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Ensembl (https://www.ensembl.org) is unique in its flexible infrastructure for access to genomic data and annotation. It has been designed to efficiently deliver annotation at scale for all eukaryotic life, and it also provides deep comprehensive annotation for key species. Genomes representing a greater diversity of species are increasingly being sequenced. In response, we have focussed our recent efforts on expediting the annotation of new assemblies. Here, we report the release of the greatest annual number of newly annotated genomes in the history of Ensembl via our dedicated Ensembl Rapid Release platform (http://rapid.ensembl.org). We have also developed a new method to generate comparative analyses at scale for these assemblies and, for the first time, we have annotated non-vertebrate eukaryotes. Meanwhile, we continually improve, extend and update the annotation for our high-value reference vertebrate genomes and report the details here. We have a range of specific software tools for specific tasks, such as the Ensembl Variant Effect Predictor (VEP) and the newly developed interface for the Variant Recoder. All Ensembl data, software and tools are freely available for download and are accessible programmatically.

The Ensembl project (https://www.ensembl.org) annotates genomes and disseminates genomic data for vertebrate species. We create detailed and comprehensive annotation of gene structures, regulatory elements and variants, and enable comparative genomics by inferring the evolutionary history of genes and genomes. Our integrated genomic data are made available in a variety of ways, including genome browsers, search interfaces, specialist tools such as the Ensembl Variant Effect Predictor, download files and programmatic interfaces. Here, we present recent Ensembl developments including two new website portals. Ensembl Rapid Release (http://rapid.ensembl.org) is designed to provide core tools and services for genomes as soon as possible and has been deployed to support large biodiversity sequencing projects. Our SARS-CoV-2 genome browser (https://covid-19.ensembl.org) integrates our own annotation with publicly available genomic data from numerous sources to facilitate the use of genomics in the international scientific response to the COVID-19 pandemic. We also report on other updates to our annotation resources, tools and services. All Ensembl data and software are freely available without restriction.

Control of limb movements may be impaired after stroke due to the loss of connectivity between the cerebral cortex and spinal cord. A notion to improve motor function in stroke survivors is to use alternate motor fibers, such as the reticulospinal tract (RST), which originate from the brainstem and terminate at different levels of spinal cord. One way of targeting the RST is to use a “StartReact” protocol to foster premature release of a preplanned movement in response to a startling stimulus. Our aim was to find support for the preservation of such StartReact effect in stroke survivors. We conducted a systematic review with meta-analysis of literature published in English up to September 2020, to explore differences in motor responses to startling stimuli in StartReact effects. Protocol of the study was registered (PROSPERO Registration No. CRD42020191581). PubMed, Google Scholar, Web of Science, PsycINFO, and Science Direct were searched for relevant literature. The meta-analysis contained six studies involving a total of 151 stroke and healthy participants. Muscle onset latency data were extracted from the qualifying studies and compared using RevMan. StartReact effect was present in both stroke and healthy groups, represented by shortened muscle onset latency when startling stimulus was present. There was considerable heterogeneity of the outcome measures, which was attributed to the range of motor impairments among stroke survivors and methodologies used. Our findings support the notion of preservation of preprogramming ability and suitability of RST and StartReact effect for motor rehabilitation following stroke.

Ensembl (https://www.ensembl.org) is unique in its flexible infrastructure for access to genomic data and annotation. It has been designed to efficiently deliver annotation at scale for all eukaryotic life, and it also provides deep comprehensive annotation for key species. Genomes representing a greater diversity of species are increasingly being sequenced. In response, we have focussed our recent efforts on expediting the annotation of new assemblies. Here, we report the release of the greatest annual number of newly annotated genomes in the history of Ensembl via our dedicated Ensembl Rapid Release platform (http://rapid.ensembl.org). We have also developed a new method to generate comparative analyses at scale for these assemblies and, for the first time, we have annotated non-vertebrate eukaryotes. Meanwhile, we continually improve, extend and update the annotation for our high-value reference vertebrate genomes and report the details here. We have a range of specific software tools for specific tasks, such as the Ensembl Variant Effect Predictor (VEP) and the newly developed interface for the Variant Recoder. All Ensembl data, software and tools are freely available for download and are accessible programmatically.

Availability of data and material (data transparency): Data can be downloaded from Brunel figshare repository. The following link is a private link that can be used for the reviewers/editors if they wish to view the data. This link does not contain my name or institute and is suitable for (double blind) peer review: https://www.figshare.com/s/e20831dfabf7236e3620. This link is suitable for 2 years, but will not be included in the final data availability statement. This link will be updated with the DOI for anyone to see once the article is published. Code availability: Not applicable. The experiment was programmed in E-Prime 2, the code can be made available upon request. Copyright © The Autrhor(s) 2022. When two (or more) tasks, each requiring a rapid response, are performed at the same time then serial processing may occur at certain processing stages, such as the response selection. There is accumulating evidence that such serial processing involves additional control processes, such as inhibition, switching, and scheduling (termed the active scheduling account). The present study tested whether the existence of serial processing in multitasking leads to a requirement for processes that coordinate processing in this way (active scheduling account) and, furthermore, whether such control processes are linked to the executive functions (EF) of working memory (WM). To test this question, we merged the psychological refractory period (PRP) paradigm with a WM task, creating a complex WM span task. Participants were presented with a sequence of letters to remember, followed by a processing block in which they had to perform either a single task or a dual task, and finally were asked to recall the letters. Results showed that WM performance, i.e. the amount of letters recalled in the correct order, decreased when performing a dual task as compared to performing a single task during the retention interval. Two further experiments supported this finding using manipulations of the dual task difficulty. We conclude that the existence of serial processing in multitasking demands additional control processes (active scheduling) and that these processes are strongly linked to the executive functions of working memory. British Academy (SG132549); Bial Foundation (142/16).

The Ensembl Variant Effect Predictor (VEP) is a freely available, open source tool for the annotation and filtering of genomic variants. It predicts variant molecular consequence using the Ensembl/GENCODE or RefSeq gene sets. It also reports phenotype associations from databases such as ClinVar, allele frequencies from studies including gnomAD, and predictions of deleteriousness from tools such as Sorting Intolerant From Tolerant (SIFT) and Combined Annotation Dependent Depletion (CADD). Ensembl VEP includes filtering options to customise variant prioritisation. It is well supported and updated roughly quarterly to incorporate the latest gene, variant and phenotype association information. Ensembl VEP analysis can be performed using a highly configurable, extensible command-line tool, a Representational State Transfer (REST) application programming interface (API) and a user-friendly web interface. These access methods are designed to suit different levels of bioinformatics experience and meet different needs in terms of data size, visualisation and flexibility. In this tutorial, we will describe performing variant annotation using the Ensembl VEP web tool, which enables sophisticated analysis through a simple interface. This article is protected by copyright. All rights reserved.

The aim of this study was to compare two methodologies employed by the British Cycling talent identification program. Specifically, the authors investigated cyclists selected to represent GB cycling team at the London 2012 Olympics using (a) a traditional talent identification methodology (British Cycling Olympic Development Program), where selection is based upon race results and (b) a detection talent identification methodology (U.K. Sport Talent Team Program), which is a multi-Olympic event initiative that identifies athletic potential from physical and skill-based tests. To facilitate this comparison, the authors calculated the speed with which expertise was acquired. A Mann–Whitney U test (U = 16.0, p = .031) indicated that the speed of acquiring expertise was quicker in detection talent identification (Mdn = 5.4) than traditional talent identification (Mdn = 7.2). Practice started later with detection talent identification than with traditional talent identification (14.12 years vs. 11.23 years, respectively), which affected the period to excellence. Thus, detection talent identification resulted in an absence of early specialization, which suggests a critical period for attaining cycling expertise. The authors hypothesize a genetic basis of talent and propose that critical periods are important in detection talent identification programs.

The COVID-19 pandemic has seen unprecedented use of SARS-CoV-2 genome sequencing for epidemiological tracking and identification of emerging variants. Understanding the potential impact of these variants on the infectivity of the virus and the efficacy of emerging therapeutics and vaccines has become a cornerstone of the fight against the disease. To support the maximal use of genomic information for SARS-CoV-2 research, we launched the Ensembl COVID-19 browser, incorporating a new Ensembl gene set, multiple variant sets (including novel variation calls), and annotation from several relevant resources integrated into the reference SARS-CoV-2 assembly. This work included key adaptations of existing Ensembl genome annotation methods to model ribosomal slippage, stringent filters to elucidate the highest confidence variants and utilisation of our comparative genomics pipelines on viruses for the first time. Since May 2020, the content has been regularly updated and tools such as the Ensembl Variant Effect Predictor have been integrated. The Ensembl COVID-19 browser is freely available at https://covid-19.ensembl.org.

The Ensembl project (https://www.ensembl.org) annotates genomes and disseminates genomic data for vertebrate species. We create detailed and comprehensive annotation of gene structures, regulatory elements and variants, and enable comparative genomics by inferring the evolutionary history of genes and genomes. Our integrated genomic data are made available in a variety of ways, including genome browsers, search interfaces, specialist tools such as the Ensembl Variant Effect Predictor, download files and programmatic interfaces. Here, we present recent Ensembl developments including two new website portals. Ensembl Rapid Release (http://rapid.ensembl.org) is designed to provide core tools and services for genomes as soon as possible and has been deployed to support large biodiversity sequencing projects. Our SARS-CoV-2 genome browser (https://covid-19.ensembl.org) integrates our own annotation with publicly available genomic data from numerous sources to facilitate the use of genomics in the international scientific response to the COVID-19 pandemic. We also report on other updates to our annotation resources, tools and services. All Ensembl data and software are freely available without restriction.

Motivation Atherosclerosis is the leading causes of death globally, but is challenging to study in vivo or in vitro due to the logistical and ethical challenges involved. A computational model has the potential to transform our ability to study the disease by being quick, simple and consistent to work with at no financial or ethical cost. However, no detailed, openly-available computational models exist. Clinical studies hint that pharmaceutical therapy may be possible. Here, we develop the first detailed, computational model of atherosclerosis to be built to systems biology standards and use it to develop multi-drug therapeutic hypotheses. Results We assembled high quality network maps and models describing atheroma development from the literature. Maps and mathematical models were produced using the Systems Biology Graphical Notation (SBGN) and Systems Biology Markup Language (SBML), respectively, and the model was constrained against laboratory and clinical data. We identified five drugs that potentially reverse advanced atheroma formation when acting in combination. Availability and Implementation The map is available from our publications in the Systems Biology Graphnical Notation Markup Language (SBGN-ML) file format. The model is available in the from the BioModels repository and from our publications, in SBML file format.

Motivation Atherosclerosis is amongst the leading causes of death globally. However, it is challenging to study in vivo or in vitro and no detailed, openly-available computational models exist. Clinical studies hint that pharmaceutical therapy may be possible. Here, we develop the first detailed, computational model of atherosclerosis and use it to develop multi-drug therapeutic hypotheses. Results We assembled a network describing atheroma development from the literature. Maps and mathematical models were produced using the Systems Biology Graphical Notation and Systems Biology Markup Language, respectively. The model was constrained against clinical and laboratory data. We identified five drugs that together potentially reverse advanced atheroma formation. Availability and implementation The map is available in the Supplementary Material in SBGN-ML format. The model is available in the Supplementary Material and from BioModels, a repository of SBML models, containing CellDesigner markup. Supplementary information Supplementary data are available at Bioinformatics online.

The Ensembl project (https://www.ensembl.org) makes key genomic data sets available to the entire scientific community without restrictions. Ensembl seeks to be a fundamental resource driving scientific progress by creating, maintaining and updating reference genome annotation and comparative genomics resources. This year we describe our new and expanded gene, variant and comparative annotation capabilities, which led to a 50% increase in the number of vertebrate genomes we support. We have also doubled the number of available human variants and added regulatory regions for many mouse cell types and developmental stages. Our data sets and tools are available via the Ensembl website as well as a through a RESTful webservice, Perl application programming interface and as data files for download.

The major goal of sequencing humans and many other species is to understand the link between genomic variation, phenotype and disease. There are numerous valuable and well-established variation resources, but collating and making sense of non-homogeneous, often large-scale data sets from disparate sources remains a challenge. Without a systematic catalogue of these data and appropriate query and annotation tools, understanding the genome sequence of an individual and assessing their disease risk is impossible. In Ensembl, we substantially solve this problem: we develop methods to facilitate data integration and broad access; aggregate information in a consistent manner and make it available a variety of standard formats, both visually and programmatically; build analysis pipelines to compare variants to comprehensive genomic annotation sets; and make all tools and data publicly available.

The development of computational approaches in systems biology has reached a state of maturity that allows their transition to systems medicine. Despite this progress, intuitive visualisation and context-dependent knowledge representation still present a major bottleneck. In this paper, we describe the Disease Maps Project, an effort towards a community-driven computationally readable comprehensive representation of disease mechanisms. We outline the key principles and the framework required for the success of this initiative, including use of best practices, standards and protocols. We apply a modular approach to ensure efficient sharing and reuse of resources for projects dedicated to specific diseases. Community-wide use of disease maps will accelerate the conduct of biomedical research and lead to new disease ontologies defined from mechanism-based disease endotypes rather than phenotypes. This work was supported by the CNRS, University of Luxembourg, Institut Curie and in part through the U-BIOPRED (IMI no. 115010 grant to C.A.) and eTRIKS (IMI no. 115446 grant to C.A., R.B. and R.S.) Consortia funded by the European Union and the European Federation of Pharmaceutical Industry Associations, the Coordinating action for the implementation of systems medicine in Europe (CASyM FP7 grant no. 305333 to C.A. and R.B.), the COLOSYS grant ANR-15-CMED-0001-04, provided by the Agence Nationale de la Recherche under the frame of ERACoSysMed-1, the ERA-Net for Systems Medicine in clinical research and medical practice (to I.K., E.B. and A.Z.). A. P. and S.W. acknowledge a research exchange grant from CASyM.

RationaleAtherosclerosis is a dynamical process that emerges from the interplay between lipid metabolism, inflammation and innate immunity. The arterial location of atherosclerosis makes it logistically and ethically difficult to study in vivo. To improve our understanding of the disease, we must find alternative ways to investigate its progression. There is currently no computational model of atherosclerosis openly available to the research community for use in future studies and for refinement and development.ObjectiveHere we develop the first predictive computational model to be made openly available and demonstrate its use for therapeutic hypothesis generation.Methods and ResultsWe compiled a dataset of relevant interactions from the literature along with available parameters. These were used to build a network model describing atherosclerotic plaque development. A visual map of the network model was produced using the Systems Biology Graphical Notation (SBGN) and a dynamic mathematical description of the network model that enables us to simulate plaque growth was developed and is made available using the Systems Biology Markup Language (SBML). We used this model to investigate whether multi-drug therapeutic interventions could be identified that stimulate plaque regression. The model produced comprised 20 cell types and 41 proteins with 89 species in total. The visual map is available for reuse and refinement using the SBGN Markup Language standard format and the mathematical model is available using the SBML standard format. We used a genetic algorithm to identify a multi-drug intervention hypothesis comprising five drugs that comprehensively reverse plaque growth within the model.ConclusionsWe have produced the first predictive mathematical and computational model of atherosclerosis that can be reused and refined by the cardiovascular research community. We demonstrated its potential as a tool for future studies of cardiovascular disease by using it to identify multi-drug intervention hypotheses.Subject CodesAtherosclerosis, Computational Biology, Lipids and Cholesterol, Cell Signaling/Signal Transduction, Cardiovascular Disease

Background and Purpose An ever‐growing wealth of information on current drugs and their pharmacological effects is available from online databases. As our understanding of systems biology increases, we have the opportunity to predict, model and quantify how drug combinations can be introduced that outperform conventional single‐drug therapies. Here, we explore the feasibility of such systems pharmacology approaches with an analysis of the mevalonate branch of the cholesterol biosynthesis pathway. Experimental Approach Using open online resources, we assembled a computational model of the mevalonate pathway and compiled a set of inhibitors directed against targets in this pathway. We used computational optimization to identify combination and dose options that show not only maximal efficacy of inhibition on the cholesterol producing branch but also minimal impact on the geranylation branch, known to mediate the side effects of pharmaceutical treatment. Key Results We describe serious impediments to systems pharmacology studies arising from limitations in the data, incomplete coverage and inconsistent reporting. By curating a more complete dataset, we demonstrate the utility of computational optimization for identifying multi‐drug treatments with high efficacy and minimal off‐target effects. Conclusion and Implications We suggest solutions that facilitate systems pharmacology studies, based on the introduction of standards for data capture that increase the power of experimental data. We propose a systems pharmacology workflow for the refinement of data and the generation of future therapeutic hypotheses.

The analysis of saccades offers an opportunity to study a number of different cognitive processes, such as visuospatial attention, working memory, and volitional conflict. A study of saccades in patients with visuospatial hemineglect, who performed a visual search task, showed repeated fixations on targets previously discovered, yet they often failed to retain the information that a particular target had previously been discovered. High-resolution structural brain scanning showed that this abnormality was due either to a lesion in the right intraparietal sulcus or the right inferior frontal lobe. Detailed analysis of the scanpaths suggested that the former location was associated with an accumulating impairment in remapping target locations across saccades or impaired memory of previously inspected target locations, whereas the latter location was more consistent with a failure to inhibit responses to rightward locations. When combined with a spatial bias to the right, such deficits might explain why many neglect patients often reexamine rightward targets, at the expense of items to their left. The functions of the supplementary eye field (SEF), in the medial frontal lobe, in relation to saccade generation are controversial. A series of studies in a patient with a focal lesion of the right SEF has indicated an important role for the SEF in the rapid self-control of saccadic eye movements and in set-switching (i.e., implementing control in situations of response conflict when ongoing saccadic plans have to be changed rapidly), rather than monitoring errors. In a recent fMRI study of normal subjects, it was shown that the SEF is involved in implementing the resolution of any volitional conflict, whereas other presupplementary motor areas are involved in the generation of volitional plans and processing volitional conflict.

Patients with unilateral neglect show a variety of impairments when reaching towards objects in contralesional space. The basis of these deficits could be perceptual, motor or at one of the intermediate stages linking these processes. Here, we review studies of visually guided reaching in neglect and integrate these results with findings from normal human and monkey action control. We consider evidence which shows that neglect patients can be slow to initiate or execute reaches particularly to a contralesional target. We discuss the directional and spatial deficits that may interact to contribute to such reaching abnormalities and highlight the importance of effective target selection and on-line guidance, exploring the idea that deficits in these mechanisms underlie increased susceptibility to ipsilesional visual distraction in neglect. We also examine the relationship between optic ataxia and neglect by considering two illustrative cases, one with pure optic ataxia and the other with optic ataxia plus neglect, which reveal differences in the anatomical substrates of the two syndromes. We conclude that many patients with neglect make abnormal visually guided reaches, but the pattern of reaching deficits is highly variable, most likely reflecting heterogeneity of lesion location across subjects. Rather than being specific to the neglect syndrome, abnormalities of reaching in these patients may correspond to the extent of damage to the visuomotor control system which involves critical regions in both the parietal and frontal cortex, the white matter tracts connecting them and subcortical regions. Thus, the action control deficits in neglect may be conceptualised as a range of impairments affecting multiple stages in the visuomotor control process.

This article is available open access through the publisher’s website at the link below. Copyright © 2008 by the Association for Research in Vision and Ophthalmology. Visual binding is the process by which the brain groups the elements belonging to one object, whilst segregating them from other scene elements. A computationally parsimonious mechanism of visual binding is the binding-by-synchrony (BBS) hypothesis. According to this hypothesis, detectors that respond to elements of a single object fire in synchrony, while detectors that respond to elements of different objects do not. Current psychophysical and physiological evidence are inconclusive about the role of BBS in the visual integration process. Here we provide psychophysical and computational evidence suggesting that the visual system implements a mechanism that synchronizes response onsets to object parts and attenuates or cancels their latency differences. In three experiments, observers had to judge the synchrony of two flickering Gabor patches embedded in a static Gabor contour, passing through fixation. We found that a smooth contour, as compared to a jagged one, impedes judgments of temporal synchrony between the targets, whilst facilitating non-temporal judgments of contrast on the same targets. We show that the results are consistent with a simple computational model that implements synchronization of responses via lateral interactions, enabling the visual system to pick up objects by synchrony among a temporally diverse background. The German Research Council and the German Academic Exchange Service.

It has been proposed recently that a deficit in keeping track of spatial locations may contribute to the severity of unilateral neglect in some right hemisphere stroke patients. However, performance on traditional spatial working memory (SWM) tasks (e.g. Corsi blocks) might be confounded by failure to encode leftward locations, rather than a true deficit of maintaining locations in SWM. Here we introduced new procedures for circumventing this to measure SWM capacity in neglect. In a first experiment, 20 right hemisphere stroke patients (10 with and 10 without neglect) were tested on a computerized vertical variant of the Corsi task. Sequences of spatial locations in a vertical column were displayed and participants had to tap out the remembered sequence on a touchscreen. Patients with left neglect were impaired on this vertical SWM task compared with all control groups. However, poor performance on this task (as for Corsi blocks) might involve impaired memory for stimulus sequence, or poor visuomotor control of manual responding, rather than reduced SWM capacity per se. A second experiment therefore employed a purer measure of vertical SWM. After the displayed sequence, a single location was now probed visually, with observers judging verbally (yes/no) if it had been in the preceding sequence. Hence order no longer mattered, and no spatial motor response was required. Again, the neglect group was impaired relative to all others, now with very little overlap between the performances of individual neglect patients versus individuals in control groups. Poor performance on the second task, which provides a purer measure of SWM capacity, correlated with severity of left neglect on cancellation tasks (but not on line bisection), consistent with recent proposals that SWM deficits can exacerbate left neglect on visual search tasks when present conjointly. Lesion anatomy indicated that neglect patients with a SWM deficit were most likely to have damage to parietal white matter, plus, in the second experiment, to the insula also. These findings demonstrate that an impairment in SWM capacity can contribute to the neglect syndrome in patients with stroke involving regions within the right parietal lobe and insula.

It is known that neuroticism impairs cognitive performance mostly in difficult tasks, but not so much in easier tasks. One pervasive situation of this type is multitasking, in which the combination of two simple tasks creates a highly demanding dual-task, and consequently high neurotics show higher dual-task costs than low neurotics. However, the functional neuroanatomical correlates of these additional performance impairments in high neurotics are unknown. To test for this, we assessed brain activity by means of functional magnetic resonance imaging (fMRI) in 17 low and 15 high neurotics while they were performing a demanding dual-task and the less demanding component tasks as single-tasks. Behavioural results showed that performance (response times and error rates) was lower in the dual-task than in the single-tasks (dual-task costs), and that these dual-task costs were significantly higher in high neurotics. Imaging data showed that high neurotics showed less dual-task specific activation in lateral (mainly middle frontal gyrus) and medial prefrontal cortices. We conclude that high levels of neuroticism impair behavioural performance in demanding tasks, and that this impairment is accompanied by reduced activation of the task-associated brain areas.

Atherosclerosis is one of the principle pathologies of cardiovascular disease with blood cholesterol a significant risk factor. The World Health Organisation estimates that approximately 2.5 million deaths occur annually due to the risk from elevated cholesterol with 39% of adults worldwide at future risk. Atherosclerosis emerges from the combination of many dynamical factors, including haemodynamics, endothelial damage, innate immunity and sterol biochemistry. Despite its significance to public health, the dynamics that drive atherosclerosis remain poorly understood. As a disease that depends on multiple factors operating on different length scales, the natural framework to apply to atherosclerosis is mathematical and computational modelling. A computational model provides an integrated description of the disease and serves as an in silico experimental system from which we can learn about the disease and develop therapeutic hypotheses. Although the work completed in this area to-date has been limited, there are clear signs that interest is growing and that a nascent field is establishing itself. This paper discusses the current state of modelling in this area, bringing together many recent results for the first time. We review the work that has been done, discuss its scope and highlight the gaps in our understanding that could yield future opportunities., in Briefings in Bioinformatics (2015)

Binocular disparity and motion parallax provide information about the spatial structure and layout of the world. Descriptive similarities between the two cues have often been noted which have been taken as evidence of a close relationship between them. Here, we report two experiments which investigate the effect of surface orientation and modulation frequency on (i) a threshold detection task and (ii) a supra-threshold depth-matching task using sinusoidally corrugated surfaces defined by binocular disparity or motion parallax. For low frequency corrugations, an orientation anisotropy was observed in both domains, with sensitivity decreasing as surface orientation was varied from horizontal to vertical. In the depth-matching task, for surfaces defined by binocular disparity the greatest depth was seen for oblique orientations. For surfaces defined by motion parallax, perceived depth was found to increase as surface orientation was varied from horizontal to vertical. In neither case was perceived depth for supra-threshold surfaces related to threshold performance in any simple manner. These results reveal clear differences between the perception of depth from binocular disparity or motion parallax, and between perception at threshold and supra-threshold levels of performance.

Exploration of the space around us is a fundamental part of human behaviour. When it breaks down there is an important opportunity to understand its underlying mechanisms. Here we show that many right-hemisphere patients with left neglect re-explore rightward locations, failing to keep track of them during search. Importantly, such re-exploration occurred despite leftward stimuli being indistinguishable in peripheral vision, so it is unlikely to result from implicit processing of neglected targets. Revisits generally occurred after visits to other targets and are therefore not immediate perseverations. Finally, manipulating the visual salience of found targets altered the degree of neglect, but not revisit rates. Space exploration appears to be modulated both by the ability to keep track of spatial locations and by stimulus salience.

In two experiments we examined the perceived grouping of grids of equidistant dots, which are rapidly modulated over time so that alternate rows or columns are presented out of phase. In Experiment 1, we report that observers were able to group the grids consistent with the temporal modulation reliably, even at contrasts/frequencies for which flicker was not detectable. Moreover, flicker thresholds decreased with stimulus duration, whilst grouping thresholds did not change. In Experiment 2, we examined the impact of visual transients, by measuring performance when, either a mask or a contrast ramp was presented before and after the stimulus. Performance dropped substantially for both conditions, but remained significantly above chance. The results are discussed in relation to the role of temporal correlations in stimulus modulations and visual transients in grouping.

Three experiments were conducted to investigate the influence of fast temporally segmented presentations of alternate rows or columns on the perception of grids of either symmetrically or asymmetrically spaced dot-like stimuli. Experiments 1a and 1b demonstrated that observers were able to discriminate between temporally segmented presentations of rows/columns stimuli, but showed a reduced performance in discrimination between non-temporally segmented stimuli and temporally segmented stimuli that were spatially unstructured. Experiment 2 confirmed the influence of temporally segmented presentations of rows and columns using elements whose mean luminance summed to the same as the display background. Experiment 3 demonstrated that the influence of temporal cues reduced when display elements were asymmetrically spaced. The results are discussed in terms of the influence of external spatio-temporal factors on the neural mechanisms of visual grouping.

Binocular disparity and motion parallax are powerful cues to the relative depth between objects. However to recover absolute depth, either additional scaling parameters are required to calibrate the information provided by each cue, or it can be recovered through the combination of information from both cues (Richards, W. (1985). Structure from stereo and motion. Journal of the Optical Society of America, 2, 343–349). However, not all tasks necessarily require a full specification of the absolute depth structure of a scene and so psychophysical performance may vary depending on the amount of information available, and the degree to which absolute depth structure is required. The experiments reported here used three different tasks that varied in the type of geometric information required in order for them to be completed successfully. These included a depth nulling task, a depth-matching task, and an absolute depth judgement (shape) task. Real world stimuli were viewed (i) monocularly with head movements, (ii) binocularly and static, or (iii) binocularly with head movements. No effect of viewing condition was found whereas there was a large effect of task. Performance was accurate on the matching and nulling tasks and much less accurate on the shape task. The fact that the same perceptual distortions were not evident in all tasks suggests that the visual system can switch strategy according to the demands of the particular task. No evidence was found to suggest that the visual system could exploit the simultaneous presence of disparity and motion parallax.

In three investigations children aged 4-9 years were given a sequence of trials on each of which they experienced pairs of objects which looked the same but felt different (such as full and empty cereal packets) or felt the same and looked different (such as chocolate bars with different coloured wrappers). On each trial the experimenter chose one of the items from a pair and children predicted whether they themselves, or another person or doll, would know which one it was just by seeing it. In two of the three investigations, even the youngest children showed clear evidence of discriminating in their knowledge judgments between the two types of pairs, but nevertheless children frequently overestimated the knowledge to be gained from seeing. Errors of overestimation when the visual input was ambiguous as to feel were correlated with those made when the visual input was ambiguous as to size, suggesting the children's problem was not specific to understanding about the modality-specific aspect of knowledge. Furthermore, making it easier for children to isolate the visual input from an object from the non-visual was ineffective in reducing errors of overestimation. These results provide no evidence that children had difficulty imagining or isolating the visual aspect of the chosen object, but suggest that they may fail to realize when the input is ambiguous.

Communication from the brain to the immune system is influenced by hemispheric lateralisation (HL). Left-HL is immunopotentiating, right-HL is immunosuppressive. Only one study has examined the effects of HL on the progression of HIV (Gruzelier et al., 1996). That study included a small sample with very little control over third variables. The present study tested whether left HL predicted higher CD4 and CD8 levels, statistically controlling for confounders.

The gene networks that comprise the circadian clock modulate biological function across a range of scales, from gene expression to performance and adaptive behaviour. The clock functions by generating endogenous rhythms that can be entrained to the external 24-h day?night cycle, enabling organisms to optimally time biochemical processes relative to dawn and dusk. In recent years, computational models based on differential equations have become useful tools for dissecting and quantifying the complex regulatory relationships underlying the clock's oscillatory dynamics. However, optimizing the large parameter sets characteristic of these models places intense demands on both computational and experimental resources, limiting the scope of in silico studies. Here, we develop an approach based on Boolean logic that dramatically reduces the parametrization, making the state and parameter spaces finite and tractable. We introduce efficient methods for fitting Boolean models to molecular data, successfully demonstrating their application to synthetic time courses generated by a number of established clock models, as well as experimental expression levels measured using luciferase imaging. Our results indicate that despite their relative simplicity, logic models can (i) simulate circadian oscillations with the correct, experimentally observed phase relationships among genes and (ii) flexibly entrain to light stimuli, reproducing the complex responses to variations in daylength generated by more detailed differential equation formulations. Our work also demonstrates that logic models have sufficient predictive power to identify optimal regulatory structures from experimental data. By presenting the first Boolean models of circadian circuits together with general techniques for their optimization, we hope to establish a new framework for the systematic modelling of complex clocks., Comment: 26 pages plus nine figures (in separate files)

This is the post-print version of the final paper published in Journal of Neuroimmunology. The published article is available from the link below. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. Copyright @ 2011 Elsevier B.V. Past studies examined relationships between hemispheric lateralisation (HL) and immune system functioning. However, there has been no up-dated systematic review of this research area. This article reviews relevant published studies, evaluates study quality and effect sizes. Eleven studies were selected: three revealing a relationship between weaker left hemisphere function and poorer immune function, three describing a relationship between weaker right hemisphere function and stronger immune functioning, and five describing both relationships. Mean effect-size of the studies was r = 0.536 (range 0.280–0.866). Collectively, studies point at left-HL and stronger immunity relationships. Limitations, mechanisms and clinical implications are discussed.

We recently reported evidence indicating that selective attention is deployed to a target location in a multi-object display, when the target event (a change of one of the objects) is preceded by subliminal flicker in the gamma range. However, concerns have been raised regarding the stimuli used in this study and the possible contribution of an artifactual cue: a “transition flash” between pretarget flicker offset and target onset. Here, we report a series of experiments investigating the existence and potential contribution to selective attention of this transition-flash cue under different presentation conditions. We find that, although the transition flash is a real phenomenon (detection rates ≃ 15% > chance), it cannot, on its own, explain the original effects of gamma flicker on the response time to target detection. Even after eliminating this flash, detection was significantly faster, or more accurate, for targets preceded (vs. not preceded) by flicker. This congruency effect (≈15 ms) demonstrates that gamma flicker on its own is sufficient to engage selective attention. This interpretation is further strengthened by a reevaluation of 1) experiment 7 reported by van Diepen and colleagues and 2) the validity effect experiment reported by Bauer and colleagues. Possible reasons for the discrepant results are also discussed.

OBJECTIVE We aimed to investigate the pattern of 24-hour ACTH and cortisol secretion in pitultary-dependent Cushing's syndrome and to evaluate the pituitary and hypothalamic contributions to the disease. PATIENTS Five women with Cushing's disease (mean age 35±5 (SEM) years) and five normal female controls (mean age 25±2 years) were studied. DESIGN AND MEASUREMENTS Plasma ACTH and cortisol levels were measured every 15 minutes for 24 hours using established IRMA and RIA respectively. ACTH and cortisol mean and trough levels, pulse number and amplitude were calculated using established computer software, programmed to identify ACTH and cortisol peaks. RESULTS Patients with Cushing's disease had a twofold increase in 24-hour mean cortisol levels and a threefold increase in 24-hour mean ACTH levels (Cushing's 5.9±1.0, controls 1.9±0.2 pmol/l, P

This is the author's accepted manuscript (under the title '50 Hz flicker triggers attentional selection without awareness'). The final published article is available from the link below, copyright @ The National Academy of Sciences. Gamma band modulations in neural activity have been proposed to mediate attentional processes. To support a causal link between gamma activity and attentional selection, we attempt to evoke gamma oscillations by a 50-Hz subliminal flicker. We find that a subliminal 50-Hz flicker at a target location, before target presentation, speeds up and enhances target detection and discrimination. This effect is specific to the middle of the gamma range because it is not evident at

In our recent review of action control deficits in hemispatial neglect we concluded that many patients with the disorder have deficits in visuomotor control [Coulthard, E., Parton, A., and Husain, M. (2006). Action control in visual neglect. Neuropsychologia, 44(13), 2717-2733]. This conclusion has been questioned and it has been argued instead that there are no action deficits in neglect [Himmelbach, M., Karnath, H.-O., and Perenin, M.-T. (2007). Action control is not affected by spatial neglect: A comment on Coulthard et al. Neuropsychologia, 45(8), 1979-1981]. We proposed that rather than being specific to the neglect syndrome, action control deficits are more likely to relate to lesion location. Although many of these impairments may contribute to the manifestation of neglect, they may also occur in brain-damaged patients without the condition. In this article, we explore this framework further, discussing how neglect behaviour may emerge from damage to a set of visuomotor or cognitive modules, or their connections. Central to our view is the idea that the critical combination of deficits leading to neglect varies considerably between cases, and that visuomotor or cognitive modules disrupted in the syndrome may not, in fact, be specific to neglect. © 2007 Elsevier Ltd. All rights reserved.

This article has been made available through the Brunel Open Access Publishing Fund and is available from the specified link - Copyright © 2006 BMJ Publishing Group. Objectives: To investigate the characteristics and neuroanatomical correlates of visual neglect after right-sided posterior cerebral artery (PCA) infarction.Methods: 15 patients with acute PCA strokes were screened for the presence of neglect on a comprehensive battery of cognitive tests. Extra tests of visual perception were also carried out on six patients. To establish which areas were critically associated with neglect, the lesions of patients with and without neglect were compared.Results: Neglect of varying severity was documented in 8 patients. In addition, higher-order visual perception was impaired in 5 of the 6 patients. Neglect was critically associated with damage to an area of white matter in the occipital lobe corresponding to a white matter tract connecting the parahippocampal gyrus with the angular gyrus of the parietal lobe. Lesions of the thalamus or splenium of the corpus callosum did not appear necessary or sufficient to cause neglect, but may mediate its severity in these patients.Conclusions: PCA stroke can result in visual neglect. Interruption of the white matter fibres connecting the parahippocampal gyrus to the angular gyrus may be important in determining whether a patient will manifest neglect.