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 - 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-Antonio
AU - Heisenberg, Carl-Philipp
ID - 4172
IS - 11
JF - Trends in Cell Biology
TI - Gastrulation dynamics: cells move into focus
VL - 14
ER -
TY - JOUR
AB - Developing cells acquire positional information by reading the graded distribution of morphogens. In Drosophila, the Dpp morphogen forms a long-range concentration gradient by spreading from a restricted source in the developing wing. It has been assumed that Dpp spreads by extracellular diffusion. Under this assumption, the main role of endocytosis in gradient formation is to downregulate receptors at the cell surface. These surface receptors bind to the ligand and thereby interfere with its long-range movement. Recent experiments indicate that Dpp spreading is mediated by Dynamin-dependent endocytosis in the target tissue, suggesting that extracellular diffusion alone cannot account for Dpp dispersal. Here, we perform a theoretical study of a model for morphogen spreading based on extracellular diffusion, which takes into account receptor binding and trafficking. We compare profiles of ligand and surface receptors obtained in this model with experimental data. To this end, we monitored directly the pool of surface receptors and extracellular Dpp with specific antibodies. We conclude that current models considering pure extracellular diffusion cannot explain the observed role of endocytosis during Dpp long-range movement.
AU - Kruse, Karsten
AU - Pantazis, Periklis
AU - Bollenbach, Tobias
AU - Julicher, Frank
AU - Gonzalez-Gaitan, Marcos
ID - 4224
IS - 19
JF - Development
TI - Dpp gradient formation by dynamin-dependent endocytosis: receptor trafficking and the diffusion model
VL - 131
ER -
TY - CHAP
AU - Harold Vladar
AU - Cipriani, Roberto
AU - Scharifker, Benjamin
AU - Bubis, Jose
ED - Hanslmeier,A.
ED - Kempe,S.
ED - Seckbach,J.
ID - 4230
T2 - Life in the Universe From the Miller Experiment to the Search for Life on Other Worlds
TI - A mechanism for the prebiotic emergence of proteins
ER -
TY - THES
AU - de Vladar,Harold Paul
ID - 4236
TI - Métodos no lineales y sus aplicaciones en dinámicas aleatorias de poblaciones celulares
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 Paul
AU - González,J. A
ID - 4238
IS - 3
JF - Journal of Theoretical Biology
TI - Dynamic response of cancer under the influence of immunological activity and therapy
VL - 227
ER -
TY - CHAP
AU - Harold Vladar
AU - Cipriani, Roberto
AU - Scharifker, Benjamin
AU - Bubis, Jose
ED - 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 - THES
AB - The enormous cost and ubiquity of software errors necessitates the need for techniques and tools that can precisely analyze large systems and prove that they meet given specifications, or if they don't, return counterexample behaviors showing how the system fails. Recent advances in model checking, decision procedures, program analysis and type systems, and a shift of focus to partial specifications common to several systems (e.g., memory safety and race freedom) have resulted in several practical verification methods. However, these methods are either precise or they are scalable, depending on whether they track the values of variables or only a fixed small set of dataflow facts (e.g., types), and are usually insufficient for precisely verifying large programs.
We describe a new technique called Lazy Abstraction (LA) which achieves both precision and scalability by localizing the use of precise information. LA automatically builds, explores and refines a single abstract model of the program in a way that different parts of the model exhibit different degrees of precision, namely just enough to verify the desired property. The algorithm automatically mines the information required by partitioning mechanical proofs of unsatisfiability of spurious counterexamples into Craig Interpolants. For multithreaded systems, we give a new technique based on analyzing the behavior of a single thread executing in a context which is an abstraction of the other (arbitrarily many) threads. We define novel context models and show how to automatically infer them and analyze the full system (thread + context) using LA.
LA is implemented in BLAST. We have run BLAST on Windows and Linux Device Drivers to verify API conformance properties, and have used it to find (or guarantee the absence of) data races in multithreaded Networked Embedded Systems (NESC) applications. BLAST is able to prove the absence of races in several cases where earlier methods, which depend on lock-based synchronization, fail.
AU - Jhala, Ranjit
ID - 4424
TI - Program verification by lazy abstraction
ER -
TY - CONF
AB - We present a type system for E code, which is an assembly language that manages the release, interaction, and termination of real-time tasks. E code specifies a deadline for each task, and the type system ensures that the deadlines are path-insensitive. We show that typed E programs allow, for given worst-case execution times of tasks, a simple schedulability analysis. Moreover, the real-time programming language Giotto can be compiled into typed E~code. This shows that typed E~code identifies an easily schedulable yet expressive class of real-time programs. We have extended the Giotto compiler to generate typed E code, and enabled the run-time system for E code to perform a type and schedulability check before executing the code.
AU - Thomas Henzinger
AU - Kirsch, Christoph M
ID - 4445
TI - A typed assembly language for real-time programs
ER -
TY - CONF
AB - The success of model checking for large programs depends crucially on the ability to efficiently construct parsimonious abstractions. A predicate abstraction is parsimonious if at each control location, it specifies only relationships between current values of variables, and only those which are required for proving correctness. Previous methods for automatically refining predicate abstractions until sufficient precision is obtained do not systematically construct parsimonious abstractions: predicates usually contain symbolic variables, and are added heuristically and often uniformly to many or all control locations at once. We use Craig interpolation to efficiently construct, from a given abstract error trace which cannot be concretized, a parsominous abstraction that removes the trace. At each location of the trace, we infer the relevant predicates as an interpolant between the two formulas that define the past and the future segment of the trace. Each interpolant is a relationship between current values of program variables, and is relevant only at that particular program location. It can be found by a linear scan of the proof of infeasibility of the trace.We develop our method for programs with arithmetic and pointer expressions, and call-by-value function calls. For function calls, Craig interpolation offers a systematic way of generating relevant predicates that contain only the local variables of the function and the values of the formal parameters when the function was called. We have extended our model checker Blast with predicate discovery by Craig interpolation, and applied it successfully to C programs with more than 130,000 lines of code, which was not possible with approaches that build less parsimonious abstractions.
AU - Thomas Henzinger
AU - Jhala, Ranjit
AU - Majumdar, Ritankar S
AU - McMillan, Kenneth L
ID - 4458
TI - Abstractions from proofs
ER -
TY - 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 -