The sorting of signaling receptors into and out of cilia relies on the BBSome, a complex of Bardet-Biedl syndrome (BBS) proteins, and on the intraflagellar transport (IFT) machinery. GTP loading onto ...the Arf-like GTPase ARL6/BBS3 drives assembly of a membrane-apposed BBSome coat that promotes cargo entry into cilia, yet how and where ARL6 is activated remains elusive. Here, we show that the Rab-like GTPase IFT27/RABL4, a known component of IFT complex B, promotes the exit of BBSome and associated cargoes from cilia. Unbiased proteomics and biochemical reconstitution assays show that, upon disengagement from the rest of IFT-B, IFT27 directly interacts with the nucleotide-free form of ARL6. Furthermore, IFT27 prevents aggregation of nucleotide-free ARL6 in solution. Thus, we propose that IFT27 separates from IFT-B inside cilia to promote ARL6 activation, BBSome coat assembly, and subsequent ciliary exit, mirroring the process by which BBSome mediates cargo entry into cilia.
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•The IFT-B subunit IFT27/RabL4 directly and selectively binds nucleotide-empty ARL6•IFT27 needs disengagement from IFT-B to recognize ARL6•The exit of BBSome and cargoes from cilia requires IFT27•The BBSome dissociates from IFT trains in the absence of IFT27
The Arf-like GTPase ARL6 triggers BBSome coat assembly and cargo entry into cilia. Now, Liew et al. find that the Rab-like GTPase IFT27 disengages from anterograde IFT complexes to bind and activate nucleotide-empty ARL6 and thereby promote the exit of the BBSome and its associated cargoes from cilia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Lutein and zeaxanthin (L/Z) are the predominant carotenoids which accumulate in the retina of ...the eye. The impact of L/Z intake on the risk and progression of age-related macular degeneration (AMD), a leading cause of blindness in the developed world, has been investigated in cohort studies and clinical trials. The aims of this review were to critically examine the literature and evaluate the current evidence relating to L/Z intake and AMD, and describe important food sources and factors that increase the bioavailability of L/Z, to inform dietary models. Cohort studies generally assessed L/Z from dietary sources, while clinical trials focused on providing L/Z as a supplement. Important considerations to take into account in relation to dietary L/Z include: nutrient-rich sources of L/Z, cooking methods, diet variety and the use of healthy fats. Dietary models include examples of how suggested effective levels of L/Z can be achieved through diet alone, with values of 5 mg and 10 mg per day described. These diet models depict a variety of food sources, not only from dark green leafy vegetables, but also include pistachio nuts and other highly bioavailable sources of L/Z such as eggs. This review and the diet models outlined provide information about the importance of diet variety among people at high risk of AMD or with early signs and symptoms of AMD.
The presence of visual impairment (VI) and hearing loss (HL) with may be a marker for subsequent cognitive decline over time in older people. A prospective, longitudinal population-based study of the ...3654 participants of the Blue Mountains Eye Study were assessed for the associations between VI and HL and a decline in mini-mental state examination (MMSE) scores over a duration of 10 years from the 5-year (baseline of this report) to the 15-year follow-up visits. MMSE was assessed at the 5-, 10- and 15-year follow-up visits. A decline ≥3 scores from 5-year to 10- or 15-year visits indicated possible cognitive decline. VI was defined as best-corrected visual acuity <6/12 in the worse-eye, HL was defined as pure-tone average >40 decibels in the worse-ear and dual sensory impairment (DSI) was defined by the co-presence of VI and HL, detected at 5-year follow-up (baseline of this report). Participants with no VI and HL over the same 5- or 10-year corresponding period were controls. Associations of VI, HL and DSI with possible cognitive decline were assessed using logistic regression models adjusting for age and sex after excluding subjects with a stroke history. The presence of VI, HL or DSI was not associated with possible cognitive decline over 5 years (odds ratio (OR) 0.84, 95% confidence-intervals (CI) 0.40-1.79, OR 1.02, 95% CI 0.61-1.70 and 1.41, 95% CI 0.54-3.72, respectively) or 10 years (OR 1.09, 95% CI 0.52-2.30, OR 1.09, 95% CI 0.65-1.82 and 1.15, 95% CI 0.28-4.73, respectively). There were no changes to these findings after adjustment for other potential confounders. Age was significantly associated with possible cognitive decline (OR 1.07, 95% CI 1.04-1.10 for both periods). Neither visual impairment, hearing loss nor dual sensory impairment was independently associated with subsequent decline in cognition.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Axonal transport of synaptic vesicle precursors (SVPs) is essential for synapse development and function. The conserved ARF-like small GTPase ARL-8 is localized to SVPs and directly activates ...UNC-104/KIF1A, the axonal-transport kinesin for SVPs in C. elegans. It is not clear how ARL-8 is activated in this process. Here we show that part of the BLOC-1-related complex (BORC), previously shown to regulate lysosomal transport, is required to recruit and activate ARL-8 on SVPs. We found mutations in six BORC subunits—blos-1/BLOS1, blos-2/BLOS2, snpn-1/Snapin, sam-4/Myrlysin, blos-7/Lyspersin, and blos-9/MEF2BNB—cause defects in axonal transport of SVPs, leading to ectopic accumulation of synaptic vesicles in the proximal axon. This phenotype is suppressed by constitutively active arl-8 or unc-104 mutants. Furthermore, SAM-4/Myrlysin, a subunit of BORC, promotes the GDP-to-GTP exchange of ARL-8 in vitro and recruits ARL-8 onto SVPs in vivo. Thus, BORC regulates the axonal transport of synaptic materials and synapse formation by controlling the nucleotide state of ARL-8. Interestingly, the other two subunits of BORC essential for lysosomal transport, kxd-1/KXD1 and blos-8/Diaskedin, are not required for the SVP transport, suggesting distinct subunit requirements for lysosomal and SVP trafficking.
•BORC is essential for the axonal transport of synaptic vesicle precursors (SVPs)•Six BORC subunits are essential for SVP transport•Essential BORC subunits are different between lysosome and SVP transport•BORC subunit SAM-4 has guanine nucleotide exchange factor (GEF) activity to ARL-8
BORC is an eight-subunit complex that is known to regulate lysosome transport. In this paper, Niwa et al. show that BORC is essential for the axonal transport of synaptic vesicle precursors and regulates the localization of synaptic vesicles. SAM-4, one of the BORC subunits, has GDP-GTP exchange activity toward small GTPase ARL-8.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
With the increasing prevalence of diabetes, annual screening for diabetic retinopathy (DR) by expert human grading of retinal images is challenging. Automated DR image assessment systems (ARIAS) may ...provide clinically effective and cost-effective detection of retinopathy. We aimed to determine whether ARIAS can be safely introduced into DR screening pathways to replace human graders.
Observational measurement comparison study of human graders following a national screening program for DR versus ARIAS.
Retinal images from 20 258 consecutive patients attending routine annual diabetic eye screening between June 1, 2012, and November 4, 2013.
Retinal images were manually graded following a standard national protocol for DR screening and were processed by 3 ARIAS: iGradingM, Retmarker, and EyeArt. Discrepancies between manual grades and ARIAS results were sent to a reading center for arbitration.
Screening performance (sensitivity, false-positive rate) and diagnostic accuracy (95% confidence intervals of screening-performance measures) were determined. Economic analysis estimated the cost per appropriate screening outcome.
Sensitivity point estimates (95% confidence intervals) of the ARIAS were as follows: EyeArt 94.7% (94.2%-95.2%) for any retinopathy, 93.8% (92.9%-94.6%) for referable retinopathy (human graded as either ungradable, maculopathy, preproliferative, or proliferative), 99.6% (97.0%-99.9%) for proliferative retinopathy; Retmarker 73.0% (72.0 %-74.0%) for any retinopathy, 85.0% (83.6%-86.2%) for referable retinopathy, 97.9% (94.9%-99.1%) for proliferative retinopathy. iGradingM classified all images as either having disease or being ungradable. EyeArt and Retmarker saved costs compared with manual grading both as a replacement for initial human grading and as a filter prior to primary human grading, although the latter approach was less cost-effective.
Retmarker and EyeArt systems achieved acceptable sensitivity for referable retinopathy when compared with that of human graders and had sufficient specificity to make them cost-effective alternatives to manual grading alone. ARIAS have the potential to reduce costs in developed-world health care economies and to aid delivery of DR screening in developing or remote health care settings.
Central serous chorioretinopathy (CSCR) is a common retinal cause of vision loss. This review surveys the epidemiology, risk factors, clinical presentation, natural history and pathophysiology of ...CSCR. Studies suggest an annual incidence rate of 10 per 100 000 in men, with CSCR occurring six times more commonly in men compared with women. Most acute CSCR cases resolve spontaneously within 2–3 months. Prognosis is highly dependent on presenting visual acuity; patients with initial visual acuities of 6/6 remain at that level, while patients with initial visual acuities of less than 6/9 recover on average two to three Snellen lines over the next few years. The main risk factors for CSCR are systemic corticosteroid use, type A personality, pregnancy and endogenous Cushing's syndrome. The pathophysiology of CSCR remains obscure, although disorders in both the choroidal circulation and retinal pigment epithelium are implicated.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
To compare the efficacy and safety of brolucizumab with aflibercept in patients with diabetic macular edema (DME).
Double-masked, 100-week, multicenter, active-controlled, randomized trials.
Subjects ...were randomized 1:1:1 to brolucizumab 3 mg/6 mg or aflibercept 2 mg in KESTREL (n = 566) or 1:1 to brolucizumab 6 mg or aflibercept 2 mg in KITE (n = 360). Brolucizumab groups received 5 loading doses every 6 weeks (q6w) followed by 12-week (q12w) dosing, with optional adjustment to every 8 weeks (q8w) if disease activity was identified at predefined assessment visits; aflibercept groups received 5 doses every 4 weeks (q4w) followed by fixed q8w dosing. The primary endpoint was best-corrected visual acuity (BCVA) change from baseline at Week 52; secondary endpoints included the proportion of subjects maintained on q12w dosing, change in Diabetic Retinopathy Severity Scale score, and anatomical and safety outcomes.
At Week 52, brolucizumab 6 mg was noninferior (NI margin 4 letters) to aflibercept in mean change in BCVA from baseline (KESTREL: +9.2 letters vs +10.5 letters; KITE: +10.6 letters vs +9.4 letters; P < .001), more subjects achieved central subfield thickness (CSFT) <280 µm, and fewer had persisting subretinal and/or intraretinal fluid vs aflibercept, with more than half of brolucizumab 6 mg subjects maintained on q12w dosing after loading. In KITE, brolucizumab 6 mg showed superior improvements in change of CSFT from baseline over Week 40 to Week 52 vs aflibercept (P = .001). The incidence of ocular serious adverse events was 3.7% (brolucizumab 3 mg), 1.1% (brolucizumab 6 mg), and 2.1% (aflibercept) in KESTREL; and 2.2% (brolucizumab 6 mg) and 1.7% (aflibercept) in KITE.
Brolucizumab 6 mg showed robust visual gains and anatomical improvements with an overall favorable benefit/risk profile in patients with DME.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose To evaluate the efficacy of spectral-domain optical coherence tomography (SD OCT) compared to indocyanine green angiography (ICGA) in detecting idiopathic polypoidal choroidal vasculopathy ...(PCV) and in differentiating between PCV and occult choroidal neovascularization (CNV). Design Retrospective observational case-control study. Methods SD OCTs of 51 eyes of 44 consecutive patients who presented with 1 or more pigment epithelial detachments (PEDs) attributable to either PCV or occult CNV were retrospectively reviewed by a grader masked to the final diagnosis. A qualitative analysis based on the following tomographic findings was performed: sharp PED peak, PED notch, hyporeflective lumen within hyperreflective lesions adherent to retinal pigment epithelium. The diagnosis based on SD OCT alone was compared with the final diagnosis made using ICGA and fluorescein angiography. Sensitivity and specificity were calculated. Patients with classic CNV and central serous chorioretinopathy were excluded. Results Among 51 eyes of 44 patients, 37 had an ICGA-confirmed diagnosis of PCV and 14 had occult CNV. SD OCT based on the features above detected 35 of 37 true-positive PCV lesions but missed 2 ICGA-confirmed lesions (false negatives). SD OCT correctly excluded 13 of 14 non-PCV lesions but misidentified 1 PCV lesion (false positive). These data showed a sensitivity of 94.6% and a specificity of 92.9% for the above SD OCT features in identifying PCV lesions. Conclusions SD OCT based on the features above allowed for good detection of PCV and differentiation between PCV and occult CNV in this selected clinic population. A careful qualitative analysis of the tomographic findings in patients presenting with PEDs may allow ophthalmologists to distinguish between PCV and occult CNV, decreasing the need for ICGA and the risks related to this procedure.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly population. To accelerate the understanding of the genetics of AMD, we conducted a ...meta-analysis of genome-wide association studies (GWAS) combining data from the International AMD Genomics Consortium AMD-2016 GWAS (16,144 advanced AMD cases and 17,832 controls), AMD-2013 GWAS (17,181 cases and 60,074 controls), and new data on 4017 AMD cases and 14,984 controls from Genetic Epidemiology Research on Aging study. We identified 12 novel AMD loci near or within C4BPA-CD55, ZNF385B, ZBTB38, NFKB1, LINC00461, ADAM19, CPN1, ACSL5, CSK, RLBP1, CLUL1, and LBP. We then replicated the associations of the novel loci in independent cohorts, UK Biobank (5860 cases and 126,726 controls) and FinnGen (1266 cases and 47,560 control). In general, the concordance in effect sizes was very high (correlation in effect size estimates 0.89), 11 of 12 novel loci were in the expected direction, 5 were associated with AMD at a nominal significance level, and rs3825991 (near gene RLBP1) after Bonferroni correction. We identified an additional 21 novel genes using a gene-based test. Most of the novel genes are expressed in retinal tissue and could be involved in the pathogenesis of AMD (i.e., complement, inflammation, and lipid pathways). These findings enhance our understanding of the genetic architecture of AMD and shed light on the biological process underlying AMD pathogenesis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Fractal analysis is a method of quantifying the branching complexity and density of the retinal vessels. We hypothesized that reduced fractal dimension, signifying a sparser vascular network, is ...associated with long-term stroke mortality.
We examined the relationship of fractal dimension and stroke mortality in a prospective, population-based cohort of 3143 participants aged 49 years or older. Fractal dimension was measured from digitized fundus photographs using a computer-automated method. Stroke mortality was documented from Australian National Death Index records. We defined reduced fractal dimension as values in the lowest quartile.
Over 12 years, there were 132 (4.2%) stroke-related deaths. Stroke-related mortality was higher in participants with reduced fractal dimension (lowest quartile) compared with the highest quartile (7.7% versus 1.3%,
<0.01). After controlling for age, gender, smoking, blood pressure, history of stroke, and other factors, participants with reduced fractal dimension had higher stroke mortality (hazard ratio, 2.42 95% CI, 1.15-5.07, lowest versus highest quartile). When modeled as a continuous variable, reduced fractal dimension was associated with increased stroke mortality (multivariable-adjusted hazard ratio, 1.26 95% CI, 1.06-1.51, per SD decrease).
Reduced retinal vascular fractal dimension is independently associated with 12-year stroke mortality. Reduced fractal dimension may indicate cerebral tissue hypoxia and increased risk of stroke.
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