TY - JOUR AB - We present a method for prediction of functional sites in a set of aligned protein sequences. The method selects sites which are both well conserved and clustered together in space, as inferred from the 3D structures of proteins included in the alignment. We tested the method using 86 alignments from the NCBI CDD database, where the sites of experimentally determined ligand and/or macromolecular interactions are annotated. In agreement with earlier investigations, we found that functional site predictions are most successful when overall background sequence conservation is low, such that sites under evolutionary constraint become apparent. In addition, we found that averaging of conservation values across spatially clustered sites improves predictions under certain conditions: that is, when overall conservation is relatively high and when the site in question involves a large macromolecular binding interface. Under these conditions it is better to look for clusters of conserved sites than to look for particular conserved sites. AU - Panchenko, Anna R AU - Fyodor Kondrashov AU - Bryant, Stephen H ID - 864 IS - 4 JF - Protein Science TI - Prediction of functional sites by analysis of sequence and structure conservation VL - 13 ER - TY - JOUR AB - Only a fraction of eukaryotic genes affect the phenotype drastically. We compared 18 parameters in 1273 human morbid genes, known to cause diseases, and in the remaining 16 580 unambiguous human genes. Morbid genes evolve more slowly, have wider phylogenetic distributions, are more similar to essential genes of Drosophila melanogaster, code for longer proteins containing more alanine and glycine and less histidine, lysine and methionine, possess larger numbers of longer introns with more accurate splicing signals and have higher and broader expressions. These differences make it possible to classify as non-morbid 34% of human genes with unknown morbidity, when only 5% of known morbid genes are incorrectly classified as non-morbid. This classification can help to identify disease-causing genes among multiple candidates. AU - Fyodor Kondrashov AU - Ogurtsov, Aleksey Yu AU - Kondrashov, Alexey S ID - 870 IS - 5 JF - Nucleic Acids Research TI - Bioinformatical assay of human gene morbidity VL - 32 ER - TY - JOUR AB - The dominance of wild-type alleles and the concomitant recessivity of deleterious mutant alleles might have evolved by natural selection or could be a by-product of the molecular and physiological mechanisms of gene action. We compared the properties of human haplosufficient genes, whose wild-type alleles are dominant over loss-of-function alleles, with haploinsufficient (recessive wild-type) genes, which produce an abnormal phenotype when heterozygous for a loss-of-function allele. The fraction of haplosufficient genes is the highest among the genes that encode enzymes, which is best compatible with the physiological theory. Haploinsufficient genes, on average, have more paralogs than haplosufficient genes, supporting the idea that gene dosage could be important for the initial fixation of duplications. Thus, haplo(in)sufficiency of a gene and its propensity for duplication might have a common evolutionary basis. AU - Fyodor Kondrashov AU - Koonin, Eugene V ID - 875 IS - 7 JF - Trends in Genetics TI - A common framework for understanding the origin of genetic dominance and evolutionary fates of gene duplications VL - 20 ER - TY - JOUR AB - The function of protein and RNA molecules depends on complex epistatic interactions between sites. Therefore, the deleterious effect of a mutation can be suppressed by a compensatory second-site substitution. In relating a list of 86 pathogenic mutations in human IRNAs encoded by mitochondrial genes to the sequences of their mammalian orthologs, we noted that 52 pathogenic mutations were present in normal tRNAs of one or several nonhuman mammals. We found at least five mechanisms of compensation for 32 pathogenic mutations that destroyed a Watson-Crick pair in one of the four tRNA stems: restoration of the affected Watson-Crick interaction (25 cases), strengthening of another pair (4 cases), creation of a new pair (8 cases), changes of multiple interactions in the affected stem (11 cases) and changes involving the interaction between the loop and stem structures (3 cases). A pathogenic mutation and its compensating substitution are fixed in a lineage in rapid succession, and often a compensatory interaction evolves convergently in different clades. At least 10%, and perhaps as many as 50%, of all nucleotide substitutions in evolving mammalian (RNAs participate in such interactions, indicating that the evolution of tRNAs proceeds along highly epistatic fitness ridges. AU - Kern, Andrew D AU - Fyodor Kondrashov ID - 889 IS - 11 JF - Nature Genetics TI - Mechanisms and convergence of compensatory evolution in mammalian mitochondrial tRNAs VL - 36 ER - TY - JOUR AB - In a number of organisms, transgenes containing transcribed inverted repeats (IRs) that produce hairpin RNA can trigger RNA-mediated silencing, which is associated with 21-24 nucleotide small interfering RNAs (siRNAs). In plants, IR-driven RNA silencing also causes extensive cytosine methylation of homologous DNA in both the transgene "trigger" and any other homologous DNA sequences--"targets". Endogenous genomic sequences, including transposable elements and repeated elements, are also subject to RNA-mediated silencing. The RNA silencing gene ARGONAUTE4 (AGO4) is required for maintenance of DNA methylation at several endogenous loci and for the establishment of methylation at the FWA gene. Here, we show that mutation of AGO4 substantially reduces the maintenance of DNA methylation triggered by IR transgenes, but AGO4 loss-of-function does not block the initiation of DNA methylation by IRs. AGO4 primarily affects non-CG methylation of the target sequences, while the IR trigger sequences lose methylation in all sequence contexts. Finally, we find that AGO4 and the DRM methyltransferase genes are required for maintenance of siRNAs at a subset of endogenous sequences, but AGO4 is not required for the accumulation of IR-induced siRNAs or a number of endogenous siRNAs, suggesting that AGO4 may function downstream of siRNA production. AU - Zilberman, Daniel AU - Cao, Xiaofeng AU - Johansen, Lisa K. AU - Xie, Zhixin AU - Carrington, James C. AU - Jacobsen, Steven E. ID - 9493 IS - 13 JF - Current Biology SN - 0960-9822 TI - Role of Arabidopsis ARGONAUTE4 in RNA-directed DNA methylation triggered by inverted repeats VL - 14 ER - TY - JOUR AB - Multicellular eukaryotes produce small RNA molecules (approximately 21–24 nucleotides) of two general types, microRNA (miRNA) and short interfering RNA (siRNA). They collectively function as sequence-specific guides to silence or regulate genes, transposons, and viruses and to modify chromatin and genome structure. Formation or activity of small RNAs requires factors belonging to gene families that encode DICER (or DICER-LIKE [DCL]) and ARGONAUTE proteins and, in the case of some siRNAs, RNA-dependent RNA polymerase (RDR) proteins. Unlike many animals, plants encode multiple DCL and RDR proteins. Using a series of insertion mutants of Arabidopsis thaliana, unique functions for three DCL proteins in miRNA (DCL1), endogenous siRNA (DCL3), and viral siRNA (DCL2) biogenesis were identified. One RDR protein (RDR2) was required for all endogenous siRNAs analyzed. The loss of endogenous siRNA in dcl3 and rdr2 mutants was associated with loss of heterochromatic marks and increased transcript accumulation at some loci. Defects in siRNA-generation activity in response to turnip crinkle virus in dcl2 mutant plants correlated with increased virus susceptibility. We conclude that proliferation and diversification of DCL and RDR genes during evolution of plants contributed to specialization of small RNA-directed pathways for development, chromatin structure, and defense. AU - Xie, Zhixin AU - Johansen, Lisa K. AU - Gustafson, Adam M. AU - Kasschau, Kristin D. AU - Lellis, Andrew D. AU - Zilberman, Daniel AU - Jacobsen, Steven E. AU - Carrington, James C. ID - 9517 IS - 5 JF - PLoS Biology SN - 1544-9173 TI - Genetic and functional diversification of small RNA pathways in plants VL - 2 ER - TY - JOUR AB - Recent progress in understanding the silencing of transposable elements in the model plant Arabidopsis has revealed an interplay between DNA methylation, histone methylation and small interfering RNAs. DNA and histone methylation are not always sufficient to maintain silencing, and RNA-based reinforcement can be needed to maintain as well as initiate it. AU - Zilberman, Daniel AU - Henikoff, Steven ID - 9511 IS - 12 JF - Genome Biology SN - 1474-760X TI - Silencing of transposons in plant genomes: kick them when they're down VL - 5 ER - TY - JOUR AB - We consider the evolution of a connected set on the plane carried by a space periodic incompressible stochastic flow. While for almost every realization of the stochastic flow at time t most of the particles are at a distance of order equation image away from the origin, there is a measure zero set of points that escape to infinity at the linear rate. We study the set of points visited by the original set by time t and show that such a set, when scaled down by the factor of t, has a limiting nonrandom shape. AU - Dolgopyat, Dmitry AU - Kaloshin, Vadim AU - Koralov, Leonid ID - 8517 IS - 9 JF - Communications on Pure and Applied Mathematics KW - Applied Mathematics KW - General Mathematics SN - 0010-3640 TI - A limit shape theorem for periodic stochastic dispersion VL - 57 ER - TY - JOUR AU - Koralov, Leonid AU - Kaloshin, Vadim AU - Dolgopyat, Dmitry ID - 8518 IS - 1A JF - The Annals of Probability SN - 0091-1798 TI - Sample path properties of the stochastic flows VL - 32 ER - TY - JOUR AB - New alleles become fixed owing to random drift of nearly neutral mutations or to positive selection of substantially advantageous mutations. After decades of debate, the fraction of fixations driven by selection remains uncertain. Within 9,390 genes, we analysed 28,196 codons at which rat and mouse differ from each other at two nucleotide sites and 1,982 codons with three differences. At codons where rat-mouse divergence involved two non-synonymous substitutions, both of them occurred in the same lineage, either rat or mouse, in 64% of cases; however, independent substitutions would occur in the same lineage with a probability of only 50%. All three non-synonymous substitutions occurred in the same lineage for 46% of codons, instead of the 25% expected. Furthermore, comparison of 12 pairs of prokaryotic genomes also shows clumping of multiple non-synonymous substitutions in the same lineage. This pattern cannot be explained by correlated mutation or episodes of relaxed negative selection, but instead indicates that positive selection acts at many sites of rapid, successive amino acid replacement. AU - Bazykin, Georgii A AU - Fyodor Kondrashov AU - Ogurtsov, Aleksey Yu AU - Sunyaev, Shamil R AU - Kondrashov, Alexey S ID - 898 IS - 6991 JF - Nature TI - Positive selection at sites of multiple amino acid replacements since rat-mouse divergence VL - 429 ER - TY - JOUR AB - We compare the functional spectrum of protein evolution in two separate animal lineages with respect to two hypotheses: (1) rates of divergence are distributed similarly among functional classes within both lineages, indicating that selective pressure on the proteome is largely independent of organismic-level biological requirements; and (2) rates of divergence are distributed differently among functional classes within each lineage, indicating species-specific selective regimes impact genome-wide substitutional patterns. Integrating comparative genome sequence with data from tissue-specific expressed-sequence-tag (EST) libraries and detailed database annotations, we find a functional genomic signature of rapid evolution and selective constraint shared between mammalian and nematode lineages despite their extensive morphological and ecological differences and distant common ancestry. In both phyla, we find evidence of accelerated evolution among components of molecular systems involved in coevolutionary change. In mammals, lineage-specific fast evolving genes include those involved in reproduction, immunity, and possibly, maternal-fetal conflict. Likelihood ratio tests provide evidence for positive selection in these rapidly evolving functional categories in mammals. In contrast, slowly evolving genes, in terms of amino acid or insertion/deletion (indel) change, in both phyla are involved in core molecular processes such as transcription, translation, and protein transport. Thus, strong purifying selection appears to act on the same core cellular processes in both mammalian and nematode lineages, whereas positive and/or relaxed selection acts on different biological processes in each lineage. AU - Castillo-Davis, Cristian I AU - Fyodor Kondrashov AU - Hartl, Daniel L AU - Kulathinal, Rob J ID - 902 IS - 5 JF - Genome Research TI - The functional genomic distribution of protein divergence in two animal phyla: Coevolution, genomic conflict, and constraint VL - 14 ER - TY - JOUR AU - Chan, Simon W.-L. AU - Zilberman, Daniel AU - Xie, Zhixin AU - Johansen, Lisa K. AU - Carrington, James C. AU - Jacobsen, Steven E. ID - 9454 IS - 5662 JF - Science KW - Multidisciplinary SN - 0036-8075 TI - RNA silencing genes control de novo DNA methylation VL - 303 ER - TY - JOUR AB - Geranylgeranyl diphosphate synthase (GGPPS, EC: 2.5.1.29) catalyzes the biosynthesis of geranylgeranyl diphosphate (GGPP), which is a key precursor for ginkgolide biosynthesis. Here we reported for the first time the cloning of a new full-length cDNA encoding GGPPS from the living fossil plant Ginkgo biloba. The full-length cDNA encoding G. biloba GGPPS (designated as GbGGPPS) was 1657bp long and contained a 1176bp open reading frame encoding a 391 amino acid protein. Comparative analysis showed that GbGGPPS possessed a 79 amino acid transit peptide at its N-terminal, which directed GbGGPPS to target to the plastids. Bioinformatic analysis revealed that GbGGPPS was a member of polyprenyltransferases with two highly conserved aspartate-rich motifs like other plant GGPPSs. Phylogenetic tree analysis indicated that plant GGPPSs could be classified into two groups, angiosperm and gymnosperm GGPPSs, while GbGGPPS had closer relationship with gymnosperm plant GGPPSs. AU - Liao, Zhihua AU - Chen, Min AU - Gong, Yifu AU - Guo, Liang AU - Tan, Qiumin AU - Feng, Xiaoqi AU - Sun, Xiaofen AU - Tan, Feng AU - Tang, Kexuan ID - 12203 IS - 2 JF - DNA Sequence KW - Endocrinology KW - Genetics KW - Molecular Biology KW - Biochemistry SN - 1042-5179 TI - A new geranylgeranyl Diphosphate synthase gene from Ginkgo biloba, which intermediates the biosynthesis of the key precursor for ginkgolides VL - 15 ER - TY - JOUR AB - Micropatterning of surfaces with several chemicals at different spatial locations usually requires multiple stamping and registration steps. Here, we describe an experimental method based on reaction–diffusion phenomena that allows for simultaneous micropatterning of a substrate with several coloured chemicals. In this method, called wet stamping (WETS), aqueous solutions of two or more inorganic salts are delivered onto a film of dry, ionically doped gelatin from an agarose stamp patterned in bas relief. Once in conformal contact, these salts diffuse into the gelatin, where they react to give deeply coloured precipitates. Separation of colours in the plane of the surface is the consequence of the differences in the diffusion coefficients, the solubility products, and the amounts of different salts delivered from the stamp, and is faithfully reproduced by a theoretical model based on a system of reaction–diffusion partial differential equations. The multicolour micropatterns are useful as non-binary optical elements, and could potentially form the basis of new applications in microseparations and in controlled delivery. AU - Klajn, Rafal AU - Fialkowski, Marcin AU - Bensemann, Igor T. AU - Bitner, Agnieszka AU - Campbell, C. J. AU - Bishop, Kyle AU - Smoukov, Stoyan AU - Grzybowski, Bartosz A. ID - 13435 JF - Nature Materials KW - Mechanical Engineering KW - Mechanics of Materials KW - Condensed Matter Physics KW - General Materials Science KW - General Chemistry SN - 1476-1122 TI - Multicolour micropatterning of thin films of dry gels VL - 3 ER - TY - JOUR AB - Thin films of ionically doped gelatin have been color-patterned with submicrometer precision using the wet-stamping technique. Inorganic salts are delivered onto the gelatin surface from an agarose stamp, and diffuse into the gelatine layer, producting deeply colored precipitates. Reaction fronts originating from different features of the stamp cease within < 1 μm of each other, leaving sharp, transparent regions in between. AU - Campbell, C. J. AU - Fialkowski, M. AU - Klajn, Rafal AU - Bensemann, I. T. AU - Grzybowski, B. A. ID - 13434 IS - 21 JF - Advanced Materials KW - Mechanical Engineering KW - Mechanics of Materials KW - General Materials Science SN - 0935-9648 TI - Color micro- and nanopatterning with counter-propagating reaction-diffusion fronts VL - 16 ER - TY - JOUR AB - The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance. AU - Brunet, Anne AU - Sweeney, Lora Beatrice Jaeger AU - Sturgill, J Fitzhugh AU - Chua, Katrin AU - Greer, Paul AU - Lin, Yingxi AU - Tran, Hien AU - Ross, Sarah AU - Mostoslavsky, Raul AU - Cohen, Haim AU - Hu, Linda AU - Chen, Hwei-Ling AU - Jedrychowski, Mark AU - Gygi, Steven AU - Sinclair, David AU - Alt, Frederick AU - Greenberg, Michael ID - 7706 IS - 5666 JF - Science SN - 0036-8075 TI - Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase VL - 303 ER - TY - JOUR AB - Nuclear pore complexes (NPCs) are large multiprotein assemblies that allow traffic between the cytoplasm and the nucleus. During mitosis in higher eukaryotes, the Nuclear Envelope (NE) breaks down and NPCs disassemble. How NPCs reassemble and incorporate into the NE upon mitotic exit is poorly understood. We demonstrate a function for the conserved Nup107-160 complex in this process. Partial in vivo depletion of Nup133 or Nup107 via RNAi in HeLa cells resulted in reduced levels of multiple nucleoporins and decreased NPC density in the NE. Immunodepletion of the entire Nup107-160 complex from in vitro nuclear assembly reactions produced nuclei with a continuous NE but no NPCs. This phenotype was reversible only if Nup107-160 complex was readded before closed NE formation. Depletion also prevented association of FG-repeat nucleoporins with chromatin. We propose a stepwise model in which postmitotic NPC assembly initiates on chromatin via early recruitment of the Nup107-160 complex. AU - Walther, Tobias C. AU - Alves, Annabelle AU - Pickersgill, Helen AU - Loı̈odice, Isabelle AU - HETZER, Martin W AU - Galy, Vincent AU - Hülsmann, Bastian B. AU - Köcher, Thomas AU - Wilm, Matthias AU - Allen, Terry AU - Mattaj, Iain W. AU - Doye, Valérie ID - 11122 IS - 2 JF - Cell KW - General Biochemistry KW - Genetics and Molecular Biology SN - 0092-8674 TI - The conserved Nup107-160 complex is critical for nuclear pore complex assembly VL - 113 ER - TY - JOUR AB - In metazoa, the nuclear envelope breaks down and reforms during each cell cycle. Nuclear pore complexes (NPCs), which serve as channels for transport between the nucleus and cytoplasm1, assemble into the reforming nuclear envelope in a sequential process involving association of a subset of NPC proteins, nucleoporins, with chromatin followed by the formation of a closed nuclear envelope fenestrated by NPCs2,3,4,5,6,7. How chromatin recruitment of nucleoporins and NPC assembly are regulated is unknown. Here we demonstrate that RanGTP production is required to dissociate nucleoporins Nup107, Nup153 and Nup358 from Importin β, to target them to chromatin and to induce association between separate NPC subcomplexes. Additionally, either an excess of RanGTP or removal of Importin β induces formation of NPC-containing membrane structures—annulate lamellae—both in vitro in the absence of chromatin and in vivo. Annulate lamellae formation is strongly and specifically inhibited by an excess of Importin β. The data demonstrate that RanGTP triggers distinct steps of NPC assembly, and suggest a mechanism for the spatial restriction of NPC assembly to the surface of chromatin. AU - Walther, Tobias C. AU - Askjaer, Peter AU - Gentzel, Marc AU - Habermann, Anja AU - Griffiths, Gareth AU - Wilm, Matthias AU - Mattaj, Iain W. AU - HETZER, Martin W ID - 11121 IS - 6949 JF - Nature KW - Multidisciplinary SN - 0028-0836 TI - RanGTP mediates nuclear pore complex assembly VL - 424 ER - TY - JOUR AB - This paper studies the multicast routing and admission control problem on unit-capacity tree and mesh topologies in the throughput model. The problem is a generalization of the edge-disjoint paths problem and is NP-hard both on trees and meshes. We study both the offline and the online version of the problem: In the offline setting, we give the first constant-factor approximation algorithm for trees, and an -factor approximation algorithm for meshes. In the online setting, we give the first polylogarithmic competitive online algorithm for tree and mesh topologies. No polylogarithmic-competitive algorithm is possible on general network topologies (Lower bounds for on-line graph problems with application to on-line circuits and optical routing, in: Proceedings of the 28th ACM Symposium on Theory of Computing, 1996, pp. 531–540) and there exists a polylogarithmic lower bound on the competitive ratio of any online algorithm on tree topologies (Making commitments in the face of uncertainity: how to pick a winner almost every time, in: Proceedings of the 28th Annual ACM Symposium on Theory of Computing, 1996, pp. 519–530). We prove the same lower bound for meshes. AU - Henzinger, Monika H AU - Leonardi, Stefano ID - 11766 IS - 3 JF - Journal of Computer and System Sciences SN - 0022-0000 TI - Scheduling multicasts on unit-capacity trees and meshes VL - 66 ER - TY - JOUR AB - In this paper we consider the online ftp problem. The goal is to service a sequence of file transfer requests given bandwidth constraints of the underlying communication network. The main result of the paper is a technique that leads to algorithms that optimize several natural metrics, such as max-stretch, total flow time, max flow time, and total completion time. In particular, we show how to achieve optimum total flow time and optimum max-stretch if we increase the capacity of the underlying network by a logarithmic factor. We show that the resource augmentation is necessary by proving polynomial lower bounds on the max-stretch and total flow time for the case where online and offline algorithms are using same-capacity edges. Moreover, we also give polylogarithmic lower bounds on the resource augmentation factor necessary in order to keep the total flow time and max-stretch within a constant factor of optimum. AU - Goel, Ashish AU - Henzinger, Monika H AU - Plotkin, Serge AU - Tardos, Eva ID - 11764 IS - 2 JF - Journal of Algorithms SN - 0196-6774 TI - Scheduling data transfers in a network and the set scheduling problem VL - 48 ER - TY - CONF AB - This paper addresses the problem of topic distillation on the World Wide Web, namely, given a typical user query to find quality documents related to the query topic. Connectivity analysis has been shown to be useful in identifying high quality pages within a topic specific graph of hyperlinked documents. The essence of our approach is to augment a previous connectivity analysis based algorithm with content analysis. We identify three problems with the existing approach and devise algorithms to tackle them. The results of a user evaluation are reported that show an improvement of precision at 10 documents by at least 45% over pure connectivity analysis. AU - Bharat, Krishna AU - Henzinger, Monika H ID - 11897 SN - 01635840 T2 - 21st annual international ACM SIGIR conference on Research and development in information retrieval TI - Improved algorithms for topic distillation in a hyperlinked environment ER - TY - CONF AB - Many daily activities present information in the form of a stream of text, and often people can benefit from additional information on the topic discussed. TV broadcast news can be treated as one such stream of text; in this paper we discuss finding news articles on the web that are relevant to news currently being broadcast.We evaluated a variety of algorithms for this problem, looking at the impact of inverse document frequency, stemming, compounds, history, and query length on the relevance and coverage of news articles returned in real time during a broadcast. We also evaluated several postprocessing techniques for improving the precision, including reranking using additional terms, reranking by document similarity, and filtering on document similarity. For the best algorithm, 84%-91% of the articles found were relevant, with at least 64% of the articles being on the exact topic of the broadcast. In addition, a relevant article was found for at least 70% of the topics. AU - Henzinger, Monika H AU - Chang, Bay-Wei AU - Milch, Brian AU - Brin, Sergey ID - 11860 SN - 978-158113680-7 T2 - Proceedings of the 12th international conference on World Wide Web TI - Query-free news search ER - TY - CONF AB - This article presents a high-level discussion of some problems that are unique to web search engines. The goal is to raise awareness and stimulate research in these areas. AU - Henzinger, Monika H AU - Motwani, Rajeev AU - Silverstein, Craig ID - 11909 SN - 1045-0823 T2 - 18th International Joint Conference on Artificial Intelligence TI - Challenges in web search engines ER - TY - JOUR AB - Among the major mathematical approaches to mirror symmetry are those of Batyrev-Borisov and Stromdnger-Yau-Zaslow (SYZ). The first is explicit and amenable to computation but is not clearly related to the physical motivation; the second is the opposite. Furthermore, it is far from obvious that mirror partners in one sense will also be mirror partners in the other. This paper concerns a class of examples that can be shown to satisfy the requirements of SYZ, but whose Hodge numbers are also equal. This provides significant evidence in support of SYZ. Moreover, the examples are of great interest in their own right: they are spaces of flat SLr-connections on a smooth curve. The mirror is the corresponding space for the Langlands dual group PGLr. These examples therefore throw a bridge from mirror symmetry to the duality theory of Lie groups and, more broadly, to the geometric Langlands program. AU - Tamas Hausel AU - Thaddeus, Michael ID - 1457 IS - 1 JF - Inventiones Mathematicae TI - Mirror symmetry, langlands duality, and the Hitchin system VL - 153 ER - TY - JOUR AB - The moduli space of stable bundles of rank $2$ and degree $1$ on a Riemann surface has rational cohomology generated by the so-called universal classes. The work of Baranovsky, King-Newstead, Siebert-Tian and Zagier provided a complete set of relations between these classes, expressed in terms of a recursion in the genus. This paper accomplishes the same thing for the noncompact moduli spaces of Higgs bundles, in the sense of Hitchin and Simpson. There are many more independent relations than for stable bundles, but in a sense the answer is simpler, since the formulas are completely explicit, not recursive. The results of Kirwan on equivariant cohomology for holomorphic circle actions are of key importance. AU - Tamas Hausel AU - Thaddeus, Michael ID - 1458 IS - 2 JF - Journal of the American Mathematical Society TI - Relations in the cohomology ring of the moduli space of rank 2 Higgs bundles VL - 16 ER - TY - JOUR AB - In this paper we explicitly calculate the analogue of the 't Hooft SU (2) Yang-Mills instantons on Gibbons-Hawking multi-centered gravitational instantons, which come in two parallel families: the multi-Eguchi-Hanson, or Ak ALE gravitational instantons and the multi-Taub-NUT spaces, or Ak ALF gravitational instantons. We calculate their energy and find the reducible ones. Following Kronheimer we also exploit the U(1) invariance of our solutions and study the corresponding explicit singular SU (2) magnetic monopole solutions of the Bogomolny equations on flat ℝ3. AU - Etesi, Gábor AU - Tamas Hausel ID - 1459 IS - 2 JF - Communications in Mathematical Physics TI - On Yang-Mills instantons over multi-centered gravitational instantons VL - 235 ER - TY - JOUR AB - For any number field k, upper bounds are established for the number of k-rational points of bounded height on non-singular del Pezzo surfaces defined over k, which are equipped with suitable conic bundle structures over k. AU - Browning, Timothy D AU - Swarbick Jones, M ID - 166 JF - Proceedings of the Bonn session in analytic number theory and diophantine equations TI - Counting rational points on del Pezzo surfaces of degree 5 VL - 360 ER - TY - JOUR AB - The molecular organization of bacterial NADH: ubiquinone oxidoreductase (complex I or NDH-1) is not established, apart from a rough separation into dehydrogenase, connecting and membrane domains. In this work, complex I was purified from Escherichia coli and fragmented by replacing dodecylmaltoside with other detergents. Exchange into decyl maltoside led to the removal of the hydrophobic subunit NuoL from the otherwise intact complex. Diheptanoyl phosphocholine led to the loss of NuoL and NuoM subunits, whereas other subunits remained in the complex. The presence of N,N-dimethyldodecylamine N-oxide or Triton X-100 led to further disruption of the membrane domain into fragments containing NuoL/M/N, NuoA/K/N, and NuoH/J subunits. Among the hydrophilic subunits, NuoCD was most readily dissociated from the complex, whereas NuoB was partially dissociated from the peripheral arm assembly in N,N-dimethyldodecylamine N-oxide. A model of subunit arrangement in bacterial complex I based on these data is proposed. Subunits NuoL and NuoM, which are homologous to antiporters and are implicated in proton pumping, are located at the distal end of the membrane arm, spatially separated from the redox centers of the peripheral arm. This is consistent with proposals that the mechanism of proton pumping by complex I is likely to involve long range conformational changes. AU - Holt, Peter J AU - Morgan, David J AU - Leonid Sazanov ID - 1959 IS - 44 JF - Journal of Biological Chemistry TI - The location of NuoL and NuoM subunits in the membrane domain of the Escherichia coli Complex I: implications for the mechanism of proton pumping VL - 278 ER - TY - JOUR AB - NADH-ubiquinone oxidoreductase (complex I or NDH-1) was purified from the BL21 strain of Escherichia coli using an improved procedure. The complex was effectively stabilized by addition of divalent cations and lipids, making the preparation suitable for structural studies. The ubiquinone reductase activity of the enzyme was fully restored by addition of native E. coli lipids. Two different two-dimensional crystal forms, with p2 and p3 symmetry, were obtained using lipids containing native E. coli extracts. Analysis of the crystals showed that they are formed by fully intact complex I in an L-shaped conformation. Activity assays and single particle analysis indicated that complex I maintains this structure in detergent solution and does not adopt a different conformation in the active state. Thus, we provide the first experimental evidence that complex I from E. coli has an L-shape in a lipid bilayer and confirm that this is also the case for the active enzyme in solution. This suggests strongly that bacterial complex I exists in an L-shaped conformation in vivo. Our results also indicate that native lipids play an important role in the activation, stabilization and, as a consequence, crystallization of purified complex I from E. coli. AU - Leonid Sazanov AU - Carroll, Joe D AU - Holt, Peter J AU - Toime, Laurence J AU - Fearnley, Ian M ID - 1960 IS - 21 JF - Journal of Biological Chemistry TI - A role for native lipids in the stabilization and two dimensional crystallization of the Escherichia coli NADH ubiquinone oxidoreductase (complex I) VL - 278 ER - TY - JOUR AU - Timothy Browning ID - 205 IS - 3 JF - Acta Arithmetica TI - Counting rational points on cubic and quartic surfaces VL - 108 ER - TY - JOUR AB - Let T ⊂ ℙ 4 be a non-singular threefold of degree at least four. Then we show that the number of points in T(ℚ), with height at most B, is o(B 3) or B → ∞. AU - Timothy Browning ID - 206 IS - 1 JF - Quarterly Journal of Mathematics TI - A note on the distribution of rational points on threefolds VL - 54 ER - TY - JOUR AU - Browning, Timothy D ID - 207 IS - 3 JF - Mathematical Proceedings of the Cambridge Philosophical Society TI - Sums of four biquadrates VL - 134 ER - TY - JOUR AB - For any ε > 0 and any diagonal quadratic form Q ∈ ℤ[x 1, x 2, x 3, x 4] with a square-free discriminant of modulus Δ Q ≠ 0, we establish the uniform estimate ≪ε B 3/2+ε + B 2+ε/Δ Q 1/6 for the number of rational points of height at most B lying in the projective surface Q = 0. AU - Timothy Browning ID - 208 IS - 1 JF - Quarterly Journal of Mathematics TI - Counting rational points on diagonal quadratic surfaces VL - 54 ER - TY - CONF AU - Lieb, Élliott H AU - Robert Seiringer ED - Karpeshina, Yulia ED - Weikard, Rudi ED - Zeng, Yanni ID - 2337 TI - Bose-Einstein condensation of dilute gases in traps VL - 327 ER - TY - JOUR AB - The classic Poincaré inequality bounds the L q-norm of a function f in a bounded domain Ω ⊂ ℝ n in terms of some L p-norm of its gradient in Ω. We generalize this in two ways: In the first generalization we remove a set Τ from Ω and concentrate our attention on Λ = Ω \ Τ. This new domain might not even be connected and hence no Poincaré inequality can generally hold for it, or if it does hold it might have a very bad constant. This is so even if the volume of Τ is arbitrarily small. A Poincaré inequality does hold, however, if one makes the additional assumption that f has a finite L p gradient norm on the whole of Ω, not just on Λ. The important point is that the Poincaré inequality thus obtained bounds the L q-norm of f in terms of the L p gradient norm on Λ (not Ω) plus an additional term that goes to zero as the volume of Τ goes to zero. This error term depends on Τ only through its volume. Apart from this additive error term, the constant in the inequality remains that of the 'nice' domain Ω. In the second generalization we are given a vector field A and replace ∇ by ∇ + iA(x) (geometrically, a connection on a U(1) bundle). Unlike the A = 0 case, the infimum of ∥(∇ + iA)f∥ p over all f with a given ∥f∥ q is in general not zero. This permits an improvement of the inequality by the addition of a term whose sharp value we derive. We describe some open problems that arise from these generalizations. AU - Lieb, Élliott H AU - Robert Seiringer AU - Yngvason, Jakob ID - 2357 IS - 3 JF - Annals of Mathematics TI - Poincaré inequalities in punctured domains VL - 158 ER - TY - JOUR AB - We investigate the ground state properties of a gas of interacting particles confined in an external potential in three dimensions and subject to rotation around an axis of symmetry. We consider the Gross-Pitaevskii (GP) limit of a dilute gas. Analysing both the absolute and the bosonic ground states of the system, we show, in particular, their different behaviour for a certain range of parameters. This parameter range is determined by the question whether the rotational symmetry in the minimizer of the GP functional is broken or not. For the absolute ground state, we prove that in the GP limit a modified GP functional depending on density matrices correctly describes the energy and reduced density matrices, independent of symmetry breaking. For the bosonic ground state this holds true if and only if the symmetry is unbroken. AU - Robert Seiringer ID - 2354 IS - 37 JF - Journal of Physics A: Mathematical and Theoretical TI - Ground state asymptotics of a dilute, rotating gas VL - 36 ER - TY - JOUR AB - A study was conducted on the one-dimensional (1D) bosons in three-dimensional (3D) traps. A rigorous analysis was carried out on the parameter regions in which various types of 1D or 3D behavior occurred in the ground state. The four parameter regions include density, transverse, longitudinal dimensions and scattering length. AU - Lieb, Élliott H AU - Robert Seiringer AU - Yngvason, Jakob ID - 2358 IS - 15 JF - Physical Review Letters TI - One-dimensional Bosons in three-dimensional traps VL - 91 ER - TY - THES AU - Uli Wagner ID - 2414 TI - On k-Sets and Their Applications ER - TY - CONF AB - We introduce the adaptive neighborhood graph as a data structure for modeling a smooth manifold M embedded in some (potentially very high-dimensional) Euclidean space ℝd. We assume that M is known to us only through a finite sample P ⊂ M, as it is often the case in applications. The adaptive neighborhood graph is a geometric graph on P. Its complexity is at most min{2O(k)(n, n2}, where n = |P| and k = dim M, as opposed to the n⌈d/2⌉ complexity of the Delaunay triangulation, which is often used to model manifolds. We show that we can provably correctly infer the connectivity of M and the dimension of M from the adaptive neighborhood graph provided a certain standard sampling condition is fulfilled. The running time of the dimension detection algorithm is d2O(k7 log k) for each connected component of M. If the dimension is considered constant, this is a constant-time operation, and the adaptive neighborhood graph is of linear size. Moreover, the exponential dependence of the constants is only on the intrinsic dimension k, not on the ambient dimension d. This is of particular interest if the co-dimension is high, i.e., if k is much smaller than d, as is the case in many applications. The adaptive neighborhood graph also allows us to approximate the geodesic distances between the points in P. AU - Giesen, Joachim AU - Uli Wagner ID - 2424 TI - Shape dimension and intrinsic metric from samples of manifolds with high co-dimension ER - TY - CONF AB - A finite set N ⊃ Rd is a weak ε-net for an n-point set X ⊃ Rd (with respect to convex sets) if N intersects every convex set K with |K ∩ X| ≥ εn. We give an alternative, and arguably simpler, proof of the fact, first shown by Chazelle et al. [7], that every point set X in Rd admits a weak ε-net of cardinality O(ε-d polylog(1/ε)). Moreover, for a number of special point sets (e.g., for points on the moment curve), our method gives substantially better bounds. The construction yields an algorithm to construct such weak ε-nets in time O(n ln(1/ε)). We also prove, by a different method, a near-linear upper bound for points uniformly distributed on the (d - 1)-dimensional sphere. AU - Matoušek, Jiří AU - Uli Wagner ID - 2423 TI - New constructions of weak epsilon-nets ER - TY - CONF AB - We prove a lower bound of 0.3288(4 n) for the rectilinear crossing number cr̄(Kn) of a complete graph on n vertices, or in other words, for the minimum number of convex quadrilaterals in any set of n points in general position in the Euclidean plane. As we see it, the main contribution of this paper is not so much the concrete numerical improvement over earlier bounds, as the novel method of proof, which is not based on bounding cr̄(Kn) for some small n. AU - Uli Wagner ID - 2422 TI - On the rectilinear crossing number of complete graphs ER - TY - JOUR AB - Patients with Hodgkin's disease can develop paraneoplastic cerebellar ataxia because of the generation of autoantibodies against mGluR1 (mGluR1-Abs). Yet, the pathophysiological mechanisms underlying their motor coordination deficits remain to be elucidated. Here, we show that application of IgG purified from the patients' serum to cerebellar slices of mice acutely reduces the basal activity of Purkinje cells, whereas application to the flocculus of mice in vivo evokes acute disturbances in the performance of their compensatory eye movements. In addition, the mGluR1-Abs block induction of long-term depression in cultured mouse Purkinje cells, whereas the cerebellar motor learning behavior of the patients is affected in that they show impaired adaptation of their saccadic eye movements. Finally, postmortem analysis of the cerebellum of a paraneoplastic cerebellar ataxia patient showed that the number of Purkinje cells was significantly reduced by approximately two thirds compared with three controls. We conclude that autoantibodies against mGluR1 can cause cerebellar motor coordination deficits caused by a combination of rapid effects on both acute and plastic responses of Purkinje cells and chronic degenerative effects. AU - Coesmans, Michiel P AU - Sillevis-Smitt, Peter A AU - Linden, David J AU - Ryuichi Shigemoto AU - Hirano, Tomoo AU - Yamakawa, Yoshinori AU - Van Alphen, Adriaan M AU - Luo, Chongde AU - Van Der Geest, Jos N AU - Kros, Johan M AU - Gaillard, Carlo A AU - Frens, Maarten A AU - De Zeeuw, Chris I ID - 2623 IS - 3 JF - Annals of Neurology TI - Mechanisms underlying cerebellar motor deficits due to mGluR1-autoantibodies VL - 53 ER - TY - JOUR AB - Metabotropic glutamate receptor 1 (mGluR1) plays a crucial role in synaptic plasticity and motor learning in the cerebellum. We have studied activity-dependent changes in mGluR1 function in mouse cultured Purkinje neurons. Depolarizing stimulation potentiated Ca2+ and current responses to an mGluR1 agonist for several hours in the cultured Purkinje neurons. It also blocked internalization of mGluR1 and increased the number of mGluR1s on the cell membrane. We found that depolarization simultaneously increased transcription of Homer1a in Purkinje neurons. Homer1a inhibited internalization and increased cell-surface expression of mGluR1 when coexpressed in human embryonic kidney (HEK)-293 cells. Depolarization-induced Homer1a expression in Purkinje neurons was blocked by a mitogen-activated protein kinase (MAPK) inhibitor. Changes in internalization and mGluR1-mediated Ca2+ response were also blocked by inhibition of MAPK activity, suggesting that localization and activity of mGluR1 were regulated in the same signalling pathway as Homer1a expression. It is thus suggested that depolarization of the Purkinje neuron leads to the increment in mGluR1 responsiveness through MAPK activity and induction of Homer1a expression, which increases active mGluR1 on the cell surface by blocking internalization of mGluR1. AU - Minami, Itsunari AU - Kengaku, Mineko AU - Smitt, Sillevis P AU - Ryuichi Shigemoto AU - Hirano, Tomoo ID - 2625 IS - 5 JF - European Journal of Neuroscience TI - Long-term potentiation of mGluR1 activity by depolarization-induced Homer1a in mouse cerebellar Purkinje neurons VL - 17 ER - TY - JOUR AB - The expression pattern of metabotropic glutamate receptor Iα (mGluR1α) was immunohistochemically investigated in substantia nigra dopaminergic neurons of the macaque monkey. In normal monkeys, mGluR1α immunoreactivity was weakly observed in the dorsal tier of the substantia nigra pars compacta (SNc-d) where calbindin-D28k-containing dopaminergic neurons invulnerable to parkinsonian degeneration are specifically located. On the other hand, mGluR1α was strongly expressed in the ventral tier of the substantia nigra pars cornpacta (SNc-v). In monkeys treated with the parkinsonism-inducing drug, I-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), mGluR1α expression was decreased in dopaminergic neurons in the SNc-v that were spared its toxic action. These results suggest that mGluR1α expression may be involved at least partly in the vulnerability of dopaminergic neurons to parkinsonian insults. AU - Kaneda, Katsuyuki AU - Imanishi, Michiko AU - Nambu, Atsushi AU - Ryuichi Shigemoto AU - Takada, Masahiko ID - 2626 IS - 7 JF - Neuroreport TI - Differential expression patterns of mGluR1α in monkey nigral dopamine neurons VL - 14 ER - TY - JOUR AB - Despite its implications for higher order functions of the brain, little is currently known about the molecular basis of left-right asymmetry of the brain. Here we report that synaptic distribution of N-methyl-D-aspartate (NMDA) receptor GluRε2 (NR2B) subunits in the adult mouse hippocampus is asymmetrical between the left and right and between the apical and basal dendrites of single neurons. These asymmetrical allocations of ε2 subunits differentiate the properties of NMDA receptors and synaptic plasticity between the left and right hippocampus. These results provide a molecular basis for the structural and functional asymmetry of the mature brain. AU - Kawakami, Ryosuke AU - Shinohara, Yoshiaki AU - Kato, Yuichiro AU - Sugiyama, Hiroyuki AU - Ryuichi Shigemoto AU - Ito, Isao ID - 2627 IS - 5621 JF - Science TI - Asymmetrical allocation of NMDA receptor ε2 subunits in hippocampal circuitry VL - 300 ER - TY - JOUR AB - The release of neurotransmitters is modulated by presynaptic metabotropic glutamate receptors (mGluRs), which show a highly selective expression and subcellular location in glutamatergic terminals in the hippocampus. Using immunocytochemistry, we investigated whether one of the receptors, mGluR7, whose level of expression is governed by the postsynaptic target, was present in GABAergic terminals and whether such terminals targeted particular cells. A total of 165 interneuron dendritic profiles receiving 466 synapses (82% mGluR7a-positive) were analysed. The presynaptic active zones of most GAD-(77%) or GABA-positive (94%) synaptic boutons on interneurons innervated by mGluR7a-enriched glutamatergic terminals (mGluR7a-decorated) were immunopositive for mGluR7a. GABAergic terminals on pyramidal cells and most other interneurons in str. oriens were mGluR7a-immunonegative. The mGluR7a-decorated cells were mostly somatostatin- and mGluR1α-immunopositive neurons in str. oriens and the alveus. Their GABAergic input mainly originated from VIP-positive terminals, 90% of which expressed high levels of mGluR7a in the presynaptic active zone. Parvalbumin-positive synaptic terminals were rare on mGluR7a-decorated cells, but on these neurons 73% of them were mGluR7a-immunopositive. Some type II synapses innervating interneurons were immunopositive for mGluR7b, as were some type I synapses. Because not all target cells of VIP-positive neurons are known it has not been possible to determine whether mGluR7 is expressed in a target-cell-specific manner in the terminals of single GABAergic cells. The activation of mGluR7 may decrease GABA release to mGluR7-decorated cells at times of high pyramidal cell activity, which elevates extracellular glutamate levels. Alternatively, the presynaptic receptor may be activated by as yet unidentified endogenous ligands released by the GABAergic terminals or the postsynaptic dendrites. AU - Somogyi, Péter AU - Dalezios, Yannis AU - Luján, Rafael AU - Roberts, John D AU - Watanabe, Masahiko AU - Ryuichi Shigemoto ID - 2629 IS - 12 JF - European Journal of Neuroscience TI - High level of mGluR7 in the presynaptic active zones of select populations of GABAergic terminals innervating interneurons in the rat hippocampus VL - 17 ER - TY - JOUR AB - We aimed to estimate the number of AMPA receptors (AMPARs) bound by the quantal transmitter packet, their single-channel conductance and their density in the postsynaptic membrane at cerebellar Purkinje cell synapses. The synaptic and extrasynaptic AMPARs were examined in Purkinje cells in 2- to 4-day-old rats, when they receive synaptic inputs solely from climbing fibres (CFs). Evoked CF EPSCs and whole-cell AMPA currents displayed roughly linear current-voltage relationships, consistent with the presence of GluR2 subunits in synaptic and extrasynaptic AMPARs. The mean quantal size, estimated from the miniature EPSCs (MEPSCs), was ∼300 pS. Peak-scaled non-stationary fluctuation analysis of spontaneous EPSCs and MEPSCs gave a weighted-mean synaptic channel conductance of ∼5 pS (∼7 pS when corrected for filtering). By applying non-stationary fluctuation analysis to extrasynaptic currents activated by brief glutamate pulses (5 mM), we also obtained a small single-channel conductance estimate for extrasynaptic AMPARs (∼11 pS). This approach allowed us to obtain a maximum open probability (Po,max) value for the extrasynaptic receptors (Po,max = 0.72). Directly resolved extrasynaptic channel openings in the continued presence of glutamate exhibited clear multiple-conductance levels. The mean area of the postsynaptic density (PSD) of these synapses was 0.074 μm2, measured by reconstructing electron-microscopic (EM) serial sections. Postembedding immunogold labelling by anti-GluR2/3 antibody revealed that AMPARs are localised in PSDs. From these data and by simulating error factors, we estimate that at least 66 AMPARs are bound by a quantal transmitter packet at CF-Purkinje cell synapses, and the receptors are packed at a minimum density of ∼900 μm-2 in the postsynaptic membrane. AU - Momiyama, Akiko AU - Silver, Rachel A AU - Häusser, Michael A AU - Notomi, Takuya AU - Wu, Yue AU - Ryuichi Shigemoto AU - Cull-Candy, Stuart G ID - 2628 IS - 1 JF - Journal of Physiology TI - The density of AMPA receptors activated by a transmitter quantum at the climbing fibre - Purkinje cell synapse in immature rats VL - 549 ER - TY - JOUR AB - Cyclic ADP-ribose (cADP-ribose) is a putative second messenger or modulator. However, the role of cADP-ribose in the downstream signals of the metabotropic glutamate receptors (mGluRs) is unclear. Here, we show that glutamate stimulates ADP-ribosyl cyclase activity in rat or mouse crude membranes of retina via group III mGluRs or in superior cervical ganglion via group I mGluRs. The retina of mGluR6-deficient mice showed no increase in the ADP-ribosyl cyclase level in response to glutamate. GTP enhanced the initial rate of basal and glutamate-stimulated cyclase activity. GTP-γ-S also stimulated basal activity. To determine whether the coupling mode of mGluRs to ADP-ribosyl cyclase is a feature common to individual cloned mGluRs, we expressed each mGluR subtype in NG108-15 neuroblastoma x glioma hybrid cells. The glutamate-induced stimulation of the cyclase occurs preferentially in NG108-15 cells over-expressing mGluRs1, 3, 5, and 6. Cells expressing mGluR2 or mGluRs4 and 7 exhibit inhibition or no coupling, respectively. Glutamate-induced activation or inhibition of the cyclase activity was eliminated after pre-treatment with cholera or pertussis toxin, respectively. Thus, the subtype-specific coupling of mGluRs to ADP-ribosyl cyclase via G proteins suggests that some glutamate-evoked neuronal functions are mediated by cADP-ribose. AU - Higashida, Haruhiro AU - Zhang, Jia-Sheng AU - Mochida, Sumiko AU - Chen, Xiao-Liang AU - Shin, Yeonsook AU - Noda, Mami AU - Hossain, Kazi Z AU - Hoshi, Naoto AU - Hashii, Minako AU - Ryuichi Shigemoto AU - Nakanishi, Shigetada AU - Fukuda, Yutaka AU - Yokoyama, Shigeru ID - 2631 IS - 5 JF - Journal of Neurochemistry TI - Subtype-specific coupling with ADP-ribosyl cyclase of metabotropic glutamate receptors in retina, cervical superior ganglion and NG108-15 cells VL - 85 ER - TY - JOUR AB - The modulation of calcium channels by metabotropic glutamate receptors (mGluRs) is a key event in the fine-tuning of neurotransmitter release. Here we report that, in cerebrocortical nerve terminals of adult rats, the inhibition of glutamate release is mediated by mGluR7. In this preparation, the major component of glutamate release is supported by P/Q-type Ca2+ channels (72.7%). However, mGluR7 selectively reduced the release component that is associated with N-type Ca2+ channels (29.9%). Inhibition of P/Q channels by mGluR7 is not masked by the higher efficiency of these channels in driving glutamate release when compared with N-type channels. Thus, activation of mGluR7 failed to reduce the release associated with P/Q channels when the extracellular calcium concentration, ([Ca2+]o), was reduced from 1.3 to 0.5 mM. Through Ca2+ imaging, we show that Ca2+ channels are distributed in a heterogeneous manner in individual nerve terminals. Indeed, in this preparation, nerve terminals were observed that contain N-type (31.1%; conotoxin GVIA-sensitive) or P/Q-type (64.3%; agatoxin IVA-sensitive) channels or that were insensitive to these two toxins (4.6%). Interestingly, the great majority of the responses to L-AP4 (95.4%) were observed in nerve terminals containing N-type channels. This specific co-localization of mGluR7 and N-type Ca2+-channels could explain the failure of the receptor to inhibit the P/Q channel-associated release component and also reveal the existence of specific targeting mechanisms to localize the two proteins in the same nerve terminal subset. AU - Millán, Carmelo AU - Castro, Enrique G AU - Torres, Magdalena AU - Ryuichi Shigemoto AU - Sánchez-Prieto, José ID - 2633 IS - 26 JF - Journal of Biological Chemistry TI - Co-expression of metabotropic glutamate receptor 7 and N-type Ca2+ channels in single cerebrocortical nerve terminals of adult rats VL - 278 ER - TY - JOUR AB - In many brain regions, hyperpolarization-activated cationic currents (Ih) are involved in the generation of rhythmic activities, but the role of Ih in olfactory oscillations remains unclear. Knowledge of the cellular and subcellular distributions of hyperpolarization-activated and cyclic nucleotide-gated channel (HCN) subunits is necessary for understanding the role of Ih in olfactory network activities. Using light microscopic immunocytochemistry, we demonstrate strong HCN1 labelling of the glomerular layer and moderate staining of granule cell, internal and external plexiform layers of the rat main olfactory bulb. In the glomerular layer, among many unlabelled neurons, two distinct subpopulations of juxtaglomerular cells are labelled. Approximately 10% of the juxtaglomerular cells strongly express HCN1. These small diameter cells are immunoreactive for GABA and comprise a subpopulation of periglomerular cells. An additional subset of juxtaglomerular cells (≈ 1%) expresses low levels of HCN1. They are large in diameter, GABA immunonegative but immunopositive for vesicular glutamate transporter 2, characterizing them as external tufted cells. Quantitative immunogold localization revealed that the somatic plasma membranes of periglomerular cells contain approximately four times more HCN1 labelling than those of external tufted cells. Unlike in cortical pyramidal cells, immunogold density for HCN1 does not significantly differ in somatic and dendritic plasma membranes of external tufted cells, indicating that post-synaptic potentials arriving at proximal and distal dendrites are modulated by the same density of I h. Our results demonstrate a cell type-dependent expression of HCN1 in the olfactory bulb and predict a differential contribution of distinct juxtaglomerular cell types to network oscillations. AU - Holderith, Noémi B AU - Ryuichi Shigemoto AU - Nusser, Zoltán ID - 2632 IS - 2 JF - European Journal of Neuroscience TI - Cell type-dependent expression of HCN1 in the main olfactory bulb VL - 18 ER - TY - JOUR AB - Metabotropic GABAB receptors mediate slow inhibitory effects presynaptically and postsynaptically. Using preembedding immunohistochemical methods combined with quantitative analysis of GABAB receptor subunit immunoreactivity, this study provides a detailed description of the cellular and subcellular localization of GABAB1a/b and GABA B2 in the rat hippocampus. At the light microscopic level, an overlapping distribution of GABAB1a/b and GABAB2 was revealed in the dendritic layers of the hippocampus. In addition, expression of the GABAB1a/b subunit was found in somata of CA1 pyramidal cells and of a subset of GABAergic interneurons. At the electron microscopic level, immunoreactivity for both subunits was observed on presynaptic and, more abundantly, on postsynaptic elements. Presynaptically, subunits were mainly detected in the extrasynaptic membrane and occasionally over the presynaptic membrane specialization of putative glutamatergic and, to a lesser extent, GABAergic axon terminals. Postsynaptically, the majority of GABAB receptor subunits were localized to the extrasynaptic plasma membrane of spines and dendritic shafts of principal cells and shafts of interneuron dendrites. Quantitative analysis revealed enrichment of GABAB1a/b around putative glutamatergic synapses on spines and an even distribution on dendritic shafts of pyramidal cells contacted by GABAergic boutons. The association of GABAB receptors with glutamatergic synapses at both presynaptic and postsynaptic sides indicates their intimate involvement in the modulation of glutamatergic neurotransmission. The dominant extrasynaptic localization of GABAB receptor subunits suggests that their activation is dependent on spillover of GABA requiring simultaneous activity of populations of GABAergic cells as it occurs during population oscillations or epileptic seizures. AU - Kulik, Ákos AU - Vida, Imre AU - Luján, Rafael AU - Haas, Carola A AU - López-Bendito, Guillermina AU - Ryuichi Shigemoto AU - Frotscher, Michael ID - 2635 IS - 35 JF - Journal of Neuroscience TI - Subcellular Localization of Metabotropic GABAB Receptor Subunits GABAB1a/b and GABAB2 in the Rat Hippocampus VL - 23 ER - TY - JOUR AB - To better understand the role of neurotransmitter receptors in neuronal differentiation and maturation a detailed knowledge of their identity, location and function in the plasma membrane of specific neuronal populations during development is required. Combining pre-embedding immunocytochemistry with cell tracking in embryonic brain slice cultures we show that virtually all neurons (∼98%) migrating through the lower intermediate zone (LIZ) on their way from the medial ganglionic eminence to the cerebral cortex, express GABA BR1. Blockade of GABABRs with a specific antagonist, CGP52432, resulted in a concentration-dependent accumulation of these tangentially migrating neurons in the ventricular/subventricular zones (VZ/SVZ) of the cortex and fewer cells were observed in the cortical plate/marginal zone (CP/MZ) and LIZ. Moreover, they had significantly shorter leading processes compared with similar migrating cells in control slices. Electrophysiological recording in LIZ and CP cells revealed no direct effect of either CGP52432 or the GABABR agonist, baclofen, on resting membrane properties suggesting that the effect of CGP52432 on migration might be mediated through a metabotropic action or the regulation of release of factors controlling migration. These results suggest that GABABRs have an important modulatory role in the migration of cortical interneurons. AU - López-Bendito, Guillermina AU - Luján, Rafael AU - Ryuichi Shigemoto AU - Ganter, Paul AU - Paulsen, Ole AU - Molnár, Zoltán ID - 2634 IS - 9 JF - Cerebral Cortex TI - Blockade of GABAB receptors alters the tangential migration of cortical neurons VL - 13 ER - TY - JOUR AB - Taste-metabotropic glutamate receptor 4 (taste-mGluR4) and the heteromers of T1R1 and T1R3 are candidate receptors involved in the sense of umami (monosodium glutamate) taste. Although the expression of group III mGluRs (taste-mGluR4) has been demonstrated in taste tissues, no mention has been made of the expression of group I mGluRs (mGluR1 and mGluR5) in taste tissues. We examined the expression of mGluR1 and mGluR5 in rat gustatory tissues by using reverse transcription-polymerase chain reaction (RT-PCR), in situ hybridization, immunohistochemistry and immunoelectron microscopy. RT-PCR assay showed that mGluR1α and mGluR1β mRNAs were expressed in circumvallate papillae, but mGluR5 mRNA was not expressed. The positive signals of mGluR1 mRNA were detected only in circumvallate taste buds by in situ hybridization analysis. In cryosections of fungiform, foliate and circumvallate papillae, the antibody against mGluRla gave intense labeling on the taste hairs in all taste pores examined. In the developing taste buds, the positive signals of mGluR1α in taste hairs gradually increased with the increase in number of taste bud cells. These results show that, in addition to taste-mGluR4 and the heteromer of T1R1 and T1R3, mGluR1α may function as a receptor for glutamate (umami) taste sensation. AU - Toyono, Takashi AU - Seta, Yuji AU - Kataoka, Shinji AU - Kawano, Shintaro AU - Ryuichi Shigemoto AU - Toyoshima, Kuniaki ID - 2630 IS - 1 JF - Cell and Tissue Research TI - Expression of metabotropic glutamate receptor group I in rat gustatory papillae VL - 313 ER - TY - JOUR AB - While the cholinergic depletion in Alzheimer's disease (AD) has been known for some time, a definitive involvement of other neurotransmitter systems has been somewhat more elusive. Our study demonstrates a clear involvement of both glutamatergic and, to a lesser extent, GABAergic neurons in an early onset transgenic mouse model of AD-like amyloid pathology. Immunohistochemical staining and subsequent quantification has revealed a statistically significant increased density of glutamatergic and GABAergic presynaptic boutons in both the plaque free and plaque adjacent cortical neuropile areas of transgenic mice as compared to non-transgenic controls. Furthermore, amyloid plaque size was shown to have a statistically significant effect on the relative area occupied by dystrophic glutamatergic neurites in the peri-plaque neuropile. These findings support our hypothesis that the amyloid pathology progresses in a time and neurotransmitter specific manner, first in the cholinergic system which appears to be most vulnerable, followed by the glutamatergic presynaptic boutons and finally the somewhat more resilient GABAergic terminals. AU - Bell, Karen F AU - De Kort, G J AU - Steggerda, S AU - Ryuichi Shigemoto AU - Ribeiro-da-Silva, Alfredo AU - Cuello, Augusto C ID - 2637 IS - 2 JF - Neuroscience Letters TI - Structural involvement of the glutamatergic presynaptic boutons in a transgenic mouse model expressing early onset amyloid pathology VL - 353 ER - TY - JOUR AB - We report the results of an experimental study of magnetohydrodynamic damping of sidewall convection in a rectangular enclosure filled with gallium. In particular we investigate the suppression of convection when a steady magnetic field is applied separately in each of the three principal directions of the flow. The strongest damping of the steady flow is found for a vertical magnetic field, which is in agreement with theory. However, we observe that the application of a field transverse to the flow provides greater damping than a longitudinal one, which seems to contradict available theory. We provide a possible resolution of this apparent dichotomy in terms of the length scale of the experiment. AU - Björn Hof AU - Juel, Anne AU - Mullin, Tom P ID - 2784 JF - Journal of Fluid Mechanics TI - Magnetohydrodynamic damping of convective flows in molten gallium VL - 482 ER - TY - JOUR AB - Experimental evidence for the scaling of the finite amplitude of perturbation theory required to promote transition in Poiseuille flow was found. The exponent is -1 and was uncovered using considerable care in the design and execution of the experiment. Interestingly, this exponent was also found in experiments on transition in boundary layers. AU - Björn Hof AU - Juel, Anne AU - Mullin, Tom P ID - 2785 IS - 24 JF - Physical Review Letters TI - Scaling of the turbulence transition threshold in a pipe VL - 91 ER - TY - JOUR AB - Plant growth is marked by its adaptability to continuous changes in environment. A regulated, differential distribution of auxin underlies many adaptation processes including organogenesis, meristem patterning and tropisms. In executing its multiple roles, auxin displays some characteristics of both a hormone and a morphogen. Studies on auxin transport, as well as tracing the intracellular movement of its molecular components, have suggested a possible scenario to explain how growth plasticity is conferred at the cellular and molecular level. The plant perceives stimuli and changes the subcellular position of auxin-transport components accordingly. These changes modulate auxin fluxes, and the newly established auxin distribution triggers the corresponding developmental response. AU - Friml, Jirí ID - 2990 IS - 1 JF - Current Opinion in Plant Biology TI - Auxin transport - Shaping the plant VL - 6 ER - TY - JOUR AB - Plants have many polarized cell types, but relatively little is known about the mechanisms that establish polarity. The orc mutant was identified originally by defects in root patterning, and positional cloning revealed that the affected gene encodes STEROL METHYLTRANSFERASE1, which is required for the appropriate synthesis and composition of major membrane sterols. smt1orc mutants displayed several conspicuous cell polarity defects. Columella root cap cells revealed perturbed polar positioning of different organelles, and in the smt1orc root epidermis, polar initiation of root hairs was more randomized. Polar auxin transport and expression of the auxin reporter DR5-β-glucuronidase were aberrant in smt1orc. Patterning defects in smt1orc resembled those observed in mutants of the PIN gene family of putative auxin efflux transporters. Consistently, the membrane localization of the PIN1 and PIN3 proteins was disturbed in smt1orc, whereas polar positioning of the influx carrier AUX1 appeared normal. Our results suggest that balanced sterol composition is a major requirement for cell polarity and auxin efflux in Arabidopsis. AU - Willemsen, Viola AU - Jirí Friml AU - Grebe, Markus AU - Van Den Toorn, Albert AU - Palme, Klaus AU - Scheres, Ben ID - 2992 IS - 3 JF - Plant Cell TI - Cell polarity and PIN protein positioning in Arabidopsis require STEROL METHYLTRANSFERASE1 function VL - 15 ER - TY - JOUR AB - Plants, compared to animals, exhibit an amazing adaptability and plasticity in their development. This is largely dependent on the ability of plants to form new organs, such as lateral roots, leaves, and flowers during postembryonic development. Organ primordia develop from founder cell populations into organs by coordinated cell division and differentiation. Here, we show that organ formation in Arabidopsis involves dynamic gradients of the signaling molecule auxin with maxima at the primordia tips. These gradients are mediated by cellular efflux requiring asymmetrically localized PIN proteins, which represent a functionally redundant network for auxin distribution in both aerial and underground organs. PIN1 polar localization undergoes a dynamic rearrangement, which correlates with establishment of auxin gradients and primordium development. Our results suggest that PIN-dependent, local auxin gradients represent a common module for formation of all plant organs, regardless of their mature morphology or developmental origin. AU - Eva Benková AU - Michniewicz, Marta AU - Sauer, Michael AU - Teichmann, Thomas AU - Seifertová, Daniela AU - Jürgens, Gerd AU - Jirí Friml ID - 2996 IS - 5 JF - Cell TI - Local, efflux-dependent auxin gradients as a common module for plant organ formation VL - 115 ER - TY - JOUR AB - Axis formation occurs in plants, as in animals, during early embryogenesis. However, the underlying mechanism is not known. Here we show that the first manifestation of the apical-basal axis in plants, the asymmetric division of the zygote, produces a basal cell that transports and an apical cell that responds to the signalling molecule auxin. This apical-basal auxin activity gradient triggers the specification of apical embryo structures and is actively maintained by a novel component of auxin efflux, PIN7, which is located apically in the basal cell. Later, the developmentally regulated reversal of PIN7 and onset of PIN1 polar localization reorganize the auxin gradient for specification of the basal root pole. An analysis of pin quadruple mutants identifies PIN-dependent transport as an essential part of the mechanism for embryo axis formation. Our results indicate how the establishment of cell polarity, polar auxin efflux and local auxin response result in apical-basal axis formation of the embryo, and thus determine the axiality of the adult plant. AU - Jirí Friml AU - Vieten, Anne AU - Sauer, Michael AU - Weijers, Dolf AU - Schwarz, Heinz AU - Hamann, Thorsten AU - Offringa, Remko AU - Jürgens, Gerd ID - 2995 IS - 6963 JF - Nature TI - Efflux dependent auxin gradients establish the apical basal axis of Arabidopsis VL - 426 ER - TY - JOUR AB - The regular arrangement of leaves around a plant's stem, called phyllotaxis, has for centuries attracted the attention of philosophers, mathematicians and natural scientists; however, to date, studies of phyllotaxis have been largely theoretical. Leaves and flowers are formed from the shoot apical meristem, triggered by the plant hormone auxin. Auxin is transported through plant tissues by specific cellular influx and efflux carrier proteins. Here we show that proteins involved in auxin transport regulate phyllotaxis. Our data indicate that auxin is transported upwards into the meristem through the epidermis and the outermost meristem cell layer. Existing leaf primordia act as sinks, redistributing auxin and creating its heterogeneous distribution in the meristem. Auxin accumulation occurs only at certain minimal distances from existing primordia, defining the position of future primordia. This model for phyllotaxis accounts for its reiterative nature, as well as its regularity and stability. AU - Reinhardt, Didier AU - Pesce, Eva-Rachele AU - Stieger, Pia AU - Mandel, Therese AU - Baltensperger, Kurt AU - Bennett, Malcolm AU - Traas, Jan AU - Jirí Friml AU - Kuhlemeier, Cris ID - 2994 IS - 6964 JF - Nature TI - Regulation of phyllotaxis by polar auxin transport VL - 426 ER - TY - JOUR AB - Plant biology is currently experiencing a growing demand for easy and reliable mRNA and protein localisation techniques. Here, we present novel whole mount in situ hybridisation and immunolocalisation protocols, suitable to localise mRNAs and proteins in Arabidopsis seedlings. We demonstrate that these methods can be used in different organs of Arabidopsis seedlings as well as in other plant species. In order to achieve better reproducibility and higher throughput, we modified these protocols for automation to be performed by a liquid handling robot. In addition, we show that other procedures such as reporter enzyme assays and tissue clearing can be similarly automated. We present examples of application of our protocols including mRNA localisation and proteins and epitope tag (co)localisations which demonstrate that these methods provide reliable and versatile tools for expression, localisation and anatomical studies in plants. AU - Jirí Friml AU - Eva Benková AU - Mayer, Ulrike AU - Palme, Klaus AU - Muster, Gerhard ID - 2993 IS - 1 JF - Plant Journal TI - Automated whole mount localisation techniques for plant seedlings VL - 34 ER - TY - JOUR AB - Biosynthesis of most peptide hormones and neuropeptides requires proteolytic excision of the active peptide from inactive proprotein precursors, an activity carried out by subtilisin-like proprotein convertases (SPCs) in constitutive or regulated secretory pathways. The Drosophila amontillado (amon) gene encodes a homolog of the mammalian PC2 protein, an SPC that functions in the regulated secretory pathway in neuroendocrine tissues. We have identified amon mutants by isolating ethylmethanesulfonate (EMS)-induced lethal and visible mutations that define two complementation groups in the amon interval at 97D1 of the third chromosome. DNA sequencing identified the amon complementation group and the DNA sequence change for each of the nine amon alleles isolated. amon mutants display partial embryonic lethality, are defective in larval growth, and arrest during the first to second instar larval molt. Mutant larvae can be rescued by heat-shock-induced expression of the amon protein. Rescued larvae arrest at the subsequent larval molt, suggesting that amon is also required for the second to third instar larval molt. Our data indicate that the amon proprotein convertase is required during embryogenesis and larval development in Drosophila and support the hypothesis that AMON acts to proteolytically process peptide hormones that regulate hatching, larval growth, and larval ecdysis. AU - Rayburn, Lowell Y AU - Gooding, Holly C AU - Choksi, Semil P AU - Maloney, Dhea AU - Kidd, Ambrose R AU - Daria Siekhaus AU - Bender, Michael ID - 3151 IS - 1 JF - Genetics TI - Amontillado, the Drosophila homolog of the prohormone processing protease PC2, is required during embryogenesis and early larval development VL - 163 ER - TY - JOUR AB - Tripartite G-protein-coupled receptors (GPCRs) represent one of the largest groups of signal transducers, transmitting signals from hormones, neuropeptides, odorants, food and light. Ligand-bound receptors catalyse GDP/GTP exchange on the G-protein α-subunit (Gα), leading to α-GTP separation from the βγ subunits and pathway activation. Activating mutations in the receptors or G proteins underlie many human diseases, including some cancers, dwarfism and premature puberty. Regulators of G-protein signalling (RGS proteins) are known to modulate the level and duration of ligand-induced signalling by accelerating the intrinsic GTPase activity of the Gα subunit, and thus reformation of the inactive GDP-bound Gα. Here we find that even in the absence of receptor, mutation of the RGS family member Sst2 (refs 6-9) permits spontaneous activation of the G-protein-coupled mating pathway in Saccharomyces cerevisiae at levels normally seen only in the presence of ligand. Our work demonstrates the occurence of spontaneous tripartite G-protein signalling in vivo and identifies a requirement for RGS proteins in preventing such receptor-independent activation. AU - Daria Siekhaus AU - Drubin, David G ID - 3150 IS - 3 JF - Nature Cell Biology TI - Spontaneous receptor-independent heterotrimeric G-protein signalling in an RGS mutant VL - 5 ER - TY - JOUR AB - We show that the fixed alphabet shortest common supersequence (SCS) and the fixed alphabet longest common subsequence (LCS) problems parameterized in the number of strings are W[1]-hard. Unless W[1]=FPT, this rules out the existence of algorithms with time complexity of O(f(k)nα) for those problems. Here n is the size of the problem instance, α is constant, k is the number of strings and f is any function of k. The fixed alphabet version of the LCS problem is of particular interest considering the importance of sequence comparison (e.g. multiple sequence alignment) in the fixed length alphabet world of DNA and protein sequences. AU - Krzysztof Pietrzak ID - 3209 IS - 4 JF - Journal of Computer and System Sciences TI - On the parameterized complexity of the fixed alphabet shortest common supersequence and longest common subsequence problems VL - 67 ER - TY - CONF AB - Luby and Rackoff showed how to construct a (super-)pseudo-random permutation {0,1}2n→ {0,1}2n from some number r of pseudo-random functions {0,1}n → {0,1}n. Their construction, motivated by DES, consists of a cascade of r Feistel permutations. A Feistel permutation 1for a pseudo-random function f is defined as (L, R) → (R,L ⊕ f (R)), where L and R are the left and right part of the input and ⊕ denotes bitwise XOR or, in this paper, any other group operation on {0,1}n. The only non-trivial step of the security proof consists of proving that the cascade of r Feistel permutations with independent uniform random functions {0,1}n → {0,1}n, denoted Ψ2nr is indistinguishable from a uniform random permutation {0,1}2n → {0,1}2n by any computationally unbounded adaptive distinguisher making at most O(2cn) combined chosen plaintext/ciphertext queries for any c < α, where a is a security parameter. Luby and Rackoff proved α = 1/2 for r = 4. A natural problem, proposed by Pieprzyk is to improve on α for larger r. The best known result, α = 3/4 for r = 6, is due to Patarin. In this paper we prove a = 1 -O(1/r), i.e., the trivial upper bound α = 1 can be approached. The proof uses some new techniques that can be of independent interest. AU - Maurer, Ueli M AU - Krzysztof Pietrzak ID - 3210 TI - The security of many round Luby Rackoff pseudo random permutations VL - 2656 ER - TY - CONF AU - Bollenbach, Mark Tobias AU - Strother, T. AU - Bauer, Wolfgang ID - 3425 TI - 3D supernova collapse calculations VL - 166 ER - TY - CHAP AU - Peter Jonas AU - Unsicker, Klaus ED - Schmidt, R. F. ID - 3458 T2 - Lehrbuch Vorklinik TI - Molekulare und zelluläre Grundlagen des Nervensystems. VL - B ER - TY - JOUR AB - Genetic engineering of the mouse brain allows investigators to address novel hypotheses in vivo. Because of the paucity of information on the network patterns of the mouse hippocampus, we investigated the electrical patterns in the behaving animal using multisite silicon probes and wire tetrodes. Theta (6-9 Hz) and gamma (40-100 Hz) oscillations were present during exploration and rapid eye movement sleep. Gamma power and theta power were comodulated and gamma power varied as a function of the theta cycle. Pyramidal cells and putative interneurons were phase-locked to theta oscillations. During immobility, consummatory behaviors and slow-wave sleep, sharp waves were present in cornu ammonis region CA1 of the hippocampus stratum radiatum associated with 140-200-Hz “ripples” in the pyramidal cell layer and population burst of CA1 neurons. In the hilus, large-amplitude “dentate spikes” occurred in association with increased discharge of hilar neurons. The amplitude of field patterns was larger in the mouse than in the rat, likely reflecting the higher neuron density in a smaller brain. We suggest that the main hippocampal network patterns are mediated by similar pathways and mechanisms in mouse and rat. AU - Buzsáki, György AU - Buhl, Derek L AU - Harris, Kenneth D AU - Jozsef Csicsvari AU - Czéh, Boldizsár AU - Morozov, Alexei ID - 3536 IS - 1 JF - Neuroscience TI - Hippocampal network patterns of activity in the mouse VL - 116 ER - TY - CONF AB - We define the Morse-Smale complex of a Morse function over a 3-manifold as the overlay of the descending and as- cending manifolds of all critical points. In the generic case, its 3-dimensional cells are shaped like crystals and are sepa- rated by quadrangular faces. In this paper, we give a combi- natorial algorithm for constructing such complexes for piece- wise linear data. AU - Herbert Edelsbrunner AU - Harer, John AU - Natarajan, Vijay AU - Pascucci, Valerio ID - 3556 TI - Morse-Smale complexes for piecewise linear 3-manifolds ER - TY - CHAP AB - Given a finite point set in R, the surface reconstruction problem asks for a surface that passes through many but not necessarily all points. We describe an unambigu- ous definition of such a surface in geometric and topological terms, and sketch a fast algorithm for constructing it. Our solution overcomes past limitations to special point distributions and heuristic design decisions. AU - Herbert Edelsbrunner ID - 3573 T2 - Discrete & Computational Geometry TI - Surface reconstruction by wrapping finite sets in space ER - TY - JOUR AB - We develop fast algorithms for computing the linking number of a simplicial complex within a filtration.We give experimental results in applying our work toward the detection of non-trivial tangling in biomolecules, modeled as alpha complexes. AU - Edelsbrunner, Herbert AU - Zomorodian, Afra ID - 3584 IS - 2 JF - Homology, Homotopy and Applications TI - Computing linking numbers of a filtration VL - 5 ER - TY - JOUR AB - Stable hybrid zones in which ecologically divergent taxa give rise to a range of recombinants are natural laboratories in which the genetic basis of adaptation and reproductive isolation can be unraveled. One such hybrid zone is formed by the fire-bellied toads Bombina bombina and B. variegata (Anura: Discoglossidae). Adaptations to permanent and ephemeral breeding habitats, respectively, have shaped numerous phenotypic differences between the taxa. All of these are, in principle, candidates for a genetic dissection via QTL mapping. We present here a linkage map of 28 codominant and 10 dominant markers in the Bombina genome. In an F2 cross, markers that were mainly microsatellites, SSCPs or allozymes were mapped to 20 linkage groups. Among the 40 isolated CA microsatellites, we noted a preponderance of compound and frequently interleaved CA-TA repeats as well as a striking polarity at the 5′ end of the repeats. AU - Nürnberger, Beate AU - Hofman, Sebastian AU - Förg-Brey, Bqruni AU - Praetzel, Gabriele AU - Maclean, Alan W AU - Szymura, Jacek M AU - Abbott, Catherine M AU - Nicholas Barton ID - 3620 IS - 2 JF - Heredity TI - A linkage map for the hybridising toads Bombina bombina and B. variegata (Anura: Discoglossidae) VL - 91 ER - TY - JOUR AB - What is the chance that some part of a stretch of genome will survive? In a population of constant size, and with no selection, the probability of survival of some part of a stretch of map length y<1 approaches View the MathML source for View the MathML source. Thus, the whole genome is certain to be lost, but the rate of loss is extremely slow. This solution extends to give the whole distribution of surviving block sizes as a function of time. We show that the expected number of blocks at time t is 1+yt and give expressions for the moments of the number of blocks and the total amount of genome that survives for a given time. The solution is based on a branching process and assumes complete interference between crossovers, so that each descendant carries only a single block of ancestral material. We consider cases where most individuals carry multiple blocks, either because there are multiple crossovers in a long genetic map, or because enough time has passed that most individuals in the population are related to each other. For species such as ours, which have a long genetic map, the genome of any individual which leaves descendants (∼80% of the population for a Poisson offspring number with mean two) is likely to persist for an extremely long time, in the form of a few short blocks of genome. AU - Baird, Stuart J AU - Nicholas Barton AU - Etheridge, Alison M ID - 3619 IS - 4 JF - Theoretical Population Biology TI - The distribution of surviving blocks of an ancestral genome VL - 64 ER - TY - JOUR AB - There are several analyses in evolutionary ecology which assume that a family of offspring has come from only two parents. Here, we present a simple test for detecting when a batch involves two or more subfamilies. It is based on the fact that the mixing of families generates associations amongst unlinked marker loci. We also present simulations illustrating the power of our method for varying numbers of loci, alleles per locus and genotyped individuals. AU - Vines, Timothy H AU - Nicholas Barton ID - 3618 IS - 7 JF - Molecular Ecology TI - A new approach to detecting mixed families VL - 12 ER - TY - JOUR AB - We use the lac operon in Escherichia coli as a prototype system to illustrate the current state, applicability, and limitations of modeling the dynamics of cellular networks. We integrate three different levels of description (molecular, cellular, and that of cell population) into a single model, which seems to capture many experimental aspects of the system. AU - Vilar,Jose M AU - Calin Guet AU - Leibler, Stanislas ID - 3752 IS - 3 JF - Journal of Cell Biology TI - Modeling network dynamics: the lac operon, a case study VL - 161 ER - TY - JOUR AU - Bauer, Wolfgang AU - Kleine Berkenbusch, Marco AU - Bollenbach, Mark Tobias ID - 3797 IS - 4 JF - Revista Mexicana De Fisica TI - Breaking atomic nuclei into little pieces: evidence for a phase transition VL - 49 ER - TY - CONF AB - Many verification, planning, and control problems can be modeled as games played on state-transition graphs by one or two players whose conflicting goals are to form a path in the graph. The focus here is on simple stochastic parity games, that is, two-player games with turn-based probabilistic transitions and omega-regular objectives formalized as parity (Rabin chain) winning conditions. An efficient translation from simple stochastic parity games to nonstochastic parity games is given. As many algorithms are known for solving the latter, the translation yields efficient algorithms for computing the states of a simple stochastic parity game from which a player can win with probability 1. An important special case of simple stochastic parity games are the Markov decision processes with Buchi objectives. For this special case a first provably subquadratic algorithm is given for computing the states from which the single player has a strategy to achieve a Buchi objective with probability 1. For game graphs with m edges the algorithm works in time O(mrootm). Interestingly, a similar technique sheds light on the question of the computational complexity of solving simple Buchi games and yields the first provably subquadratic algorithm, with a running time of O(n(2)/log n) for game graphs with n vertices and O(n) edges. AU - Krishnendu Chatterjee AU - Jurdziński, Marcin AU - Thomas Henzinger ID - 3897 TI - Simple stochastic parity games VL - 2803 ER - TY - CONF AB - We study the problem of determining stack boundedness and the exact maximum stack size for three classes of interrupt-driven programs. Interrupt-driven programs axe used in many real-time applications that require responsive interrupt handling. In order to ensure responsiveness, programmers often enable interrupt processing in the body of lower-priority interrupt handlers. In such programs a programming error can allow interrupt handlers to be interrupted in cyclic fashion to lead to an unbounded stack, causing the system to crash. For a restricted class of interrupt-driven programs, we show that there is a polynomial-time procedure to check stack boundedness, while determining the exact maximum stack size is PSPACE-complete. For a larger class of programs, the two problems are both PSPACE-complete, and for the largest class of programs we consider, the two problems are PSPACE-hard and can be solved in exponential time. AU - Krishnendu Chatterjee AU - Ma, Di AU - Majumdar, Ritankar S AU - Zhao, Tian AU - Thomas Henzinger AU - Palsberg, Jens ID - 3898 TI - Stack size analysis for interrupt-driven programs VL - 2694 ER - TY - JOUR AB - We present algorithms for constructing a hierarchy of increasingly coarse Morse-Smale complexes that decompose a piecewise linear 2-manifold. While these complexes are defined only in the smooth category, we extend the construction to the piecewise linearcategory by ensuring structural integrity and simulating differentiability. We then simplify Morse-Smale complexes by canceling pairs of critical points in order of increasing persistence. AU - Herbert Edelsbrunner AU - Harer, John AU - Zomorodian, Afra ID - 3993 IS - 1 JF - Discrete & Computational Geometry TI - Hierarchical Morse-Smale complexes for piecewise linear 2-manifolds VL - 30 ER - TY - JOUR AB - The body defined by a finite collection of disks is a subset of the plane bounded by a tangent continuous curve, which we call the skin. We give analytic formulas for the area, the perimeter, the area derivative, and the perimeter derivative of the body. Given the filtrations of the Delaunay triangulation and the Voronoi diagram of the disks, all formulas can be evaluated in time proportional to the number of disks. AU - Cheng, Ho-Lun AU - Herbert Edelsbrunner ID - 3994 IS - 2 JF - Computational Geometry: Theory and Applications TI - Area, perimeter and derivatives of a skin curve VL - 26 ER - TY - GEN AB - Significant advances have been made during the past few years in our understanding of how the spinal monosynaptic reflex develops. Transcription factors in the Neurogenin, Runt, ETS, and LIM families control sequential steps of the specification of various subtypes of dorsal root ganglia sensory neurons. The initiation of muscle spindle differentiation requires neuregulin 1, derived from Ia afferent sensory neurons, and signaling through ErbB receptors in intrafusal muscle fibers. Several retrograde signals from the periphery are important for the establishment of late connectivity in the reflex circuit. Finally, neurotrophin 3 released from muscle spindles regulates the strength of sensory-motor connections within the spinal cord postnatally. AU - Chen, Hsiao Huei AU - Simon Hippenmeyer AU - Arber, Silvia AU - Frank, Eric ID - 3139 IS - 1 T2 - Current Opinion in Neurobiology TI - Development of the monosynaptic stretch reflex circuit VL - 13 ER - TY - CONF AB - Reconstructing a 3-D scene from more than one camera is a classical problem in computer vision. One of the major sources of difficulty is the fact that not all scene elements are visible from all cameras. In the last few years, two promising approaches have been developed 11,12 that formulate the scene reconstruction problem in terms of energy minimization, and minimize the energy using graph cuts. These energy minimization approaches treat the input images symmetrically, handle visibility constraints correctly, and allow spatial smoothness to be enforced. However, these algorithm propose different problem formulations, and handle a limited class of smoothness terms. One algorithm 11 uses a problem formulation that is restricted to two-camera stereo, and imposes smoothness between a pair of cameras. The other algorithm 12 can handle an arbitrary number of cameras, but imposes smoothness only with respect to a single camera. In this paper we give a more general energy minimization formulation for the problem, which allows a larger class of spatial smoothness constraints. We show that our formulation includes both of the previous approaches as special cases, as well as permitting new energy functions. Experimental results on real data with ground truth are also included. AU - Vladimir Kolmogorov AU - Zabih, Ramin AU - Gortler, Steven ID - 3171 TI - Generalized multi camera scene reconstruction using graph cuts VL - 2683 ER - TY - CONF AB - We address visual correspondence problems without assuming that scene points have similar intensities in different views. This situation is common, usually due to non-lambertian scenes or to differences between cameras. We use maximization of mutual information, a powerful technique for registering images that requires no a priori model of the relationship between scene intensities in different views. However, it has proven difficult to use mutual information to compute dense visual correspondence. Comparing fixed-size windows via mutual information suffers from the well-known problems of fixed windows, namely poor performance at discontinuities and in low-texture regions. In this paper, we show how to compute visual correspondence using mutual information without suffering from these problems. Using 'a simple approximation, mutual information can be incorporated into the standard energy minimization framework used in early vision. The energy can then be efficiently minimized using graph cuts, which preserve discontinuities and handle low-texture regions. The resulting algorithm combines the accurate disparity maps that come from graph cuts with the tolerance for intensity changes that comes from mutual information. AU - Kim, Junhwan AU - Vladimir Kolmogorov AU - Zabih, Ramin ID - 3174 TI - Visual correspondence using energy minimization and mutual information VL - 2 ER - TY - CONF AB - Geodesic active contours and graph cuts are two standard image segmentation techniques. We introduce a new segmentation method combining some of their benefits. Our main intuition is that any cut on a graph embedded in some continuous space can be interpreted as a contour (in 2D) or a surface (in 3D). We show how to build a grid graph and set its edge weights so that the cost of cuts is arbitrarily close to the length (area) of the corresponding contours (surfaces) for any anisotropic Riemannian metric. There are two interesting consequences of this technical result. First, graph cut algorithms can be used to find globally minimum geodesic contours (minimal surfaces in 3D) under arbitrary Riemannian metric for a given set of boundary conditions. Second, we show how to minimize metrication artifacts in existing graph-cut based methods in vision. Theoretically speaking, our work provides an interesting link between several branches of mathematics -differential geometry, integral geometry, and combinatorial optimization. The main technical problem is solved using Cauchy-Crofton formula from integral geometry. AU - Boykov, Yuri AU - Vladimir Kolmogorov ID - 3170 TI - Computing geodesics and minimal surfaces via graph cuts VL - 1 ER - TY - JOUR AB - Neurons can produce action potentials with high temporal precision(1). A fundamental issue is whether, and how, this capability is used in information processing. According to the `cell assembly' hypothesis, transient synchrony of anatomically distributed groups of neurons underlies processing of both external sensory input and internal cognitive mechanisms(2-4). Accordingly, neuron populations should be arranged into groups whose synchrony exceeds that predicted by common modulation by sensory input. Here we find that the spike times of hippocampal pyramidal cells can be predicted more accurately by using the spike times of simultaneously recorded neurons in addition to the animals location in space. This improvement remained when the spatial prediction was refined with a spatially dependent theta phase modulation(5-8). The time window in which spike times are best predicted from simultaneous peer activity is 10-30 ms, suggesting that cell assemblies are synchronized at this timescale. Because this temporal window matches the membrane time constant of pyramidal neurons(9), the period of the hippocampal gamma oscillation(10) and the time window for synaptic plasticity(11), we propose that cooperative activity at this timescale is optimal for information transmission and storage in cortical circuits. AU - Harris, Kenneth D AU - Jozsef Csicsvari AU - Hirase, Hajima AU - Dragoi, George AU - Buzsáki, György ID - 3526 IS - 6948 JF - Nature TI - Organization of cell assemblies in the hippocampus VL - 424 ER - TY - JOUR AB - Parallel recording of neuronal activity in the behaving animal is a prerequisite for our understanding of neuronal representation and storage of information. Here we describe the development of micro-machined silicon microelectrode arrays for unit and local field recordings. The two-dimensional probes with 96 or 64 recording sites provided high-density recording of unit and field activity with minimal tissue displacement or damage. The on-chip active circuit eliminated movement and other artifacts and greatly reduced the weight of the headgear. The precise geometry of the recording tips allowed for the estimation of the spatial location of the recorded neurons and for high-resolution estimation of extracellular current source density. Action potentials could be simultaneously recorded from the soma and dendrites of the same neurons. Silicon technology is a promising approach for high-density, high-resolution sampling of neuronal activity in both basic research and prosthetic devices. AU - Jozsef Csicsvari AU - Henze, Darrell A AU - Jamieson, Brian G AU - Harris, Kenneth D AU - Sirota, Anton M AU - Bartho, Peter AU - Wise, Kensall D AU - Buzsáki, György ID - 3529 IS - 2 JF - Journal of Neurophysiology TI - Massively parallel recording of unit and local field potentials with silicon-based electrodes VL - 90 ER - TY - JOUR AB - Gamma frequency oscillations (30-100 Hz) have been suggested to underlie various cognitive and motor functions. Here, we examine the generation of gamma oscillation currents in the hippocampus, using two-dimensional, 96-site silicon probes. Two gamma generators were identified, one in the dentate gyrus and another in the CA3-CA1 regions. The coupling strength between the two oscillators varied during both theta and nontheta states. Both pyramidal cells and interneurons were phase-locked to gamma waves. Anatomical connectivity, rather than physical distance, determined the coupling strength of the oscillating neurons. CA3 pyramidal neurons discharged CA3 and CA1 interneurons at latencies indicative of monosynaptic connections. Intrahippocampal gamma oscillation emerges in the CA3 recurrent system, which entrains the CA1 region via its interneurons. AU - Jozsef Csicsvari AU - Jamieson, Brian G AU - Wise, Kensall D AU - Buzsáki, György ID - 3528 IS - 2 JF - Neuron TI - Mechanisms of gamma oscillations in the hippocampus of the behaving rat VL - 37 ER - TY - JOUR AB - Both neocortical and hippocampal networks organize the firing patterns of their neurons by prominent oscillations during sleep, but the functional role of these rhythms is not well understood. Here, we show a robust correlation of neuronal discharges between the somatosensory cortex and hippocampus on both slow and fine time scales in the mouse and rat. Neuronal bursts in deep cortical layers, associated with sleep spindles and delta waves/slow rhythm, effectively triggered hippocampal discharges related to fast (ripple) oscillations. We hypothesize that oscillation-mediated temporal links coordinate specific information transfer between neocortical and hippocampal cell assemblies. Such a neocortical-hippocampal interplay may be important for memory consolidation. AU - Sirota, Anton M AU - Jozsef Csicsvari AU - Buhl, Derek L AU - Buzsáki, György ID - 3543 IS - 4 JF - PNAS TI - Communication between neocortex and hippocampus during sleep in rodents VL - 100 ER - TY - JOUR AB - Temporal logics such as Computation Tree Logic (CTL) and Linear Temporal Logic (LTL) have become popular for specifying temporal properties over a wide variety of planning and verification problems. In this paper we work towards building a generalized framework for automated reasoning based on temporal logics. We present a powerful extension of CTL with first-order quantification over the set of reachable states for reasoning about extremal properties of weighted labeled transition systems in general. The proposed logic, which we call Weighted Quantified Computation Tree Logic (WQCTL), captures the essential elements common to the domain of planning and verification problems and can thereby be used as an effective specification language in both domains. We show that in spite of the rich, expressive power of the logic, we are able to evaluate WQCTL formulas in time polynomial in the size of the state space times the length of the formula. Wepresent experimental results on the WQCTL verifier. AU - Krishnendu Chatterjee AU - Dasgupta, Pallab AU - Chakrabarti, Partha P ID - 3593 IS - 2 JF - Journal of Automated Reasoning TI - A branching time temporal framework for quantitative reasoning VL - 30 ER - TY - THES AU - Christoph Lampert ID - 3678 T2 - Bonner Mathematische Schriften TI - The Neumann operator in strictly pseudoconvex domains with weighted Bergman metric VL - 356 ER - TY - JOUR AB - The combination of high-resolution atomic force microscopy (AFM) imaging and single-molecule force-spectroscopy was employed to unfold single bacteriorhodopsins (BR) from native purple membrane patches at various physiologically relevant temperatures. The unfolding spectra reveal detailed insight into the stability of individual structural elements of BR against mechanical unfolding. Intermittent states in the unfolding process are associated with the stepwise unfolding of alpha-helices, whereas other states are associated with the unfolding of polypeptide loops connecting the alpha-helices. It was found that the unfolding forces of the secondary structures considerably decreased upon increasing the temperature from 8 to 52°C. Associated with this effect, the probability of individual unfolding pathways of BR was significantly influenced by the temperature. At lower temperatures, transmembrane alpha-helices and extracellular polypeptide loops exhibited sufficient stability to individually establish potential barriers against unfolding, whereas they predominantly unfolded collectively at elevated temperatures. This suggests that increasing the temperature decreases the mechanical stability of secondary structural elements and changes molecular interactions between secondary structures, thereby forcing them to act as grouped structures. AU - Harald Janovjak AU - Kessler, Max AU - Oesterhelt, Dieter AU - Gaub, Hermann AU - Mueller, Daniel J ID - 3725 IS - 19 JF - EMBO Journal TI - Unfolding pathways of native bacteriorhodopsin depend on temperature VL - 22 ER - TY - JOUR AB - Kv3 channels are thought to be essential for the fast-spiking (FS) phenotype in GABAergic interneurons, but how these channels confer the ability to generate action potentials (APs) at high frequency is unknown. To address this question, we developed a fast dynamic-clamp system (approximately 50 kHz) that allowed us to add a Kv3 model conductance to CA1 oriens alveus (OA) interneurons in hippocampal slices. Selective pharmacological block of Kv3 channels by 0.3 mm 4-aminopyridine or 1 mm tetraethylammonium ions led to a marked broadening of APs during trains of short stimuli and a reduction in AP frequency during 1 sec stimuli. The addition of artificial Kv3 conductance restored the original AP pattern. Subtraction of Kv3 conductance by dynamic clamp mimicked the effects of the blockers. Application of artificial Kv3 conductance also led to FS in OA interneurons after complete K+ channel block and even induced FS in hippocampal pyramidal neurons in the absence of blockers. Adding artificial Kv3 conductance with altered deactivation kinetics revealed a nonmonotonic relationship between mean AP frequency and deactivation rate, with a maximum slightly above the original value. Insertion of artificial Kv3 conductance with either lowered activation threshold or inactivation also led to a reduction in the mean AP frequency. However, the mechanisms were distinct. Shifting the activation threshold induced adaptation, whereas adding inactivation caused frequency-dependent AP broadening. In conclusion, Kv3 channels are necessary for the FS phenotype of OA interneurons, and several of their gating properties appear to be optimized for high-frequency repetitive activity. AU - Lien, Cheng-Chang AU - Peter Jonas ID - 3804 IS - 6 JF - Journal of Neuroscience TI - Kv3 potassium conductance is necessary and kinetically optimized for high-frequency action potential generation in hippocampal interneurons VL - 23 ER - TY - JOUR AB - To probe exocytosis at a cortical glutamatergic synapse, we made capacitance measurements in whole-cell recorded hippocampal mossy fiber terminals. Evaluation of different methods by using a morphology-based equivalent electrical model revealed that quantitative capacitance measurements are possible in this presynaptic structure. Voltage pulses leading to presynaptic Ca2+ inflow evoked large capacitance signals that showed saturation with increasing pulse duration. The mean peak capacitance increase was 100 fF, corresponding to a pool of approximately 1,400 releasable vesicles. Thus hippocampal mossy fiber synapses have a vesicular "maxipool." Large pool size and rapid vesicle recycling may underlie the uniquely large extent of activity-dependent plasticity in this synapse. AU - Hallermann, Stefan AU - Pawlu, Christian AU - Peter Jonas AU - Heckmann, Manfred ID - 3806 IS - 15 JF - PNAS TI - A large pool of releasable vesicles in a cortical glutamatergic synapse VL - 100 ER - TY - JOUR AB - Unlike most social insects, many Cardiocondyla ant species have two male morphs: wingless (ergatoid) males, who remain in the natal nest, and winged males who disperse but, strangely, before leaving may also mate within the nest. Whereas ergatoid males are highly intolerant of each other and fight among themselves, they tend to tolerate their winged counterparts. This is despite the fact that these winged males, like ergatoid males, represent mating competition. Why should ergatoid males tolerate their winged rivals? We developed a mathematical model to address this question. Our model focuses on a number of factors likely toinfluence whether ergatoid males are tolerant of winged males: ergatoid male–winged male relatedness, number of virgin queens, number of winged males, and the number of ejaculates a winged male has (winged males are sperm limited, whereas ergatoid males have lifelong spermatogenesis). Surprisingly, we found that increasing the number of virgin queens favors a kill strategy, whereas an increase in the other factors favors a let-live strategy; these predictions appear true for C. obscurior and for a number of other Cardiocondyla species. Two further aspects, unequal insemination success and multiple mating in queens, were also incorporated into the model and predictions made about their effects on toleration of winged males. The model is applicable more generally in species that have dimorphic males, such as some other ants, bees, and fig wasps. AU - Anderson, Carl AU - Cremer, Sylvia AU - Heinze, Jürgen ID - 3921 IS - 1 JF - Behavioral Ecology TI - Live and let die: Why fighter males of the ant Cardiocondyla kill each other but tolerate their winged rivals VL - 14 ER - TY - JOUR AB - Dispersal is advantageous, but, at the same time, it implies high costs and risks. Due to these counteracting selection pressures, many species evolved dispersal polymorphisms, which, in ants, are typically restricted to the female sex (queens). Male polymorphism is presently only known from a few genera, such as Cardiocondyla, in which winged dispersing males coexist with wingless fighter males that mate exclusively inside their maternal nests. We studied the developmental mechanisms underlying these alternative male morphs and found that, first, male dimorphism is not genetically determined, but is induced by environmental conditions (decreasing temperature and density). Second, male morph is not yet fixed at the egg stage, but it differentiates during larval development. This flexible developmental pattern of male morphs allows Cardiocondyla ant colonies to react quickly to changes in their environment. Under good conditions, they invest exclusively in philopatric wingless males. But, when environmental conditions turn bad, colonies start to produce winged dispersal males, even though these males require a many times higher investment by the colony than their much smaller wingless counterparts. Cardiocondyla ants share this potential of optimal resource allocation with other colonial animals and some seed dimorphic plants. AU - Cremer, Sylvia AU - Heinze, Jürgen ID - 3922 IS - 3 JF - Current Biology TI - Stress grows wings: Environmental induction of winged dispersal males in Cardiocondyla ants VL - 13 ER - TY - JOUR AB - Male dimorphism is not genetically determined, but is induced by environmental conditions particularly decreasing temperature and density. AU - Cremer, Sylvia AU - Heinze, Jürgen ID - 3917 IS - 15 JF - Blick in die Wissenschaft TI - Zwischen Hochzeitsflug und Brudermord: reproduktive Taktiken bei Ameisenmännchen VL - 12 ER - TY - THES AB - Methods for the formal specification and verification of systems are indispensible for the development of complex yet correct systems. In formal verification, the designer describes the system in a modeling language with a well-defined semantics, and this system description is analyzed against a set of correctness requirements. Model checking is an algorithmic technique to check that a system description indeed satisfies correctness requirements given as logical specifications. While successful in hardware verification, the potential for model checking for software and embedded systems has not yet been realized. This is because traditional model checking focuses on systems modeled as finite state-transition graphs. While a natural model for hardware (especially synchronous hardware), state-transition graphs often do not capture software and embedded systems at an appropriate level of granularity. This dissertation considers two orthogonal extensions to finite state-transition graphs making model checking techniques applicable to both a wider class of systems and a wider class of properties. The first direction is an extension to infinite-state structures finitely represented using constraints and operations on constraints. Infinite state arises when we wish to model variables with unbounded range (e.g., integers), or data structures, or real time. We provide a uniform framework of symbolic region algebras to study model checking of infinite-state systems. We also provide sufficient language-independent termination conditions for symbolic model checking algorithms on infinite state systems. The second direction supplements verification with game theoretic reasoning. Games are natural models for interactions between components. We study game theoretic behavior with winning conditions given by temporal logic objectives both in the deterministic and in the probabilistic context. For deterministic games, we provide an extremal model characterization of fixpoint algorithms that link solutions of verification problems to solutions for games. For probabilistic games we study fixpoint characterization of winning probabilities for games with omega-regular winning objectives, and construct (epsilon-)optimal winning strategies. AU - Majumdar, Ritankar ID - 4416 TI - Symbolic algorithms for verification and control ER - TY - THES AB - Giotto provides a time-triggered programmer’s model for the implementation of embedded control systems with hard real-time constraints. Giotto’s precise semantics and predictabil- ity make it suitable for safety-critical applications. Giotto is based around the idea that time-triggered task invocation together with time-triggered mode switching can form a useful programming model for real-time systems. To substantiate this claim, we describe the use of Giotto to refactor the software of a small, autonomous helicopter. The ease with which Giotto expresses the existing software provides evidence that Giotto is an appropriate programming language for control systems. Since Giotto is a real-time programming language, ensuring that Giotto programs meet their deadlines is crucial. To study precedence-constrained Giotto scheduling, we first examine single-mode, single-processor scheduling. We extend to an infinite, periodic setting the classical problem of meeting deadlines for a set of tasks with release times, deadlines, precedence constraints, and preemption. We then develop an algorithm for scheduling Giotto programs on a single processor by representing Giotto programs as instances of the extended scheduling problem. Next, we study multi-mode, single-processor Giotto scheduling. This problem is different from classical scheduling problems, since in our precedence-constrained approach, the deadlines of tasks may vary depending on the mode switching behavior of the program. We present conditional scheduling models which capture this varying-deadline behavior. We develop polynomial-time algorithms for some conditional scheduling models, and prove oth- ers to be computationally hard. We show how to represent multi-mode Giotto programs as instances of the model, resulting in an algorithm for scheduling multi-mode Giotto programs on a single processor. Finally, we show that the problem of scheduling Giotto programs for multiple net- worked processors is strongly NP-hard. AU - Horowitz, Benjamin ID - 4425 TI - Giotto: A time-triggered language for embedded programming ER - TY - JOUR AB - We study the free expansion of a pancake-shaped Bose-condensed gas, which is initially trapped under harmonic confinement and containing a vortex at its centre. In the case of a radial expansion holding the axial confinement fixed we consider various models for the interactions, depending on the thickness of the condensate relative to the value of the scattering length. We are thus able to evaluate different scattering regimes ranging from quasi-three-dimensional (Q3D) to strictly two-dimensional (2D). We find that as the system goes from Q3D to 2D the expansion rate of the condensate increases whereas that of the vortex core decreases. In the Q3D scattering regime we also examine a fully free expansion in 3D and find oscillatory behaviour for the vortex core radius: an initial fast expansion of the vortex core is followed by a slowing down. Such a nonuniform expansion rate of the vortex core implies that the timing of its observation should be chosen appropriately. AU - Onur Hosten AU - Vignolo, Patrizia AU - Minguzzi, Anna AU - Tanatar, Bilal AU - Tosi, Mario P ID - 576 IS - 12 JF - Journal of Physics B: Atomic, Molecular and Optical Physics TI - Free expansion of two-dimensional condensates with a vortex VL - 36 ER -