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"Calvert, Peter"
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Functional compartmentalization of photoreceptor neurons
Retinal photoreceptors are neurons that convert dynamically changing patterns of light into electrical signals that are processed by retinal interneurons and ultimately transmitted to vision centers in the brain. They represent the essential first step in seeing without which the remainder of the visual system is rendered moot. To support this role, the major functions of photoreceptors are segregated into three main specialized compartments—the outer segment, the inner segment, and the pre-synaptic terminal. This compartmentalization is crucial for photoreceptor function—disruption leads to devastating blinding diseases for which therapies remain elusive. In this review, we examine the current understanding of the molecular and physical mechanisms underlying photoreceptor functional compartmentalization and highlight areas where significant knowledge gaps remain.
Journal Article
Steric volume exclusion sets soluble protein concentrations in photoreceptor sensory cilia
Proteins segregate into discrete subcellular compartments via a variety of mechanisms, including motor protein transport, local binding, and diffusion barriers. This physical separation of cell functions serves, in part, as a mechanism for controlling compartment activity by allowing regulation of local protein concentrations. In this study we explored how soluble protein size impacts access to the confined space within the retinal photoreceptor outer segment signaling compartment and discovered a strikingly steep relationship. We find that GFP monomers, dimers, and trimers expressed transgenically in frog rods are present in the outer segment at 1.8-, 2.9-, and 6.8-fold lower abundances, relative to the cell body, than the small soluble fluorescent marker, calcein. Theoretical analysis, based on statistical–mechanical models of molecular access to polymer meshes, shows that these observations can be explained by the steric hindrance of molecules occupying the highly constrained spaces between outer segment disc membranes. This mechanism may answer a long-standing question of how the soluble regulatory protein, arrestin, is effectively excluded from the outer segments of dark-adapted rods and cones. Generally, our results suggest an alternate mode for the control of protein access to cell domains based on dynamic, size-dependent compartmental partitioning that does not require diffusion barriers, active transport, or large numbers of immobile binding sites.
Journal Article
Compartmentalization of Photoreceptor Sensory Cilia
Functional compartmentalization of cells is a universal strategy for segregating processes that require specific components, undergo regulation by modulating concentrations of those components, or that would be detrimental to other processes. Primary cilia are hair-like organelles that project from the apical plasma membranes of epithelial cells where they serve as exclusive compartments for sensing physical and chemical signals in the environment. As such, molecules involved in signal transduction are enriched within cilia and regulating their ciliary concentrations allows adaptation to the environmental stimuli. The highly efficient organization of primary cilia has been co-opted by major sensory neurons, olfactory cells and the photoreceptor neurons that underlie vision. The mechanisms underlying compartmentalization of cilia are an area of intense current research. Recent findings have revealed similarities and differences in molecular mechanisms of ciliary protein enrichment and its regulation among primary cilia and sensory cilia. Here we discuss the physiological demands on photoreceptors that have driven their evolution into neurons that rely on a highly specialized cilium for signaling changes in light intensity. We explore what is known and what is not known about how that specialization appears to have driven unique mechanisms for photoreceptor protein and membrane compartmentalization.
Journal Article
Editorial to “Incidence of nausea/vomiting following propofol sedation with adaptive‐servo ventilation for atrial fibrillation ablation”
The incidence of nausea, vomiting, and symptoms relating to vagal nerve injury remains high after atrial fibrillation ablation, with many patients reporting symptoms in the hours to months after their procedure. These are often underreported in literature, and this editorial piece opines about a study assessing this in detail.
Journal Article
Regulation of Rhodopsin-eGFP Distribution in Transgenic Xenopus Rod Outer Segments by Light
The rod outer segment (OS), comprised of tightly stacked disk membranes packed with rhodopsin, is in a dynamic equilibrium governed by a diurnal rhythm with newly synthesized membrane inserted at the OS base balancing membrane loss from the distal tip via disk shedding. Using transgenic Xenopus and live cell confocal imaging, we found OS axial variation of fluorescence intensity in cells expressing a fluorescently tagged rhodopsin transgene. There was a light synchronized fluctuation in intensity, with higher intensity in disks formed at night and lower intensity for those formed during the day. This fluctuation was absent in constant light or dark conditions. There was also a slow modulation of the overall expression level that was not synchronized with the lighting cycle or between cells in the same retina. The axial variations of other membrane-associated fluorescent proteins, eGFP-containing two geranylgeranyl acceptor sites and eGFP fused to the transmembrane domain of syntaxin, were greatly reduced or not detectable, respectively. In acutely light-adapted rods, an arrestin-eGFP fusion protein also exhibited axial variation. Both the light-sensitive Rho-eGFP and arrestin-eGFP banding were in phase with the previously characterized birefringence banding (Kaplan, Invest. Ophthalmol. Vis. Sci. 21, 395-402 1981). In contrast, endogenous rhodopsin did not exhibit such axial variation. Thus, there is an axial inhomogeneity in membrane composition or structure, detectable by the rhodopsin transgene density distribution and regulated by the light cycle, implying a light-regulated step for disk assembly in the OS. The impact of these results on the use of chimeric proteins with rhodopsin fused to fluorescent proteins at the carboxyl terminus is discussed.
Journal Article
Predictors of the need for atrioventricular nodal ablation following redo ablation for atrial fibrillation
Background
Patients who have recurrent atrial fibrillation (AF) following redo catheter ablation may eventually be managed with a pace‐and‐ablate approach, involving pacemaker implant followed by atrioventricular nodal ablation (AVNA). We sought to determine which factors would predict subsequent AVNA in patients undergoing redo AF ablation.
Methods
We analyzed patients undergoing redo AF ablations between 2013 and 2019 at our institution. Follow‐up was censored on December 31, 2021. Patients with no available follow‐up data were excluded. Time‐to‐event analysis with Cox proportional hazard regression was used to compare those who underwent AVNA to those who did not.
Results
A total of 467 patients were included, of whom 39 (8.4%) underwent AVNA. After multivariable adjustment, female sex (aHR 4.68 [95% CI 2.30–9.50]; p < 0.001), ischemic heart disease (aHR 2.99 [95% CI 1.25–7.16]; p = 0.014), presence of a preexisting pacemaker (aHR 3.25 [95% CI 1.10–9.60]; p = 0.033), and persistent AF (aHR 2.22 [95% CI 1.07–4.59]; p = 0.032) were associated with increased risk of subsequent AVNA requirement.
Conclusion
Female sex, ischemic heart disease, and persistent AF may be useful clinical predictors of the requirement for subsequent AVNA and may be considered as part of shared clinical decision making.
Atrioventricular (AV) nodal ablation may be required for the treatment of atrial fibrillation (AF) when rhythm control measures fail. Our study found that female sex, ischemic heart disease, preexisting pacemaker, and persistent AF were independent predictors of the need for subsequent AV node ablation.
Journal Article
Dynamic Voltage Mapping of the Post-infarct Ventricular Tachycardia Substrate: A Practical Technique to Help Differentiate Scar from Borderzone Tissue
During catheter ablation of post-infarct ventricular tachycardia (VT), substrate mapping is used when VT is non-inducible or poorly tolerated. Substrate mapping aims to identify regions of slowly conducting myocardium (borderzone) within and surrounding myocardial scar for ablation. Historically, these tissue types have been identified using bipolar voltage mapping, with areas of low bipolar voltage (<0.50 mV) defined as scar, and areas with voltages between 0.50 mV and 1.50 mV as borderzone. In the era of high-density mapping, studies have demonstrated slow conduction within areas of bipolar voltage <0.50 mV, suggesting that this historical cut-off is outdated. While electrophysiologists often adapt voltage cut-offs to account for this, the optimal scar-borderzone threshold is not known. In this review, we discuss dynamic voltage mapping, a novel substrate mapping technique we have developed, which superimposes data from both activation and voltage maps, to help delineate the post-infarct VT circuit through identification of the optimal scar-borderzone voltage threshold.
Journal Article
Randomised controlled trial of population screening for atrial fibrillation in people aged 70 years and over to reduce stroke: protocol for the SAFER trial
IntroductionThere is a lack of evidence that the benefits of screening for atrial fibrillation (AF) outweigh the harms. Following the completion of the Screening for Atrial Fibrillation with ECG to Reduce stroke (SAFER) pilot trial, the aim of the main SAFER trial is to establish whether population screening for AF reduces incidence of stroke risk.Methods and analysisApproximately 82 000 people aged 70 years and over and not on oral anticoagulation are being recruited from general practices in England. Patients on the palliative care register or residents in a nursing home are excluded. Eligible people are identified using electronic patient records from general practices and sent an invitation and consent form to participate by post. Consenting participants are randomised at a ratio of 2:1 (control:intervention) with clustering by household. Those randomised to the intervention arm are sent an information leaflet inviting them to participate in screening, which involves use of a handheld single-lead ECG four times a day for 3 weeks. ECG traces identified by an algorithm as possible AF are reviewed by cardiologists. Participants with AF are seen by a general practitioner for consideration of anticoagulation. The primary outcome is stroke. Major secondary outcomes are: death, major bleeding and cardiovascular events. Follow-up will be via electronic health records for an average of 4 years. The primary analysis will be by intention-to-treat using time-to-event modelling. Results from this trial will be combined with follow-up data from the cluster-randomised pilot trial by fixed-effects meta-analysis.Ethics and disseminationThe London—Central National Health Service Research Ethics Committee (19/LO/1597) provided ethical approval. Dissemination will include public-friendly summaries, reports and engagement with the UK National Screening Committee.Trial registration number ISRCTN72104369.
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