the fraction of fixations driven by selection remains uncertain. Within 9,390 genes, we analysed 28,196 codons at which rat and mouse differ from each other at two nucleotide sites and 1,982 codons with three differences. At codons where rat-mouse divergence involved two non-synonymous substitutions, both of them occurred in the same lineage, either rat or mouse, in 64% of cases; however, independent substitutions would occur in the same lineage with a probability of only 50%. All three non-synonymous substitutions occurred in the same lineage for 46% of codons, instead of the 25% expected. Furthermore, comparison of 12 pairs of prokaryotic genomes also shows clumping of multiple non-synonymous substitutions in the same lineage. This pattern cannot be explained by correlated mutation or episodes of relaxed negative selection, but instead indicates that positive selection acts at many sites of rapid, successive amino acid replacement.
AU - Bazykin, Georgii A
AU - Fyodor Kondrashov
AU - Ogurtsov, Aleksey Yu
AU - Sunyaev, Shamil R
AU - Kondrashov, Alexey S
ID - 898
IS - 6991
JF - Nature
TI - Positive selection at sites of multiple amino acid replacements since rat-mouse divergence
VL - 429
ER -
TY - JOUR
AB - We compare the functional spectrum of protein evolution in two separate animal lineages with respect to two hypotheses: (1) rates of divergence are distributed similarly among functional classes within both lineages, indicating that selective pressure on the proteome is largely independent of organismic-level biological requirements; and (2) rates of divergence are distributed differently among functional classes within each lineage, indicating species-specific selective regimes impact genome-wide substitutional patterns. Integrating comparative genome sequence with data from tissue-specific expressed-sequence-tag (EST) libraries and detailed database annotations, we find a functional genomic signature of rapid evolution and selective constraint shared between mammalian and nematode lineages despite their extensive morphological and ecological differences and distant common ancestry. In both phyla, we find evidence of accelerated evolution among components of molecular systems involved in coevolutionary change. In mammals, lineage-specific fast evolving genes include those involved in reproduction, immunity, and possibly, maternal-fetal conflict. Likelihood ratio tests provide evidence for positive selection in these rapidly evolving functional categories in mammals. In contrast, slowly evolving genes, in terms of amino acid or insertion/deletion (indel) change, in both phyla are involved in core molecular processes such as transcription, translation, and protein transport. Thus, strong purifying selection appears to act on the same core cellular processes in both mammalian and nematode lineages, whereas positive and/or relaxed selection acts on different biological processes in each lineage.
AU - Castillo-Davis, Cristian I
AU - Fyodor Kondrashov
AU - Hartl, Daniel L
AU - Kulathinal, Rob J
ID - 902
IS - 5
JF - Genome Research
TI - The functional genomic distribution of protein divergence in two animal phyla: Coevolution, genomic conflict, and constraint
VL - 14
ER -
TY - JOUR
AB - We study the space of L2 harmonic forms on complete manifolds with metrics of fibred boundary or fibred cusp type. These metrics generalize the geometric structures at infinity of several different well-known classes of metrics, including asymptotically locally Euclidean manifolds, the (known types of) gravitational instantons, and also Poincaré metrics on ℚ-rank 1 ends of locally symmetric spaces and on the complements of smooth divisors in Kähler manifolds. The answer in all cases is given in terms of intersection cohomology of a stratified compactification of the manifold. The L2 signature formula implied by our result is closely related to the one proved by Dai and more generally by Vaillant and identifies Dai's τ-invariant directly in terms of intersection cohomology of differing perversities. This work is also closely related to a recent paper of Carron and the forthcoming paper of Cheeger and Dai. We apply our results to a number of examples, gravitational instantons among them, arising in predictions about L2 harmonic forms in duality theories in string theory.
AU - Tamas Hausel
AU - Hunsicker, Eugénie
AU - Mazzeo, Rafe R
ID - 1456
IS - 3
JF - Duke Mathematical Journal
TI - Hodge cohomology of gravitational instantons
VL - 122
ER -
TY - JOUR
AB - The moduli space of stable vector bundles on a Riemann surface is smooth when the rank and degree are coprime, and is diffeomorphic to the space of unitary connections of central constant curvature. A classic result of Newstead and Atiyah and Bott asserts that its rational cohomology ring is generated by the universal classes, that is, by the Kunneth components of the Chern classes of the universal bundle.
This paper studies the larger, non-compact moduli space of Higgs bundles, as introduced by Hitchin and Simpson, with values in the canonical bundle K. This is diffeomorphic to the space of all connections of central constant curvature, whether unitary or not. The main result of the paper is that, in the rank 2 case, the rational cohomology ring of this space is again generated by universal classes.
The spaces of Higgs bundles with values in K(n) for n > 0 turn out to be essential to the story. Indeed, we show that their direct limit has the homotopy type of the classifying space of the gauge group, and hence has cohomology generated by universal classes. 2000 Mathematics Subject Classification 14H60 (primary), 14D20, 14H81, 32Q55, 58D27 (secondary).
AU - Tamas Hausel
AU - Thaddeus, Michael
ID - 1464
IS - 3
JF - Proceedings of the London Mathematical Society
TI - Generators for the cohomology ring of the moduli space of rank 2 higgs bundles
VL - 88
ER -
TY - JOUR
AB - The simultaneous multiple volume (SMV) approach in navigator-gated MRI allows the use of the whole motion range or the entire scan time for the reconstruction of final images by simultaneously acquiring different image volumes at different motion states. The motion tolerance range for each volume is kept small, thus SMV substantially increases the scan efficiency of navigator methods while maintaining the effectiveness of motion suppression. This article reports a general implementation of the SMV approach using a multiprocessor scheduling algorithm. Each motion state is regarded as a processor and each volume is regarded as a job. An efficient scheduling that completes all jobs in minimal time is maintained even when the motion pattern changes. Initial experiments demonstrated that SMV significantly increased the scan efficiency of navigatorgated MRI.
AU - Vladimir Kolmogorov
AU - Nguyen, Thành D
AU - Nuval, Anthony
AU - Spincemaille, Pascal
AU - Prince, Martin R
AU - Zabih, Ramin
AU - Wang, Yusu
ID - 3172
IS - 2
JF - Magnetic Resonance in Medicine
TI - Multiprocessor scheduling implementation of the simultaneous multiple volume SMV navigator method
VL - 52
ER -
TY - JOUR
AB - In the last few years, several new algorithms based on graph cuts have been developed to solve energy minimization problems in computer vision. Each of these techniques constructs a graph such that the minimum cut on the graph also minimizes the energy. Yet, because these graph constructions are complex and highly specific to a particular energy function, graph cuts have seen limited application to date. In this paper, we give a characterization of the energy functions that can be minimized by graph cuts. Our results are restricted to functions of binary variables. However, our work generalizes many previous constructions and is easily applicable to vision problems that involve large numbers of labels, such as stereo, motion, image restoration, and scene reconstruction. We give a precise characterization of what energy functions can be minimized using graph cuts, among the energy functions that can be written as a sum of terms containing three or fewer binary variables. We also provide a general-purpose construction to minimize such an energy function. Finally, we give a necessary condition for any energy function of binary variables to be minimized by graph cuts. Researchers who are considering the use of graph cuts to optimize a particular energy function can use our results to determine if this is possible and then follow our construction to create the appropriate graph. A software implementation is freely available.
AU - Vladimir Kolmogorov
AU - Zabih, Ramin
ID - 3173
IS - 2
JF - IEEE Transactions on Pattern Analysis and Machine Intelligence
TI - What energy functions can be minimized via graph cuts?
VL - 26
ER -
TY - CONF
AB - Feature space clustering is a popular approach to image segmentation, in which a feature vector of local properties (such as intensity, texture or motion) is computed at each pixel. The feature space is then clustered, and each pixel is labeled with the cluster that contains its feature vector. A major limitation of this approach is that feature space clusters generally lack spatial coherence (i.e., they do not correspond to a compact grouping of pixels). In this paper, we propose a segmentation algorithm that operates simultaneously in feature space and in image space. We define an energy function over both a set of clusters and a labeling of pixels with clusters. In our framework, a pixel is labeled with a single cluster (rather than, for example, a distribution over clusters). Our energy function penalizes clusters that are a poor fit to the data in feature space, and also penalizes clusters whose pixels lack spatial coherence. The energy function can be efficiently minimized using graph cuts. Our algorithm can incorporate both parametric and non-parametric clustering methods. It can be applied to many optimization-based clustering methods, including k-means and k-medians, and can handle models which are very close in feature space. Preliminary results are presented on segmenting real and synthetic images, using both parametric and non-parametric clustering.
AU - Zabih, Ramin
AU - Vladimir Kolmogorov
ID - 3177
TI - Spatially coherent clustering using graph cuts
VL - 2
ER -
TY - JOUR
AB - Minimum cut/maximum flow algorithms on graphs have emerged as an increasingly useful tool for exactor approximate energy minimization in low-level vision. The combinatorial optimization literature provides many min-cut/max-flow algorithms with different polynomial time complexity. Their practical efficiency, however, has to date been studied mainly outside the scope of computer vision. The goal of this paper is to provide an experimental comparison of the efficiency of min-cut/max flow algorithms for applications in vision. We compare the running times of several standard algorithms, as well as a new algorithm that we have recently developed. The algorithms we study include both Goldberg-Tarjan style "push -relabel" methods and algorithms based on Ford-Fulkerson style "augmenting paths." We benchmark these algorithms on a number of typical graphs in the contexts of image restoration, stereo, and segmentation. In many cases, our new algorithm works several times faster than any of the other methods, making near real-time performance possible. An implementation of our max-flow/min-cut algorithm is available upon request for research purposes.
AU - Boykov, Yuri
AU - Vladimir Kolmogorov
ID - 3178
IS - 9
JF - IEEE Transactions on Pattern Analysis and Machine Intelligence
TI - An experimental comparison of min-cut/max-flow algorithms for energy minimization in vision
VL - 26
ER -
TY - CONF
AB - The problem of efficient, interactive foreground/background segmentation in still images is of great practical importance in image editing. Classical image segmentation tools use either texture (colour) information, e.g. Magic Wand, or edge (contrast) information, e.g. Intelligent Scissors. Recently, an approach based on optimization by graph-cut has been developed which successfully combines both types of information. In this paper we extend the graph-cut approach in three respects. First, we have developed a more powerful, iterative version of the optimisation. Secondly, the power of the iterative algorithm is used to simplify substantially the user interaction needed for a given quality of result. Thirdly, a robust algorithm for "border matting" has been developed to estimate simultaneously the alpha-matte around an object boundary and the colours of foreground pixels. We show that for moderately difficult examples the proposed method outperforms competitive tools.
AU - Rother, Carsten
AU - Vladimir Kolmogorov
AU - Blake, Andrew
ID - 3179
IS - 3
TI - "GrabCut" - Interactive foreground extraction using iterated graph cuts
VL - 23
ER -
TY - CONF
AB - A new technique for proving the adaptive indistinguishability of two systems, each composed of some component systems, is presented, using only the fact that corresponding component systems are non-adaptively indistinguishable. The main tool is the definition of a special monotone condition for a random system F, relative to another random system G, whose probability of occurring for a given distinguisher D is closely related to the distinguishing advantage ε of D for F and G, namely it is lower and upper bounded by ε and (1+ln1), respectively.
A concrete instantiation of this result shows that the cascade of two random permutations (with the second one inverted) is indistinguishable from a uniform random permutation by adaptive distinguishers which may query the system from both sides, assuming the components’ security only against non-adaptive one-sided distinguishers.
As applications we provide some results in various fields as almost k-wise independent probability spaces, decorrelation theory and computational indistinguishability (i.e., pseudo-randomness).
AU - Maurer, Ueli M
AU - Krzysztof Pietrzak
ID - 3208
TI - Composition of random systems: When two weak make one strong
VL - 2951
ER -
TY - JOUR
AB - The folding and stability of transmembrane proteins is a fundamental and unsolved biological problem. Here, single bacteriorhodopsin molecules were mechanically unfolded from native purple membranes using atomic force microscopy and force spectroscopy. The energy landscape of individual transmembrane α helices and polypeptide loops was mapped by monitoring the pulling speed dependence of the unfolding forces and applying Monte Carlo simulations. Single helices formed independently stable units stabilized by a single potential barrier. Mechanical unfolding of the helices was triggered by 3.9–7.7 Å extension, while natural unfolding rates were of the order of 10−3 s−1. Besides acting as individually stable units, helices associated pairwise, establishing a collective potential barrier. The unfolding pathways of individual proteins reflect distinct pulling speed-dependent unfolding routes in their energy landscapes. These observations support the two-stage model of membrane protein folding in which α helices insert into the membrane as stable units and then assemble into the functional protein.
AU - Harald Janovjak
AU - Struckmeier, Jens
AU - Hubain, Maurice
AU - Kessler, Max
AU - Kedrov, Alexej
AU - Mueller, Daniel J
ID - 3419
IS - 5
JF - Structure
TI - Probing the energy landscape of the membrane protein bacteriorhodopsin
VL - 12
ER -
TY - JOUR
AB - Single-molecule force-spectroscopy was employed to unfold and refold single sodium-proton antiporters (NhaA) of Escherichia coli from membrane patches. Although transmembrane α-helices and extracellular polypeptide loops exhibited sufficient stability to individually establish potential barriers against unfolding, two helices predominantly unfolded pairwise, thereby acting as one structural unit. Many of the potential barriers were detected unfolding NhaA either from the C-terminal or the N-terminal end. It was found that some molecular interactions stabilizing secondary structural elements were directional, while others were not. Additionally, some interactions appeared to occur between the secondary structural elements. After unfolding ten of the 12 helices, the extracted polypeptide was allowed to refold back into the membrane. After five seconds, the refolded polypeptide established all secondary structure elements of the native protein. One helical pair showed a characteristic spring like “snap in” into its folded conformation, while the refolding process of other helices was not detected in particular. Additionally, individual helices required characteristic periods of time to fold. Correlating these results with the primary structure of NhaA allowed us to obtain the first insights into how potential barriers establish and determine the folding kinetics of the secondary structure elements.
AU - Kedrov, Alexej
AU - Ziegler, Christine
AU - Harald Janovjak
AU - Kühlbrandt, Werner
AU - Mueller, Daniel J
ID - 3420
IS - 5
JF - Journal of Molecular Biology
TI - Controlled unfolding and refolding of a single sodium/proton antiporter using atomic force microscopy
VL - 340
ER -
TY - CHAP
AU - Herbert Edelsbrunner
ID - 3574
T2 - Handbook of Discrete and Computational Geometry
TI - Biological applications of computational topology
ER -
TY - CHAP
AB - The Jacobi set of two Morse functions defined on a common - manifold is the set of critical points of the restrictions of one func- tion to the level sets of the other function. Equivalently, it is the set of points where the gradients of the functions are parallel. For a generic pair of Morse functions, the Jacobi set is a smoothly embed- ded 1-manifold. We give a polynomial-time algorithm that com- putes the piecewise linear analog of the Jacobi set for functions specified at the vertices of a triangulation, and we generalize all results to more than two but at most Morse functions.
AU - Herbert Edelsbrunner
AU - Harer, John
ID - 3575
T2 - Foundations of Computational Mathematics
TI - Jacobi sets of multiple Morse functions
VL - 312
ER -
TY - GEN
AB - Genome sizes vary enormously. This variation in DNA content correlates with effective population size, suggesting that deleterious additions to the genome can accumulate in small populations. On this view, the increased complexity of biological functions associated with large genomes partly reflects evolutionary degeneration.
AU - Charlesworth, Brian
AU - Nicholas Barton
ID - 3595
IS - 6
T2 - Current Biology
TI - Genome size: Does bigger mean worse?
VL - 14
ER -
TY - JOUR
AB - We analyze the changes in the mean and variance components of a quantitative trait caused by changes in allele frequencies, concentrating on the effects of genetic drift. We use a general representation of epistasis and dominance that allows an arbitrary relation between genotype and phenotype for any number of diallelic loci. We assume initial and final Hardy-Weinberg and linkage equilibrium in our analyses of drift-induced changes. Random drift generates transient linkage disequilibria that cause correlations between allele frequency fluctuations at different loci. However, we show that these have negligible effects, at least for interactions among small numbers of loci. Our analyses are based on diffusion approximations that summarize the effects of drift in terms of F, the inbreeding coefficient, interpreted as the expected proportional decrease in heterozygosity at each locus. For haploids, the variance of the trait mean after a population bottleneck is var(Δz̄) =inline imagewhere n is the number of loci contributing to the trait variance, VA(1)=VA is the additive genetic variance, and VA(k) is the kth-order additive epistatic variance. The expected additive genetic variance after the bottleneck, denoted (V*A), is closely related to var(Δz̄); (V*A) (1 –F)inline imageThus, epistasis inflates the expected additive variance above VA(1 –F), the expectation under additivity. For haploids (and diploids without dominance), the expected value of every variance component is inflated by the existence of higher order interactions (e.g., third-order epistasis inflates (V*AA)). This is not true in general with diploidy, because dominance alone can reduce (V*A) below VA(1 –F) (e.g., when dominant alleles are rare). Without dominance, diploidy produces simple expressions: var(Δz̄)=inline image=1 (2F) kVA(k) and (V*A) = (1 –F)inline imagek(2F)k-1VA(k) With dominance (and even without epistasis), var(Δz̄)and (V*A) no longer depend solely on the variance components in the base population. For small F, the expected additive variance simplifies to (V*A)(1 –F) VA+ 4FVAA+2FVD+2FCAD, where CAD is a sum of two terms describing covariances between additive effects and dominance and additive × dominance interactions. Whether population bottlenecks lead to expected increases in additive variance depends primarily on the ratio of nonadditive to additive genetic variance in the base population, but dominance precludes simple predictions based solely on variance components. We illustrate these results using a model in which genotypic values are drawn at random, allowing extreme and erratic epistatic interactions. Although our analyses clarify the conditions under which drift is expected to increase VA, we question the evolutionary importance of such increases.
AU - Nicholas Barton
AU - Turelli, Michael
ID - 3614
IS - 10
JF - Evolution; International Journal of Organic Evolution
TI - Effects of allele frequency changes on variance components under a general model of epistasis
VL - 58
ER -
TY - JOUR
AB - We investigate three alternative selection-based scenarios proposed to maintain polygenic variation: pleiotropic balancing selection, G x E interactions (with spatial or temporal variation in allelic effects), and sex-dependent allelic effects. Each analysis assumes an additive polygenic trait with n diallelic loci under stabilizing selection. We allow loci to have different effects and consider equilibria at which the population mean departs from the stabilizing-selection optimum. Under weak selection, each model produces essentially identical, approximate allele-frequency dynamics. Variation is maintained under pleiotropic balancing selection only at loci for which the strength of balancing selection exceeds the effective strength of stabilizing selection. In addition, for all models, polymorphism requires that the population mean be close enough to the optimum that directional selection does not overwhelm balancing selection. This balance allows many simultaneously stable equilibria, and we explore their properties numerically. Both spatial and temporal G x E can maintain variation at loci for which the coefficient of variation (across environments) of the effect of a substitution exceeds a critical value greater than one. The critical value depends on the correlation between substitution effects at different loci. For large positive correlations (e.g., ρ2ij > 3/4), even extreme fluctuations in allelic effects cannot maintain variation. Surprisingly, this constraint on correlations implies that sex-dependent allelic effects cannot maintain polygenic variation. We present numerical results that support our analytical approximations and discuss our results in connection to relevant data and alternative variance-maintaining mechanisms.
AU - Turelli, Michael
AU - Nicholas Barton
ID - 3615
IS - 2
JF - Genetics
TI - Polygenic variation maintained by balancing selection: pleiotropy, sex-dependent allelic effects and GxE interactions
VL - 166
ER -
TY - GEN
AU - Nicholas Barton
ID - 3616
IS - 15
T2 - Current Biology
TI - Speciation: Why, how, where and when?
VL - 14
ER -
TY - JOUR
AB - The coalescent process can describe the effects of selection at linked loci only if selection is so strong that genotype frequencies evolve deterministically. Here, we develop methods proposed by Kaplan, Darden, and Hudson to find the effects of weak selection. We show that the overall effect is given by an extension to Price's equation: the change in properties such as moments of coalescence times is equal to the covariance between those properties and the fitness of the sample of genes. The distribution of coalescence times differs substantially between allelic classes, even in the absence of selection. However, the average coalescence time between randomly chosen genes is insensitive to the current allele frequency and is affected significantly by purifying selection only if deleterious mutations are common and selection is strong (i.e., the product of population size and selection coefficient, Ns > 3). Balancing selection increases mean coalescence times, but the effect becomes large only when mutation rates between allelic classes are low and when selection is extremely strong. Our analysis supports previous simulations that show that selection has surprisingly little effect on genealogies. Moreover, small fluctuations in allele frequency due to random drift can greatly reduce any such effects. This will make it difficult to detect the action of selection from neutral variation alone.
AU - Nicholas Barton
AU - Etheridge, Alison M
ID - 3617
IS - 2
JF - Genetics
TI - The effect of selection on genealogies
VL - 166
ER -
TY - CONF
AB - Capturing images of documents using handheld digital cameras has a variety of applications in academia, research, knowledge management, retail, and office settings. The ultimate goal of such systems is to achieve image quality comparable to that currently achieved with flatbed scanners even for curved, warped, or curled pages. This can be achieved by high-accuracy 3D modeling of the page surface, followed by a "flattening" of the surface. A number of previous systems have either assumed only perspective distortions, or used techniques like structured lighting, shading, or side-imaging for obtaining 3D shape. This paper describes a system for handheld camera-based document capture using general purpose stereo vision methods followed by a new document dewarping technique. Examples of shape modeling and dewarping of book images is shown.
AU - Ulges, Adrian
AU - Christoph Lampert
AU - Breuel,Thomas M
ID - 3688
TI - Document capture using stereo vision
ER -
TY - JOUR
AB - 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 - CHAP
AU - Ulrich, Florian
AU - Heisenberg, Carl-Philipp J
ED - Korzh, Vladimir
ED - Gong, Zhiyuan
ID - 3587
T2 - Fish development and genetics : the zebrafish and medaka models
TI - Gastrulation in zebrafish
VL - 2
ER -
TY - JOUR
AB - During vertebrate gastrulation, a relatively limited number of blastodermal cells undergoes a stereotypical set of cellular movements that leads to formation of the three germ layers: ectoderm, mesoderm and endoderm. Gastrulation, therefore, provides a unique developmental system in which to study cell movements in vivo in a fairly simple cellular context. Recent advances have been made in elucidating the cellular and molecular mechanisms that underlie cell movements during zebrafish gastrulation. These findings can be compared with observations made in other model systems to identify potential general mechanisms of cell migration during development.
AU - Montero, Juan
AU - Heisenberg, Carl-Philipp J
ID - 4172
IS - 11
JF - Trends in Cell Biology
TI - Gastrulation dynamics: cells move into focus
VL - 14
ER -
TY - JOUR
AB - The dynamical basis of tumoral growth has been controversial. Many models have been proposed to explain cancer development. The descriptions employ exponential, potential, logistic or Gompertzian growth laws. Some of these models are concerned with the interaction between cancer and the immunological, system. Among other properties, these models are concerned with the microscopic behavior of tumors and the emergence of cancer. We propose a modification of a previous model by Stepanova, which describes the specific immunological response against cancer. The modification consists of the substitution of a Gompertian law for the exponential rate used for tumoral growth. This modification is motivated by the numerous works confirming that Gompertz's equation correctly describes solid tumor growth. The modified model predicts that near zero, tumors always tend to grow. Immunological contraposition never suffices to induce a complete regression of the tumor. Instead, a stable microscopic equilibrium between cancer and immunological activity can be attained. In other words, our model predicts that the theory of immune surveillance is plausible. A macroscopic equilibrium in which the system develops cancer is also possible. In this case, immunological activity is depleted. This is consistent with the phenomena of cancer tolerance. Both equilibrium points can coexist or can exist without the other. In all cases the fixed point at zero tumor size is unstable. Since immunity cannot induce a complete tumor regression, a therapy is required. We include constant-dose therapies and show that they are insufficient. Final levels of immunocompetent cells and tumoral cells are finite, thus post-treatment regrowth of the tumor is certain. We also evaluate late-intensification therapies which are successful. They induce an asymptotic regression to zero tumor size. Immune response is also suppressed by the therapy, and thus plays a negligible role in the remission. We conclude that treatment evaluation should be successful without taking into account immunological effects. (C) 2003 Elsevier Ltd. All rights reserved.
AU - de Vladar, Harold
AU - González, J.
ID - 4238
IS - 3
JF - Journal of Theoretical Biology
TI - Dynamic response of cancer under the influence of immunological activity and therapy
VL - 227
ER -
TY - 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 - THES
AU - de Vladar, Harold
ID - 4236
TI - Métodos no lineales y sus aplicaciones en dinámicas aleatorias de poblaciones celulares
ER -
TY - THES
AB - The enormous cost and ubiquity of software errors necessitates the need for techniques and tools that can precisely analyze large systems and prove that they meet given specifications, or if they don't, return counterexample behaviors showing how the system fails. Recent advances in model checking, decision procedures, program analysis and type systems, and a shift of focus to partial specifications common to several systems (e.g., memory safety and race freedom) have resulted in several practical verification methods. However, these methods are either precise or they are scalable, depending on whether they track the values of variables or only a fixed small set of dataflow facts (e.g., types), and are usually insufficient for precisely verifying large programs.
We describe a new technique called Lazy Abstraction (LA) which achieves both precision and scalability by localizing the use of precise information. LA automatically builds, explores and refines a single abstract model of the program in a way that different parts of the model exhibit different degrees of precision, namely just enough to verify the desired property. The algorithm automatically mines the information required by partitioning mechanical proofs of unsatisfiability of spurious counterexamples into Craig Interpolants. For multithreaded systems, we give a new technique based on analyzing the behavior of a single thread executing in a context which is an abstraction of the other (arbitrarily many) threads. We define novel context models and show how to automatically infer them and analyze the full system (thread + context) using LA.
LA is implemented in BLAST. We have run BLAST on Windows and Linux Device Drivers to verify API conformance properties, and have used it to find (or guarantee the absence of) data races in multithreaded Networked Embedded Systems (NESC) applications. BLAST is able to prove the absence of races in several cases where earlier methods, which depend on lock-based synchronization, fail.
AU - Jhala, Ranjit
ID - 4424
TI - Program verification by lazy abstraction
ER -
TY - JOUR
AB - We consider the evolution of a connected set on the plane carried by a space periodic incompressible stochastic flow. While for almost every realization of the stochastic flow at time t most of the particles are at a distance of order equation image away from the origin, there is a measure zero set of points that escape to infinity at the linear rate. We study the set of points visited by the original set by time t and show that such a set, when scaled down by the factor of t, has a limiting nonrandom shape.
AU - Dolgopyat, Dmitry
AU - Kaloshin, Vadim
AU - Koralov, Leonid
ID - 8517
IS - 9
JF - Communications on Pure and Applied Mathematics
KW - Applied Mathematics
KW - General Mathematics
SN - 0010-3640
TI - A limit shape theorem for periodic stochastic dispersion
VL - 57
ER -
TY - JOUR
AU - Koralov, Leonid
AU - Kaloshin, Vadim
AU - Dolgopyat, Dmitry
ID - 8518
IS - 1A
JF - The Annals of Probability
SN - 0091-1798
TI - Sample path properties of the stochastic flows
VL - 32
ER -