@article{4285, abstract = {One of the oldest hypotheses for the advantage of recombination is that recombination allo rvs beneficial mutations that arise in different individuals to be placed together on the same chromosome. Unless recombination occurs, one of the beneficial alleles is doomed to extinction, slowing the rate at which adaptive mutations are incorporated within a population. We model the effects of a modifier of recombination on the fixation probability of beneficial mutations when beneficial alleles are segregating at other loci. We find that modifier alleles that increase recombination do increase the fixation probability of beneficial mutants and subsequently hitchhike along as the mutants rise in frequency. The strength of selection favoring a modifier that increases recombination is proportional to lambda(2)S delta r/r when linkage is tight and lambda(2)S(3) delta r/N when linkage is loose, where lambda is the beneficial mutation rate per genome per generation throughout a population of size N, S is the average mutant effect, r is the average recombination rate, and delta ris the amount that recombination is modified. We conclude that selection for recombination will be substantial only if there is tight linkage within the genome or if many loci are subject to directional selection as during periods of rapid evolutionary change.}, author = {Otto, Sarah and Barton, Nicholas H}, issn = {0016-6731}, journal = {Genetics}, number = {2}, pages = {879 -- 906}, publisher = {Genetics Society of America}, title = {{The evolution of recombination: Removing the limits to natural selection}}, doi = {10.1093/genetics/147.2.879}, volume = {147}, year = {1997}, } @article{4286, abstract = {A local barrier to gene flow will delay the spread of an advantageous allele. Exact calculations for the deterministic case show that an allele that is favorable when rare is delayed very little even by a strong barrier; its spread is allowed by a time proportional to log((B/σ)√2S)/S, where B is the barrier strength, σ the dispersal range, and fitnesses are 1:1 + S:1 + 2S. However, when there is selection against heterozytes, such that the allele cannot increase from low frequency, a barrier can cause a much greater delay. If gene flow is reduced below a critical value, spread is entirely prevented. Stochastic simulations show that with additive selection, random drift slows down the spread of the allele, below the deterministic speed of σ√2S. The delay to the advance of an advantageous allele caused by a strong barrier can be substantially increased by random drift and increases with B/(2Sρσ2) in a one-dimensional habitat of density ρ. However, with selection against heterozygotes, drift can facilitate the spread and can free an allele that would otherwise be trapped indefinitely by a strong barrier. We discuss the implications of these results for the evolution of chromosome rearrangements.}, author = {Piálek, Jaroslav and Barton, Nicholas H}, issn = {0016-6731}, journal = {Genetics}, number = {2}, pages = {493 -- 504}, publisher = {Genetics Society of America}, title = {{The spread of an advantageous allele across a barrier: the effects of random drift and selection against heterozygotes}}, doi = {10.1093/genetics/145.2.493}, volume = {145}, year = {1997}, } @article{4287, abstract = {We evaluate Sewall Wright's three-phase "shifting balance" theory of evolution, examining both the theoretical issues and the relevant data from nature and the laboratory. We conclude that while phases I and II of Wright's theory (the movement of populations from one "adaptive peak" to another via drift and selection) can occur under some conditions, genetic drift is often unnecessary for movement between peaks. Phase III of the shifting balance, in which adaptations spread from particular populations to the entire species, faces two major theoretical obstacles: (1) unlike adaptations favored by simple directional selection, adaptations whose fixation requires some genetic drift are often prevented from spreading by barriers to gene flow; and (2) it is difficult to assemble complex adaptations whose constituent parts arise via peak shifts in different demes. Our review of the data from nature shows that although there is some evidence for individual phases of the shifting balance process, there are few empirical observations explained better by Wright's three-phase mechanism than by simple mass selection. Similarly, artificial selection experiments fail to show that selection in subdivided populations produces greater response than does mass selection in large populations. The complexity of the shifting balance process and the difficulty of establishing that adaptive valleys have been crossed by genetic drift make it impossible to test Wright's claim that adaptations commonly originate by this process. In view of these problems, it seems unreasonable to consider the shifting balance process as an important explanation for the evolution of adaptations. }, author = {Coyne, Jerry and Barton, Nicholas H and Turelli, Michael}, issn = {0014-3820}, journal = {Evolution; International Journal of Organic Evolution}, number = {3}, pages = {643 -- 671}, publisher = {Wiley-Blackwell}, title = {{Perspective: A critique of Sewall Wright's shifting balance theory of evolutionight's shifting balance theory of evolution}}, doi = {10.1111/j.1558-5646.1997.tb03650.x}, volume = {51}, year = {1997}, } @article{4288, abstract = {We measured the heterozygous effects on net fitness of a sample of 12 wild-type third chromosomes in D. melanogaster. Effects on fitness were assessed by competing the wild-type chromosomes against balancer chromosomes, to prevent the production of recombinants. The measurements were carried out in the population cage environment in which the life history had been evolving, in an undisturbed population with overlapping generations, and replicated measurements were made on each chromosome to control for confounding effects such as mutation accumulation. We found significant variation among the wild type chromosomes in their additive genetic effect on net fitness. The system provides an opportunity to obtain an accurate estimate of the distribution of heterozygous effects on net fitness, the contribution of different fitness components including male mating success, and the role of intra-chromosomal epistasis in fitness variation.}, author = {Fowler, Kevin and Semple, Colin and Barton, Nicholas H and Partridge, Linda}, issn = {0962-8452}, journal = {Proceedings of the Royal Society of London Series B Biological Sciences}, number = {1379}, pages = {191 -- 199}, publisher = {The Royal Society}, title = {{Genetic variation for total fitness in Drosophila melanogaster}}, doi = {10.1098/rspb.1997.0027}, volume = {264}, year = {1997}, } @article{4289, abstract = {A worldwide survey of polymorphic molecular markers shows that the human population is genetically homogeneous, in close agreement with evidence from quite different genes and traits.}, author = {Barton, Nicholas H}, issn = {0960-9822}, journal = {Current Biology}, number = {12}, pages = {757 -- 758}, publisher = {Cell Press}, title = {{Population genetics: A new apportionment of human diversity}}, doi = {10.1016/S0960-9822(06)00397-6}, volume = {7}, year = {1997}, } @misc{4290, author = {Barton, Nicholas H}, booktitle = {Genetical Research}, issn = {0016-6723}, number = {2}, pages = {178 -- 180}, publisher = {Cambridge University Press}, title = {{Natural hybridization and evolution}}, volume = {70}, year = {1997}, } @misc{4291, author = {Barton, Nicholas H}, booktitle = {Genetical Research}, issn = {0016-6723}, number = {2}, pages = {180 -- 181}, publisher = {Cambridge University Press}, title = {{The ecological detective: Confronting models with data}}, volume = {70}, year = {1997}, } @inbook{4293, abstract = {Natural populations differ from the simplest models in ways which can significantly affect their evolution. Real populations are rarely all of the same size; the rates of migration into and out of populations vary in space and time; some populations go extinct, and new ones are established, while all populations fluctuate in size. Furthermore, the genetic properties of real species are not like those assumed in simple models. Alleles are exposed to a wide variety of selection mutation rarely creates novel genotypes with each mutation event, generations overlap, and environments vary from place to place. Evolution in a metapopulation can be substantially different from the predictions of single-population models and, indeed, very different from the simplest models of subdivided species.}, author = {Barton, Nicholas H and Whitlock, Michael}, booktitle = {Metapopulation Biology}, editor = {Hanski, Illka and Gilpin, Michael E.}, isbn = {9780123234452}, pages = {183 -- 210}, publisher = {Academic Press}, title = {{The evolution of metapopulations}}, doi = {10.1016/B978-012323445-2/50012-2}, year = {1997}, } @inproceedings{4438, abstract = {In temporal-logic model checking, we verify the correctness of a program with respect to a desired behavior by checking whether a structure that models the program satisfies a temporal-logic formula that specifies the behavior. The model-checking problem for the branching-time temporal logic CTL can be solved in linear running time, and model-checking tools for CTL are used successfully in industrial applications. The development of programs that must meet rigid real-time constraints has brought with it a need for real-time temporal logics that enable quantitative reference to time. Early research on real-time temporal logics uses the discrete domain of the integers to model time. Present research on real-time temporal logics focuses on continuous time and uses the dense domain of the reals to model time. There, model checking becomes significantly more complicated. For example, the model-checking problem for TCTL, a continuous-time extension of the logic CTL, is PSPACE-complete. In this paper we suggest a reduction from TCTL model checking to CTL model checking. The contribution of such a reduction is twofold. Theoretically, while it has long been known that model-checking methods for untimed temporal logics can be extended quite easily to handle discrete time, it was not clear whether and how untimed methods can handle the reset quantifier of TCTL, which resets a realvalued clock. Practically, our reduction enables anyone who has a tool for CTL model checking to use it for TCTL model checking. The TCTL model-checking algorithm that follows from our reduction is in PSPACE, matching the known bound for this problem. In addition, it enjoys the wide distribution of CTL model-checking tools and the extensive and fruitful research efforts and heuristics that have been put into these tools.}, author = {Henzinger, Thomas A and Kupferman, Orna}, booktitle = {Proceedings of the 5th International Workshop on Hybrid and Real-Time Systems}, isbn = {9783540626008}, location = {Grenoble, France}, pages = {48 -- 62}, publisher = {Springer}, title = {{From quantity to quality}}, doi = {10.1007/BFb0014712}, volume = {1201}, year = {1997}, } @inproceedings{4441, abstract = {Rectangular hybrid automata model digital control programs of analog plant environments. We study rectangular hybrid automata where the plant state evolves continuously in real-numbered time, and the controller samples the plant state and changes the control state discretely, only at the integer points in time. We prove that rectangular hybrid automata have finite bisimilarity quotients when all control transitions happen at integer times, even if the constraints on the derivatives of the variables vary between control states. This is sharply in contrast with the conventional model where control transitions may happen at any real time, and already the reachability problem is undecidable. Based on the finite bisimilarity quotients, we give an exponential algorithm for the symbolic sampling-controller synthesis of rectangular automata. We show our algorithm to be optimal by proving the problem to be EXPTIME-hard. We also show that rectangular automata form a maximal class of systems for which the sampling-controller synthesis problem can be solved algorithmically.}, author = {Henzinger, Thomas A and Kopke, Peter}, booktitle = {Proceedings of the 24th International Colloquium on Automata, Languages and Programming}, isbn = {9783540631651}, location = {Bologna, Italy}, pages = {582 -- 593}, publisher = {Springer}, title = {{Discrete-time control for rectangular hybrid automata}}, doi = {10.1007/3-540-63165-8_213}, volume = {1256}, year = {1997}, } @article{4493, abstract = {A hybrid system is a dynamical system whose behavior exhibits both discrete and continuous change. A hybrid automaton is a mathematical model for hybrid systems, which combines, in a single formalism, automaton transitions for capturing discrete change with differential equations for capturing continuous change. HyTech is a symbolic model checker for linear hybrid automata, a subclass of hybrid automata that can be analyzed automatically by computing with polyhedral state sets. A key feature of HyTech is its ability to perform parametric analysis, i.e., to determine the values of design parameters for which a linear hybrid automaton satisfies a temporal-logic requirement.}, author = {Henzinger, Thomas A and Ho, Pei and Wong Toi, Howard}, issn = {1433-2779}, journal = {Software Tools For Technology Transfer}, number = {1-2}, pages = {110 -- 122}, publisher = {Springer}, title = {{HyTech: A model checker for hybrid systems}}, doi = {10.1007/s100090050008}, volume = {1}, year = {1997}, } @inproceedings{4494, abstract = {A hybrid system consists of a collection of digital programs that interact with each other and with an analog environment. Examples of hybrid systems include medical equipment, manufacturing controllers, automotive controllers, and robots. The formal analysis of the mixed digital-analog nature of these systems requires a model that incorporates the discrete behavior of computer programs with the continuous behavior of environment variables, such as temperature and pressure. Hybrid automata capture both types of behavior by combining finite automata with differential inclusions (i.e. differential inequalities). HyTech is a symbolic model checker for linear hybrid automata, an expressive, yet automatically analyzable, subclass of hybrid automata. A key feature of HyTech is its ability to perform parametric analysis, i.e. to determine the values of design parameters for which a linear hybrid automaton satisfies a temporal requirement.}, author = {Henzinger, Thomas A and Ho, Pei and Wong Toi, Howard}, isbn = {9783540631668}, location = {Haifa, Israel}, pages = {460 -- 463}, publisher = {Springer}, title = {{HyTech: A model checker for hybrid systems}}, doi = {10.1007/3-540-63166-6_48}, volume = {1254}, year = {1997}, } @inproceedings{4496, abstract = {The simulation preorder for labeled transition systems is defined locally as a game that relates states with their immediate successor states. Liveness assumptions about transition systems are typically modeled using fairness constraints. Existing notions of simulation for fair transition systems, however, are not local, and as a result, many appealing properties of the simulation preorder are lost. We extend the local definition of simulation to account for fairness: system S fairly simulates system I iff in the simulation game, there is a strategy that matches with each fair computation of I a fair computation of S. Our definition enjoys a fully abstract semantics and has a logical characterization: S fairly simulates I iff every fair computation tree embedded in the unrolling of I can be embedded also in the unrolling of S or, equivalently, iff every Fair-AFMC formula satisfied by I is satisfied also by S (AFMC is the universal fragment of the alternation-free -calculus). The locality of the definition leads us to a polynomial-time algorithm for checking fair simulation for finite-state systems with weak and strong fairness constraints. Finally, fair simulation implies fair trace-containment, and is therefore useful as an efficientlycomputable local criterion for proving linear-time abstraction hierarchies.}, author = {Henzinger, Thomas A and Kupferman, Orna and Rajamani, Sriram}, booktitle = {Proceedings of the 8th International Conference on Concurrency Theory}, isbn = {9783540631415}, location = {Warsaw, Poland}, pages = {273 -- 287}, publisher = {Springer}, title = {{Fair simulation}}, doi = {10.1007/3-540-63141-0_19}, volume = {1243}, year = {1997}, } @inproceedings{4520, abstract = {We define robust timed automata, which are timed automata that accept all trajectories robustly: if a robust timed automaton accepts a trajectory, then it must accept neighboring trajectories also; and if a robust timed automaton rejects a trajectory, then it must reject neighboring trajectories also. We show that the emptiness problem for robust timed automata is still decidable, by modifying the region construction for timed automata. We then show that, like timed automata, robust timed automata cannot be determinized. This result is somewhat unexpected, given that in temporal logic, the removal of realtime equality constraints is known to lead to a decidable theory that is closed under all boolean operations.}, author = {Gupta, Vineet and Henzinger, Thomas A and Jagadeesan, Radha}, booktitle = {Proceedings of the 5th International Workshop on Hybrid and Real-Time Systems}, isbn = {9783540626008}, location = {Grenoble, France}, pages = {331 -- 345}, publisher = {Springer}, title = {{Robust timed automata}}, doi = {10.1007/BFb0014736}, volume = {1201}, year = {1997}, } @article{2492, abstract = {The metabotropic glutamate receptor subtypes mGluR2 and mGluR5, which are thought to be coupled respectively to the inhibitory cyclic adenosine monophosphate (cAMP) cascade and the phosphatidylinositol hydrolysis/Ca2+ cascade, are known to be expressed on Golgi cells in the granular layer of the rat cerebellar cortex. In the present immunohistochemical study with a monoclonal antibody against mGluR2 and a polyclonal antibody for mGluR5, we examined whether or not mGluR2- and mGluR5-like immunoreactivities were both present in single Golgi cells in the rat cerebellar cortex. In double immunofluorescence histochemistry, no Golgi cells showed mGluR2- and mGluR5-like immunoreactivities simultaneously. Of the total number of Golgi cells immunoreactive for mGluR2 or mGluR5, about 90% were mGluR2-like immunoreactive, and about 10% were mGluR5-like immunoreactive. Golgi cells with mGluR2-like immunoreactivity were distributed evenly in the granular layer of all the cerebellar regions, while those with mGluR5-like immunoreactivity were distributed more frequently in the I, II, VII-X lobules of the vermis and the copula pyramidis of the hemisphere than in other cerebellar regions. The results indicate that Golgi cells containing mGluR2 are segregated from those possessing mGluR5. These two populations of Golgi cells, each equipped with a different metabolic glutamate receptor coupled to a different intracellular signal transduction system, may play different roles in the glutamatergic neuronal circuits in the cerebellar cortex.}, author = {Neki, Akio and Ohishi, Hitoshi and Kaneko, Takeshi and Shigemoto, Ryuichi and Nakanishi, Shigetada and Mizuno, Noboru}, issn = {0306-4522}, journal = {Neuroscience}, number = {3}, pages = {815 -- 826}, publisher = {Elsevier}, title = {{Metabotropic glutamate receptors mGluR2 and mGluR5 are expressed in two non-overlapping populations of Golgi cells in the rat cerebellum}}, doi = {10.1016/0306-4522(96)00316-8}, volume = {75}, year = {1996}, } @article{2562, abstract = {A monoclonal antibody against a metabotropic glutamate receptor, mGluR2, was produced by using a glutathione S-transferase (GST) fusion protein containing an N-terminal sequence of rat mGluR2. Intense mGluR2-like immunoreactivity (mGluR2-LI) was seen mainly in neuropil of the cerebral cortical regions, hippocampus, olfactory bulb, some diencephalic nuclei, dorsal cochlear nucleus and cerebellar cortex. In the cerebellar cortex, mGluR2-LI was seen only in Golgi cells. In Ammon's hem, mGluR2-LI was marked in the stratum lucidum of CA3 and the stratum lacunosum-moleculare of CA1-CA3, but not detected in the stratum pyramidale. The results indicate that mGluR2 is located not only presynaptically but also postsynaptically.}, author = {Neki, Akio and Ohishi, Hitoshi and Kaneko, Takeshi and Shigemoto, Ryuichi and Nakanishi, Shigetada and Mizuno, Noboru}, issn = {0304-3940}, journal = {Neuroscience Letters}, number = {3}, pages = {197 -- 200}, publisher = {Elsevier}, title = {{Pre- and postsynaptic localization of a metabotropic glutamate receptor, mGluR2, in the rat brain: An immunohistochemical study with a monoclonal antibody}}, doi = {10.1016/0304-3940(95)12248-6}, volume = {202}, year = {1996}, } @article{2564, abstract = {The distribution of the neuromedin K receptor (NK3; NKR) in the central nervous system was investigated in the adult rat by using in situ hybridization and immunohistochemical techniques. The rabbit anti-NKR antibody was raised against a bacterial fusion protein containing a C- terminal portion of NKR and affinity purified with a Sepharose 4B column conjugated to the fusion protein. Immunoblot analysis was performed to test the reactivity and specificity of the antibody. Crude membrane was prepared from cDNA-transfected Chinese hamster ovary (CHO) cells expressing each of the rat NKR, substance P receptor (NK1; SPR), and substance K receptor (NK2; SKR) and from the hypothalamus, cerebral cortex, and cerebellum. Immunoreactive bands were observed specifically in the NKR-CHO cells, hypothalamus, and cerebral cortex but not in the SPR- or SKR-CHO cells, nor in the cerebellum. Molecular weights of the immunoreactive bands ranged from 73 to 89 kDa and from 59 to 83 kDa in the NKR-CHO cells and tissues, respectively. The distribution of NKR-like immunoreactivity coincided with that of NKR mRNA. The expression of NKR was indicated on neuronal cell bodies and dendrites. NKR was found to be expressed intensely or moderately in neurons in the glomerular and granule cell layers of the main olfactory bulb; glomerular and mitral cell layers of the accessory olfactory bulb; layers IV and V of the cerebral neocortex; medial septal nucleus; nucleus of the diagonal band; bed nucleus of the stria terminalis; globus pallidus; ventral pallidum; paraventricular nucleus; supraoptic nucleus; zona incerta; dorsal, lateral, and posterior hypothalamic areas; amygdaloid nuclei; medial habenular nucleus; ventral tegmental area; midbrain periaqueductal gray; interpeduncular nuclei; substantia nigra pars compacta; linear, median, dorsal, and pontine raphe nuclei; posteromedial tegmental nucleus; sphenoid nucleus; nucleus of the solitary tract; intermediate and rostroventrolateral reticular nuclei; and lamina II of the caudal spinal trigeminal nucleus and spinal dorsal horn. These findings are discussed in relation to the physiological functions associated with neuromedin K.}, author = {Ding, Yu and Shigemoto, Ryuichi and Takada, Masahiko and Ohishi, Hitoshi and Nakanishi, Shigetada and Mizuno, Noboru}, issn = {0021-9967}, journal = {Journal of Comparative Neurology}, number = {2}, pages = {290 -- 310}, publisher = {Wiley-Blackwell}, title = {{Localization of the neuromedin K receptor (NK3) in the central nervous system of the rat}}, doi = {10.1002/(SICI)1096-9861(19960108)364:2<290::AID-CNE8>3.0.CO;2-0}, volume = {364}, year = {1996}, } @article{2565, abstract = {Immunoreactivity for the metabotropic glutamate receptor 7 (mGluR7) and that for phosphate-activated glutaminase (PAG) were examined in the trigeminal (TG), dorsal root (DRG), nodose (NG), superior cervical, celiac, and pelvic ganglia of the rat. Virtually all neuronal cell bodies showed mGluR7-like immunoreactivity (mGluR7-LI) in these ganglia. On the other hand, PAG-like immunoreactivity (PAG) was seen in almost all neuronal cell bodies in the TG, DRG and NG, but not in the other ganglia. Co-existence of mGluR7- and PAG-LI in the TG, DRG and NG was confirmed by a double-immunofluorescence immunohistochemical method. The results indicate that virtually all sensory ganglion neurons are glutamatergic and equipped with mGluR7.}, author = {Li, Jin and Ohishi, Hitoshi and Kaneko, Takeshi and Shigemoto, Ryuichi and Neki, Akio and Nakanishi, Shigetada and Mizuno, Noboru}, issn = {0304-3940}, journal = {Neuroscience Letters}, number = {1-2}, pages = {9 -- 12}, publisher = {Elsevier}, title = {{Immunohistochemical localization of a metabotropic glutamate receptor, mGluR7, in ganglion neurons of the rat; with special reference to the presence in glutamatergic ganglion neurons}}, doi = {10.1016/0304-3940(95)12299-0}, volume = {204}, year = {1996}, } @article{2566, abstract = {The present study indicated presynaptic localization of a metabotropic glutamate receptor, mGluR8, in projection neurons of the main olfactory bulb of rat. An antibody was produced by using a peptide corresponding to C-terminal 23 amino acids of mouse mGluR8. It was confirmed that the C-terminal 23 amino acids of rat mGluR8 were the same as those of mouse mGluR8 except for one, and that the antibody specifically recognized mGluR8 in the rat rhinencephalon. In layer Ia of the piriform cortex (a target area of projection fibers from the main olfactory bulb), mGluR8-like immunoreactivity (mGluR8-LI) was reduced after transection of the lateral olfactory tract, and mGluR8-LI was observed in axon terminals which were filled with round synaptic vesicles and made asymmetric synapses with dendritic spines.}, author = {Kinoshita, Ayae and Ohishi, Hitoshi and Neki, Akio and Nomura, Sakashi and Shigemoto, Ryuichi and Takada, Masahiko and Nakanishi, Shigetada and Mizuno, Noboru}, issn = {0304-3940}, journal = {Neuroscience Letters}, number = {1}, pages = {61 -- 64}, publisher = {Elsevier}, title = {{Presynaptic localization of a metabotropic glutamate receptor, mGluR8, in the rhinencephalic areas: A light and electron microscope study in the rat}}, doi = {10.1016/0304-3940(96)12489-7}, volume = {207}, year = {1996}, } @article{2567, abstract = {Trigeminothalamic and spinothalamic-tact neurons provided with substance P receptor (SPR) were examined in the rat by SPR immunofluorescence histochemistry combined with Fluoro-Gold (FG) fluorescent retrograde labeling. After FG injection in the thalamic regions, FG-labeled cells with SPR-like immunoreactivity were seen mainly in laminae I and m of the medullary and spinal dorsal horns and lateral spinal nucleus. In these regions, about one-fourth to one-third of FG-labeled cells showed SPR-like immunoreactivity.}, author = {Li, Jin and Ding, Yu and Shigemoto, Ryuichi and Mizuno, Noboru}, issn = {0006-8993}, journal = {Brain Research}, number = {1-2}, pages = {207 -- 212}, publisher = {Elsevier}, title = {{Distribution of trigeminothalamic and spinothalamic-tract neurons showing substance P receptor-like immunoreactivity in the rat}}, doi = {10.1016/0006-8993(96)00064-9}, volume = {719}, year = {1996}, }