TY - JOUR AB - Although nuclear envelope (NE) assembly is known to require the GTPase Ran, the membrane fusion machinery involved is uncharacterized. NE assembly involves formation of a reticular network on chromatin, fusion of this network into a closed NE and subsequent expansion. Here we show that p97, an AAA-ATPase previously implicated in fusion of Golgi and transitional endoplasmic reticulum (ER) membranes together with the adaptor p47, has two discrete functions in NE assembly. Formation of a closed NE requires the p97–Ufd1–Npl4 complex, not previously implicated in membrane fusion. Subsequent NE growth involves a p97–p47 complex. This study provides the first insights into the molecular mechanisms and specificity of fusion events involved in NE formation. AU - HETZER, Martin W AU - Meyer, Hemmo H. AU - Walther, Tobias C. AU - Bilbao-Cortes, Daniel AU - Warren, Graham AU - Mattaj, Iain W. ID - 11125 IS - 12 JF - Nature Cell Biology KW - Cell Biology SN - 1465-7392 TI - Distinct AAA-ATPase p97 complexes function in discrete steps of nuclear assembly VL - 3 ER - TY - JOUR AB - We present the first fully dynamic algorithm for maintaining a minimum spanning forest in time 𝑜(𝑛√) per operation. To be precise, the algorithm uses O(n1/3 log n) amortized time per update operation. The algorithm is fairly simple and deterministic. An immediate consequence is the first fully dynamic deterministic algorithm for maintaining connectivity and bipartiteness in amortized time O(n1/3 log n) per update, with O(1) worst case time per query. AU - Henzinger, Monika H AU - King, Valerie ID - 11892 IS - 2 JF - SIAM Journal on Computing SN - 0097-5397 TI - Maintaining minimum spanning forests in dynamic graphs VL - 31 ER - TY - CONF AB - Previous studies of the Web graph structure have focused on the graph structure at the level of individual pages. In actuality the Web is a hierarchically nested graph, with domains, hosts and Web sites introducing intermediate levels of affiliation and administrative control. To better understand the growth of the Web we need to understand its macro-structure, in terms of the linkage between Web sites. We approximate this by studying the graph of the linkage between hosts on the Web. This was done based on snapshots of the Web taken by Google in Oct 1999, Aug 2000 and Jun 2001. The connectivity between hosts is represented by a directed graph, with hosts as nodes and weighted edges representing the count of hyperlinks between pages on the corresponding hosts. We demonstrate how such a "hostgraph" can be used to study connectivity properties of hosts and domains over time, and discuss a modified "copy model" to explain observed link weight distributions as a function of subgraph size. We discuss changes in the Web over time in the size and connectivity of Web sites and country domains. We also describe a data mining application of the hostgraph: a related host finding algorithm which achieves a precision of 0.65 at rank 3. AU - Bharat, K. AU - Chang, Bay-Wei AU - Henzinger, Monika H AU - Ruhl, M. ID - 11914 SN - 15504786 T2 - 1st IEEE International Conference on Data Mining TI - Who links to whom: Mining linkage between Web sites ER - TY - GEN AB - A molecular classification method is based on a space filling description of a molecule. The three dimensional body corresponding to the space filling molecular structure is divided into Voronoi regions to provide a basis for efficiently processing local structural information. A Delaunay triangulation provides a basis for systematically processing information relating to the Voronoi regions into shape descriptors in the form of topological elements. Preferably, additional shape and/or property descriptors are included in the classification method. The classification methods generally are used to identify similarities between molecules that can be used as property predictors for a variety of applications. Generally, the property predictions are the basis for selection of compounds for incorporation into efficacy evaluations. AU - Liang, Jie AU - Edelsbrunner, Herbert ID - 3507 TI - Molecular classification for property prediction ER - TY - BOOK AB - The book combines topics in mathematics (geometry and topology), computer science (algorithms), and engineering (mesh generation). The original motivation for these topics was the difficulty faced (both conceptually and in the technical execution) in any attempt to combine elements of combinatorial and of numerical algorithms. Mesh generation is a topic where a meaningful combination of these different approaches to problem solving is inevitable. The book develops methods from both areas that are amenable to combination, and explains recent breakthrough solutions to meshing that fit into this category.The book should be an ideal graduate text for courses on mesh generation. The specific material is selected giving preference to topics that are elementary, attractive, lend themselves to teaching, useful, and interesting. AU - Edelsbrunner, Herbert ID - 3586 SN - 0-521-79309-2 TI - Geometry and Topology for Mesh Generation VL - 7 ER - TY - CONF AU - Krishnendu Chatterjee AU - Dasgupta, Pallab AU - Chakrabarti, Partha P ID - 3447 TI - Weighted quantified computation tree logic ER - TY - JOUR AB - For diffeomorphisms of smooth compact manifolds, we consider the problem of how fast the number of periodic points with period $n$grows as a function of $n$. In many familiar cases (e.g., Anosov systems) the growth is exponential, but arbitrarily fast growth is possible; in fact, the first author has shown that arbitrarily fast growth is topologically (Baire) generic for $C^2$ or smoother diffeomorphisms. In the present work we show that, by contrast, for a measure-theoretic notion of genericity we call ``prevalence'', the growth is not much faster than exponential. Specifically, we show that for each $\delta > 0$, there is a prevalent set of ( $C^{1+\rho}$ or smoother) diffeomorphisms for which the number of period $n$ points is bounded above by $\operatorname{exp}(C n^{1+\delta})$ for some $C$ independent of $n$. We also obtain a related bound on the decay of the hyperbolicity of the periodic points as a function of $n$. The contrast between topologically generic and measure-theoretically generic behavior for the growth of the number of periodic points and the decay of their hyperbolicity shows this to be a subtle and complex phenomenon, reminiscent of KAM theory. AU - Kaloshin, Vadim AU - Hunt, Brian R. ID - 8522 IS - 4 JF - Electronic Research Announcements of the American Mathematical Society KW - General Mathematics SN - 1079-6762 TI - A stretched exponential bound on the rate of growth of the number of periodic points for prevalent diffeomorphisms I VL - 7 ER - TY - JOUR AB - We continue the previous article's discussion of bounds, for prevalent diffeomorphisms of smooth compact manifolds, on the growth of the number of periodic points and the decay of their hyperbolicity as a function of their period $n$. In that article we reduced the main results to a problem, for certain families of diffeomorphisms, of bounding the measure of parameter values for which the diffeomorphism has (for a given period $n$) an almost periodic point that is almost nonhyperbolic. We also formulated our results for $1$-dimensional endomorphisms on a compact interval. In this article we describe some of the main techniques involved and outline the rest of the proof. To simplify notation, we concentrate primarily on the $1$-dimensional case. AU - Kaloshin, Vadim AU - Hunt, Brian R. ID - 8521 IS - 5 JF - Electronic Research Announcements of the American Mathematical Society KW - General Mathematics SN - 1079-6762 TI - A stretched exponential bound on the rate of growth of the number of periodic points for prevalent diffeomorphisms II VL - 7 ER - TY - JOUR AB - A number α∈R is diophantine if it is not well approximable by rationals, i.e. for some C,ε>0 and any relatively prime p,q∈Z we have |αq−p|>Cq−1−ε. It is well-known and is easy to prove that almost every α in R is diophantine. In this paper we address a noncommutative version of the diophantine properties. Consider a pair A,B∈SO(3) and for each n∈Z+ take all possible words in A, A -1, B, and B - 1 of length n, i.e. for a multiindex I=(i1,i1,…,im,jm) define |I|=∑mk=1(|ik|+|jk|)=n and \( W_n(A,B ) = \{W_{\cal I}(A,B) = A^{i_1} B^{j_1} \dots A^{i_m} B^{j_m}\}_{|{\cal I|}=n \).¶Gamburd—Jakobson—Sarnak [GJS] raised the problem: prove that for Haar almost every pair A,B∈SO(3) the closest distance of words of length n to the identity, i.e. sA,B(n)=min|I|=n∥WI(A,B)−E∥, is bounded from below by an exponential function in n. This is the analog of the diophantine property for elements of SO(3). In this paper we prove that s A,B (n) is bounded from below by an exponential function in n 2. We also exhibit obstructions to a “simple” proof of the exponential estimate in n. AU - Kaloshin, Vadim AU - Rodnianski, I. ID - 8524 IS - 5 JF - Geometric And Functional Analysis SN - 1016-443X TI - Diophantine properties of elements of SO(3) VL - 11 ER - TY - JOUR AB - Epigenetic silenced alleles of the Arabidopsis SUPERMANlocus (the clark kent alleles) are associated with dense hypermethylation at noncanonical cytosines (CpXpG and asymmetric sites, where X = A, T, C, or G). A genetic screen for suppressors of a hypermethylated clark kent mutant identified nine loss-of-function alleles of CHROMOMETHYLASE3(CMT3), a novel cytosine methyltransferase homolog. These cmt3 mutants display a wild-type morphology but exhibit decreased CpXpG methylation of the SUP gene and of other sequences throughout the genome. They also show reactivated expression of endogenous retrotransposon sequences. These results show that a non-CpG DNA methyltransferase is responsible for maintaining epigenetic gene silencing. AU - Lindroth, A. M. AU - Cao, Xiaofeng AU - Jackson, James P. AU - Zilberman, Daniel AU - McCallum, Claire M. AU - Henikoff, Steven AU - Jacobsen, Steven E. ID - 9444 IS - 5524 JF - Science KW - Multidisciplinary SN - 0036-8075 TI - Requirement of CHROMOMETHYLASE3 for maintenance of CpXpG methylation VL - 292 ER - TY - CONF AB - A controller is an environment for a system that achieves a particular control objective by providing inputs to the system without constraining the choices of the system. For synchronous systems, where system and controller make simultaneous and interdependent choices, the notion that a controller must not constrain the choices of the system can be formalized by type systems for composability. In a previous paper, we solved the control problem for static and dynamic types: a static type is a dependency relation between inputs and outputs, and composition is well-typed if it does not introduce cyclic dependencies; a dynamic type is a set of static types, one for each state. Static and dynamic types, however, cannot capture many important digital circuits, such as gated clocks, bidirectional buses, and random-access memory. We therefore introduce more general type systems, so-called dependent and bidirectional types, for modeling these situations, and we solve the corresponding control problems. In a system with a dependent type, the dependencies between inputs and outputs are determined gradually through a game of the system against the controller. In a system with a bidirectional type, also the distinction between inputs and outputs is resolved dynamically by such a game. The game proceeds in several rounds. In each round the system and the controller choose to update some variables dependent on variables that have already been updated. The solution of the control problem for dependent and bidirectional types is based on algorithms for solving these games. AU - De Alfaro, Luca AU - Henzinger, Thomas A AU - Mang, Freddy ID - 4634 SN - 9783540424970 T2 - Proceedings of the 12th International Conference on on Concurrency Theory TI - The control of synchronous systems, Part II VL - 2154 ER - TY - CONF AB - A procedure for the analysis of state spaces is called symbolic if it manipulates not individual states, but sets of states that are represented by constraints. Such a procedure can be used for the analysis of infinite state spaces, provided termination is guaranteed. We present symbolic procedures, and corresponding termination criteria, for the solution of infinite-state games, which occur in the control and modular verification of infinite-state systems. To characterize the termination of symbolic procedures for solving infinite-state games, we classify these game structures into four increasingly restrictive categories: 1 Class 1 consists of infinite-state structures for which all safety and reachability games can be solved. 2 Class 2 consists of infinite-state structures for which all ω-regular games can be solved. 3 Class 3 consists of infinite-state structures for which all nested positive boolean combinations of ω-regular games can be solved. 4 Class 4 consists of infinite-state structures for which all nested boolean combinations of ω-regular games can be solved. We give a structural characterization for each class, using equivalence relations on the state spaces of games which range from game versions of trace equivalence to a game version of bisimilarity. We provide infinite-state examples for all four classes of games from control problems for hybrid systems. We conclude by presenting symbolic algorithms for the synthesis of winning strategies (“controller synthesis”) for infinitestate games with arbitrary ω-regular objectives, and prove termination over all class-2 structures. This settles, in particular, the symbolic controller synthesis problem for rectangular hybrid systems. AU - De Alfaro, Luca AU - Henzinger, Thomas A AU - Majumdar, Ritankar ID - 4633 SN - 9783540424970 T2 - Proceedings of the 12th International Conference on on Concurrency Theory TI - Symbolic algorithms for infinite-state games VL - 2154 ER - TY - CONF AB - Abstract. Dynamic programs, or fixpoint iteration schemes, are useful for solving many problems on state spaces, including model checking on Kripke structures (“verification”), computing shortest paths on weighted graphs (“optimization”), computing the value of games played on game graphs (“control”). For Kripke structures, a rich fixpoint theory is available in the form of the µ-calculus. Yet few connections have been made between different interpretations of fixpoint algorithms. We study the question of when a particular fixpoint iteration scheme ϕ for verifying an ω-regular property Ψ on a Kripke structure can be used also for solving a two-player game on a game graph with winning objective Ψ. We provide a sufficient and necessary criterion for the answer to be affirmative in the form of an extremal-model theorem for games: under a game interpretation, the dynamic program ϕ solves the game with objective Ψ if and only if both (1) under an existential interpretation on Kripke structures, ϕ is equivalent to ∃Ψ, and (2) under a universal interpretation on Kripke structures, ϕ is equivalent to ∀Ψ. In other words, ϕ is correct on all two-player game graphs iff it is correct on all extremal game graphs, where one or the other player has no choice of moves. The theorem generalizes to quantitative interpretations, where it connects two-player games with costs to weighted graphs. While the standard translations from ω-regular properties to the µ-calculus violate (1) or (2), we give a translation that satisfies both conditions. Our construction, therefore, yields fixpoint iteration schemes that can be uniformly applied on Kripke structures, weighted graphs, game graphs, and game graphs with costs, in order to meet or optimize a given ω-regular objective. AU - De Alfaro, Luca AU - Henzinger, Thomas A AU - Majumdar, Ritankar ID - 4636 SN - 076951281X T2 - Proceedings of the 16th Annual IEEE Symposium on Logic in Computer Science TI - From verification to control: dynamic programs for omega-regular objectives ER - TY - CONF AB - We show how model checking techniques can be applied to the analysis of connectivity and cost-of-traversal properties of Web sites. AU - De Alfaro, Luca AU - Henzinger, Thomas A AU - Mang, Freddy ID - 4635 SN - 9781581133486 T2 - Proceedings of the 10th international conference on World Wide Web TI - MCWEB: A model-checking tool for web-site debugging ER - TY - CONF AB - We present a compositional trace-based model for probabilistic systems. The behavior of a system with probabilistic choice is a stochastic process, namely, a probability distribution on traces, or “bundle.” Consequently, the semantics of a system with both nondeterministic and probabilistic choice is a set of bundles. The bundles of a composite system can be obtained by combining the bundles of the components in a simple mathematical way. Refinement between systems is bundle containment. We achieve assume-guarantee compositionality for bundle semantics by introducing two scoping mechanisms. The first mechanism, which is standard in compositional modeling, distinguishes inputs from outputs and hidden state. The second mechanism, which arises in probabilistic systems, partitions the state into probabilistically independent regions. AU - De Alfaro, Luca AU - Henzinger, Thomas A AU - Jhala, Ranjit ID - 4632 SN - 9783540424970 T2 - Proceedings of the 12th International Conference on on Concurrency Theory TI - Compositional methods for probabilistic systems VL - 2154 ER - TY - CONF AB - Model checking is a practical tool for automated debugging of embedded software. In model checking, a high-level description of a system is compared against a logical correctness requirement to discover inconsistencies. Since model checking is based on exhaustive state-space exploration and the size of the state space of a design grows exponentially with the size of the description, scalability remains a challenge. We have thus developed techniques for exploiting modular design structure during model checking, and the model checker jMocha (Java MOdel-CHecking Algorithm) is based on this theme. Instead of manipulating unstructured state-transition graphs, it supports the hierarchical modeling framework of reactive modules. jMocha is a growing interactive software environment for specification, simulation and verification, and is intended as a vehicle for the development of new verification algorithms and approaches. It is written in Java and uses native C-code BDD libraries from VIS. jMocha offers: (1) a GUI that looks familiar to Windows/Java users; (2) a simulator that displays traces in a message sequence chart fashion; (3) requirements verification both by symbolic and enumerative model checking; (4) implementation verification by checking trace containment; (5) a proof manager that aids compositional and assume-guarantee reasoning; and (6) SLANG (Scripting LANGuage) for the rapid and structured development of new verification algorithms. jMocha is available publicly at ; it is a successor and extension of the original Mocha tool that was entirely written in C. AU - Alur, Rajeev AU - De Alfaro, Luca AU - Grosu, Radu AU - Henzinger, Thomas A AU - Kang, Myong AU - Kirsch, Christoph AU - Majumdar, Ritankar AU - Mang, Freddy AU - Wang, Bow ID - 4600 SN - 0769510507 T2 - Proceedings of the 23rd International Conference on Software Engineering TI - jMocha: A model-checking tool that exploits design structure ER - TY - JOUR AB - State-space explosion is a fundamental obstacle in the formal verification of designs and protocols. Several techniques for combating this problem have emerged in the past few years, among which two are significant: partial-order reduction and symbolic state-space search. In asynchronous systems, interleavings of independent concurrent events are equivalent, and only a representative interleaving needs to be explored to verify local properties. Partial-order methods exploit this redundancy and visit only a subset of the reachable states. Symbolic techniques, on the other hand, capture the transition relation of a system and the set of reachable states as boolean functions. In many cases, these functions can be represented compactly using binary decision diagrams (BDDs). Traditionally, the two techniques have been practiced by two different schools—partial-order methods with enumerative depth-first search for the analysis of asynchronous network protocols, and symbolic breadth-first search for the analysis of synchronous hardware designs. We combine both approaches and develop a method for using partial-order reduction techniques in symbolic BDD-based invariant checking. We present theoretical results to prove the correctness of the method, and experimental results to demonstrate its efficacy. AU - Alur, Rajeev AU - Brayton, Robert AU - Henzinger, Thomas A AU - Qadeer, Shaz AU - Rajamani, Sriram ID - 4599 IS - 2 JF - Formal Methods in System Design SN - 0925-9856 TI - Partial-order reduction in symbolic state-space exploration VL - 18 ER - TY - CONF AB - Conventional type systems specify interfaces in terms of values and domains. We present a light-weight formalism that captures the temporal aspects of software component interfaces. Specifically, we use an automata-based language to capture both input assumptions about the order in which the methods of a component are called, and output guarantees about the order in which the component calls external methods. The formalism supports automatic compatability checks between interface models, and thus constitutes a type system for component interaction. Unlike traditional uses of automata, our formalism is based on an optimistic approach to composition, and on an alternating approach to design refinement. According to the optimistic approach, two components are compatible if there is some environment that can make them work together. According to the alternating approach, one interface refines another if it has weaker input assumptions, and stronger output guarantees. We show that these notions have game-theoretic foundations that lead to efficient algorithms for checking compatibility and refinement. AU - De Alfaro, Luca AU - Henzinger, Thomas A ID - 4622 SN - 9781581133905 T2 - Proceedings of the 8th European software engineering conference TI - Interface automata ER - TY - CONF AB - We classify component-based models of computation into component models and interface models. A component model specifies for each component howthe component behaves in an arbitrary environment; an interface model specifies for each component what the component expects from the environment. Component models support compositional abstraction, and therefore component-based verification. Interface models support compositional refinement, and therefore componentbased design. Many aspects of interface models, such as compatibility and refinement checking between interfaces, are properly viewed in a gametheoretic setting, where the input and output values of an interface are chosen by different players. AU - De Alfaro, Luca AU - Henzinger, Thomas A ID - 4623 SN - 9783540426738 T2 - Proceedings of the 1st International Workshop on Embedded Software TI - Interface theories for component-based design VL - 2211 ER - TY - CONF AB - This paper presents a concept for integrating the embedded programming methodology Giotto and the object-oriented AOCS Framework to create an environment for the rapid development of distributed software for safety-critical embedded control systems with hard real-time requirements of the kind typically found in aerospace applications. AU - Brown, Timothy AU - Pasetti, Alessandro AU - Pree, Wolfgang AU - Henzinger, Thomas A AU - Kirsch, Christoph ID - 4564 SN - 0780370341 T2 - Proceedings of the 20th Digital Avionics Systems Conference TI - A reusable and platform-independent framework for distributed control systems ER - TY - CONF AB - The assume-guarantee paradigm is a powerful divide-and-conquer mechanism for decomposing a verification task about a system into subtasks about the individual components of the system. The key to assume-guarantee reasoning is to consider each component not in isolation, but in conjunction with assumptions about the context of the component. Assume-guarantee principles are known for purely concurrent contexts, which constrain the input data of a component, as well as for purely sequential contexts, which constrain the entry configurations of a component. We present a model for hierarchical system design which permits the arbitrary nesting of parallel as well as serial composition, and which supports an assume-guarantee principle for mixed parallel-serial contexts. Our model also supports both discrete and continuous processes, and is therefore well-suited for the modeling and analysis of embedded software systems which interact with real-world environments. Using an example of two cooperating robots, we show refinement between a high-level model which specifies continuous timing constraints and an implementation which relies on discrete sampling. AU - Henzinger, Thomas A AU - Minea, Marius AU - Prabhu, Vinayak ID - 4477 SN - 9783540418665 T2 - Proceedings of the 4th International Workshop on Hybrid Systems TI - Assume-guarantee reasoning for hierarchical hybrid systems VL - 2034 ER - TY - CONF AB - Giotto is a principled, tool-supported design methodology for implementing embedded control systems on platforms of possibly distributed sensors, actuators, CPUs, and networks. Giotto is based on the principle that time-triggered task invocations plus time-triggered mode switches can form the abstract essence of programming real-time control systems. Giotto consists of a programming language with a formal semantics, and a retargetable compiler and runtime library. Giotto supports the automation of control system design by strictly separating platform-independent functionality and timing concerns from platform-dependent scheduling and communication issues. The time-triggered predictability of Giotto makes it particularly suitable for safety-critical applications with hard real-time constraints. We illustrate the platform-independence and time-triggered execution of Giotto by coordinating a heterogeneous flock of Intel x86 robots and Lego Mindstorms robots. AU - Henzinger, Thomas A AU - Horowitz, Benjamin AU - Kirsch, Christoph ID - 4478 SN - 9781581134254 T2 - Proceedings of the 2nd ACM SIGPLAN workshop on Languages, compilers and tools for embedded systems TI - Embedded control systems development with Giotto ER - TY - CONF AB - Giotto provides an abstract programmer’s model for the implementation of embedded control systems with hard real-time constraints. A typical control application consists of periodic software tasks together with a mode switching logic for enabling and disabling tasks. Giotto specifies time-triggered sensor readings, task invocations, and mode switches independent of any implementation platform. Giotto can be annotated with platform constraints such as task-to-host mappings, and task and communication schedules. The annotations are directives for the Giotto compiler, but they do not alter the functionality and timing of a Giotto program. By separating the platform-independent from the platform-dependent concerns, Giotto enables a great deal of flexibility in choosing control platforms as well as a great deal of automation in the validation and synthesis of control software. The time-triggered nature of Giotto achieves timing predictability, which makes Giotto particularly suitable for safety-critical applications. AU - Henzinger, Thomas A AU - Horowitz, Benjamin AU - Kirsch, Christoph ID - 4479 SN - 9783540426738 T2 - Proceedings of the 1st International Workshop on Embedded Software TI - Giotto: A time-triggered language for embedded programming VL - 2211 ER - TY - CONF AB - We provide an overview of the current status of HYTECH, and reflect on some of the lessons learned from our experiences with the tool. HYTECH is a symbolic model checker for mixed discrete-continuous systems that are modeled as automata with piecewise-constant polyhedral differential inclusions. The use of a formal input language and automated procedures for state-space traversal lay the foundation for formally verifying properties of hybrid dynamical systems. We describe some recent experiences analyzing three hybrid systems. We point out the successes and limitations of the tool. The analysis procedure has been extended in a number of ways to address some of the tool's shortcomings. We evaluate these extensions, and conclude with some desiderata for verification tools for hybrid systems. AU - Henzinger, Thomas A AU - Preussig, Joerg AU - Wong Toi, Howard ID - 4475 SN - 0780370619 T2 - Proceedings of the 40th IEEE Conference on Decision and Control TI - Some lessons from the HYTECH experience VL - 3 ER - TY - GEN AB - Embedded software is software that interacts with physical processes. As em- bedded systems increasingly permeate our daily lives on all levels, from micros- copic devices to international networks, the cost-efficient development of reliable embedded software is one of the grand challenges in computer science today. The purpose of the workshop is to bring together researchers in all areas of computer science that are traditionally distinct but relevant to embedded software develop- ment, and to incubate a research community in this way. The workshop aims to cover all aspects of the design and implementation of embedded software, inclu- ding operating systems and middleware, programming languages and compilers, modeling and validation, software engineering and programming methodologies, scheduling and execution time analysis, networking and fault tolerance, as well as application areas, such as embedded control, real-time signal processing, and telecommunications. ED - Henzinger, Thomas A ID - 4449 SN - 9783540426738 TI - EMSOFT: Embedded Software VL - 2211 ER - TY - CHAP AB - The ability of species to migrate that has interested ecologists for many years. Now that so many species and ecosystems face major environmental change, the ability of species to adapt to these changes by dispersing, migrating, or moving between different patches of habitat can be crucial to ensuring their survivial. This book provides a timely and wide-ranging overview of the study of dispersal and incorporates much of the latest research. The causes, mechanisms, and consequences of dispersal at the individual, population, species and community levels are considered. The potential of new techniques and models for studying dispersal, drawn from molecular biology and demography, is also explored. Perspectives and insights are offered from the fields of evolution, conservation biology and genetics. Throughout the book, theoretical approaches are combined with empirical data, and care has been taken to include examples from as wide a range of species as possible. AU - Barton, Nicholas H ID - 4278 SN - 9780198506591 T2 - Dispersal TI - The evolutionary consequences of gene flow and local adaptation: Future approaches ER - TY - JOUR AB - Zebrafish embryos homozygous for the masterblind (mb1) mutation exhibit a striking phenotype in which the eyes and telencephalon are reduced or absent and diencephalic fates expand to the front of the brain. Here we show that mb1(-/-) embryos carry an amino-acid change at a conserved site in the Wnt pathway scaffolding protein, Axin1. The amino-acid substitution present in the mbl allele abolishes the binding of Axin to Gsk3 and affects Tcf-dependent transcription. Therefore, Gsk3 activity may be decreased in mbl(-/-) embryos and in support of this possibility, overexpression of either wild-type Axin1 or Gsk3 beta can restore eye and telencephalic fates to mb1(-/-) embryos. Our data reveal a crucial role for Axin1-dependent inhibition of the Wnt pathway in the early regional subdivision of the anterior neural plate into telencephalic, diencephalic, and eye-forming territories. AU - Heisenberg, Carl-Philipp J AU - Houart, Corinne AU - Take Uchi, Masaya AU - Rauch, Gerd AU - Young, Neville AU - Coutinho, Pedro AU - Masai, Ichiro AU - Caneparo, Luca AU - Concha, Miguel AU - Geisler, Robert AU - Dale, Trevor AU - Wilson, Stephen AU - Stemple, Derek ID - 4200 IS - 11 JF - Genes and Development SN - 0890-9369 TI - A mutation in the Gsk3-binding domain of zebrafish Masterblind/Axin1 leads to a fate transformation of telencephalon and eyes to diencephalon VL - 15 ER - TY - JOUR AB - Hybridization may influence evolution in a variety of ways. If hybrids are less fit, the geographical range of ecologically divergent populations may be limited, and prezygotic reproductive isolation may be reinforced. If some hybrid genotypes are fitter than one or both parents, at least in some environments, then hybridization could make a positive contribution. Single alleles that are at an advantage in the alternative environment and genetic background will introgress readily, although such introgression may be hard to detect. 'Hybrid speciation', in which fit combinations of alleles are established, is more problematic; its likelihood depends on how divergent populations meet, and on the structure of epistasis. These issues are illustrated using Fisher's model of stabilizing selection on multiple traits, under which reproductive isolation evolves as a side-effect of adaptation in allopatry. This confirms a priori arguments that while recombinant hybrids are less fit on average, some gene combinations may be fitter than the parents, even in the parental environment. Fisher's model does predict heterosis in diploid F1s, asymmetric incompatibility in reciprocal backcrosses, and (when dominance is included) Haldane's Rule. However, heterosis arises only when traits are additive, whereas the latter two patterns require dominance. Moreover, because adaptation is via substitutions of small effect, Fisher's model does not generate the strong effects of single chromosome regions often observed in species crosses. AU - Barton, Nicholas H ID - 4266 IS - 3 JF - Molecular Ecology SN - 962-1083 TI - The role of hybridization in evolution VL - 10 ER - TY - JOUR AB - The reasons that sex and recombination are so widespread remain elusive. One popular hypothesis is that sex and recombination promote adaptation to a changing environment. The strongest evidence that increased recombination may evolve because recombination promotes adaptation comes from artificially selected populations. Recombination rates have been found to increase as a correlated response to selection on traits unrelated to recombination in several artificial selection experiments and in a comparison of domesticated and nondomesticated mammals. There are, however, several alternative explanations for the increase in recombination in such populations, including two different evolutionary explanations. The first is that the form of selection is epistatic, generating linkage disequilibria among selected loci, which can indirectly favor modifier alleles that increase recombination. The second is that random genetic drift in selected populations tends to generate disequilibria such that beneficial alleles are often found in different individuals; modifier alleles that increase recombination can bring together such favorable alleles and thus may be found in individuals with greater fitness. In this paper, we compare the evolutionary forces acting on recombination in finite populations subject to strong selection, To our surprise, we found that drift accounted for the majority of selection for increased recombination observed in simulations of small to moderately large populations, suggesting that, unless selected populations are large, epistasis plays a secondary role in the evolution of recombination. AU - Otto, Sarah AU - Barton, Nicholas H ID - 4265 IS - 10 JF - Evolution; International Journal of Organic Evolution SN - 0014-3820 TI - Selection for recombination in small populations VL - 55 ER - TY - JOUR AB - Bacteriophage of the family Leviviridae have played an important role in molecular biology where representative species, such as Qβ and MS2, have been studied as model systems for replication, translation, and the role of secondary structure in gene regulation. Using nucleotide sequences from the coat and replicase genes we present the first statistical estimate of phylogeny for the family Leviviridae using maximum-likelihood and Bayesian estimation. Our analyses reveal that the coliphage species are a monophyletic group consisting of two clades representing the genera Levivirus and Allolevivirus. The Pseudomonas species PP7 diverged from its common ancestor with the coliphage prior to the ancient split between these genera and their subsequent diversification. Differences in genome size, gene composition, and gene expression are shown with a high probability to have changed along the lineage leading to the Allolevivirus through gene expansion. The change in genome size of the Allolevivirus ancestor may have catalyzed subsequent changes that led to their current genome organization and gene expression. AU - Bollback, Jonathan P AU - Huelsenbeck, John ID - 4229 IS - 2 JF - Journal of Molecular Evolution SN - 0022-2844 TI - Phylogeny, genome evolution, and host specificity of single-stranded RNA bacteriophage (Family Leviviridae) VL - 52 ER - TY - JOUR AB - The study of speciation has become one of the most active areas of evolutionary biology, and substantial progress has been made in documenting and understanding phenomena ranging from sympatric speciation and reinforcement to the evolutionary genetics of postzygotic isolation. This progress has been driven largely by empirical results, and most useful theoretical work has concentrated on making sense of empirical patterns. Given the complexity of speciation, mathematical theory is subordinate to verbal theory and generalizations about data. Nevertheless, mathematical theory can provide a useful classification of verbal theories; can help determine the biological plausibility of verbal theories; can determine whether alternative mechanisms of speciation are consistent with empirical patterns; and can occasionally provide predictions that go beyond empirical generalizations. We discuss recent examples of progress in each of these areas. AU - Turelli, Michael AU - Barton, Nicholas H AU - Coyne, Jerry ID - 4264 IS - 7 JF - Trends in Ecology and Evolution SN - 0169-5347 TI - Theory and speciation VL - 16 ER - TY - CHAP AB - The flow of genes from the dense and well-adapted centre of a species' distribution interferes with adaptation to marginal environments, and may sharply limit a species' range. Deterministic models of a linear habitat suggest that populations could in principle adapt to very steep environmental gradients, by increasing their genetic variability. However, random fluctuations in sparse populations reduce this variance, and may be crucial in limiting the species' range. AU - Barton, Nicholas H ID - 4267 SN - 9780521840002 T2 - Integrating ecology and evolution in a spatial context TI - Adaptation at the edge of a species' range ER - TY - JOUR AB - Shape deformation refers to the continuous change of one geometric object to another. We develop a software tool for planning, analyzing and visualizing deformations between two shapes in R-2. The deformation is generated automatically without any user intervention or specification of feature correspondences. A unique property of the tool is the explicit availability of a two-dimensional shape space, which can be used for designing the deformation either automatically by following constraints and objectives or manually by drawing deformation paths. AU - Cheng, Siu AU - Edelsbrunner, Herbert AU - Fu, Ping AU - Lam, Ka ID - 4002 IS - 2-3 JF - Computational Geometry: Theory and Applications SN - 0925-7721 TI - Design and analysis of planar shape deformation VL - 19 ER - TY - JOUR AB - The construction of shape spaces is studied from a mathematical and a computational viewpoint. A program is outlined reducing the problem to four tasks: the representation of geometry, the canonical deformation of geometry, the measuring of distance in shape space, and the selection of base shapes. The technical part of this paper focuses on the second task: the specification of a deformation mixing two or more shapes in continuously changing proportions. (C) 2001 Elsevier Science B.V All rights reserved. AU - Cheng, Ho AU - Edelsbrunner, Herbert AU - Fu, Ping ID - 4001 IS - 2-3 JF - Computational Geometry: Theory and Applications SN - 0925-7721 TI - Shape space from deformation VL - 19 ER - TY - CONF AB - This paper describes an algorithm for maintaining an approximating triangulation of a deforming surface in R-3. The triangulation adapts dynamically to changing shape, curvature, and topology of the surface. AU - Cheng, Ho AU - Dey, Tamal AU - Edelsbrunner, Herbert AU - Sullivan, John ID - 4005 SN - 9780898714906 T2 - Proceedings of the 12th annual ACM-SIAM symposium on Discrete algorithms TI - Dynamic skin triangulation ER - TY - JOUR AB - This paper describes an algorithm for maintaining an approximating triangulation of a deforming surface in R 3 . The surface is the envelope of an infinite family of spheres defined and controlled by a finite collection of weighted points. The triangulation adapts dynamically to changing shape, curvature, and topology of the surface. AU - Cheng, Ho AU - Dey, Tamal AU - Edelsbrunner, Herbert AU - Sullivan, John ID - 4007 IS - 4 JF - Discrete & Computational Geometry SN - 0179-5376 TI - Dynamic skin triangulation VL - 25 ER - TY - JOUR AB - The 180 models collected in this paper are produced by sampling and wrapping point sets on tubes. The surfaces are represented as triangulated 2-manifolds and available as st1-files from the author's web site at www.cs.duke.edu/similar toedels. Each tube is obtained by thickening a circle or a smooth torus knot, and for some we use the degrees of freedom in the thickening process to encode meaningful information, such as curvature or torsion. AU - Edelsbrunner, Herbert ID - 4006 IS - 5 JF - Journal of Universal Computer Science SN - 0948-695X TI - 180 wrapped tubes VL - 7 ER - TY - JOUR AB - Regulated adhesion of leukocytes to the extracellular matrix is essential for transmigration of blood vessels and subsequent migration into the stroma of inflamed tissues. Although beta(2)-integrins play an indisputable role in adhesion of polymorphonuclear granulocytes (PMN) to endothelium, we show here that beta(1)- and beta(3)-integrins but not beta(2)-integrin are essential for the adhesion to and migration on extracellular matrix molecules of the endothelial cell basement membrane and subjacent interstitial matrix. Mouse wild type and beta(2)-integrin null PMN and the progranulocytic cell line 32DC13 were employed in in vitro adhesion and migration assays using extracellular matrix molecules expressed at sites of extravasation in vivo, in particular the endothelial cell laminins 8 and 10. Wild type and beta(2)-integrin null PMN showed the same pattern of ECM binding, indicating that beta(2)-integrins do not mediate specific adhesion of PMN to the extracellular matrix molecules tested; binding was observed to the interstitial matrix molecules, fibronectin and vitronectin, via integrins alpha(5)beta(1) and alpha(v)beta(3), respectively; to laminin 10 via alpha(6)beta(1); but not to laminins 1, 2, and 8, collagen type I and IV, perlecan, or tenascin-C. PMN binding to laminins 1, 2, and 8 could not be induced despite surface expression of functionally active integrin alpha(6)beta(1), a major laminin receptor, demonstrating that expression of alpha(6)beta(1) alone is insufficient for ligand binding and suggesting the involvement of accessory factors. Nevertheless, laminins 1, 8, and 10 supported PMN migration, indicating that differential cellular signaling via laminins is independent of the extent of adhesion. The data demonstrate that adhesive and nonadhesive interactions with components of the endothelial cell basement membrane and subjacent interstitium play decisive roles in controlling PMN movement into sites of inflammation and illustrate that beta(2)-integrins are not essential for such interactions. AU - Sixt, Michael K AU - Hallmann, Rupert AU - Wendler, Olaf AU - Scharffetter Kochanek, Karin AU - Sorokin, Lydia ID - 3928 IS - 22 JF - Journal of Biological Chemistry SN - 0021-9258 TI - Cell adhesion and migration properties of β2-integrin negative polymorphonuclear granulocytes on defined extracellular matrix molecules. Relevance for leukocyte extravasation VL - 276 ER - TY - JOUR AB - TNF-alpha has been clearly identified as central mediator of T cell activation-induced acute hepatic injury in mice, e.g., Con A hepatitis. In this model, liver injury depends on both TNFRs, i.e., the 55-kDa TNFR1 as well as the 75-kDa TNFR2. We show in this report that the hepatic TNFRs are not transcriptionally regulated, but are regulated by receptor shedding. TNF directly mediates hepatocellular death by activation of TNFR1 but also induces the expression of inflammatory proteins, such as cytokines and adhesion molecules. Here we provide evidence that resistance of TNFR1(-/-) and TNFR2(-/-) mice against Con A hepatitis is not due to an impaired production of the central mediators TNF and IFN-gamma. Con A injection results in a massive induction of ICAM-1, VCAM-1, and E-selectin in the liver. Lack of either one of both TNFRs did not change adhesion molecule expression in the livers of Con A-treated mice, presumably reflecting the fact that other endothelial cell-activating cytokines up-regulated adhesion molecule expression. However, treatment of TNFR1(-/-) and TNFR2(-/-) mice with murine rTNF revealed a predominant role for TNFR1 for the induction of hepatic adhesion molecule expression. Pretreatment with blocking Abs against E- and P-selectin or of ICAM(-/-) mice with anti-VCAM-1 Abs failed to prevent Con A hepatitis, although accumulation of the critical cell population, i.e., CD4(+) T cells was significantly inhibited. Hence, up-regulation of adhesion molecules during acute hepatitis unlikely contributes to organ injury but rather represents a defense mechanism. AU - Wolf, Dominik AU - Hallmann, Rupert AU - Sass, Gabriele AU - Sixt, Michael K AU - Küsters, Sabine AU - Fregien, Bastian AU - Trautwein, Christian AU - Tiegs, Gisa ID - 3927 IS - 2 JF - Journal of Immunology SN - 0022-1767 TI - TNF-α-induced expression of adhesion molecules in the liver is under the control of TNFR1--relevance for concanavalin A-induced hepatitis VL - 166 ER - TY - JOUR AB - An active involvement of blood-brain barrier endothelial cell basement membranes in development of inflammatory lesions in the central nervous system (CNS) has not been considered to date. Here we investigated the molecular composition and possible function of the extracellular matrix encountered by extravasating T lymphocytes during experimental autoimmune encephalomyelitis (EAE). Endothelial basement membranes contained laminin 8 (alpha4beta1gamma1) and/or 10 (alpha5beta1gamma1) and their expression was influenced by proinflammatory cytokines or angiostatic agents. T cells emigrating into the CNS during EAE encountered two biochemically distinct basement membranes, the endothelial (containing laminins 8 and 10) and the parenchymal (containing laminins 1 and 2) basement membranes. However, inflammatory cuffs occurred exclusively around endothelial basement membranes containing laminin 8, whereas in the presence of laminin 10 no infiltration was detectable. In vitro assays using encephalitogenic T cell lines revealed adhesion to laminins 8 and 10, whereas binding to laminins 1 and 2 could not be induced. Downregulation of integrin alpha6 on cerebral endothelium at sites of T cell infiltration, plus a high turnover of laminin 8 at these sites, suggested two possible roles for laminin 8 in the endothelial basement membrane: one at the level of the endothelial cells resulting in reduced adhesion and, thereby, increased penetrability of the monolayer; and secondly at the level of the T cells providing direct signals to the transmigrating cells. AU - Sixt, Michael K AU - Engelhardt, Britta AU - Pausch, Friederike AU - Hallmann, Rupert AU - Wendler, Olaf AU - Sorokin, Lydia ID - 3930 IS - 5 JF - Journal of Cell Biology SN - 0021-9525 TI - Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis VL - 153 ER - TY - JOUR AB - The extent of genetic variation in fitness and its components and genetic variation's dependence on environmental conditions remain key issues in evolutionary biology. We present measurements of genetic variation in preadult viability in a laboratory-adapted population of Drosophila melanogaster, made at four different densities. By crossing flies heterozygous for a wild-type chromosome and one of two different balancers (TM1, TM2), we measure both heterozygous (TM1/+, TM2/+) and homozygous (+/+) viability relative to a standard genotype (TM1/TM2). Forty wild-type chromosomes were tested, of which 10 were chosen to be homozygous viable. The mean numbers produced varied significantly between chromosome lines, with an estimated between-line variance in loge numbers of 0.013. Relative viabilities also varied significantly across chromosome lines, with a variance in loge homozygous viability of 1.76 and of loge heterozygous viability of 0.165. The between-line variance for numbers emerging increased with density, from 0.009 at lowest density to 0.079 at highest. The genetic variance in relative viability increases with density, but not significantly. Overall, the effects of different chromosomes on relative viability were remarkably consistent across densities and across the two heterozygous genotypes (TM1, TM2). The 10 lines that carried homozygous viable wild-type chromosomes produced significantly more adults than the 30 lethal lines at low density and significantly fewer adults at the highest density. Similarly, there was a positive correlation between heterozygous viability and mean numbers at low density, but a negative correlation at high density. AU - Gardner, Michael AU - Fowler, Kevin AU - Patridge, Linda AU - Barton, Nicholas H ID - 3622 IS - 8 JF - Evolution SN - 0014-3820 TI - Genetic variation for preadult viability in Drosophila melanogaster VL - 55 ER - TY - GEN AU - Barton, Nicholas H ID - 3596 SN - 0168-9479 T2 - Trends in Genetics TI - Mendel and mathematics VL - 17 ER - TY - JOUR AB - Local versus distant coherence of hippocampal CA1 pyramidal cells was investigated in the behaving rat. Temporal cross-correlation of pyramidal cells revealed a significantly stronger relationship among local (<140 <mu>m) pyramidal neurons compared with distant (>300 mum) neurons during non-theta-associated immobility and sleep but not during theta-associated running and walking. In contrast, cross-correlation between local pyramidal cell-interneuron pairs was significantly stronger than between distant pairs during theta oscillations but were similar during non-theta-associated behaviors. We suggest that network state-dependent functional clustering of neuronal activity emerges because of the differential contribution of the main excitatory inputs, the perforant path, and Schaffer collaterals during theta and non-theta behaviors. AU - Hirase, Hajima AU - Leinekugel, Xavier AU - Csicsvari, Jozsef L AU - Czurkó, András AU - Buzsáki, György ID - 3546 IS - 10 JF - Journal of Neuroscience SN - 0270-6474 TI - Behavior-dependent states of the hippocampal network affect functional clustering of neurons VL - 21 ER - TY - JOUR AB - What determines the firing rate of cortical neurons in the absence of external sensory input or motor behavior, such as during sleep? Hero we report that, in a familiar environment, the discharge frequency of simultaneously recorded individual CA1 pyramidal neurons and the coactivation of cell pairs remain highly correlated across sleep-wake-steep sequences. However, both measures were affected when new sets of neurons were activated in a novel environment. Nevertheless, the grand mean firing rate of the whole pyramidal cell population remained constant across behavioral states and testing conditions. The findings suggest that long-term firing patterns of single cells can be modified by experience. We hypothesize that increased firing rates of recently used neurons are associated with a concomitant decrease in the discharge activity of the remaining population, leaving the mean excitability of the hippocampal network unaltered. AU - Hirase, Hajima AU - Leinekugel, Xavier AU - Czurkó, András AU - Csicsvari, Jozsef L AU - Buzsáki, György ID - 3540 IS - 16 JF - PNAS SN - 0027-8424 TI - Firing rates of hippocampal neurons are preserved during subsequent sleep episodes and modified by novel awake experience VL - 98 ER - TY - JOUR AB - Mutual synaptic interactions between GABAergic interneurons are thought to be of critical importance for the generation of network oscillations and for temporal encoding of information in the hippocampus. However, the functional properties of synaptic transmission between hippocampal interneurons are largely unknown. We have made paired recordings from basket cells (BCs) in the dentate gyrus of rat hippocampal slices, followed by correlated light and electron microscopical analysis. Unitary GABAAreceptor-mediated IPSCs at BC–BC synapses recorded at the soma showed a fast rise and decay, with a mean decay time constant of 2.5 ± 0.2 msec (32°C). Synaptic transmission at BC–BC synapses showed paired-pulse depression (PPD) (32 ± 5% for 10 msec interpulse intervals) and multiple-pulse depression during repetitive stimulation. Detailed passive cable model simulations based on somatodendritic morphology and localization of synaptic contacts further indicated that the conductance change at the postsynaptic site was even faster, decaying with a mean time constant of 1.8 ± 0.6 msec. Sequential triple recordings revealed that the decay time course of IPSCs at BC–BC synapses was approximately twofold faster than that at BC–granule cell synapses, whereas the extent of PPD was comparable. To examine the consequences of the fast postsynaptic conductance change for the generation of oscillatory activity, we developed a computational model of an interneuron network. The model showed robust oscillations at frequencies >60 Hz if the excitatory drive was sufficiently large. Thus the fast conductance change at interneuron–interneuron synapses may promote the generation of high-frequency oscillations observed in the dentate gyrusin vivo. AU - Bartos, Marlene AU - Vida, Imre AU - Frotscher, Michael AU - Geiger, Jörg AU - Jonas, Peter M ID - 3494 IS - 8 JF - Journal of Neuroscience SN - 0270-6474 TI - Rapid signaling at inhibitory synapses in a dentate gyrus interneuron network. VL - 21 ER - TY - JOUR AB - The mossy fiber-CA3 pyramidal neuron synapse is a main component of the hippocampal trisynaptic circuitry. Recent studies, however, suggested that inhibitory interneurons are the major targets of the mossy fiber system. To study the regulation of mossy fiber-interneuron excitation, we examined unitary and compound excitatory postsynaptic currents in dentate gyrus basket cells, evoked by paired recording between granule and basket cells or extracellular stimulation of mossy fiber collaterals. The application of an associative high-frequency stimulation paradigm induced posttetanic potentiation (PTP) followed by homosynaptic long-term potentiation (LTP). Analysis of numbers of failures, coefficient of variation, and paired-pulse modulation indicated that both PTP and LTP were expressed presynaptically. The Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA) did not affect PTP or LTP at a concentration of 10 mM but attenuated LTP at a concentration of 30 mM. Both forskolin, an adenylyl cyclase activator, and phorbolester diacetate, a protein kinase C stimulator, lead to a long-lasting increase in excitatory postsynaptic current amplitude. H-89, a protein kinase A inhibitor, and bisindolylmaleimide, a protein kinase C antagonist, reduced PTP, whereas only bisindolylmaleimide reduced LTP. These results may suggest a differential contribution of protein kinase A and C pathways to mossy fiber-interneuron plasticity. Interneuron PTP and LTP may provide mechanisms to maintain the balance between synaptic excitation of interneurons and that of principal neurons in the dentate gyrus-CA3 network. AU - Alle, Henrik AU - Jonas, Peter M AU - Geiger, Jörg ID - 3496 IS - 25 JF - PNAS SN - 0027-8424 TI - PTP and LTP at a hippocampal mossy fiber-interneuron synapse VL - 98 ER - TY - JOUR AB - High Ca2+ permeability and its control by voltage-dependent Mg2+ block are defining features of NMDA receptors. These features are lost if the principal NR1 subunit carries an asparagine (N) to arginine (R) substitution in a critical channel site at NR1 position 598. NR1(R) expression from a single allele in gene-targeted NR1+/R mice is lethal soon after birth, precluding analysis of altered synaptic functions later in life. We therefore employed the forebrain specific αCaMKII promoter to drive tTA-mediated tetracyclin sensitive transcription of transgenes for NR1(R) and for lacZ as reporter. Transgene expression was observed in cortex, striatum, hippocampus, amygdala and olfactory bulb and was mosaic in all these forebrain regions. It was highest in olfactory bulb granule cells, in most of which Ca2+ permeability and voltage-dependent Mg2+ block of NMDA receptors were reduced to different extents. This indicates significant impairment of NMDA receptor function by NR1(R) in presence of the wild-type NR1 complement. Indeed, even though NR1(R) mRNA constituted only 18% of the entire NR1 mRNA population in forebrain, the transgenic mice died during adolescence unless transgene expression was suppressed by doxycycline. Thus, glutamate receptor function can be altered in the mouse by regulated NR1(R) transgene expression. AU - Jerecic, Jasna AU - Schulze, Christian AU - Jonas, Peter M AU - Sprengel, Rolf AU - Seeburg, Peter AU - Bischofberger, Joseph ID - 3495 IS - 1-2 JF - Molecular Brain Research SN - 0169-328X TI - Impaired NMDA receptor function in mouse olfactory bulb neurons by tetracycline-sensitive NR1 (N598R) expression VL - 94 ER - TY - JOUR AB - A modular multichannel microdrive ('hyperdrive') is described. The microdrive uses printed circuit board technology and flexible fused silica capillaries. The modular design allows for the fabrication of 4-32 independently movable electrodes or `tetrodes'. The drives are re-usable and re-loading the drive with electrodes is simple. AU - Szabo, Imre AU - Czurkó, András AU - Csicsvari, Jozsef L AU - Hirase, Hajima AU - Leinekugel, Xavier AU - Buzsáki, György ID - 3517 IS - 1 JF - Journal of Neuroscience Methods SN - 0165-0270 TI - The application of printed circuit board technology for fabrication of multi-channel micro-drives VL - 105 ER - TY - JOUR AB - Although agonists and competitive antagonists presumably occupy overlapping binding sites on ligand-gated channels, these interactions cannot be identical because agonists cause channel opening whereas antagonists do not. One explanation is that only agonist binding performs enough work on the receptor to cause the conformational changes that lead to gating. This idea is supported by agonist binding rates at GABAA and nicotinic acetylcholine receptors that are slower than expected for a diffusion-limited process, suggesting that agonist binding involves an energy-requiring event. This hypothesis predicts that competitive antagonist binding should require less activation energy than agonist binding. To test this idea, we developed a novel deconvolution-based method to compare binding and unbinding kinetics of GABAA receptor agonists and antagonists in outside-out patches from rat hippocampal neurons. Agonist and antagonist unbinding rates were steeply correlated with affinity. Unlike the agonists, three of the four antagonists tested had binding rates that were fast, independent of affinity, and could be accounted for by diffusion- and dehydration-limited processes. In contrast, agonist binding involved additional energy-requiring steps, consistent with the idea that channel gating is initiated by agonist-triggered movements within the ligand binding site. Antagonist binding does not appear to produce such movements, and may in fact prevent them. AU - Jones, M.V AU - Jonas, Peter M AU - Sahara, Y. AU - Westbrook, G. ID - 3493 IS - 5 JF - Biophysical Journal SN - 0006-3495 TI - Microscopic kinetics and energetics distinguish GABAA receptor agonists from antagonists VL - 81 ER - TY - JOUR AB - The elimination voltammetry with linear scan (EVLS) was used to study adenine and cytosine reduction signals at the mercury electrode. In comparison with the linear scan voltammetry (which provides only one unresolved peak), two elimination functions provide good resolution of individual peaks and significant increase of sensitivity. The first elimination function eliminates the kinetic current (Ik) and conserves the diffusion current (Id). The second elimination function eliminates kinetic and charging currents (Ik and Ic) simultaneously and conserves the diffusion current (Id). Both functions give two well-resolved peaks of adenine and cytosine in a wide concentration range, while the linear sweep voltammetry gives badly resolved peaks due to hydrogen evolution. The best resolution of peaks is observed in acetate buffer at pH 3.8 and the detection limit for both substances is 500 nM. The concentration dependence of EVLS peak heights for one substance at the constant concentration of the other substance is linear. The peak potentials differ in these elimination functions. The difference in EVLS peak potentials gives the possibility to evaluate αna. Elimination voltammetry with linear scan contributes to the resolution of cathodic signals of purine and pyrimidine bases at very negative potentials near supporting electrolyte discharge. Copyright © 2001 Elsevier Science B.V. AU - Trnková, Libuše AU - Friml, Jirí AU - Dračka, Oldřich ID - 2985 IS - 2 JF - Bioelectrochemistry SN - 1567-5394 TI - Elimination voltammetry of adenine and cytosine mixtures VL - 54 ER - TY - CONF AB - Several new algorithms for visual correspondence based on graph cuts [7, 14, 17] have recently been developed. While these methods give very strong results in practice, they do not handle occlusions properly. Specifically, they treat the two input images asymmetrically, and they do not ensure that a pixel corresponds to at most one pixel in the other image. In this paper, we present a new method which properly addresses occlusions, while preserving the advantages of graph cut algorithms. We give experimental results for stereo as well as motion, which demonstrate that our method performs well both at detecting occlusions and computing disparities. AU - Kolmogorov, Vladimir AU - Zabih, Ramin ID - 3169 SN - 0769511430 T2 - Proceedings of the 8th IEEE International Conference on Computer Vision TI - Computing visual correspondence with occlusions using graph cuts VL - 2 ER - TY - JOUR AB - High molecular weight DNA was extracted from the primary Neotropical malaria vector, Anopheles darlingi from Capanema, Pará, Brazil, to create a small insert genomic library, and then a phagemid library. Enriched sublibraries were constructed from the phagemid library using a microsatellite oligo primed second strand synthesis protocol. The resulting 242 760 individual clones were screened. The mean clone size of the positive clones was 302 bp. Flanking primers were designed for each suitable microsatellite sequence. Eight polymorphic loci were optimized and characterized. The allele size ranges are based on 253 samples of A. darlingi from eastern Amazonian and central Brazil. AU - Conn, Jan AU - Bollback, Jonathan P AU - Onyabe, David AU - Robinson, Tessa AU - Wilkerson, Richard AU - Povoa, Marinete ID - 3439 IS - 4 JF - Molecular Ecology Notes SN - 1471-8278 TI - Isolation of polymorphic microsatellite markers from the malaria vector Anopheles darlingi VL - 1 ER - TY - JOUR AB - Several methods have been proposed to infer the states at the ancestral nodes on a phylogeny. These methods assume a specific tree and set of branch lengths when estimating the ancestral character state. Inferences of the ancestral states, then, are conditioned on the tree and branch lengths being true. We develop a hierarchical Bayes method for inferring the ancestral states on a tree. The method integrates over uncertainty in the tree, branch lengths, and substitution model parameters by using Markov chain Monte Carlo. We compare the hierarchical Bayes inferences of ancestral states with inferences of ancestral states made under the assumption that a specific tree is correct. We find that the methods are correlated, but that accommodating uncertainty in parameters of the phylogenetic model can make inferences of ancestral states even more uncertain than they would be in an empirical Bayes analysis. AU - Huelsenbeck, John AU - Bollback, Jonathan P ID - 3440 IS - 3 JF - Systematic Biology SN - 0039-7989 TI - Empirical and hierarchical Bayesian estimation of ancestral states VL - 50 ER - TY - JOUR AB - As a discipline, phylogenetics is becoming transformed by a flood of molecular data. These data allow broad questions to be asked about the history of life, but also present difficult statistical and computational problems. Bayesian inference of phylogeny brings a new perspective to a number of outstanding issues in evolutionary biology, including the analysis of large phylogenetic trees and complex evolutionary models and the detection of the footprint of natural selection in DNA sequences. AU - Huelsenbeck, John AU - Ronquist, Fredrik AU - Nielsen, Rasmus AU - Bollback, Jonathan P ID - 3438 IS - 5550 JF - Science SN - 0036-8075 TI - Bayesian inference of phylogeny and its impact on evolutionary biology VL - 294 ER - TY - CHAP AB - This chapter contains sections titled: Introduction - History - Developing an Intuition of Likelihood - Method of Maximum Likelihood - Bayesian Inference - Markov Chain Monte Carlo - Assessing Uncertainty of Phylogenies - Hypothesis Testing and Model Choice - Comparative Analysis - Conclusions - References AU - Huelsenbeck, John AU - Bollback, Jonathan P ED - Balding, David ED - Bishop, Martin ED - Cannings, Chriss ID - 3434 SN - 9781119429142 T2 - Handbook of Statistical Genetics TI - Application of the likelihood function in phylogenetic analysis ER - TY - JOUR AB - Polar auxin transport is crucial for the regulation of auxin action and required for some light-regulated responses during plant development. We have found that two mutants of Arabidopsis - doc1, which displays altered expression of light-regulated genes, and tir3, known for its reduced auxin transport - have similar defects and define mutations in a single gene that we have renamed BIG. BIG is very similar to the Drosophila gene Calossin/Pushover, a member of a gene family also present in Caenorhabditis elegans and human genomes. The protein encoded by BIG is extraordinary in size, 560 kD, and contains several putative Zn-finger domains. Expression-profiling experiments indicate that altered expression of multiple light-regulated genes in doc1 mutants can be suppressed by elevated levels of auxin caused by overexpression of an auxin biosynthetic gene, suggesting that normal auxin distribution is required to maintain low-level expression of these genes in the dark. Double mutants of tir3 with the auxin mutants pin1, pid, and axr1 display severe defects in auxin-dependent growth of the inflorescence. Chemical inhibitors of auxin transport change the intracellular localization of the auxin efflux carrier PIN1 in doc1/tir3 mutants, supporting the idea that BIG is required for normal auxin efflux. AU - Gil, Pedro AU - Dewey, Elizabeth AU - Friml, Jirí AU - Zhao, Yunde AU - Snowden, Kimberley AU - Putterill, Jo AU - Palme, Klaus AU - Estelle, Mark AU - Chory, Joanne ID - 2982 IS - 15 JF - Genes and Development SN - 0890-9369 TI - BIG: A calossin-like protein required for polar auxin transport in Arabidopsis VL - 15 ER - TY - JOUR AB - Auxins represent an important class of plant hormone that regulate plant development. Plants use specialized carrier proteins to transport the auxin indole-3-acetic acid (IAA) to target tissues. To date, efflux carrier-mediated polar auxin transport has been assumed to represent the sole mode of long distance IAA movement. Localization of the auxin permease AUX1 in the Arabidopsis root apex has revealed a novel phloem-based IAA transport pathway. AUX1, asymmetrically localized to the plasma membrane of root protophloem cells, is proposed to promote the acropetal, post-phloem movement of auxin to the root apex. MS analysis shows that IAA accumulation in aux1 mutant root apices is impaired, consistent with an AUX1 phloem unloading function. AUX1 localization to columella and lateral root cap tissues of the Arabidopsis root apex reveals that the auxin permease regulates a second IAA transport pathway. Expression studies using an auxin-regulated reporter suggest that AUX1 is necessary for root gravitropism by facilitating basipetal auxin transport to distal elongation zone tissues. AU - Swarup, Ranjan AU - Friml, Jirí AU - Marchant, Alan AU - Ljung, Karin AU - Sandberg, Göran AU - Palme, Klaus AU - Bennett, Malcolm ID - 2984 IS - 20 JF - Genes and Development SN - Genes and Development TI - Localization of the auxin permease AUX1 suggests two functionally distinct hormone transport pathways operate in the Arabidopsis root apex VL - 15 ER - TY - JOUR AB - Plants contain a novel unique subfamily of Rho GTPases, vital components of cellular signalling networks. Here we report a general role for some members of this family in polarized plant growth processes. We show that Arabidopsis AtRop4 and AtRop6 encode functional GTPases with similar intrinsic GTP hydrolysis rates. We localized AtRop proteins in root meristem cells to the cross-wall and cell plate membranes. Polar localization of AtRops in trichoblasts specifies the growth sites for emerging root hairs. These sites were visible before budding and elongation of the Arabidopsis root hair when AtRops accumulated at their tips. Expression of constitutively active AtRop4 and AtRop6 mutant proteins in root hairs of transgenic Arabidopsis plants abolished polarized growth and delocalized the tip-focused Ca2+ gradient. Polar localization of AtRops was inhibited by brefeldin A, but not by other drugs such as latrunculin B, cytochalasin D or caffeine. Our results demonstrate a general function of AtRop GTPases in tip growth and in polar diffuse growth. AU - Molendijk, Arthur AU - Bischoff, Friedrich AU - Rajendrakumar, Chadalavada AU - Friml, Jirí AU - Braun, Markus AU - Gilroy, Simon AU - Palme, Klaus ID - 2981 IS - 11 JF - EMBO Journal SN - 0261-4189 TI - Arabidopsis thaliana Rop GTPases are localized to tips of root hairs and control polar growth VL - 20 ER - TY - JOUR AB - Polar transport of the phytohormone auxin mediates various processes in plant growth and development, such as apical dominance, tropisms, vascular patterning and axis formation. This view is based largely on the effects of polar auxin transport inhibitors. These compounds disrupt auxin efflux from the cell but their mode of action is unknown. It is thought that polar auxin flux is caused by the asymmetric distribution of efflux carriers acting at the plasma membrane. The polar localization of efflux carrier candidate PIN1 supports this model. Here we show that the seemingly static localization of PIN1 results from rapid actin-dependent cycling between the plasma membrane and endosomal compartments. Auxin transport inhibitors block PIN1 cycling and inhibit trafficking of membrane proteins that are unrelated to auxin transport. Our data suggest that PIN1 cycling is of central importance for auxin transport and that auxin transport inhibitors affect efflux by generally interfering with membrane-trafficking processes. In support of our conclusion, the vesicle-trafficking inhibitor brefeldin A mimics physiological effects of auxin transport inhibitors. AU - Geldner, Niko AU - Friml, Jirí AU - Stierhof, York AU - Jürgens, Gerd AU - Palme, Klaus ID - 2983 IS - 6854 JF - Nature SN - 0028-0836 TI - Auxin transport inhibitors block PIN1 cycling and vesicle trafficking VL - 413 ER - TY - JOUR AB - We consider the time evolution of N bosonic particles interacting via a mean field Coulomb potential. Suppose the initial state is a product wavefunction. We show that at any finite time the correlation functions factorize in the limit N → ∞. Furthermore, the limiting one particle density matrix satisfies the nonlinear Hartree equation. The key ingredients are the uniqueness of the BBGKY hierarchy for the correlation functions and a new apriori estimate for the many-body Schrödinger equations. AU - Erdös, László AU - Yau, Horng ID - 2736 IS - 6 JF - Advances in Theoretical and Mathematical Physics SN - 1095-0761 TI - Derivation of the nonlinear Schrödinger equation from a many body Coulomb system VL - 5 ER - TY - JOUR AB - We establish the exact low-energy asymptotics of the integrated density of states (Lifschitz tail) in a homogeneous magnetic field and Poissonian impurities with a repulsive single-site potential of Gaussian decay. It has been known that the Gaussian potential tail discriminates between the so-called “classical” and “quantum” regimes, and precise asymptotics are known in these cases. For the borderline case, the coexistence of the classical and quantum regimes was conjectured. Here we settle this last remaining open case to complete the full picture of the magnetic Lifschitz tails. AU - Erdös, László ID - 2735 IS - 2 JF - Probability Theory and Related Fields SN - 0044-3719 TI - Lifschitz tail in a magnetic field: Coexistence of classical and quantum behavior in the borderline case VL - 121 ER - TY - JOUR AB - In this paper we describe an intrinsically geometric way of producing magnetic fields on S3 and R3 for which the corresponding Dirac operators have a non-trivial kernel. In many cases we are able to compute the dimension of the kernel. In particular we can give examples where the kernel has any given dimension. This generalizes the examples of Loss and Yau [1]. AU - Erdös, László AU - Solovej, Jan ID - 2734 IS - 10 JF - Reviews in Mathematical Physics SN - 0129-055X TI - The kernel of Dirac operators on S3 and R3 VL - 13 ER - TY - JOUR AB - Research using animal models of neuropathic pain has revealed sympathetic sprouting onto dorsal root ganglion cells. More recently, sensory fibre sprouting onto dorsal root ganglion cells has also been observed. Previous work in our laboratory demonstrated persistent sympathetic fibre sprouting in the skin of the rat lower lip following sensory denervation of this region. Therefore, we applied immunocytochemistry to determine the effects of sympathectomies on the terminal fields of sensory fibres. The superior cervical ganglia were removed bilaterally and the effects on the innervation of the skin of the rat lower lip were observed 1, 2, 3, 4, 6 and 8 weeks post-surgery. Substance P and dopamine-β-hydroxylase immunoreactivities were used to identify a subset of sensory and sympathetic fibres, respectively. We also assessed neurokinin-1 receptor immunoreactivity. Quantitative data was obtained with the aid of an image analysis system. In controls, the epidermis and upper dermis were innervated by substance P-immunoreactive fibres only and upper dermal blood vessels possessed the highest density of neurokinin-1 receptor immunoreactivity. Blood vessels in the lower dermis were innervated by both substance P- and dopamine-β-hydroxylase-immunoreactive fibres. Following sympathectomies, substance P-immunoreactive fibres in the epidermis and upper dermis were more intensely labelled only 1 and 2 weeks post-surgery when compared to sham controls. The length of substance P-immunoreactive fibres in this region was also increased only on the second week. Neurokinin-1 receptor immunoreactivity in the upper dermis was slightly decreased 1 and 2 weeks post-surgery. In the lower dermis, substance P-immunoreactive fibres associated with blood vessels were more intensely labelled only 1 and 2 weeks post-surgery, and at all post-surgical time points studied, blood vessels in this region were devoid of dopamine-β-hydroxylase-immunoreactive fibres. The length of substance P-immunoreactive fibres was increased from the first to the third week post-surgery in the lower dermis. These results indicate that sympathectomies lead to transient changes in substance P-immunoreactive fibre innervation and neurokinin-1 receptor expression in rat lower lip skin. The effects are most prominent in the lower dermis probably due to a greater local concentration of nerve growth factor in this region. The plasticity of the interactions between sensory and sympathetic fibres may prove important in the regulation of skin microcirculation and in the generation of painful sensations under normal conditions or following peripheral nerve injuries. AU - Ruocco, Isabella AU - Cuello, Augusto AU - Shigemoto, Ryuichi AU - Ribeiro Da Silva, Alfredo ID - 2611 IS - 1 JF - Neuroscience SN - 0306-4522 TI - Sympathectomies lead to transient substance P-immunoreactive sensory fibre plasticity in the rat skin VL - 108 ER - TY - JOUR AB - We examined immunoreactivities for γ-aminobutyric acidB-receptor (GABABR) subtypes, GABABR1 and GABABR2, in the mesencephalic trigeminal nucleus neurons (MTN neurons) of the rat. Immunoreactivity for GABABR1 was prominent in cell bodies of MTN, whereas that for GABABR2 was very weak, if existed. For electron microscopy, the immunogold-silver method for GABABR1 was combined with the immunoperoxidase method for glutamic acid decarboxylase (GAD: the synthetic enzyme of GABA). Immunogold-silver particles indicating GABABR1 immunoreactivity were distributed widely in the cytoplasm of the cell bodies postsynaptic to GAD-immunoreactive axon terminals, but were rarely associated with synaptic membrane specialization or extrasynaptic sites of plasma membrane. It has been indicated that GABABR1 may not be transported to plasma membrane when no GABABR2 exists. Thus, it was presumed that GABABR1 in the cell body of the rat MTN neurons might not be involved in the synaptic transmission. AU - Li, Jin AU - Shigemoto, Ryuichi AU - Kulik, Ákos AU - Chen, Peng AU - Nomura, Sakashi AU - Kaneko, Takeshi AU - Mizuno, Noboru ID - 2612 IS - 1-2 JF - Neuroscience Letters SN - 0304-3940 TI - Immunocytochemical localization of GABAB receptors in mesencephalic trigeminal nucleus neurons in the rat VL - 315 ER - TY - CHAP AU - Erdös, László ID - 2709 SN - 9781571460851 T2 - 13th International Congress of Mathematical Physics TI - Long time dynamics of an electron in a weakly coupled phonon field ER - TY - JOUR AB - To study the role of mGlu7 receptors (mGluR7), we used homologous recombination to generate mice lacking this metabotropic receptor subtype (mGluR7 -/-). After the serendipitous discovery of a sensory stimulus-evoked epileptic phenotype, we tested two convulsant drugs, pentylenetetrazole (PTZ) and bicuculline. In animals aged 12 weeks and older, subthreshold doses of these drugs induced seizures in mGluR7 -/-, but not in mGluR7 +/-, mice. PTZ-induced seizures were inhibited by three standard anticonvulsant drugs, but not by the group III selective mGluR agonist (R,S)-4-phosphonophenylglycine (PPG). Consistent with the lack of signs of epileptic activity in the absence of specific stimuli, mGluR7 -/- mice showed no major changes in synaptic properties in two slice preparations. However, slightly increased excitability was evident in hippocampal slices. In addition, there was slower recovery from frequency facilitation in cortical slices, suggesting a role for mGluR7 as a frequency-dependent regulator in presynaptic terminals. Our findings suggest that mGluR7 receptors have a unique role in regulating neuronal excitability and that these receptors may be a novel target for the development of anticonvulsant drugs. AU - Sansig, Gilles AU - Bushell, Trevor AU - Clarke, Vernon AU - Rozov, Andrei AU - Burnashev, Nail AU - Portet, Chantal AU - Gasparini, Fabrizio AU - Schmutz, Markus AU - Klebs, Klaus AU - Shigemoto, Ryuichi AU - Flor, Peter AU - Kühn, Rainer AU - Knoepfel, Thomas AU - Schroeder, Markus AU - Hampson, David AU - Collett, Valerie AU - Zhang, Congxiao AU - Duvoisin, Robert AU - Collingridge, Graham AU - Van Der Putten, Herman ID - 2610 IS - 22 JF - Journal of Neuroscience SN - 0270-6474 TI - Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7 VL - 21 ER - TY - JOUR AB - The metabotropic glutamate receptors (mGluRs) have distinct distribution patterns in the CNS but subtypes within group I or group III mGluRs share similar ultrastructural localization relative to neurotransmitter release sites: group I mGluRs are concentrated in an annulus surrounding the edge of the postsynaptic density, whereas group III mGluRs are concentrated in the presynaptic active zone. One of the group II subtypes, mGluR2, is expressed in both pre- and postsynaptic elements, having no close association with synapses. In order to determine if such a distribution is common to another group II subtype, mGluR3, an antibody was raised against a carboxy-terminus of mGluR3 and used for light and electron microscopic immunohistochemistry in the mouse CNS. The antibody reacted strongly with mGluR3, but it also reacted, though only weakly, with mGluR2. Therefore, to examine mGluR3-selective distribution, we used mGluR2-deficient mice as well as wild-type mice. Strong immunoreactivity for mGluR3 was found in the cerebral cortex, striatum, dentate gyrus of the hippocampus, olfactory tubercle, lateral septal nucleus, lateral and basolateral amygdaloid nuclei, and nucleus of the lateral olfactory tract. Pre-embedding immunoperoxidase and immunogold methods revealed mGluR3 labeling in both presynaptic and postsynaptic elements, and also in glial profiles. Double labeling revealed that the vast majority of mGluR3 in presynaptic elements is not closely associated with glutamate and GABA release sites in the striatum and thalamus, respectively. However, in the spines of the dentate granule cells, the highest receptor density was found in perisynaptic sites (20% of immunogold particles within 60 nm from the edge of postsynaptic membrane specialization) followed by a decreasing receptor density away from the synapses (to ∼5% of particles per 60 nm). Furthermore, 19% of immunogold particles were located in asymmetrical postsynaptic specialization, indicating an association of mGluR3 to glutamatergic synapses. The present results indicate that the localization of mGluR3 is rather similar to that of group I mGluRs in the postsynaptic elements, suggesting a unique functional role of mGluR3 in glutamatergic neurotransmission in the CNS. AU - Tamaru, Y AU - Nomura, Sakashi AU - Mizuno, Noboru AU - Shigemoto, Ryuichi ID - 2609 IS - 3 JF - Neuroscience SN - 0306-4522 TI - Distribution of metabotropic glutamate receptor mGluR3 in the mouse CNS: Differential location relative to pre- and postsynaptic sites VL - 106 ER - TY - JOUR AB - The regulation of neurotransmitter receptors during synapse formation has been studied extensively at the neuromuscular junction, but little is known about the development of excitatory neurotransmitter receptors during synaptogenesis in central synapses. In this study we show qualitatively and quantitatively that a receptor undergoes changes in localisation on the surface of rat Purkinje cells during development in association with its excitatory synapses. The presence of mGluR1α at parallel and climbing fibre synapses on developing Purkinje cells was studied using high-resolution immunoelectron microscopy. Immunoreactivity for mGluR1α was detected from embryonic day 18 in Purkinje cells, and showed dramatic changes in its localisation with age. At early postnatal ages (P0 and P3), mGluR1α was found both in somata and stem dendrites but was not usually associated with synaptic contacts. At P7, mGluR1α became concentrated in somatic spines associated with climbing fibres and in the growing dendritic arborisation even before innervation by parallel fibres. During the second and third postnatal week, when spines and parallel fibre synapses were generated, mGluR1α became progressively concentrated in the molecular layer, particularly in the synaptic specialisations. As a result, during the fourth postnatal week, the pattern and level of mGluR1α expression became similar to the adult and mGluR1α appeared in high density in perisynaptic sites. Our results indicate that mGluR1α is present in the developing Purkinje cells prior to their innervation by climbing and parallel fibres and demonstrate that this receptor undergoes a dynamic and specific regulation during postnatal development in association with the establishment of synaptic inputs to Purkinje cell. AU - López Bendito, Guillermina AU - Shigemoto, Ryuichi AU - Luján, Rafael AU - Juíz, José ID - 2608 IS - 2 JF - Neuroscience SN - 0306-4522 TI - Developmental changes in the localisation of the mGluR1α subtype of metabotropic glutamate receptors in Purkinje cells VL - 105 ER - TY - JOUR AB - Alternative splicing in the mGluR5 gene generates two different receptor isoforms, of which expression is developmentally regulated. However, little is known about the functional significance of mGluR5 splice variants. We have examined the functional coupling, subcellular targeting, and effect on neuronal differentiation of epitope-tagged mGluR5 isoforms by expression in neuroblastoma NG108-15 cells. We found that both mGluR5 splice variants give rise to comparable [Ca2+]i transients and have similar pharmacological profile. Tagged receptors were shown by immunofluorescence to be inserted in the plasma membrane. In undifferentiated cells the subcellular localization of the two mGluR5 isoforms was partially segregated, whereas in differentiated cells the labeling largely redistributed to the newly formed neurites. Interestingly, we demonstrate that mGluR5 splice variants dramatically influence the formation and maturation of neurites; mGluR5a hinders the acquisition of mature neuronal traits and mGluR5b fosters the elaboration and extension of neurites. These effects are partly inhibited by MPEP. AU - Mion, Silvia AU - Corti, Corrado AU - Neki, Akio AU - Shigemoto, Ryuichi AU - Corsi, Mauro AU - Fumagalli, Guido AU - Ferraguti, Francesco ID - 2607 IS - 6 JF - Molecular and Cellular Neuroscience SN - 1044-7431 TI - Bidirectional regulation of neurite elaboration by alternatively spliced metabotropic glutamate receptor 5 (mGluR5) isoforms VL - 17 ER - TY - JOUR AB - The granular layer of the cerebellar cortex consists of densely packed neuronal cells, classified into granule cells and large interneurons. In this study, we provide a comparative survey of large granular layer interneurons in the adult rat cerebellum based on both morphological and neurochemical criteria. To this end, double immunofluorescence histochemistry was performed by combining antibodies against the cytoplasmic antigen Rat-303, calretinin, the metabotropic glutamate receptor mGluR2 and somatostatin. Based on Rat-303/calretinin double immunohistochemistry, three distinct populations of large granular layer interneurons could be discerned: cells immunopositive for Rat-303, calretinin or both. Rat-303 or calretinin single-labeled cells represented Golgi cells and unipolar brush cells, respectively. Rat-303/calretinin double-labeled cells located just underneath the Purkinje cell layer represented Lugaro cells. Morphometrical analysis distinguished two populations of Rat-303-positive Golgi cells according to their location: vermis versus hemisphere. Immunostaining for the metabotropic glutamate receptor mGluR2 combined with Rat-303 or calretinin revealed that the majority of Golgi cells (about 90%) appeared to be mGluR2 positive. Lugaro cells were mGluR2 negative. In addition, a limited population of large polymorphous interneurons in the depth of the granular layer with morphological features resembling Golgi cells also displayed Rat-303/calretinin immunoreactivity and were mGluR2 negative. Double immunohistochemistry for Rat-303 and somatostatin revealed three populations of labeled cells in the depth of the granular layer. Besides double-labeled Golgi cells, Rat-303 or somatostatin single-labeled cells were present. Based on mGluR2/somatostatin and calretinin/somatostatin double immunostainings, Rat-303 single-labeled cells were found to correspond to Rat-303/calretinin-positive, mGluR2-negative Golgi-like cells, while the identity of somatostatin single-labeled cells remained unclear. The data presented in this article elaborate previous reports on the morphological and neurochemical differentiation of large interneurons in the rat cerebellar granular layer. In addition, they indicate that the current classification of these cells into Golgi cells, Lugaro cells and unipolar brush cells does not describe the observed neurochemical heterogeneity. AU - Geurts, Frederik AU - Timmermans, Jean AU - Shigemoto, Ryuichi AU - De Schutter, Erik ID - 2605 IS - 2 JF - Neuroscience SN - 0306-4522 TI - Morphological and neurochemical differentiation of large granular layer interneurons in the adult rat cerebellum VL - 104 ER - TY - JOUR AB - Cutaneous antidromic vasodilatation and plasma extravasation, two phenomena that occur in neurogenic inflammation, are partially blocked by substance P (SP) receptor antagonists and are known to be mediated in part by mast cell-released substances, such as histamine, serotonin, and nitric oxide. In an attempt to provide a morphological substrate for the above phenomena, we applied light and electron microscopic immunocytochemistry to investigate the pattern of SP innervation of blood vessels and its relationship to mast cells in the skin of the rat lower lip. Furthermore, we examined the distribution of SP (neurokinin-1) receptors and their relationship to SP-immunoreactive (IR) fibers. Our results confirmed that SP-IR fibers are found in cutaneous nerves and that terminal branches are observed around blood vessels and penetrating the epidermis. SP-IR fibers also innervated hair follicles and sebaceous glands. At the ultrastructural level, SP-IR varicosities were observed adjacent to arterioles, capillaries, venules, and mast cells. The varicosities possessed both dense core vesicles and agranular synaptic vesicles. We quantified the distance between SP-IR varicosities and blood vessel endothelial cells. SP-IR terminals were located within 0.23-5.99 μm from the endothelial cell layer in 82.7% of arterioles, in 90.2% of capillaries, and in 86.9% of venules. Although there was a trend for SP-IR fibers to be located closer to the endothelium of venules, this difference was not significant. Neurokinin-1 receptor (NK-1r) immunoreactivity was most abundant in the upper dermis and was associated with the wall of blood vessels. NK-1r were located in equal amounts on the walls of arterioles, capillaries, and venules that were innervated by SP-IR fibers. The present results favor the concept of a participation of SP in cutaneous neurogenic vasodilatation and plasma extravasation both by an action on blood vessels after binding to the NK-1r and by causing the release of substances from mast cells after diffusion through the connective tissue. AU - Ruocco, Isabella AU - Cuello, Augusto AU - Shigemoto, Ryuichi AU - Ribeiro Da Silva, Alfredo ID - 2604 IS - 4 JF - Journal of Comparative Neurology SN - 0021-9967 TI - Light and electron microscopic study of the distribution of substance P-immunoreactive fibers and neurokinin-1 receptors in the skin of the rat lower lip VL - 432 ER - TY - JOUR AB - Glutamate receptors have been linked to the regulation of several developmental events in the CNS. By using cortical slices of early postnatal mice, we show that in layer I cells, glutamate produces intracellular calcium ([Ca2+]i) elevations mediated by ionotropic and metabotropic glutamate receptors (mGluRs). The contribution of mGluRs to these responses was demonstrated by application of tACPD, an agonist to groups I and II mGluRs, which evoked [Ca2+]i increases that could be reversibly blocked by MCPG, an antagonist to groups I and II mGluRs. In the absence of extracellular Ca2+, repetitive applications of tACPD or quisqualate, an agonist to group I mGluRs, elicited decreasing [Ca2+]i responses that were restored by refilling a thapsigargin-sensitive Ca2+ store. The use of specific group I mGluR agonists CHPG and DHPG indicated that the functional mGluR in layer I was of the mGluR1 subtype. Subtype specific antibodies confirmed the presence of mGlur1α, but not mGluR5, in Cajal-Retzius (Reelin-immunoreactive) neurons. AU - Martínez, Galán AU - López Bendito, Guillermina AU - Luján, Rafael AU - Shigemoto, Ryuichi AU - Fairén, Alfonso AU - Valdeolmillos, Miguel ID - 2606 IS - 6 JF - European Journal of Neuroscience SN - 0953-816X TI - Cajal-Retzius cells in early postnatal mouse cortex selectively express functional metabotropic glutamate receptors VL - 13 ER - TY - JOUR AB - For an absolutely continuous probability measure μ. on ℝd and a nonnegative integer k, let S̃k(μ, 0) denote the probability that the convex hull of k + d + 1 random points which are i.i.d. according to μ contains the origin 0. For d and k given, we determine a tight upper bound on S̃k(μ, 0), and we characterize the measures in ℝd which attain this bound. As we will see, this result can be considered a continuous analogue of the Upper Bound Theorem for the maximal number of faces of convex polytopes with a given number of vertices. For our proof we introduce so-called h-functions, continuous counterparts of h-vectors of simplicial convex polytopes. AU - Wagner, Uli AU - Welzl, Emo ID - 2419 IS - 2 JF - Discrete & Computational Geometry SN - 0179-5376 TI - A continuous analogue of the Upper Bound Theorem VL - 26 ER - TY - JOUR AB - This paper concerns the asymptotic ground state properties of heavy atoms in strong, homogeneous magnetic fields. In the limit when the nuclear charge Z tends to ∞ with the magnetic field B satisfying B ≫ Z4/3 all the electrons are confined to the lowest Landau band. We consider here an energy functional, whose variable is a sequence of one-dimensional density matrices corresponding to different angular momentum functions in the lowest Landau band. We study this functional in detail and derive various interesting properties, which are compared with the density matrix (DM) theory introduced by Lieb, Solovej and Yngvason. In contrast to the DM theory the variable perpendicular to the field is replaced by the discrete angular momentum quantum numbers. Hence we call the new functional a discrete density matrix (DDM) functional. We relate this DDM theory to the lowest Landau band quantum mechanics and show that it reproduces correctly the ground state energy apart from errors due to the indirect part of the Coulomb interaction energy. AU - Hainzl, Christian AU - Seiringer, Robert ID - 2348 IS - 1 JF - Communications in Mathematical Physics SN - 0010-3616 TI - A discrete density matrix theory for atoms in strong magnetic fields VL - 217 ER - TY - JOUR AB - We consider the ground state properties of an inhomogeneous two-dimensional Bose gas with a repulsive, short range pair interaction and an external confining potential. In the limit when the particle number N is large but ρ̅a 2 is small, where ρ̅ is the average particle density and a the scattering length, the ground state energy and density are rigorously shown to be given to leading order by a Gross–Pitaevskii (GP) energy functional with a coupling constant g~1/|1n(ρ̅a 2)|. In contrast to the 3D case the coupling constant depends on N through the mean density. The GP energy per particle depends only on Ng. In 2D this parameter is typically so large that the gradient term in the GP energy functional is negligible and the simpler description by a Thomas–Fermi type functional is adequate. AU - Lieb, Élliott AU - Seiringer, Robert AU - Yngvason, Jakob ID - 2347 IS - 1 JF - Communications in Mathematical Physics SN - 0010-3616 TI - A rigorous derivation of the Gross-Pitaevskii energy functional for a two-dimensional Bose gas VL - 224 ER - TY - JOUR AB - We give upper bounds for the number of spin-1/2 particles that can be bound to a nucleus of charge Z in the presence of a magnetic field B, including the spin-field coupling. We use Lieb's strategy, which is known to yield Nc < 2Z + 1 for magnetic fields that go to zero at infinity, ignoring the spin-field interaction. For particles with fermionic statistics in a homogeneous magnetic field our upper bound has an additional term of the order of Z × min {(B/Z3)2/5, 1 + | 1n(B/Z3)|2}. AU - Seiringer, Robert ID - 2345 IS - 9 JF - Journal of Physics A: Mathematical and General SN - 0305-4470 TI - On the maximal ionization of atoms in strong magnetic fields VL - 34 ER - TY - JOUR AB - We study the ground state properties of an atom with nuclear charge Z and N bosonic "electrons" in the presence of a homogeneous magnetic field B. We investigate the mean field limit N→∞ with N / Z fixed, and identify three different asymptotic regions, according to B≪Z2,B∼Z2,andB≫Z2 . In Region 1 standard Hartree theory is applicable. Region 3 is described by a one-dimensional functional, which is identical to the so-called Hyper-Strong functional introduced by Lieb, Solovej and Yngvason for atoms with fermionic electrons in the region B≫Z3 ; i.e., for very strong magnetic fields the ground state properties of atoms are independent of statistics. For Region 2 we introduce a general magnetic Hartree functional, which is studied in detail. It is shown that in the special case of an atom it can be restricted to the subspace of zero angular momentum parallel to the magnetic field, which simplifies the theory considerably. The functional reproduces the energy and the one-particle reduced density matrix for the full N-particle ground state to leading order in N, and it implies the description of the other regions as limiting cases. AU - Baumgartner, Bernhard AU - Seiringer, Robert ID - 2341 IS - 1 JF - Annales Henri Poincare SN - 1424-0637 TI - Atoms with bosonic "electrons" in strong magnetic fields VL - 2 ER - TY - JOUR AB - By means of a generalization of the Fefferman - de la Llave decomposition we derive a general lower bound on the interaction energy of one-dimensional quantum systems. We apply this result to a specific class of lowest Landau band wave functions. AU - Hainzl, Christian AU - Seiringer, Robert ID - 2346 IS - 2 JF - Letters in Mathematical Physics SN - 0377-9017 TI - Bounds on one-dimensional exchange energies with application to lowest Landau band quantum mechanics VL - 55 ER - TY - CONF AB - Recent experimental breakthroughs in the treatment of dilute Bose gases have renewed interest in their quantum mechanical description, respectively in approximations to it. The ground state properties of dilute Bose gases confined in external potentials and interacting via repulsive short range forces are usually described by means of the Gross-Pitaevskii energy functional. In joint work with Elliott H. Lieb and Jakob Yngvason its status as an approximation for the quantum mechanical many-body ground state problem has recently been rigorously clarified. We present a summary of this work, for both the two-and three-dimensional case. AU - Seiringer, Robert ED - Demuth, Michael ED - Schultze, Bert ID - 2340 SN - 9783034894838 TI - Bosons in a trap: Asymptotic exactness of the Gross-Pitaevskii ground state energy formula VL - 126 ER - TY - JOUR AB - In this Note we present pairs of hyperkähler orbifolds which satisfy two different versions of mirror symmetry. On the one hand, we show that their Hodge numbers (or more precisely, stringy E-polynomials) are equal. On the other hand, we show that they satisfy the prescription of Strominger, Yau, and Zaslow (which in the present case goes back to Bershadsky, Johansen, Sadov and Vafa): that a Calabi-Yau and its mirror should fiber over the same real manifold, with special Lagrangian fibers which are tori dual to each other. Our examples arise as moduli spaces of local systems on a curve with structure group SL(n); the mirror is the corresponding space with structure group PGL(n). The special Lagrangian tori come from an algebraically completely integrable Hamiltonian system: the Hitchin system. AU - Hausel, Tamas AU - Thaddeus, Michael ID - 1452 IS - 4 JF - Comptes Rendus de l'Academie des Sciences - Series I: Mathematics SN - 0764-4442 TI - Examples of mirror partners arising from integrable systems VL - 333 ER - TY - JOUR AB - BACKGROUND: Detection of changes in a protein's evolutionary rate may reveal cases of change in that protein's function. We developed and implemented a simple relative rates test in an attempt to assess the rate constancy of protein evolution and to detect cases of functional diversification between orthologous proteins. The test was performed on clusters of orthologous protein sequences from complete bacterial genomes (Chlamydia trachomatis, C. muridarum and Chlamydophila pneumoniae), complete archaeal genomes (Pyrococcus horikoshii, P. abyssi and P. furiosus) and partially sequenced mammalian genomes (human, mouse and rat). RESULTS: Amino-acid sequence evolution rates are significantly correlated on different branches of phylogenetic trees representing the great majority of analyzed orthologous protein sets from all three domains of life. However, approximately 1% of the proteins from each group of species deviates from this pattern and instead shows variation that is consistent with an acceleration of the rate of amino-acid substitution, which may be due to functional diversification. Most of the putative functionally diversified proteins from all three species groups are predicted to function at the periphery of the cells and mediate their interaction with the environment. CONCLUSIONS: Relative rates of protein evolution are remarkably constant for the three species groups analyzed here. Deviations from this rate constancy are probably due to changes in selective constraints associated with diversification between orthologs. Functional diversification between orthologs is thought to be a relatively rare event. However, the resolution afforded by the test designed specifically for genomic-scale datasets allowed us to identify numerous cases of possible functional diversification between orthologous proteins. AU - Jordan, Ingo AU - Kondrashov, Fyodor AU - Rogozin, Igor AU - Tatusov, Roman AU - Wolf, Yuri AU - Koonin, Eugene ID - 888 IS - 12 JF - Genome Biology SN - 1465-6906 TI - Constant relative rate of protein evolution and detection of functional diversification among bacterial, archaeal and eukaryotic proteins VL - 2 ER - TY - JOUR AB - In this Letter we exhibit a one-parameter family of new Taub-NUT instantons parameterized by a half-line. The endpoint of the half-line will be the reducible Yang-Mills instanton corresponding to the Eguchi-Hanson-Gibbons L2 harmonic 2-form, while at an inner point we recover the Pope-Yuille instanton constructed as a projection of the Levi-Civitá connection onto the positive su(2)+ ⊂ so(4) subalgebra. Our method imitates the Jackiw-Nohl-Rebbi construction originally designed for flat R4. That is we find a one-parameter family of harmonic functions on the Taub-NUT space with a point singularity, rescale the metric and project the obtained Levi-Civitá connection onto the other negative su(2)- ⊂ so(4) part. Our solutions will possess the full U(2) symmetry, and thus provide more solutions to the recently proposed U(2) symmetric ansatz of Kim and Yoon. AU - Etesi, Gábor AU - Hausel, Tamas ID - 1453 IS - 1-2 JF - Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics SN - 0370-2693 TI - Geometric construction of new Yang-Mills instantons over Taub-NUT space VL - 514 ER - TY - JOUR AB - We address the problem of finding Abelian instantons of finite energy on the Euclidean Schwarzschild manifold. This amounts to construct self-dual L2 harmonic 2-forms on the space. Gibbons found a non-topological L2 harmonic form in the Taub-NUT metric, leading to Abelian instantons with continuous energy. We imitate his construction in the case of the Euclidean Schwarzschild manifold and find a non-topological self-dual L2 harmonic 2-form on it. We show how this gives rise to Abelian instantons and identify them with SU(2)-instantons of Pontryagin number 2n2 found by Charap and Duff in 1977. Using results of Dodziuk and Hitchin we also calculate the full L2 harmonic space for the Euclidean Schwarzschild manifold. AU - Etesi, Gábor AU - Hausel, Tamas ID - 1454 IS - 1-2 JF - Journal of Geometry and Physics SN - 0393-0440 TI - Geometric interpretation of Schwarzschild instantons VL - 37 ER - TY - JOUR AB - Motivation: The context of the start codon (typically, AUG) and the features of the 5′ Untranslated Regions (5′ UTRs) are important for understanding translation regulation in eukaryotic mRNAs and for accurate prediction of the coding region in genomic and cDNA sequences. The presence of AUG triplets in 5′ UTRs (upstream AUGs) might effect the initiation rate and, in the context of gene prediction, could reduce the accuracy of the identification of the authentic start. To reveal potential connections between the presence of upstream AUGs and other features of 5′ UTRs, such as their length and the start codon context, we undertook a systematic analysis of the available eukaryotic 5′ UTR sequences. Results: We show that a large fraction of 5′ UTRs in the available cDNA sequences, 15-53% depending on the organism, contain upstream ATGs. A negative correlation was observed between the information content of the translation start signal and the length of the 5′ UTR. Similarly, a negative correlation exists between the 'strength' of the start context and the number of upstream ATGs. Typically, cDNAs containing long 5′ UTRs with multiple upstream ATGs have a 'weak' start context, and in contrast, cDNAs containing short 5′ UTRs without ATGs have 'strong' starts. These counter-intuitive results may be interpreted in terms of upstream AUGs having an important role in the regulation of translation efficiency by ensuring low basal translation level via double negative control and creating the potential for additional regulatory mechanisms. One of such mechanisms, supported by experimental studies of some mRNAs, includes removal of the AUG-containing portion of the 5′ UTR by alternative splicing. AU - Rogozin, Igor AU - Kochetov, Alex AU - Kondrashov, Fyodor AU - Koonin, Eugene AU - Milanesi, Luciano ID - 855 IS - 10 JF - Bioinformatics SN - 1367-4803 TI - Presence of ATG triplets in 5′ untranslated regions of eukaryotic cDNAs correlates with a 'weak'context of the start codon VL - 17 ER - TY - JOUR AB - Sex is thought to facilitate accumulation of initially rare beneficial mutations by allowing simultaneous allele replacements at many loci. However, this advantage of sex depends on a restrictive assumption that the fitness of a genotype is determined by fitness potential, a single intermediate variable to which all loci contribute additively, so that new alleles can accumulate in any order. Individual-based simulations of sexual and asexual populations reveal that under generic selection, sex often retards adaptive evolution. When new alleles are beneficial only if they accumulate in a prescribed order, a sexual population may evolve two or more times slower than an asexual population because only asexual reproduction allows some overlap of successive allele replacements. Many other fitness surfaces lead to an even greater disadvantage of sex. Thus, either sex exists in spite of its impact on the rate of adaptive allele replacements, or natural fitness surfaces have rather specific properties, at least at the scale of intrapopulation genetic variability. AU - Kondrashov, Fyodor AU - Kondrashov, Alexey ID - 874 IS - 21 JF - PNAS SN - 0027-8424 TI - Multidimensional epistasis and the disadvantage of sex VL - 98 ER - TY - JOUR AB - Genes with new functions often evolve by gene duplication. Alternative splicing is another means of evolutionary innovation in eukaryotes, which allows a single gene to encode functionally diverse proteins. We investigate a connection between these two evolutionary phenomena. For ∼10% of the described cases of substitution alternative splicing, such that either one or another amino acid sequence is included into the protein, evidence of origin by tandem exon duplication was found. This is a conservative estimate because alternative exons are typically short and, on many occasions, duplicates may have diverged beyond recognition. Dating exon duplications through a combination of the available experimental data on alternative splicing in orthologous genes from different species and computational analysis indicates that most of the duplications antedate at least the radiation of mammalian orders or even the radiation of vertebrate classes. At present, tandem exon duplication is the only mechanism of evolution of substitution alternative splicing that can be specifically demonstrated. Along with gene duplication, this could be a major route for generating functional diversity during evolution of multicellular eukaryotes. AU - Kondrashov, Fyodor AU - Koonin, Eugene ID - 867 IS - 23 JF - Human Molecular Genetics SN - 0964-6906 TI - Origin of alternative splicing by tandem exon duplication VL - 10 ER - TY - JOUR AB - The study and comparison of mutation(al) spectra is an important problem in molecular biology, because these spectra often reflect on important features of mutations and their fixation. Such features include the interaction of DNA with various mutagens, the function of repair/replication enzymes, and properties of target proteins. It is known that mutability varies significantly along nucleotide sequences, such that mutations often concentrate at certain positions, called "hotspots," in a sequence. In this paper, we discuss in detail two approaches for mutation spectra analysis: the comparison of mutation spectra with a HG-PUBL program, (FTP: sunsite.unc.edu/pub/academic/ biology/dna-mutations/hyperg) and hotspot prediction with the CLUSTERM program (www.itba.mi.cnr.it/webmutation; ftp.bionet.nsc.ru/pub/biology/dbms/clusterm.zip). Several other approaches for mutational spectra analysis, such as the analysis of a target protein structure, hotspot context revealing, multiple spectra comparisons, as well as a number of mutation databases are briefly described. Mutation spectra in the lacI gene of E. coli and the human p53 gene are used for illustration of various difficulties of such analysis. AU - Rogozin, Igor AU - Kondrashov, Fyodor AU - Glazko, Galina ID - 851 IS - 2 JF - Human Mutation SN - 1059-7794 TI - Use of mutation spectra analysis software VL - 17 ER - TY - JOUR AU - Wolf, Yuri AU - Kondrashov, Fyodor AU - Koonin, Eugene ID - 841 IS - 9 JF - Trends in Genetics SN - 0168-9479 TI - Footprints of primordial introns on the eukaryotic genome: still no clear traces VL - 17 ER - TY - JOUR AB - Hyperlink analysis algorithms significantly improve the relevance of the search results on the Web, so much so that all major Web search engines claim to use some type of hyperlink analysis. However, the search engines do not disclose details about the type of hyperlink analysis they perform, mostly to avoid manipulation of search results by Web-positioning companies. The article discusses how hyperlink analysis can be applied to ranking algorithms, and surveys other ways Web search engines can use this analysis. AU - Henzinger, Monika H ID - 11755 IS - 1 JF - IEEE Internet Computing SN - 1089-7801 TI - Hyperlink analysis for the Web VL - 5 ER -