Showing papers by "University of Oxford published in 1988"

The Immunoglobulin Superfamily—Domains for Cell Surface Recognition

Abstract: When Ig chains were first sequenced, segments within the constant regions of H and L chains showed sequence similarities, and this led to the idea that the Ig chains had all evolved from a primordial gene coding for about 100 amino acids (1). The domains within the Ig chains all contained a characteristic intrachain disulfide bond, and the idea of the domain as an independent structural unit was proposed (2). The domain hypothesis was firmly established when the structures of V and C domains were determined to reveal a common fold forming a sandwich of two p-sheets that was stabilized by the conserved disulfide bond (3, 4). Beta-2 microglobulin (P2-m), identified in the urine of patients with kidney disease, was the first nonimmunoglobulin structure found to share sequence similarities with Ig-domains. The pz-m sequence looked like an Ig C-domain (5, 6). P2-m was subsequently discovered to be part of the major histocompatibility complex (MH C) class I structure, and sequencing of the class I heavy chain showed that a segment of sequence adjacent to the transmembrane region was also similar to Ig C-domains (7, 7a). MHC antigens were known to play some role in the specificity of T lymphocyte

Crustal contributions to arc magmatism in the Andes of Central Chile

Abstract: Fifteen andesite-dacite stratovolcanoes on the volcanic front of a single segment of the Andean arc show along-arc changes in isotopic and elemental ratios that demonstrate large crustal contributions to magma genesis. All 15 centers lie 90 km above the Benioff zone and 280±20 km from the trench axis. Rate and geometry of subduction and composition and age of subducted sediments and seafloor are nearly constant along the segment. Nonetheless, from S to N along the volcanic front (at 57.5% SiO2) K2O rises from 1.1 to 2.4 wt %, Ba from 300 to 600 ppm, and Ce from 25 to 50 ppm, whereas FeO*/MgO declines from >2.5 to 1.4. Ce/Yb and Hf/Lu triple northward, in part reflecting suppression of HREE enrichment by deep-crustal garnet. Rb, Cs, Th, and U contents all rise markedly from S to N, but Rb/Cs values double northward — opposite to prediction were the regional alkali enrichment controlled by sediment subduction. K/Rb drops steeply and scatters greatly within many (biotite-free) andesitic suites. Wide diversity in Zr/Hf, Zr/Rb, Ba/Ta, and Ba/La within and among neighboring suites (which lack zircon and alkali feldspar) largely reflects local variability of intracrustal (not slab or mantle) contributions. Pb-isotope data define a limited range that straddles the Stacey-Kramers line, is bracketed by values of local basement rocks, in part plots above the field of Nazca plate sediment, and shows no indication of a steep (mantle+sedimentary) Pb mixing trend. 87Sr/86Sr values rise northward from 0.7036 to 0.7057, and 143Nd/144Nd values drop from 0.5129 to 0.5125. A northward climb in basal elevation of volcanic-front edifices from 1350 m to 4500 m elevation coincides with a Bougueranomaly gradient from −95 to −295 mgal, interpreted to indicate thickening of the crust from 30–35 km to 50–60 km. Complementary to the thickening crust, the mantle wedge beneath the front thins northward from about 60 km to 30–40 km (as slab depth is constant). The thick northern crust contains an abundance of Paleozoic and Triassic rocks, whereas the proportion of younger arc-intrusive basement increases southward. Primitive basalts are unknown anywhere along the arc. Base-level isotopic and chemical values for each volcano are established by blending of subcrustal and deep-crustal magmas in zones of melting, assimilation, storage and homogenization (MASH) at the mantle-crust transition. Scavenging of mid-to upper-crustal silicic-alkalic melts and intracrustal AFC (prominent at the largest center) can subsequently modify ascending magmas, but the base-level geochemical signature at each center reflects the depth of its MASH zone and the age, composition, and proportional contribution of the lowermost crust.

Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides

Abstract: Murine embryonic stem (ES) cells are pluripotent cell lines established directly from the early embryo which can contribute differentiated progeny to all adult tissues, including the germ-cell lineage, after re-incorporation into the normal embryo. They provide both a cellular vector for the generation of transgenic animals and a useful system for the identification of polypeptide factors controlling differentiation processes in early development. In particular, medium conditioned by Buffalo rat liver cells contains a polypeptide factor, ES cell differentiation inhibitory activity (DIA), which specifically suppresses the spontaneous differentiation of ES cells in vitro, thereby permitting their growth as homogeneous stem cell populations in the absence of heterologous feeder cells. ES cell pluripotentiality, including the ability to give rise to functional gametes, is preserved after prolonged culture in Buffalo rat liver media as a source of DIA. Here, we report that purified DIA is related in structure and function to the recently identified hematopoietic regulatory factors human interleukin for DA cells and leukaemia inhibitory factor. DIA and human interleukin DA/leukaemia inhibitory factor have thus been identified as related multifunctional regulatory factors with distinct biological activities in both early embryonic and hematopoietic stem cell systems.

Cell-Surface Anchoring of Proteins via Glycosyl-Phosphatidylinositol Structures

Abstract: A class of membrane molecules has been identified whose primary translation product includes a COOH-terminal protein sequence that signals attachment of a glycosyl-phosphatidylinositol anchor at a COOH-terminal residue that is newly formed by cleavage of the signaling sequence. This class includes a wide diversity of protein types from eukaryotes at many stages of evolution. The structures of the glycosyl-phosphatidylinositol anchors are being resolved, but their functions aside from membrane attachment and dynamics remain to be determined.

Stromal Stem Cells: Marrow‐Derived Osteogenic Precursors

Abstract: Evidence is discussed for the hypothesis that there are stromal stem cells present in the soft connective tissues associated with marrow and bone surfaces that are able to give rise to a number of different cell lines including the osteogenic line. Fibroblastic colonies, each derived from a single colony-forming unit fibroblastic (CFU-F), are formed when marrow cells are cultured in vitro. In vivo assays of CFU-F have demonstrated that some CFU-F have a high ability for self renewal and multipotentiality whereas some have more limited potential. In vitro studies also support the hypothesis and have shown that CFU-F are a heterogeneous population of stem and progenitor cells and that their differentiation in vitro can be modified at the colony level. Factors added to the medium can activate osteogenesis in a range of multipotential and more committed precursors. Different stromal cell lines can be promoted under different culture conditions. The number and hierarchy of cell lines belonging to the stromal fibroblastic system are not yet fully elucidated and more specific markers for the different lines are required before a better understanding can be achieved.

GABA-containing neurons in the septum control inhibitory interneurons in the hippocampus.

Abstract: The hippocampus, in particular the neocortex-hippocampus-neocortex circuit, is widely believed to be crucial in memory. Information flow in this circuit is strongly influenced by relatively sparse afferents derived from subcortical centres, such as the septum, involved in arousal, emotions and autonomic control. A powerful mechanism, by which numerically small inputs can produce profound effects, is feed-forward inhibition, that is, the activation of local inhibitory interneurons, which, in turn, control the activity of large populations of principal cells in the hippocampus. An example is the cholinergic input to the hippocampus from the septum, which is likely to be involved in feed-forward operations. Here, we demonstrate the existence of a circuit underlying another powerful mechanism of subcortical control of hippocampal information processing. We show that GABA-containing afferents originating in the septum innervate most of the GABA-containing interneurons in the hippocampus, making many synaptic contacts with each of them. Activation of the GABA-containing neurons in the septum is likely to lead to disinhibition of the principal neurons in the hippocampal formation and so this pathway is probably crucial in the induction of hippocampal electrical activity patterns, and may be involved in NMDA (N-methyl-D-aspartate) receptor-mediated functions, such as memory, in a permissive manner.

How many species are there on Earth

Abstract: This article surveys current answers to the factual question posed in the title and reviews the kinds of information that are needed to make these answers more precise. Various factors affecting diversity are also reviewed. These include the structure of food webs, the relative abundance of species, the number of species and of individuals in different categories of body size, along with other determinants of the commonness and rarity of organisms.

Randomised trial of prophylactic daily aspirin in British male doctors

Abstract: A six year randomised trial was conducted among 5139 apparently healthy male doctors to see whether 500 mg aspirin daily would reduce the incidence of and mortality from stroke, myocardial infarction, or other vascular conditions Though total mortality was 10% lower in the treated than control group, this difference was not statistically significant and chiefly involved diseases other than stroke or myocardial infarction Likewise, there was no significant difference in the incidence of non-fatal myocardial infarction or stroke—indeed, disabling strokes were somewhat commoner among those allocated aspirin The lower confidence limit for the effect of aspirin on non-fatal stroke or myocardial infarction, however, was a substantial 25% reduction Migraine and certain types of musculoskeletal pain were reported significantly less often in the treated than control group, but as the control group was not given a placebo the relevance of these findings was difficult to assess There was no apparent reduction in the incidence of cataract in the treated group The lack of any apparent reduction in disabling stroke or vascular death contrasts with the established value of antiplatelet treatment after occlusive vascular disease

Topological quantum field theories

Abstract: © Publications mathematiques de l’I.H.E.S., 1988, tous droits reserves. L’acces aux archives de la revue « Publications mathematiques de l’I.H.E.S. » (http://www. ihes.fr/IHES/Publications/Publications.html), implique l’accord avec les conditions generales d’utilisation (http://www.numdam.org/legal.php). Toute utilisation commerciale ou impression systematique est constitutive d’une infraction penale. Toute copie ou impression de ce fichier doit contenir la presente mention de copyright.

Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women

Abstract: We sought information worldwide on mortality according to assigned treatment in all randomized trials that began before 1985 of adjuvant tamoxifen or cytotoxic therapy for early breast cancer (with or without regional lymph-node involvement). Coverage was reasonably complete for most countries. In 28 trials of tamoxifen nearly 4000 of 16,513 women had died, and in 40 chemotherapy trials slightly more than 4000 of 13,442 women had died. The 8106 deaths were approximately evenly distributed over years 1, 2, 3, 4, and 5+ of follow-up, with little useful information beyond year 5. Systematic overviews of the results of these trials demonstrated reductions in mortality due to treatment that were significant when tamoxifen was compared with no tamoxifen (P less than 0.0001), any chemotherapy with no chemotherapy (P = 0.003), and polychemotherapy with single-agent chemotherapy (P = 0.001). In tamoxifen trials, there was a clear reduction in mortality only among women 50 or older, for whom assignment to tamoxifen reduced the annual odds of death during the first five years by about one fifth. In chemotherapy trials there was a clear reduction only among women under 50, for whom assignment to polychemotherapy reduced the annual odds of death during the first five years by about one quarter. Direct comparisons showed that combination chemotherapy was significantly more effective than single-agent therapy, but suggested that administration of chemotherapy for 8 to 24 months may offer no survival advantage over administration of the same chemotherapy for 4 to 6 months. Because it involved several thousand women, this overview was able to demonstrate particularly clearly that both tamoxifen and cytotoxic therapy can reduce five-year mortality.

Marrow stromal stem cells.

Abstract: Summary Evidence for the hypothesis that there are stromal stem cells present in the soft connective tissues associated with marrow and bone surfaces that are able to give rise to a number of different cell lines is reviewed. The lines are currently designated fibroblastic, reticular, adipocytic and osteogenic. Fibroblastic colonies, each derived from a single colony-forming unit fibroblastic (CFU-F), are formed when marrow cells are cultured in vitro. In vivo assays of tissue formed by CFU-F in open transplant or in diffusion chambers, have demonstrated that some CFU-F have a high ability for self renewal and multipotentiality whereas some have more limited potential. Preliminary investigations in vitro also support the hypothesis and have shown that CFU-F are a heterogeneous population of stem and progenitor cells and that their differentiation in vitro can be modified at the colony level. The stromal cells which survive and proliferate in vitro are highly dependent on culture conditions. The number and hierarchy of cell lines belonging to the stromal fibroblastic system are not yet fully elucidated and more specific markers and better assays for the different phenotypes are required before a greater understanding can be achieved. The possibility that the marrow stromal system is part of a wider stromal cell system of the body is proposed.

Statistical inference for spatial processes

Abstract: Introduction 1. Likelihood analysis for spatial Gaussian processes 2. Edge correction for spatial point processes 3. Parameter estimation for Gibbsian point processes 4. Modelling spatial images 5. Summarizing binary images.

Reactivity of cytosine and thymine in single-base-pair mismatches with hydroxylamine and osmium tetroxide and its application to the study of mutations

Abstract: The chemical reactivity of thymine (T), when mismatched with the bases cytosine, guanine, and thymine, and of cytosine (C), when mismatched with thymine, adenine, and cytosine, has been examined. Heteroduplex DNAs containing such mismatched base pairs were first incubated with osmium tetroxide (for T and C mismatches) or hydroxylamine (for C mismatches) and then incubated with piperidine to cleave the DNA at the modified mismatched base. This cleavage was studied with an internally labeled strand containing the mismatched T or C, such that DNA cleavage and thus reactivity could be detected by gel electrophoresis. Cleavage at a total of 13 T and 21 C mismatches isolated (by at least three properly paired bases on both sides) single-base-pair mismatches was identified. All T or C mismatches studied were cleaved. By using end-labeled DNA probes containing T or C single-base-pair mismatches and conditions for limited cleavage, we were able to show that cleavage was at the base predicted by sequence analysis and that mismatches in a length of DNA could be readily detected by such an approach. This procedure may enable detection of all single-base-pair mismatches by use of sense and antisense probes and thus may be used to identify the mutated base and its position in a heteroduplex.

Glycosyl-phosphatidylinositol moiety that anchors Trypanosoma brucei variant surface glycoprotein to the membrane

Abstract: Two forms of protein-membrane anchor have been described for the externally disposed glycoproteins of eukaryotic plasma membranes; namely, the hydrophobic transmembrane polypeptide and the complex glycosylphosphatidylinositol (G-PI) moiety. The chemical structures of the major species of G-PI anchors found on a single variant surface glycoprotein (VSG) of the parasitic protozoan Trypanosoma brucei were determined by a combination of nuclear magnetic resonance spectroscopy, mass spectrometry, chemical modification, and exoglycosidase digestions. The G-PI anchor was found to be heterogeneous with respect to monosaccharide sequence, and several novel glycosidic linkages were present. The results are pertinent to the mechanism of the biosynthesis of G-PI anchors.

Exchange Rate Pass-Through When Market Share Matters

Abstract: We investigate pricing to market when the exchange rate changes in cases where firms' future demands depend on their current market shares. We show that i) profit maximizing foreign firms may either raise or lower their domestic currency export prices when the domestic exchange rate appreciates temporarily (i.e. the "pass-through" from exchange rate changes to import prices may be perverse); ii) current import prices may be more sensitive to the expected future exchange rate than to the current exchange rate; iii) current import prices fall in response to an increase in uncertainty about the future exchange rate. We present evidence that suggests the behavior of expected future exchange rates may provide a clue to the puzzling behavior of U.S. import prices during the 1980s.

A prospective study of acute cerebrovascular disease in the community: the Oxfordshire Community Stroke Project 1981-86. 1. Methodology, demography and incident cases of first-ever stroke.

Abstract: A prospective study of acute cerebrovascular disease in a community of about 105,000 people is reported. The study protocol combined rapid clinical assessment of patients with accurate diagnosis of the pathological type of stroke by CT or necropsy, whether or not they were admitted to hospital. The study population was defined as those people who were registered with one of 50 collaborating general practitioners (GPs). Referrals to the study were primarily from the GPs though, to ensure complete case ascertainment, hospital casualty and admission registers, death certificates and special data from the Oxford Record Linkage Study were also scrutinized. Six hundred and seventy five cases of clinically definite first-ever in a lifetime stroke were registered in four years yielding a crude annual incidence of 1.60/1,000 or 2.00/1,000 when adjusted to the 1981 population of England and Wales. The age and sex specific incidence rates for first stroke showed a steep rise with age for both sexes. The odds of a male sustaining a first stroke were 26% greater than those of a female. Ninety one per cent of patients were examined in a median time of four days after the event by a study neurologist and 88% had cerebral CT or necropsy.

The structure of 2Zn pig insulin crystals at 1.5 A resolution.

Abstract: The paper describes the arrangement of the atoms within rhombohedral crystals of 2Zn pig insulin as seen in electron density maps calculated from X-ray data extending to 1.5 A (1 A = 10(-10) m = 10(-1) nm) at room temperature and refined to R = 0.153. The unit cell contains 2 zinc ions, 6 insulin molecules and about 3 x 283 water molecules. The atoms in the protein molecules appear well defined, 7 of the 102 side chains in the asymmetric unit have been assigned alternative disordered positions. The electron density over the water molecules has been interpreted in terms of 349 sites, 217 weighted 1.0, 126 weighted 0.5, 5 at 0.33 and 1 at 0.25 giving ca. 282 molecules. The positions and contacts of all the residues belonging to the two A and B chains of the asymmetric unit are shown first and then details of their arrangement in the two insulin molecules, 1 and 2, which are different. The formation from these molecules of a compact dimer and the further aggregation of three dimers to form a hexamer around two zinc ions, follows. It appears that in the packing of the hexamers in the crystal there are conflicting influences; too-close contacts between histidine B5 residues in neighbouring hexamers are probably responsible for movements of atoms at the beginning of the A chain of one of the two molecules of the dimer that initiate movements in other parts, particularly near the end of the B chain. At every stage of the building of the protein structure, residues to chains of definite conformation, molecules, dimers, hexamers and crystals, we can trace the effect of the packing of like groups to like, aliphatic groups together, aromatic groups together, hydrogen-bonded structures, positive and negative ions. Between the protein molecules, the water is distributed in cavities and channels that are continuous throughout the crystals. More than half the water molecules appear directly hydrogen bonded to protein atoms. These are generally in contact with other water molecules in chains and rings of increasing disorder, corresponding with their movement through the crystals. Within the established crystal structure we survey next the distribution of hydrogen bonds within the protein molecules and between water and protein and water and water; all but eight of the active atoms in the protein form at least one hydrogen bond.(ABSTRACT TRUNCATED AT 400 WORDS)

Understanding Z: A Specification Language and its Formal Semantics

Abstract: By providing a formal semantics for Z, this book justifies the claim that Z is a precise specification language, and provides a standard framework for understanding Z specifications. It makes a detailed theoretical comparison between schemas, the Z construct for breaking specifications into modules, and the analogous facilities in other languages such as CLEAR and ASL. The final chapter contains a number of studies in Z style, showing that Z can be used for a wide variety of specification tasks.

Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes.

Abstract: Morphometric analysis of the endocrine and exocrine pancreas was done on immunoperoxidase stained post-mortem tissue from 15 Type 2 diabetic and 10 age-matched control subjects. Thirteen of the 15 Type 2 diabetic patients had islet amyloid deposits (mean, 6.5% islet area) in the corpus (body, tail and anterior part of the head) but not in the caput (the "pancreatic polypeptide rich" part of the head) whereas none was seen in control subjects. In the corpus in diabetic subjects, the pancreatic area density of B-cells was decreased by 24% (p = 0.005) and A-cells increased by 58% (p less than 0.001) compared with control subjects. The mean A/B-cell ratio increased in the corpus from 0.27 in control subjects to 0.57 in Type 2 diabetic patients. Positive immunoreactivity for the amyloid constituent peptide, Diabetes Associated Peptide, was demonstrated in islet amyloid of diabetic subjects and in B-cells of control and diabetic subjects. The increase in A-cells may contribute to the hyperglucagonaemia and hyperglycaemia of Type 2 diabetes. The impaired insulin secretion in Type 2 diabetes may be due to a decrease in B-cells and to disruption of the islet structure by amyloid. Exocrine fat was similar in the control and diabetic subjects with both groups having more in the corpus than the caput. Diabetic subjects had increased exocrine fibrosis in the corpus region (p less than 0.001), but not in the caput. Exocrine fibrosis may be secondary to disordered islet cell function.

The dose-effect relationship between "unopposed" oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk.

Abstract: The 'unopposed oestrogen hypothesis' for endometrial cancer maintains that risk is increased by exposure to endogenous or exogenous oestrogen that is not opposed simultaneously by a progestagen, and that this increased risk is due to the induced mitotic activity of the endometrial cells. Investigation of the mitotic rate during the menstrual cycle shows that increases in plasma oestrogen concentration above the relatively low levels of the early follicular phase do not produce any further increase in the mitotic rate of endometrial cells. A modification of the unopposed oestrogen hypothesis which includes this upper limit in the response of endometrial cells to oestrogen is consistent with the known dose-effect relationships between endometrial cancer risk and both oestrogen replacement therapy and postmenopausal obesity; it also suggests that the mechanism by which obesity increases risk in premenopausal women involves progesterone deficiency rather than oestrogen excess, and that the protective effect of cigarette smoking may be greater in postmenopausal than in premenopausal women. Detailed analysis of the age-incidence curve for endometrial cancer in the light of this hypothesis suggests that there will be lifelong effects of even short duration use of exogenous hormones. In particular, 5 years of combination-type oral contraceptive use is likely to reduce a woman's lifetime risk of endometrial cancer by some 60%; whereas 5 years of unopposed oestrogen replacement therapy is likely to increase her subsequent lifetime risk by at least 90%; and even 5 years of 'adequately' opposed therapy is likely to increase subsequent lifetime risk by at least 50%.

Unitary Phase Operator in Quantum Mechanics

Abstract: The difficulties in formulating a natural and simple operator description of the phase of a quantum oscillator or single-mode electromagnetic field have been known for some time. We present a unitary phase operator whose eigenstates are well-defined phase states and whose properties coincide with those normally associated with a phase. The corresponding phase eigenvalues form only a dense subset of the real numbers. A natural extension to the definition of a time-measurement operator yields a corresponding countable infinity of eigenvalues.

The Ecological Context of Life History Evolution

Abstract: There is now a good theoretical understanding of life history evolution, and detailed explicit optimality models have been constructed. These present a challenge for empirical work examining some of the assumptions, such as the extent and mechanisms of the costs of growth and reproduction. In addition, there is an obvious need for comparative tests of the models. These tests, properly applied, may be particularly informative because they can deal with multiple independent variables, including ecological variables, and can reveal broad trends against a background of constraints on optima and the rate of evolutionary approach to them. Life histories are the probabilities of survival and the rates of reproduction at each age in the life-span. Reproduction is costly, so that fertility at all ages cannot simultaneously be maximized by natural selection. Allocation of reproductive effort has evolved in response to the demographic impact of different environments but is constrained by genetic variance and evolutionary history.

Pancreatic amylin and calcitonin gene-related peptide cause resistance to insulin in skeletal muscle in vitro

Abstract: Insulin resistance occurs in a variety of conditions, including diabetes, obesity and essential hypertension, but its underlying molecular mechanisms are unclear. In type 2 (non-insulin-dependent) diabetes mellitus, it is insulin-resistance in skeletal muscle, the chief site of insulin-mediated glucose disposal in humans, that predominantly accounts for the low rates of glucose clearance from the blood, and hence for impaired glucose tolerance. Human type 2 diabetes is characterized by a decrease in non-oxidative glucose storage (muscle glycogen synthesis), and by the deposition of amyloid in the islets of Langerhans. Amylin is a 37-amino-acid peptide which is a major component of islet amyloid and has structural similarity to human calcitonin gene-related peptide-2 (CGRP-2; ref. 8). CGRP is a neuropeptide which may be involved in motor activity in skeletal muscle. We now report that human pancreatic amylin and rat CGRP-1 are potent inhibitors of both basal and insulin-stimulated rates of glycogen synthesis in stripped rat soleus muscle in vitro. These results may provide a basis for a new understanding of the molecular mechanisms that cause insulin resistance in skeletal muscle.