Showing papers by "University of Cambridge published in 1992"

Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis.

Abstract: In this contribution we put forward a novel hypothesis concerning the aetiology of Type 2 (non-insulin dependent) diabetes mellitus. The concept underlying our hypothesis is that poor foetal and early post-natal nutrition imposes mechanisms of nutritional thrift upon the growing individual. We propose that one of the major long-term consequences of inadequate early nutrition is impaired development of the endocrine pancreas and a greatly increased susceptibility to the development of Type 2 diabetes. In the first section we outline our research which has led to this hypothesis. We will then review the relevant literature. Finally we show that the hypothesis suggests a reinterpretation of some findings and an explanation of others which are at present not easy to understand.

Semantic dementia. Progressive fluent aphasia with temporal lobe atrophy.

Abstract: We report five patients with a stereotyped clinical syndrome characterized by fluent dysphasia with severe anomia, reduced vocabulary and prominent impairment of single-word comprehension, progressing to a stage of virtually complete dissolution of the semantic components of language. A marked reduction in the ability to generate exemplars from restricted semantic categories (e.g. animals, vehicles, etc.) was a consistent and early feature. Tests of semantic memory demonstrated a radically impoverished knowledge about a range of living and man-made items. In contrast, phonology and grammar of spoken language were largely preserved, as was comprehension of complex syntactic commands. Reading showed a pattern of surface dyslexia. Autobiographical and day-to-day (episodic) memory were relatively retained. Non-verbal memory, perceptual and visuospatial abilities were also strikingly preserved. In some cases, behavioural and personality changes may supervene; one patient developed features of the Kluver-Bucy Syndrome. Radiological investigations have shown marked focal temporal atrophy in all five patients, and functional imaging by single positron emission tomography and positron emission tomography (one case) have implicated the dominant temporal lobe in all five. In the older literature, such cases would have been subsumed under the rubric of Pick's disease. Others have been included in series with progressive aphasia. We propose the term semantic dementia, first coined by Snowden et al. (1989), to designate this clinical syndrome.

Role of poly(ADP-ribose) formation in DNA repair

Abstract: THE abundant nuclear enzyme poly(ADP-ribose) polymerase catalyses the synthesis of poly(ADP-ribose) from nicotinamide adenine dinucleotide (NAD+)1–5. This protein has an N-terminal DNA-binding domain containing two zinc-fingers, which is linked to the C-terminal NAD+-binding domain by a short region containing several glutamic acid residues that are sites of auto-poly(ADP-ribosyl)ation6–8. The intracellular production of poly(ADP-ribose) is induced by agents that generate strand interruptions in DNA7. The branched homopolymer chains may attain a size of 200–300 residues9 but are rapidly degraded after synthesis. The function of poly(ADP-ribose) synthesis is not clear, although it seems to be required for DNA repair10,11. Here we describe a human cell-free system that enables the role of poly(ADP-ribose) synthesis in DNA repair to be characterized. The results indicate that unmodified polymerase molecules bind tightly to DNA strand breaks; auto-poly(ADP-ribosyl)ation of the protein then effects its release and allows access to lesions for DNA repair enzymes.

The impact of postnatal depression on infant development.

Abstract: A large sample of primiparous women was screened for depression after childbirth. Those identified as depressed, women with a previous history of depression and a control group were followed up to 18 months, when their infants were assessed on measures of cognitive, social and behavioral development. Infants of postnatally depressed mothers performed worse on object concept tasks, were more insecurely attached to their mothers and showed more mild behavioural difficulties. Postnatal depression had no effect on general cognitive and language development, but appeared to make infants more vulnerable to adverse effects of lower social class and male gender.

A loop-shaping design procedure using H/sub infinity / synthesis

Abstract: A design procedure is introduced which incorporates loop shaping methods to obtain performance/robust stability tradeoffs, and a particular H/sub infinity / optimization problem to guarantee closed-loop stability and a level of robust stability at all frequencies. Theoretical justification of this technique is given, and the effect of loop shaping on closed-loop behavior is examined. The procedure is illustrated in a controller design for a flexible space platform. >

The mechanism of Z alpha 1-antitrypsin accumulation in the liver.

Abstract: Most northern Europeans have only the normal M form of the plasma protease inhibitor alpha 1-antitrypsin, but some 4% are heterozygotes for the Z deficiency variant. For reasons that have not been well-understood, the Z mutation results in a blockage in the final stage of processing of antitrypsin in the liver such that in the Z homozygote only 15% of the protein is secreted into the plasma. The 85% of the alpha 1-antitrypsin that is not secreted accumulates in the endoplasmic reticulum of the hepatocyte; much of it is degraded but the remainder aggregates to form insoluble intracellular inclusions. These inclusions are associated with hepatocellular damage, and 10% of newborn Z homozygotes develop liver disease which often leads to a fatal childhood cirrhosis. Here we demonstrate the molecular pathology underlying this accumulation and describe how the Z mutation in antitrypsin results in a unique molecular interaction between the reactive centre loop of one molecule and the gap in the A-sheet of another. This loop-sheet polymerization of Z antitrypsin occurs spontaneously at 37 degrees C and is completely blocked by the insertion of a specific peptide into the A-sheet of the antitrypsin molecule. Z antitrypsin polymerized in vitro has identical properties and ultrastructure to the inclusions isolated from hepatocytes of a Z homozygote. The concentration and temperature dependence of this loop-sheet polymerization has implications for the management of the liver disease of the newborn Z homozygote.

Fetal nuchal translucency: ultrasound screening for chromosomal defects in first trimester of pregnancy.

Abstract: OBJECTIVE--To examine the significance of fetal nuchal translucency at 10-14 weeks' gestation in the prediction of abnormal fetal karyotype. DESIGN--Prospective screening study. SETTING--The Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London. SUBJECTS--827 fetuses undergoing first trimester karyotyping by amniocentesis or chorionic villus sampling. MAIN OUTCOME MEASURE--Incidence of chromosomal defects. RESULTS--The incidence of chromosomal defects was 3% (28 of 827 cases). In the 51 (6%) fetuses with nuchal translucency 3-8 mm thick the incidence of chromosomal defects was 35% (18 cases). In contrast, only 10 of the remaining 776 (1%) fetuses were chromosomally abnormal. CONCLUSION--Fetal nuchal translucency > or = 3 mm is a useful first trimester marker for fetal chromosomal abnormalities.

Statics and Kinematics of Granular Materials

Abstract: 1. Introduction 2. The analysis of stress and strain rate 3. The ideal Coulomb material 4. Coulomb's method of wedges 5. The method of differential slices 6. Determination of physical properties 7. Exact stress analysis 8. Velocity distributions 9. The conical yield function 10. The prediction of mass flow rate Problems Appendices Index.

Relativistic fireballs: energy conversion and time-scales

Abstract: The expansion energy of a relativistic fireball can be reconverted into radiation when it interacts with an external medium. For expansion with Lorentz factors greater than or approximately equal to 1000 into a typical galactic environment, the corresponding time-scale in the frame of the observer is of the order of seconds. This mechanism would operate in any cosmological scenario of gamma-ray bursts involving initial energies of order a percent of a stellar rest mass, and implies photon energies and time-scales compatible with those observed in gamma-ray bursts.

Fronto-striatal cognitive deficits at different stages of parkinson's disease

Abstract: Groups of patients with idiopathic Parkinson's disease, either medicated or unmedicated, were compared with matched groups of normal controls on a computerized battery previously shown to be sensitive to frontal lobe dysfunction, including tests of planning, spatial working memory and attentional set-shifting. In a series of problems based on the 'Tower of London' test, medicated patients with Parkinson's disease were shown to be impaired in the amount of time spent thinking about (planning) the solution to each problem. Additionally, an impairment in terms of the accuracy of the solution produced on this test was only evident in those patients with more severe clinical symptoms and was accompanied by deficits in an associated test of spatial short-term memory. Medicated patients with both mild and severe clinical symptoms were also impaired on a related test of spatial working memory. In contrast, a group of patients who were unmedicated and 'early in the course' of the disease were unimpaired in all three of these tests. However, all three Parkinson's disease groups were impaired in the test of attentional set-shifting ability, although unimpaired in a test of pattern recognition which is insensitive to frontal lobe damage. These data are compared with those previously published from a group of young neurosurgical patients with localized excisions of the frontal lobes and are discussed in terms of the specific nature of the cognitive deficit at different stages of Parkinson's disease.

Cell movements : from molecules to motility

Abstract: 1. Cell Swimming 2. Migration of Cells over Surfaces 3. Cell Behavior 4. The Cytoskeleton 5. Actin Filaments 6. Actin and Membranes 7. Myosin 8. Firoblast Locomotion 9. The Molecular Basis of Muscle Contraction 10. Muscle Development 11. Microtubules 12. Organelle Transport 13. Mitosis 14. Cilia 15. Centrioles and Basal Bodies 16. Bacterial Movements 17. Intermediate Filaments 18. Cell Mechanics 19. Cell Shape 20. Cell Movements and Embyogenesis

Monstrous moonshine and monstrous Lie superalgebras

Abstract: We prove Conway and Norton's moonshine conjectures for the infinite dimensional representation of the monster simple group constructed by Frenkel, Lepowsky and Meurman. To do this we use the no-ghost theorem from string theory to construct a family of generalized Kac-Moody superalgebras of rank 2, which are closely related to the monster and several of the other sporadic simple groups. The denominator formulas of these superalgebras imply relations between the Thompson functions of elements of the monster (i.e. the traces of elements of the monster on Frenkel, Lepowsky, and Meurman's representation), which are the replication formulas conjectured by Conway and Norton. These replication formulas are strong enough to verify that the Thompson functions have most of the "moonshine" properties conjectured by Conway and Norton, and in particular they are modular functions of genus 0. We also construct a second family of Kac-Moody superalgebras related to elements of Conway's sporadic simple group Col. These superalgebras have even rank between 2 and 26; for example two of the Lie algebras we get have ranks 26 and 18, and one of the superalgebras has rank 10. The denominator formulas of these algebras give some new infinite product identities, in the same way that the denominator formulas of the a n n e Kac-Moody algebras give the Macdonald identities.

The folding of hen lysozyme involves partially structured intermediates and multiple pathways.

Abstract: The folding of hen lysozyme involves partially structured intermediates and multiple pathways

Chronology protection conjecture

Abstract: It has been suggested that an advanced civilization might have the technology to warp spacetime so that closed timelike curves would appear, allowing travel into the past This paper examines this possibility in the case that the causality violations appear in a finite region of spacetime without curvature singularities There will be a Cauchy horizon that is compactly generated and that in general contains one or more closed null geodesics which will be incomplete One can define geometrical quantities that measure the Lorentz boost and area increase on going round these closed null geodesics If the causality violation developed from a noncompact initial surface, the averaged weak energy condition must be violated on the Cauchy horizon This shows that one cannot create closed timelike curves with finite lengths of cosmic string Even if violations of the weak energy condition are allowed by quantum theory, the expectation value of the energy-momentum tensor would get very large if timelike curves become almost closed It seems the back reaction would prevent closed timelike curves from appearing These results strongly support the chronology protection conjecture: The laws of physics do not allow the appearance of closed timelike curves

Chemical tuning of electroluminescent copolymers to improve emission efficiencies and allow patterning

Abstract: ONE advantage of using conjugated polymers in semiconductor applications is that they can be processed using techniques well established for conventional polymers. We reported recently that poly(p-phenylenevinylene) could be used as the active layer in a light-emitting diode1, producing yellow/green emission. We have now found that related copolymers, comprising a combination of different arylene units, can be chemically tuned to provide a range of materials with considerably improved properties for this and other applications. By incorporating two different leaving groups into a precursor copolymer, we can selectively eliminate one of these, to give a conjugated/non-conjugated copolymer, or both, to give a fully conjugated copolymer. This allows us to induce local variations in the Π-Π* electronic energy gap at both the molecular and supramolecular level. Variations at the molecular level can act to trap excitons, hindering their migration to quenching sites, and we find that these materials give strongly enhanced quantum yields for electroluminescence (by a factor of up to 30). They also allow control of the colour of emission. Variations at the supramolecular level, by patterning the films to control the progress of conversion, allow the production of structures suitable for multicolour displays. The ability to pattern the film also allows for fabrication of optical waveguides, as regions with different energy gaps have different refractive indices.

Presupernova Evolution in Massive Interacting Binaries

Abstract: The way in which binary interaction affects the presupernova evolution of massive close binaries and the resulting supernova explosions is investigated systematically by means of a Henyey-type stellar evolution code that was modified to allow its application to binary stellar evolution calculations. The code makes it possible to trace the effects of mass and angular momentum loss from the binary, as well as mass transfer within the binary system. It is found that a large number of binary scenarios can be distinguished, depending on the type of binary interaction and the evolutionary stage of the supernova progenitor at the time of the interaction. Monte Carlo simulations are performed to estimate the frequencies of the occurrence of various scenarios. It is found that, because of a previous binary interaction, 15-30 percent of all massive stars (with initial masses greater than about 8 solar masses) become helium stars, and another 5 percent of all massive stars end their lives as blue supergiants rather than as red supergiants.

A quantitative account of the activation steps involved in phototransduction in amphibian photoreceptors.

Abstract: 1. We have undertaken a theoretical analysis of the steps contributing to the phototransduction cascade in vertebrate photoreceptors. We have explicitly considered only the activation steps, i.e. we have not dealt with the inactivation reactions. 2. From the theoretical analysis we conclude that a single photoisomerization leads to activation of the phosphodiesterase (PDE) with a time course which approximates a delayed ramp; the delay is contributed by several short first-order delay stages. 3. We derive a method for extracting the time course of PDE activation from the measured electrical response, and we apply this method to recordings of the photoresponse from salamander rods. The results confirm the prediction that the time course of PDE activation is a delayed ramp, with slope proportional to light intensity; the initial delay is about 10-20 ms. 4. We derive approximate analytical solutions for the electrical response of the photoreceptor to light, both for bright flashes (isotropic conditions) and for single photons (involving longitudinal diffusion of cyclic GMP in the outer segment). The response to a brief flash is predicted to follow a delayed Gaussian function of time, i.e. after an initial short delay the response should begin rising in proportion to t2. Further, the response-intensity relation is predicted to obey an exponential saturation. 5. These predictions are compared with experiment, and it is shown that the rising phase of the flash response is accurately described over a very wide range of intensities. We conclude that the model provides a comprehensive description of the activation steps of phototransduction at a molecular level.

L-dopa withdrawal in Parkinson's disease selectively impairs cognitive performance in tests sensitive to frontal lobe dysfunction

Abstract: A group of ten patients with idiopathic Parkinson's disease (PD) was tested on a series of automated tests of learning, memory, planning and attention whilst either on or off L-dopa medication Controlled withdrawal of L-dopa interfered with aspects of performance on three of the tests that had previously been shown to be sensitive to frontal lobe dysfunction; a spatial working memory task, the Tower of London planning test, and a visual discrimination paradigm that also included intra- and extra-dimensional shift tests of selective attention More specifically, errors were increased in the spatial working memory test, and both the accuracy and latency of thinking were impaired Thinking time was significantly slowed following L-dopa withdrawal, even though the possible contaminating effects on motor slowing were fully controlled by a yoked control procedure Nine out of ten patients reached a further stage of the visual discrimination, set-shifting paradigm when on, rather than off, L-dopa medication Spatial span was also impaired off medication, but there were no effects of L-dopa withdrawal on tests of pattern and spatial recognition memory, simultaneous and delayed matching to sample or visuospatial conditional associative learning Comparisons with a large control group confirmed previous findings that PD is associated with deficits on the majority of these tests The results are discussed in terms of the fronto-striatal, dopamine dependent nature of some of the cognitive deficits found in PD, but the apparent dopamine-independent nature of deficits in other aspects of cognitive functioning, notably in tests of visual recognition memory and associative learning

Cytogenetic analysis by chromosome painting using dop-pcr amplified flow-sorted chromosomes

Abstract: A novel polymerase chain reaction (PCR) technique has been combined with chromosome flow sorting to characterise two lymphoblastoid cell lines and one medullary thyroid carcinoma cell line carrying translocations close to the locus for multiple endocrine neoplasia type 2A (MEN 2A). Five hundred copies of the derivative chromosome(s) were flow sorted from each cell line and amplified by degenerate oligonucleotide-primed-polymerase chain reaction (DOP-PCR). This generated pools of DNA sequences corresponding to the abnormal chromosomes, which were then used as probes in fluorescence in situ hybridisation (FISH) experiments on normal metaphase cells. The resultant chromosome paints revealed the portions of the normal chromosomes related to those involved in the translocations. By this technique, translocation breakpoints in bands p15, q11.2, and q21 of chromosome 10 were defined in the above cell lines, in two cases refining previous cytogenetic data. This study shows that flow sorting of aberrant chromosomes and chromosome painting can be used as a rapid aid to cytogenetic analysis, particularly in cases of difficult karyotypes, such as tumours. Furthermore, the DOP-PCR technique described here will have applications to other areas of genome analysis, such as cloning of new markers; its design will allow a general and representative amplification to occur from any starting DNA in any species.