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Researchers in Oxford have carried out the world’s first gene therapy operation to tackle the root cause of age-related macular degeneration (AMD), the UK’s most common cause of sight loss.
Information needs of stroke survivors and their family members regarding post-stroke cognition: a scoping review protocol.
OBJECTIVE: The aim of this review is to map current evidence describing the information needs of stroke survivors and family members regarding cognition. INTRODUCTION: Managing cognitive changes is the most frequently reported unmet need among stroke survivors; hence, there is an urgent need to improve support for post-stroke cognitive impairment. While there is evidence that psychoeducation may help stroke survivors and their family members develop awareness about cognitive impairment and self-management strategies, it is unclear what information stroke survivors and their family members want to receive and how their needs change over time. INCLUSION CRITERIA: This review will consider peer-reviewed articles describing information needs relating to the following cognitive domains: memory, language, attention, executive function, praxis, and number processing. Stroke survivors and/or their family members must comprise at least 50% of the study population and must be aged at least 18 years. Quantitative, qualitative, and mixed methods studies will be included. METHODS: The review will be conducted in line with the JBI methodology for scoping reviews. A full literature search will be conducted in MEDLINE (PubMed), PsycINFO (Ovid), Embase, CINAHL (EBSCOhost), and Scopus using a search strategy developed in consultation with an expert university librarian. Articles will be screened by title, abstract, and full text; then, data will be extracted by 2 independent reviewers. The reference lists of included articles will be hand-searched for additional material. Data analysis and reporting will involve qualitative (textual narrative synthesis) and quantitative (descriptive statistics) methods.
Rescue of cone and rod photoreceptor function in a CDHR1-model of age-related retinal degeneration.
Age-related macular degeneration is the most common cause of untreatable blindness in the developed world. Recently, CDHR1 has been identified as the cause of a subset of age-related macular degeneration that has the appearance the 'dry' form, or geographic atrophy. Biallelic variants in CDHR1 - a specialised protocadherin highly expressed in cone and rod photoreceptors - result in blindness from shortened photoreceptor outer segments and progressive photoreceptor cell death. Here we demonstrate long-term morphological, ultrastructural, functional and behavioural rescue following CDHR1 gene therapy in a relevant murine model, sustained to 23-months post-injection. This represents the first demonstration of rescue of a monogenic cadherinopathy in vivo. Moreover, the durability of CDHR1 gene therapy appears to be near complete - with morphological findings of the rescued retina not obviously different to wildtype throughout the lifespan of the mouse model. A follow-on clinical trial in patients with CDHR1-associated retinal degeneration is warranted. Hypomorphic CDHR1 variants may mimic advanced dry age-related macular degeneration. Accurate clinical classification is now critical as their pathogenesis and treatment are distinct.
Domain-specific cognitive impairments, mood and quality of life 6 months after stroke.
PURPOSE: To identify which acute and 6-month domain-specific cognitive impairments impact mood, participation, and stroke-related quality of life 6 months post-stroke. MATERIALS AND METHODS: A prospective cohort of 430 stroke survivors completed the Oxford Cognitive Screen (OCS) acutely and 6 months post-stroke. Participants completed the Stroke Impact Scale (SIS) and Hospital Depression and Anxiety Scale (HADS) at 6 months. Multivariable regression analyses assessed whether severity of, and domain-specific, cognitive impairment acutely and at 6 months was associated with composite 6-month SIS scores, each SIS subscale, and HADS scores. RESULTS: Increased severity of acute and 6-month cognitive impairment was associated with lower 6-month SIS composite scores independent of age, sex, education years, and stroke severity (both p
Unraveling interindividual variation of trimethylamine N-oxide and its precursors at the population level
Trimethylamine N-oxide (TMAO) is a circulating microbiome-derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO-to-precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in-depth analysis of their genetic, gut microbial, and dietary determinants. The analyses were conducted in five Dutch prospective cohort studies including 7834 individuals. To further investigate association results, Mendelian Randomization (MR) was also explored. We found only plasma choline levels (hazard ratio [HR] 1.17, [95% CI 1.07; 1.28]) and not TMAO to be associated with CVD risk. Our association analyses uncovered 10 genome-wide significant loci, including novel genomic regions for betaine (6p21.1, 6q25.3), choline (2q34, 5q31.1), and deoxycarnitine (10q21.2, 11p14.2) comprising several metabolic gene associations, for example, CPS1 or PEMT. Furthermore, our analyses uncovered 68 gut microbiota associations, mainly related to TMAO-to-precursors ratios and the Ruminococcaceae family, and 16 associations of food groups and metabolites including fish-TMAO, meat-carnitine, and plant-based food-betaine associations. No significant association was identified by the MR approach. Our analyses provide novel insights into the TMAO pathway, its determinants, and pathophysiological impact on the general population.
Molecular basis for pH sensing in the KDEL trafficking receptor.
Trafficking receptors control protein localization through the recognition of specific signal sequences that specify unique cellular locations. Differences in luminal pH are important for the vectorial trafficking of cargo receptors. The KDEL receptor is responsible for maintaining the integrity of the ER by retrieving luminally localized folding chaperones in a pH-dependent mechanism. Structural studies have revealed the end states of KDEL receptor activation and the mechanism of selective cargo binding. However, precisely how the KDEL receptor responds to changes in luminal pH remains unclear. To explain the mechanism of pH sensing, we combine analysis of X-ray crystal structures of the KDEL receptor at neutral and acidic pH with advanced computational methods and cell-based assays. We show a critical role for ordered water molecules that allows us to infer a direct connection between protonation in different cellular compartments and the consequent changes in the affinity of the receptor for cargo.
Sedation Research in Critically Ill Pediatric Patients: Proposals for Future Study Design From the Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research IV Workshop.
OBJECTIVES: Sedation and analgesia for infants and children requiring mechanical ventilation in the PICU is uniquely challenging due to the wide spectrum of ages, developmental stages, and pathophysiological processes encountered. Studies evaluating the safety and efficacy of sedative and analgesic management in pediatric patients have used heterogeneous methodologies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) IV hosted a series of multidisciplinary meetings to establish consensus statements for future clinical study design and implementation as a guide for investigators studying PICU sedation and analgesia. DESIGN: Twenty-five key elements framed as consensus statements were developed in five domains: study design, enrollment, protocol, outcomes and measurement instruments, and future directions. SETTING: A virtual meeting was held on March 2-3, 2022, followed by an in-person meeting in Washington, DC, on June 15-16, 2022. Subsequent iterative online meetings were held to achieve consensus. SUBJECTS: Fifty-one multidisciplinary, international participants from academia, industry, the U.S. Food and Drug Administration, and family members of PICU patients attended the virtual and in-person meetings. Participants were invited based on their background and experience. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Common themes throughout the SCEPTER IV consensus statements included using coordinated multidisciplinary and interprofessional teams to ensure culturally appropriate study design and diverse patient enrollment, obtaining input from PICU survivors and their families, engaging community members, and using developmentally appropriate and validated instruments for assessments of sedation, pain, iatrogenic withdrawal, and ICU delirium. CONCLUSIONS: These SCEPTER IV consensus statements are comprehensive and may assist investigators in the design, enrollment, implementation, and dissemination of studies involving sedation and analgesia of PICU patients requiring mechanical ventilation. Implementation may strengthen the rigor and reproducibility of research studies on PICU sedation and analgesia and facilitate the synthesis of evidence across studies to improve the safety and quality of care for PICU patients.
Digital twinning of the human ventricular activation sequence to Clinical 12-lead ECGs and magnetic resonance imaging using realistic Purkinje networks for in silico clinical trials.
Cardiac in silico clinical trials can virtually assess the safety and efficacy of therapies using human-based modelling and simulation. These technologies can provide mechanistic explanations for clinically observed pathological behaviour. Designing virtual cohorts for in silico trials requires exploiting clinical data to capture the physiological variability in the human population. The clinical characterisation of ventricular activation and the Purkinje network is challenging, especially non-invasively. Our study aims to present a novel digital twinning pipeline that can efficiently generate and integrate Purkinje networks into human multiscale biventricular models based on subject-specific clinical 12-lead electrocardiogram and magnetic resonance recordings. Essential novel features of the pipeline are the human-based Purkinje network generation method, personalisation considering ECG R wave progression as well as QRS morphology, and translation from reduced-order Eikonal models to equivalent biophysically-detailed monodomain ones. We demonstrate ECG simulations in line with clinical data with clinical image-based multiscale models with Purkinje in four control subjects and two hypertrophic cardiomyopathy patients (simulated and clinical QRS complexes with Pearson's correlation coefficients > 0.7). Our methods also considered possible differences in the density of Purkinje myocardial junctions in the Eikonal-based inference as regional conduction velocities. These differences translated into regional coupling effects between Purkinje and myocardial models in the monodomain formulation. In summary, we demonstrate a digital twin pipeline enabling simulations yielding clinically consistent ECGs with clinical CMR image-based biventricular multiscale models, including personalised Purkinje in healthy and cardiac disease conditions.
Acute to long-term characteristics of impedance recordings during neurostimulation in humans.
Objective:This study aims to characterize the time course of impedance, a crucial electrophysiological proper-ty of brain tissue, in the human thalamus (THL), amygdala-hippocampus (AMG-HPC), and poste-rior hippocampus (post-HPC) over an extended period.Approach:Impedance was periodically sampled every 5-15 minutes over several months in five subjects with drug-resistant epilepsy using an experimental neuromodulation device. Initially, we employed de-scriptive piecewise and continuous mathematical models to characterize the impedance response for approximately three weeks post-electrode implantation. We then explored the temporal dynamics of impedance during periods when electrical stimulation was temporarily halted, observing a mono-tonic increase (rebound) in impedance before it stabilized at a higher value. Lastly, we assessed the stability of amplitude and phase over the 24-hour impedance cycle throughout the multi-month re-cording.Main results:IImmediately post-implantation, the impedance decreased, reaching a minimum value in all brain regions within approximately two days, and then increased monotonically over about 14 days to a stable value. The models accounted for the variance in short-term impedance changes. Notably, the minimum impedance of the THL in the most epileptogenic hemisphere was significantly lower than in other regions. During the gaps in electrical stimulation, the impedance rebound decreased over time and stabilized around 200 days post-implant, likely indicative of the foreign body re-sponse and fibrous tissue encapsulation around the electrodes. The amplitude and phase of the 24-hour impedance oscillation remained stable throughout the multi-month recording, with circadian variation in impedance dominating the long-term measures.Significance:Our findings illustrate the complex temporal dynamics of impedance in implanted electrodes and the impact of electrical stimulation. The data suggest that the temporal dynamics of impedance are dependent on the anatomical location and tissue epileptogenicity. These insights may offer additional guidance for the delivery of therapeutic stimulation at various time points post-implantation for neuromodulation therapy.
Microbial Primer: Cooperation in bacteria.
The growth and success of many bacteria appear to rely on a stunning range of cooperative behaviours. But what is cooperation and how is it studied?
Chloroplast biogenesis: control of plastid development, protein import, division and inheritance.
The chloroplast is a multi-copy cellular organelle that not only performs photosynthesis but also synthesizes amino acids, lipids and phytohormones. The plastid also responds to environmental stimuli such as gravitropism. Biogenesis of chloroplasts is initiated from proplastids in shoot meristems, and involves a series of important events. In the last decade, considerable progress has been made towards understanding various aspects of chloroplast biogenesis at the molecular level, via studies in model systems such as Arabidopsis. This review focuses on two important aspects of chloroplast biogenesis, synthesis/assembly and division/transmission. Chloroplasts originated through endosymbiosis from an ancestor of extant cyanobacteria, and thus contain their own genomes. DNA in chloroplasts is organized into complexes with proteins, and these are called nucleoids. The synthesis of chloroplast proteins is regulated at various steps. However, a majority of proteins are synthesized in the cytosol, and their proper import into chloroplast compartments is a prerequisite for chloroplast development. Fundamental aspects of plastid gene expression/regulation and chloroplast protein transport are described, together with recent proteome analyses of the organelle. Chloroplasts are not de novo synthesized, but instead are propagated from pre-existing plastids. In addition, plastids are transmitted from generation to generation with a unique mode of inheritance. Our current knowledge on the division machinery and the inheritance of plastids is described.
Long-Term Impact of Urgent Secondary Prevention After Transient Ischemic Attack and Minor Stroke: Ten-Year Follow-Up of the EXPRESS Study.
BACKGROUND AND PURPOSE: Urgent assessment aimed at reducing stroke risk after transient ischemic attack or minor stroke is cost-effective over the short-term. However, it is unclear if the short-term impact is lost on long-term follow-up, with recurrent events being delayed rather than prevented. By 10-year follow-up of the EXPRESS study (Early Use of Existing Preventive Strategies for Stroke), previously showing urgent assessment reduced 90-day stroke risk by 80%, we determined whether that early benefit was still evident long-term for stroke risk, disability, and costs. METHODS: EXPRESS was a prospective population-based before (phase 1: April 2002-September 2004; n=310) versus after (phase 2: October 2004-March 2007; n=281) study of the effect of early assessment and treatment of transient ischemic attack/minor stroke on early recurrent stroke risk, with an external control. This report assesses the effect on 10-year recurrent stroke risk, functional outcomes, quality-of-life, and costs. RESULTS: A reduction in stroke risk in phase 2 was still evident at 10 years (55/23.3% versus 82/31.6%; hazard ratio=0.68 [95% CI, 0.48-0.95]; P=0.024), as was the impact on risk of disabling or fatal stroke (17/7.7% versus 32/13.1%; hazard ratio=0.54 [0.30-0.97]; P=0.036). These effects were due to maintenance of the early reduction in stroke risk, with neither additional benefit nor rebound catch-up after 90 days (post-90 days hazard ratio=0.88 [0.65-1.44], P=0.88; and hazard ratio=0.83 [0.42-1.65], P=0.59, respectively). Disability-free life expectancy was 0.59 (0.03-1.15; P=0.043) years higher in patients in phase 2, as was quality-adjusted life expectancy (0.49 [0.03-0.95]; P=0.036). Overall, 10-year costs were nonsignificantly higher in patients attending the phase 2 clinic ($1022 [-3865-5907]; P=0.66). The additional cost per quality-adjusted life year gained in phase 2 versus phase 1 was $2103, well below current cost-effectiveness thresholds. CONCLUSIONS: Urgent assessment and treatment of patients with transient ischemic attack or minor stroke resulted in a long-term reduction in recurrent strokes and improved outcomes, with little atrophy of the early benefit over time, representing good value for money even with a 10-year time horizon. Our results suggest that other effective acute treatments in transient ischemic attack/minor stroke in the short-term will also have the potential to have long-term benefit.
brainlife.io: a decentralized and open-source cloud platform to support neuroscience research.
Neuroscience is advancing standardization and tool development to support rigor and transparency. Consequently, data pipeline complexity has increased, hindering FAIR (findable, accessible, interoperable and reusable) access. brainlife.io was developed to democratize neuroimaging research. The platform provides data standardization, management, visualization and processing and automatically tracks the provenance history of thousands of data objects. Here, brainlife.io is described and evaluated for validity, reliability, reproducibility, replicability and scientific utility using four data modalities and 3,200 participants.
Post-stroke upper limb recovery is correlated with dynamic resting-state network connectivity.
Motor recovery is still limited for people with stroke especially those with greater functional impairments. In order to improve outcome, we need to understand more about the mechanisms underpinning recovery. Task-unbiased, blood flow-independent post-stroke neural activity can be acquired from resting brain electrophysiological recordings and offers substantial promise to investigate physiological mechanisms, but behaviourally relevant features of resting-state sensorimotor network dynamics have not yet been identified. Thirty-seven people with subcortical ischaemic stroke and unilateral hand paresis of any degree were longitudinally evaluated at 3 weeks (early subacute) and 12 weeks (late subacute) after stroke. Resting-state magnetoencephalography and clinical scores of motor function were recorded and compared with matched controls. Magnetoencephalography data were decomposed using a data-driven hidden Markov model into 10 time-varying resting-state networks. People with stroke showed statistically significantly improved Action Research Arm Test and Fugl-Meyer upper extremity scores between 3 weeks and 12 weeks after stroke (both P < 0.001). Hidden Markov model analysis revealed a primarily alpha-band ipsilesional resting-state sensorimotor network which had a significantly increased life-time (the average time elapsed between entering and exiting the network) and fractional occupancy (the occupied percentage among all networks) at 3 weeks after stroke when compared with controls. The life-time of the ipsilesional resting-state sensorimotor network positively correlated with concurrent motor scores in people with stroke who had not fully recovered. Specifically, this relationship was observed only in ipsilesional rather in contralesional sensorimotor network, default mode network or visual network. The ipsilesional sensorimotor network metrics were not significantly different from controls at 12 weeks after stroke. The increased recruitment of alpha-band ipsilesional resting-state sensorimotor network at subacute stroke served as functionally correlated biomarkers exclusively in people with stroke with not fully recovered hand paresis, plausibly reflecting functional motor recovery processes.
Correction: Modified minimal-size fragments of heparan sulfate as inhibitors of endosulfatase-2 (Sulf-2).
Correction for 'Modified minimal-size fragments of heparan sulfate as inhibitors of endosulfatase-2 (Sulf-2)' by Alice Kennett et al., Chem. Commun., 2024, 60, 436-439, https://doi.org/10.1039/D3CC02565A.
The bistable mitotic switch in fission yeast.
In favorable conditions, eukaryotic cells proceed irreversibly through the cell division cycle (G1-S-G2-M) in order to produce two daughter cells with the same number and identity of chromosomes of their progenitor. The integrity of this process is maintained by 'checkpoints' that hold a cell at particular transition points of the cycle until all requisite events are completed. The crucial functions of these checkpoints seem to depend on irreversible bistability of the underlying checkpoint control systems. Bistability of cell cycle transitions has been confirmed experimentally in frog egg extracts, budding yeast cells and mammalian cells. For fission yeast cells, a recent paper by Patterson et al. (2021) provides experimental evidence for an abrupt transition from G2 phase into mitosis, and we show that these data are consistent with a stochastic model of a bistable switch governing the G2/M checkpoint. Interestingly, our model suggests that their experimental data could also be explained by a reversible/sigmoidal switch, and stochastic simulations confirm this supposition. We propose a simple modification of their experimental protocol that could provide convincing evidence for (or against) bistability of the G2/M transition in fission yeast.
A cognitive map for value-guided choice in ventromedial prefrontal cortex.
The prefrontal cortex is crucial for economic decision-making and representing the value of options. However, how such representations facilitate flexible decisions remains unknown. We reframe economic decision-making in prefrontal cortex in line with representations of structure within the medial temporal lobe because such cognitive map representations are known to facilitate flexible behaviour. Specifically, we framed choice between different options as a navigation process in value space. Here we show that choices in a 2D value space defined by reward magnitude and probability were represented with a grid-like code, analogous to that found in spatial navigation. The grid-like code was present in ventromedial prefrontal cortex (vmPFC) local field potential theta frequency and the result replicated in an independent dataset. Neurons in vmPFC similarly contained a grid-like code, in addition to encoding the linear value of the chosen option. Importantly, both signals were modulated by theta frequency - occurring at theta troughs but on separate theta cycles. Furthermore, we found sharp-wave ripples - a key neural signature of planning and flexible behaviour - in vmPFC, which were modulated by accuracy and reward. These results demonstrate that multiple cognitive map-like computations are deployed in vmPFC during economic decision-making, suggesting a new framework for the implementation of choice in prefrontal cortex.