Opicapone to Treat Early Wearing-off in Parkinson's Disease Patients: The Korean ADOPTION Trial.

BACKGROUND: Increasing levodopa (L-dopa)/dopa decarboxylase inhibitor (DDCI) daily dose or adding a catechol-O-methyltransferase (COMT) inhibitor to levodopa/DDCI therapy are strategies used to manage wearing-off symptoms in Parkinson's disease (PD) patients. OBJECTIVES: To evaluate the COMT inhibitor opicapone versus an additional dose of levodopa to treat early wearing-off in PD patients. METHODS: ADOPTION was a randomized, parallel-group, open-label, Phase 4 study conducted in Korea. At baseline, eligible patients were randomized (1:1) to opicapone 50 mg (n = 87) or L-dopa 100 mg (n = 81) (added to current L-dopa/DDCI therapy) for 4 weeks. The main efficacy endpoint was change from baseline to end of study in absolute off time. Other endpoints included changes in on time, in Movement Disorder Society-Unified Parkinson's Disease Rating Scale and 8-item PD Questionnaire scores, and the Clinical and Patient Global Impression of Improvement/Change. RESULTS: The adjusted mean in absolute off time was significantly greater for opicapone 50 mg than for L-dopa 100 mg (-62.1 vs. -16.7 minutes; P = 0.0015). Opicapone-treated patients also reported a greater reduction in the percentage of off time (P = 0.0015), a greater increase in absolute on time (P = 0.0338) and a greater increase in the percentage of on time (P = 0.0015). There were no significant differences in other secondary endpoints. The L-dopa equivalent daily dose was significantly higher in the opicapone group (750.9 vs. 690.0 mg; P = 0.0247), when a 0.5 conversion factor is applied. CONCLUSIONS: Opicapone 50 mg was more effective than an additional 100 mg L-dopa dose at decreasing off time in patients with PD and early wearing-off.

Outcomes of epiretinal proliferation embedding technique in the surgery for full-thickness macular hole.

To compare visual and anatomical outcomes between peeling and embedding of epiretinal proliferation in patients with full-thickness macular holes (FTMH) with epiretinal proliferation (EP), this retrospective cohort study classified patients into two groups based on whether EP was completely peeled (peeling group, n = 25 eyes), or embedded into the hole (embedding group, n = 31 eyes) during surgery. Preoperative characteristics and postoperative outcomes, including best-corrected visual acuity and the length of the disrupted external limiting membrane and ellipsoid zone, were compared. Preoperative features including visual acuity and hole size did not differ between the two groups. All studied eyes achieved closure of the macular hole postoperatively. Visual acuity significantly improved at 3, 6, and 12 months postoperatively in both groups. The visual acuity 1-month after surgery was better in the embedding group than that in the peeling group (0.28 ± 0.29 vs. 0.50 ± 0.42 logarithm of the minimum angle of resolution, P = 0.016), although the difference was not noted after 3 months postoperatively. The embedding group showed shorter disruption of the external limiting membrane than the peeling group postoperatively (62.6 ± 40.2 µm vs. 326.2 ± 463.9 µm at postoperative 12 months, P = 0.045). In conclusion, the embedding technique during surgical repair of a FTMH with EP facilitates recovery of the outer foveal layers and promotes earlier restoration of visual function.

Evaluating the validity and reliability of the Korean version of Scales for Outcomes in Parkinson's Disease-Cognition.

Objective: The Scales for Outcomes in Parkinson's Disease-Cognition (SCOPA-Cog) was developed to screen for cognition in PD. In this study, we aimed to evaluate the validity and reliability of the Korean version of the SCOPA-cog. Methods: We recruited 129 PD patients from 31 clinics with movement disorders in South Korea. The original version of the SCOPA-cognition was translated into Korean using the translation-retranslation method. The test-rest method with an intraclass correlation coefficient (ICC) and Cronbach's alpha coefficient were used to assess reliability. The Spearman's Rank correlation analysis with Montreal Cognitive Assessment-Korean version (MOCA-K) and Korean Mini-Mental State Examination (K-MMSE) were used to assess concurrent validity. Results: The Cronbach's alpha coefficient was 0.797, and the ICC was 0.887. Spearman's rank correlation analysis showed a significant correlation with the K-MMSE and MOCA-K scores (r = 0.546 and r = 0.683, respectively). Conclusions: Our results demonstrate that K-SCOPA-Cog exhibits good reliability and validity.

Macular hole with epiretinal proliferation: diagnostic value of en-face optical coherence tomography and clinical characteristics.

PURPOSE: To elucidate the clinical features and surgical outcomes of full-thickness macular hole (FTMH) with epiretinal proliferation (EP) diagnosed by both en-face and B-mode optical coherence tomography (OCT). METHOD: This retrospective cohort study classified idiopathic FTMHs into two groups, based on B-scan and en-face OCT imaging: FTMH with EP (EP group) and without EP (non-EP group). The preoperative features, as well as postoperative outcomes up to 12 months, were compared between the two groups. RESULT: Among 318 eyes of idiopathic FTMH that met the inclusion criteria, 59 eyes (18.6%) were in the EP group, and others were in the non-EP group. In 9 eyes (15.3%) out of the EP group, EP was not detected in the preoperative B-mode OCT but was identified through the en-face OCT. Baseline features showed a higher male proportion (47.5% vs. 27.8%, P = 0.005) and a lower incidence of vitreofoveal traction (P < 0.001) in the EP group than in the non-EP group. The EP group showed worse visual recovery than the non-EP group (- 0.23 vs. - 0.41 logarithm of the minimum angle of the resolution at 12 months, P = 0.001). CONCLUSION: The en-face OCT enhances diagnostic accuracy of EP in FTMH eyes, especially in the case with smaller extent of EP. Eyes with FTMH with EP showed a worse visual recovery than FTMH without EP.

Multiple horizontal gene transfer events have shaped plant glycosyl hydrolase diversity and function.

Plant glycosyl hydrolases (GHs) play a crucial role in selectively breaking down carbohydrates and glycoconjugates during various cellular processes, such as reserve mobilization, pathogen defense, and modification/disassembly of the cell wall. In this study, we examined the distribution of GH genes in the Archaeplastida supergroup, which encompasses red algae, glaucophytes, and green plants. We identified that the GH repertoire expanded from a few tens of genes in early archaeplastidians to over 400 genes in modern angiosperms, spanning 40 GH families in land plants. Our findings reveal that major evolutionary transitions were accompanied by significant changes in the GH repertoire. Specifically, we identified at least 23 GH families acquired by green plants through multiple horizontal gene transfer events, primarily from bacteria and fungi. We found a significant shift in the subcellular localization of GH activity during green plant evolution, with a marked increase in extracellular-targeted GH proteins associated with the diversification of plant cell wall polysaccharides and defense mechanisms against pathogens. In conclusion, our study sheds light on the macroevolutionary processes that have shaped the GH repertoire in plants, highlighting the acquisition of GH families through horizontal transfer and the role of GHs in plant adaptation and defense mechanisms.

Development of a rectally administrable Dnase1 to treat septic shock by targeting NETs.

AIMS: Neutrophil extracellular trap (NET), which is formed by DNA threads, induces septic shock by aggravating systemic inflammation. An intravenous administration of deoxyribonuclease is regarded as a compelling modality for treating septic shock. However, alternative routes should be chosen when cutaneous veins are all collapsed due to hypotension. In this study, we genetically engineered this enzyme to develop a rectal suppository formulation to treat septic shock. MAIN METHODS: Dnase1 was mutated at two amino acid residues to increase its stability in the blood and fused with a cell-penetrating peptide CR8 to increase its absorption through the rectal mucosa, which is designated AR-CR8. The life-saving effect of AR-CR8 was evaluated in a LPS-induced shock mouse model. KEY FINDINGS: AR-CR8 was shown to remove NETs effectively in human neutrophils. When AR-CR8 was administered to the mouse rectum, the deoxyribonuclease activity in the mouse serum was significantly increased. In the LPS-induced shock model, 90 % of the control mice died over 72 h after LPS injection. In contrast, the rectal administration of AR-CR8 showed a mortality rate of 30 % by 72 h after LPS injection. The Log-rank test revealed that the survival rate is significantly higher in the AR-CR8 group. The NET markers in the mouse serum were enhanced by LPS, and significantly downregulated in the AR-CR8 group. These results suggest that AR-CR8 ameliorates LPS-induced shock by degrading NETs. SIGNIFICANCE: The engineered DNASE1 could be developed as a rectal suppository formulation to treat septic shock urgently at out-of-hospital places where no syringe is available.

Rationale and protocol paper for the Asia Pacific Network for inherited eye diseases.

PURPOSE: There are major gaps in our knowledge of hereditary ocular conditions in the Asia-Pacific population, which comprises approximately 60% of the world's population. Therefore, a concerted regional effort is urgently needed to close this critical knowledge gap and apply precision medicine technology to improve the quality of lives of these patients in the Asia-Pacific region. DESIGN: Multi-national, multi-center collaborative network. METHODS: The Research Standing Committee of the Asia-Pacific Academy of Ophthalmology and the Asia-Pacific Society of Eye Genetics fostered this research collaboration, which brings together renowned institutions and experts for inherited eye diseases in the Asia-Pacific region. The immediate priority of the network will be inherited retinal diseases (IRDs), where there is a lack of detailed characterization of these conditions and in the number of established registries. RESULTS: The network comprises 55 members from 35 centers, spanning 12 countries and regions, including Australia, China, India, Indonesia, Japan, South Korea, Malaysia, Nepal, Philippines, Singapore, Taiwan, and Thailand. The steering committee comprises ophthalmologists with experience in consortia for eye diseases in the Asia-Pacific region, leading ophthalmologists and vision scientists in the field of IRDs internationally, and ophthalmic geneticists. CONCLUSIONS: The Asia Pacific Inherited Eye Disease (APIED) network aims to (1) improve genotyping capabilities and expertise to increase early and accurate genetic diagnosis of IRDs, (2) harmonise deep phenotyping practices and utilization of ontological terms, and (3) establish high-quality, multi-user, federated disease registries that will facilitate patient care, genetic counseling, and research of IRDs regionally and internationally.

Regulated Self-Folding in Multi-Layered Hydrogels Considered with an Interfacial Layer.

Multi-layered hydrogels consisting of bi- or tri-layers with different swelling ratios are designed to soft hydrogel actuators by self-folding. The successful use of multi-layered hydrogels in this application greatly relies on the precise design and fabrication of the curvature of self-folding. In general, however, the self-folding often results in an undesired mismatch with the expecting value. To address this issue, this study introduces an interfacial layer formed between each layered hydrogel, and this layer is evaluated to enhance the design and fabrication precision. By considering the interfacial layer, which forms through diffusion, as an additional layer in the multi-layered hydrogel, the degree of mismatch in the self-folding is significantly reduced. Experimental results show that as the thickness of the interfacial layer increases, the multi-layered hydrogel exhibits a 3.5-fold increase in its radius of curvature during the self-folding. In addition, the diffusion layer is crucial for creating robust systems by preventing the separation of layers in the muti-layered hydrogel during actuation, thereby ensuring the integrity of the system in operation. This new strategy for designing multi-layered hydrogels including an interfacial layer would greatly serve to fabricate precise and robust soft hydrogel actuators.

RISK OF EXUDATION IN EYES WITH NONEXUDATIVE POLYPOIDAL CHOROIDAL VASCULOPATHY.

PURPOSE: To investigate the characteristics and natural history of treatment-naive nonexudative polypoidal choroidal vasculopathy (PCV) and to determine biomarkers predicting exudative conversion. METHODS: Patients diagnosed with nonexudative PCV based on indocyanine green angiography and optical coherence tomography were included. Incidence of exudative conversion in nonexudative PCV patients and cumulative estimates for overall risk were assessed. Indocyanine green angiography and optical coherence tomography imaging-based features were analyzed to identify risk factors for exudative conversion. RESULTS: The study included 42 eyes of 40 patients with nonexudative PCV. The mean follow-up duration was 54.3 ± 35.5 months. Of the 42 eyes with nonexudative PCV, exudative conversion developed in 23 eyes (54.8%) after 42.2 ± 28.3 months (range, 8-103 months). Kaplan-Meier analysis showed that the exudation-free survival at 5 years after baseline was estimated to be 53.6%. Multivariate regression analysis showed that sequentially increased protrusion of retinal pigment epithelium in the polyp area was a significant risk factor for exudation in nonexudative PCV (odds ratio = 10.16; 95% CI 1.78-57.81; P = 0.01). CONCLUSION: Exudative conversion has been noted in nearly half of the nonexudative PCV cases in 5 years. The progressive protrusion of polypoidal lesions on optical coherence tomography examination may be a significant biomarker for predicting the near-term onset of exudation.

Biomarkers determining treatment interval of diabetic macular edema after initial resolution by anti-vascular endothelial growth factor.

PURPOSE: To identify predictive factors that help determine the interval of intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection after the initial resolution of diabetic macular edema (DME). METHODS: This retrospective case-control study enrolled treatment-naïve DME patients who had achieved DME resolution after intravitreal anti-VEGF injections. Patients were classified into the recurrence and no-recurrence groups, depending on the development of recurrent DME after deferring intravitreal anti-VEGF injection. The demographics and clinical features, including optical coherence tomography findings, were compared between the two groups. RESULTS: We enrolled 105 eyes. Sixty eyes (57.1%) belonged to the no-recurrence group, and 45 (42.9%), belonged to the recurrence group. The severity of diabetic retinopathy at baseline was related to early DME recurrence (P = 0.009). At the treatment deferring point, the non-recurrence group had both thinner central subfield thickness (289.5 ± 27.2 µm vs. 307.0 ± 38.2 µm, P = 0.011) and thinner central retinal thickness (214.9 ± 41.4 µm vs. 231.8 ± 41.2 µm, P = 0.043) compared to the recurrence group. Intraretinal cyst was observed in 34 eyes (56.7%) in the no-recurrence group and 42 eyes (93.3%) in the recurrence group at the deferring point (P < 0.001). CONCLUSION: A low risk of early DME recurrence is anticipated in the eyes with foveal thinning and no intraretinal cyst when anti-VEGF injection is deferred. These predictive biomarkers can be useful for patient monitoring and determining treatment strategies for DME patients.

Genetic and clinical characteristics of PROM1-related retinal degeneration in Korean.

This scientific report aims to comprehensively describe the genetic and clinical characteristics of PROM1-related retinal degeneration in Korean patients. Medical records of patients diagnosed with retinal dystrophy who underwent comprehensive ophthalmologic examination and genetic testing at Samsung Medical Center between January 2016 and April 2023 were retrospectively reviewed. Genetic testing included targeted gene panel sequencing and Sanger sequencing, with diagnosis based on the presence of a "Likely Pathogenic" or "Pathogenic Variant" in the PROM1 gene, as determined by the ACMG criteria. The study identified seven patients from five unrelated families with PROM1-related retinal degeneration, all carrying the autosomal dominant variant PROM1 p.R373C; no other PROM1 gene variants were detected. All patients exhibited degenerative retinal area within the macula, with peripheral retinal degeneration observed in five patients. Substantial interfamilial and intrafamilial variability was observed in the extent of macular and peripheral degeneration. Ultra-widefield autofluorescence imaging and fluorescein angiography aided in the detection of mild peripheral degeneration in one case. In conclusion, the autosomal dominant variant PROM1 p.R373C constitutes a significant proportion of PROM1-related retinal degeneration cases in the Korean population. The observed clinical heterogeneity may suggests the potential influence of additional genetic, epigenetic, and environmental factors on disease phenotypes.

Defense against phytopathogens relies on efficient antimicrobial protein secretion mediated by the microtubule-binding protein TGNap1.

Plant immunity depends on the secretion of antimicrobial proteins, which occurs through yet-largely unknown mechanisms. The trans-Golgi network (TGN), a hub for intracellular and extracellular trafficking pathways, and the cytoskeleton, which is required for antimicrobial protein secretion, are emerging as pathogen targets to dampen plant immunity. In this work, we demonstrate that tgnap1-2, a loss-of-function mutant of Arabidopsis TGNap1, a TGN-associated and microtubule (MT)-binding protein, is susceptible to Pseudomonas syringae (Pst DC3000). Pst DC3000 infected tgnap1-2 is capable of mobilizing defense pathways, accumulating salicylic acid (SA), and expressing antimicrobial proteins. The susceptibility of tgnap1-2 is due to a failure to efficiently transport antimicrobial proteins to the apoplast in a partially MT-dependent pathway but independent from SA and is additive to the pathogen-antagonizing MIN7, a TGN-associated ARF-GEF protein. Therefore, our data demonstrate that plant immunity relies on TGNap1 for secretion of antimicrobial proteins, and that TGNap1 is a key immunity element that functionally links secretion and cytoskeleton in SA-independent pathogen responses.

Local ocular factors associated with the development of diabetic macular edema: an inter-eye study.

To investigate local ocular factors associated with the development of diabetic macular edema (DME), we classified each eye of patients with unilateral DME as the DME eyes or the fellow eyes (without DME). We compared the clinical characteristics, optical coherence tomography (OCT), and OCT angiography (OCTA), ultra-wide field fundus photography, and angiography features of each eye. As a result, fifty-five patients with unilateral DME were enrolled. Although the diabetic retinopathy stage was not different between each group of eyes, DME eyes showed a higher prevalence of venous beading and a larger area of nonperfusion region than did fellow eyes (all P < 0.05). OCTA features of DME eyes also showed a larger foveal avascular zone in the deep capillary plexus and a lower vascular density in both the superficial and deep capillary plexuses (all P < 0.05). This study highlighted ocular features reflecting retinal ischemia, such as venous beading, area of nonperfusion region, and vascular density in the central retinal area, are associated with the development of DME. OCTA and ultra-wide field fluorescein angiography may be useful for evaluating the parameters of retinal ischemia and the risk of DME development.

A selective ER-phagy exerts neuroprotective effects via modulation of α-synuclein clearance in parkinsonian models.

The endoplasmic reticulum (ER) is selectively degraded by ER-phagy to maintain cell homeostasis. α-synuclein accumulates in the ER, causing ER stress that contributes to neurodegeneration in Parkinson's disease (PD), but the role of ER-phagy in α-synuclein modulation is largely unknown. Here, we investigated the mechanisms by which ER-phagy selectively recognizes α-synuclein for degradation in the ER. We found that ER-phagy played an important role in the degradation of α-synuclein and recovery of ER function through interaction with FAM134B, where calnexin is required for the selective FAM134B-mediated α-synuclein clearance via ER-phagy. Overexpression of α-synuclein in the ER of the substantia nigra (SN) resulted in marked loss of dopaminergic neurons and motor deficits, mimicking PD characteristics. However, enhancement of ER-phagy using FAM134B overexpression in the SN exerted neuroprotective effects on dopaminergic neurons and recovered motor performance. These data suggest that ER-phagy represents a specific ER clearance mechanism for the degradation of α-synuclein.

Cell- and development-specific degradation controls the levels of mixed-linkage glucan in sorghum leaves.

Mixed-linkage glucan (MLG) is a component of the cell wall (CW) of grasses and is composed of glucose monomers linked by ß-1,3 and ß-1,4 bonds. MLG is believed to have several biological functions, such as the mobilizable storage of carbohydrates and structural support of the CW. The extracellular levels of MLG are largely controlled by rates of synthesis mediated by cellulose synthase-like (CSL) enzymes, and turnover by lichenases. Economically important crops like sorghum accumulate MLG to variable levels during development. While in sorghum, like other grasses, there is one major MLG synthase (CSLF6), the identity of lichenases is yet unknown. To fill this gap, we identified three sorghum lichenases (SbLCH1-3) and characterized them in leaves in relation to the expression of SbCSLF6, and the abundance of MLG and starch. We established that SbLCH1-3 are secreted to the apoplast, consistent with a role of degrading MLG extracellularly. Furthermore, while SbCSLF6 expression was associated with cell development, the SbLCH genes exhibited distinct development-, cell-type-specific and diel-regulated expression. Therefore, our study identifies three functional sorghum MLG lichenases and highlights that MLG accumulation in sorghum leaves is likely controlled by the activity of lichenases that tune MLG levels, possibly to suit distinct cell and developmental needs in planta. These findings have important implications for improving the growth, yield, and composition of sorghum as a feedstock.

Properties of Red Mud Neutralized with Sulfuric Acid and Effects on Cement Mortar.

The purpose of this study was to recycle red mud, an industrial byproduct that generates 300,000 tons per year, into the construction industry. Red mud was prepared as a liquid, neutralized with sulfuric acid, and replaced with cement mortar. The properties of liquefied red mud (LRM) neutralized with sulfuric acid (LRM + S) were investigated as well as its effect on cement mortar's mechanical and hydration characteristics. The pH of LRM + S stabilized at 7.6; its SO3 content was ~4.19% higher than that of LRM. Sulfites were contributed by calcium and sodium sulfate. The flows and setting times of the mortars containing LRM and LRM + S decreased as the substitution rate increased. The compressive strength of mortar that replaced 5% of cement with LRM + S was similar to that of the plain cement mortar. Scanning electron microscopy and X-ray diffraction revealed that the hydration products of LRM + S-containing cement mortar were similar to those of the plain cement mortar. Thus, LRM + S can be used as a cement substitute.

Immune activation during Pseudomonas infection causes local cell wall remodeling and alters AGP accumulation.

The plant cell boundary generally comprises constituents of the primary and secondary cell wall (CW) that are deposited sequentially during development. Although it is known that the CW acts as a barrier against phytopathogens and undergoes modifications to limit their invasion, the extent, sequence, and requirements of the pathogen-induced modifications of the CW components are still largely unknown, especially at the level of the polysaccharide fraction. To address this significant knowledge gap, we adopted the compatible Pseudomonas syringae-Arabidopsis thaliana system. We found that, despite systemic signaling actuation, Pseudomonas infection leads only to local CW modifications. Furthermore, by utilizing a combination of CW and immune signaling-deficient mutants infected with virulent or non-virulent bacteria, we demonstrated that the pathogen-induced changes in CW polysaccharides depend on the combination of pathogen virulence and the host's ability to mount an immune response. This results in a pathogen-driven accumulation of CW hexoses, such as galactose, and an immune signaling-dependent increase in CW pentoses, mainly arabinose, and xylose. Our analyses of CW changes during disease progression also revealed a distinct spatiotemporal pattern of arabinogalactan protein (AGP) deposition and significant modifications of rhamnogalacturonan sidechains. Furthermore, genetic analyses demonstrated a critical role of AGPs, specifically of the Arabinoxylan Pectin Arabinogalactan Protein1, in limiting pathogen growth. Collectively, our results provide evidence for the actuation of significant remodeling of CW polysaccharides in a compatible host-pathogen interaction, and, by identifying AGPs as critical elements of the CW in plant defense, they pinpoint opportunities to improve plants against diverse pathogens.

Diabetes-Related Risk Factors for Exudative Age-Related Macular Degeneration: A Nationwide Cohort Study of a Diabetic Population.

Purpose: The purpose of this study was to identify diabetes-related risk factors for exudative age-related macular degeneration (AMD). Methods: This was a nationwide population-based cohort study using authorized clinical data provided by the Korean National Health Insurance Service. A total of 1,768,018 participants with diabetes over 50 years of age participated in the Korean National Health Screening Program between 2009 and 2012. Data on covariates, including age, sex, income level, systemic comorbidities, behavioral factors, and diabetes-related parameters, including duration of diabetes, use of insulin for diabetes control, number of oral hypoglycemic agents used, and accompanying vision-threatening diabetic retinopathy, were collected from health screening results and claims data. Patients were followed up until December 2018. Incident cases of exudative AMD were identified using registered diagnostic codes from the claims data. The prospective association of diabetes-related parameters with incident exudative AMD was investigated using the multivariable-adjusted Cox proportional hazard model. Results: During an average follow-up period of 5.93 years, 7331 patients were newly diagnosed with exudative AMD. Compared to those who had diabetes for less than 5 years, individuals with diabetes for 5 years or more had a greater risk of future exudative AMD development, with a hazard ratio (95% confidence interval) of 1.13 (1.07-1.18) in the fully adjusted model. Use of insulin for diabetes control and the presence of vision-threatening diabetic retinopathy were also associated with an increased risk of exudative AMD with a hazard ratio (95% confidence interval) of 1.16 (1.07-1.25) and 1.40 (1.23-1.61), respectively. Conclusions: A longer duration of diabetes, administration of insulin for diabetes control, and comorbid vision-threatening diabetic retinopathy were associated with an increased risk of developing exudative AMD.