The assessment of executive function abilities in healthy and neurodegenerative aging-A selective literature review.

Numerous studies have examined executive function (EF) abilities in cognitively healthy older adults and those living with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Currently, there are no standard accepted protocols for testing specific EFs; thus, researchers have used their preferred tool, which leads to variability in assessments of decline in a particular ability across studies. Therefore, there is a need for guidance as to the most sensitive tests for assessing EF decline. A search of the most current literature published between 2000 and 2022 on EF studies assessing cognitively healthy older adults and individuals living with MCI and AD was conducted using PubMed/Medline, PsycINFO, Embase, Web of Science, and Google Scholar. Emphasis was placed on the EF's dual-tasking, inhibition, shifting or switching, and working memory updating. Many tasks and their outcomes were reviewed. Of particular importance was the difference in outcomes for tasks applied to the same group of participants. These various EF assessment tools demonstrate differences in effectively identifying decline in EF ability due to the aging process and neurodegenerative conditions, such as MCI and AD. This review identifies various factors to consider in using particular EF tasks in particular populations, including task demand and stimuli factors, and also when comparing differing results across studies.

A systematic review with meta-analysis of the StartReact effect on motor responses in stroke survivors and healthy individuals.

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.

The working memory costs of a central attentional bottleneck in multitasking.

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.

Annotating and prioritizing genomic variants using the Ensembl Variant Effect Predictor-A tutorial.

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 consequences 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 and Combined Annotation Dependent Depletion. Ensembl VEP includes filtering options to customize variant prioritization. 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 application programming interface, 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, visualization, 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.

Ensembl 2022.

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 COVID-19 resource: ongoing integration of public SARS-CoV-2 data.

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; the first virus to be encompassed within the Ensembl platform. This resource incorporates a new Ensembl gene set, multiple variant sets, and annotation from several relevant resources aligned to the reference SARS-CoV-2 assembly. Since the first release in May 2020, the content has been regularly updated using our new rapid release workflow, 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.

TACE/ADAM17 substrates associate with ACS (Ep-CAM, HB-EGF) and follow-up MACE (TNFR1 and TNFR2).

Background and aims: TACE/ADAM17 is a membrane bound metalloprotease, which cleaves substrates involved in immune and inflammatory responses and plays a role in coronary artery disease (CAD). We measured TACE and its substrates in CAD patients to identify potential biomarkers within this molecular pathway with potential for acute coronary syndrome (ACS) and major adverse cardiovascular events (MACE) prediction. Methods: Blood samples were obtained from consecutive patients (n = 229) with coronary angiographic evidence of CAD admitted with ACS or electively. MACE were recorded after a median 3-year follow-up. Controls (n = 115) had a <10% CAD risk as per the HeartSCORE. TACE and TIMP3 protein and mRNA levels were measured by ELISA and RT-qPCR respectively. TACE substrates were measured using a multiplex proximity extension assay. Results: TACE mRNA and cell protein levels (p < 0.01) and TACE substrates LDLR (p = 0.006), TRANCE (p = 0.045), LAG-3 (p < 0.001) and ACE2 (p < 0.001) plasma levels were significantly higher in CAD patients versus controls. TACE inhibitor TIMP3 mRNA levels were significantly lower in CAD patients and tended to be lower in the ACS population (p < 0.05). TACE substrates TNFR1 (OR:3.237,CI:1.514-6.923,p = 0.002), HB-EGF (OR:0.484,CI:0.288-0.813,p = 0.006) and Ep-CAM (OR:0.555,CI:0.327-0.829,p = 0.004) accurately classified ACS patients with HB-EGF and Ep-CAM levels being lower compared to electively admitted patients. TNFR1 (OR:2.317,CI:1.377-3.898,p = 0.002) and TNFR2 (OR:1.902,CI:1.072-3.373,p = 0.028) were significantly higher on admission in those patients who developed MACE within 3 years. Conclusions: We demonstrate a possible role of TACE substrates LAG-3, HB-EGF and Ep-CAM in atherosclerotic plaque development and stability. We also underline the importance of measuring TNFR1 and TNFR2 earlier than previously appreciated for MACE prediction. We report an important role of TIMP3 in regulating TACE levels.

The COVID-19 Data Portal: accelerating SARS-CoV-2 and COVID-19 research through rapid open access data sharing.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic will be remembered as one of the defining events of the 21st century. The rapid global outbreak has had significant impacts on human society and is already responsible for millions of deaths. Understanding and tackling the impact of the virus has required a worldwide mobilisation and coordination of scientific research. The COVID-19 Data Portal (https://www.covid19dataportal.org/) was first released as part of the European COVID-19 Data Platform, on April 20th 2020 to facilitate rapid and open data sharing and analysis, to accelerate global SARS-CoV-2 and COVID-19 research. The COVID-19 Data Portal has fortnightly feature releases to continue to add new data types, search options, visualisations and improvements based on user feedback and research. The open datasets and intuitive suite of search, identification and download services, represent a truly FAIR (Findable, Accessible, Interoperable and Reusable) resource that enables researchers to easily identify and quickly obtain the key datasets needed for their COVID-19 research.

Ensembl 2021.

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.

Ensembl 2020.

The Ensembl (https://www.ensembl.org) is a system for generating and distributing genome annotation such as genes, variation, regulation and comparative genomics across the vertebrate subphylum and key model organisms. The Ensembl annotation pipeline is capable of integrating experimental and reference data from multiple providers into a single integrated resource. Here, we present 94 newly annotated and re-annotated genomes, bringing the total number of genomes offered by Ensembl to 227. This represents the single largest expansion of the resource since its inception. We also detail our continued efforts to improve human annotation, developments in our epigenome analysis and display, a new tool for imputing causal genes from genome-wide association studies and visualisation of variation within a 3D protein model. Finally, we present information on our new website. Both software and data are made available without restriction via our website, online tools platform and programmatic interfaces (available under an Apache 2.0 license) and data updates made available four times a year.

Ensembl 2019.

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.

New models of atherosclerosis and multi-drug therapeutic interventions.

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.

Ensembl variation resources.

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.

Systems medicine disease maps: community-driven comprehensive representation of disease mechanisms.

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.

Randomised, double-blind, placebo-controlled crossover study of single-dose guanfacine in unilateral neglect following stroke.

OBJECTIVE: Unilateral neglect is a poststroke disorder that impacts negatively on functional outcome and lacks established, effective treatment. This multicomponent syndrome is characterised by a directional bias of attention away from contralesional space, together with impairments in several cognitive domains, including sustained attention and spatial working memory. This study aimed to test the effects of guanfacine, a noradrenergic alpha-2A agonist, on ameliorating aspects of neglect. METHODS: Thirteen right hemisphere stroke patients with leftward neglect were included in a randomised, double-blind, placebo-controlled proof-of-concept crossover study that examined the effects of a single dose of guanfacine. Patients were tested on a computerised, time-limited cancellation paradigm, as well as tasks that independently assessed sustained attention and spatial working memory. RESULTS: On guanfacine, there was a statistically significant improvement in the total number of targets found on the cancellation task when compared with placebo (mean improvement of 5, out of a possible 64). However, there was no evidence of a change in neglect patients' directional attention bias. Furthermore, Bayesian statistical analysis revealed reliable evidence against any effects of guanfacine on search organisation and performance on our sustained attention and spatial working memory tasks. CONCLUSIONS: Guanfacine improves search in neglect by boosting the number of targets found but had no effects on directional bias or search organisation, nor did it improve sustained attention or working memory on independent tasks. Further work is necessary to determine whether longer term treatment with guanfacine may be effective for some neglect patients and whether it affects functional outcome measures. TRIAL REGISTRATION NUMBER: NCT00955253.

Is systems pharmacology ready to impact upon therapy development? A study on the cholesterol biosynthesis pathway.

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.

Neuroticism related differences in the functional neuroanatomical correlates of multitasking. An fMRI study.

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.

Implant-based three-dimensional superimposition of the growing mandible in a rabbit model.

BACKGROUND: The reliable assessment of craniofacial morphological changes during growth requires invariant regions for image registration. As these regions have not yet been identified in three dimensions, intra-osseous implants are required as fiducial markers for the reliable assessment of three-dimensional (3D) mandibular growth changes. The objective of this study was to develop an animal model for the assessment of the 3D morphological changes of the mandible during growth, using implants as fiducial markers. MATERIALS AND METHODS: Titanium implants were placed in the body of the mandible of six New Zealand White rabbits. Cone beam computed tomography (CBCT) scans were taken 1-week following implant placement and after an additional 8-weeks of growth. Segmentations of CBCT images were exported into custom-made scripts, implant centroids were identified, implant stability during growth calculated, and the segmented mandibles were registered on the implant centroids. RESULTS: The buccal cortical bone of the body of the mandible was stable during growth and suitable for fiducial marker placement. Bilateral implants resulted in more accurate rigid registration of the growing rabbit mandible than only unilateral implants. 3D mandibular growth changes were visualised by means of semi-transparencies. CONCLUSIONS: This animal model appears to be feasible for the assessment of the 3D morphological changes occurring during mandibular growth. To the best of our knowledge this is the first time that the implant superimposition method has been combined with 3D imaging to accurately reveal mandibular growth changes.

Computational modelling of atherosclerosis.

Atherosclerosis is one of the principle pathologies of cardiovascular disease with blood cholesterol a significant risk factor. The World Health Organization estimates that approximately 2.5 million deaths occur annually because of 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 article 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.

Prospective relationship between hemispheric lateralisation and CD4+ T cells in human immunodeficiency virus type 1.

OBJECTIVES: Neuromodulation of the immune system has been proposed to be influenced by hemispheric lateralisation (HL). The present study tested whether HL predicted CD4+ levels, statistically controlling for confounders. METHODS: Employing two assessments of HL, 68 human immunodeficiency virus (HIV)-1+ patients were followed prospectively. Numerous exclusion criteria and confounder assessments were employed (e.g. age/medication). RESULTS: Left HL significantly positively predicted CD4+ levels at follow-up, and this was qualified by medication (HAART) status: only in HAART-naïve patients did HL predict CD4 levels. Furthermore, HL significantly predicted whether patients had clinically significantly high/low CD4+ counts. CONCLUSIONS: Using a more rigorous methodology than a previous study, the present work partly corroborated the theory of HL influences on immunity, extended it to HIV immunity and identified a possible moderator: HAART medication. Implications for future research and treatments are provided.