Showing papers by "University of Oxford published in 2000"

Inference of population structure using multilocus genotype data

Abstract: We describe a model-based clustering method for using multilocus genotype data to infer population structure and assign individuals to populations. We assume a model in which there are K populations (where K may be unknown), each of which is characterized by a set of allele frequencies at each locus. Individuals in the sample are assigned (probabilistically) to populations, or jointly to two or more populations if their genotypes indicate that they are admixed. Our model does not assume a particular mutation process, and it can be applied to most of the commonly used genetic markers, provided that they are not closely linked. Applications of our method include demonstrating the presence of population structure, assigning individuals to populations, studying hybrid zones, and identifying migrants and admixed individuals. We show that the method can produce highly accurate assignments using modest numbers of loci— e.g. , seven microsatellite loci in an example using genotype data from an endangered bird species. The software used for this article is available from http://www.stats.ox.ac.uk/~pritch/home.html.

Biodiversity hotspots for conservation priorities

Abstract: Conservationists are far from able to assist all species under threat, if only for lack of funding. This places a premium on priorities: how can we support the most species at the least cost? One way is to identify 'biodiversity hotspots' where exceptional concentrations of endemic species are undergoing exceptional loss of habitat. As many as 44% of all species of vascular plants and 35% of all species in four vertebrate groups are confined to 25 hotspots comprising only 1.4% of the land surface of the Earth. This opens the way for a 'silver bullet' strategy on the part of conservation planners, focusing on these hotspots in proportion to their share of the world's species at risk.

Multiple view geometry in computer vision

Abstract: From the Publisher: A basic problem in computer vision is to understand the structure of a real world scene given several images of it. Recent major developments in the theory and practice of scene reconstruction are described in detail in a unified framework. The book covers the geometric principles and how to represent objects algebraically so they can be computed and applied. The authors provide comprehensive background material and explain how to apply the methods and implement the algorithms directly.

Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study

Abstract: Objective: To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. Design: Prospective observational study. Setting: 23 hospital based clinics in England, Scotland, and Northern Ireland. Participants: 4585 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk. Outcome measures: Primary predefined aggregate clinical outcomes: any end point or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photo-coagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 1% reduction in updated mean HbA 1c adjusted for possible confounders at diagnosis of diabetes. Results: The incidence of clinical complications was significantly associated with glycaemia. Each 1% reduction in updated mean HbA 1c was associated with reductions in risk of 21% for any end point related to diabetes (95% confidence interval 17% to 24%, P Conclusions: In patients with type 2 diabetes the risk of diabetic complications was strongly associated with previous hyperglycaemia. Any reduction in HbA 1c is likely to reduce the risk of complications, with the lowest risk being in those with HbA 1c values in the normal range (

Greed and Grievance in Civil War

Abstract: Of the 27 major armed conflicts that occurred in 1999, all but two took place within national boundaries. As an impediment to development, internal rebellion especially hurts the world's poorest countries. What motivates civil wars? Greed or grievance? Collier and Hoeffler compare two contrasting motivations for rebellion: greed and grievance. Most rebellions are ostensibly in pursuit of a cause, supported by a narrative of grievance. But since grievance assuagement through rebellion is a public good that a government will not supply, economists predict such rebellions would be rare. Empirically, many rebellions appear to be linked to the capture of resources (such as diamonds in Angola and Sierra Leone, drugs in Colombia, and timber in Cambodia). Collier and Hoeffler set up a simple rational choice model of greed-rebellion and contrast its predictions with those of a simple grievance model. Some countries return to conflict repeatedly. Are they conflict-prone or is there a feedback effect whereby conflict generates grievance, which in turn generates further conflict? The authors show why such a feedback effect might be present in both greed-motivated and grievance rebellions. The authors' results contrast with conventional beliefs about the causes of conflict. A stylized version of conventional beliefs would be that grievance begets conflict, which begets grievance, which begets further conflict. With such a model, the only point at which to intervene is to reduce the level of objective grievance. Collier and Hoeffler's model suggests that what actually happens is that opportunities for predation (controlling primary commodity exports) cause conflict and the grievances this generates induce dias-poras to finance further conflict. The point of policy intervention here is to reduce the absolute and relative attraction of primary commodity predation and to reduce the ability of diasporas to fund rebel movements. This paper - a product of the Development Research Group - is part of a larger effort in the group to study civil war and criminal violence. For more on this effort, go to www.worldbank.org/research/conflict. Paul Collier may be contacted at pcollier@worldbank.org.

Spectral Methods in MATLAB

Abstract: Preface 1 Differentiation matrices 2 Unbounded grids: the semidiscrete Fourier transform 3 Periodic grids: the DFT and FFT 4 Smoothness and spectral accuracy 5 Polynomial interpolation and clustered grids 6 Chebyshev differentiation matrices 7 Boundary value problems 8 Chebyshev series and the FFT 9 Eigenvalues and pseudospectra 10 Time-stepping and stability regions 11 Polar coordinates 12 Integrals and quadrature formulas 13 More about boundary conditions 14 Fourth-order problems Afterword Bibliography Index

A new method for the nonlinear transformation of means and covariances in filters and estimators

Abstract: This paper describes a new approach for generalizing the Kalman filter to nonlinear systems. A set of samples are used to parametrize the mean and covariance of a (not necessarily Gaussian) probability distribution. The method yields a filter that is more accurate than an extended Kalman filter (EKF) and easier to implement than an EKF or a Gauss second-order filter. Its effectiveness is demonstrated using an example.

Multilocus sequence typing for characterization of methicillin-resistant and methicillin-susceptible clones of Staphylococcus aureus.

Abstract: A multilocus sequence typing (MLST) scheme has been developed for Staphylococcus aureus. The sequences of internal fragments of seven housekeeping genes were obtained for 155 S. aureus isolates from patients with community-acquired and hospital-acquired invasive disease in the Oxford, United Kingdom, area. Fifty-three different allelic profiles were identified, and 17 of these were represented by at least two isolates. The MLST scheme was highly discriminatory and was validated by showing that pairs of isolates with the same allelic profile produced very similar SmaI restriction fragment patterns by pulsed-field gel electrophoresis. All 22 isolates with the most prevalent allelic profile were methicillin-resistant S. aureus (MRSA) isolates and had allelic profiles identical to that of a reference strain of the epidemic MRSA clone 16 (EMRSA-16). Four MRSA isolates that were identical in allelic profile to the other major epidemic MRSA clone prevalent in British hospitals (clone EMRSA-15) were also identified. The majority of isolates (81%) were methicillin-susceptible S. aureus (MSSA) isolates, and seven MSSA clones included five or more isolates. Three of the MSSA clones included at least five isolates from patients with community-acquired invasive disease and may represent virulent clones with an increased ability to cause disease in otherwise healthy individuals. The most prevalent MSSA clone (17 isolates) was very closely related to EMRSA-16, and the success of the latter clone at causing disease in hospitals may be due to its emergence from a virulent MSSA clone that was already a major cause of invasive disease in both the community and hospital settings. MLST provides an unambiguous method for assigning MRSA and MSSA isolates to known clones or assigning them as novel clones via the Internet.

Regulation of chromatin structure by site-specific histone H3 methyltransferases

Abstract: The organization of chromatin into higher-order structures influences chromosome function and epigenetic gene regulation. Higher-order chromatin has been proposed to be nucleated by the covalent modification of histone tails and the subsequent establishment of chromosomal subdomains by non-histone modifier factors. Here we show that human SUV39H1 and murine Suv39h1—mammalian homologues of Drosophila Su(var)3-9 and of Schizosaccharomyces pombe clr4—encode histone H3-specific methyltransferases that selectively methylate lysine 9 of the amino terminus of histone H3 in vitro. We mapped the catalytic motif to the evolutionarily conserved SET domain, which requires adjacent cysteine-rich regions to confer histone methyltransferase activity. Methylation of lysine 9 interferes with phosphorylation of serine 10, but is also influenced by pre-existing modifications in the amino terminus of H3. In vivo, deregulated SUV39H1 or disrupted Suv39h activity modulate H3 serine 10 phosphorylation in native chromatin and induce aberrant mitotic divisions. Our data reveal a functional interdependence of site-specific H3 tail modifications and suggest a dynamic mechanism for the regulation of higher-order chromatin.

A flat Universe from high-resolution maps of the cosmic microwave background radiation

Abstract: The blackbody radiation left over from the Big Bang has been transformed by the expansion of the Universe into the nearly isotropic 2.73 K cosmic microwave background. Tiny inhomogeneities in the early Universe left their imprint on the microwave background in the form of small anisotropies in its temperature. These anisotropies contain information about basic cosmological parameters, particularly the total energy density and curvature of the Universe. Here we report the first images of resolved structure in the microwave background anisotropies over a significant part of the sky. Maps at four frequencies clearly distinguish the microwave background from foreground emission. We compute the angular power spectrum of the microwave background, and find a peak at Legendre multipole l_(peak) = (197 ± 6), with an amplitude ΔT_(200) = (69 ± 8) µK. This is consistent with that expected for cold dark matter models in a flat (euclidean) Universe, as favoured by standard inflationary models.

A DNA-fuelled molecular machine made of DNA

Abstract: Molecular recognition between complementary strands of DNA allows construction on a nanometre length scale. For example, DNA tags may be used to organize the assembly of colloidal particles, and DNA templates can direct the growth of semiconductor nanocrystals and metal wires. As a structural material in its own right, DNA can be used to make ordered static arrays of tiles, linked rings and polyhedra. The construction of active devices is also possible--for example, a nanomechanical switch, whose conformation is changed by inducing a transition in the chirality of the DNA double helix. Melting of chemically modified DNA has been induced by optical absorption, and conformational changes caused by the binding of oligonucleotides or other small groups have been shown to change the enzymatic activity of ribozymes. Here we report the construction of a DNA machine in which the DNA is used not only as a structural material, but also as 'fuel'. The machine, made from three strands of DNA, has the form of a pair of tweezers. It may be closed and opened by addition of auxiliary strands of 'fuel' DNA; each cycle produces a duplex DNA waste product.

Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study

Abstract: OBJECTIVE: To determine the relation between systolic blood pressure over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. DESIGN: Prospective observational study. SETTING: 23 hospital based clinics in England, Scotland, and Northern Ireland. PARTICIPANTS: 4801 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk. OUTCOME MEASURES: Primary predefined aggregate clinical outcomes: any complications or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, lower extremity amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photocoagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 10 mm Hg decrease in updated mean systolic blood pressure adjusted for specific confounders. RESULTS: The incidence of clinical complications was significantly associated with systolic blood pressure, except for cataract extraction. Each 10 mm Hg decrease in updated mean systolic blood pressure was associated with reductions in risk of 12% for any complication related to diabetes (95% confidence interval 10% to 14%, P<0.0001), 15% for deaths related to diabetes (12% to 18%, P<0.0001), 11% for myocardial infarction (7% to 14%, P<0.0001), and 13% for microvascular complications (10% to 16%, P<0.0001). No threshold of risk was observed for any end point. CONCLUSIONS: In patients with type 2 diabetes the risk of diabetic complications was strongly associated with raised blood pressure. Any reduction in blood pressure is likely to reduce the risk of complications, with the lowest risk being in those with systolic blood pressure less than 120 mm Hg.

Association Mapping in Structured Populations

Abstract: The use, in association studies, of the forthcoming dense genomewide collection of single-nucleotide polymorphisms (SNPs) has been heralded as a potential breakthrough in the study of the genetic basis of common complex disorders. A serious problem with association mapping is that population structure can lead to spurious associations between a candidate marker and a phenotype. One common solution has been to abandon case-control studies in favor of family-based tests of association, such as the transmission/disequilibrium test (TDT), but this comes at a considerable cost in the need to collect DNA from close relatives of affected individuals. In this article we describe a novel, statistically valid, method for case-control association studies in structured populations. Our method uses a set of unlinked genetic markers to infer details of population structure, and to estimate the ancestry of sampled individuals, before using this information to test for associations within subpopulations. It provides power comparable with the TDT in many settings and may substantially outperform it if there are conflicting associations in different subpopulations.

Venture Capital and the Professionalization of Start-Up Firms: Empirical Evidence

Abstract: This paper examines empirical evidence on the impact that venture capitalists can have on the development path of new firms. We use a hand-collected data set on Silicon Valley start-up companies that allows us to "look inside the black box" and analyze the influence of venture capital on the professionalization of firms' internal organization. The evidence suggests that there is a "soft" facet to venture capitalists, in terms of supporting companies to build up their human resources within the organization. Venture capital is also important at the top, in that venture capital backed companies are more likely and faster to bring in outsiders as CEOs. These CEO replacements are often accompanied with the founder departing from the company, suggesting that venture capitalists also exhibit a "hard" facet in terms of exercising control. The paper examines how these various roles are interrelated, and shows how the role of venture capital varies with the state of the company.

Fabrication of photonic crystals for the visible spectrum by holographic lithography

Abstract: The term 'photonics' describes a technology whereby data transmission and processing occurs largely or entirely by means of photons. Photonic crystals are microstructured materials in which the dielectric constant is periodically modulated on a length scale comparable to the desired wavelength of operation. Multiple interference between waves scattered from each unit cell of the structure may open a 'photonic bandgap'--a range of frequencies, analogous to the electronic bandgap of a semiconductor, within which no propagating electromagnetic modes exist. Numerous device principles that exploit this property have been identified. Considerable progress has now been made in constructing two-dimensional structures using conventional lithography, but the fabrication of three-dimensional photonic crystal structures for the visible spectrum remains a considerable challenge. Here we describe a technique--three-dimensional holographic lithography--that is well suited to the production of three-dimensional structures with sub-micrometre periodicity. With this technique we have made microperiodic polymeric structures, and we have used these as templates to create complementary structures with higher refractive-index contrast.

The Orbitofrontal Cortex and Reward

Abstract: The primate orbitofrontal cortex contains the secondary taste cortex, in which the reward value of taste is represented. It also contains the secondary and tertiary olfactory cortical areas, in which information about the identity and also about the reward value of odors is represented. The orbitofrontal cortex also receives information about the sight of objects and faces from the temporal lobe cortical visual areas, and neurons in it learn and reverse the visual stimulus to which they respond when the association of the visual stimulus with a primary reinforcing stimulus (such as a taste reward) is reversed. However, the orbitofrontal cortex is involved in representing negative reinforcers (punishers) too, such as aversive taste, and in rapid stimulus–reinforcement association learning for both positive and negative primary reinforcers. In complementary neuroimaging studies in humans it is being found that areas of the orbitofrontal cortex (and connected subgenual cingulate cortex) are activated by pleasant touch, by painful touch, by rewarding and aversive taste, and by odor. Damage to the orbitofrontal cortex in humans can impair the learning and reversal of stimulus– reinforcement associations, and thus the correction of behavioral responses when these are no longer appropriate because previous reinforcement contingencies change. This evidence thus shows that the orbitofrontal cortex is involved in decoding and representing some primary reinforcers such as taste and touch; in learning and reversing associations of visual and other stimuli to these primary reinforcers; and in controlling and correcting reward-related and punishment-related behavior, and thus in emotion. The prefrontal cortex is the cortex that receives projections from the mediodorsal nucleus of the thalamus and is situated in front of the motor and premotor cortices (areas 4 and 6) in the frontal lobe. Based on the divisions of the mediodorsal nucleus, the prefrontal cortex may be divided into three main regions (Fuster, 1997). First, the magnocellular, medial, part of the mediodorsal nucleus projects to the orbital (ventral) surface of the prefrontal cortex (which includes areas 13 and 12). This part of the prefrontal cortex is called the orbitofrontal cortex, and receives information from the ventral or object-processing visual stream, and taste, olfactory and somatosensory inputs. Second, the parvocellular, lateral, part of the mediodorsal nucleus projects to the dorsolateral prefrontal cortex. This part of the prefrontal cortex receives inputs from the parietal cortex and is involved in tasks such as spatial short-term memory tasks (Fuster, 1997; Rolls

The economic burden of back pain in the UK

Abstract: This paper reports the results of a 'cost-of-illness' study of the socio-economic costs of back pain in the UK. It estimates the direct health care cost of back pain in 1998 to be pound1632 million. Approximately 35% of this cost relates to services provided in the private sector and thus is most likely paid for directly by patients and their families. With respect to the distribution of cost across different providers, 37% relates to care provided by physiotherapists and allied specialists, 31% is incurred in the hospital sector, 14% relates to primary care, 7% to medication, 6% to community care and 5% to radiology and imaging used for investigation purposes. However, the direct cost of back pain is insignificant compared to the cost of informal care and the production losses related to it, which total pound10668 million. Overall, back pain is one of the most costly conditions for which an economic analysis has been carried out in the UK and this is in line with findings in other countries. Further research is needed to establish the cost-effectiveness of alternative back pain treatments, so as to minimise cost and maximise the health benefit from the resources used in this area.

The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages

Abstract: The cellular response to hypoxia includes the hypoxia-inducible factor-1 (HIF-1)-induced transcription of genes involved in diverse processes such as glycolysis and angiogenesis. Induction of the HIF-regulated genes, as a consequence of the microenvironment or genetic changes, is known to have an important role in the growth of experimental tumors. Hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) are known to dimerize with the aryl hydrocarbon receptor nuclear translocator in mediating this response. Because regulation of the α chain protein level is a primary determinant of HIF activity, our aim was to investigate the distribution of HIF-1α and HIF-2α by immunohistochemistry in normal and pathological tissues using monoclonal antibodies (mAb). We raised a new mAb to detect HIF-1α, designated 122, and used our previously validated mAb 190b to HIF-2α. In the majority of solid tumors examined, including bladder, brain, breast, colon, ovarian, pancreatic, prostate, and renal carcinomas, nuclear expression of HIF-1α and -2α was observed in varying subsets of the tumor cells. HIF-2α was also strongly expressed by subsets of tumor-associated macrophages, sometimes in the absence of any tumor cell expression. Less frequently staining was observed in other stromal cells within the tumors and in normal tissue adjacent to tumor margins. In contrast, in normal tissue neither molecule was detectable except within subsets of bone marrow macrophages, where HIF-2α was strongly expressed.

Complete Genome Sequence of Neisseria meningitidis Serogroup B Strain MC58

Abstract: The 2,272,351-base pair genome of Neisseria meningitidis strain MC58 (serogroup B), a causative agent of meningitis and septicemia, contains 2158 predicted coding regions, 1158 (53.7%) of which were assigned a biological role. Three major islands of horizontal DNA transfer were identified; two of these contain genes encoding proteins involved in pathogenicity, and the third island contains coding sequences only for hypothetical proteins. Insights into the commensal and virulence behavior of N. meningitidis can be gleaned from the genome, in which sequences for structural proteins of the pilus are clustered and several coding regions unique to serogroup B capsular polysaccharide synthesis can be identified. Finally, N. meningitidis contains more genes that undergo phase variation than any pathogen studied to date, a mechanism that controls their expression and contributes to the evasion of the host immune system.

Ancient DNA: Do It Right or Not at All

Abstract: At the recent 5th International Ancient DNA Conference in Manchester, U.K., reported by Erik Stokstad in his News Focus article “Divining diet and disease from DNA” (28 Jul., p. [530][1]), one presentation boldly opened with the claim that the field was now mature and could move ahead with

MAXIMA-1: A measurement of the cosmic microwave background anisotropy on angular scales of 10′-5°

Abstract: We present a map and an angular power spectrum of the anisotropy of the cosmic microwave background (CMB) from the first flight of MAXIMA. MAXIMA is a balloon-borne experiment with an array of 16 bolometric photometers operated at 100 mK. MAXIMA observed a 124 deg region of the sky with 10' resolution at frequencies of 150, 240 and 410 GHz. The data were calibrated using in-flight measurements of the CMB dipole anisotropy. A map of the CMB anisotropy was produced from three 150 and one 240 GHz photometer without need for foreground subtractions. Analysis of this CMB map yields a power spectrum for the CMB anisotropy over the range 36 {le} {ell} {le} 785. The spectrum shows a peak with an amplitude of 78 {+-} 6 {mu}K at {ell} {approx_equal} 220 and an amplitude varying between {approx} 40 {mu}K and {approx} 50 {mu}K for 400 {approx}< {ell} {approx}< 785.

Dealing with label switching in mixture models

Abstract: Summary. In a Bayesian analysis of finite mixture models, parameter estimation and clustering are sometimes less straightforward than might be expected. In particular, the common practice of estimating parameters by their posterior mean, and summarizing joint posterior distributions by marginal distributions, often leads to nonsensical answers. This is due to the so-called 'label switching' problem, which is caused by symmetry in the likelihood of the model parameters. A frequent response to this problem is to remove the symmetry by using artificial identifiability constraints. We demonstrate that this fails in general to solve the problem, and we describe an alternative class of approaches, relabelling algorithms, which arise from attempting to minimize the posterior expected loss under a class of loss functions. We describe in detail one particularly simple and general relabelling algorithm and illustrate its success in dealing with the label switching problem on two examples.

Articulated body motion capture by annealed particle filtering

Abstract: The main challenge in articulated body motion tracking is the large number of degrees of freedom (around 30) to be recovered. Search algorithms, either deterministic or stochastic, that search such a space without constraint, fall foul of exponential computational complexity. One approach is to introduce constraints: either labelling using markers or colour coding, prior assumptions about motion trajectories or view restrictions. Another is to relax constraints arising from articulation, and track limbs as if their motions were independent. In contrast, we aim for general tracking without special preparation of objects or restrictive assumptions. The principal contribution of the paper is the development of a modified particle filter for search in high dimensional configuration spaces. It uses a continuation principle based on annealing to introduce the influence of narrow peaks in the fitness function, gradually. The new algorithm, termed annealed particle filtering, is shown to be capable of recovering full articulated body motion efficiently.

The importance of repairing stalled replication forks

Abstract: The bacterial SOS response to unusual levels of DNA damage has been recognized and studied for several decades. Pathways for re-establishing inactivated replication forks under normal growth conditions have received far less attention. In bacteria growing aerobically in the absence of SOS-inducing conditions, many replication forks encounter DNA damage, leading to inactivation. The pathways for fork reactivation involve the homologous recombination systems, are nonmutagenic, and integrate almost every aspect of DNA metabolism. On a frequency-of-use basis, these pathways represent the main function of bacterial DNA recombination systems, as well as the main function of a number of other enzymatic systems that are associated with replication and site-specific recombination.

An Introduction to the Adjoint Approach to Design

Abstract: Optimal design methods involving the solution of an adjoint system of equations are an active area of research in computational fluid dynamics, particularly for aeronautical applications. This paper presents an introduction to the subject, emphasising the simplicity of the ideas when viewed in the context of linear algebra. Detailed discussions also include the extension to p.d.e.'s, the construction of the adjoint p.d.e. and its boundary conditions, and the physical significance of the adjoint solution. The paper concludes with examples of the use of adjoint methods for optimising the design of business jets.

Generating solitons by phase engineering of a bose-einstein condensate

Abstract: Quantum phase engineering is demonstrated with two techniques that allow the spatial phase distribution of a Bose-Einstein condensate (BEC) to be written and read out. A quantum state was designed and produced by optically imprinting a phase pattern onto a BEC of sodium atoms, and matter-wave interferometry with spatially resolved imaging was used to analyze the resultant phase distribution. An appropriate phase imprint created solitons, the first experimental realization of this nonlinear phenomenon in a BEC. The subsequent evolution of these excitations was investigated both experimentally and theoretically.