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Showing papers by "University of Cambridge published in 2003"


Journal ArticleDOI
04 Sep 2003-BMJ
TL;DR: A new quantity is developed, I 2, which the authors believe gives a better measure of the consistency between trials in a meta-analysis, which is susceptible to the number of trials included in the meta- analysis.
Abstract: Cochrane Reviews have recently started including the quantity I 2 to help readers assess the consistency of the results of studies in meta-analyses. What does this new quantity mean, and why is assessment of heterogeneity so important to clinical practice? Systematic reviews and meta-analyses can provide convincing and reliable evidence relevant to many aspects of medicine and health care.1 Their value is especially clear when the results of the studies they include show clinically important effects of similar magnitude. However, the conclusions are less clear when the included studies have differing results. In an attempt to establish whether studies are consistent, reports of meta-analyses commonly present a statistical test of heterogeneity. The test seeks to determine whether there are genuine differences underlying the results of the studies (heterogeneity), or whether the variation in findings is compatible with chance alone (homogeneity). However, the test is susceptible to the number of trials included in the meta-analysis. We have developed a new quantity, I 2, which we believe gives a better measure of the consistency between trials in a meta-analysis. Assessment of the consistency of effects across studies is an essential part of meta-analysis. Unless we know how consistent the results of studies are, we cannot determine the generalisability of the findings of the meta-analysis. Indeed, several hierarchical systems for grading evidence state that the results of studies must be consistent or homogeneous to obtain the highest grading.2–4 Tests for heterogeneity are commonly used to decide on methods for combining studies and for concluding consistency or inconsistency of findings.5 6 But what does the test achieve in practice, and how should the resulting P values be interpreted? A test for heterogeneity examines the null hypothesis that all studies are evaluating the same effect. The usual test statistic …

45,105 citations


Journal ArticleDOI
TL;DR: In this article, a unit root test for dynamic heterogeneous panels based on the mean of individual unit root statistics is proposed, which converges in probability to a standard normal variate sequentially with T (the time series dimension) →∞, followed by N (the cross sectional dimension)→∞.

12,838 citations


Journal ArticleDOI
19 Oct 2003
TL;DR: Xen, an x86 virtual machine monitor which allows multiple commodity operating systems to share conventional hardware in a safe and resource managed fashion, but without sacrificing either performance or functionality, considerably outperform competing commercial and freely available solutions.
Abstract: Numerous systems have been designed which use virtualization to subdivide the ample resources of a modern computer. Some require specialized hardware, or cannot support commodity operating systems. Some target 100% binary compatibility at the expense of performance. Others sacrifice security or functionality for speed. Few offer resource isolation or performance guarantees; most provide only best-effort provisioning, risking denial of service.This paper presents Xen, an x86 virtual machine monitor which allows multiple commodity operating systems to share conventional hardware in a safe and resource managed fashion, but without sacrificing either performance or functionality. This is achieved by providing an idealized virtual machine abstraction to which operating systems such as Linux, BSD and Windows XP, can be ported with minimal effort.Our design is targeted at hosting up to 100 virtual machine instances simultaneously on a modern server. The virtualization approach taken by Xen is extremely efficient: we allow operating systems such as Linux and Windows XP to be hosted simultaneously for a negligible performance overhead --- at most a few percent compared with the unvirtualized case. We considerably outperform competing commercial and freely available solutions in a range of microbenchmarks and system-wide tests.

6,326 citations


Journal ArticleDOI
TL;DR: In this paper, a simple alternative test where the standard unit root regressions are augmented with the cross section averages of lagged levels and first-differences of the individual series is also considered.
Abstract: A number of panel unit root tests that allow for cross section dependence have been proposed in the literature, notably by Bai and Ng (2002), Moon and Perron (2003), and Phillips and Sul (2002) who use orthogonalization type procedures to asymptotically eliminate the cross dependence of the series before standard panel unit root tests are applied to the transformed series. In this paper we propose a simple alternative test where the standard DF (or ADF) regressions are augmented with the cross section averages of lagged levels and first-differences of the individual series. A truncated version of the CADF statistics is also considered. New asymptotic results are obtained both for the individual CADF statistics, and their simple averages. It is shown that the CADF_i statistics are asymptotically similar and do not depend on the factor loadings under joint asymptotics where N (cross section dimension) and T (time series dimension) tends to infinity, such that N/T tends to k, where k is a fixed finite non-zero constant. But they are asymptotically correlated due to their dependence on the common factor. Despite this it is shown that the limit distribution of the average CADF statistic exists and its critical values are tabulated. The small sample properties of the proposed tests are investigated by Monte Carlo experiments, for a variety of models. It is shown that the cross sectionally augmented panel unit root tests have satisfactory size and power even for relatively small values of N and T. This is particularly true of cross sectionally augmented and truncated versions of the simple average t-test of Im, Pesaran and Shin, and Choi's inverse normal combination test.

6,169 citations


Journal ArticleDOI
18 Dec 2003-Nature
TL;DR: The manner in which a newly synthesized chain of amino acids transforms itself into a perfectly folded protein depends both on the intrinsic properties of the amino-acid sequence and on multiple contributing influences from the crowded cellular milieu.
Abstract: The manner in which a newly synthesized chain of amino acids transforms itself into a perfectly folded protein depends both on the intrinsic properties of the amino-acid sequence and on multiple contributing influences from the crowded cellular milieu. Folding and unfolding are crucial ways of regulating biological activity and targeting proteins to different cellular locations. Aggregation of misfolded proteins that escape the cellular quality-control mechanisms is a common feature of a wide range of highly debilitating and increasingly prevalent diseases.

4,440 citations


Journal ArticleDOI
15 Feb 2003-Proteins
TL;DR: Geometrical validation around the Cα is described, with a new Cβ measure and updated Ramachandran plot, and Favored and allowed ϕ,ψ regions are also defined for Pro, pre‐Pro, and Gly (important because Gly ϕ‐ψ angles are more permissive but less accurately determined).
Abstract: Geometrical validation around the Calpha is described, with a new Cbeta measure and updated Ramachandran plot. Deviation of the observed Cbeta atom from ideal position provides a single measure encapsulating the major structure-validation information contained in bond angle distortions. Cbeta deviation is sensitive to incompatibilities between sidechain and backbone caused by misfit conformations or inappropriate refinement restraints. A new phi,psi plot using density-dependent smoothing for 81,234 non-Gly, non-Pro, and non-prePro residues with B < 30 from 500 high-resolution proteins shows sharp boundaries at critical edges and clear delineation between large empty areas and regions that are allowed but disfavored. One such region is the gamma-turn conformation near +75 degrees,-60 degrees, counted as forbidden by common structure-validation programs; however, it occurs in well-ordered parts of good structures, it is overrepresented near functional sites, and strain is partly compensated by the gamma-turn H-bond. Favored and allowed phi,psi regions are also defined for Pro, pre-Pro, and Gly (important because Gly phi,psi angles are more permissive but less accurately determined). Details of these accurate empirical distributions are poorly predicted by previous theoretical calculations, including a region left of alpha-helix, which rates as favorable in energy yet rarely occurs. A proposed factor explaining this discrepancy is that crowding of the two-peptide NHs permits donating only a single H-bond. New calculations by Hu et al. [Proteins 2002 (this issue)] for Ala and Gly dipeptides, using mixed quantum mechanics and molecular mechanics, fit our nonrepetitive data in excellent detail. To run our geometrical evaluations on a user-uploaded file, see MOLPROBITY (http://kinemage.biochem.duke.edu) or RAMPAGE (http://www-cryst.bioc.cam.ac.uk/rampage).

3,963 citations


Journal ArticleDOI
16 Jan 2003-Nature
TL;DR: It is found that genes of similar functions are clustered in distinct, multi-megabase regions of individual chromosomes; genes in these regions tend to share transcriptional profiles.
Abstract: A principal challenge currently facing biologists is how to connect the complete DNA sequence of an organism to its development and behaviour. Large-scale targeted-deletions have been successful in defining gene functions in the single-celled yeast Saccharomyces cerevisiae, but comparable analyses have yet to be performed in an animal. Here we describe the use of RNA interference to inhibit the function of ∼86% of the 19,427 predicted genes of C. elegans. We identified mutant phenotypes for 1,722 genes, about two-thirds of which were not previously associated with a phenotype. We find that genes of similar functions are clustered in distinct, multi-megabase regions of individual chromosomes; genes in these regions tend to share transcriptional profiles. Our resulting data set and reusable RNAi library of 16,757 bacterial clones will facilitate systematic analyses of the connections among gene sequence, chromosomal location and gene function in C. elegans.

3,529 citations


Journal ArticleDOI
TL;DR: Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age and for variation in risk by mutation position for both genes, and some evidence for a reduction in risk in women from earlier birth cohorts is found.
Abstract: Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.

3,384 citations


Journal ArticleDOI
TL;DR: This work summarizes the Systems Biology Markup Language (SBML) Level 1, a free, open, XML-based format for representing biochemical reaction networks, a software-independent language for describing models common to research in many areas of computational biology.
Abstract: Motivation: Molecular biotechnology now makes it possible to build elaborate systems models, but the systems biology community needs information standards if models are to be shared, evaluated and developed cooperatively. Results: We summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, XML-based format for representing biochemical reaction networks. SBML is a software-independent language for describing models common to research in many areas of computational biology, including cell signaling pathways, metabolic pathways, gene regulation, and others. ∗ To whom correspondence should be addressed. Availability: The specification of SBML Level 1 is freely available from http://www.sbml.org/.

3,205 citations


Journal ArticleDOI
TL;DR: This work suggests that equally important in a wide range of conditions are processes involving the management of Na(+) movements within the plant, and requires more knowledge of cell-specific transport processes and the consequences of manipulation of transporters and signalling elements in specific cell types.

2,998 citations


Journal ArticleDOI
13 Nov 2003-Nature
TL;DR: It is proposed that telomere-initiated senescence reflects a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres.
Abstract: Most human somatic cells can undergo only a limited number of population doublings in vitro. This exhaustion of proliferative potential, called senescence, can be triggered when telomeres--the ends of linear chromosomes-cannot fulfil their normal protective functions. Here we show that senescent human fibroblasts display molecular markers characteristic of cells bearing DNA double-strand breaks. These markers include nuclear foci of phosphorylated histone H2AX and their co-localization with DNA repair and DNA damage checkpoint factors such as 53BP1, MDC1 and NBS1. We also show that senescent cells contain activated forms of the DNA damage checkpoint kinases CHK1 and CHK2. Furthermore, by chromatin immunoprecipitation and whole-genome scanning approaches, we show that the chromosome ends of senescent cells directly contribute to the DNA damage response, and that uncapped telomeres directly associate with many, but not all, DNA damage response proteins. Finally, we show that inactivation of DNA damage checkpoint kinases in senescent cells can restore cell-cycle progression into S phase. Thus, we propose that telomere-initiated senescence reflects a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres.

Journal ArticleDOI
01 Sep 2003-Proteins
TL;DR: In terms of producing binding energy estimates, the Goldscore function appears to perform better than the Chemscore function and the two consensus protocols, particularly for faster search settings.
Abstract: The Chemscore function was implemented as a scoring function for the protein-ligand docking program GOLD, and its performance compared to the original Goldscore function and two consensus docking protocols, "Goldscore-CS" and "Chemscore-GS," in terms of docking accuracy, prediction of binding affinities, and speed. In the "Goldscore-CS" protocol, dockings produced with the Goldscore function are scored and ranked with the Chemscore function; in the "Chemscore-GS" protocol, dockings produced with the Chemscore function are scored and ranked with the Goldscore function. Comparisons were made for a "clean" set of 224 protein-ligand complexes, and for two subsets of this set, one for which the ligands are "drug-like," the other for which they are "fragment-like." For "drug-like" and "fragment-like" ligands, the docking accuracies obtained with Chemscore and Goldscore functions are similar. For larger ligands, Goldscore gives superior results. Docking with the Chemscore function is up to three times faster than docking with the Goldscore function. Both combined docking protocols give significant improvements in docking accuracy over the use of the Goldscore or Chemscore function alone. "Goldscore-CS" gives success rates of up to 81% (top-ranked GOLD solution within 2.0 A of the experimental binding mode) for the "clean list," but at the cost of long search times. For most virtual screening applications, "Chemscore-GS" seems optimal; search settings that give docking speeds of around 0.25-1.3 min/compound have success rates of about 78% for "drug-like" compounds and 85% for "fragment-like" compounds. In terms of producing binding energy estimates, the Goldscore function appears to perform better than the Chemscore function and the two consensus protocols, particularly for faster search settings. Even at docking speeds of around 1-2 min/compound, the Goldscore function predicts binding energies with a standard deviation of approximately 10.5 kJ/mol.

Journal ArticleDOI
TL;DR: In this article, the authors highlight the recent developments in the copper-mediated (both stoichiometric and catalytic) reactions of aryl boronic acids as reaction partners in both O- and N-arylation.
Abstract: The copper-mediated C(aryl)N, C(aryl)O, and C(aryl)S bond formation is an important transformation and has been developed to include a wide range of substrates. This Review highlights the recent developments in the copper-mediated (both stoichiometric and catalytic) reactions of aryl boronic acids, aryl halides, iodonium salts, siloxanes, stannanes, plumbanes, bismuthates, and trifluoroborate salts as aryl donors. In particular, the recent introduction of boronic acids as reaction partners in both O- and N-arylation has been a significant discovery and will occupy centre-stage in this review. Clear improvements can be obtained by the correct choice of copper source, base, ligands, and other additives. Mechanistic investigations should provide insight into the catalytically active species, which would aid in the development of milder, more-efficient methods.

Journal ArticleDOI
TL;DR: In this article, the authors argue that the cluster concept should carry a public policy health warning: there is much about it that is problematic, and the rush to employ cluster ideas has run ahead of many fundamental conceptual, theoretical and empirical questions.
Abstract: Over the past decade, there has been growing interest in local industrial agglomeration and specialization, not only by economic geographers but also by economists and by policy-makers. Of the many ideas and concepts to have emerged from this new-found focus, Michael Porter's work on ‘clusters’ has proved by far the most influential. His ‘cluster theory’ has become the standard concept in the field, and policy-makers the world over have seized upon Porter's cluster model as a tool for promoting national, regional, and local competitiveness, innovation and growth. But the mere popularity of a construct is by no means a guarantee of its profundity. Seductive though the cluster concept is, there is much about it that is problematic, and the rush to employ ‘cluster ideas’ has run ahead of many fundamental conceptual, theoretical and empirical questions. Our aim is to deconstruct the cluster concept in order to reveal and highlight these issues. Our concerns relate to the definition of the cluster concept, its theorization, its empirics, the claims made for its benefits and advantages, and its use in policy-making. Whilst we do not wish to debunk the cluster idea outright, we do argue for a much more cautious and circumspect use of the notion, especially within a policy context: the cluster concept should carry a public policy health warning.

Journal ArticleDOI
29 May 2003-Nature
TL;DR: In this article, the authors identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4) as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes.
Abstract: Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)—which encodes a vital negative regulatory molecule of the immune system—as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1?kb 3′ region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.

01 Jan 2003
TL;DR: In this article, a monolithic terahertz injection laser that is based on interminiband transitions in the conduction band of a semiconductor (GaAs/AlGaAs) heterostructure is presented.
Abstract: Semiconductor devices have become indispensable for generating electromagnetic radiation in everyday applications. Visible and infrared diode lasers are at the core of information technology, and at the other end of the spectrum, microwave and radio-frequency emitters enable wireless communications. But the terahertz region (1-10 THz; 1 THz = 10(12) Hz) between these ranges has remained largely underdeveloped, despite the identification of various possible applications--for example, chemical detection, astronomy and medical imaging. Progress in this area has been hampered by the lack of compact, low-consumption, solid-state terahertz sources. Here we report a monolithic terahertz injection laser that is based on interminiband transitions in the conduction band of a semiconductor (GaAs/AlGaAs) heterostructure. The prototype demonstrated emits a single mode at 4.4 THz, and already shows high output powers of more than 2 mW with low threshold current densities of about a few hundred A cm(-2) up to 50 K. These results are very promising for extending the present laser concept to continuous-wave and high-temperature operation, which would lead to implementation in practical photonic systems.

Journal ArticleDOI
17 Jul 2003-Nature
TL;DR: The findings suggest that the insulin/IGF-I pathway ultimately exerts its effect on lifespan by upregulating a wide variety of genes, including cellular stress-response, antimicrobial and metabolic genes, and by downregulating specific life-shortening genes.
Abstract: Ageing is a fundamental, unsolved mystery in biology. DAF-16, a FOXO-family transcription factor, influences the rate of ageing of Caenorhabditis elegans in response to insulin/insulin-like growth factor 1 (IGF-I) signalling. Using DNA microarray analysis, we have found that DAF-16 affects expression of a set of genes during early adulthood, the time at which this pathway is known to control ageing. Here we find that many of these genes influence the ageing process. The insulin/IGF-I pathway functions cell non-autonomously to regulate lifespan, and our findings suggest that it signals other cells, at least in part, by feedback regulation of an insulin/IGF-I homologue. Furthermore, our findings suggest that the insulin/IGF-I pathway ultimately exerts its effect on lifespan by upregulating a wide variety of genes, including cellular stress-response, antimicrobial and metabolic genes, and by downregulating specific life-shortening genes.

Journal ArticleDOI
27 Mar 2003-Nature
TL;DR: It is shown here that RHD2 is an NADPH oxidase, a protein that transfers electrons from NADPH to an electron acceptor leading to the formation of reactive oxygen species (ROS) and that ROS accumulate in growing wild-type (WT) root hairs but their levels are markedly decreased in rhd2 mutants.
Abstract: Cell expansion is a central process in plant morphogenesis, and the elongation of roots and root hairs is essential for uptake of minerals and water from the soil. Ca2+ influx from the extracellular store is required for (and sets the rates of) cell elongation in roots. Arabidopsis thaliana rhd2 mutants are defective in Ca2+ uptake and consequently cell expansion is compromised--rhd2 mutants have short root hairs and stunted roots. To determine the regulation of Ca2+ acquisition in growing root cells we show here that RHD2 is an NADPH oxidase, a protein that transfers electrons from NADPH to an electron acceptor leading to the formation of reactive oxygen species (ROS). We show that ROS accumulate in growing wild-type (WT) root hairs but their levels are markedly decreased in rhd2 mutants. Blocking the activity of the NADPH oxidase with diphenylene iodonium (DPI) inhibits ROS formation and phenocopies Rhd2-. Treatment of rhd2 roots with ROS partly suppresses the mutant phenotype and stimulates the activity of plasma membrane hyperpolarization-activated Ca2+ channels, the predominant root Ca2+ acquisition system. This indicates that NADPH oxidases control development by making ROS that regulate plant cell expansion through the activation of Ca2+ channels.

Journal ArticleDOI
TL;DR: In this paper, the authors present the results of a large library of cosmological N-body simulations, using power-law initial spectra, for the first order cosmologies.
Abstract: We present the results of a large library of cosmological N-body simulations, using power-law initial spectra.

Journal ArticleDOI
21 Mar 2003-Science
TL;DR: Using distinct stimuli to indicate the probability of reward, it was found that the phasic activation of dopamine neurons varied monotonically across the full range of probabilities, supporting past claims that this response codes the discrepancy between predicted and actual reward.
Abstract: Uncertainty is critical in the measure of information and in assessing the accuracy of predictions. It is determined by probability P, being maximal at P = 0.5 and decreasing at higher and lower probabilities. Using distinct stimuli to indicate the probability of reward, we found that the phasic activation of dopamine neurons varied monotonically across the full range of probabilities, supporting past claims that this response codes the discrepancy between predicted and actual reward. In contrast, a previously unobserved response covaried with uncertainty and consisted of a gradual increase in activity until the potential time of reward. The coding of uncertainty suggests a possible role for dopamine signals in attention-based learning and risk-taking behavior.

Journal ArticleDOI
08 Feb 2003-BMJ
TL;DR: Time to stop arguing about the process and examine the outcomes of the EU referendum.
Abstract: Problem based learning is used in many medical schools in the United Kingdom and worldwide. This article describes this method of learning and teaching in small groups and explains why it has had an important impact on medical education. ![][1] The group learning process: acquiring desirable learning skills In problem based learning (PBL) students use “triggers” from the problem case or scenario to define their own learning objectives. Subsequently they do independent, self directed study before returning to the group to discuss and refine their acquired knowledge. Thus, PBL is not about problem solving per se, but rather it uses appropriate problems to increase knowledge and understanding. The process is clearly defined, and the several variations that exist all follow a similar series of steps. #### Generic skills and attitudes Group learning facilitates not only the acquisition of knowledge but also several other desirable attributes, such as communication skills, teamwork, problem solving, independent responsibility for learning, sharing information, and respect for others. PBL can therefore be thought of as a small group teaching method that combines the acquisition of knowledge with the development of generic skills and attitudes. Presentation of clinical material as the stimulus for learning enables students to understand the relevance of underlying scientific knowledge and principles in clinical practice. However, when PBL is introduced into a curriculum, several other issues for curriculum design and implementation need to be tackled. PBL is generally introduced in the context of a defined core curriculum and integration of basic and clinical sciences. It has implications for staffing and learning resources and demands a different approach to timetabling, workload, and assessment. PBL is often used to deliver core material in non-clinical parts of the … [1]: /embed/graphic-1.gif

Journal ArticleDOI
TL;DR: In this paper, a set of high-redshift supernovae were used to confirm previous supernova evidence for an accelerating universe, and the supernova results were combined with independent flat-universe measurements of the mass density from CMB and galaxy redshift distortion data, they provided a measurement of $w=-1.05^{+0.15}-0.09$ if w is assumed to be constant in time.
Abstract: We report measurements of $\Omega_M$, $\Omega_\Lambda$, and w from eleven supernovae at z=0.36-0.86 with high-quality lightcurves measured using WFPC-2 on the HST. This is an independent set of high-redshift supernovae that confirms previous supernova evidence for an accelerating Universe. Combined with earlier Supernova Cosmology Project data, the new supernovae yield a flat-universe measurement of the mass density $\Omega_M=0.25^{+0.07}_{-0.06}$ (statistical) $\pm0.04$ (identified systematics), or equivalently, a cosmological constant of $\Omega_\Lambda=0.75^{+0.06}_{-0.07}$ (statistical) $\pm0.04$ (identified systematics). When the supernova results are combined with independent flat-universe measurements of $\Omega_M$ from CMB and galaxy redshift distortion data, they provide a measurement of $w=-1.05^{+0.15}_{-0.20}$ (statistical) $\pm0.09$ (identified systematic), if w is assumed to be constant in time. The new data offer greatly improved color measurements of the high-redshift supernovae, and hence improved host-galaxy extinction estimates. These extinction measurements show no anomalous negative E(B-V) at high redshift. The precision of the measurements is such that it is possible to perform a host-galaxy extinction correction directly for individual supernovae without any assumptions or priors on the parent E(B-V) distribution. Our cosmological fits using full extinction corrections confirm that dark energy is required with $P(\Omega_\Lambda>0)>0.99$, a result consistent with previous and current supernova analyses which rely upon the identification of a low-extinction subset or prior assumptions concerning the intrinsic extinction distribution.

Journal ArticleDOI
TL;DR: This work uses a new observer-independent method to relate the degree of damage within a specific prefrontal region to performance on a stop-signal task that is sensitive to the neurodevelopmental aspects of stopping behavior and to attention-deficit/hyperactivity disorder (ADHD) as well as its amelioration by methylphenidate.
Abstract: The precise localization of executive functions such as response inhibition within the prefrontal cortex (PFC), although theoretically crucial, has proven to be controversial and difficult1. Functional neuroimaging has contributed importantly to this debate1,2,3,4,5,6,7, but as human cortical lesions are seldom discrete, the literature still lacks definitive neuropsychological evidence that a specific region is necessary for task performance. We overcame this limitation by using a new observer-independent method to relate the degree of damage within a specific prefrontal region to performance on a stop-signal task that is sensitive to the neurodevelopmental aspects of stopping behavior2 and to attention-deficit/hyperactivity disorder (ADHD) as well as its amelioration by methylphenidate5,8.

Journal ArticleDOI
01 Sep 2003-Polymer
TL;DR: The experimental percolation threshold for the aligned carbon nanotubes used in this paper represents the lowest threshold observed for carbon-nanotube-based polymer composites yet reported.

Journal ArticleDOI
TL;DR: The 'new view' of these diseases suggests that other degenerative conditions could have similar underlying origins to those of the amyloidoses, and suggests some intriguing new factors that could be of great significance in the evolution of biological molecules and the mechanisms that regulate their behaviour.
Abstract: The deposition of proteins in the form of amyloid fibrils and plaques is the characteristic feature of more than 20 degenerative conditions affecting either the central nervous system or a variety of peripheral tissues. As these conditions include Alzheimer's, Parkinson's and the prion diseases, several forms of fatal systemic amyloidosis, and at least one condition associated with medical intervention (haemodialysis), they are of enormous importance in the context of present-day human health and welfare. Much remains to be learned about the mechanism by which the proteins associated with these diseases aggregate and form amyloid structures, and how the latter affect the functions of the organs with which they are associated. A great deal of information concerning these diseases has emerged, however, during the past 5 years, much of it causing a number of fundamental assumptions about the amyloid diseases to be re-examined. For example, it is now apparent that the ability to form amyloid structures is not an unusual feature of the small number of proteins associated with these diseases but is instead a general property of polypeptide chains. It has also been found recently that aggregates of proteins not associated with amyloid diseases can impair the ability of cells to function to a similar extent as aggregates of proteins linked with specific neurodegenerative conditions. Moreover, the mature amyloid fibrils or plaques appear to be substantially less toxic than the pre-fibrillar aggregates that are their precursors. The toxicity of these early aggregates appears to result from an intrinsic ability to impair fundamental cellular processes by interacting with cellular membranes, causing oxidative stress and increases in free Ca2+ that eventually lead to apoptotic or necrotic cell death. The 'new view' of these diseases also suggests that other degenerative conditions could have similar underlying origins to those of the amyloidoses. In addition, cellular protection mechanisms, such as molecular chaperones and the protein degradation machinery, appear to be crucial in the prevention of disease in normally functioning living organisms. It also suggests some intriguing new factors that could be of great significance in the evolution of biological molecules and the mechanisms that regulate their behaviour.

Journal ArticleDOI
TL;DR: In this article, the authors present the results of a systematic study of the rest-frame UV spectroscopic properties of Lyman break galaxies (LBGs) and isolate some of the major trends in LBG spectra that are least compromised by selection effects.
Abstract: We present the results of a systematic study of the rest-frame UV spectroscopic properties of Lyman break galaxies (LBGs). The database of almost 1000 LBG spectra proves useful for constructing high signal-to-noise composite spectra. The composite spectrum of the entire sample reveals a wealth of features attributable to hot stars, H II regions, dust, and outflowing neutral and ionized gas. By grouping the database according to galaxy parameters such as Lyα equivalent width, UV spectral slope, and interstellar kinematics, we isolate some of the major trends in LBG spectra that are least compromised by selection effects. We find that LBGs with stronger Lyα emission have bluer UV continua, weaker low-ionization interstellar absorption lines, smaller kinematic offsets between Lyα and the interstellar absorption lines, and lower star formation rates. There is a decoupling between the dependence of low- and high-ionization outflow features on other spectral properties. Additionally, galaxies with rest-frame WLyα ≥ 20 A in emission have weaker than average high-ionization lines and nebular emission lines that are significantly stronger than in the sample as a whole. Most of the above trends can be explained in terms of the properties of the large-scale outflows seen in LBGs. According to this scenario, the appearance of LBG spectra is determined by a combination of the covering fraction of outflowing neutral gas, which contains dust and the range of velocities over which this gas is absorbing. In contrast, the strengths of collisionally excited nebular emission lines should not be affected by the nature of the outflow, and variations in these lines may indicate differences in the temperatures and metallicities in H II regions of galaxies with very strong Lyα emission. Higher sensitivity and spectral resolution observations are still required for a full understanding of the covering fraction and velocity dispersion of the outflowing neutral gas in LBGs and its relationship to the escape fraction of Lyman continuum radiation in galaxies at z ~ 3.

Journal ArticleDOI
TL;DR: The mix zone is introduced-a new construction inspired by anonymous communication techniques-together with metrics for assessing user anonymity, based on frequently changing pseudonyms.
Abstract: As location-aware applications begin to track our movements in the name of convenience, how can we protect our privacy? This article introduces the mix zone-a new construction inspired by anonymous communication techniques-together with metrics for assessing user anonymity. It is based on frequently changing pseudonyms.

Journal ArticleDOI
TL;DR: In this paper, the nucleotide sequence of the MC4R gene in 500 children with severe childhood obesity was determined, and the results were correlated with the signaling properties of mutant receptors.
Abstract: Background Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form of obesity. However, the clinical spectrum and mode of inheritance have not been defined, pathophysiological mechanisms leading to obesity are poorly understood, and there is little information regarding genotype–phenotype correlations. Methods We determined the nucleotide sequence of the MC4R gene in 500 probands with severe childhood obesity. Family studies were undertaken to examine cosegregation of identified mutations with obesity. Subjects with MC4R deficiency underwent metabolic and endocrine evaluation; the results were correlated with the signaling properties of mutant receptors. Results Twenty-nine probands (5.8 percent) had mutations in MC4R; 23 were heterozygous, and 6 were homozygous. Mutation carriers had severe obesity, increased lean mass, increased linear growth, hyperphagia, and severe hyperinsulinemia; homozygotes were more severely affected than heterozygotes. Subjects with mutations retaining residual...

Journal ArticleDOI
TL;DR: It was found that not only is α-synuclein degraded by the proteasome, but it is also degraded by autophagy, which merits consideration as a potential therapeutic for Parkinsons disease, as it is designed for chronic use in humans.

Journal ArticleDOI
01 Aug 2003-Methods
TL;DR: A library of bacterial strains corresponding to roughly 86% of the estimated 19,000 predicted genes in C. elegans is constructed, and this library is used to perform genome-wide analyses of gene function.