The ZFP36 family of RNA binding proteins regulates homeostatic and autoreactive T cell responses.

RNA binding proteins are important regulators of T cell activation, proliferation, and cytokine production. The zinc finger protein 36 (ZFP36) family genes (Zfp36, Zfp36l1, and Zfp36l2) encode RNA binding proteins that promote the degradation of transcripts containing AU-rich elements. Numerous studies have demonstrated both individual and shared functions of the ZFP36 family in immune cells, but their collective function in T cells remains unclear. Here, we found a redundant and critical role for the ZFP36 proteins in regulating T cell quiescence. T cell-specific deletion of all three ZFP36 family members in mice resulted in early lethality, immune cell activation, and multiorgan pathology characterized by inflammation of the eyes, central nervous system, kidneys, and liver. Mice with T cell-specific deletion of any two Zfp36 genes were protected from this spontaneous syndrome. Triply deficient T cells overproduced proinflammatory cytokines, including IFN-γ, TNF, and GM-CSF, due to increased mRNA stability of these transcripts. Unexpectedly, T cell-specific deletion of both Zfp36l1 and Zfp36l2 rendered mice resistant to experimental autoimmune encephalomyelitits due to failed priming of antigen-specific CD4+ T cells. ZFP36L1 and ZFP36L2 double-deficient CD4+ T cells had poor proliferation during in vitro T helper cell polarization. Thus, the ZFP36 family redundantly regulates T cell quiescence at homeostasis, but ZFP36L1 and ZFP36L2 are specifically required for antigen-specific T cell clonal expansion.

Cerebral angiographic features of central retinal artery occlusion patients treated with intra-arterial thrombolysis.

BACKGROUND: Central retinal artery occlusion (CRAO) is an ischemic stroke of the eye. The atherosclerotic lesions in the intracranial segment of the carotid artery (CA) and the ophthalmic artery (OphA) are not well defined. We aimed to investigate the cerebral angiographic features of CRAO patients and assess the relationship between the angiographic features and outcomes after intra-arterial thrombolysis (IAT). METHODS: We included 101 acute non-arteritic CRAO patients treated with IAT. We analyzed the detailed angiographic features of the OphA and ipsilateral CA, visual acuity, fundus photography, and fluorescein angiography. RESULTS: Of the 101 patients, 38 patients (37.6%) had steno-occlusive lesions in the OphA, and 62 patients (61.4%) had atherosclerotic lesions in the ipsilateral CA. The patients with a higher degree of stenosis in the OphA showed a higher degree of stenosis (P=0.049) and a more severe morphology of plaque (P=0.000) in the ipsilateral CA. Additionally, although the visual outcome was not associated with these angiographic features, the lower degree of stenosis and less severe morphology of plaque in the ipsilateral CA resulted in a significant improvement in early reperfusion rate (P=0.018 and P=0.014, respectively) and arm-to-retina circulation (P=0.016 and P=0.002, respectively) of the eye after IAT. CONCLUSIONS: There was a significant correlation in the severity of steno-occlusive lesions between the OphA and the ipsilateral CA in patients with CRAO. The patients with less severe angiographic features in the CA showed a more improved retinal reperfusion after IAT. The angiographic findings in the CA may serve as a predictive marker for the vessel integrity of the OphA and recanalization outcome after IAT.

Assessment of Trends in the Incidence Rates of Central Retinal Artery Occlusion in Korea From 2002 to 2015.

IMPORTANCE: Central retinal artery occlusion (CRAO) is associated with and shares common risk factors with cardiovascular diseases. Over the past several decades, the incidence rates of stroke and ischemic heart disease have substantially decreased in high-income industrialized countries. However, little is known regarding current trends in CRAO incidence rates. OBJECTIVE: To estimate trends in the incidence rates of CRAO in Korea. DESIGN, SETTING, AND PARTICIPANTS: This nationwide population-based cohort study was designed on September 7, 2017, and used data from the Korean National Health Insurance Service from January 1, 2002, to December 31, 2015. Individuals with incident CRAO between 2002 and 2015 were identified using the CRAO diagnostic code (H34.1) from the International Classification of Diseases, Tenth Revision. Unadjusted CRAO incidence rates were calculated using the number of CRAO cases identified and the corresponding midyear population, which was obtained from resident registration data. Standardized incidence rates were calculated based on the 2015 census population, and weighted mean annual incidence rates with 95% CIs were computed based on the Poisson distribution. To identify trends in incidence rates, joinpoint regression analysis was performed using standardized incidence rates, and annual percentage changes (APCs) were calculated across the 12-year study period. Data were analyzed from May 1, 2019, to April 30, 2020. MAIN OUTCOMES AND MEASURES: Temporal trends in CRAO incidence rates (measured as cases per 100 000 person-years) and age-standardized APCs in CRAO incidence rates using joinpoint and birth cohort analyses. RESULTS: Among 50 million residents of Korea, 9892 individuals (5884 men [59.5%]) with incident CRAO between 2002 and 2015 were identified. The mean age of Korean individuals diagnosed with CRAO was 62.4 years (range, 0-97 years); among men and women, the mean age was 61.5 years (range, 0-96 years) and 63.6 years (range, 0-97 years), respectively. The mean standardized incidence rate of CRAO was 2.00 cases per 100 000 person-years (95% CI, 1.97-2.04 cases per 100 000 person-years) among the entire population, 2.43 cases per 100 000 person-years (95% CI, 2.37-2.49 cases per 100 000 person-years) among men, and 1.61 cases per 100 000 person-years (95% CI, 1.57-1.66 cases per 100 000 person-years) among women. The highest incidence rate (9.85 cases per 100 000 person-years; 95% CI, 9.10-10.60 cases per 100 000 person-years) was observed among those aged 80 to 84 years (13.74 cases per 100 000 person-years [95% CI, 12.16-15.32 cases per 100 000 person-years] for men and 8.04 cases per 100 000 person-years [95% CI, 7.21-8.86 cases per 100 000 person-years] for women). The incidence rate in the overall study population decreased over time (APC, -3.46%; 95% CI, -4.3% to -2.6%), and this decreasing trend was more evident in women (APC, -4.56%; 95% CI, -5.7% to -3.4%) than in men (APC, -2.90%; 95% CI, -3.9% to -1.9%). The decrease in the incidence rate was more evident among participants younger than 65 years (APC, -6.80%; 95% CI, -8.3% to -5.2%) than among those 65 years and older (APC, -0.57%; 95% CI, -1.5% to -0.4%). Among participants born after 1930, a decrease in the CRAO incidence rate over time was observed in every age group, while the same decreasing trend was not present among those born before 1930. CONCLUSIONS AND RELEVANCE: This study found that the CRAO incidence rate has been decreasing among residents of Korea, especially among women, individuals younger than 65 years, and individuals born after 1930. This observed decrease may be associated with the development of a national health care system and the general improvement in chronic disease management.

TEMPORAL CHANGES OF PARAFOVEAL MICROVASCULATURE AFTER EPIRETINAL MEMBRANE SURGERY: An Optical Coherence Tomography Angiography Study.

PURPOSE: To investigate whether the parafoveal capillary architecture predicts clinical course and visual outcomes after epiretinal membrane (ERM) surgery. METHODS: A total of 71 eyes of 71 patients treated with vitrectomy for idiopathic ERM were enrolled. The parafoveal capillary displacement and fractal geometries were compared according to the stage of ERM. Correlations between the parafoveal capillary displacement in the superficial capillary plexus, the fractal dimension and lacunarity in the deep capillary plexus (DCP), foveal thickness, and visual outcomes were evaluated. RESULTS: Compared with eyes with mild ERM, eyes with severe ERM exhibited higher parafoveal capillary displacement in the superficial capillary plexus, lower fractal dimension and higher lacunarity in the DCP, and greater foveal thickness (P < 0.05). The parafoveal capillary displacement in the superficial capillary plexus and fractal dimension and lacunarity in the DCP improved significantly, particularly at 1 month postoperatively (P < 0.05) and reached a plateau thereafter. The preoperative fractal dimension in the DCP showed a significant correlation with the best-corrected visual acuity at all follow-up time points (P < 0.05). CONCLUSION: The parafoveal fractal dimension in the DCP was significantly correlated with the visual acuity before and after ERM surgery. The parafoveal fractal dimension may serve as a predictive marker for visual outcomes after ERM surgery.

YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation.

Angiogenesis is a multistep process that requires coordinated migration, proliferation, and junction formation of vascular endothelial cells (ECs) to form new vessel branches in response to growth stimuli. Major intracellular signaling pathways that regulate angiogenesis have been well elucidated, but key transcriptional regulators that mediate these signaling pathways and control EC behaviors are only beginning to be understood. Here, we show that YAP/TAZ, a transcriptional coactivator that acts as an end effector of Hippo signaling, is critical for sprouting angiogenesis and vascular barrier formation and maturation. In mice, endothelial-specific deletion of Yap/Taz led to blunted-end, aneurysm-like tip ECs with fewer and dysmorphic filopodia at the vascular front, a hyper-pruned vascular network, reduced and disarranged distributions of tight and adherens junction proteins, disrupted barrier integrity, subsequent hemorrhage in growing retina and brain vessels, and reduced pathological choroidal neovascularization. Mechanistically, YAP/TAZ activates actin cytoskeleton remodeling, an important component of filopodia formation and junction assembly. Moreover, YAP/TAZ coordinates EC proliferation and metabolic activity by upregulating MYC signaling. Overall, these results show that YAP/TAZ plays multifaceted roles for EC behaviors, proliferation, junction assembly, and metabolism in sprouting angiogenesis and barrier formation and maturation and could be a potential therapeutic target for treating neovascular diseases.

Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation.

The activation of transcriptional coactivators YAP and its paralog TAZ has been shown to promote resistance to anti-cancer therapies. YAP/TAZ activity is tightly coupled to actin cytoskeleton architecture. However, the influence of actin remodeling on cancer drug resistance remains largely unexplored. Here, we report a pivotal role of actin remodeling in YAP/TAZ-dependent BRAF inhibitor resistance in BRAF V600E mutant melanoma cells. Melanoma cells resistant to the BRAF inhibitor PLX4032 exhibit an increase in actin stress fiber formation, which appears to promote the nuclear accumulation of YAP/TAZ. Knockdown of YAP/TAZ reduces the viability of resistant melanoma cells, whereas overexpression of constitutively active YAP induces resistance. Moreover, inhibition of actin polymerization and actomyosin tension in melanoma cells suppresses both YAP/TAZ activation and PLX4032 resistance. Our siRNA library screening identifies actin dynamics regulator TESK1 as a novel vulnerable point of the YAP/TAZ-dependent resistance pathway. These results suggest that inhibition of actin remodeling is a potential strategy to suppress resistance in BRAF inhibitor therapies.

Actin remodelling factors control ciliogenesis by regulating YAP/TAZ activity and vesicle trafficking.

Primary cilia exert a profound impact on cell signalling and cell cycle progression. Recently, actin cytoskeleton destabilization has been recognized as a dominant inducer of ciliogenesis, but the exact mechanisms regulating ciliogenesis remain poorly understood. Here we show that the actin cytoskeleton remodelling controls ciliogenesis by regulating transcriptional coactivator YAP/TAZ as well as ciliary vesicle trafficking. Cytoplasmic retention of YAP/TAZ correlates with active ciliogenesis either in spatially confined cells or in cells treated with an actin filament destabilizer. Moreover, knockdown of YAP/TAZ is sufficient to induce ciliogenesis, whereas YAP/TAZ hyperactivation suppresses serum starvation-mediated ciliogenesis. We also identify actin remodelling factors LIMK2 and TESK1 as key players in the ciliogenesis control network in which YAP/TAZ and directional vesicle trafficking are integral components. Our work provides new insights for understanding the link between actin dynamics and ciliogenesis.

Myosin heavy chain 10 (MYH10) is required for centriole migration during the biogenesis of primary cilia.

The actin cytoskeleton has been implicated in the assembly of cilia, but roles of actin-dependent motor proteins in ciliogenesis remain unclear. Myosin heavy chain 10 (MYH10), one of the isoforms of non-muscle myosin II, is known to mediate centrosome reorientation during cell migration. Here we show that MYH10 is required for centriole migration to the apical plasma membrane, which occurs at the onset of ciliogenesis. Knockdown of MYH10 in RPE1 cells caused a reduction in the levels of cortical filamentous actin (F-actin) and its binding protein EZRIN. Moreover, both centriole migration and subsequent cilium assembly were defective in MYH10 depleted cells. We further found that MYH10 influences centrosomal recruitment of IFT88, which is required for the transport of building blocks to the ciliary tip. The role of MYH10 in IFT88 recruitment appears to be indirect in that there is a correlation between centriolar IFT88 levels and centriolar positions along the apical-basal axis during ciliogenesis. Our results indicate that MYH10 contributes to ciliogenesis in RPE1 cells by promoting cortical actin-dependent centriole migration.

Validity and reliability of head posture measurement using Microsoft Kinect.

AIMS: To investigate the validity and reliability of Microsoft Kinect-based head tracker (KHT) for measuring head posture. METHODS: Considering the cervical range of motion (CROM) as a reference, one-dimensional and three-dimensional (1D and 3D) head postures of 12 normal subjects (28-58 years of age; 6 women and 6 men) were obtained using the KHT. The KHT was validated by Pearson's correlation coefficient and intraclass correlation (ICC) coefficient. Test-retest reliability of the KHT was determined by its 95% limit of agreement (LoA) with the Bland-Altman plot. Face recognition success rate was evaluated for each head posture. RESULTS: Measurements of 1D and 3D head posture performed using the KHT were very close to those of the CROM with correlation coefficients of 0.99 and 0.97 (p<0.05), respectively, as well as with an ICC of >0.99 and 0.98, respectively. The reliability tests of the KHT in terms of 1D and 3D head postures had 95% LoA angles of approximately ±2.5° and ±6.5°, respectively. CONCLUSIONS: The KHT showed good agreement with the CROM and relatively favourable test-retest reliability. Considering its high performance, convenience and low cost, KHT could be clinically used as a head posture-measuring system.

Ocular findings in children with single umbilical artery: a case series of 14 children.

PURPOSE: Single umbilical artery (SUA) is the most common malformation of the umbilical cord. However, there have been no studies on the ocular findings in SUA, except for one case report. This study aimed to investigate the ocular findings in children with SUA. METHODS: Fourteen children (eight boys and six girls) with SUA were evaluated retrospectively. All children underwent a complete ophthalmologic examination. RESULTS: The prevalence of abnormal ocular findings in children was up to 42.9%. Refractive errors are detected in four eyes (14.3%): myopia ≥-1.50 diopters (D) in one eye (3.6%) and hyperopia ≥+2.00 D in three eyes (10.7%). Epiblepharon was found in three children (21.4%), and strabismus was detected in one child (7.1%). CONCLUSIONS: Approximately half of the children with SUA showed abnormal ocular findings, therefore, our case series highlight the need for a comprehensive ocular examination and larger prospective research studies in young patients with SUA.

Long-term temporal changes of peripapillary retinal nerve fiber layer thickness before and after panretinal photocoagulation in severe diabetic retinopathy.

PURPOSE: To analyze the long-term changes of peripapillary retinal nerve fiber layer (RNFL) thickness before and after panretinal photocoagulation (PRP) in patients with severe diabetic retinopathy. METHODS: In this retrospective observational case series, we reviewed the records of 46 patients (68 eyes) with severe diabetic retinopathy, who were treated with PRP and could be followed for more than 6 months. Peripapillary RNFL thickness and foveal thickness were measured at baseline, 3-month intervals until 1 year post-PRP, and 6- to 12-month intervals after 1 year post-PRP using optical coherence tomography. Long-term changes of peripapillary RNFL thickness and foveal thickness as well as the correlation between the two parameters were analyzed. RESULTS: The average RNFL thickness (360° measurement) decreased significantly from 108.4 µm to 103.5 µm at 2 years post-PRP. The average RNFL thickness increased slightly during the initial 3 months post-PRP and thereafter gradually decreased, showing statistically significant reductions at 2 years post-PRP (false discovery rate adjusted P = 0.0051). The superior and inferior quadrant RNFL thicknesses were significantly decreased at 2 years post-PRP (false discovery rate adjusted P = 0.0119 and 0.0051, respectively). The decrease in the nasal quadrant RNFL thickness showed borderline significance at 2 years post-PRP (false discovery rate adjusted P = 0.0854). However, there was no significant decrease in RNFL thickness for the temporal quadrant at any follow-up time. In addition, there was no significant difference in the foveal thickness. But, the pattern of temporal changes in foveal thickness showed a similar pattern with that of temporal RNFL thickness. CONCLUSION: This study shows that average RNFL thickness after PRP undergoes early thickening and subsequent progressive thinning throughout the 2 years post-PRP. This temporal change varies according to the peripapillary RNFL quadrant. Our results also indicate that temporal RNFL and foveal thickness have a similar pattern of long-term change after PRP.

Nintendo Wii remote controllers for head posture measurement: accuracy, validity, and reliability of the infrared optical head tracker.

PURPOSE: To evaluate the accuracy, validity, and reliability of a newly developed infrared optical head tracker (IOHT) using Nintendo Wii remote controllers (WiiMote; Nintendo Co. Ltd., Kyoto, Japan) for measurement of the angle of head posture. METHODS: The IOHT consists of two infrared (IR) receivers (WiiMote) that are fixed to a mechanical frame and connected to a monitoring computer via a Bluetooth communication channel and an IR beacon that consists of four IR light-emitting diodes (LEDs). With the use of the Cervical Range of Motion (CROM; Performance Attainment Associates, St. Paul, MN) as a reference, one- and three-dimensional (1- and 3-D) head postures of 20 normal adult subjects (20-37 years of age; 9 women and 11 men) were recorded with the IOHT. RESULTS: In comparison with the data from the CROM, the IOHT-derived results showed high consistency. The measurements of 1- and 3-D positions of the human head with the IOHT were very close to those of the CROM. The correlation coefficients of 1- and 3-D positions between the IOHT and the CROM were more than 0.99 and 0.96 (P < 0.05, Pearson's correlation test), respectively. Reliability tests of the IOHT for the normal adult subjects for 1- and 3-D positions of the human head had 95% limits of agreement angles of approximately ±4.5° and ±8.0°, respectively. CONCLUSIONS: The IOHT showed strong concordance with the CROM and relatively good test-retest reliability, thus proving its validity and reliability as a head-posture-measuring device. Considering its high performance, ease of use, and low cost, the IOHT has the potential to be widely used as a head-posture-measuring device in clinical practice.

Distance stereotest using a 3-dimensional monitor for adult subjects.

PURPOSE: To evaluate the validity and test-retest reliability of a contour-based 3-dimensional (3-D) monitor distance stereotest (distance 3-D stereotest) and to measure the maximum horizontal disparity that can be fused with disparity vergence for determining the largest measurable disparity of true stereopsis. DESIGN: Observational case series. METHODS: Sixty-four normal adult subjects (age range, 23 to 39 years) were recruited. Contour-based circles (crossed disparity, 5000 to 20 seconds of arc; Microsoft Visual Studio C(++) 6.0; Microsoft, Inc, Seattle, Washington, USA) were generated on a 3-D monitor (46-inch stereoscopic display) using polarization glasses and were presented to subjects with normal binocularity at 3 m. While the position of the stimulus changed among 4 possible locations, the subjects were instructed to press the corresponding position of the stimulus on a keypad. The results with the new distance 3-D stereotest were compared with those from the distance Randot stereotest. RESULTS: The results of the distance 3-D stereotest and the distance Randot stereotests were identical in 64% and within 1 disparity level in 97% of normal adults. Scores obtained with the 2 tests showed a statistically significant correlation (r = 0.324, P = .009). The half-width of the 95% limit of agreement was 0.47 log seconds of arc (1.55 octaves) using the distance 3-D stereotest--similar to or better than that obtained with conventional distance stereotests. The maximum binocular disparity that can be fused with vergence was 1828 ± 794 seconds of arc (range, 4000 to 500). CONCLUSIONS: The distance 3-D stereotest showed good concordance with the distance Randot stereotest and relatively good test-retest reliability, supporting the validity of the distance 3-D stereotest. The normative data set obtained from the present study can serve as a useful reference for quantitative assessment of a wide range of binocular sensory abnormalities.

Combined photodynamic therapy and intravitreal bevacizumab injection for the treatment of adult Coats' disease: a case report.

A 68-year-old woman presented with a visual field defect in her right eye. The fundus of her right eye showed multiple telangiectatic vessels, retinal hemorrhages, and subretinal exudates in the inferior peripheral retina. Nine months later, the subretinal exudates extended to the fovea despite treatment with laser photocoagulation. Cryotherapy was not possible at the time because of the posterior location of the retinal telangiectatic vessels. She was treated with a combination of photodynamic therapy (PDT) and intravitreal bevacizumab injection: three injections were given at 2-month intervals. After this combined therapy, her right fundus revealed a significant regression of abnormal retinal vessels and subretinal exudates. A fluorescein angiography showed no leakage from the abnormal retinal vessels. At 9 months after the combined therapy, she was able to maintain a stable visual acuity and visual field. This is the first case report that demonstrates the efficacy of the combined treatment of PDT and intravitreal bevacizumab injection in Coats's disease. This combined therapy is a kind of treatment modality for adult Coats' disease in cases which cryotherapy cannot be employed and are refractory to laser photocoagulation.

Long-term temporal changes of macular thickness and visual outcome after vitrectomy for idiopathic epiretinal membrane.

PURPOSE: To evaluate the long-term correlation of visual outcome and macular thickness after vitrectomy for idiopathic epiretinal membrane and to identify prognostic factors for good visual outcome. DESIGN: Retrospective, observational case series. METHODS: We reviewed the records of 52 patients with idiopathic epiretinal membrane who were treated with vitrectomy and could be followed up for more than 12 months. The main outcome measures were best-corrected visual acuity (BCVA) and central macular thickness at baseline; at 1, 3, 6, and 12 months after surgery; and at the final follow-up visit. The correlation between BCVA and central macular thickness was analyzed and the receiver operating characteristic curve analysis was performed to obtain cutoff values for visual prognosis. RESULTS: Most of the changes in BCVA and central macular thickness took place during the first 3 months and reached a plateau at 12 months after surgery. Despite the lack of changes in BCVA after 12 months of follow-up, significant reduction in central macular thickness could still be observed over 12 months after surgery. The final BCVA was correlated significantly with preoperative BCVA and central macular thickness and early postoperative central macular thickness. Among them, the postoperative central macular thickness at 1 month showed the largest area under the receiver operating characteristic curve. CONCLUSIONS: Given the removal of the confounding effect of cataract, postoperative follow-up of 12 months may be sufficient to reach the final BCVA after surgery. However, more time is needed to achieve final central macular thickness. Because of the significant correlation between final BCVA and early postoperative central macular thickness, serial optical coherence tomography images in the early postoperative period were needed to predict visual outcome after epiretinal membrane removal.