Showing papers by "Imperial College London published in 1987"

Localization of the gene for familial adenomatous polyposis on chromosome 5.

Abstract: Colorectal cancer is the second most common cancer in the United Kingdom and other developed countries in the West. Although it is usually not familial, there is a rare dominantly inherited susceptibility to colon cancer, familial adenomatous polyposis (FAP; also often previously called familial polyposis coli). During adolescence affected individuals develop from a few hundred to over a thousand adenomatous polyps in their large bowel. These are sufficiently likely to give rise to adenocarcinomas to make prophylactic removal of the colon usual in diagnosed FAP individuals. Adenomas may occur elsewhere in the gastrointestinal tract and the condition is often associated with other extracolonic lesions, such as epidermoid cysts, jaw osteomata and fibrous desmoid tumours1–4. Adenomata have been suggested to be precancerous states for most colorectal tumours5,6. Knudson7 has suggested that the mutation for a dominantly inherited cancer susceptibility may be the first step in a recessive change in the tumour cells, and that the same gene may be involved in both familial and non-familial cases of a given tumour. Following up a case report of an interstitial deletion of chromosome 5 in a mentally retarded individual with multiple developmental abnormalities and FAP8, we have now shown that the FAP gene is on chromosome 5, most probably near bands 5q21–q22.

Parameter Orthogonality and Approximate Conditional Inference

Abstract: On propose une statistique du rapport de vraisemblance construite a partir de la distribution conditionnelle des observations, etant donne les estimateurs du maximum de vraisemblance pour les parametres de nuisance

The closing of Tethys and the tectonics of the Himalaya

Abstract: Recent geological and geophysical data from southern Tibet allow refinement of models for the closing of southern (Neo-) Tethys and formation of the Himalaya. Shelf sediments of the Indian passive continental margin which pass northward into deep-sea Tethyan sediments of the Indus-Tsangpo suture zone were deposited in the Late Cretaceous. An Andean-type margin with a 2,500-km-long Trans-Himalayan (Kohistan-Ladakh-Gangdese) granitoid batholith formed parallel to the southern margin of the Lhasa block, together with extensive andesites, rhyolites, and ignimbrites (Lingzizong Formation). The southern part of the Lhasa block was uplifted, deformed, and eroded between the Cenomanian and the Eocene. In the western Himalaya, the Kohistan island arc became accreted to the northern plate at this time. The northern part of the Lhasa block was affected by Jurassic metamorphism and plutonism associated with the mid-Jurassic closure of the Bangong-Nujiang suture zone to the north. The timing of collision between the two continental plates (ca. 50-40 Ma) marking the closing of Tethys is shown by (1) the change from marine (flysch-like) to continental (molasse-like) sedimentation in the Indus-Tsangpo suture zone, (2) the end of Gangdese I-type granitoid injection, (3) Eocene S-type anatectic granites and migmatites in the Lhasa block, and (4) the start of compressional tectonics in the Tibetan-Tethys and Indus-Tsangpo suture zone (south-facing folds, south-directed thrusts). After the Eocene closure of Tethys, deformation spread southward across the Tibetan-Tethys zone to the High Himalaya. Deep crustal thrusting, Barrovian metamorphism, migmatization, and generation of Oligocene-Miocene leucogranites were accompanied by south-verging recumbent nappes inverting metamorphic isograds and by south-directed intracontinental shear zones associated with the Main Central thrust. Continued convergence in the late Tertiary resulted in large-scale north-directed backthrusting along the Indus-Tsangpo suture zone. More than 500 km shortening is recorded in the foreland thrust zones of the Indian plate, south of the suture, and > 150 km shortening is recorded across the Indian shelf (Zanskar Range) and the Indus suture in Ladakh. There was also large-scale shortening of the Karakoram and Tibetan microplates north of the suture; as much as 1,000 km shortening occurred in Tibet. The more recent deformation, however, involved the spreading of this thickened crust and the lateral motion of the Tibetan block along major approximately east-west–trending strike-slip fault zones.

The gene for familial polyposis coli maps to the long arm of chromosome 5.

Abstract: The inherited genetic defect in adenomatous polyposis has been localized to a small region on the long arm of chromosome 5. Sixteen DNA marker loci were used to construct a linkage map of the chromosome. When five kindreds segregating a gene for adenomatous polyposis coli were characterized with a number of the markers, significant linkage was found between one marker and the disease gene. Linkage analysis determined the location of the defective gene within a primary genetic map of chromosome 5.

Some Models for Rainfall Based on Stochastic Point Processes

Abstract: Stochastic models are discussed for the variation of rainfall intensity at a fixed point in space. First, models are analysed in which storm events arise in a Poisson process, each such event being associated with a period of rainfall of random duration and constant but random intensity. Total rainfall intensity is formed by adding the contributions from all storm events. Then similar but more complex models are studied in which storms arise in a Poisson process, each storm giving rise to a cluster of rain cells and each cell being associated with a random period of rain. The main properties of these models are determined analytically. Analysis of some hourly rainfall data from Denver, Colorado shows the clustered models to be much the more satisfactory.

An extended quasi-likelihood function

Abstract: SUMMARY Wedderburn's original definition of quasi-likelihood for generalized linear models is extended to allow the comparison of variance functions as well as those of linear predictors and link functions. The relationship between generalized linear models and the use of transformations of the response variable is explored, and the ideas are illustrated by three examples. generalized linear models by allowing the full distributional assumption about the random component in the model to be replaced by a much weaker assumption in which only the first and second moments were defined. In making this extension Wedderburn widened the scope of generalized linear models in a way very similar to that of Gauss when he replaced the assumption of normality in classical linear models by that of equal variance. For generalized linear models with distributions in the exponential family, likelihood ratio and score tests are used for testing hypotheses concerning nested subsets of covariates in the linear predictor and for assessing hypothesized link functions. These methods are also applicable with Wedderburn's form of quasi-likelihood. However neither of these methods is suitable for the comparison of different variance functions. In this paper we introduce an extended quasi-likelihood function which allows for the comparison of various forms of all the components of a generalized linear model, i.e. the linear predictor, the link function, and the variance function. We then apply the ideas to the analysis of several sets of data.

Experimental study of scattering from characterized random surfaces

Abstract: An experimental investigation of light scattering from random rough surfaces is described. The surfaces, whose height fluctuations approximately follow Gaussian statistics, are fabricated in photoresist with a metal overcoating. When the lateral correlation length is larger than a wavelength and the surface slopes are mild, measurements of diffuse scattering are found to agree with the Beckmann theory, as long as the angle of incidence is not too large. For other surfaces that have stronger slopes, depolarization and enhanced backscattering may be observed in the diffuse scattering. Though we are unaware of theoretical calculations that compare with the measurements, the effects of multiple scattering are shown to be consistent with the major features of the observations.

Chemical structure of the morphogen differentiation inducing factor from Dictyostelium discoideum

Abstract: Morphogens are signal molecules presumed to exist in embryos and to be involved in establishing the spatial pattern of cells during development. Differentiation inducing factor (DIF) has the properties of a morphogen required for producing the prestalk/prespore pattern in the aggregate formed by cells of the slime mould Dictyostelium in response to starvation. DIF-1, the major bioactive species after purification, has now been identified using a combined microchemical, spectroscopic and synthetic approach. The structure is defined as 1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl)-1-hexanone, and represents a new class of effector molecule. The availability of relatively large quantities of synthetic and isotopically labelled materials should now allow progress towards a detailed understanding of the pattern-forming processes in Dictyostelium development.

Rational modification of enzyme catalysis by engineering surface charge.

Abstract: Changing the surface charge of subtilisin by site-directed mutagenesis produces enzymes with significantly shifted pH-activity profiles, higher catalytic activities and altered specificities. Insight into water as a dielectric, the role of ions in electrostatic shielding and the field effects on catalysis is obtained and suggests rules for tailoring pH-activity profiles.

Spatial resolution and measurement of turbulence in the viscous sublayer using subminiature hot-wire probes

Abstract: Measurements in the viscous sublayer of a flat-plate turbulent boundary layer in air, using single hot-wire sensors with lengths from 1–60 viscous length scales show that, at a given distance from the surface, the turbulence intensity, flatness factor, and skewness factor of the longitudinal velocity fluctuation are nearly independent of wire length when the latter is less than 20–25 times the viscous length scale (i.e. 20–25 “wall units”), and decrease significantly and abruptly for larger wire lengths. This conclusion is consistent with other workers' probability density functions of streak spacing: the lateral spacing of “streaks” in the viscous sublayer is 80–100 wall units on average with minimum spacing of 20–25 wall units, which implies that signals would be strongly attenuated by wires whose length exceeds 20–25 wall units. To achieve wire lengths of less than 20–25 wall units, subminiature hot wire probes like those described by Ligrani and Bradshaw (1987), having lengths as small as 150 μm, are necessary for sublayer measurements in typical laboratory wind tunnels. As well as the measurements mentioned above, dissipation spectra are presented, to show the effect of spanwise averaging on the high-frequency motions, which is necessarily more severe than the effect on overall intensities.

The Declarative Past and Imperative Future: Executable Temporal Logic for Interactive Systems

Abstract: We propose a new paradigm in executable logic, that of the declarative past and imperative future. A future statement of temporal logic can be understood in two ways: the declarative way, that of describing the future as a temporal extension; and the imperative way, that of making sure that the future will happen the way we want it. Since the future has not yet happened, we have a language which can be both declarative and imperative. We regard our theme as a natural meeting between the imperative and declarative paradigms.

F.A.B.-Mass Spectrometry of Carbohydrates

Abstract: Publisher Summary This chapter provides an overview of fast atom bombardment-mass spectrometry (FAB-MS) of carbohydrates. It focuses on those carbohydrate chemists who are not specialists in mass spectrometry and discusses the experimental aspects of FAB-MS. It also gives an indication of the types of problems that can now be solved by using the technique. The FAB-MS technique currently plays two major roles in carbohydrate structure analysis: (1) molecular weight determination, for which it has superseded field-desorption-mass spectrometry (FD-MS) and, to a large extent, chemical ionization and (2) sequence assignment, where it has very largely replaced direct-probe, electron-impact mass spectrometry, particularly for high-molecular weight compounds. On its own, FAB-MS cannot solve the complete structure of a carbohydrate and it should always be incorporated into experimental programs that include the well established methods of methylation analysis, enzymic digestion, chemical degradation, and nuclear magnetic resonance (NMR) spectroscopy. The chapter discusses the principles of FAB-MS technique and describes the choice of supporting matrix and matrix additives. It also provides an overview of sample purity and the analysis of mixtures in FAB-MS and elaborates the FAB-MS of high-molecular weight samples.

A candidate for the cystic fibrosis locus isolated by selection for methylation-free islands

Abstract: A genomic sequence close to the cystic fibrosis locus with the characteristics of an HTF island has been selectively cloned and characterized. Two markers flanking this sequence, which is conserved throughout mammalian evolution, show a very much greater disequilibrium than that found with any existing marker. A single mutational event accounts for most cases of cystic fibrosis. The sequence is expressed, and is a candidate for the cystic fibrosis gene.

Failure of familial Alzheimer's disease to segregate with the A4-amyloid gene in several European families.

Abstract: The gene coding for the amyloid protein, a component of neuritic plaques found in brain tissue from patients with Alzheimer's disease, has been localized to chromosome 21, and neighbouring polymorphic DNA markers segregate with Alzheimer's disease in several large families. These data, and the association of Alzheimer's disease with Down's syndrome, suggest that overproduction of the amyloid protein, or production of an abnormal variant of the protein, may be the underlying pathological change causing Alzheimer's disease. We have identified a restriction fragment length polymorphism of the A4-amyloid gene, and find recombinants in two Alzheimer's disease families between Alzheimer's disease and the A4-amyloid locus. This demonstrates that the gene for plaque core A4-amyloid cannot be the locus of a defect causing Alzheimer's disease in these families. These data indicate that alterations in the plaque core amyloid gene cannot explain the molecular pathology for all cases of Alzheimer's disease.

An experimental study of the steady and unsteady flow characteristics of stirred reactors

Abstract: Liquid flow in a baffled stirred reactor vessel driven by a six-blade disk impeller has been investigated experimentally. Laser-slit photography provided an overview of the flows which were quantified by measurements of velocity characteristics, obtained with a laser-Doppler anemometer, for an impeller rotational speed of 300 r.p.m. and for three impeller clearances from the bottom of the vessel. The mean flow results show an inclination of the impeller stream and the formation of ring vortices above and below the impeller, which depend on the clearance; the flow was strongly three-dimensional with large regions having circumferential velocities in a direction opposite to that of the impeller rotation. Impeller-induced torque measurements show that the Power number is invariant with clearance for turbulent-flow Reynolds numbers ([ges ] 40000) and increases with impeller diameter. The flow structure was controlled mainly by convection and pressure forces with turbulent mixing important in the impeller region.

Structure of holo-glyceraldehyde-3-phosphate dehydrogenase from Bacillus stearothermophilus at 1.8 A resolution.

Abstract: The structure of holo-glyceraldehyde-3-phosphate dehydrogenase from Bacillus stearothermophilus has been crystallographically refined at 1.8 A resolution using restrained least-squares refinement methods. The final crystallographic R-factor for 93,120 reflexions with F > 3σ(F) is 0.177. The asymmetric unit of the crystal contains a complete tetramer, the final model of which incorporates a total of 10,272 unique protein and coenzyme atoms together with 677 bound solvent molecules. The structure has been analysed with respect to molecular symmetry, intersubunit contacts, coenzyme binding and active site geometry. The refined model shows the four independent subunits to be remarkably similar apart from local deviations due to intermolecular contacts within the crystal lattice. A number of features are revealed that had previously been misinterpreted from an earlier 2.7 A electron density map. Arginine at position 195 (previously thought to be a glycine) contributes to the formation of the anion binding sites in the active site pocket, which are involved in binding of the substrate and inorganic phosphates during catalysis. This residue seems to be structurally equivalent to the conserved Argl94 in the enzyme from other sources. In the crystal both of the anion binding sites are occupied by sulphate ions. The ND atom of the catalytically important His176 is hydrogen-bonded to the mainchain carbonyl oxygen of Ser177, thus fixing the plane of the histidine imidazole ring and preventing rotation. The analysis has revealed the presence of several internal salt-bridges stabilizing the tertiary and quaternary structure. A significant number of buried water molecules have been found that play an important role in the structural integrity of the molecule.

Origin of reflection high-energy electron-diffraction intensity oscillations during molecular-beam epitaxy: A computational modeling approach.

Abstract: Modele pour etudier l'origine de ces oscillations avec lequel on peut reproduire toutes les principales caracteristiques des mesures RHEED recentes. Ceci montre les avantages considerables que l'on tire de l'adoption de modeles de croissance monoatomiques simples a la place des modeles complexes utilises pour etudier la croissance des composes semiconducteurs