@article{1947, abstract = {Mitochondrial transhydrogenase has been reported previously to be inhibited by high, rather non-physiological concentrations (in the range of 2-20 mM) of divalent cations. We show that the enzyme could be activated by low (from about 1 μM to 1 mM) concentrations of Ca2+ and Mg2+, which are within physiological range. These results bring in line the effects observed with mitochondrial enzyme to the findings with bacterial transhydrogenases. The activation of transhydrogenase by divalent cations is interpreted as an increase in affinity of the NADP(H)-binding site of the enzyme-NAD(H) complex. Reported effects of the metal ions could be important for the enzyme function in vivo.}, author = {Sazanov, Leonid A and Jackson, Julie}, issn = {0005-2728}, journal = {Biochimica et Biophysica Acta - Bioenergetics}, number = {2}, pages = {225 -- 228}, publisher = {Elsevier}, title = {{Activation and inhibition of mitochondrial transhydrogenase by metal ions}}, doi = {10.1016/0005-2728(93)90177-H}, volume = {1144}, year = {1993}, } @article{1948, author = {Sazanov, Leonid A and Jackson, Julie}, issn = {0300-5127}, journal = {Biochemical Society Transactions}, number = {3}, pages = {260}, publisher = {Portland Press}, title = {{Possible functions of the NADP-linked isocitrate dehydrogenase and H+ -transhydrogenase in heart mitochondria }}, doi = {10.1042/bst021260s}, volume = {21}, year = {1993}, } @article{1950, author = {Jackson, Julie and Cotton, N P J and Williams, Ross and Bizouarn, Tania and Hutton, Mike and Sazanov, Leonid A and Thomas, Christopher}, issn = {0300-5127}, journal = {Biochemical Society Transactions}, number = {4}, pages = {1010 -- 1013}, publisher = {Portland Press}, title = {{Proton-translocating transhydrogenase in bacteria}}, doi = {10.1042/bst0211010}, volume = {21}, year = {1993}, } @article{2487, abstract = {Distribution of the mRNA for a metabotropic glutamate receptor, mGluR3, which is coupled to the inhibitory cAMP cascade, was examined in the central nervous system of the adult albino rat by in situ hybridization. The hybridization signals of mGluR3 were detected not only on neuronal cells but also on many glial cells throughout the brain and spinal cord. In the neuronal cells, prominent expression of mGluR3 mRNA was seen in the thalamic reticular nucleus. Moderately labeled neurons were seen in the anterior olfactory nucleus, cerebral neo- and mesocortical regions, lateral amygdaloid nucleus, ventral part of the basolateral amygdaloid nucleus, dorsal endopiriform nucleus, supraoptic nucleus, superficial layers of the superior colliculus, inferior colliculus, interpeduncular nucleus, superior olivary nuclei, and Golgi cells in the cerebellar cortex. Weakly labeled neurons were observed in the striatum, nucleus accumbens, ventral pallidum, globus pallidus, entopeduncular nucleus, lateral hypothalamic area, hypothalamic paraventricular nucleus, medial habenular nucleus, anterior pretectal nucleus, Barrington's nucleus, Nucleus O, paragenual nucleus, trigeminal sensory complex, cochlear nuclei, dorsal motor nucleus of the trigeminal nerve, dorsal cap of the inferior olive, spinal dorsal horn, and lamina X of the spinal cord. The stellate cells in the cerebellar cortex, and neurons in the deep cerebellar nuclei were also labeled weakly. The granule cell layer of the dentate gyrus, as a whole, appeared to be labeled intensely, but each of the granule cells was labeled only weakly. No significant labeling was detected in the mitral and tufted cells in the olfactory bulb, hippocampal pyramidal cells, Purkinje and granule cells in the cerebellar cortex, or somatic motoneurons. The distribution of mGluR3 mRNA in particular neurons and glial cells indicates specific roles of mGluR3 in the glutamatergic system of the central nervous system.}, author = {Ohishi, Hitoshi and Shigemoto, Ryuichi and Nakanishi, Shigetada and Mizuno, Noboru}, issn = {0021-9967}, journal = {Journal of Comparative Neurology}, number = {2}, pages = {252 -- 266}, publisher = {Wiley-Blackwell}, title = {{ Distribution of the mRNA for a metabotropic glutamate receptor (mGluR3) in the rat brain: An in situ hybridization study}}, doi = {10.1002/cne.903350209}, volume = {335}, year = {1993}, } @article{2536, abstract = {A cDNA clone for a new metabotropic glutamate receptor, termed mGluR6, was isolated from a rat retinal cDNA library by cross-hybridization with the previously isolated cDNA clone for a metabotropic glutamate receptor. The cloned mGluR6 subtype consists of 871 amino acid residues and exhibits a structural architecture common to the metabotropic receptor family, possessing a large extracellular domain preceding the seven putative membrane-spanning domains. mGluR6 shows the highest sequence similarity to mGluR4 among the metabotropic receptor subtypes and inhibits the forskolin- stimulated cyclic AMP accumulation in Chinese hamster ovary cells transfected with the cloned cDNA. mGluR6 potently reacts with L-2-amino-4- phosphonobutyrate (L-AP4) and L-serine-O-phosphate, and the potencies of these compounds are one order of magnitude greater than that of L-glutamate. Blot and in situ hybridization analyses indicated that mGluR6 mRNA is restrictedly expressed in the inner nuclear layer of the retina where ON- bipolar cells are distributed. The metabotropic receptor that responds strongly to L-AP4 and L-serine-O-phosphate in ON-bipolar cells is known to mediate glutamate synaptic transmission between photoreceptor cells and ON- bipolar cells. On the basis of the agonist selectivity of mGluR6 and its specific expression in retinal cells, the physiological role of this receptor subtype in the visual system is discussed.}, author = {Nakajima, Yoshiaki and Iwakabe, Hideki and Akazawa, Chihiro and Nawa, Hiroyuki and Shigemoto, Ryuichi and Mizuno, Noboru and Nakanishi, Shigetada}, issn = {0021-9258}, journal = {Journal of Biological Chemistry}, number = {16}, pages = {11868 -- 11873}, publisher = {American Society for Biochemistry and Molecular Biology}, title = {{Molecular characterization of a novel retinal metabotropic glutamate receptor mGluR6 with a high agonist selectivity for L-2-amino-4- phosphonobutyrate}}, doi = {10.1016/S0021-9258(19)50280-0}, volume = {268}, year = {1993}, } @article{2537, abstract = {The metabotropic glutamate receptors are coupled to intracellular signal transduction via G-proteins and consist of a family of at least five different subtypes, termed mGluR1-mGluR5. We studied the signal transduction mechanism and pharmacological characteristics of the rat mGluR3 and mGluR4 subtypes in Chinese hamster ovary cells permanently expressing the cloned receptors. Both mGluR3 and mGluR4 inhibit the forskolin-stimulated accumulation of intracellular cAMP formation in response to agonist interaction. Consistent with the high degree of sequence similarity to mGluR2, mGluR3 closely resembles mGluR2 in its agonist selectivity; the potency rank order of agonists is L-glutamate > trans-1-aminocyclopentane- 1,3-dicarboxylate > ibotenate > quisqualate. mGluR4 is totally different in its agonist specificity from any other member of the metabotropic receptors. This receptor potently reacts with L-2-amino-4-phosphonobutyrate(L-AP4) in a stereo-selective manner and moderately responds to L-serine-O-phosphate. mGluR4 thus corresponds well to the putative L-AP4 receptor characterized from brain preparations. Blot and in situ hybridization analyses indicated that both mRNAs are widely distributed in the rat brain. mGluR3 mRNA is highly expressed in neuronal cells of the cerebral cortex and the caudate- putamen, and in granule cells of the hippocampal dentate gyrus. The expression pattern of mGluR4 mRNA is more restricted, and this expression is prominent in the cerebellum, olfactory bulb, and thalamus. Furthermore, the mGluR3 mRNA, unlike the other mRNAs for the metabotropic receptors, is highly expressed in glial cells throughout the brain regions. The metabotropic glutamate receptor subtypes can thus be classified into three subgroups according to the similarity in their amino acid sequences, signal transduction, and agonist selectivity: mGluR1/mGluR5, mGluR2/mGluR3, and mGluR4. The mRNAs for the individual receptor subtypes, however, show overlapping but distinct patterns of expression in the rat CNS.}, author = {Tanabe, Yasuto and Nomura, Akinori and Masu, Masayuki and Shigemoto, Ryuichi and Mizuno, Noboru and Nakanishi, Shigetada}, issn = {0270-6474}, journal = {Journal of Neuroscience}, number = {4}, pages = {1372 -- 1378}, publisher = {Society for Neuroscience}, title = {{Signal transduction, pharmacological properties, and expression patterns of two rat metabotropic glutamate receptors, mGluR3 and mGluR4}}, doi = {10.1523/JNEUROSCI.13-04-01372.1993}, volume = {13}, year = {1993}, } @article{2539, abstract = {cDNA clones for four different N-methyl-D-aspartate (NMDA) receptor subunits (NMDAR2A-NMDAR2D) were isolated through polymerase chain reactions followed by molecular screening of a rat brain cDNA library. These subunits are only about 15% identical with the key subunit of the NMDA receptor (NMDAR1) but are highly homologous (~50% homology) with one another. They also commonly possess large hydrophilic domains at both amino- and carboxyl- terminal sides of the four putative transmembrane segments. NMDAR2A and NMDAR2C expressed individually in Xenopus oocytes showed no electrophysiological response to agonists. However, these subunits in combined expression with NMDAR1 markedly potentiated the NMDAR1 activity and produced functional variability in the affinity of agonists, the effectiveness of antagonists, and the sensitivity to Mg2+ blockade. Thus, NMDAR1 is essential for the function of the NMDA receptor, and multiple NMDAR2 subunits potentiate and differentiate the function of the NMDA receptor by forming different heteromeric configurations with NMDAR1. Northern blotting and in situ hybridization analyses revealed that the expressions of individual mRNAs for the NMDAR2 subunits overlap in some brain regions but are also specialized in many other regions. This investigation demonstrates the anatomical and functional differences of the NMDAR2 subunits, which provide the molecular basis for the functional diversity of the NMDA receptor.}, author = {Ishii, Takahiro and Moriyoshi, Koki and Sugihara, Hidemitsu and Sakurada, Kazuhir and Kadotani, Hiroshi and Yokoi, Mineto and Akazawa, Chihiro and Shigemoto, Ryuichi and Mizuno, Noboru and Masu, Masayuki and Nakanishi, Shigetada}, issn = {0021-9258}, journal = {Journal of Biological Chemistry}, number = {4}, pages = {2836 -- 2843}, publisher = {American Society for Biochemistry and Molecular Biology}, title = {{Molecular characterization of the family of the N-methyl-D-aspartate receptor subunits}}, doi = {10.1016/s0021-9258(18)53849-7 }, volume = {268}, year = {1993}, } @article{2540, abstract = {Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, which is coupled to the inhibitory cyclic AMP cascade, was investigated in the central nervous system of the adult rat by in situ hybridization. Transcripts of mGluR2 were specifically localized to neuronal cells of the brain. Although the hybridization signals were widely distributed in the brain, the most prominent expression of mGluR2 messenger RNA was seen in Golgi cells of the cerebellum. Marked expression of mGluR2 messenger RNA was further observed in the mitral cells of the accessory olfactory bulb, neurons in the external part of the anterior olfactory nucleus, and pyramidal neurons in the entorhinal and parasubicular cortical regions. The granule cells of the accessory olfactory bulb, and many pyramidal and non-pyramidal neurons in the neocortical, cingulate, retrosplenial and subicular cortices, were moderately labeled. All of the granule cells in the dentate gyrus were also labeled moderately, whereas no significant hybridization signals were detected in Ammon's horn. In the basal forebrain regions, moderately labeled neurons were distributed in the triangular septal nucleus, in the lateral, basolateral and basomedial amygdaloid nuclei, and in the medial mammillary nucleus. Weakly labeled neurons were sparsely scattered in the striatum, globus pallidus, ventral pallidum and claustrum. The subthalamic nucleus was also labeled weakly. No significant labeling was found in the entopeduncular nucleus and substantia nigra. In the thalamus, moderately labeled neurons were distributed in the anterodorsal, anteromedial, ventromedial, intralaminar and midline nuclei; the ventrolateral part of the anteroventral nucleus and the rostral pole of the ventrolateral nucleus also contained moderately labeled neurons. No significant labeling was found in the thalamic reticular, submedius, ventroposterior, lateral geniculate and medial geniculate nuclei. In the lower brainstem, labeling was generally weak. No significant hybridization signals were found in the spinal cord. Some neurons in the inner part of the inner nuclear layer of the retina and some retinal ganglion cells were labeled moderately. The pattern of distribution of mGluR2 messenger RNA revealed in the present study indicates specific roles of mGluR2 in the glutamatergic system in the brain.}, author = {Ohishi, Hitoshi and Shigemoto, Ryuichi and Nakanishi, Shigetada and Mizuno, Noboru}, issn = {0306-4522}, journal = {Neuroscience}, number = {4}, pages = {1009 -- 1018}, publisher = {Elsevier}, title = {{Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat}}, doi = {10.1016/0306-4522(93)90485-X}, volume = {53}, year = {1993}, } @article{2538, abstract = {Rat mRNAs encoding two subtypes of the endothelin (ET) receptor (ET(A) and ET(B)) were studied in the rat ovary and fallopian tube by means of Northern blotting and in situ hybridization. The mRNA transcripts for the endothelin- 1-specific type receptor (ET(A)) in pooled RNA from the ovary and fallopian tube were 4.2 and 5.2 kilonucleotides, and that for the nonselective type receptor (ET(B)) was 4.7 kilonucleotides; these were similar to transcripts for endothelin receptors from other tissues. ET(A) mRNA expression was abundant in the muscle cell layer of the fallopian tube, but low in the ovary. On the other hand, ET(B) mRNA was abundant in the granulosa cells in the developing follicles, but low in atretic follicles and absent in the fallopian tube. These results demonstrated that the mRNAs for the two subtypes of the rat endothelin receptor have different expression profiles in the ovary and fallopian tube. ETs may mainly affect the granulosa cells in the dominant follicles as well as the muscle cells of the fallopian tube through ET(B) and ET(A), respectively.}, author = {Iwai, Masazumi and Hori, Seiji and Shigemoto, Ryuichi and Kanzaki, Hideharu and Mori, Takahide and Nakanishi, Shigetada}, issn = {0006-3363}, journal = {Biology of Reproduction}, number = {4}, pages = {675 -- 680}, publisher = {Society for the Study of Reproduction}, title = {{Localization of endothelin receptor messenger ribonucleic acid in the rat ovary and fallopian tube by in situ hybridization}}, doi = {10.1095/biolreprod49.4.675}, volume = {49}, year = {1993}, } @article{2544, abstract = {VARIOUS functions of glutamate transmission are mediated by both ionotropic and metabotropic glutamate receptors1. The metabotropic glutamate receptors (mGluRs) consist of at least six different subtypes that are classified into three subgroups, mGluR1/mGluR5, mGluR2/mGluR3, and mGluR4/mGluR6 (refs 1-5), but their physiological roles are largely unknown. Here we report the identification of a very potent agonist for mGluR2/mGluR3, DCG-IV, and the specific localization of mGluR2 in granule cell dendrites that form dendrodendritic synapses with mitral cells in the accessory olfactory bulb. Using the DCG-IV agonist for mGluR2 in combination with slice patchrecording, we demonstrate that the granule cell mGluR2 presynaptically suppresses inhibitory GABA (γ-aminobutyrate) transmission to the mitral cell. Our results indicate that mGluR2 in granule cells plays an important role in the persistent excitation of olfactory sensory transmission in the accessory olfactory bulb by relieving mitral cells from the GABA inhibition.}, author = {Hayashi, Yasunori and Momiyama, Akiko and Takahashi, Tomoyuki and Ohishi, Hitoshi and Ogawa Meguro, Reiko and Shigemoto, Ryuichi and Mizuno, Noboru and Nakanishi, Shigetada}, issn = {0028-0836}, journal = {Nature}, number = {6456}, pages = {687 -- 690}, publisher = {Nature Publishing Group}, title = {{Role of a metabotropic glutamate receptor in synaptic modulation in the accessory olfactory bulb}}, doi = {10.1038/366687a0}, volume = {366}, year = {1993}, } @article{2543, abstract = {Pituitary adenylate cyclase-activating polypeptide (PACAP) is a polypeptide hormone related to vasoactive intestinal polypeptide (VIP). Rat PACAP receptor cDNA was isolated from a brain cDNA library by cross-hybridization with rat VIP receptor cDNA. The recombinant PACAP receptor expressed in COS cells bound PACAP with about 1000 times higher affinity than VIP, and PACAP stimulated adenylate cyclase through the cloned PACAP receptor. The rat PACAP receptor consists of 495 amino acids, contains seven transmembrane segments, and has a significant similarity with other Gs-coupled receptors, such as VIP, glucagon, and secretin receptors. PACAP receptor mRNA was abundantly expressed in the brain, but not in the peripheral tissues except for the adrenal gland. In situ hybridization revealed a high level of expression of PACAP receptor mRNA in the hippocampal dentate gyrus, olfactory bulb, and cerebellar cortex.}, author = {Hashimoto, Hitoshi and Ishihara, Takeshi and Shigemoto, Ryuichi and Mori, Kensaku and Nagata, Shigekazu}, issn = {0896-6273}, journal = {Neuron}, number = {2}, pages = {333 -- 342}, publisher = {Elsevier}, title = {{ Molecular cloning and tissue distribution of a receptor for pituitary adenylate cyclase-activating polypeptide}}, doi = {10.1016/0896-6273(93)90188-W}, volume = {11}, year = {1993}, } @article{2542, abstract = {A trpE-fusion protein containing a C-terminal sequence of a rat metabotropic glutamate receptor, mGluR5, was used to produce an antibody. On immunoblot, the antibody specifically reacted with mGluR5 expressed in mammalian cells and rat brain. Immunohistochemical analysis revealed intense mGluR5-like immunoreactivity (LI) in the olfactory bulb, anterior olfactory nuclei, olfactory tubercle, cerebral cortex, hippocampus, lateral septum, striatum, nucleus accumbens, inferior colliculus, and spinal trigeminal nuclei. The distribution pattern of mGluR5-LI corresponds very well with that of mGluR5 mRNA. Electron microscope analysis of the striatum revealed dense accumulation of immunoreaction products in dendrites which were often provided with asymmetrical synapses. These results suggest that mGluR5 is predominantly located in postsynaptic elements.}, author = {Shigemoto, Ryuichi and Nomura, Sakashi and Ohishi, Hitoshi and Sugihara, Hidemitsu and Nakanishi, Shigetada and Mizuno, Noboru}, issn = {0304-3940}, journal = {Neuroscience Letters}, number = {1}, pages = {53 -- 57}, publisher = {Elsevier}, title = {{Immunohistochemical localization of a metabotropic glutamate receptor, mGluR5, in the rat brain}}, doi = {10.1016/0304-3940(93)90227-C}, volume = {163}, year = {1993}, } @article{2541, abstract = {A trp E fusion protein containing a C-terminal portion of the rat substance P receptor (SPR) was expressed in bacteria and used to produce an antibody. The antibody specifically reacted with SPR expressed in a mammalian cell line and rat striatum. Light and electron microscope analyses of the rat striatum revealed intense SPR-like immunoreactivity in neuronal somata and dendrites. These immunoreactive neurons constituted ∼ 3% of the total population of striatal neurons; they were putative interneurons of large and medium-sized aspiny types.}, author = {Shigemoto, Ryuichi and Nakaya, Yoshifumi and Nomura, Sakashi and Ogawa Meguro, Reiko and Ohishi, Hitoshi and Kaneko, Takeshi and Nakanishi, Shigetada and Mizuno, Noboru}, issn = {0304-3940}, journal = {Neuroscience Letters}, number = {2}, pages = {157 -- 160}, publisher = {Elsevier}, title = {{Immunocytochemical localization of rat substance P receptor in the striatum}}, doi = {10.1016/0304-3940(93)90311-8}, volume = {153}, year = {1993}, } @article{2546, abstract = {Immunochemical characteristics of neostriatal neurons producing substance P receptor (SPR) were examined in adult rats by double- and triple-immunofluorescence methods. In the neostriatum, SPR immunoreactivity was detected in large and medium-sized aspiny neurons. Virtually all SPR-immunoreactive neurons in the neostriatum contained somatostatin (SS) or choline acetyltransferase (ChAT), but not parvalbumin. All SS- and ChAT-immunoreactive neurons in the neostriatum showed SPR immunoreactivity. The co-existence of SS and ChAT was, however, not found in single neurons expressing SPR immunoreactivity. The present results indicate that neostriatal neurons immunoreactive for SPR are segregated into 2 groups: (1) medium-sized, aspiny somatostatinergic, and (2) large, aspiny cholinergic neurons.}, author = {Kaneko, Takeshi and Shigemoto, Ryuichi and Nakanishi, Shigetada and Mizuno, Noboru}, issn = {0006-8993}, journal = {Brain Research}, number = {2}, pages = {297 -- 303}, publisher = {Elsevier}, title = {{Substance P receptor-immunoreactive neurons in the rat neostriatum are segregated into somatostatinergic and cholinergic aspiny neurons}}, doi = {10.1016/0006-8993(93)91548-7}, volume = {631}, year = {1993}, } @article{2723, abstract = {The ground-state density of the Pauli operator in the case of a nonconstant magnetic field with constant direction is studied. It is shown that in the large field limit, the naturally rescaled ground-state density function is bounded from above by the megnetic field, and under some additional conditions, the limit density function is equal to the magnetic field. A restatement of this result yields an estimate on the density of complex orthogonal polynomials with respect to a fairly general weight function. We also prove a special case of the paramagnetic inequality. }, author = {Erdös, László}, issn = {0377-9017}, journal = {Letters in Mathematical Physics}, number = {3}, pages = {219 -- 240}, publisher = {Springer}, title = {{Ground-state density of the Pauli operator in the large field limit}}, doi = {10.1007/BF00761110}, volume = {29}, year = {1993}, } @article{3474, abstract = {1. Excitatory postsynaptic currents (EPSCs) were recorded in CA3 pyramidal cells of hippocampal slices of 15- to 24-day-old rats (22 degrees C) using the whole-cell configuration of the patch clamp technique. 2. Composite EPSCs were evoked by extracellular stimulation of the mossy fibre tract. Using the selective blockers 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and D-2-amino-5-phosphonopentanoic acid (APV), a major alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate receptor-mediated component and a minor NMDA receptor-mediated component with slower time course were distinguished. For the AMPA/kainate receptor-mediated component, the peak current-voltage (I-V) relation was linear, with a reversal potential close to 0 mV. The half-maximal blocking concentration of CNQX was 353 nM. 3. Unitary EPSCs of the mossy fibre terminal (MF)-CA3 pyramidal cell synapse were evoked at membrane potentials of -70 to -90 mV by low-intensity extracellular stimulation of granule cell somata using fine-tipped pipettes. The EPSC peak amplitude as a function of stimulus intensity showed all-or-none behaviour. The region of low threshold was restricted to a few micrometres. This suggests that extracellular stimulation was focal, and that the stimulus-evoked EPSCs were unitary. 4. Latency and rise time histograms of EPSCs evoked by granule cell stimulation showed narrow unimodal distributions within each experiment. The mean latency was 4.2 +/- 1.0 ms, and the mean 20-80% rise time was 0.6 +/- 0.1 ms (23 cells). When fitted within the range 0.7 ms to 20 ms after the peak, the decay of the EPSCs with the fastest rise (rise time 0.5 ms or less) could be described by a single exponential function; the mean time constant was in the range 3.0-6.6 ms with a mean of 4.8 ms (8 cells). 5. Peak amplitudes of the EPSCs evoked by suprathreshold granule cell stimulation fluctuated between trials. The apparent EPSC peak conductance in normal extracellular solution (2 mM Ca2+, 1 mM Mg2+), excluding failures, was 1 nS. Reducing the Ca2+ concentration and increasing the Mg2+ concentration reduced the mean peak amplitude in a concentration-dependent manner. 6. Peaks in EPSC peak amplitude distributions were apparent in low Ca2+ and high Mg2+. Using the criteria of equidistance and the presence of peaks and dips in the autocorrelation function, five of nine EPSC peak amplitude distributions were judged to be quantal.}, author = {Jonas, Peter M and Major, Guy and Sakmann, Bert}, issn = {0022-3751}, journal = {Journal of Physiology}, pages = {615 -- 663}, publisher = {Wiley-Blackwell}, title = {{Quantal components of unitary EPSCs at the mossy fibre synapse on CA3 pyramidal cells of rat hippocampus}}, doi = {10.1113/jphysiol.1993.sp019965}, volume = {472}, year = {1993}, } @article{3473, abstract = {Sixteen different K+ channel subtypes have been cloned from mammalian tissue. Considering their sequence homology to Drosophila Shaker, Shab, Shaw and Shal channels, they were classified into four corresponding classes Kv1-4. All K+ channels belonging to these classes consist of four subunits with each six hydrophobic segments (S1-S6) and a characteristic structure-function relationship of certain domains in their amino acid sequence. These domains are, the inactivation gate in the N-terminal region of the sequence, the voltage sensor in the fourth hydrophobic segment (S4), and the pore-region in the H5 segment between S5 and S6. In some functional properties K+ channels cloned from the mammalian brain, however, differ from Drosophila K+ channels. These are pharmacological differences, differences in the threshold of activation and in regulation of inactivation. Part of these differences are important to understand their physiological role in the brain. Based on their functional characteristics the expression pattern of cloned K+ channels in the rat brain can be correlated with the properties of K+ currents measured in central neurones.}, author = {Ruppersberg, Peter and Ermler, Mamfred and Knopf, Martin and Kues, Wilfried and Jonas, Peter M and Koenen, Michael}, issn = {1015-8987}, journal = {Cellular Physiology and Biochemistry}, pages = {250 -- 269}, publisher = {S. Karger AG}, title = {{Properties of Shaker-homologous potassium channels expressed in the mammalian brain.}}, doi = {10.1159/000154691}, volume = {3}, year = {1993}, } @inbook{3569, author = {Edelsbrunner, Herbert}, booktitle = {Current Trends in Theoretical Computer Science, Essays and Tutorials}, isbn = {978-9810214623}, pages = {1 -- 48}, publisher = {World Scientific Publishing}, title = {{Computational geometry}}, year = {1993}, } @inbook{3568, author = {Edelsbrunner, Herbert}, booktitle = {Handbook of Convex Geometry}, isbn = {978-0-444-89596-7}, pages = {699 -- 735}, publisher = {North Holland}, title = {{Geometric algorithms}}, doi = {10.1016/C2009-0-15705-7}, year = {1993}, } @article{4041, abstract = {The zone theorem for an arrangement of n hyperplanes in d-dimensional real space says that the total number of faces bounding the cells intersected by another hyperplane is O(n(d-1)). This result is the basis of a time-optimal incremental algorithm that constructs a hyperplane arrangement and has a host of other algorithmic and combinatorial applications. Unfortunately, the original proof of the zone theorem, for d greater-than-or-equal-to 3, turned out to contain a serious and irreparable error. This paper presents a new proof of the theorem. The proof is based on an inductive argument, which also applies in the case of pseudohyperplane arrangements. The fallacies of the old proof along with some ways of partially saving that approach are briefly discussed.}, author = {Edelsbrunner, Herbert and Seidel, Raimund and Sharir, Micha}, issn = {0097-5397}, journal = {SIAM Journal on Computing}, number = {2}, pages = {418 -- 429}, publisher = {SIAM}, title = {{On the zone theorem for hyperplane arrangements}}, doi = {10.1137/0222031}, volume = {22}, year = {1993}, } @article{4036, abstract = {This paper presents a randomized incremental algorithm for computing a single face in an arrangement of n line segments in the plane that is fairly simple to implement. The expected running time of the algorithm is O(nα(n)log n). The analysis of the algorithm uses a novel approach that generalizes and extends the Clarkson-Shor analysis technique [in Discrete Comput. Geom., 4(1989), pp. 387-421]. A few extensions of the technique, obtaining efficient randomized incremental algorithms for constructing the entire arrangement of a collection of line segments and for computing a single face in an arrangement of Jordan arcs are also presented.}, author = {Chazelle, Bernard and Edelsbrunner, Herbert and Guibas, Leonidas and Sharir, Micha and Snoeyink, Jack}, issn = {0097-5397}, journal = {SIAM Journal on Computing}, number = {6}, pages = {1286 -- 1302}, publisher = {SIAM}, title = {{Computing a face in an arrangement of line segments and related problems}}, doi = {10.1137/0222077 }, volume = {22}, year = {1993}, } @article{4040, abstract = {A plane geometric graph C in ℝ2 conforms to another such graph G if each edge of G is the union of some edges of C. It is proved that, for every G with n vertices and m edges, there is a completion of a Delaunay triangulation of O(m2 n) points that conforms to G. The algorithm that constructs the points is also described.}, author = {Edelsbrunner, Herbert and Tan, Tiow}, issn = {0179-5376}, journal = {Discrete & Computational Geometry}, number = {1}, pages = {197 -- 213}, publisher = {Springer}, title = {{An upper bound for conforming Delaunay triangulations}}, doi = {10.1007/BF02573974}, volume = {10}, year = {1993}, } @article{4303, abstract = {In a stably subdivided population with symmetric migration, the chance that a favoured allele will be fixed is independent of population structure. However, random extinction introduces an extra component of sampling drift, and reduces the probability of fixation. In this paper, the fixation probability is calculated using the diffusion approximation; comparison with exact solution of the discrete model shows this to be accurate. The key parameters are the rates of selection, migration and extinction, scaled relative to population size (S = 4Ns, M = 4Nm, Λ = 4Nλ); results apply to a haploid model, or to diploids with additive selection. If new colonies derive from many demes, the fixation probability cannot be reduced by more than half. However, if colonies are initially homogeneous, fixation probability can be much reduced. In the limit of low migration and extinction rates (M, Λ 1), it is 2s/{1 + (Λ/MS)(1 −exp(−S))}, whilst in the opposite limit (S 1), it is 4sM/{Λ(Λ + M)}. In the limit of weak selection (M, Λ 1), it is 4sM/{Λ(Λ + M)}. These factors are not the same as the reduction in effective population size (Ne/N), showing that the effects of population structure on selected alleles cannot be understood from the behaviour of neutral markers.}, author = {Barton, Nicholas H}, issn = {0016-6723}, journal = {Genetics Research}, number = {2}, pages = {149 -- 158}, publisher = {Cambridge University Press}, title = {{The probability of fixation of a favoured allele in a subdivided population}}, doi = {10.1017/S0016672300031748}, volume = {62}, year = {1993}, } @misc{4302, author = {Barton, Nicholas H}, booktitle = {Genetical Research}, issn = {0016-6723}, number = {1}, pages = {77 -- 85}, publisher = {Cambridge University Press}, title = {{Review of "The causes of molecular evolution" by J.H. Gillespie}}, doi = {10.1017/S001667230003158X }, volume = {62}, year = {1993}, } @inbook{4301, author = {Barton, Nicholas H and Gale, Katherine}, booktitle = {Hybrid zones and the evolutionary process}, editor = {Harrison, Richard}, isbn = { 0-19-506917-X}, pages = {13 -- 45}, publisher = {Oxford University Press}, title = {{Genetic analysis of hybrid zones}}, doi = {10.1046/j.1420-9101.1994.7050631.x}, year = {1993}, } @article{4304, author = {Barton, Nicholas H}, issn = {0960-9822}, journal = {Current Biology}, number = {11}, pages = {797 -- 799}, publisher = {Cell Press}, title = {{Why species and subspecies?}}, doi = {10.1016/0960-9822(93)90036-N}, volume = {3}, year = {1993}, } @inbook{3452, abstract = {In recent years, considerable progress in our understanding of the molecular events underlying excitatory synaptic transmission has been made. This progress was mainly achieved by technical advances, among them the patch-clamp technique in brain slices (Edwards et al., 1989), fast application of agonists (Franke et al., 1987), and cloning and functional expression of GluR channels of the nonNMDA type (e.g., Hollmann et al., 1989). A suitable model for studying excitatory postsynaptic currents (EPSCs) in the brain slice with patch-clamp techniques is the mossy fiber synapse on CA3 pyramidal cells of rat hippocampus (MF-CA3 synapse). This synapse is located close to the cell soma and should provide almost ideal space-clamp conditions. A comparison of MF-CA3 EPSCs with the currents activated by fast application of glutamate on membrane patches isolated from CA3 cell somata suggests that the concentration of glutamate in the synaptic cleft during excitatory synaptic transmission is high (about 1 mM) and that the transmitter remains in the synaptic cleft only briefly (about 1 ms). It seems likely that desensitization influences the peak amplitude of the EPSC in several ways. Brief pulses of glutamate cause desensitization, from which the glutamate receptor channels recover only slowly, and micromolar ambient glutamate concentrations produce desensitization at equilibrium. From the functional properties of recombinant GluR channels, in situ hybridization data, and patch-clamp experiments on different neuronal and nonneuronal cell types, a picture of the molecular identity of native channels emerges. In neurons of the hippocampus the pharmacological features of these channels were similar to recombinant channels assembled from subunits of the AMPA/kainate subtype which are strongly expressed in these cells. The native channels are characterized by outward rectification of the steady-state I-V and low Ca permeability, similar to recombinant channels containing the GluR-B subunit. This is consistent with the ubiquitous expression of this subunit in hippocampal neurones. In contrast, GluR channels from cerebellar glial cells, which uniquely in the central nervous system lack the expression of GluR-B subunits, show double rectification and high Ca permeability. The results suggest that the native functional nonNMDA glutamate receptor channels in the CNS are assembled form subunits of the AMPA/kainate subtype in a cell-specific way, with the functional properties of GluR channels in neurones being dominated by the GluR-B subunit.}, author = {Jonas, Peter M}, booktitle = {Nonselective cation channels: Pharmacology, Physiology and Biophysics.}, editor = {Siemen, Detlef}, isbn = {978-3-0348-7327-7}, pages = {61 -- 76}, publisher = {Birkhäuser}, title = {{AMPA-type glutamate receptors - nonselective cation channels mediating fast excitatory transmission in the CNS}}, doi = {10.1007/978-3-0348-7327-7_4}, volume = {66}, year = {1993}, } @article{3446, abstract = {An effective character recognition procedure implemented on a new type of hardware system and using a new architecture called CNND is proposed. This CNND contains one or more analog cellular neural networks (CNNs) and some digital logic, combining the advantages of the fast analog CNN signal processing and the fast and easy decision capability of digital logic. It is shown that the CNND system can be used for recognition of multifont printed or handwritten characters and could recognize 100,000 char/s with a recognition rate of more than 95%. The more advantage of the system over competing types is that there is not an extra feature extraction procedure implemented in slow hardware}, author = {Sziranyi, Tamas and Csicsvari, Jozsef L}, issn = {1057-7130}, journal = {IEEE Transactions on Circuits and Systems II: Analog and Digital Signal Processing}, number = {3}, pages = {223 -- 231}, publisher = {IEEE}, title = {{High-speed character recognition using a dual cellular neural network architecture (CNND)}}, doi = {10.1109/82.222823}, volume = {40}, year = {1993}, } @inbook{3451, author = {Jonas, Peter M}, booktitle = {Molecular Basis of Ion Channels and Receptors Involved in Nerve Excitation, Synaptic Transmission, and Muscle Contraction}, pages = {126 -- 135}, publisher = {New York Academy of Sciences}, title = {{Glutamate receptors in the central nervous system}}, doi = {10.1111/j.1749-6632.1993.tb38048.x}, volume = {707}, year = {1993}, } @article{3643, abstract = {We investigate the establishment and spread of new adaptive peaks within Wright's ‘shifting balance’. The third phase of the ‘shifting balance’ involves a kind of group selection, since demes in which a superior peak has been established contain more individuals, and so send out more migrants. We assume that population size, N, increases with mean fitness, , according to the exponential relation, . Here, k is a measure of the weakness of density-dependent regulation, and equals the inverse of the regression of log (fitness) on log(N). In the island model, we find that just as with soft selection (k = 0), two distinct types of behaviour exist: group selection makes no qualitative difference. With low numbers of migrants, demes fluctuate almost independently, and only one equilibrium exists. With large numbers of migrants, all the demes evolve towards the same adaptive peak, and so the whole population can move towards one or other of the peaks. Group selection can be understood in terms of an effective mean fitness function. Its main consequence is to increase the effect of selection relative to drift (Ns), and so increase the bias towards the fitter peak. However, this increased bias depends on the ratio between k and the deme size (k/N), and so is very small when density-dependence is reasonably strong.}, author = {Rouhani, Shahin and Barton, Nicholas H}, issn = {0016-6723}, journal = {Genetical Research}, number = {2}, pages = {127 -- 136}, publisher = {Cambridge University Press}, title = {{Group selection and the 'shifting balance'}}, doi = {10.1017/S0016672300031232}, volume = {61}, year = {1993}, } @article{3644, abstract = {Wright proposed that there is a ' shifting balance' between selection within demes, random drift, and selection between demes at different 'adaptive peaks'. We investigate the establishment and spread of new adaptive peaks, considering a chromosome rearrangement, and a polygenic character under disruptive selection. When the number of migrants (Nm) is small, demes fluctuate independently, with a bias towards the fitter peak. When Nm is large, the whole population can move to one of two stable equilibria, and so can be trapped near the lower peak. These two regimes are separated by a sharp transition at a critical Nm of order 1. Just below this critical point, adaptation is most efficient, since the shifting balance greatly increases the proportion of demes that reach the global optimum. This is so even if one peak is only slightly fitter than the other (AWx \/N), and for both strong and weak selection (Ns <§ 1 or Ns > 1). Provided that Nm varies sufficiently gradually from place to place, the fitter peak can be established in regions where Nm « 1, and can then spread through the rest of the range. Our analysis confirms Wright's argument that if selection, migration and drift are of the same order, the ' shifting balance' leads to efficient evolution towards the global optimum.}, author = {Barton, Nicholas H and Rouhani, Shahin}, issn = {0016-6723}, journal = {Genetical Research}, number = {1}, pages = {57 -- 74}, publisher = {Cambridge University Press}, title = {{Adaptation and the 'shifting balance'}}, doi = {10.1017/S0016672300031098 }, volume = {61}, year = {1993}, } @article{4044, abstract = {Edge insertion iteratively improves a triangulation of a finite point set in ℜ2 by adding a new edge, deleting old edges crossing the new edge, and retriangulating the polygonal regions on either side of the new edge. This paper presents an abstract view of the edge insertion paradigm, and then shows that it gives polynomial-time algorithms for several types of optimal triangulations, including minimizing the maximum slope of a piecewise-linear interpolating surface.}, author = {Bern, Marshall and Edelsbrunner, Herbert and Eppstein, David and Mitchell, Stephen and Tan, Tiow}, issn = {0179-5376}, journal = {Discrete & Computational Geometry}, number = {1}, pages = {47 -- 65}, publisher = {Springer}, title = {{Edge insertion for optimal triangulations}}, doi = {10.1007/BF02573962}, volume = {10}, year = {1993}, } @article{4045, abstract = {We apply Megiddo's parametric searching technique to several geometric optimization problems and derive significantly improved solutions for them. We obtain, for any fixed ε>0, an O(n1+ε) algorithm for computing the diameter of a point set in 3-space, an O(8/5+ε) algorithm for computing the width of such a set, and on O(n8/5+ε) algorithm for computing the closest pair in a set of n lines in space. All these algorithms are deterministic.}, author = {Chazelle, Bernard and Edelsbrunner, Herbert and Guibas, Leonidas and Sharir, Micha}, issn = {0179-5376}, journal = {Discrete & Computational Geometry}, number = {1}, pages = {183 -- 196}, publisher = {Springer}, title = {{Diameter, width, closest line pair, and parametric searching}}, doi = {10.1007/BF02573973}, volume = {10}, year = {1993}, } @article{4042, abstract = {It is shown that a triangulation of a set of n points in the plane that minimizes the maximum edge length can be computed in time 0(n2). The algorithm is reasonably easy to implement and is based on the theorem that there is a triangulation with minmax edge length that contains the relative neighborhood graph of the points as a subgraph. With minor modifications the algorithm works for arbitrary normed metrics.}, author = {Edelsbrunner, Herbert and Tan, Tiow}, issn = {0097-5397}, journal = {SIAM Journal on Computing}, number = {3}, pages = {527 -- 551}, publisher = {SIAM}, title = {{A quadratic time algorithm for the minmax length triangulation}}, doi = {10.1137/0222036 }, volume = {22}, year = {1993}, } @article{4177, abstract = {Thyroid hormones play an important role in brain development, but the mechanism(s) by which triiodothyronine (T3) mediates neuronal differentiation is poorly understood. Here we demonstrate that T3 regulates the neurotrophic factor, neurotrophin-3 (NT-3), in developing rat cerebellar granule cells both in cell culture and in vivo. In situ hybridization experiments showed that developing Purkinje cells do not express NT-3 mRNA but do express trkC, the putative neuronal receptor for NT-3. Addition of recombinant NT-3 to cerebellar cultures from embryonic rat brain induces hypertrophy and neurite sprouting of Purkinje cells, and upregulates the mRNA encoding the calcium-binding protein, calbindin-28 kD. The present study demonstrates a novel interaction between cerebellar granule neurons and developing Purkinje cells in which NT-3 induced by T3 in the granule cells promotes Purkinje cell differentiation.}, author = {Lindholm, Dan and Castrén, Eero and Tsoulfas, Pantelis and Kolbeck, Roland and Berzaghi, Maria and Leingärtner, Axel and Heisenberg, Carl-Philipp J and Tesarollo, Lino and Parada, Luis and Thoenen, Hans}, issn = {0021-9525}, journal = {Journal of Cell Biology}, number = {2}, pages = {443 -- 450}, publisher = {Rockefeller University Press}, title = {{Neurotrophin-3 induced by tri-iodothyronine in cerebellar granule cells promotes Purkinje cell differentiation}}, doi = {10.1083/jcb.122.2.443}, volume = {122}, year = {1993}, } @article{4175, abstract = {We have studied the effects of different neurotrophins on the survival and proliferation of rat cerebellar granule cells in culture. These neurons express trkB and trkC, the putative neuronal receptors for brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) respectively. Binding studies using iodinated BDNF and NT-3 demonstrated that both BDNF and NT-3 bind to the cerebellar granule neurons with a similar affinity of approximately 2 x 10(-9) M. The number of receptors per granule cell was surprisingly high, approximately 30 x 10(-4) and 2 x 10(5) for BDNF and NT-3, respectively. Both NT-3 and BDNF elevated c-fos mRNA in the granule neurons, but only BDNF up-regulated the mRNA encoding the low-affinity neurotrophin receptor (p75). In contrast to NT-3, BDNF acted as a survival factor for the granule neurons. BDNF also induced sprouting of the granule neurons and significantly protected them against neurotoxicity induced by high (1 mM) glutamate concentrations. Cultured granule neurons also expressed low levels of BDNF mRNA which were increased by kainic acid, a glutamate receptor agonist. Thus, BDNF, but not NT-3, is a survival factor for cultured cerebellar granule neurons and activation of glutamate receptor(s) up-regulates BDNF expression in these cells.}, author = {Lindholm, Dan and Dechant, Georg and Heisenberg, Carl-Philipp J and Thoenen, Hans}, issn = {0953-816X}, journal = {European Journal of Neuroscience}, number = {11}, pages = {1455 -- 1464}, publisher = {Wiley-Blackwell}, title = {{Brain-derived neurotrophic factor is a survival factor for cultured rat cerebellar granule neurons and protects them against glutamate-induced neurotoxicity}}, doi = {10.1111/j.1460-9568.1993.tb00213.x}, volume = {5}, year = {1993}, } @article{4299, abstract = {Evolutionary explanations of aging (or senescence) fall into two classes. First, organisms might have evolved the optimal life history, in which survival and fertility late in life are sacrificed for the sake of early reproduction or high pre-adult survival. Second, the life history might be depressed below this optimal compromise by the influx of deleterious mutations; since selection against late-acting mutations is weaker, deleterious mutations will impose a greater load on late life. We discuss ways in which these theories might be investigated and distinguished, with reference to experimental work withDrosophila. While genetic correlations between life history traits determine the immediate response to selection, they are hard to measure, and may not reflect the fundamental constraints on life history. Long term selection experiments are more likely to be informative. The third approach of using experimental manipulations suffers from some of the same problems as measures of genetic correlations; however, these two approaches may be fruitful when used together. The experimental results so far suggest that aging inDrosophila has evolved in part as a consequence of selection for an optimal life history, and in part as a result of accumulation of predominantly late-acting deleterious mutations. Quantification of these effects presents a major challenge for the future.}, author = {Partridge, Linda and Barton, Nicholas H}, issn = {0016-6707}, journal = {Genetica}, number = {1-3}, pages = {89 -- 98}, publisher = {Springer}, title = {{Evolution of aging: Testing the theory using Drosophila}}, doi = {10.1007/BF01435990}, volume = {91}, year = {1993}, } @article{4300, abstract = {Evolutionary explanations of ageing fall into two classes. Organisms might have evolved the optimal life history, in which survival and fertility late in life are sacrificed for the sake of early reproduction and survival. Alternatively, the life history might be depressed below this optimal compromise by deleterious mutations: because selection against late-acting mutations is weaker, these will impose a greater load on late life. Evidence for the importance of both is emerging, and unravelling their relative importance presents experimentalists with a major challenge.}, author = {Partridge, Linda and Barton, Nicholas H}, issn = {0028-0836}, journal = {Nature}, pages = {305 -- 311}, publisher = {Nature Publishing Group}, title = {{Optimality, mutation and the evolution of ageing}}, doi = {10.1038/362305a0}, volume = {362}, year = {1993}, } @inproceedings{4506, abstract = {We propose a formal framework for designing hybrid systems by stepwise refinement. Starting with a specification in hybrid temporal logic, we make successively more transitions explicit until we obtain an executable system.}, author = {Henzinger, Thomas A and Manna, Zohar and Pnueli, Amir}, booktitle = {International Hybrid Systems Workshop}, editor = {Grossman, Robert and Nerode, Anil and Ravn, Anders and Rischel, Hans}, isbn = {978-3-540-57318-0}, pages = {60 -- 76}, publisher = {Springer}, title = {{Towards refining temporal specifications into hybrid systems}}, doi = {10.1007/3-540-57318-6_24}, volume = {736}, year = {1993}, } @article{4589, abstract = {The theory of the natural numbers with linear order and monadic predicates underlies propositional linear temporal logic. To study temporal logics that are suitable for reasoning about real-time systems, we combine this classical theory of infinite state sequences with a theory of discrete time, via a monotonic function that maps every state to its time. The resulting theory of timed state sequences is shown to be decidable, albeit nonelementary, and its expressive power is characterized by ω-regular sets. Several more expressive variants are proved to be highly undecidable. This framework allows us to classify a wide variety of real-time logics according to their complexity and expressiveness. Indeed, it follows that most formalisms proposed in the literature cannot be decided. We are, however, able to identify two elementary real-time temporal logics as expressively complete fragments of the theory of timed state sequences, and we present tableau-based decision procedures for checking validity. Consequently, these two formalisms are well-suited for the specification and verification of real-time systems. Copyright © 1993 Academic Press. All rights reserved.}, author = {Alur, Rajeev and Henzinger, Thomas A}, issn = {0890-5401}, journal = {Information and Computation}, number = {1}, pages = {35 -- 77}, publisher = {Elsevier}, title = {{Real-time logics: Complexity and expressiveness}}, doi = {10.1006/inco.1993.1025}, volume = {104}, year = {1993}, } @inproceedings{4618, abstract = {We introduce the framework of hybrid automata as a model and specification language for hybrid systems. Hybrid automata can be viewed as a generalization of timed automata, in which the behavior of variables is governed in each state by a set of differential equations. We show that many of the examples considered in the workshop can be defined by hybrid automata. While the reachability problem is undecidable even for very restricted classes of hybrid automata, we present two semidecision procedures for verifying safety properties of piecewiselinear hybrid automata, in which all variables change at constant rates. The two procedures are based, respectively, on minimizing and computing fixpoints on generally infinite state spaces. We show that if the procedures terminate, then they give correct answers. We then demonstrate that for many of the typical workshop examples, the procedures do terminate and thus provide an automatic way for verifying their properties.}, author = {Alur, Rajeev and Courcoubetis, Costas and Henzinger, Thomas A and Ho, Pei}, booktitle = {Hybrid Systems}, editor = {Grossman, Robert and Nerode, Anil and Ravn, Anders and Rischel, Hans}, pages = {209 -- 229}, publisher = {Springer}, title = {{Hybrid automata: An algorithmic approach to the specification and verification of hybrid systems}}, doi = {10.1007/3-540-57318-6_30}, volume = {736}, year = {1993}, } @inproceedings{4616, abstract = {We present a model checking procedure and its implementation for the automatic verification of embedded systems. Systems are represented by hybrid automata - machines with finite control and real-valued variables modeling continuous environment parameters such as time, pressure, and temperature. System properties are specified in a real-time temporal logic and verified by symbolic computation. The verification procedure, implemented in Mathematica, is used to prove digital controllers and distributed algorithms correct. The verifier checks safety, liveness, time-bounded, and duration properties of hybrid automata}, author = {Alur, Rajeev and Henzinger, Thomas A and Ho, Pei}, booktitle = {1993 Proceedings Real-Time Systems Symposium}, isbn = {0-8186-4480-X}, location = {Raleigh, NC, United States of America}, pages = {2 -- 11}, publisher = {IEEE}, title = {{Automatic symbolic verification of embedded systems}}, doi = {10.1109/REAL.1993.393520 }, year = {1993}, } @inproceedings{4620, abstract = {We present a verification algorithm for duration properties of finite-state real-time systems. While simple real-time properties constrain the total elapsed time between events, duration properties constrain the accumulated time during which certain state predicates hold. We formalize the concept of durations by introducing duration measures for (dense-time) timed automata. Given a timed automaton with a duration measure, a start and a target state, and a duration constraint, the duration-bounded reachability problem asks if there is a run of the automaton from the start state to the target state such that the accumulated duration along the run satisfies the constraint. Our main result is a novel decision procedure for solving the duration-bounded reachability problem. We also prove that the problem is PSPACE-complete and demonstrate how the solution can be used to verify interesting duration properties of real-time systems.}, author = {Alur, Rajeev and Courcoubetis, Costas and Henzinger, Thomas A}, booktitle = {5th International Conference on Computer Aided Verification}, location = {Elounda, Greece}, pages = {181 -- 193}, publisher = {Springer}, title = {{Computing accumulated delays in real-time systems}}, doi = {10.1007/3-540-56922-7_16}, volume = {697}, year = {1993}, } @inproceedings{4619, abstract = {Traditional approaches to the algorithmic verification of real-time systems are limited to checking program correctness with respect to concrete timing properties (e.g., "message delivery within 10 milliseconds"). We address the more realistic and more ambitious problem of deriving symbolic constraints on the timing properties required of real-time systems (e.g., "message delivery within the time it takes to execute two assignment statements"). To model this problem, we introduce parametric timed automata -- finite-state machines whose transitions are constrained with parametric timing requirements. The emptiness question for parametric timed automata is central to the verification problem. On the negative side, we show that in general this question is undecidable. On the positive side, we provide algorithms for checking the emptiness of restricted classes of parametric timed automata. The practical relevance of these classes is illustrated with several verification examples. There remains a gap between the automata classes for which we know that emptiness is decidable and undecidable, respectively, and this gap is related to various hard and open problems of logic and automata theory.}, author = {Alur, Rajeev and Henzinger, Thomas A and Vardi, Moshe}, booktitle = {Proceedings of the 25th annual ACM symposium on Theory of Computing}, location = {San Diego, CA, United States of America}, pages = {592 -- 601}, publisher = {ACM}, title = {{Parametric real-time reasoning}}, doi = {10.1145/167088.167242}, year = {1993}, }