Heritable changes of epialleles near genes in maize can be triggered in the absence of CHH methylation.

Trans-chromosomal interactions resulting in changes in DNA methylation during hybridization have been observed in several plant species. However, little is known about the causes or consequences of these interactions. Here, we compared DNA methylomes of F1 hybrids that are mutant for a small RNA biogenesis gene, Mop1 (Mediator of paramutation1), with that of their parents, wild-type siblings, and backcrossed progeny in maize (Zea mays). Our data show that hybridization triggers global changes in both trans-chromosomal methylation (TCM) and trans-chromosomal demethylation (TCdM), most of which involved changes in CHH methylation. In more than 60% of these TCM differentially methylated regions (DMRs) in which small RNAs are available, no significant changes in the quantity of small RNAs were observed. Methylation at the CHH TCM DMRs was largely lost in the mop1 mutant, although the effects of this mutant varied depending on the location of these DMRs. Interestingly, an increase in CHH at TCM DMRs was associated with enhanced expression of a subset of highly expressed genes and suppressed expression of a small number of lowly expressed genes. Examination of the methylation levels in backcrossed plants demonstrates that both TCM and TCdM can be maintained in the subsequent generation, but that TCdM is more stable than TCM. Surprisingly, although increased CHH methylation in most TCM DMRs in F1 plants required Mop1, initiation of a new epigenetic state of these DMRs did not require a functional copy of this gene, suggesting that initiation of these changes is independent of RNA-directed DNA methylation.

The mop1 mutation affects the recombination landscape in maize.

Meiotic recombination is a fundamental process that generates genetic diversity and ensures the accurate segregation of homologous chromosomes. While a great deal is known about genetic factors that regulate recombination, relatively little is known about epigenetic factors, such as DNA methylation. In maize, we examined the effects on meiotic recombination of a mutation in a component of the RNA-directed DNA methylation pathway, Mop1 (Mediator of paramutation1), as well as a mutation in a component of the trans-acting small interference RNA biogenesis pathway, Lbl1 (Leafbladeless1). MOP1 is of particular interest with respect to recombination because it is responsible for methylation of transposable elements that are immediately adjacent to transcriptionally active genes. In the mop1 mutant, we found that meiotic recombination is uniformly decreased in pericentromeric regions but is generally increased in gene rich chromosomal arms. This observation was further confirmed by cytogenetic analysis showing that although overall crossover numbers are unchanged, they occur more frequently in chromosomal arms in mop1 mutants. Using whole genome bisulfite sequencing, our data show that crossover redistribution is driven by loss of CHH (where H = A, T, or C) methylation within regions near genes. In contrast to what we observed in mop1 mutants, no significant changes were observed in the frequency of meiotic recombination in lbl1 mutants. Our data demonstrate that CHH methylation has a significant impact on the overall recombination landscape in maize despite its low frequency relative to CG and CHG methylation.

Analysis of CACTA transposase genes unveils the mechanism of intron loss and distinct small RNA silencing pathways underlying divergent evolution of Brassica genomes.

In comparison with retrotransposons, DNA transposons make up a smaller proportion of most plant genomes. However, these elements are often proximal to genes to affect gene expression depending on the activity of the transposons, which is largely reflected by the activity of the transposase genes. Here, we show that three AT-rich introns were retained in the TNP2-like transposase genes of the Bot1 (Brassica oleracea transposon 1) CACTA transposable elements in Brassica oleracea, but were lost in the majority of the Bot1 elements in Brassica rapa. A recent burst of transposition of Bot1 was observed in B. oleracea, but not in B. rapa. This burst of transposition is likely related to the activity of the TNP2-like transposase genes as the expression values of the transposase genes were higher in B. oleracea than in B. rapa. In addition, distinct populations of small RNAs (21, 22 and 24 nt) were detected from the Bot1 elements in B. oleracea, but the vast majority of the small RNAs from the Bot1 elements in B. rapa are 24 nt in length. We hypothesize that the different activity of the TNP2-like transposase genes is likely associated with the three introns, and intron loss is likely reverse transcriptase mediated. Furthermore, we propose that the Bot1 family is currently undergoing silencing in B. oleracea, but has already been silenced in B. rapa. Taken together, our data provide new insights into the differentiation of transposons and their role in the asymmetric evolution of these two closely related Brassica species.

Ganglion Cell Complex Thickness and Macular Vessel Density Loss in Primary Open-Angle Glaucoma.

PURPOSE: To characterize the change rate of ganglion cell complex (GCC) thickness and macular vessel density in healthy, preperimetric glaucoma and primary open-angle glaucoma (POAG) eyes. DESIGN: Prospective, longitudinal study. PARTICIPANTS: One hundred thirty-nine eyes (23 healthy eyes, 36 preperimetric glaucoma eyes, and 80 POAG eyes) of 94 patients who had at least 3 visits were included from the Diagnostic Innovations in Glaucoma Study. The mean follow-up was 2.0 years for healthy eyes, 2.6 years for preperimetric glaucoma eyes, and 2.6 years for POAG eyes. METHODS: OCT angiography (OCTA)-based vessel density and OCT-based structural thickness of the same 3×3-mm2 GCC scan slab were evaluated. The dynamic range-based normalized rates of vessel density and thickness change were calculated and compared within each diagnostic group. The association between the rates of thickness and vessel density change and potential factors were evaluated. MAIN OUTCOME MEASURES: The rates of GCC thinning and macular vessel density loss. RESULTS: Significant rates of GCC thinning and macular vessel density decrease were detectable in all diagnostic groups (all P < 0.05). In healthy eyes and preperimetric glaucoma eyes, the normalized rates of GCC thinning and macular vessel density decrease were comparable (all P > 0.1). In contrast, the normalized rate (mean, 95% confidence interval) of macular vessel density decrease in the POAG eyes (-7.12 [-8.36, -5.88]%/year) was significantly faster than GCC thinning (-2.13 [-3.35, -0.90]%/year; P < 0.001). In the POAG group, more than two thirds of the eyes showed faster macular vessel density decrease than GCC thinning; faster macular vessel density decrease rate was associated significantly with worse glaucoma severity (P = 0.037). The association between GCC thinning rate and glaucoma severity was not significant (P = 0.586). Intraocular pressure during follow-up significantly affected the rate of GCC thinning in all groups (all P < 0.05) but showed no association with the rate of macular vessel density decrease. CONCLUSIONS: Both GCC thinning and macular vessel density decrease were detectable over time in all diagnostic groups. In POAG eyes, macular vessel density decrease was faster than GCC thinning and was associated with severity of disease. Macular vessel density is useful for evaluating glaucoma progression, particularly in more advanced disease.

Aqueous Angiography in Living Nonhuman Primates Shows Segmental, Pulsatile, and Dynamic Angiographic Aqueous Humor Outflow.

PURPOSE: To evaluate the feasibility of safely performing aqueous angiography in intact eyes of living nonhuman primates (NHPs) for evaluating aqueous humor outflow and segmental patterns. DESIGN: Cross-sectional, observational study. SUBJECTS: Six nonhuman primates. METHODS: Aqueous angiography was performed in 6 nonhuman primates. After anesthesia, an anterior chamber (AC) maintainer was placed through a temporal 1-mm side-port wound. Indocyanine green (ICG; 0.4%) or 2.5% fluorescein was introduced (individually or in sequence) into the eye with a gravity-driven constant-pressure system. Aqueous angiography images were obtained with a Spectralis HRA+OCT (Heidelberg Engineering GmbH, Heidelberg, Germany) suspended over the NHP eye using a custom-designed surgical boom arm. Concurrent anterior segment optical coherence tomography (OCT) was performed on distally angiographically positive and negative regions. MAIN OUTCOME MEASURES: Angiographic patterns described by location, time-course, choice of tracer, and anterior-segment OCT. RESULTS: Aqueous angiography in the living NHP eye demonstrated mostly stable angiographic patterns. With multimodal imaging, angiographically positive signal co-localized with episcleral veins as identified by infrared imaging and intrascleral lumens, as demonstrated by anterior segment OCT. Sequential aqueous angiography in individual eyes with ICG followed by fluorescein showed similar angiographic patterns. A pulsatile nature of aqueous angiographic outflow was sometimes observed. Aqueous angiographic patterns could also dynamically change. In some instances, positive angiographic flow suddenly arose in regions previously without an angiographic signal. Alternatively, an angiographic signal could suddenly disappear from regions in which an angiographic signal was initially documented. CONCLUSIONS: Aqueous angiography in living NHPs demonstrated segmental and pulsatile patterns with a newly described ability to dynamically shift. These characteristics further the understanding of live aqueous humor outflow biology and may be useful in improving glaucoma surgeries aimed at trabecular meshwork bypass.

Changes of visual field and optic nerve fiber layer in patients with OSAS.

BACKGROUND: The prevalence of primary open-angle glaucoma (POAG) increases in obstructive sleep apnea syndrome (OSAS). OSAS could increase cerebrospinal fluid pressure (CSFP) and binocular papilledema. METHODS: In this cross-sectional study, intraocular pressure (IOP), CSFP, mean deviation (MD), pattern standard deviation (PSD), optic disc indices, and retinal nerve fiber layer (RNFL) were compared among four groups with different extents of OSAS. Regression analysis was performed to correlate MD, PSD, and RNFL to polysomnography (PSG) index. For subgroups with severe OSAS, IOP and CSFP were compared. The prevalence of POAG was calculated. RESULTS: The severe OSAS had a significantly higher CSFP than the other three groups (p = 0.002, 0.036, and 0.017). Both moderate and severe groups showed significantly higher IOP than control group (p = 0.022 and 0.001). MD was correlated with average oxygen saturation (MSaO2) (p = 0.001). PSD was correlated with oxygen desaturation index (ODI) (p = 0.004). Significant differences were found in nasal RNFL and inferior RNFL among the four groups (p = 0.013, p = 0.004). Nasal RNFL correlated with the ODI (p = 0.048). For severe group, compared to normal RNFL group, CSFP was significantly lower in the thinned RNFL group (p = 0.039) and higher in the thickened RNFL group (p = 0.034). Totally, the prevalence of POAG was 5.49 %. CONCLUSIONS: OSAS had a high prevalence of POAG. Visual field was damaged and the RNFL was thinned. Due to diverse CSFP, RNFL changed differently in the patients with severe OSAS.

[The comparison of short-term outcome between aqueous drainage pathway reconstruction surgery versus canaloplasty for open angle glaucoma].

OBJECTIVE: To compare the safety and efficacy between canaloplasty and aqueous drainage pathway reconstruction surgery in patients with open-angle glaucoma (OAG). METHODS: It is a retrospective case series study. Thirty-one eyes (25 patients) with OAG were divided into canaloplasty (n = 17; 54.8%) group or aqueous drainage pathway reconstruction (n = 14; 45.2%) group. The intraocular pressure (IOP), numbers of IOP-lowering medications and incidence of complications were recorded at 1 day, 1 week, 1, 3, 6 and 12 months after the operation. Independent-samples T test was used to compare the IOP, numbers of IOP-lowering medications before and 1, 3, 6, 12, 24 months after surgery between two groups. Kaplan-Meier Survival Analysis was used to analyze the success rate of these two surgical methods. Log rank test was used to compare the difference of cumulative success rate at 6, 12 months after surgery. RESULTS: The mean IOP values were (24.7 ± 8.7) , (14.5 ± 2.5), (14.9 ± 2.5) , (14.9 ± 2.5), (14.7 ± 2.1) and (15.4 ± 2.3) mmHg (1 mmHg = 0.133 kPa) in canaloplasty group at before surgery, 1, 3, 6, 12 and 24 months after surgery. The same values were (28.5 ± 10.6), (14.3 ± 3.6), (14.2 ± 3.2), (14.3 ± 3.6), (15.9 ± 3.2) and (14.6 ± 0.7) mmHg in aqueous drainage pathway reconstruction group. There was no difference in the extent of IOP reduction between these two groups (preoperative: t = -1.1014, P = 0.278; postoperative 1 month: t = 0.696, P = 0.492;3 month: t = 0.594, P = 0.557; 6 month: t = 0.536, P = 0.596; 12 month: t = -1.127, P = 0.273; 24 month: t = 0.455, P = 0.656). There were significant differences (P < 0.01) in post-surgery IOP lowering medication usage between these two groups, while pre-surgery medication usage were similar. The incidence of hyphema was significantly lower in aqueous drainage pathway reconstruction surgery group (2 eyes) than that in canaloplasty group (11 eyes). CONCLUSIONS: Both canaloplasty and aqueous drainage pathway reconstruction could reduce IOP effectively for open-angle glaucoma. The incidence of complication was lower in the aqueous drainage pathway reconstruction group than canaloplasty group. However, long-term efficacy between these two groups is yet to be determined.

Effect of Different Postures on Intraocular Pressure in Open-Angle Glaucoma.

INTRODUCTION: This study aims to investigate the pattern of intraocular pressure (IOP) changes in different postures among patients with open-angle glaucoma (OAG). METHODS: A observational study was conducted on a total of 74 patients with OAG (148 eyes). IOP measurements were taken in a variety of positions, including supine, left lateral decubitus, right lateral decubitus, head tilted downwards position with immediate head-up (transient head tilted downwards), seated, seated with head tilted downwards, standing, and walking. Each position was held for 5 min before measurement. In all positions, the patient maintains both eyes looking forward and remains alert. In the head tilted downwards position, the angle of head tilt with respect to the sagittal plane was 30°. RESULTS: The overall trend of IOP changes showed a significant decrease with an increase in the position height (r = 0.037, p < 0.001). The IOP was significantly higher in the supine, left lateral decubitus, right lateral decubitus, and head tilted downwards positions than in the seated position (p < 0.001). Compared with the seated position with eyes at primary gaze, IOP decreased significantly when standing (p = 0.008) or walking (p < 0.001). The IOP in the left lateral decubitus and right lateral decubitus was significantly higher than in the supine position (p = 0.008, p = 0.001, respectively). The IOP decreased significantly during walking compared with standing (p < 0.001). CONCLUSIONS: The magnitude of IOP strongly correlates with the body position during IOP measurement. The head tilted downwards, supine, left lateral decubitus, and right lateral decubitus positions result in a higher IOP than IOP at the seated position. Patients with OAG can potentially reduce IOP fluctuations by adjusting their daily postures.

Noninvasive intracranial pressure estimation by orbital subarachnoid space measurement: the Beijing Intracranial and Intraocular Pressure (iCOP) study.

INTRODUCTION: The orbital subarachnoid space surrounding the optic nerve is continuous with the circulation system for cerebrospinal fluid (CSF) and can be visualized by using magnetic resonance imaging (MRI). We hypothesized that the orbital subarachnoid space width (OSASW) is correlated with and can serve as a surrogate for intracranial pressure (ICP). Our aim was to develop a method for a noninvasive measurement of the intracranial CSF-pressure (CSF-P) based on MRI-assisted OSASW. METHODS: The prospective observational comparative study included neurology patients who underwent lumbar CSF-P measurement and 3.0-Tesla orbital magnetic resonance imaging (MRI) for other clinical reasons. The width of the orbital subarachnoid space (OSASW) around the optic nerve was measured with MRI at 3, 9, and 15 mm behind the globe. The study population was randomly divided into a training group and a test group. After adjusting for body mass index (BMI) and mean arterial blood pressure (MABP), algorithms for the associations between CSF-P and OSASW were calculated in the training group. The algorithms were subsequently verified in the test group. Main outcome measures were the width of the orbital subarachnoid space (OSASW) and the lumbar cerebrospinal fluid pressure (CSF-P). RESULTS: Seventy-two patients were included in the study. In the training group, the algorithms for the associations between CSF-P and OSASW were as follows: (a) CSF-P = 9.31 × OSASW (at 3 mm) + 0.48 × BMI + 0.14 × MABP-19.94; (b) CSF-P = 16.95 × OSASW (at 9 mm) + 0.39 × BMI + 0.14 × MABP-20.90; and (c) CSF-P = 17.54 × OSASW (at 15 mm) + 0.47 × BMI + 0.13 × MABP-21.52. Applying these algorithms in the independent test group, the measured lumbar CSF-P (13.6 ± 5.1 mm Hg) did not differ significantly from the calculated MRI-derived CSF-P (OSASW at 3 mm: 12.7 ± 4.2 mm Hg (P = 0.07); at 9 mm: 13.4 ± 5.1 mm Hg (P = 0.35); and at 15 mm: 14.0 ± 4.9 mm Hg (P = 0.87)). Intraclass correlation coefficients (ICCs) were higher for the CSF-P assessment based on OSASW at 9 mm and at 15 mm behind the globe (all ICCs, 0.87) than for OSASW measurements at 3 mm (ICC, 0.80). CONCLUSIONS: In patients with normal, moderately decreased or elevated ICP, MRI-assisted measurement of the OSASW appears to be useful for the noninvasive quantitative estimation of ICP, if BMI and MABP as contributing parameters are taken into account. TRIAL REGISTRATION: Clinical trial registered with the Chinese Clinical Trial Registry: ChiCTR-OCC-11001271.

Heritable changes of epialleles in maize can be triggered in the absence of DNA methylation.

Trans-chromosomal interactions resulting in changes in DNA methylation during hybridization have been observed in several plant species. However, very little is known about the causes or consequences of these interactions. Here, we compared DNA methylomes of F1 hybrids that are mutant for a small RNA biogenesis gene, Mop1 (mediator of paramutation1) with that of their parents, wild type siblings, and backcrossed progeny in maize. Our data show that hybridization triggers global changes in both trans-chromosomal methylation (TCM) and trans-chromosomal demethylation (TCdM), most of which involved changes in CHH methylation. In more than 60% of these TCM differentially methylated regions (DMRs) in which small RNAs are available, no significant changes in the quantity of small RNAs were observed. Methylation at the CHH TCM DMRs was largely lost in the mop1 mutant, although the effects of this mutant varied depending on the location of the CHH DMRs. Interestingly, an increase in CHH at TCM DMRs was associated with enhanced expression of a subset of highly expressed genes and suppressed expression of a small number of lowly expressed genes. Examination of the methylation levels in backcrossed plants demonstrates that TCM and TCdM can be maintained in the subsequent generation, but that TCdM is more stable than TCM. Surprisingly, although increased CHH methylation in F1 plants did require Mop1, initiation of the changes in the epigenetic state of TCM DMRs did not require a functional copy of this gene, suggesting that initiation of these changes is not dependent on RNA-directed DNA methylation.

Association between contrast sensitivity function and structural damage in primary open-angle glaucoma.

AIMS: To evaluate the association between contrast sensitivity function (CSF) and glaucomatous structural damage in primary open-angle glaucoma (POAG). METHODS: A cross-sectional study was performed with 103 patients (103 eyes) aged 25-50 years who had POAG without any other ocular disease. CSF measurements were obtained by the quick CSF method, a novel active learning algorithm that covers 19 spatial frequencies and 128 contrast levels. The peripapillary retinal nerve fibre layer (pRNFL), macular ganglion cell complex (mGCC), radial peripapillary capillary (RPC) and macular vasculature were measured by optical coherence tomography and angiography. Correlation and regression analyses were used to assess the association of area under log CSF (AULCSF), CSF acuity and contrast sensitivities at multiple spatial frequencies with structural parameters. RESULTS: AULCSF and CSF acuity were positively associated with pRNFL thickness, RPC density, mGCC thickness and superficial macular vessel density (p<0.05). Those parameters were also significantly associated with contrast sensitivity at 1, 1.5, 3, 6, 12, 18 cycles per degree spatial frequencies (p<0.05) and, the lower the spatial frequency, the higher the correlation coefficient. RPC density (p=0.035, p=0.023) and mGCC thickness (p=0.002, p=0.011) had significant predictive value for contrast sensitivity at 1 and 1.5 cycles per degree, with adjusted R 2 of 0.346 and 0.343, respectively. CONCLUSIONS: Full spatial frequency contrast sensitivity impairment, most notably at low spatial frequencies, is a characteristic change in POAG. Contrast sensitivity is a potential functional endpoint for the measurement of glaucoma severity.

Retinal microvasculature is a potential biomarker for acute mountain sickness.

Increased cerebral blood flow resulting from altered capillary level autoregulation at high altitudes leads to capillary overperfusion and then vasogenic cerebral edema, which is the leading hypothesis of acute mountain sickness (AMS). However, studies on cerebral blood flow in AMS have been mostly restricted to gross cerebrovascular endpoints as opposed to the microvasculature. This study aimed to investigate ocular microcirculation alterations, the only visualized capillaries in the central neural system (CNS), during early-stage AMS using a hypobaric chamber. This study found that after high altitude simulation, the optic nerve showed retinal nerve fiber layer thickening (P=0.004-0.018) in some locations, and the area of the optic nerve subarachnoid space (P=0.004) enlarged. Optical coherence tomography angiography (OCTA) showed increased retinal radial peripapillary capillary (RPC) flow density (P=0.003-0.046), particularly on the nasal side of the nerve. The AMS-positive group had the largest increases in RPC flow density in the nasal sector (AMS-positive, Δ3.21±2.37; AMS-negative, Δ0.01±2.16, P=0.004). Among multiple ocular changes, OCTA increase in RPC flow density was associated with simulated early-stage AMS symptoms (beta=0.222, 95%CI, 0.009-0.435, P=0.042). The area under the receiver operating characteristics curve (AUC) for the changes in RPC flow density to predict early-stage AMS outcomes was 0.882 (95%CI, 0.746-0.998). The results further confirmed that overperfusion of microvascular beds is the key pathophysiologic change in early-stage AMS. RPC OCTA endpoints may serve as a rapid, noninvasive potential biomarker for CNS microvascular changes and AMS development during risk assessment of individuals at high altitudes.

Orbital cerebrospinal fluid space in glaucoma: the Beijing intracranial and intraocular pressure (iCOP) study.

OBJECTIVE: Low cerebrospinal fluid pressure (CSF-P) may be involved in the pathogenesis of glaucoma. We measured the optic nerve subarachnoid space width (ONSASW) as a surrogate for orbital CSF-P in patients with primary open-angle glaucoma (POAG) with normal and high pressure and a control group. DESIGN: Prospective observational study. PARTICIPANTS: The study included 39 patients with POAG; 21 patients had normal pressure (intraocular pressure [IOP] 21 mmHg), and 18 patients had high pressure (IOP >21 mmHg); 21 subjects formed the control group. METHODS: By using magnetic resonance imaging (MRI) with fat-suppressed fast recovery fast spin echo (FRFSE) T2-weighted sequence, we determined the ONSASW at 3, 9, and 15 mm posterior to the globe. MAIN OUTCOME MEASURES: The ONSASW and optic nerve diameter. RESULTS: At all 3 measurement locations of 3, 9, and 15 mm, the ONSASW was significantly (P<0.001, P<0.001, and P = 0.003, respectively) narrower in the normal-pressure group (0.67±0.16, 0.55±0.09, and 0.51±0.12 mm, respectively) than in the high-pressure group (0.93±0.21, 0.70±0.12, and 0.62±0.11 mm, respectively) or the control group (0.87±0.15, 0.67±0.07, and 0.61±0.07 mm, respectively). The high-pressure and control groups did not vary significantly at 3, 9, and 15 mm (P = 0.31, P = 0.39, and P = 0.44, respectively). At all 3 measurement locations, ONSASW was narrower in the normal-pressure group compared with the high-pressure and control groups after adjustment for optic nerve diameter (P<0.01). Correspondingly, the width of the optic nerve subarachnoid space measured at 3, 9, and 15 mm behind the globe, respectively, was significantly (all P<0.05) associated with IOP after adjustment for optic nerve diameter and visual field defect. CONCLUSIONS: The narrower orbital optic nerve subarachnoid space in patients with POAG with normal pressure compared with high pressure suggests a lower orbital CSF-P in patients with POAG with normal pressure.

Intraocular pressure vs intracranial pressure in disease conditions: a prospective cohort study (Beijing iCOP study).

BACKGROUND: The correlation between intracranial pressure (ICP) and intraocular pressure (IOP) is still controversial in literature and hence whether IOP can be used as a non-invasive surrogate of ICP remains unknown. The aim of the current study was to further clarify the potential correlation between ICP and IOP. METHODS: The IOP measured with Goldmann applanation tonometer was carried out on 130 patients whose ICP was determined via lumber puncture. The Pearson correlation coefficient between ICP and IOP was calculated, the fisher line discriminated analysis to evaluate the effectivity of using IOP to predict the ICP level. RESULTS: A significant correlation between ICP and IOP was found. ICP was correlated significantly with IOP of the right eyes (p < 0.001) and IOP of the left eyes (p = 0.001) and mean IOP of both eyes (p < 0.001), respectively. However, using IOP as a measurement to predict ICP, the accuracy rate was found to be 65.4%. CONCLUSION: Our data suggested that although a significant correlation exists between ICP and IOP, caution needs to be taken when using IOP readings by Goldmann applanation tonometer as a surrogate for direct cerebrospinal fluid pressure measurement of ICP.

Comparison of the Effects of Latanoprostene Bunod and Timolol on Retinal Blood Vessel Density: A Randomized Clinical Trial.

PURPOSE: To compare the differences in retinal vessel density (VD) between topical administration of latanoprostene bunod (LBN) ophthalmic solution 0.024% and timolol maleate 0.5% in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT) and normal subjects. DESIGN: Randomized, single center, crossover clinical trial. METHODS: Eligible subjects were examined during 6 study visits over 12 weeks. All subjects were randomized in a 1:1 ratio to LBN dosed once daily or timolol dosed twice daily in both eyes (OU) for a duration of 4 weeks each, separated by a 2-week washout period. A comprehensive eye examination OU was performed at each visit. Testing was performed with optical coherence tomography and optical coherence tomography angiography (optic nerve and macula), as well as visual field examination, on the study eye at baseline and before and after each treatment. RESULTS: One eye from each of 50 patients was enrolled (10 healthy patients, 26 patients with OHT, and 14 patients with OAG). After administration of LBN there was significantly increased macular VD (0.76% [0.20%-1.33%], P = 0.009) and a trend in increasing peripapillary VD in patients with OAG and patients with OHT. In contrast, after administration of timolol, there were no differences in macular VD, and a decrease in peripapillary VD only was observed in the nasal inferior sector (-0.56% [-1.08% to -0.03%], P = .04) in patients with OAG and patients with OHT. No change in peripapillary or macular VD was observed in the normal subjects (P > .05 for all). CONCLUSIONS: Topical administration of LBN enhanced macular VD in patients with OAG or patients with OHT. In contrast, timolol administration did not have any effect on VD.

Neddylation of Coro1a determines the fate of multivesicular bodies and biogenesis of extracellular vesicles.

Multivesicular bodies (MVBs) fuse with not only the plasma membranes to release extracellular vesicles (EVs) but also lysosomes for degradation. Rab7 participates in the lysosomal targeting of MVBs. However, the proteins on MVB that directly bind Rab7, causing MVB recruitment of Rab7 remain unidentified. Here, we show that Coro1a undergoes neddylation modification at K233 by TRIM4. Neddylated Coro1a is associated with the MVB membrane and facilitates MVB recruitment and activation of Rab7 by directly binding Rab7. Subsequently, MVBs are targeted to lysosomes for degradation in a Rab7-dependent manner, leading to reduced EV secretion. Furthermore, a decrease in neddylated Coro1a enhances the production of tumour EVs, thereby promoting tumour progression, indicating that neddylated Coro1a is an ideal target for the regulation of EV biogenesis. Altogether, our data identify a novel substrate of neddylation and reveal an unknown mechanism for MVB recruitment of Rab7, thus providing new insight into the regulation of EV biogenesis.

Correlation Between Office-Hour and Peak Nocturnal Intraocular Pressure in Patients Treated with Prostaglandin Analogs.

PURPOSE: To test the hypothesis that the correlation between office-hour intraocular pressure (IOP) and peak nocturnal IOP is weakened after using a prostaglandin analog. DESIGN: Before-and-after study. METHODS: Twenty-four-hour IOP data obtained in a sleep laboratory of 51 patients (22 patients with open-angle glaucoma and 29 patients with ocular hypertension) were reviewed. Patients had no IOP-lowering medication upon study entry and were then treated with prostaglandin monotherapy for 4 weeks. Measurements of IOP were taken every 2 hours in the sitting and supine positions during the diurnal/wake period (7:30 AM-9:30 PM) and in the supine position during the nocturnal/sleep period (11:30 PM-5:30 AM). Individual and average IOP readings during office hours (9:30 AM-3:30 PM) and peak IOP during the nocturnal/sleep hours were analyzed using the Pearson correlation coefficient and linear regression. RESULTS: There were statistically significant correlations for all the paired variables for the analyses. Average office-hour IOP had a higher correlation with peak nocturnal IOP than individual office-hour IOP. After the treatment with prostaglandin analog, the correlation between average office-hour IOP and nocturnal peak IOP in the sitting position (r = 0.373) and the supine position (r = 0.386) were reduced from the sitting baseline (r = 0.517) and the supine baseline (r = 0.573) in right eyes. Similar change patterns appeared in left eyes. CONCLUSION: There is a correlation between office-hour IOP reading and peak nocturnal IOP under no IOP-lowering treatment as well as under prostaglandin monotherapy. The strength of correlation was weaker under the treatment compared with baseline.

Finite element analysis of trans-lamina cribrosa pressure difference on optic nerve head biomechanics: the Beijing Intracranial and Intraocular Pressure Study.

The present study aims to assess the potential difference of biomechanical response of the optic nerve head to the same level of trans-lamina cribrosa pressure difference (TLCPD) induced by a reduced cerebrospinal fluid pressure (CSFP) or an elevated intraocular pressure (IOP). A finite element model of optic nerve head tissue (pre- and post-laminar neural tissue, lamina cribrosa, sclera, and pia mater) was constructed. Computed stresses, deformations, and strains were compared at each TLCPD step caused by reduced CSFP or elevated IOP. The results showed that elevating TLCPD increased the strain in optic nerve head, with the largest strains occurring in the neural tissue around the sclera ring. Relative to a baseline TLCPD of 10 mmHg, at a same TLCPD of 18 mmHg, the pre-laminar neural tissue experienced 11.10% first principal strain by reduced CSFP and 13.66% by elevated IOP, respectively. The corresponding values for lamina cribrosa were 6.09% and 6.91%. In conclusion, TLCPD has a significant biomechanical impact on optic nerve head tissue and, more prominently, within the pre-laminar neural tissue and lamina cribrosa. Comparatively, reducing CSFP showed smaller strain than elevating IOP even at a same level of TLCPD on ONH tissue, indicating a different potential role of low CSFP in the pathogenesis of glaucoma.

Capillary Density Measured by Optical Coherence Tomography Angiography in Glaucomatous Optic Disc Phenotypes.

PURPOSE: To compare optical coherence tomography angiography (OCTA)-measured capillary density of the optic disc among 4 glaucomatous optic disc phenotypes. DESIGN: Cross-sectional study. METHODS: Circumpapillary capillary density (cpCD) of 4 glaucomatous optic disc phenotypes in 193 eyes of 141 glaucoma patients and cpCD in 92 eyes of 55 healthy subjects from the Diagnostic Innovations in Glaucoma Study (DIGS) were compared. Areas under the receiver operating characteristic (AUROC) curves were used to evaluate diagnostic accuracy among groups after adjusting for confounders. RESULTS: Four glaucoma phenotypes were assessed: focal ischemic (n = 45), generalized cup enlargement (n = 60), myopic glaucoma (n = 38), and senile sclerotic (n = 50). Sex, mean ocular perfusion pressure, intraocular pressure, mean deviation, and the quality score did not differ among phenotypes. However, there were differences in age (P = .050), race (P = .039), axial length (P = .033), and retinal nerve fiber layer thickness (P < .001) among the groups. After adjusting for confounders, senile sclerotic discs had the lowest cpCD (37.1% [95% confidence interval, 35.3-38.8]), followed by focal ischemic (41.8% [40.0-43.6]), myopic glaucoma (42.1% [40-44.2]), and generalized cup enlargement (45.5% [44-47]) (P < .001) discs. The adjusted AUROC curves of cpCD for discriminating between healthy and glaucomatous eyes were highest in senile sclerotic eyes (0.928) and lowest in generalized cup enlargement eyes (0.704). CONCLUSIONS: OCTA-measured vessel density differs among optic disc phenotypes. Clinicians should be aware that the performance of OCTA for glaucoma diagnosis may be influenced by the optic disc phenotype.