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PubMed2000

Cross-referencing radiation hybrid data to the recombination map: lessons from mouse chromosome 18.

We are building a framework map of known-order anchor markers between the mouse T31 radiation hybrid (RH) panel and the recombination map based on The Jackson Laboratory (TJL) interspecific backcross panels using the established genetic order to evaluate and strengthen the RH results. In making this map comparison, we have elucidated several problems inherent in RH mapping and minimized these by careful attention to data gathering and interpretation methods. We describe lessons and pitfalls of developing radiation hybrid maps, using the example of mouse Chromosome 18, for which we have built a framework map of microsatellite anchor loci spanning the entire chromosome at significant LOD with no gaps. Sixty-five D18Mit- simple sequence length polymorphism (SSLP) markers form a continuous linkage along the T31 RH Chromosome 18 (RH map length 1598 cR, genetic length 41 cM) with all LODs greater than 6. These markers are also placed on TJL interspecific backcrosses, and the order of the markers in the two systems is in complete agreement. We are continuing to cross-reference the RH data to TJL backcross data for the other mouse chromosomes to improve further the power of RH mapping and to integrate more precisely the extensive existing recombination mapping data for the mouse with the incoming radiation hybrid map data.

Alleles↗
PubMed1991

Autoantibody-encoding kappa L chain genes frequently rearranged in lambda L chain-expressing chronic lymphocytic leukemia.

Patients with kappa L chain expressing chronic lymphocytic leukemia (CLL) frequently have leukemia cells reactive with a murine mAb, designated 17.109. Raised against a monoclonal IgM rheumatoid factor autoantibody, this mAb recognizes a major kappa-L chain-associated cross reactive Id, designated 17.109-CRI. Molecular studies reveal that the 17.109-CRI in CLL is a serologic marker for expression of a conserved kappa L chain V region gene (V Kappa gene) of the V Kappa 3 subgroup, designated Humkv325. We isolated an upstream gene fragment of Humkv325 to examine for Ig gene rearrangements of this and other closely related V Kappa 3 genes by Southern analyses. Consistent with Humkv325 encoding the 17.109-CRI, we find that the genomic DNA from all 17.109-reactive leukemia cell populations have gene rearrangements that are detected using this probe. In addition, we observe V Kappa 3 gene rearrangements frequently in the genomic DNA of lambda L chain-expressing leukemia cells. Of the genomic DNA from 33 lambda-L chain-expressing CLL samples, 8 (24%) had additional nongerm-line bands detected with the Humkv325 probe. Consistent with these bands representing Ig gene rearrangements, the additional band in each but one sample also hybridized with probes specific for the J Kappa region and/or the kappa-deleting element. Using the polymerase chain reaction (PCR), we examined the genomic DNA from all lambda L chain-expressing CLL for V Kappa 3 gene rearrangements to J Kappa and/or Kde. PCR on each DNA sample with V Kappa 3 gene rearrangements detected by Southern analysis generated gene fragments that hybridized specifically with oligonucleotides corresponding to framework or CDR of the Humkv325 gene. Nucleic acid sequence analyses of representative samples confirmed that these DNA contained abortive Humkv325 gene rearrangements. PCR for rearranged V Kappa 3 genes in the DNA of other lambda-L chain-expressing CLL either did not generate any PCR product or produced fragments that failed to hybridize with all Humkv325 oligonucleotide probes. Nucleic acid sequence analyses of the latter demonstrated that these represent abortive V Kappa gene rearrangements involving another conserved V Kappa 3 gene, designated Vg. These studies indicate that Humkv325 and Vg frequently may undergo Ig gene rearrangement independent of their expression. As such, the frequent use of Humkv325 in CLL may be secondary, in part, to an enhanced propensity of this V Kappa 3 gene to undergo genetic rearrangement during B cell ontogeny.

Amino Acid Sequence↗
PubMed2004

Hybrid cluster-cages formed via cyanometalate condensation: Cs subset Co(4)Ru(6)S(2)(CN)(12), Co(4)Ru(9)S(6)(CN)(9), and Rh(4)Ru(9)S(6)(CN)(9) frameworks.

Condensation of cyanometalates and cluster building blocks leads to the formation of hybrid molecular cyanometalate cages. Specifically, the reaction of [Cs subset [CpCo(CN)(3)](4)[CpRu](3)] and [(cymene)(2)Ru(3)S(2)(NCMe)(3)]PF(6) produced [Cs subset [CpCo(CN)(3)](4)[(cymene)(2)Ru(3)S(2)][CpRu](3)](PF(6))(2), Cs subset Co(4)Ru(6)S(2)(2+). Single-crystal X-ray diffraction, NMR spectroscopy, and ESI-MS measurements show that Cs subset Co(4)Ru(6)S(2)(2+ ) consists of a Ru(4)Co(4)(CN)(12) box fused with a Ru(3)S(2) cluster via a common Ru atom. The reaction of PPN[CpCo(CN)(3)] and 0.75 equiv of [(cymene)(2)(MeCN)(3)Ru(3)S(2)](PF(6))(2) in MeCN solution produced [[CpCo(CN)(3)](4)[(cymene)(2)Ru(3)S(2)](3)](PF(6))(2), Co(4)Ru(9)S(6)(2+). Crystallographic analysis, together with NMR and ESI-MS measurements, shows that Co(4)Ru(9)S(6)(2+ ) consists of a Ru(3)Co(4)(CN)(9) "defect box" core, wherein each Ru is fused to a Ru(3)S(2) clusters. The analogous condensation using [CpRh(CN)(3)](-) in place of [CpCo(CN)(3)](-) produced the related cluster-cage Rh(4)Ru(9)S(6)(2+). Electrochemical analyses of both Co(4)Ru(9)S(6)(2+) and Rh(4)Ru(9)S(6)(2+) can be rationalized in the context of reduction at the cluster and the Co(III) subunits, the latter being affected by the presence of alkali metal cations.

Journal Article↗
PubMed2004

Highly ordered hybrid mesoporous bifunctional thin films.

Highly ordered mixed framework mesoporous cubic (Im3m) thin films of (M(1-x)(Si-R)(x))O(2) bearing organic groups (M = Ti or Zr, R = propylamine, propylthiol or phenyl, x < or = 0.2) are obtained by one-pot dip-coating; a second organic function (R' = hexadecyl, phenyl, thiol) can be added by post-grafting with a molecule presenting a group capable to anchor to the M sites, thus leading to bifunctional accessible mesopores.

Journal Article↗
PubMed2004

A hybrid neural network model for consciousness.

A new framework for consciousness is introduced based upon traditional artificial neural network models. This framework reflects explicit connections between two parts of the brain: one global working memory and distributed modular cerebral networks relating to specific brain functions. Accordingly this framework is composed of three layers, physical mnemonic layer and abstract thinking layer, which cooperate together through a recognition layer to accomplish information storage and cognition using algorithms of how these interactions contribute to consciousness: (1) the reception process whereby cerebral subsystems group distributed signals into coherent object patterns; (2) the partial recognition process whereby patterns from particular subsystems are compared or stored as knowledge; and (3) the resonant learning process whereby global workspace stably adjusts its structure to adapt to patterns' changes. Using this framework, various sorts of human actions can be explained, leading to a general approach for analyzing brain functions.

Algorithms↗
PubMed1990

Reliable hybridization of oligonucleotides as short as six nucleotides.

Although there are many new applications for hybridizing short, synthetic oligonucleotide probes to DNA, such applications have not included determining unknown sequences of DNA. The lack of clear discrimination in hybridization of oligo probes shorter than 11 nucleotides and the lack of a theoretical understanding of factors influencing hybridization of short oligos have hampered the development of their use. We have found conditions for reliable hybridization of oligonucleotides as short as seven nucleotides to cloned DNA or to oligonucleotides attached to filters. Low-temperature hybridization and washing conditions, in contrast to the high stringency conditions currently used in hybridization experiments, have the potential for allowing the simple use of all oligos of six nucleotides or longer in meaningful hybridizations. We also present the hybridization discrimination theory that provides the conceptual framework for understanding these results.

DNA Fingerprinting↗
PubMed2003

[CH(3)(CH(2))(11)NH(3)]SnI(3): a hybrid semiconductor with MoO(3)-type tin(II) iodide layers.

The organic-inorganic hybrid [CH(3)(CH(2))(11)NH(3)]SnI(3) presents a lamellar structure with a Sn-I framework isotypic to that of MoO(3). The SnI(3)(-) layer consists of edge and corner-sharing SnI(6) octahedra in which one of the six Sn-I bonds is distinctly elongated (e.g., 3.62 A), indicating lone-pair stereoactivity for the Sn(II) atom. The overall electronic character remains comparable with that of the well-studied SnI(4)(2)(-)-based perovskite semiconductors, such as [CH(3)(CH(2))(11)NH(3)](2)SnI(4), with a red-shifted and broadened exciton peak associated with the band gap, apparently due to the increased dimensionality of the Sn-I framework. The title compound offers, aside from the hybrid perovskites, a new type of solution-processable Sn-I network for potential applications in semiconductive devices.

Journal Article↗
PubMed2003

Hybrid global optimization algorithms for protein structure prediction: alternating hybrids.

Hybrid global optimization methods attempt to combine the beneficial features of two or more algorithms, and can be powerful methods for solving challenging nonconvex optimization problems. In this paper, novel classes of hybrid global optimization methods, termed alternating hybrids, are introduced for application as a tool in treating the peptide and protein structure prediction problems. In particular, these new optimization methods take the form of hybrids between a deterministic global optimization algorithm, the alphaBB, and a stochastically based method, conformational space annealing (CSA). The alphaBB method, as a theoretically proven global optimization approach, exhibits consistency, as it guarantees convergence to the global minimum for twice-continuously differentiable constrained nonlinear programming problems, but can benefit from computationally related enhancements. On the other hand, the independent CSA algorithm is highly efficient, though the method lacks theoretical guarantees of convergence. Furthermore, both the alphaBB method and the CSA method are found to identify ensembles of low-energy conformers, an important feature for determining the true free energy minimum of the system. The proposed hybrid methods combine the desirable features of efficiency and consistency, thus enabling the accurate prediction of the structures of larger peptides. Computational studies for met-enkephalin and melittin, employing sequential and parallel computing frameworks, demonstrate the promise for these proposed hybrid methods.

Algorithms↗
PubMed1993

Physical localization of 70 polymorphic markers to human chromosome 5 by fluorescence in situ hybridization.

We used fluorescence in situ hybridization (FISH) to prepare a cytogenetic framework map of 21 polymorphic markers that had been used previously to construct a genetic linkage anchor map of chromosome 5. In addition, we localized 49 other markers that have been genotyped on CEPH families. This study demonstrates that FISH can be used to confirm genetic linkage data, and that it can provide a means of determining the cytogenetic locations and relative order of markers whose order could not be assigned by genetic linkage analysis alone. The cytogenetic map prepared by FISH may help to identify probes of interest for regional mapping studies.

Chromosome Mapping↗
PubMed2000

ComboScreen facilitates the multiplex hybridization-based screening of high-density clone arrays.

MOTIVATION: The construction of physical maps based on bacterial clones [e.g. bacterial artificial chromosomes (BACs)] is valuable for a number of molecular genetics applications, including the high-resolution mapping of genomic regions of interest and the identification of clones suitable for systematic sequencing. A common approach for large-scale screening of bacterial clone libraries involves the hybridization of high-density arrays of immobilized, lysed colonies with collections of DNA probes. The use of a multiplex hybridization screening strategy, whereby pooled probes are analysed en masse, simplifies the effort by reducing the total number of parallel experiments required. However, this approach generates large amounts of hybridization-based data that must be carefully analysed, assimilated, and disambiguated in a careful but efficient manner. RESULTS: To facilitate the screening of high-density clone arrays by a multiplex hybridization approach, we have written a program called ComboScreen. This program provides an organizational framework and analytical tools required for the high-throughput hybridization screening of clone arrays with pools of probes. We have used this program extensively for constructing mouse sequence-ready BAC contig maps.

Chromosomes, Artificial, Bacterial↗
PubMed2005

Salt-inclusion synthesis of two new polar solids, Ba6Mn4Si12O34Cl3 and Ba6Fe5Si11O34Cl3.

A new family of salt-containing, mixed-metal silicates (CU-14), Ba6Mn4Si12O34Cl3 (1) and Ba6Fe5Si11O34Cl3 (2), was synthesized via the BaCl2 salt-inclusion reaction. These compounds crystallize in the noncentrosymmetric (NCS) space group Pmc2(1) (No. 26), adopting 1 of the 10 NCS polar, nonchiral crystal classes, mm2 (C2v). The cell dimensions are a = 6.821(1) A, b = 9.620(2) A, c = 13.172(3) A, and V = 864.4(3) A3 for 1 and a = 6.878(1) A, b = 9.664(2) A, c = 13.098(3) A, and V = 870.6(3) A3 for 2. The structures form a composite framework made of the (M(4+x)Si(12-x)O34)9- (M = Mn, x = 0; M = Fe, x = 1) covalent oxide and (Ba6Cl3)9+ ionic chloride sublattices. The covalent framework exhibits a pseudo-one-dimensional channel where the extended barium chloride lattice (Ba3Cl1.5)(infinity) resides, and it consists of fused eight-membered meta-silicate rings propagating along [100] via sharing two opposite [Si2O7]6- units to form an acentric lattice. Single-crystal structure studies also reveal the ClBa4 unit adopting an interesting seesaw configuration, in which the lone pair electrons of chlorine preferentially face the oxide anions of the transition metal silicate channel, thus forming the observed polar frameworks. Similar to the synthesis of organic-inorganic hybrid materials, the salt-inclusion method facilitates a promising approach for the directed synthesis of special framework solids, including NCS compounds, via composite lattices.

Journal Article↗
PubMed2004

Computational exploration of structural information from cryo-electron tomograms.

Cryo-electron tomography aims to act as an interface between in vivo cell imaging and techniques achieving atomic resolution. This attempt to bridge the resolution gap is facilitated by recent software and hardware advances. Information provided by atomically resolved macromolecules and molecular interaction data need to be put into a common framework in order to create a hybrid multidimensional cellular image. A major partner in this enterprise is the development of regularization and pattern recognition techniques, which try to identify macromolecular complexes as a function of their structural signature in cryo-electron tomograms of living cells.

Animals↗
PubMed1997

Fast numerical algorithms for fitting multiresolution hybrid shape models to brain MRI.

In this paper, we present new and fast numerical algorithms for shape recovery from brain MRI using multiresolution hybrid shape models. In this modeling framework, shapes are represented by a core rigid shape characterized by a superquadric function and a superimposed displacement function which is characterized by a membrane spline discretized using the finite-element method. Fitting the model to brain MRI data is cast as an energy minimization problem which is solved numerically. We present three new computational methods for model fitting to data. These methods involve novel mathematical derivations that lead to efficient numerical solutions of the model fitting problem. The first method involves using the nonlinear conjugate gradient technique with a diagonal Hessian preconditioner. The second method involves the nonlinear conjugate gradient in the outer loop for solving global parameters of the model and a preconditioned conjugate gradient scheme for solving the local parameters of the model. The third method involves the nonlinear conjugate gradient in the outer loop for solving the global parameters and a combination of the Schur complement formula and the alternating direction-implicit method for solving the local parameters of the model. We demonstrate the efficiency of our model fitting methods via experiments on several MR brain scans.

Algorithms↗
PubMed1999

A YAC-based physical map of the mouse genome.

A physical map of the mouse genome is an essential tool for both positional cloning and genomic sequencing in this key model system for biomedical research. Indeed, the construction of a mouse physical map with markers spaced at an average interval of 300 kb is one of the stated goals of the Human Genome Project. Here we report the results of a project at the Whitehead Institute/MIT Center for Genome Research to construct such a physical map of the mouse. We built the map by screening sequenced-tagged sites (STSs) against a large-insert yeast artificial chromosome (YAC) library and then integrating the STS-content information with a dense genetic map. The integrated map shows the location of 9,787 loci, providing landmarks with an average spacing of approximately 300 kb and affording YAC coverage of approximately 92% of the mouse genome. We also report the results of a project at the MRC UK Mouse Genome Centre targeted at chromosome X. The project produced a YAC-based map containing 619 loci (with 121 loci in common with the Whitehead map and 498 additional loci), providing especially dense coverage of this sex chromosome. The YAC-based physical map directly facilitates positional cloning of mouse mutations by providing ready access to most of the genome. More generally, use of this map in addition to a newly constructed radiation hybrid (RH) map provides a comprehensive framework for mouse genomic studies.

Animals↗
PubMed2005

The logical basis of phylogenetic taxonomy.

Phylogenetic taxonomy, like modern Linnean taxonomy, was modeled on a phylogenetic tree rather than a cladogram and, like its predecessor, perpetuates the use of morphology as a means of recognizing clades. Both practices have generated confusion in graphical representation, operational terminology, and definitional rationale in phylogenetic taxonomy, the history of which is traced. The following points are made: (1) cladograms, rather than trees or hybrid cladogram-trees, provide the framework for the simplest graphical depiction of phylogenetic definitions; (2) a complete notational scheme for phylogenetic definitions is presented that distinguishes symbolic notation from shorthand and longhand versions; (3) phylogenetic definitions are composed of three components (paradigm, specifier, qualifier) arranged in two fundamental patterns-node and stem; (4) apomorphies do not constitute a fundamental definitional pattern but rather serve to qualify a stem-based definition (as do time and geographic range); (5) formulation of phylogenetic definitions involves three heuristic criteria (stability, simplicity, prior use); (6) reasoned definitional revision is encouraged and better defined (textual substitution, first-and second-order revision); and (7) a database, TaxonSearch, allows rapid recall of taxonomic and definitional information.

Classification↗
PubMed2005

Computational analysis in vitro: dynamics and plasticity of a neuro-robotic system.

When the brain interacts with the environment it constantly adapts by representing the environment in a form that is called an internal model. The neurobiological basis for internal models is provided by the connectivity and the dynamical properties of neurons. Thus, the interactions between neural tissues and external devices provide a fundamental means for investigating the connectivity and dynamical properties of neural populations. We developed this idea, suggested in the 1980s by Valentino Braitenberg, for investigating and representing the dynamical behavior of neuronal populations in the brainstem of the lamprey. The brainstem was maintained in vitro and connected in a closed loop with two types of artificial device: (a) a simulated dynamical system and (b) a small mobile robot. In both cases, the device was controlled by recorded extracellular signals and its output was translated into electrical stimuli delivered to the neural system. The goal of the first study was to estimate the dynamical dimension of neural preparation in a single-input/single-output configuration. The dynamical dimension is the number of state variables that together with the applied input determine the output of a system. The results indicate that while this neural system has significant dynamical properties, its effective complexity, as established by the dynamical dimension, is rather moderate. In the second study, we considered a more specific situation, in which the same portion of the nervous system controls a robotic device in a two-input/two-output configuration. We fitted the input-output data from the neuro-robotic preparation to neural network models having different internal dynamics and we observed the generalization error of each model. Consistent with the first study, this second experiment showed that a simple recurrent dynamical model was able to capture the behavior of the hybrid system. This experimental and computational framework provides the means for investigating neural plasticity and internal representations in the context of brain-machine interfaces.

Animals↗
PubMed1999

Equilibrium structures and pretransitional fluctuations in a very thin hybrid nematic film.

The stability of different structures of a nematic liquid crystal in a planar hybrid film is examined within the framework of a Gaussian description of order fluctuations. In a very thin film the director field is not bent smoothly but exhibits a steplike change if the anchorings at the confining substrates are strong (G approximately > or =10(-3) J/m(2)) and comparable in magnitude. A (dis)continuous structural transition to the bent-director state which occurs with increasing film thickness or decreasing temperature is governed by the lowest bending director fluctuation mode. Its relaxation rate exhibits a critical slowdown when the film thickness approaches the "supercooling" limit or transition point, respectively. The (dis)continuity of the structural transition depends on the temperature and film thickness. The upper limit for the corresponding tricritical point is determined. The lowest order parameter mode, which corresponds to fluctuations of the position of the central exchange region, is characterized by a nearly critical behavior of the relaxation rate. The spectra of the two noncritical biaxial fluctuation modes are degenerate, whereas the fluctuation profiles are just mirror images with respect to the middle plane of the film.

Journal Article↗
PubMed2002

Minor quantitative trait loci underlie floral traits associated with mating system divergence in Mimulus.

The genetic basis of species differences provides insight into the mode and tempo of phenotypic divergence. We investigate the genetic basis of floral differences between two closely related plant taxa with highly divergent mating systems, Mimulus guttatus (large-flowered outcrosser) and M. nasutus (small-flowered selfer). We had previously constructed a framework genetic linkage map of the hybrid genome containing 174 markers spanning approximately 1800 cM on 14 linkage groups. In this study, we analyze the genetics of 16 floral, reproductive, and vegetative characters measured in a large segregating M. nasutus x M. guttatus F2 population (N = 526) and in replicates of the parental lines and F1 hybrids. Phenotypic analyses reveal strong genetic correlations among floral traits and epistatic breakdown of male and female fertility traits in the F2 hybrids. We use multitrait composite interval mapping to jointly locate and characterize quantitative trait loci (QTLs) underlying interspecific differences in seven floral traits. We identified 24 floral QTLs, most of which affected multiple traits. The large number of QTLs affecting each trait (mean = 13, range = 11-15) indicates a strikingly polygenic basis for floral divergence in this system. In general, QTL effects are small relative to both interspecific differences and environmental variation within genotypes, ruling out QTLs of major effect as contributors to floral divergence between M. guttatus and M. nasutus. QTLs show no pattern of directional dominance. Floral characters associated with pollinator attraction (corolla width) and self-pollen deposition (stigma-anther distance) share several pleiotropic or linked QTLs, but unshared QTLs may have allowed selfing to evolve independently from flower size. We discuss the polygenic nature of divergence between M. nasutus and M. guttatus in light of theoretical work on the evolution of selfing, genetics of adaptation, and maintenance of variation within populations.

Biological Evolution↗