Neural consequences of binaural beat stimulation on auditory sentence comprehension: an EEG study.

A growing literature has shown that binaural beat (BB)-generated by dichotic presentation of slightly mismatched pure tones-improves cognition. We recently found that BB stimulation of either beta (18 Hz) or gamma (40 Hz) frequencies enhanced auditory sentence comprehension. Here, we used electroencephalography (EEG) to characterize neural oscillations pertaining to the enhanced linguistic operations following BB stimulation. Sixty healthy young adults were randomly assigned to one of three listening groups: 18-Hz BB, 40-Hz BB, or pure-tone baseline, all embedded in music. After listening to the sound for 10 min (stimulation phase), participants underwent an auditory sentence comprehension task involving spoken sentences that contained either an object or subject relative clause (task phase). During the stimulation phase, 18-Hz BB yielded increased EEG power in a beta frequency range, while 40-Hz BB did not. During the task phase, only the 18-Hz BB resulted in significantly higher accuracy and faster response times compared with the baseline, especially on syntactically more complex object-relative sentences. The behavioral improvement by 18-Hz BB was accompanied by attenuated beta power difference between object- and subject-relative sentences. Altogether, our findings demonstrate beta oscillations as a neural correlate of improved syntactic operation following BB stimulation.

Prior conscious experience modulates the impact of audiovisual temporal correspondence on unconscious visual processing.

Conscious visual experiences are enriched by concurrent auditory information, implying audiovisual interactions. In the present study, we investigated how prior conscious experience of auditory and visual information influences the subsequent audiovisual temporal integration under the surface of awareness. We used continuous flash suppression (CFS) to render perceptually invisible a ball-shaped object constantly moving and bouncing inside a square frame window. To examine whether audiovisual temporal correspondence facilitates the ball stimulus to enter awareness, the visual motion was accompanied by click sounds temporally congruent or incongruent with the bounces of the ball. In Experiment 1, where no prior experience of the audiovisual events was given, we found no significant impact of audiovisual correspondence on visual detection time. However, when the temporally congruent or incongruent bounce-sound relations were consciously experienced prior to CFS in Experiment 2, congruent sounds yielded faster detection time compared to incongruent sounds during CFS. In addition, in Experiment 3, explicit processing of the incongruent bounce-sound relation prior to CFS slowed down detection time when the ball bounces became later congruent with sounds during CFS. These findings suggest that audiovisual temporal integration may take place outside of visual awareness though its potency is modulated by previous conscious experiences of the audiovisual events. The results are discussed in light of the framework of multisensory causal inference.

Sensorimotor and working memory systems jointly support development of perceptual rhythm processing.

We studied the role of sensorimotor and working memory systems in supporting development of perceptual rhythm processing with 119 participants aged 7-12 years. Children were assessed for their abilities in sensorimotor synchronization (SMS; beat tapping), auditory working memory (AWM; digit span), and rhythm discrimination (RD; same/different judgment on a pair of musical rhythm sequences). Multiple regression analysis revealed that children's RD performance was independently predicted by higher beat tapping consistency and greater digit span score, with all other demographic variables (age, sex, socioeconomic status, music training) controlled. The association between RD and SMS was more robust in the slower tempos (60 and 100 beats-per-minute (BPM)) than faster ones (120 and 180 BPM). Critically, the relation of SMS to RD was moderated by age in that RD performance was predicted by beat tapping consistency in younger children (age: 7-9 years), but not in older children (age: 10-12 years). AWM was the only predictor of RD in older children. Together, the current findings demonstrate that the sensorimotor and working memory systems jointly support RD processing during middle-to-late childhood and that the degree of association between the two systems and perceptual rhythm processing is shifted before entering into early adolescence.

Beta and gamma binaural beats enhance auditory sentence comprehension.

Binaural beats-an auditory illusion produced when two pure tones of slightly different frequencies are dichotically presented-have been shown to modulate various cognitive and psychological states. Here, we investigated the effects of binaural beat stimulation on auditory sentence processing that required interpretation of syntactic relations (Experiment 1) or an evaluation of syntactic well formedness (Experiment 2) with a large cohort of healthy young adults (N = 200). In both experiments, participants performed a language task after listening to one of four sounds (i.e., between-subject design): theta (7 Hz), beta (18 Hz), and gamma (40 Hz) binaural beats embedded in music, or the music only (baseline). In Experiment 1, 100 participants indicated the gender of a noun linked to a transitive action verb in spoken sentences containing either a subject or object-relative center-embedded clause. We found that both beta and gamma binaural beats yielded better performance, compared to the baseline, especially for syntactically more complex object-relative sentences. To determine if the binaural beat effect can be generalized to another type of syntactic analysis, we conducted Experiment 2 in which another 100 participants indicated whether or not there was a grammatical error in spoken sentences. However, none of the binaural beats yielded better performance for this task indicating that the benefit of beta and gamma binaural beats may be specific to the interpretation of syntactic relations. Together, we demonstrate, for the first time, the positive impact of binaural beats on auditory language comprehension. Both theoretical and practical implications are discussed.

Role of the JAK/STAT pathway in a streptozotocin-induced diabetic retinopathy mouse model.

PURPOSE: The Janus tyrosine kinase and signal transducers and activators of transcription (JAK/STAT) pathway is involved in vascular endothelial growth factor (VEGF) expression, but the role of this pathway in diabetic retinopathy (DR) remains unclear. We investigated the role of the JAK/STAT pathway on DR and VEGF expression using a streptozotocin (STZ)-induced DR mouse model. METHODS: Cultured ARPE-19 cells were exposed to high-glucose conditions and treated with JAK/STAT inhibitors (JAK inhibitor I [JAKiI], tofacitinib, STAT3 inhibitor [STAT3i]) for 48 h. Reverse-transcription polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay were used to investigate p-JAK/STAT and VEGF expression. Diabetes was induced by intraperitoneal injection of STZ (50 mg/kg) in C57BL/6 mice for 5 days. DR development was evaluated every 4 weeks. JAK/STAT inhibitors were administered for 8 weeks. Immunofluorescence was used to measure the activation status of the JAK/STAT pathway and VEGF production in the retinal tissue. RESULTS: In ARPE-19 cells exposed to high-glucose conditions, the mRNA and secretory protein levels of VEGF, p-JAK1, p-JAK2, p-STAT3, and p-STAT5 levels were significantly increased. Treatment with JAKiI, tofacitinib, and STAT3i significantly suppressed VEGF to basal levels at both the mRNA and secretory levels in vitro. In STZ-induced mice, retinal vascular leakage, p-JAK1, p-JAK2, p-JAK3, p-STAT3, and VEGF were significantly increased after diabetes induction. Diabetes-induced retinal vascular leakage was significantly reduced by treatment with JAKiI and tofacitinib. Increased p-JAK1 and VEGF in STZ-induced mice were significantly reduced by JAKiI (p < 0.05, p < 0.001) and tofacitinib (p < 0.001, respectively). CONCLUSION: JAK1 may be more involved in VEGF production and DR progression in mice than JAK2, JAK3, and STAT3.

Title: efficacy of intravitreal dexamethasone implant on hard exudate in diabetic macular edema.

BACKGROUND: To investigate the effect of intravitreal dexamethasone implant (DEX implant) on hard exudate (HE) accompanying diabetic macular edema (DME). METHODS: This study was a non-comparative non-randomized 1-year prospective interventional study. Patients with DME and HE were treated using DEX implant two or three times. Color fundus photography and optical coherence tomography (OCT) were performed at every visit. HE area was measured semi-automatically from the fundus photographs. RESULTS: Thirty-five patients completed the study. Eleven patients (31.4%) received two injections, while the remaining received three times. HE area (primary outcome) significantly decreased from 1.404±2.094 mm2 (baseline) to 0.212±0.592 mm2 (last visit), which was 24% of the baseline HE area (P<0.001). HE1500 (HE within 1500 µm from the fovea) area also decreased significantly from 0.382±0.467 mm2 to 0.066±0.126 mm2 (P<0.001). Furthermore, anaverage best corrected visual acuity (BCVA) improvement of 4.4 Early Treatment Diabetic Retinopathy Study (ETDRS) letters was observed (from 49.9±18.3 to 54.3±20.4 letters) (P= 0.008). Central macular thickness (CMT) decreased from 455.8±23.6 µm to 366.8±31.1 µm (P=0.009). Repetitive measurements for entire study duration was analyzed using generalized estimating equations (GEE), where BCVA was related to age, CMT, and HE1500 area in multivariate analyses. CONCLUSION: DEX implant could reduce and suppress HE in DME for one year with two or three injections. And centrally located HE area (HE1500 area) is related to vision. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02399657 , Registered 26 March 2015.

One-Year Results of Treatment of Diabetic Macular Edema with Aflibercept Using the Treat-and-Extend Dosing Regimen: the VIBIM Study.

INTRODUCTION: The purpose of this study was to report the one-year results of treatment of diabetic macular edema (DME) with aflibercept using a treat-and-extend regimen (TER). METHODS: This was a prospective, multicenter, single-arm study planned for 2 years. The eyes received 5 consecutive intravitreal injections of 2 mg of aflibercept every 4 weeks, and the interval between injections was then adjusted by 2 weeks based on changes in the central subfield macular thickness (CSMT). If the CSMT was worse, stable, or better, the interval was shortened, extended, or maintained, respectively. The primary outcome measure was the change in best-corrected visual acuity (BCVA) from baseline to 104 weeks, and the secondary outcome was the change in BCVA from baseline to 52 weeks. RESULTS: Of the 48 patients enrolled, 46 completed a 1-year visit. BCVA improved significantly by 9.1 letters (95% confidence interval: 5.3-13.0 letters) from 56.2 letters at baseline (p < 0.001), and CSMT decreased by -171.7 µm from 489.4 to 317.7 µm (p < 0.001). The proportion of eyes having 20/40 or better vision increased from 17.4 to 41.3%, and the proportion of eyes that gained ≥15 letters was 28.3%. The mean number of injections was 8.5 times for 52 weeks. Worsening of macular edema did not occur in 76.1% of eyes during the extension period, and the interval between injections was extended to 12 weeks in 73.9% of eyes at 52 weeks. CONCLUSIONS: The TER showed 1-year efficacy comparable to that of the fixed dosing regimen of pivotal trials, and its flexible dosing would prevent overtreatment.

Type I pig collagen enhances the efficacy of PEDF 34-mer peptide in a mouse model of laser-induced choroidal neovascularization.

BACKGROUND: Pigment epithelium-derived factor (PEDF)-derived 34-mer peptide (PEDF34, Asp44-Asn77) has anti-angiogenic activity but has limitations in clinical application because of an inverted bell-shaped dose-effect relationship and a short half-life. In this study, we attempted to mitigate these problems by mixing PEDF34 with type I collagen. METHODS: The anti-angiogenic activity of the PEDF34/atelocollagen mixture was evaluated by HUVEC tube formation assay and in a laser-induced choroidal neovascular (CNV) mouse model. PEDF34 and/or collagen were administrated using intravitreal injections or eye drops. CNV lesion size was quantified using FITC-dextran-perfused retinal whole mounts. Western blot analysis and inhibitor assays were used to define the action mechanisms of PEDF34 and the mixture. RESULTS: Collagen broadened the effective dose range of PEDF34 in the tube formation assay by > 250 times (from 0.2 to 50 nM). In the CNV model, five intravitreal injections of PEDF34 were required for therapeutic effect, whereas the mixture had a significant therapeutic effect following a single injection. Eye drops of the mixture showed significantly stronger CNV-suppressive effects than drops of PEDF34 alone. The anti-angiogenic activity of PEDF34 might be mediated by inhibition of ERK and JNK activation by VEGF, and collagen potentiated these effects. CONCLUSIONS: Collagen can serve as a carrier and reservoir of PEDF34. PEDF peptide/collagen mixture is easy to prepare than conventional methods for maintaining the therapeutic effect of PEDF peptide.

Efficacy of fixed-dosing aflibercept for treating polypoidal choroidal vasculopathy: 1-year results of the VAULT study.

PURPOSE: To investigate fixed-dosing aflibercept for treating polypoidal choroidal vasculopathy (PCV). METHODS: This phase IV, prospective, single-arm, interventional case series was conducted in eight centers. Forty treatment-naïve PCV patients were administered three monthly doses of intravitreal aflibercept (2.0 mg) and an injection every 2 months thereafter. Best-corrected visual acuity (BCVA) and central subfield macular thickness (CSMT) were measured at each visit. Fluorescein and indocyanine green angiography (ICGA) were performed at baseline, 3 and 12 months. The primary outcome measure was the proportion of patients who maintained BCVA (<15 letters loss) at 12 months. Changes in BCVA, macular appearance, and polypoidal lesion appearance were also examined. RESULTS: Thirty-five eyes (87.5 %) had maintained BCVA at 12 months. Average BCVA was significantly higher at 12 months (20/53, 64.2 letters) than at baseline (20/80, 55.1 letters, 9-letter gain; P < .001). Mean CSMT was significantly lower at 12 months (253.6 µm) than at baseline (365.2 µm, P < .001). The macula was dry in 32 (76.2 %), 27 (64.3 %), and 24 eyes (60.0 %) at 3, 6, and 12 months respectively. Fourteen eyes (33.3 %) had a fluid recurrence or increase at 6 months, and they had a significantly lower vision gain (P = .005) than other patients at 12 months. Complete polyp regression occurred in 26 eyes (66.7 %) at 12 months. CONCLUSIONS: Fixed-dosing aflibercept showed favorable outcomes in PCV patients at 12 months. However, some patients had worse outcomes because of fluid recurrence during maintenance dosing, and these patients would require additional treatments.

TOPOGRAPHIC CHANGES OF THE MACULA AFTER CLOSURE OF IDIOPATHIC MACULAR HOLE.

PURPOSE: To investigate retinal displacement in the macula after surgical closure of idiopathic macular hole and to identify factors correlated with displacement. METHODS: This retrospective multicenter study included 73 eyes of 73 patients having idiopathic macular hole. A custom program was developed to compare the position of the retinal vessels in the macula between preoperative and postoperative photographs. En face images of a 6 mm × 6 mm optical coherence tomography volume scans were registered to calculate the scale. A grid comprising 16 sectors in 2 rings (inner; 2-4 mm and outer; 4-6 mm) was superimposed. The displacement of the retinal vessels was measured as a vector value by comparing the location of the retinal vessels in each sector. The correlation between displacement and various clinical parameters was analyzed. RESULTS: The average displacement was 57.2 µm at an angle of -3.3° (nasal and slightly inferior). Displacement was larger in the inner ring (79.2 µm) than in the outer ring (35.3 µm, P < 0.001), and larger in the temporal sectors than in the corresponding nasal sectors (P ≤ 0.008). Inferior and superior displacement was noted in the superior and inferior sectors, respectively. Multiple regression analysis revealed that basal horizontal macular hole diameter and size of internal limiting membrane removal were independent factors of displacement. CONCLUSION: The macula was displaced centripetally, nasally, and slightly inferiorly after surgical closure of idiopathic macular hole. Hole closure, contraction of the nerve fiber layer, and gravity are the suggested mechanisms of macular displacement caused by internal limiting membrane peeling.

Changes of choroidal neovascularization in indocyanine green angiography after intravitreal ranibizumab injection.

PURPOSE: To investigate vascular structural changes of choroidal neovascularization (CNV) followed by intravitreal ranibizumab injections using indocyanine green angiography. METHODS: A total of 31 patients with exudative age-related macular degeneration and CNV whose structures were identifiable in indocyanine green angiography were included. Ranibizumab was injected into the vitreous cavity once a month for 3 months and then as needed for the next 3 months prospectively. Indocyanine green angiography was performed at baseline, 3, and 6 months. Early to midphase images of the indocyanine green angiography in the details of vascular structure of the CNV were discerned the best were used in the image analysis. Vascular structures of CNV were described as arteriovenular and capillary components, and structural changes were assessed. RESULTS: Arteriovenular components were observed in 29 eyes (94%). Regression of the capillary components was observed in most cases. Although regression of arteriovenular component was noted in 14 eyes (48%), complete resolution was not observed. The eyes were categorized into 3 groups according to CNV structural changes: the regressed (Group R, 10 eyes, 31%), the matured (Group M, 7 eyes, 23%), and the growing (Group G, 14 eyes, 45%). In Group R, there was no regrowth of CNV found at 6 months. In Group M, distinct vascular structures were observed at 3 months and persisted without apparent changes at 6 months. In Group G, growth or reperfusion of capillary components from the persisting arteriovenular components was noted at 6 months. CONCLUSION: Both capillary and arteriovenular components were regressed during monthly ranibizumab injections. However, CNV regrowth was observed in a group of patients during the as-needed treatment phase.

Wafer-Scale Characterization of 1692-Pixel-Per-Inch Blue Micro-LED Arrays with an Optimized ITO Layer.

Wafer-scale blue micro-light-emitting diode (micro-LED) arrays were fabricated with a pixel size of 12 µm, a pixel pitch of 15 µm, and a pixel density of 1692 pixels per inch, achieved by optimizing the properties of e-beam-deposited and sputter-deposited indium tin oxide (ITO). Although the sputter-deposited ITO (S-ITO) films exhibited a densely packed morphology and lower resistivity compared to the e-beam-deposited ITO (E-ITO) films, the forward voltage (VF) values of a micro-LED with the S-ITO films were higher than those with the E-ITO films. The VF values for a single pixel and for four pixels with E-ITO films were 2.82 V and 2.83 V, respectively, while the corresponding values for S-ITO films were 3.50 V and 3.52 V. This was attributed to ion bombardment damage and nitrogen vacancies in the p-GaN layer. Surprisingly, the VF variations of a single pixel and of four pixels with the optimized E-ITO spreading layer from five different regions were only 0.09 V and 0.10 V, respectively. This extremely uniform VF variation is suitable for creating micro-LED displays to be used in AR and VR applications, circumventing the bottleneck in the development of long-lifespan and high-brightness organic LED devices for industrial mass production.

Rhythmic motor behavior explains individual differences in grammar skills in adults.

A growing body of literature has reported the relationship between music and language, particularly between individual differences in perceptual rhythm skill and grammar competency in children. Here, we investigated whether motoric aspects of rhythm processing-as measured by rhythmic finger tapping tasks-also explain the rhythm-grammar connection in 150 healthy young adults. We found that all expressive rhythm skills (spontaneous, synchronized, and continued tapping) along with rhythm discrimination skill significantly predicted receptive grammar skills on either auditory sentence comprehension or grammaticality well-formedness judgment (e.g., singular/plural, past/present), even after controlling for verbal working memory and music experience. Among these, synchronized tapping and rhythm discrimination explained unique variance of sentence comprehension and grammaticality judgment, respectively, indicating differential associations between different rhythm and grammar skills. Together, we demonstrate that even simple and repetitive motor behavior can account for seemingly high-order grammar skills in the adult population, suggesting that the sensorimotor system continue to support syntactic operations.

Incidence and Risk Factors of Recurrent Anterior Uveitis in Initial Acute-Onset Vogt-Koyanagi-Harada Disease.

PURPOSE: We report the estimated incidence of, and risk factors for, recurrent anterior uveitis in patients with initial acute-onset Vogt-Koyanagi-Harada (VKH) disease using survival analyses. METHODS: Patients who were diagnosed with initial acute-onset VKH disease during 2003-2022 at two university hospitals were included. Recurrent anterior uveitis was defined as the first occurrence of the granulomatous anterior uveitis with anterior chamber cells and flare of 2+ or more by the Standardization of Uveitis Nomenclature (SUN) Working Group grading scheme, after the disappearance of conspicuous uveitis and serous retinal detachment for at least 3 months, regardless of systemic or local treatment. The univariate log-rank test and multivariate Cox regression analyses were performed, including patients' demographic characteristics, underlying diseases, presence of prodromal symptoms, duration of visual symptoms, visual acuity, slit-lamp and fundus findings, and height of serous retinal detachment. The treatment method and response to treatment were also included. RESULTS: The estimated incidence was 39.3% at 10 years. Fifteen of 55 patients (27.3%) had recurrent anterior uveitis during the mean follow-up of 4.5 years. The presence of focal posterior synechiae at the diagnosis increased the risk of recurrent anterior uveitis 6.97-fold compared to the absence of synechiae (95% confidence interval [CI], 2.20-22.11; p < 0.001). Use of systemic high-dose steroid therapy more than 7 days after the development of visual symptoms resulted in a hazard ratio of 4.55 (95% CI, 1.27-16.40; p = 0.020). CONCLUSIONS: This study reports the estimated incidence and risk factors of recurrent anterior uveitis in VKH disease from survival analyses. However, because of the retrospective nature of this study, it is hard to confirm the consistency of the medical records regarding risk factors, thus, the presence of focal posterior synechiae can be inconclusive as a risk factor. Further studies are warranted.

Expression of Stat3 and indoleamine 2, 3-dioxygenase in cornea keratocytes as factor of ocular immune privilege.

PURPOSE: Ocular immune privilege is a multifactorial phenomenon evolutionally selected to prevent immunogenic inflammation from disrupting the visual axis and causing blindness. Here, we investigated the role of signal transducers and activators of transcription (Stat3) and indoleamine 2,3-dioxygenase (IDO) in ocular immune privilege in corneal stromal cells. METHODS: Human keratocytes were isolated and cultured in vitro, and Stat3 and IDO expression on keratocytes was investigated by reverse transcription polymerase chain reaction (RT-PCR). The active form of Stat3 was detected by flow-cytometry, and IDO enzyme activity following IFN-γ stimulation of keratocytes was measured by tryptophan to kynurenine conversion with photometric determination of kynurenine concentration in the supernatant. RESULTS: Stat3 was constitutively expressed in cultured keratocytes and up-regulated following IFN-γ stimulation. The active form of Stat3 was also up-regulated following IFN-γ stimulation. IDO expression and enzyme activity was markedly induced following IFN-γ stimulation, but this induction was prevented by the IDO specific inhibitor, 1-methyl tryptophan (1-MT). CONCLUSIONS: On the basis of this study, Stat3 and IDO may act as a factor of ocular immune privilege in corneal keratocytes. Thus, focus on these inhibitory molecules should be considered in studies aimed at developing therapeutic agents for controlling ocular inflammatory or immune diseases.

Effect of lipoic acid on expression of angiogenic factors in diabetic rat retina.

BACKGROUND: This study evaluated the effect of a lipoic acid on reactive oxygen species formation and the simultaneous changes of several angiogenic factors in an experimental diabetic rat retina. METHODS: Diabetes was induced chemically by intraperitoneal injection of streptozotocin in 30 Sprague-Dawley rats. After inducing diabetes, lipoic acid (10 mg/kg) was administered to 10 rats orally. The rats were divided into normal, diabetes mellitus, and lipoic acid-treated groups (each group n = 10). The eyeballs were harvested 8 weeks after inducing diabetes. The expression of vascular endothelial growth factor, erythropoietin, angiopoietin 1 and 2 and NADPH oxidase was examined in the rat retina using reverse transcription-polymerase chain reaction and Western blot. Superoxide formation was examined using dihydroethidium stain. RESULTS: Dihydroethidium analyses showed increased superoxide formation in the retina of the diabetic group. The superoxide formation was suppressed with lipoic acid treatment. Western blot analysis showed that NADPH oxidase was decreased in the diabetic group and returned to normal level in the lipoic acid-treated group. Treatment with lipoic acid blocked hyperglycaemia induced increases of vascular endothelial growth factor, angiopoietin 2 and erythropoietin shown by reverse transcription-polymerase chain reaction and Western blot analysis. CONCLUSIONS: Lipoic acid treatment suppressed expression of vascular endothelial growth factor, angiopoietin 2 and erythropoietin via blockade of superoxide formation. Antioxidant treatment is suspected to have an antiangiogenic effect.

Bionanohybrid composed of metalloprotein/DNA/MoS2/peptides to control the intracellular redox states of living cells and its applicability as a cell-based biomemory device.

The development of cell-based bioelectronic devices largely depends on the direct control of intracellular redox states. However, most related studies have focused on the accurate measurement of electrical signals from living cells, whereas direct intracellular state control remains largely unexplored. Here, we developed a biocompatible transmembranal bionanohybrid structure composed of a recombinant metalloprotein, DNA, molybdenum disulfide nanoparticles (MoS2), and peptides to control intracellular redox states, which can be used as a cell-based biomemory device. Using the capacitance of MoS2 located inside the cell, the bionanohybrid controled the intracellular redox states of living cells by recording and extracting intracellular charges, which inturn was achieved by activating (writing) and deactivating (erasing) the cells. As a proof of concept, cell-based biomemory functions including writing, reading, and erasing were successfully demonstrated and confirmed via electrochemical methods and patch-clamp analyses, resulting in the development of the first in vitro cell-based biomemory device. This newly developed bionanohybrid provides a novel approach to control cellular redox states for cell-based bioelectronic applications, and can be applicable in a wide range of biological fields including bioelectronic medicine and intracellular redox status regulation.

3D Neural Network Composed of Neurospheroid and Bionanohybrid on Microelectrode Array to Realize the Spatial Input Signal Recognition in Neurospheroid.

There have been several studies for demonstration of 2D neural network using living cells or organic/inorganic molecules, but to date, there is no report of development of a 3D neural network in vitro. Based on developed bionanohybrid composed of protein, DNA, molybdenum disulfide nanoparticles, and peptides for controlling electrophysiological states of living cells, here, the in vitro 3D neural network composed of the bionanohybrid, 3D neurospheroid and the microelectrode array (MEA) is developed. After production of the 3D neurospheroid derived from human neural stem cells, the bionanohybrid developed on the MEA successfully semi-penetrates the neurites of the 3D neurospheroid and forms the 3D neural network. The developed 3D neural network successfully exhibited the electrophysiological output signals of the 3D neurospheroid by transmitting the input signal applied by the bionanohybrid. Moreover, by using the selectively immobilized bionanohybrid on the MEA, the spatial input signal recognition in the neurospheroid of 3D neural network is realized for the first time. This newly developed in vitro 3D neural network provides a promising strategy to be applied in brain-on-a-chip, brain disease-related drug efficacy evaluation, bioelectronics, and bioelectronic medicine.

Simvastatin suppresses expression of angiogenic factors in the retinas of rats with streptozotocin-induced diabetes.

BACKGROUND: Angiogenic factors such as vascular endothelial growth factor (VEGF), erythropoietin, and angiopoietin play important roles in the pathophysiology of diabetic retinopathy. Increased amounts of reactive oxygen species (ROS) are also known to associated with diabetic retinopathy and VEGF expression. This study evaluated the effect of a simvastatin on ROS generation and the changes in various angiogenic factors in the retinas of diabetic rats. METHODS: The rats were divided into normal, diabetes mellitus (DM), and simvastatin-treated groups (each group, n = 10). Diabetes was induced by intraperitoneal injection of streptozotocin into 20 Sprague-Dawley rats. After diabetic induction, simvastatin (5mg/kg) was administered orally to ten rats. The expression levels of VEGF, erythropoietin, angiopoietin 1 and 2, and NADPH oxidase were examined in rat retinas by RT-PCR and Western blot. Superoxide formation was examined by dihydroethidium (DHE) staining. RESULTS: DHE analysis revealed increased superoxide formation in the retinas of the diabetic group, which was decreased in the group treated with simvastatin. Western blot analysis showed that NADPH oxidase levels were decreased in the diabetic group and remained normal in the simvastatin-treated group. Simvastatin treatment blocked hyperglycemia-induced increases in VEGF, angiopoietin 2 and erythropoietin levels, as demonstrated by RT-PCR and Western blot analysis. CONCLUSIONS: Simvastatin treatment led to suppression of superoxide formation and decreased expression of VEGF, angiopoietin 2 and erythropoietin in diabetic rat retinas.

One-year Results of Aflibercept Treatment for Polypoidal Choroidal Vasculopathy with Good Visual Acuity.

PURPOSE: To evaluate the one-year efficacy of intravitreal aflibercept injection in polypoidal choroidal vasculopathy (PCV) with best-corrected visual acuity (BCVA) of 20 / 40 or better. METHODS: This was a multicenter retrospective study. The medical records of patients diagnosed with treatment-naïve PCV were retrospectively reviewed. Patients with an initial BCVA of 20 / 40 or better and who had undergone intravitreal aflibercept injection were included. Patients were treated with three consecutive monthly injections, followed by pro re nata regimen according to the clinician's discretion at variable interval visits. The proportions of eyes for which BCVA was maintained (≤ 0.2 logarithm of the minimum angle of resolution change) or improved at 12 months were evaluated. The changes of BCVA, central subfield macular thickness (CSMT), pigment epithelial detachment, and subretinal fluid also were assessed. RESULTS: A total of 86 eyes were included. The mean number of injections for 12 months of treatment was 5.4 ± 1.7. BCVA was maintained or improved in 94.2% (81 / 86) of cases. Mean BCVA (logarithm of the minimum angle of resolution) had changed from the baseline (0.23 ± 0.09) at 3 months (0.21 ± 0.14), 6 months (0.24 ± 0.22), and 12 months (0.20 ± 0.18), but with no statistical significance. CSMT had improved significantly from the baseline (336.1 ± 97.3 µm) at 3 months (223.6 ± 47.22 µm), 6 months (239.6 ± 64.2 µm), and 12 months (223.8 ± 47.9 µm). Pigment epithelial detachment was observed in 93% of cases at the baseline, 72.1% at 3 months, and 69.8% at 12 months, showing a significant decrease at all observation points. Subretinal fluid was observed in 91.9% of cases at the baseline, 20.9% at 3 months, and 29.1% at 12 months, showing a significant decrease at all observation points. CONCLUSIONS: In cases of PCV with good visual acuity, intravitreal aflibercept injections decreased CSMT and were effective in maintaining visual acuity.