@article{867, abstract = {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.}, author = {Kondrashov, Fyodor and Koonin, Eugene}, issn = {0964-6906}, journal = {Human Molecular Genetics}, number = {23}, pages = {2661 -- 2669}, publisher = {Oxford University Press}, title = {{Origin of alternative splicing by tandem exon duplication}}, doi = {10.1093/hmg/10.23.2661}, volume = {10}, year = {2001}, } @article{874, abstract = {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.}, author = {Kondrashov, Fyodor and Kondrashov, Alexey}, issn = {0027-8424}, journal = {PNAS}, number = {21}, pages = {12089 -- 12092}, publisher = {National Academy of Sciences}, title = {{Multidimensional epistasis and the disadvantage of sex}}, doi = {10.1073/pnas.211214298}, volume = {98}, year = {2001}, } @article{888, abstract = {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.}, author = {Jordan, Ingo and Kondrashov, Fyodor and Rogozin, Igor and Tatusov, Roman and Wolf, Yuri and Koonin, Eugene}, issn = {1465-6906}, journal = {Genome Biology}, number = {12}, publisher = {BioMed Central}, title = {{Constant relative rate of protein evolution and detection of functional diversification among bacterial, archaeal and eukaryotic proteins }}, doi = {10.1186/gb-2001-2-12-research0053}, volume = {2}, year = {2001}, } @article{9444, abstract = {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.}, author = {Lindroth, A. M. and Cao, Xiaofeng and Jackson, James P. and Zilberman, Daniel and McCallum, Claire M. and Henikoff, Steven and Jacobsen, Steven E.}, issn = {1095-9203}, journal = {Science}, keywords = {Multidisciplinary}, number = {5524}, pages = {2077--2080}, publisher = {American Association for the Advancement of Science}, title = {{Requirement of CHROMOMETHYLASE3 for maintenance of CpXpG methylation}}, doi = {10.1126/science.1059745}, volume = {292}, year = {2001}, } @article{4599, abstract = {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.}, author = {Alur, Rajeev and Brayton, Robert and Henzinger, Thomas A and Qadeer, Shaz and Rajamani, Sriram}, issn = {0925-9856}, journal = {Formal Methods in System Design}, number = {2}, pages = {97 -- 116}, publisher = {Springer}, title = {{Partial-order reduction in symbolic state-space exploration}}, doi = {10.1023/A:1008767206905}, volume = {18}, year = {2001}, } @inproceedings{4600, abstract = {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.}, author = {Alur, Rajeev and De Alfaro, Luca and Grosu, Radu and Henzinger, Thomas A and Kang, Myong and Kirsch, Christoph and Majumdar, Ritankar and Mang, Freddy and Wang, Bow}, booktitle = {Proceedings of the 23rd International Conference on Software Engineering}, isbn = {0769510507}, pages = {835 -- 836}, publisher = {IEEE}, title = {{jMocha: A model-checking tool that exploits design structure}}, doi = {10.1109/ICSE.2001.919196}, year = {2001}, } @inproceedings{4622, abstract = {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.}, author = {De Alfaro, Luca and Henzinger, Thomas A}, booktitle = {Proceedings of the 8th European software engineering conference}, isbn = {9781581133905}, location = {Vienna, Austria}, pages = {109 -- 120}, publisher = {ACM}, title = {{Interface automata}}, doi = {10.1145/503209.503226}, year = {2001}, } @inproceedings{4623, abstract = {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.}, author = {De Alfaro, Luca and Henzinger, Thomas A}, booktitle = {Proceedings of the 1st International Workshop on Embedded Software}, isbn = {9783540426738}, location = {Tahoe City, CA, USA}, pages = {148 -- 165}, publisher = {ACM}, title = {{Interface theories for component-based design}}, doi = {10.1007/3-540-45449-7_11}, volume = {2211}, year = {2001}, } @inproceedings{4632, abstract = {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.}, author = {De Alfaro, Luca and Henzinger, Thomas A and Jhala, Ranjit}, booktitle = {Proceedings of the 12th International Conference on on Concurrency Theory}, isbn = {9783540424970}, location = {Aalborg, Denmark}, pages = {351 -- 365}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Compositional methods for probabilistic systems}}, doi = {10.1007/3-540-44685-0_24}, volume = {2154}, year = {2001}, } @inproceedings{4633, abstract = {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.}, author = {De Alfaro, Luca and Henzinger, Thomas A and Majumdar, Ritankar}, booktitle = {Proceedings of the 12th International Conference on on Concurrency Theory}, isbn = {9783540424970}, location = {Aalborg, Denmark}, pages = {536 -- 550}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Symbolic algorithms for infinite-state games}}, doi = {10.1007/3-540-44685-0_36}, volume = {2154}, year = {2001}, } @inproceedings{4634, abstract = {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.}, author = {De Alfaro, Luca and Henzinger, Thomas A and Mang, Freddy}, booktitle = {Proceedings of the 12th International Conference on on Concurrency Theory}, isbn = {9783540424970}, location = {Aalborg, Denmark}, pages = {566 -- 581}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{The control of synchronous systems, Part II}}, doi = {10.1007/3-540-44685-0_38}, volume = {2154}, year = {2001}, } @inproceedings{4635, abstract = {We show how model checking techniques can be applied to the analysis of connectivity and cost-of-traversal properties of Web sites.}, author = {De Alfaro, Luca and Henzinger, Thomas A and Mang, Freddy}, booktitle = {Proceedings of the 10th international conference on World Wide Web}, isbn = {9781581133486}, location = {Hong Kong, Hong Kong}, pages = {86 -- 87}, publisher = {ACM}, title = {{MCWEB: A model-checking tool for web-site debugging}}, year = {2001}, } @inproceedings{4636, abstract = {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.}, author = {De Alfaro, Luca and Henzinger, Thomas A and Majumdar, Ritankar}, booktitle = {Proceedings of the 16th Annual IEEE Symposium on Logic in Computer Science}, isbn = {076951281X}, location = {Boston, MA, USA}, pages = {279 -- 290}, publisher = {IEEE}, title = {{From verification to control: dynamic programs for omega-regular objectives}}, doi = {10.1109/LICS.2001.932504}, year = {2001}, } @inbook{3434, abstract = {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}, author = {Huelsenbeck, John and Bollback, Jonathan P}, booktitle = {Handbook of Statistical Genetics}, editor = {Balding, David and Bishop, Martin and Cannings, Chriss}, isbn = {9781119429142 }, pages = {415 -- 439}, publisher = {Wiley-Blackwell}, title = {{Application of the likelihood function in phylogenetic analysis}}, doi = {10.1002/9780470061619.ch15}, year = {2001}, } @article{3438, abstract = {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.}, author = {Huelsenbeck, John and Ronquist, Fredrik and Nielsen, Rasmus and Bollback, Jonathan P}, issn = {0036-8075}, journal = {Science}, number = {5550}, pages = {2310 -- 2314}, publisher = {American Association for the Advancement of Science}, title = {{Bayesian inference of phylogeny and its impact on evolutionary biology}}, doi = {10.1126/science.1065889}, volume = {294}, year = {2001}, } @article{3439, abstract = {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.}, author = {Conn, Jan and Bollback, Jonathan P and Onyabe, David and Robinson, Tessa and Wilkerson, Richard and Povoa, Marinete}, issn = {1471-8278}, journal = {Molecular Ecology Notes}, number = {4}, pages = {223 -- 225}, publisher = {Wiley-Blackwell}, title = {{Isolation of polymorphic microsatellite markers from the malaria vector Anopheles darlingi}}, doi = { 10.1046/j.1471-8278.2001.00078.x}, volume = {1}, year = {2001}, } @article{3440, abstract = {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. }, author = {Huelsenbeck, John and Bollback, Jonathan P}, issn = {0039-7989}, journal = {Systematic Biology}, number = {3}, pages = {351 -- 366}, publisher = {Oxford University Press}, title = {{Empirical and hierarchical Bayesian estimation of ancestral states}}, doi = {10.1080/10635150119871}, volume = {50}, year = {2001}, } @inproceedings{3447, author = {Krishnendu Chatterjee and Dasgupta, Pallab and Chakrabarti, Partha P}, publisher = {Elsevier}, title = {{Weighted quantified computation tree logic}}, year = {2001}, } @article{3493, abstract = {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.}, author = {Jones, M.V and Jonas, Peter M and Sahara, Y. and Westbrook, G.}, issn = {0006-3495}, journal = {Biophysical Journal}, number = {5}, pages = {2660 -- 2670}, publisher = {Biophysical Society}, title = {{Microscopic kinetics and energetics distinguish GABAA receptor agonists from antagonists}}, doi = {10.1016/S0006-3495(01)75909-7 }, volume = {81}, year = {2001}, } @article{3494, abstract = {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. }, author = {Bartos, Marlene and Vida, Imre and Frotscher, Michael and Geiger, Jörg and Jonas, Peter M}, issn = {0270-6474}, journal = {Journal of Neuroscience}, number = {8}, pages = {2687 -- 2698}, publisher = {Society for Neuroscience}, title = {{Rapid signaling at inhibitory synapses in a dentate gyrus interneuron network.}}, doi = {10.1523/JNEUROSCI.21-08-02687.2001}, volume = {21}, year = {2001}, }