Showing papers by "University College London published in 2007"

PAML 4: Phylogenetic Analysis by Maximum Likelihood

Abstract: PAML, currently in version 4, is a package of programs for phylogenetic analyses of DNA and protein sequences using maximum likelihood (ML). The programs may be used to compare and test phylogenetic trees, but their main strengths lie in the rich repertoire of evolutionary models implemented, which can be used to estimate parameters in models of sequence evolution and to test interesting biological hypotheses. Uses of the programs include estimation of synonymous and nonsynonymous rates (d(N) and d(S)) between two protein-coding DNA sequences, inference of positive Darwinian selection through phylogenetic comparison of protein-coding genes, reconstruction of ancestral genes and proteins for molecular restoration studies of extinct life forms, combined analysis of heterogeneous data sets from multiple gene loci, and estimation of species divergence times incorporating uncertainties in fossil calibrations. This note discusses some of the major applications of the package, which includes example data sets to demonstrate their use. The package is written in ANSI C, and runs under Windows, Mac OSX, and UNIX systems. It is available at -- (http://abacus.gene.ucl.ac.uk/software/paml.html).

The resurgence of platinum-based cancer chemotherapy

Abstract: The accidental discovery of the anticancer properties of cisplatin and its clinical introduction in the 1970s represent a major landmark in the history of successful anticancer drugs. Although carboplatin--a second-generation analogue that is safer but shows a similar spectrum of activity to cisplatin--was introduced in the 1980s, the pace of further improvements slowed for many years. However, in the past several years interest in platinum drugs has increased. Key developments include the elucidation of mechanisms of tumour resistance to these drugs, the introduction of new platinum-based agents (oxaliplatin, satraplatin and picoplatin), and clinical combination studies using platinum drugs with resistance modulators or new molecularly targeted drugs.

Strong Association of De Novo Copy Number Mutations with Autism

Abstract: We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.

The Chlamydomonas Genome Reveals the Evolution of Key Animal and Plant Functions

Abstract: Chlamydomonas reinhardtii is a unicellular green alga whose lineage diverged from land plants over 1 billion years ago. It is a model system for studying chloroplast-based photosynthesis, as well as the structure, assembly, and function of eukaryotic flagella (cilia), which were inherited from the common ancestor of plants and animals, but lost in land plants. We sequenced the approximately 120-megabase nuclear genome of Chlamydomonas and performed comparative phylogenomic analyses, identifying genes encoding uncharacterized proteins that are likely associated with the function and biogenesis of chloroplasts or eukaryotic flagella. Analyses of the Chlamydomonas genome advance our understanding of the ancestral eukaryotic cell, reveal previously unknown genes associated with photosynthetic and flagellar functions, and establish links between ciliopathy and the composition and function of flagella.

The Hawthorne Effect: a randomised, controlled trial

Abstract: The 'Hawthorne Effect' may be an important factor affecting the generalisability of clinical research to routine practice, but has been little studied. Hawthorne Effects have been reported in previous clinical trials in dementia but to our knowledge, no attempt has been made to quantify them. Our aim was to compare minimal follow-up to intensive follow-up in participants in a placebo controlled trial of Ginkgo biloba for treating mild-moderate dementia. Participants in a dementia trial were randomised to intensive follow-up (with comprehensive assessment visits at baseline and two, four and six months post randomisation) or minimal follow-up (with an abbreviated assessment at baseline and a full assessment at six months). Our primary outcomes were cognitive functioning (ADAS-Cog) and participant and carer-rated quality of life (QOL-AD). We recruited 176 participants, mainly through general practices. The main analysis was based on Intention to treat (ITT), with available data. In the ANCOVA model with baseline score as a co-variate, follow-up group had a significant effect on outcome at six months on the ADAS-Cog score (n = 140; mean difference = -2.018; 95%CI -3.914, -0.121; p = 0.037 favouring the intensive follow-up group), and on participant-rated quality of life score (n = 142; mean difference = -1.382; 95%CI -2.642, -0.122; p = 0.032 favouring minimal follow-up group). There was no significant difference on carer quality of life. We found that more intensive follow-up of individuals in a placebo-controlled clinical trial of Ginkgo biloba for treating mild-moderate dementia resulted in a better outcome than minimal follow-up, as measured by their cognitive functioning. Current controlled trials: ISRCTN45577048

Gradient methods for minimizing composite objective function

Abstract: In this paper we analyze several new methods for solving optimization problems with the objective function formed as a sum of two convex terms: one is smooth and given by a black-box oracle, and another is general but simple and its structure is known. Despite to the bad properties of the sum, such problems, both in convex and nonconvex cases, can be solved with eciency typical for the good part of the objective. For convex problems of the above structure, we consider primal and dual variants of the gradient method (converge as O ‡ 1 k · ), and an accelerated multistep version with convergence rate O ‡ 1 k2 · , where k is the iteration counter. For all methods, we suggest some ecient “line search” procedures and show that the additional computational work necessary for estimating the unknown problem class parameters can only multiply the complexity of each iteration by a small constant factor. We present also the results of preliminary computational experiments, which confirm the superiority of the accelerated scheme.

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

Abstract: We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Designing and evaluating complex interventions to improve health care

Abstract: Determining the effectiveness of complex interventions can be difficult and time consuming. Neil C Campbell and colleagues explain the importance of ground work in getting usable results

A Whole-Genome Association Study of Major Determinants for Host Control of HIV-1

Abstract: Understanding why some people establish and maintain effective control of HIV-1 and others do not is a priority in the effort to develop new treatments for HIV/AIDS. Using a whole-genome association strategy, we identified polymorphisms that explain nearly 15% of the variation among individuals in viral load during the asymptomatic set-point period of infection. One of these is found within an endogenous retroviral element and is associated with major histocompatibility allele human leukocyte antigen (HLA)-B*5701, whereas a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated two genes, one of which encodes an RNA polymerase I subunit. These findings emphasize the importance of studying human genetic variation as a guide to combating infectious agents.

Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility.

Abstract: A genome-wide association scan in individuals with Crohn's disease by the Wellcome Trust Case Control Consortium detected strong association at four novel loci. We tested 37 SNPs from these and other loci for association in an independent case-control sample. We obtained replication for the autophagy-inducing IRGM gene on chromosome 5q33.1 (replication P = 6.6 x 10(-4), combined P = 2.1 x 10(-10)) and for nine other loci, including NKX2-3, PTPN2 and gene deserts on chromosomes 1q and 5p13.

Educational outreach visits: effects on professional practice and health care outcomes

Abstract: Background Educational outreach visits (EOVs) have been identified as an intervention that may improve the practice of healthcare professionals. This type of face-to-face visit has been referred to as university-based educational detailing, academic detailing, and educational visiting. Objectives To assess the effects of EOVs on health professional practice or patient outcomes. Search methods For this update, we searched the Cochrane EPOC register to March 2007. In the original review, we searched multiple bibliographic databases including MEDLINE and CINAHL. Selection criteria Randomised trials of EOVs that reported an objective measure of professional performance or healthcare outcomes. An EOV was defined as a personal visit by a trained person to healthcare professionals in their own settings. Data collection and analysis Two reviewers independently extracted data and assessed study quality. We used bubble plots and box plots to visually inspect the data. We conducted both quantitative and qualitative analyses. We used meta-regression to examine potential sources of heterogeneity determined a priori. We hypothesised eight factors to explain variation across effect estimates. In our primary visual and statistical analyses, we included only studies with dichotomous outcomes, with baseline data and with low or moderate risk of bias, in which the intervention included an EOV and was compared to no intervention. Main results We included 69 studies involving more than 15,000 health professionals. Twenty-eight studies (34 comparisons) contributed to the calculation of the median and interquartile range for the main comparison. The median adjusted risk difference (RD) in compliance with desired practice was 5.6% (interquartile range 3.0% to 9.0%). The adjusted RDs were highly consistent for prescribing (median 4.8%, interquartile range 3.0% to 6.5% for 17 comparisons), but varied for other types of professional performance (median 6.0%, interquartile range 3.6% to 16.0% for 17 comparisons). Meta-regression was limited by the large number of potential explanatory factors (eight) with only 31 comparisons, and did not provide any compelling explanations for the observed variation in adjusted RDs. There were 18 comparisons with continuous outcomes, with a median adjusted relative improvement of 21% (interquartile range 11% to 41%). There were eight trials (12 comparisons) in which the intervention included an EOV and was compared to another type of intervention, usually audit and feedback. Interventions that included EOVs appeared to be slightly superior to audit and feedback. Only six studies evaluated different types of visits in head-to-head comparisons. When individual visits were compared to group visits (three trials), the results were mixed. Authors' conclusions EOVs alone or when combined with other interventions have effects on prescribing that are relatively consistent and small, but potentially important. Their effects on other types of professional performance vary from small to modest improvements, and it is not possible from this review to explain that variation.

The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis.

Abstract: Stress influences circulating inflammatory markers, and these effects may mediate the influence of psychosocial factors on cardiovascular risk and other conditions such as psoriasis and rheumatoid arthritis. Inflammatory responses can be investigated under controlled experimental conditions in humans, and evidence is beginning to emerge showing that circulating inflammatory factors respond to acute psychological stress under laboratory conditions. However, research published to date has varied greatly in the composition of study groups, the timing of samples, assay methods, and the type of challenge imposed. The purpose of this review is to synthesize existing data using meta-analytic techniques. Thirty studies met inclusion criteria. Results showed robust effects for increased levels of circulating IL-6 (r=0.19, p=0.001) and IL-1beta (r=0.58, p<0.001) following acute stress, and marginal effects for CRP (r=0.12, p=0.088). The effects of stress on stimulated cytokine production were less consistent. Significant variation in the inflammatory response was also related to the health status of participants and the timing of post-stress samples. A number of psychobiological mechanisms may underlie responses, including stress-induced reductions in plasma volume, upregulation of synthesis, or enlargement of the cell pool contributing to synthesis. The acute stress-induced inflammatory response may have implications for future health, and has become an important topic of psychoneuroimmunological research.

Probabilistic Linear Discriminant Analysis for Inferences About Identity

Abstract: Many current face recognition algorithms perform badly when the lighting or pose of the probe and gallery images differ. In this paper we present a novel algorithm designed for these conditions. We describe face data as resulting from a generative model which incorporates both within-individual and between-individual variation. In recognition we calculate the likelihood that the differences between face images are entirely due to within-individual variability. We extend this to the non-linear case where an arbitrary face manifold can be described and noise is position-dependent. We also develop a "tied" version of the algorithm that allows explicit comparison across quite different viewing conditions. We demonstrate that our model produces state of the art results for (i) frontal face recognition (ii) face recognition under varying pose.

STAT3 Mutations in the Hyper-IgE Syndrome

Abstract: Background The hyper-IgE syndrome (or Job's syndrome) is a rare disorder of immunity and connective tissue characterized by dermatitis, boils, cyst-forming pneumonias, elevated serum IgE levels, retained primary dentition, and bone abnormalities. Inheritance is autosomal dominant; sporadic cases are also found. Methods We collected longitudinal clinical data on patients with the hyper-IgE syndrome and their families and assayed the levels of cytokines secreted by stimulated leukocytes and the gene expression in resting and stimulated cells. These data implicated the signal transducer and activator of transcription 3 gene (STAT3) as a candidate gene, which we then sequenced. Results We found increased levels of proinflammatory gene transcripts in unstimulated peripheral-blood neutrophils and mononuclear cells from patients with the hyper-IgE syndrome, as compared with levels in control cells. In vitro cultures of mononuclear cells from patients that were stimulated with lipopolysaccharide, with or without ...

Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric testing plan.

Abstract: This article presents the revision process, major innovations, and clinimetric testing program for the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (UPDRS), known as the MDS-UPDRS. The UPDRS is the most widely used scale for the clinical study of Parkinson's disease (PD). The MDS previously organized a critique of the UPDRS, which cited many strengths, but recommended revision of the scale to accommodate new advances and to resolve problematic areas. An MDS-UPDRS committee prepared the revision using the recommendations of the published critique of the scale. Subcommittees developed new material that was reviewed by the entire committee. A 1-day face-to-face committee meeting was organized to resolve areas of debate and to arrive at a working draft ready for clinimetric testing. The MDS-UPDRS retains the UPDRS structure of four parts with a total summed score, but the parts have been modified to provide a section that integrates nonmotor elements of PD: I, Nonmotor Experiences of Daily Living; II, Motor Experiences of Daily Living; III, Motor Examination; and IV, Motor Complications. All items have five response options with uniform anchors of 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Several questions in Part I and all of Part II are written as a patient/caregiver questionnaire, so that the total rater time should remain approximately 30 minutes. Detailed instructions for testing and data acquisition accompany the MDS-UPDRS in order to increase uniform usage. Multiple language editions are planned. A three-part clinimetric program will provide testing of reliability, validity, and responsiveness to interventions. Although the MDS-UPDRS will not be published until it has successfully passed clinimetric testing, explanation of the process, key changes, and clinimetric programs allow clinicians and researchers to understand and participate in the revision process.

Epigenetic stem cell signature in cancer.

Abstract: Embryonic stem cells rely on Polycomb group proteins to reversibly repress genes required for differentiation. We report that stem cell Polycomb group targets are up to 12-fold more likely to have cancer-specific promoter DNA hypermethylation than non-targets, supporting a stem cell origin of cancer in which reversible gene repression is replaced by permanent silencing, locking the cell into a perpetual state of self-renewal and thereby predisposing to subsequent malignant transformation.

The EUV Imaging Spectrometer for Hinode

Abstract: The EUV Imaging Spectrometer (EIS) on Hinode will observe solar corona and upper transition region emission lines in the wavelength ranges 170 – 210 A and 250 – 290 A. The line centroid positions and profile widths will allow plasma velocities and turbulent or non-thermal line broadenings to be measured. We will derive local plasma temperatures and densities from the line intensities. The spectra will allow accurate determination of differential emission measure and element abundances within a variety of corona and transition region structures. These powerful spectroscopic diagnostics will allow identification and characterization of magnetic reconnection and wave propagation processes in the upper solar atmosphere. We will also directly study the detailed evolution and heating of coronal loops. The EIS instrument incorporates a unique two element, normal incidence design. The optics are coated with optimized multilayer coatings. We have selected highly efficient, backside-illuminated, thinned CCDs. These design features result in an instrument that has significantly greater effective area than previous orbiting EUV spectrographs with typical active region 2 – 5 s exposure times in the brightest lines. EIS can scan a field of 6×8.5 arc min with spatial and velocity scales of 1 arc sec and 25 km s−1 per pixel. The instrument design, its absolute calibration, and performance are described in detail in this paper. EIS will be used along with the Solar Optical Telescope (SOT) and the X-ray Telescope (XRT) for a wide range of studies of the solar atmosphere.

The perception of and adaptation to climate change in Africa

Abstract: The objective of this paper is to determine the ability of farmers in Africa to detect climate change, and to ascertain how they have adapted to whatever climate change they believe has occurred. The paper also asks farmers whether they perceive any barriers to adaptation and attempts to determine the characteristics of those farmers who, despite claiming to have witnessed climate change, have not yet responded to it. The study is based on a large-scale survey of agriculturalists in 11 African countries. The survey reveals that significant numbers of farmers believe that temperatures have already increased and that precipitation has declined. Those with the greatest experience of farming are more likely to notice climate change. Further, neighboring farmers tell a consistent story. There are important differences in the propensity of farmers living in different locations to adapt and there may be institutional impediments to adaptation in some countries. Although large numbers of farmers perceive no barriers to adaptation, those that do perceive them tend to cite their poverty and inability to borrow. Few if any farmers mentioned lack of appropriate seed, security of tenure, or market accessibility as problems. Those farmers who perceive climate change but fail to respond may require particular incentives or assistance to do what is ultimately in their own best interests. Although experienced farmers are more likely to perceive climate change, it is educated farmers who are more likely to respond by making at least one adaptation.

Systemic sclerosis: a prototypic multisystem fibrotic disorder.

Abstract: A unique feature of systemic sclerosis (SSc) that distinguishes it from other fibrotic disorders is that autoimmunity and vasculopathy characteristically precede fibrosis. Moreover, fibrosis in SSc is not restricted to a single organ, but rather affects many organs and accounts for much of the morbidity and mortality associated with this disease. Although immunomodulatory drugs have been used extensively in the treatment of SSc, no therapy to date has been able to reverse or slow the progression of tissue fibrosis or substantially modify the natural progression of the disease. In this Review, we highlight recent studies that shed light on the cellular and molecular mechanisms underlying the fibrotic process in SSc and that identify cellular processes and intra- and extracellular proteins as potential novel targets for therapy in this prototypic multisystemic fibrotic disease.

Tonic dopamine: opportunity costs and the control of response vigor.

Abstract: Rationale Dopamine neurotransmission has long been known to exert a powerful influence over the vigor, strength, or rate of responding. However, there exists no clear understanding of the computational foundation for this effect; predominant accounts of dopamine’s computational function focus on a role for phasic dopamine in controlling the discrete selection between different actions and have nothing to say about response vigor or indeed the freeoperant tasks in which it is typically measured. Objectives We seek to accommodate free-operant behavioral tasks within the realm of models of optimal control and thereby capture how dopaminergic and motivational manipulations affect response vigor. Methods We construct an average reward reinforcement learning model in which subjects choose both which action to perform and also the latency with which to perform it. Optimal control balances the costs of acting quickly against the benefits of getting reward earlier and thereby chooses a best response latency. Results In this framework, the long-run average rate of reward plays a key role as an opportunity cost and mediates motivational influences on rates and vigor of responding. We review evidence suggesting that the average reward rate is reported by tonic levels of dopamine putatively in the nucleus accumbens. Conclusions Our extension of reinforcement learning models to free-operant tasks unites psychologically and computationally inspired ideas about the role of tonic dopamine in striatum, explaining from a normative point of view why higher levels of dopamine might be associated with more vigorous responding.

Photometric calibration of the Swift ultraviolet/optical telescope

Abstract: We present the photometric calibration of the Swift Ultraviolet/Optical Telescope (UVOT) which includes: optimum photometric and background apertures, effective area curves, colour transformations, conversion factors for count rates to flux and the photometric zero-points (which are accurate to better than 4 per cent) for each of the seven UVOT broad-band filters. The calibration was performed with observations of standard stars and standard star fields that represent a wide range of spectral star types. The calibration results include the position-dependent uniformity, and instrument response over the 1600‐8000 A operational range. Because the UVOT is a photon-counting instrument, we also discuss the effect of coincidence loss on the calibration results. We provide practical guidelines for using the calibration in UVOT data analysis. The results presented here supersede previous calibration results.

Remembering the past and imagining the future: a neural model of spatial memory and imagery

Abstract: The authors model the neural mechanisms underlying spatial cognition, integrating neuronal systems and behavioral data, and address the relationships between long-term memory, short-term memory, and imagery, and between egocentric and allocentric and visual and ideothetic representations. Long-term spatial memory is modeled as attractor dynamics within medial-temporal allocentric representations, and short-term memory is modeled as egocentric parietal representations driven by perception, retrieval, and imagery and modulated by directed attention. Both encoding and retrieval/imagery require translation between egocentric and allocentric representations, which are mediated by posterior parietal and retrosplenial areas and the use of head direction representations in Papez's circuit. Thus, the hippocampus effectively indexes information by real or imagined location, whereas Papez's circuit translates to imagery or from perception according to the direction of view. Modulation of this translation by motor efference allows spatial updating of representations, whereas prefrontal simulated motor efference allows mental exploration. The alternating temporal-parietal flows of information are organized by the theta rhythm. Simulations demonstrate the retrieval and updating of familiar spatial scenes, hemispatial neglect in memory, and the effects on hippocampal place cell firing of lesioned head direction representations and of conflicting visual and ideothetic inputs.

Psychological treatments for chronic post-traumatic stress disorder : Systematic review and meta-analysis

Abstract: Background The relative efficacy of different psychological treatments for chronic post-traumatic stress disorder (PTSD) is unclear. Aims To determine the efficacy of specific psychological treatments for chronic PTSD. Method In a systematic review of randomised controlled trials, eligible studies were assessed against methodological quality criteria and data were extracted and analysed. Results Thirty-eight randomised controlled trials were included in the meta-analysis. Trauma-focused cognitive–behavioural therapy (TFCBT), eye movement desensitisation and reprocessing (EMDR), stress management and group cognitive–behavioural therapy improved PTSD symptoms more than waiting-list or usual care. There was inconclusive evidence regarding other therapies. There was no evidence of a difference in efficacy between TFCBT and EMDR but there was some evidence that TFCBT and EMDR were superior to stress management and other therapies, and that stress management was superior to other therapies. Conclusions The first-line psychological treatment for PTSD should be trauma-focused (TFCBT or EMDR).