High-accuracy 3D segmentation of wet age-related macular degeneration via multi-scale and cross-channel feature extraction and channel attention.

Wet age-related macular degeneration (AMD) is the leading cause of visual impairment and vision loss in the elderly, and optical coherence tomography (OCT) enables revolving biotissue three-dimensional micro-structure widely used to diagnose and monitor wet AMD lesions. Many wet AMD segmentation methods based on deep learning have achieved good results, but these segmentation results are two-dimensional, and cannot take full advantage of OCT's three-dimensional (3D) imaging characteristics. Here we propose a novel deep-learning network characterizing multi-scale and cross-channel feature extraction and channel attention to obtain high-accuracy 3D segmentation results of wet AMD lesions and show the 3D specific morphology, a task unattainable with traditional two-dimensional segmentation. This probably helps to understand the ophthalmologic disease and provides great convenience for the clinical diagnosis and treatment of wet AMD.

A wireless battery-free eye modulation patch for high myopia therapy.

The proper axial length of the eye is crucial for achieving emmetropia. In this study, we present a wireless battery-free eye modulation patch designed to correct high myopia and prevent relapse. The patch consists of piezoelectric transducers, an electrochemical micro-actuator, a drug microneedle array, µ-LEDs, a flexible circuit, and biocompatible encapsulation. The system can be wirelessly powered and controlled using external ultrasound. The electrochemical micro-actuator plays a key role in precisely shortening the axial length by driving the posterior sclera inward. This ensures accurate scene imaging on the retina for myopia eye. The drug microneedle array delivers riboflavin to the posterior sclera, and µ-LEDs' blue light induces collagen cross-linking, reinforcing sclera strength. In vivo experiments demonstrate that the patch successfully reduces the rabbit eye's axial length by ~1217 µm and increases sclera strength by 387%. The system operates effectively within the body without the need for batteries. Here, we show that the patch offers a promising avenue for clinically treating high myopia.

Characterization and biological activities of polysaccharides extracted from Auricularia auricula with different extraction methods.

Polysaccharides derived from Auricularia auricula exhibit diverse biological activities and hold significant potential for commercial utilization as functional food ingredients. In this investigation, polysaccharides from A. auricula were obtained using six extraction techniques (ammonium oxalate solution extraction, sodium hydroxide solution extraction, hot water extraction, pectinase and cellulase-assisted extraction, ultrasonic-assisted extraction, and microwave-assisted extraction). Subsequently, a comprehensive comparison was conducted to evaluate their physicochemical properties and biological functionalities. The ammonium oxalate solution extraction method yielded a higher extraction rate (11.76%) and polysaccharide content (84.12%), as well as a higher uronic acid content (10.13%). Although the six Auricularia polysaccharides had different molecular weight distributions, monosaccharide molar ratios, similar monosaccharide compositions, and characteristic functional groups of polysaccharides, they exhibited different surface morphology. In vitro assays showed that polysaccharides extracted by ammonium oxalate solution possessed good scavenging ability against DPPH free radical, hydroxyl free radical and superoxide anion free radical as well as reduction power of iron ion. At the same time, both polysaccharides extracted by ammonium oxalate solution and sodium hydroxide solution promoted NO production in mouse macrophages along with the secretion of cytokines TNF-α, IL-1ß, and IL-6. These results indicated significant differences in the structure and characteristics among Auricularia polysaccharides prepared by various extraction methods, which may be related to the variety or origin of A. auricula; furthermore, their bioactivities varied accordingly in vitro assays where the ammonium oxalate solution extraction method was found more beneficial for obtaining high-quality bioactive Auricularia polysaccharides.

New findings on choroidal features in healthy people by ultra-widefield swept-source optical coherence tomography angiography.

To evaluate the distribution of choroidal thickness (CT) and its trend with age in healthy people using 120° ultra-wide field swept-source optical coherence tomography angiography (UWF SS-OCTA). In this cross-sectional observational study, healthy volunteers underwent single imaging of the fundus with UWF SS-OCTA at a field of view (FOV) of 120° (24 mm × 20 mm) centered on the macula. The characteristics of CT distribution in different regions and its changes with age were analyzed. A total of 128 volunteers with a mean age of 34.9 ± 20.1 years and 210 eyes were enrolled in the study. The thickest mean choroid thickness (MCT) was located at the macular region and supratemporal region, followed by the nasal side of the optic disc, and thinnest below the optic disc. The maximum MCT was: 213.40 ± 36.65 µm for the group aged 20-29, and the minimum MCT was: 162.11 ± 31.96 µm for the group aged ≥ 60. After the age of 50, MCT was significantly and negatively correlated decreased with age (r = - 0.358, p = 0.002), and the MCT in the macular region decreased more remarkably compared to other regions. The 120° UWF SS-OCTA can observe the distribution of choroidal thickness in the range of 24 mm × 20 mm and its variation with age. It was revealed that MCT decreased more rapidly in the macular region relative to other regions after 50 years old.

SARS-CoV-2 Mpro Protease Variants of Concern Display Altered Viral Substrate and Cell Host Target Galectin-8 Processing but Retain Sensitivity toward Antivirals.

The main protease of SARS-CoV-2 (Mpro) is the most promising drug target against coronaviruses due to its essential role in virus replication. With newly emerging variants there is a concern that mutations in Mpro may alter the structural and functional properties of protease and subsequently the potency of existing and potential antivirals. We explored the effect of 31 mutations belonging to 5 variants of concern (VOCs) on catalytic parameters and substrate specificity, which revealed changes in substrate binding and the rate of cleavage of a viral peptide. Crystal structures of 11 Mpro mutants provided structural insight into their altered functionality. Additionally, we show Mpro mutations influence proteolysis of an immunomodulatory host protein Galectin-8 (Gal-8) and a subsequent significant decrease in cytokine secretion, providing evidence for alterations in the escape of host-antiviral mechanisms. Accordingly, mutations associated with the Gamma VOC and highly virulent Delta VOC resulted in a significant increase in Gal-8 cleavage. Importantly, IC50s of nirmatrelvir (Pfizer) and our irreversible inhibitor AVI-8053 demonstrated no changes in potency for both drugs for all mutants, suggesting Mpro will remain a high-priority antiviral drug candidate as SARS-CoV-2 evolves.

Early changes to retinal structure in patients with diabetic retinopathy as determined by ultrawide swept-source optical coherence tomography-angiography.

Purpose: To investigate retinal vascular changes in patients with diabetic retinopathy (DR) using the newly developed ultrawide rapid scanning swept-source optical coherence tomography angiography (SS-OCTA) device. Methods: This cross-sectional, observational study enrolled 24 patients (47 eyes) with DR, 45 patients (87 eyes) with diabetes mellitus (DM) without DR, and 36 control subjects (71 eyes). All subjects underwent 24 × 20 mm SS-OCTA examination. Vascular density (VD) and the thickness of the central macula (CM; 1 mm diameter) and temporal fan-shaped areas of 1-3 mm (T3), 3-6 mm (T6), 6-11 mm (T11), 11-16 mm (T16), and 16-21 mm (T21) were compared among groups. The VD and the thicknesses of the superficial vascular complex (SVC) and deep vascular complex (DVC) were analyzed separately. The predictive values of VD and thickness changes in DM and DR patients were evaluated by receiver operating characteristic (ROC) curve analysis. Results: The average VDs of the SVC in the CM and the T3, T6, T11, T16, and T21 areas were significantly lower in the DR than in the control group, whereas only the average VD of the SVC in the T21 area was significantly lower in the DM group. The average VD of the DVC in the CM was significantly increased in the DR group, whereas the average VDs of the DVC in the CM and T21 area were significantly decreased in the DM group. Evaluation of the DR group showed significant increases in the thicknesses of SVC-nourishing segments in the CM and T3, T6, and T11 areas and significant increases in the thicknesses of DVC-nourishing segments in the CM and T3 and T6 areas. In contrast, none of these parameters showed significant changes in the DM group. ROC curve analysis showed that the average VD of the SVC in the CM, T3, and T21 had better ability to predict DR, with areas under the ROC curves (AUCs) of 0.8608, 0.8505, and 0.8353, respectively. The average VD of the DVC in the CM was also predictive of DR, with an AUC of 0.8407. Conclusions: The newly developed ultrawide SS-OCTA device was better able to reveal early peripheral retinal vascular changes than traditional devices.

Different scan areas affect the detection rates of diabetic retinopathy lesions by high-speed ultra-widefield swept-source optical coherence tomography angiography.

Introduction: The study aimed to determine the effect of the scanning area used for high-speed ultra-widefield swept-source optical coherence tomography angiography (SS-OCTA) on the detection rate of diabetic retinopathy (DR) lesions. Methods: This prospective, observational study involved diabetic patients between October 2021 and April 2022. The participants underwent a comprehensive ophthalmic examination and high-speed ultra-widefield SS-OCTA using a 24 mm × 20 mm scanning protocol. A central area denoted as "12 mm × 12 mm-central" was extracted from the 24 mm × 20 mm image, and the remaining area was denoted as "12 mm~24mm-annulus." The rates of detection of DR lesions using the two scanning areas were recorded and compared. Results: In total, 172 eyes (41 eyes with diabetes mellitus without DR, 40 eyes with mild to moderate non-proliferative diabetic retinopathy (NPDR), 51 eyes with severe NPDR, and 40 eyes with proliferative diabetic retinopathy (PDR) from 101 participants were included. The detection rates of microaneurysms (MAs), intraretinal microvascular abnormalities (IRMAs), and neovascularization (NV) for the 12 mm × 12 mm central and 24 mm × 20 mm images were comparable (p > 0.05). The detection rate of NPAs for the 24 mm × 20 mm image was 64.5%, which was significantly higher than that for the 12 mm × 12 mm central image (52.3%, p < 0.05). The average ischemic index (ISI) was 15.26% for the 12 mm~24mm-annulus, which was significantly higher than that for the 12 mm × 12 mm central image (5.62%). Six eyes had NV and 10 eyes had IRMAs that only existed in the 12 mm~24mm-annulus area. Conclusions: The newly developed high-speed ultra-widefield SS-OCTA can capture a 24 mm × 20 mm retinal vascular image during a single scan, which improves the accuracy of detecting the degree of retinal ischemia and detection rate of NV and IRMAs.

Crystallization of Feline Coronavirus Mpro With GC376 Reveals Mechanism of Inhibition.

Coronaviruses infect a variety of hosts in the animal kingdom, and while each virus is taxonomically different, they all infect their host via the same mechanism. The coronavirus main protease (Mpro, also called 3CLpro), is an attractive target for drug development due to its essential role in mediating viral replication and transcription. An Mpro inhibitor, GC376, has been shown to treat feline infectious peritonitis (FIP), a fatal infection in cats caused by internal mutations in the feline enteric coronavirus (FECV). Recently, our lab demonstrated that the feline drug, GC373, and prodrug, GC376, are potent inhibitors of SARS-CoV-2 Mpro and solved the structures in complex with the drugs; however, no crystal structures of the FIP virus (FIPV) Mpro with the feline drugs have been published so far. Here, we present crystal structures of FIPV Mpro-GC373/GC376 complexes, revealing the inhibitors covalently bound to Cys144 in the active site, similar to SARS-CoV-2 Mpro. Additionally, GC376 has a higher affinity for FIPV Mpro with lower nanomolar Ki values compared to SARS-CoV and SARS-CoV-2 Mpro. We also show that improved derivatives of GC376 have higher potency for FIPV Mpro. Since GC373 and GC376 represent strong starting points for structure-guided drug design, determining the crystal structures of FIPV Mpro with these inhibitors are important steps in drug optimization and structure-based broad-spectrum antiviral drug discovery.

Overexpression of Twist1 in vascular endothelial cells promotes pathological retinal angiogenesis in mice.

Retinal angiogenesis is a critical process for normal retinal function. However, uncontrolled angiogenesis can lead to pathological neovascularization (NV), which is closely related to most irreversible blindness-causing retinal diseases. Understanding the molecular basis behind pathological NV is important for the treatment of related diseases. Twist-related protein 1 (TWIST1) is a well-known transcription factor and principal inducer of epithelial-mesenchymal transition (EMT) in many human cancers. Our previous study showed that Twist1 expression is elevated in pathological retinal NV. To date, however, the role of TWIST1 in retinal pathological angiogenesis remains to be elucidated. To study the role of TWIST1 in pathological retinal NV and identify specific molecular targets for antagonizing pathological NV, we generated an inducible vascular endothelial cell (EC)-specific Twist1 transgenic mouse model ( Tg-Twist1 iEC+ ). Whole-mount retinas from Tg-Twist1 iEC+ mice showed retarded vascular progression and increased vascular density in the front end of the growing retinal vasculature, as well as aneurysm-like pathological retinal NV. Furthermore, overexpression of Twist1 in the ECs promoted cell proliferation but disturbed cell polarity, thus leading to uncontrolled retinal angiogenesis. TWIST1 promoted pathological NV by activating the Wnt/ß-catenin signaling pathway and inducing the expression of NV formation-related genes, thereby acting as a 'valve' in the regulation of pathological angiogenesis. This study identified the critical role of TWIST1 in retinal pathological NV, thus providing a potential therapeutic target for pathological NV.

EVALUATION OF ARTIFICIAL INTELLIGENCE-BASED QUANTITATIVE ANALYSIS TO IDENTIFY CLINICALLY SIGNIFICANT SEVERE RETINOPATHY OF PREMATURITY.

PURPOSE: To evaluate the screening potential of a deep learning algorithm-derived severity score by determining its ability to detect clinically significant severe retinopathy of prematurity (ROP). METHODS: Fundus photographs were collected, and standard panel diagnosis was generated for each examination by combining three independent image-based gradings. All images were analyzed using a deep learning algorithm, and a quantitative assessment of retinal vascular abnormality (DeepROP score) was assigned on a 1 to 100 scale. The area under the receiver operating curve and distribution pattern of all diagnostic parameters and categories of ROP were analyzed. The correlation between the DeepROP score and expert rank ordering according to overall ROP severity of 50 examinations was calculated. RESULTS: A total of 9,882 individual examinations with 54,626 images from 2,801 infants were analyzed. Fifty-six examinations (0.6%) demonstrated Type 1 ROP and 54 examinations (0.5%) demonstrated Type 2 ROP. The DeepROP score had an area under the receiver operating curve of 0.981 for detecting Type 1 ROP and 0.986 for Type 2 ROP. There was a statistically significant correlation between the expert rank ordering of overall disease severity and the DeepROP score (correlation coefficient 0.758, P < 0.001). When hypothetical referral cutoff score of 35 was selected, all cases of severe ROP (Type 1 and Type 2 ROP) was captured and 8,562 eyes (87.6%) with no or mild ROP were excluded. CONCLUSION: The DeepROP score determined by deep learning algorithm was an objective and quantitative indicator for the severity of ROP, and it had potential in automated detecting clinically significant severe ROP.