@article{18748, abstract = {We present models for dusty high–redshift Lyα emitting galaxies by combining the Press–Schechter formalism with a treatment of inhomogeneous dust distribution inside galaxies. These models reproduce the surface density of emitters inferred from recent observations, and also agree with previous non–detections. Although a detailed determination of the individual model parameters is precluded by uncertainties, we find that (i) the dust content of primordial galaxies builds up in no more than ∼ 5 × 10^8 yr, (ii) the galactic HII regions are nhomogeneous with a cloud covering factor of order unity, and (iii) the overall star formation efficiency is at least ∼ 5%. Future observations should be able to detect Lyα galaxies upto redshifts of z ∼ 8. If the universe is reionized at zr ∼< 8, the corresponding decline in the number of Lyα emitters at z ∼> zr could prove to be a useful probe of the reionization epoch. }, author = {Haiman, Zoltán and Spaans, M.}, journal = {AIP Conference Proceedings}, location = {College Park, MD, United States}, number = {1}, pages = {63--67}, publisher = {AIP Publishing}, title = {{Models for high-redshift Lyα emitters}}, doi = {10.1063/1.58635}, volume = {470}, year = {1999}, } @article{18750, abstract = {Empirical studies of the first generation of stars and quasars in the Universe will likely become feasible over the next decade. The Next Generation Space Telescope will provide direct imaging and photometry of sub-galactic objects at (math formular) while microwave anisotropy experiments, such as MAP or Planck, will set constraints on the ionization history of the intergalactic medium due to these sources. We describe the expected signals that will be detectable with these future instruments.}, author = {Haiman, Zoltán and Loeb, A.}, journal = {AIP Conference Proceedings}, number = {1}, pages = {34--47}, publisher = {AIP Publishing}, title = {{Empirical constraints on the first stars and quasars}}, doi = {10.1063/1.58620}, volume = {470}, year = {1999}, } @article{2592, abstract = {Metabotropic glutamate receptors (mGluRs) consist of eight different subtypes and exert their effects or second messengers and ion channels via G- proteins. The function of individual mGluR subtypes in the CNS, however, largely remains to be clarified. We examined the fear response of freezing after electric shock in wild-type and mGluR7(-/-) knockout littermates. Wild- type mice displayed freezing immediately after and 1 d after footshock. In comparison, mGluR7(-/-) knockout mice showed significantly reduced levels in both immediate postshock and delayed freezing responses. However, the knockout mice exhibited no abnormalities in pain sensitivity and locomotor activity. To further examine amygdala-dependent behavior, we performed conditioned taste aversion (CTA) experiments. In wild-type mice, the administration of saccharin followed by intraperitoneal injection of the malaise-inducing agent LiCl resulted in an association between saccharin and LiCl. This association caused strong CTA toward saccharin n contrast, mGluR7(-/-) knockout mice failed to associate between the taste and the negative reinforcer in CTA experiments. Again, the knockout mice showed no abnormalities in taste preference and in the sensitivity to LiCl toxicity. These results indicate that mGluR7 deficiency causes an impairment of two distinct amygdala-dependent behavioral paradigms. Immunohistochemical and immunoelectron-microscopic analyses showed that mGluR7 is highly expressed in amygdala and preferentially localized at the presynaptic axon terminals of glutamatergic neurons. Together, these findings strongly suggest that mGluR7 is involved in neural processes subserving amygdala-dependent averse responses.}, author = {Masugi, Miwako and Yokoi, Mineto and Shigemoto, Ryuichi and Muguruma, Keiko and Watanabe, Yasuyoshi and Sansig, Gilles and Van Der Putten, Herman and Nakanishi, Shigetada}, issn = {0270-6474}, journal = {Journal of Neuroscience}, number = {3}, pages = {955 -- 963}, publisher = {Society for Neuroscience}, title = {{Metabotropic glutamate receptor subtype 7 ablation causes deficit in fear response and conditioned taste aversion}}, doi = {10.1523/JNEUROSCI.19-03-00955.1999}, volume = {19}, year = {1999}, } @article{2593, abstract = {In cat and monkey, lamina I cells can be classified into three basic morphological types (fusiform, pyramidal, and multipolar), and recent intracellular labeling evidence in the cat indicates that fusiform and multipolar lamina I cells are two different types of nociceptive cells, whereas pyramidal cells are innocuous thermoreceptive-specific. Because earlier observations indicated that only nociceptive dorsal horn neurons respond to substance P (SP), we examined which morphological types of lamina I neurons express receptors for SP (NK-1r). We categorized NK-1r- immunoreactive (IR) lamina I neurons in serial horizontal sections from the cervical and lumbar enlargements of four monkeys. Consistent results were obtained by two independent teams of observers. Nearly all NK-1r-IR cells were fusiform (42%) or multipolar (43%), but only 6% were pyramidal (with 9% unclassified). We obtained similar findings in three monkeys in which we used double-labeling immunocytochemistry to identify NK-1r-IR and spinothalamic lamina I neurons retrogradely labeled with cholera toxin subunit b from the thalamus; most NK-1r-IR lamina I spinothalamic neurons were fusiform (48%) or multipolar (33%), and only 10% were pyramidal. In contrast, most (~75%) pyramidal and some (~25%) fusiform and multipolar lamina I spinothalamic neurons did not display NK-1r immunoreactivity. These data indicate that most fusiform and multipolar lamina I neurons in the monkey can express NK-1r, consistent with the idea that both types are nociceptive, whereas only a small proportion of lamina I pyramidal cells express this receptor, consistent with the previous finding that they are nonnociceptive. However, these findings also indicate that not all nociceptive lamina I neurons express receptors for SP.}, author = {Yu, Xiao and Zhang, En and Craig, Arthur and Shigemoto, Ryuichi and Ribeiro Da Silva, Alfredo and De Koninck, Yves}, issn = {0270-6474}, journal = {Journal of Neuroscience}, number = {9}, pages = {3545 -- 3555}, publisher = {Society for Neuroscience}, title = {{NK-1 receptor immunoreactivity in distinct morphological types of lamina I neurons of the primate spinal cord}}, doi = {10.1523/JNEUROSCI.19-09-03545.1999}, volume = {19}, year = {1999}, } @article{3444, abstract = {This study examined intermittent, high-frequency (100-200 Hz) oscillatory patterns in the CA1 region of the hippocampus in the absence of theta activity, i.e., during and in between sharp wave (SPW) bursts. Pyramidal and interneuronal activity was phase-locked not only to large amplitude (>7 SD from baseline) oscillatory events, which are present mainly during SPWs, but to smaller amplitude (<4 SD) patterns, as well. Large-amplitude events were in the 140-200 Hz, "ripple" frequency range. Lower-amplitude events, however, contained slower, 100-130 Hz ("slow") oscillatory patterns. Fast ripple waves reversed just below the CA1 pyramidal layer, whereas slow oscillatory potentials reversed in the stratum radiatum and/or in the stratum oriens. Parallel CA1-CA3 recordings revealed correlated CA3 field and unit activity to the slow CA1 waves but not to fast ripple waves. These findings suggest that fast ripples emerge in the CA1 region, whereas slow (100-130 Hz) oscillatory patterns are generated in the CA3 region and transferred to the CA1 field.}, author = {Csicsvari, Jozsef L and Hirase, Hajima and Czurkó, András and Mamiya, Akira and Buzsáki, György}, issn = {0270-6474}, journal = {Journal of Neuroscience}, number = {16}, publisher = {Society for Neuroscience}, title = {{Fast network oscillations in the hippocampal CA1 region of the behaving rat}}, doi = {10.1523/JNEUROSCI.19-16-j0001.1999}, volume = {19}, year = {1999}, } @article{3445, abstract = {The medial septal region and the hippocampus are connected reciprocally via GABAergic neurons, but the physiological role of this loop is still not well understood. In an attempt to reveal the physiological effects of the hippocamposeptal GABAergic projection, we cross-correlated hippocampal sharp wave (SPW) ripples or theta activity and extracellular units recorded in the medial septum and diagonal band of Broca (MSDB) in freely moving rats. The majority of single MSDB cells (60%) were significantly suppressed during SPWs. Most cells inhibited during SPW (80%) fired rhythmically and phase-locked to the negative peak of the CA1 pyramidal layer theta waves. Because both SPW and the negative peak of local theta waves correspond to the maximum discharge probability of CA1 pyramidal cells and interneuron classes, the findings indicate that the activity of medial septal neurons can be negatively (during SPW) or positively (during theta waves) correlated with the activity of hippocampal interneurons. We hypothesize that the functional coupling between medial septal neurons and hippocampal interneurons varies in a state-dependent manner.}, author = {Dragoi, George and Carpi, Daniel and Recce, Michael and Csicsvari, Jozsef L and Buzsáki, György}, issn = {0270-6474}, journal = {Journal of Neuroscience}, number = {14}, pages = {6191 -- 6199}, publisher = {Society for Neuroscience}, title = {{Interactions between hippocampus and medial septum during sharp waves and theta oscillation in the behaving rat}}, doi = {10.1523/JNEUROSCI.19-14-06191.1999}, volume = {19}, year = {1999}, } @article{3518, abstract = {Information in neuronal networks may be represented by the spatiotemporal patterns of spikes. Here we examined the temporal coordination of pyramidal cell spikes in the rat hippocampus during slow-wave sleep. In addition, rats were trained to run in a defined position in space (running wheel) to activate a selected group of pyramidal cells. A template-matching method and a joint probability map method were used for sequence search. Repeating spike sequences in excess of chance occurrence were examined by comparing the number of repeating sequences in the original spike trains and in surrogate trains after Monte Carlo shuffling of the spikes. Four different shuffling procedures were used to control for the population dynamics of hippocampal neurons. Repeating spike sequences in the recorded cell assemblies were present in both the awake and sleeping animal in excess of what might be predicted by random variations. Spike sequences observed during wheel running were “replayed” at a faster timescale during single sharp-wave bursts of slow-wave sleep. We hypothesize that the endogenously expressed spike sequences during sleep reflect reactivation of the circuitry modified by previous experience. Reactivation of acquired sequences may serve to consolidate information.}, author = {Nádasdy, Zoltán and Hirase, Hajima and Czurkó, András and Csicsvari, Jozsef L and Buzsáki, György}, issn = {0270-6474}, journal = {Journal of Neuroscience}, number = {21}, pages = {9497 -- 9507}, publisher = {Society for Neuroscience}, title = {{Replay and time compression of recurring spike sequences in the hippocampus}}, doi = {10.1523/JNEUROSCI.19-21-09497.1999}, volume = {19}, year = {1999}, } @article{3524, abstract = {We examined whether excitation and inhibition are balanced in hippocampal cortical networks. Extracellular field and single-unit activity were recorded by multiple tetrodes and multisite silicon probes to reveal the timing of the activity of hippocampal CAI pyramidal cells and classes of interneurons during theta waves and sharp wave burst (SPW)-associated field ripples. The somatic and dendritic inhibition of pyramidal cells was deduced from the activity of interneurons in the pyramidal layer [int(p)] and in the alveus and st. oriens [int(a/o)], respectively. int(p) and int(a/o) discharged an average of 60 and 20 degrees before the population discharge of pyramidal cells during the theta cycle, respectively. SPW ripples were associated with a 2.5-fold net increase of excitation. The discharge frequency of int(a/o) increased, decreased (”anti-SPW” cells), or did not change (”SPW-independent” cells) during SPW suggesting that not all interneurons are innervated by pyramidal cells. Int(p) either fired together with (unimodal cells) or both before and after (bimodal cells) the pyramidal cell burst. During fast-ripple oscillation, the activity of interneurons in both the int(p) and int(a/o) groups lagged the maximum discharge probability of pyramidal neurons by 1-2 msec. Network state changes, as reflected by field activity, covaried with changes in the spike train dynamics of single cells and their interactions. Summed activity of parallel-recorded interneurons, but not of pyramidal cells, reliably predicted theta cycles, whereas the reverse was true for the ripple cycles of SPWs. We suggest that network-driven excitability changes provide temporal windows of opportunity for single pyramidal cells to suppress, enable, or facilitate selective synaptic inputs.}, author = {Csicsvari, Jozsef L and Hirase, Hajima and Czurkó, András and Mamiya, Akira and Buzsáki, György}, issn = {0270-6474}, journal = {Journal of Neuroscience}, number = {1}, pages = {274 -- 287}, publisher = {Society for Neuroscience}, title = {{Oscillatory coupling of hippocampal pyramidal cells and interneurons in the behaving rat}}, doi = {10.1523/JNEUROSCI.19-01-00274.1999}, volume = {19}, year = {1999}, } @article{3582, abstract = {We study edge contractions in simplicial complexes and local conditions under which they preserve the topological type. The conditions are based on a generalized notion of boundary, which lends itself to defining a nested hierarchy of triangulable spaces measuring the distance to being a manifold.}, author = {Dey, Tamal and Edelsbrunner, Herbert and Guha, Sumanta and Nekhayev, Dmitry}, issn = {0350-1302}, journal = {Publications de l'Institut Mathématique}, pages = {23 -- 45}, publisher = {Mathematical Institute, Serbian Academy of Sciences and Arts}, title = {{Topology preserving edge contraction}}, volume = {66}, year = {1999}, } @article{1449, abstract = {In this paper we consider a canonical compactification of M, the moduli space of stable Higgs bundles with fixed determinant of odd degree over a Riemann surface Σ, producing a projective variety M̄ = M ∪ Z. We give a detailed study of the spaces M̄, Z and M. In doing so we reprove some assertions of Laumon and Thaddeus on the nilpotent cone.}, author = {Hausel, Tamas}, issn = {1435-5345}, journal = {Journal fur die Reine und Angewandte Mathematik}, number = {503}, pages = {169 -- 192}, publisher = {Walter de Gruyter}, title = {{Compactification of moduli of Higgs bundles}}, doi = {10.1515/crll.1998.096}, volume = {1998}, year = {1998}, } @article{1450, abstract = {In this paper we consider the topological side of a problem which is the analogue of Sen's S-duality testing conjecture for Hitchin's moduli space M of rank 2 stable Higgs bundles of fixed determinant of odd degree over a Riemann surface ∑. We prove that all intersection numbers in the compactly supported cohomology of M vanish, i.e. "there are no topological L2 harmonic forms on M". This result generalizes the well known vanishing of the Euler characteristic of the moduli space of rank 2 stable bundles N of fixed determinant of odd degree over ∑. Our proof shows that the vanishing of all intersection numbers of H* cpt(M) is given by relations analogous to the Mumford relations in the cohomology ring of N.}, author = {Hausel, Tamas}, issn = {1095-0761}, journal = {Advances in Theoretical and Mathematical Physics}, number = {5}, pages = {1011 -- 1040}, publisher = {International Press}, title = {{Vanishing of intersection numbers on the moduli space of Higgs bundles}}, doi = {10.4310/ATMP.1998.v2.n5.a3}, volume = {2}, year = {1998}, } @article{17839, abstract = {We study the observational signatures of a potential population of low-luminosity quasars at high redshifts in a ΛCDM cosmology. We derive the evolution of the quasar luminosity function at fainter luminosities and higher redshifts than currently detected based on three assumptions: (1) the formation of dark matter halos follows the Press-Schechter theory, (2) the ratio of central black hole mass to halo mass is the same for all halos, and (3) the light curve of quasars, in Eddington units, is universal. We show that a universal light curve provides an excellent fit to the observed quasar luminosity function at redshifts 2.6 < z < 4.5. By extrapolating the evolution of this luminosity function to higher redshifts (4.5 < z < 20), we find that the associated early population of low-luminosity quasars reionizes the universe at a redshift z ~ 12. The reprocessing of the UV light of these quasars by dust from early Type II supernovae distorts the microwave background spectrum by a Compton y-parameter y ~ 10-5, comparable to the lower limit set by COBE. The Next Generation Space Telescope could detect tens of quasars per arcmin-2 from redshifts z > 10 with its proposed 1 nJy sensitivity at 1-3.5 μm. Absorption spectra of several such quasars would reveal the reionization history of the universe.}, author = {Haiman, Zoltán and Loeb, Abraham}, issn = {1538-4357}, journal = {The Astrophysical Journal}, number = {2}, pages = {505--517}, publisher = {American Astronomical Society}, title = {{Observational signatures of the first quasars}}, doi = {10.1086/306017}, volume = {503}, year = {1998}, } @article{1955, abstract = {The plastid genomes of several plants contain homologues, termed ndh genes, of genes encoding subunits of the NADH:ubiquinone oxidoreductase or complex I of mitochondria and eubacteria. The functional significance of the Ndh proteins in higher plants is uncertain. We show here that tobacco chloroplasts contain a protein complex of 550 kDa consisting of at least three of the ndh gene products: NdhI, NdhJ and NdhK. We have constructed mutant tobacco plants with disrupted ndhC, ndhK and ndhJ plastid genes, indicating that the Ndh complex is dispensible for plant growth under optimal growth conditions. Chlorophyll fluorescence analysis shows that in vivo the Ndh complex catalyses the post-illumination reduction of the plastoquinone pool and in the light optimizes the induction of photosynthesis under conditions of water stress. We conclude that the Ndh complex catalyses the reduction of the plastoquinone pool using stromal reductant and so acts as a respiratory complex. Overall, our data are compatible with the participation of the Ndh complex in cyclic electron flow around the photosystem I complex in the light and possibly in a chloroplast respiratory chain in the dark.}, author = {Burrows, Paul and Sazanov, Leonid A and Sváb, Zóra and Maliga, Pàl and Nixon, Peter}, issn = {0261-4189}, journal = {EMBO Journal}, number = {4}, pages = {868 -- 876}, publisher = {Wiley-Blackwell}, title = {{Identification of a functional respiratory complex in chloroplasts through analysis of tobacco mutants containing disrupted plastid ndh genes}}, doi = {10.1093/emboj/17.4.868}, volume = {17}, year = {1998}, } @article{1956, abstract = { The plastid genomes of several plants contain ndh genes-homologues of genes encoding subunits of the proton-pumping NADH:ubiquinone oxidoreductase, or complex I, involved in respiration in mitochondria and eubacteria. From sequence similarities with these genes, the ndh gene products have been suggested to form a large protein complex (Ndh complex); however, the structure and function of this complex remains to be established. Herein we report the isolation of the Ndh complex from the chloroplasts of the higher plant Pisum sativum. The purification procedure involved selective solubilization of the thylakoid membrane with dodecyl maltoside, followed by two anion-exchange chromatography steps and one size-exclusion chromatography step. The isolated Ndh complex has an apparent total molecular mass of approximately 550 kDa and according to SDS/PAGE consists of at least 16 subunits including NdhA, NdhI, NdhJ, NdhK, and NdhH, which were identified by N-terminal sequencing and immunoblotting. The Ndh complex showed an NADH- and deamino-NADH-specific dehydrogenase activity, characteristic of complex I, when either ferricyanide or the quinones menadione and duroquinone were used as electron acceptors. This study describes the isolation of the chloroplast analogue of the respiratory complex I and provides direct evidence for the function of the plastid Ndh complex as an NADH:plastoquinone oxidoreductase. Our results are compatible with a dual role for the Ndh complex in the chloro-respiratory and cyclic photophosphorylation pathways.}, author = {Sazanov, Leonid A and Burrows, Paul and Nixon, Peter}, issn = {0027-8424}, journal = {PNAS}, number = {3}, pages = {1319 -- 1324}, publisher = {National Academy of Sciences}, title = {{The plastid ndh genes code for an NADH-specific dehydrogenase: Isolation of a complex I analogue from pea thylakoid membranes}}, doi = {10.1073/pnas.95.3.1319}, volume = {95}, year = {1998}, } @article{3488, abstract = {We have examined gating and pharmacological characteristics of somatic K+ channels in fast-spiking interneurons and regularly spiking principal neurons of hippocampal slices. In nucleated patches isolated from basket cells of the dentate gyrus, a fast delayed rectifier K+ current component that was highly sensitive to tetraethylammonium (TEA) and 4-aminopyridine (4- AP) (half-maximal inhibitory concentrations <0.1 mM) predominated, contributing an average of 58% to the total K+ current in these cells. By contrast, in pyramidal neurons of the CA1 region a rapidly inactivating A- type K+ current component that was TEA-resistant prevailed, contributing 61% to the total K+ current. Both types of neurons also showed small amounts of the K+ current component mainly found in the other type of neuron and, in addition, a slow delayed rectifier K+ current component with intermediate properties (sow inactivation, intermediate sensitivity to TEA). Single-cell RT-PCR analysis of mRNA revealed that Kv3 (Kv3.1, Kv3.2) subunit transcripts were expressed in almost all (89%) of the interneurons but only in 17% of the pyramidal neurons. In contrast, Kv4 (Kv4.2, Kv4.3) subunit mRNAs were present in 87% of pyramidal neurons but only in 55% of interneurons. Selective block of fast delayed rectifier K+ channels, presumably assembled from Kv3 subunits, by 4-AP reduced substantially the action potential frequency in interneurons. These results indicate that the differential expression of Kv3 and Kv4 subunits shapes the action potential phenotypes of principal neurons and interneurons in the cortex.}, author = {Martina, Marco and Schultz, Jobst and Ehmke, Heimo and Monyer, Hannah and Jonas, Peter M}, issn = {0270-6474}, journal = {Journal of Neuroscience}, number = {20}, pages = {8111 -- 8125}, publisher = {Society for Neuroscience}, title = {{Functional and molecular differences between voltage-gated K+ channels of fast-spiking interneurons and pyramidal neurons of rat hippocampus}}, doi = {10.1523/JNEUROSCI.18-20-08111.1998}, volume = {18}, year = {1998}, } @misc{3506, abstract = {A method of geometric morphing between a first object having a first shape and a second object having a second shape. The method includes the steps of generating a first Delaunay complex corresponding to the first shape and a second Delaunay complex corresponding to the second shape and generating a plurality of intermediary Delaunay complexes defined by a continuous family of mixed shapes corresponding to a mixing of the first shape and the second shape. The method further includes the steps of constructing a first skin corresponding to the first Delaunay complex and a second skin corresponding to the second Delaunay complex and constructing a plurality of intermediary skins corresponding to the plurality of intermediary Delaunay complexes. The first skin, second skin and plurality of intermediary skins may be visually displayed on an output device.}, author = {Edelsbrunner, Herbert and Fu, Ping}, title = {{Apparatus and method for geometric morphing}}, year = {1998}, } @article{3628, abstract = {Determining the way in which deleterious mutations interact in their effects on fitness is crucial to numerous areas in population genetics and evolutionary biology. For example, if each additional mutation leads to a greater decrease in log fitness than the last (synergistic epistasis), then the evolution of sex and recombination may be favored to facilitate the elimination of deleterious mutations. However, there is a severe shortage of relevant data. Three relatively simple experimental methods to test for epistasis between deleterious mutations in haploid species have recently been proposed. These methods involve crossing individuals and examining the mean and/or skew in log fitness of the offspring and parents. The main aim of this paper is to formalize these methods, and determine the most effective way in which tests for epistasis could be carried out. We show that only one of these methods is likely to give useful results: crossing individuals that have very different numbers of deleterious mutations, and comparing the mean log fitness of the parents with that of their offspring. We also reconsider experimental data collected on Chlamydomonas moewussi using two of the three methods. Finally, we suggest how the test could be applied to diploid species.}, author = {West, Stuart and Peters, Andrew and Barton, Nicholas H}, issn = {0016-6731}, journal = {Genetics}, number = {1}, pages = {435 -- 444}, publisher = {Genetics Society of America}, title = {{Testing for epistasis between deleterious mutations}}, doi = {10.1093/genetics/149.1.435}, volume = {149}, year = {1998}, } @article{4013, abstract = {The shape of a protein is important for its functions, This includes the location and size of identifiable regions in its complement space. We formally define pockets as regions in the complement with limited accessibility from the outside. Pockets can be efficiently constructed by an algorithm based on alpha complexes. The algorithm is implemented and applied to proteins with known three-dimensional conformations. 1998 Published by Elsevier Science B.V. All rights reserved.}, author = {Edelsbrunner, Herbert and Facello, Michael and Liang, Jie}, issn = {0166-218X}, journal = {Discrete Applied Mathematics}, number = {1-3}, pages = {83 -- 102}, publisher = {Elsevier}, title = {{On the definition and the construction of pockets in macromolecules}}, doi = {10.1016/S0166-218X(98)00067-5}, volume = {88}, year = {1998}, } @article{4017, abstract = {Identification and size characterization of surface pockets and occluded cavities are initial steps in protein structure-based ligand design. A new program, CAST, for automatically locating and measuring protein pockets and cavities, is based on precise computational geometry methods, including alpha shape and discrete flow theory. CAST identifies and measures pockets and pocket mouth openings, as well as cavities. The program specifies the atoms lining pockets, pocket openings. and buried cavities; the volume and area of pockets and cavities; and the area and circumference of mouth openings. CAST analysis of over 100 proteins has been carried out; proteins examined include a set of 51 monomeric enzyme-ligand structures, several elastase-inhibitor complexes, the FK506 binding protein, 30 HIV-1 protease-inhibitor complexes, and a number of small and large protein inhibitors, Medium-sized globular proteins typically have 10-20 pockets/cavities. Most often, binding sites are pockets with 1-2 mouth openings; much less frequently they are cavities. Ligand binding pockets vary widely in size, most within the range 10(2)-10(3) Angstrom(3). Statistical analysis reveals that the number of pockets and cavities is correlated with protein size, but there is no correlation between the size of the protein and the size of binding sites. Most frequently, the largest pocket/cavity is thp active site, but there are a number of instructive exceptions. Ligand volume and binding site volume are somewhat correlated when binding site volume is less than or equal to 700 Angstrom(3), but the ligand seldom occupies the entire site. Auxiliary pockets near the active site have been suggested as additional binding surface for designed ligands (Mattos C ct al., 1993, Nat Struct Biol 1:55-58). Analysis of elastase-inhibitor complexes suggests that CAST can identify ancillary pockets, suitable for recruitment in ligand design strategies. Analysis of the FK506 binding protein, and of compounds developed in SAR by NMR (Shuker SE et al.. 1996, Science 274:1531-1534), indicates that CAST pocket computation may provide a priori identification of target proteins for Linked-fragment design. CAST analysis of 30 HIV-1 protease-inhibitor complexes shows that the flexible active site pocket can vary over a range of 853-1,566 Angstrom(3), and that there are two pockets near or adjoining the active site that may be recruited for ligand design.}, author = {Liang, Jie and Edelsbrunner, Herbert and Woodward, Clare}, issn = {0961-8368}, journal = {Protein Science}, number = {9}, pages = {1884 -- 1897}, publisher = {Wiley-Blackwell}, title = {{Anatomy of protein pockets and cavities: Measurement of binding site geometry and implications for ligand design}}, doi = {10.1002/pro.5560070905}, volume = {7}, year = {1998}, } @article{4492, abstract = {Hybrid automata model systems with both digital and analog components, such as embedded control programs. Many verification tasks for such programs can be expressed as reachability problems for hybrid automata. By improving on previous decidability and undecidability results, we identify a boundary between decidability and undecidability for the reachability problem of hybrid automata. On the positive side, we give an (optimal) PSPACE reachability algorithm for the case of initialized rectangular automata, where all analog variables follow independent trajectories within piecewise-linear envelopes and are reinitialized whenever the envelope changes. Our algorithm is based on the construction of a timed automaton that contains all reachability information about a given initialized rectangular automaton. The translation has practical significance for verification, because it guarantees the termination of symbolic procedures for the reachability analysis of initialized rectangular automata. The translation also preserves theω-languages of initialized rectangular automata with bounded nondeterminism. On the negative side, we show that several slight generalizations of initialized rectangular automata lead to an undecidable reachability problem. In particular, we prove that the reachability problem is undecidable for timed automata augmented with a single stopwatch.}, author = {Henzinger, Thomas A and Kopke, Peter and Puri, Anuj and Varaiya, P.}, isbn = {0022-0000}, journal = {Journal of Computer and System Sciences}, number = {1}, pages = {94 -- 124}, publisher = {Elsevier}, title = {{What's decidable about hybrid automata?}}, doi = {10.1006/jcss.1998.1581}, volume = {57}, year = {1998}, }