Efficacy of RCI001 as a therapeutic candidate of dry eye disease in a modified mixed dry eye model.

BACKGROUND: To evaluate the therapeutic effects of topical RCI001 (RCI) and compare its efficacy with that of 1% prednisolone acetate (PDE) and 5% Lifitegrast in a modified mixed dry eye disease (DED) model. METHODS: The environmental DED model was induced in BALB/c mice in a dry chamber with scopolamine. The eyes of the mice were treated topically with phosphate buffered saline (PBS), PDE, Lifitegrast or RCI twice daily for 1 week. Ocular surface staining (OSS), tear secretion, inflammatory cytokines in the ocular surface and lacrimal gland, and immunofluorescence staining in the conjunctiva and cornea(CC) were assessed. RESULTS: The RCI group demonstrated better improvement of OSS and tear secretion than the PBS group (OSS, PBS: 13.0 ± 1.6, RCI: 9.4 ± 3.0; tear secretion, PBS: 5.0 ± 0.4 mm, RCI: 7.0 ± 0.3 mm, each P < 0.001) and better clinical efficacy than PDE and Lifitegrast groups on Day 7 (improvement rate of OSS, RCI: 32.45%, Lifitegrast: 13.13%, PDE: 12.25%). The RCI group resulted in significantly lower expression of oxidative stress markers in the CC than the PBS group (4-HNE, NOX2, and NOX4 in the conjunctiva; NOX2 in the cornea, each P < 0.05). However, the PDE and Lifitegrast groups did not show significant differences compared with the PBS group. There were no significant differences of inflammatory cytokines in the ocular surface and lacrimal gland between all groups. CONCLUSION: Topical RCI001 showed excellent therapeutic effects in environmental DED models by stimulating tear secretion, modulating oxidative stress and improving corneal epithelial healing compared to 1% PDE and 5% Lifitegrast.

CRISPR screening identifies BET and mTOR inhibitor synergy in cholangiocarcinoma through serine glycine one carbon.

Patients with cholangiocarcinoma have poor clinical outcomes due to late diagnoses, poor prognoses, and limited treatment strategies. To identify drug combinations for this disease, we have conducted a genome-wide CRISPR screen anchored on the bromodomain and extraterminal domain (BET) PROTAC degrader ARV825, from which we identified anticancer synergy when combined with genetic ablation of members of the mTOR pathway. This combination effect was validated using multiple pharmacological BET and mTOR inhibitors, accompanied by increased levels of apoptosis and cell cycle arrest. In a xenograft model, combined BET degradation and mTOR inhibition induced tumor regression. Mechanistically, the 2 inhibitor classes converged on H3K27ac-marked epigenetic suppression of the serine glycine one carbon (SGOC) metabolism pathway, including the key enzymes PHGDH and PSAT1. Knockdown of PSAT1 was sufficient to replicate synergy with single-agent inhibition of either BET or mTOR. Our results tie together epigenetic regulation, metabolism, and apoptosis induction as key therapeutic targets for further exploration in this underserved disease.

Etiology and outcome of penetrating keratoplasty in bullous keratopathy post-cataract surgery vs post-glaucoma surgery.

PURPOSE: To investigate the causes of bullous keratopathy (BK) in the Korean population and analyze the results of penetrating keratoplasty (PK) in BK eyes associated with the top two causes: pseudophakic bullous keratopathy (PBK) and glaucoma surgery-associated BK (GBK). METHODS: Medical records were reviewed of patients diagnosed with BK at a tertiary referral center between 2010 and 2020. The predisposing conditions, clinical characteristics and therapeutic outcomes after PK were analyzed and compared. RESULTS: Of total 340 BK eyes, 70% (238 eyes) were associated with ocular surgery; most commonly, cataract surgery (48%, 162 eyes) and glaucoma surgery/laser (21%, 70 eyes). The BK onset was faster following glaucoma surgery/laser (91.7 ± 94.4 months) than following cataract surgery (160.7 ± 138.0 months, p < 0.001). The median survival time of allografts was shorter in GBK than in PBK (24.0 vs 51.0 months, p = 0.020). Best-corrected logMAR visual acuities were lower in GBK than in PBK after PK (1.4 ± 0.7 vs 0.9 ± 0.6, p = 0.017 at one year; 1.8 ± 0.7 vs 1.1 ± 0.8, p = 0.043 at three years). CONCLUSIONS: Intraocular surgery is the major predisposing condition of BK in Korea. GBK developed earlier and its therapeutic outcome was poorer, compared to PBK.

Microcantilever-integrated photonic circuits for broadband laser beam scanning.

Laser beam scanning is central to many applications, including displays, microscopy, three-dimensional mapping, and quantum information. Reducing the scanners to microchip form factors has spurred the development of very-large-scale photonic integrated circuits of optical phased arrays and focal plane switched arrays. An outstanding challenge remains to simultaneously achieve a compact footprint, broad wavelength operation, and low power consumption. Here, we introduce a laser beam scanner that meets these requirements. Using microcantilevers embedded with silicon nitride nanophotonic circuitry, we demonstrate broadband, one- and two-dimensional steering of light with wavelengths from 410 nm to 700 nm. The microcantilevers have ultracompact ~0.1 mm2 areas, consume ~31 to 46 mW of power, are simple to control, and emit a single light beam. The microcantilevers are monolithically integrated in an active photonic platform on 200-mm silicon wafers. The microcantilever-integrated photonic circuits miniaturize and simplify light projectors to enable versatile, power-efficient, and broadband laser scanner microchips.

Machine Learning-Based Air-to-Ground Channel Model Selection Method for UAV Communications Using Digital Surface Model Data.

This paper proposes an automatic air-to-ground (A2G) channel model selection method based on machine learning (ML) using digital surface model (DSM) terrain data. In order to verify whether a communication network for a new non-terrestrial user service such as Urban Air Mobility (UAM) satisfies the required performance, it is necessary to perform a simulation reflecting the characteristics of the corresponding terrain environments as accurately as possible. For this simulation, A2G channel models corresponding to various terrain environments and a method of automatically classifying the terrain type of the simulation area must be provided. Many A2G channel models based on actual measurement results exist, but the practical automatic topography classification method still needs to be developed. This paper proposes the first practical automatic topography classification method using a two-step neural network-based classifier utilizing various geographic feature data as input. Since there is no open topography dataset to evaluate the accuracy of the proposed method, we built a new dataset for five topography classes that reflect the characteristics of Korea's topography, which is also a contribution of our study. The simulation results using the new data set show that the proposed ML-based method could increase the selection accuracy compared to the technique for direct classification by humans or the existing cross-correlation-based classification method. Since the proposed method utilizes the DSM data, open to the public, it can easily reflect the different terrain characteristics of each country. Therefore, the proposed method can be effectively used in the realistic performance evaluation of new non-terrestrial communication networks utilizing vast airspace such as UAM or 6G mobile communications.

Clinical outcome of Descemet membrane endothelial keratoplasty (DMEK) with imported donor corneas in eyes of Asian patients; endothelium-in versus endothelium-out method.

OBJECTIVE: We investigated whether (1) imported pre-cut tissue is feasible for Descemet membrane endothelial keratoplasty (DMEK) in eyes of Asian patients, (2) the clinical outcome is comparable between the endothelium-in and endothelium-out methods, and (3) the corneal edema-induced anterior curvature changes may have an effect on the refractive error. METHODS: The medical records of 32 DMEK patients who underwent either the endothelium-out or endothelium-in method using imported pre-cut grafts with a 3-day pre-cut-to-use time were retrospectively analyzed. Fuchs' endothelial dystrophy (37.5%) and bullous keratopathy (62.5%) cases were included. The main clinical outcome measures were graft survival, best corrected visual acuity (BCVA), endothelial cell density (ECD), corneal thickness (CT), and complications. Correlation of the anterior curvature changes with refractive error was analyzed in the DMEK with cataract surgery group. RESULTS: The overall survival rate was 71.9%. Final graft failures were caused by rejection, glaucoma, and infection. Visual acuities improved by 89.3%. BCVA better than 20/40 and 20/20 was found in 75% and 28.6% of patients, respectively. The ECDs at 3 months and 1 year were 1400 and 1083 cells/mm2, respectively. The mean survival time, ECD, BCVA, CT, and complication rates were not different between the endothelium-in and endothelium-out methods. A hyperopic shift by +0.42 D was not related to the anterior curvature changes. CONCLUSION: Imported pre-cut tissues with a ≤ 3-day pre-cut-to-use time are feasible for DMEK in the treatment of corneal endothelial edema in eyes of Asian patients, and both endothelium-in and endothelium-out methods appear to be comparatively effective. Edema-induced anterior curvature change may not affect the refractive shift.

Low-loss broadband bi-layer edge couplers for visible light.

Low-loss broadband fiber-to-chip coupling is currently challenging for visible-light photonic-integrated circuits (PICs) that need both high confinement waveguides for high-density integration and a minimum feature size above foundry lithographical limit. Here, we demonstrate bi-layer silicon nitride (SiN) edge couplers that have ≤ 4 dB/facet coupling loss with the Nufern S405-XP fiber over a broad optical wavelength range from 445 to 640 nm. The design uses a thin layer of SiN to expand the mode at the facet and adiabatically transfers the input light into a high-confinement single-mode waveguide (150-nm thick) for routing, while keeping the minimum nominal lithographic feature size at 150 nm. The achieved fiber-to-chip coupling loss is about 3 to 5 dB lower than that of single-layer designs with the same waveguide confinement and minimum feature size limitation.

Non-Deep Simple Morphophysiological Dormancy and Germination Characteristics of Gentiana triflora var. japonica (Kusn.) H. Hara (Gentianaceae), a Rare Perennial Herb in Korea.

This study investigated the kind of seed dormancy and seed germination of Gentiana triflora var. japonica (Kusn.) H. Hara for developing a seed propagation method. The seeds were collected in October 2020 from plants at Mt. Sobaeksan, Korea. In a water imbibition experiment, seed weights increased by >101.9% of their initial masses over 12 h. Effects of incubation temperature (5, 15, 20, 25, 15/6, or 25/15 °C), cold stratification period (5 °C; 0, 4, 8, or 12 weeks), and gibberellic acid (GA3; 0, 10, 100, or 1000 mg∙L-1) and potassium nitrate treatment (KNO3; 0, 1000, 2000, or 4000 mg∙L-1) on seed germination were investigated to characterize seed dormancy. These seeds exhibited underdeveloped embryos during seed dispersal. The seeds failed to reach the final germination of 15.0% after treatment at 5, 15, 20, 25, 15/6, or 25/15 °C. After cold stratification for 8 weeks, the germination increased dramatically by >90.0% compared to that at 0 weeks. After the GA3 treatment, the germination reached >80.0% within 5 days. The final germination was 90.0% in the 100 mg∙L-1 GA3 treatment group. However, the KNO3 treatment had no effect on seed germination. Therefore, the G. triflora var. japonica seeds exhibited non-deep simple morphophysiological dormancy.

Clinical outcomes in post-epikeratophakic eyes after removal of epikeratoplasty lenticule.

BACKGROUND: Assessment of the optical outcome and adverse events in post-epikeratopathic eyes after removal of the epikeratoplasty lenticule (EKPL). METHODS: This was a retrospective case-series study of patients who underwent EKPL removal between 2002 and 2020. Ten eyes were included in the analysis. We compared the clinical characteristics of the patients before surgery, 6 months after surgery, before lenticular removal, and after removal, and reported optical or ocular surface complications. RESULTS: We removed EKPL due to the lenticular opacity in five eyes (50%), intraocular lens (IOL) insertion (n = 4, 40%) after cataract surgery (n = 3) or in aphakic eyes (n = 1), and lenticule-induced irregular astigmatism in one eye (10%). After EKPL removal, the mean refractive power of the cornea (Km) revealed a tendency to increase. Out of nine cases, six cases showed corneal steepening and three cases revealed corneal flattening. When the keratometric readings of pre-epikeratoplasty and post-lenticular removal were compared within the same case, the average difference was 5.1 D ± 4.0 (n = 8). Complications were observed in 3 of 10 cases (excessive corneal flatness, ectatic change, and abnormal epithelial cell ingrowth) after removal. CONCLUSIONS: The surgeon should expect the corneal refractive power to steepen or flatten in some cases with abnormal astigmatism and irregularity. Epikeratophakic eyes may exhibit serious ectatic changes, and abnormal epithelial cell ingrowth after removal of epikeratophakic lenticules.

Improving Restoration Efficiency by Modeling Optimal Sowing Periods: A Case Study of Two Native Plants and Restoration of a Site.

Efficient ecological restoration techniques are urgently required to minimize seed consumption and labor requirements. Here, we determined the optimal sowing period for two native species, Agastache rugosa (Korean mint) and Astilbe rubra (False goat's beard), toward their use for ecological restoration of Mt. Gariwang, a site damaged by the 2018 PyeongChang Winter Olympics' activities. We investigated the effects of daily mean temperature (DMT) and daily temperature range (DTR) on seed germination percentage, which decreased for both species with decreasing DTR and was optimal at a DMT of 25 °C and 17.5 °C for A. rugosa and A. rubra, respectively. We developed a single multiple regression equation that evaluated the effects of DMT and DTR simultaneously and determined the temperature scores when the germination percentage reached 85%. We applied the developed multiple regression equation by analyzing the temperature data of the restoration site. In addition, precipitation data analysis was added to set the optimal sowing period. As a result, the optimal sowing period for the two species was determined from May 21 to the end of May. This makes it possible to minimize seed consumption and labor requirements when sowing seeds. The model developed herein will be useful not only to guide the ecological restoration of Mt. Gariwang, but also for other regions using site-specific temperature data.

Preserved corneal lamellar transplantation for infectious and noninfectious scleral defects: Three case reports and literature review.

RATIONALE: : Reinforcement of thinned or necrotizing sclera has been conducted using various materials, including allogeneic sclera, allogenic cornea, amniotic membrane, fascia lata, pericardium, periosteum, and perichondrium. Among them, good outcomes have traditionally been obtained using preserved scleral grafts. However, scleral patch grafts have complications such as graft retraction, thinning, dehiscence, and necrosis. Furthermore, to promote epithelial healing, scleral patch grafting must be accompanied by procedures such as amniotic membrane transplantation (AMT) or grafting using conjunctival flaps or autografts. Recently, acellular preserved human corneas have been used in various ophthalmic surgeries, with emerging evidence supporting its use for treating scleral defects as an option that does not require AMT or conjunctival autografting. We investigated whether corneal patch grafting would show wound healing and tectonic success rate outcomes comparable to those of existing techniques. PATIENT PRESENTATION: : Three patients presented with intractable ocular pain. Slit-lamp examination showed marked scleral thinning at the nasal side. DIAGNOSIS: : Scleral thinning progressed with conservative treatment; microbial staining and culturing were performed. Infectious or non-infectious scleritis was diagnosed according to slit-lamp examination and microbial culture results. INTERVENTIONS: : A preserved corneal lamellar patch was grafted at the scleral thinning area. OUTCOMES: All patients achieved tectonic success with reduction of inflammation following corneal patch grafting. Two patients achieved complete re-epithelialization within 7 days, while 25 days were required for the third patient. No patients experienced graft thinning, rejection, or infection. LESSONS: : Our report suggests the feasibility of using acellular preserved human cornea patch grafts to reinforce inflammatory scleral defects and obtain successful outcomes in terms of wound healing. This technique shows a comparable tectonic success rate and superior effect on scleral defect healing without the need for adjunctive AMT or conjunctival autografting.

Age-Dependent Distinct Distributions of Dendritic Cells in Autoimmune Dry Eye Murine Model.

We investigated whether aging-dependent changes in dendritic cell (DC) distributions are distinct in autoimmune dry eye compared with an aging-related murine model. Corneal staining and tear secretion were evaluated in young and aged C57BL/6 (B6) and NOD.B10.H2b mice (NOD). In the corneolimbus, lacrimal gland (LG), and mesenteric lymph node (MLN), CD11b- and CD11b+ DCs, CD103+ DCs and MHC-IIhi B cells were compared between young and aged B6 and NOD mice. With increased corneal staining, tear secretion decreased in both aged B6 and NOD mice (p < 0.001). In both aged B6 and NOD mice, the percentages of corneolimbal CD11b+ DCs were higher (p < 0.05) than those in young mice. While, the percentages of lymph nodal CD103+ DCs were higher in aged B6 and NOD mice (p < 0.05), the percentages of corneolimbal CD103+ DCs were only higher in aged NOD mice (p < 0.05). In aged NOD mice, the proportions of lacrimal glandial and lymph nodal MHC-IIhi B cells were also higher than those in young mice (p < 0.05). It indicates that corneolimbal or lacrimal glandial distribution of CD103+ DCs or MHC-IIhi B cells may be distinct in aged autoimmune dry eye models compared to those in aged immune competent murine models.

Implantable photonic neural probes for light-sheet fluorescence brain imaging.

Significance: Light-sheet fluorescence microscopy (LSFM) is a powerful technique for high-speed volumetric functional imaging. However, in typical light-sheet microscopes, the illumination and collection optics impose significant constraints upon the imaging of non-transparent brain tissues. We demonstrate that these constraints can be surmounted using a new class of implantable photonic neural probes. Aim: Mass manufacturable, silicon-based light-sheet photonic neural probes can generate planar patterned illumination at arbitrary depths in brain tissues without any additional micro-optic components. Approach: We develop implantable photonic neural probes that generate light sheets in tissue. The probes were fabricated in a photonics foundry on 200-mm-diameter silicon wafers. The light sheets were characterized in fluorescein and in free space. The probe-enabled imaging approach was tested in fixed, in vitro, and in vivo mouse brain tissues. Imaging tests were also performed using fluorescent beads suspended in agarose. Results: The probes had 5 to 10 addressable sheets and average sheet thicknesses < 16 µ m for propagation distances up to 300 µ m in free space. Imaging areas were as large as ≈ 240 µ m × 490 µ m in brain tissue. Image contrast was enhanced relative to epifluorescence microscopy. Conclusions: The neural probes can lead to new variants of LSFM for deep brain imaging and experiments in freely moving animals.

Evidence That Runt Acts as a Counter-Repressor of Groucho During Drosophila melanogaster Primary Sex Determination.

Runx proteins are bifunctional transcription factors that both repress and activate transcription in animal cells. Typically, Runx proteins work in concert with other transcriptional regulators, including co-activators and co-repressors to mediate their biological effects. In Drosophila melanogaster the archetypal Runx protein, Runt, functions in numerous processes including segmentation, neurogenesis and sex determination. During primary sex determination Runt acts as one of four X-linked signal element (XSE) proteins that direct female-specific activation of the establishment promoter (Pe) of the master regulatory gene Sex-lethal (Sxl). Successful activation of SxlPe requires that the XSE proteins overcome the repressive effects of maternally deposited Groucho (Gro), a potent co-repressor of the Gro/TLE family. Runx proteins, including Runt, contain a C-terminal peptide, VWRPY, known to bind to Gro/TLE proteins to mediate transcriptional repression. We show that Runt's VWRPY co-repressor-interaction domain is needed for Runt to activate SxlPe Deletion of the Gro-interaction domain eliminates Runt-ability to activate SxlPe, whereas replacement with a higher affinity, VWRPW, sequence promotes Runt-mediated transcription. This suggests that Runt may activate SxlPe by antagonizing Gro function, a conclusion consistent with earlier findings that Runt is needed for Sxl expression only in embryonic regions with high Gro activity. Surprisingly we found that Runt is not required for the initial activation of SxlPe Instead, Runt is needed to keep SxlPe active during the subsequent period of high-level Sxl transcription suggesting that Runt helps amplify the difference between female and male XSE signals by counter-repressing Gro in female, but not in male, embryos.

Characteristics and Treatment of Anaphylaxis in Children Visiting a Pediatric Emergency Department in Korea.

Anaphylaxis is a serious life-threatening allergic disease in children. This study is aimed at determining the characteristics of pediatric patients who experienced anaphylaxis along with treatments administered in order to determine the usefulness of tryptase level assessment as a marker of anaphylaxis in Korean children. A total of 107 patients who were diagnosed with anaphylaxis in a single pediatric emergency center over a 3-year period were included in the study. Patient clinical characteristics, symptoms, signs, allergy history, trigger factors, treatments, and laboratory findings, including serum tryptase levels, were included in the analysis. Food allergies (39.3%) were the most commonly reported patient allergic history, and 58 patients (54.2%) were triggered by food. Among this group, nuts and milk exposure were the most common, affecting 15 patients (25.9%). History of anaphylaxis and asthma were more common in severe anaphylaxis compared to mild or moderate anaphylaxis cases. Epinephrine intramuscular injection was administrated to 76 patients (71.0%), and a self-injectable epinephrine was prescribed to 18 patients (16.8%). The median tryptase level was 4.80 ng/mL (range: 2.70-10.40) which was lower than the 11.4 ng/mL value commonly documented for standard evaluation in adults with anaphylaxis. The most common cause of pediatric anaphylaxis was food including nuts and milk. The rate of epinephrine injection was relatively high in our pediatric emergency department. The median tryptase level associated with anaphylaxis reactions in children was lower than 11.4 ng/mL. Further studies are needed to help improve diagnostic times and treatment accuracy in pediatric patients who develop anaphylaxis.

Asthma predictive index as a useful diagnostic tool in preschool children: a cross-sectional study in Korea.

BACKGROUND: It is challenging to diagnose asthma in preschool children. The asthma predictive index (API) has been used to predict asthma and decide whether to initiate treatment in preschool children. PURPOSE: This study aimed to investigate the association between questionnaire-based current asthma with API, pulmonary function, airway hyperreactivity (AHR), fractional expiratory nitric oxide (FeNO), and atopic sensitization in preschool children. METHODS: We performed a population-based cross-sectional study in 916 preschool children aged 4-6 years. We defined current asthma as the presence of both physician-diagnosed asthma and at least one wheezing episode within the previous 12 months using a modified International Study of Asthma and Allergies in Childhood questionnaire. Clinical and laboratory parameters were compared between groups according to the presence of current asthma. RESULTS: The prevalence of current asthma was 3.9% in the study population. Children with current asthma showed a higher rate of positive bronchodilator response and loose and stringent API scores than children without current asthma. The stringent API was associated with current asthma with 72.2% sensitivity and 82.0% specificity. The diagnostic accuracy of the stringent API for current asthma was 0.771. However, no intergroup differences in spirometry results, methacholine provocation test results, FeNO level, or atopic sensitization rate were observed. CONCLUSION: The questionnaire-based diagnosis of current asthma is associated with API, but not with spirometry, AHR, FeNO, or atopic sensitization in preschool children.

Prenatal particulate matter affects new asthma via airway hyperresponsiveness in schoolchildren.

BACKGROUND: The most relevant time of PM10 exposure to affect airway hyperresponsiveness (AHR) and new development of asthma in school-aged children is unclear. The aims of this study were to investigate the most critical time of PM10 exposure to affect AHR and new diagnosis of asthma from AHR in school-aged children. METHODS: Elementary schoolchildren (n = 3570) have been enrolled in a nationwide prospective 4-year follow-up survey in Korea from 2005 to 2006. Individual annual PM10 exposure was estimated by using an ordinary kriging method from the prenatal period to 7 years of age. AHR at 7 years was defined by a methacholine PC20 ≤8 mg/mL. RESULTS: PM10 exposure during pregnancy and at 1 year of age showed significant effects on AHR (aOR: 1.694, 95% CI: 1.298-2.209; and aOR: 1.750, 95% CI: 1.343-2.282, respectively). PM10 exposure during pregnancy was associated with the risk of a new diagnosis of asthma (aOR: 2.056, 95% CI: 1.240-3.409), with the highest risk in children with AHR at age 7 (aOR: 6.080, 95% CI: 2.150-17.195). PM10 exposure in the second trimester was associated with the highest risk of a new diagnosis of asthma in children with AHR at age 7 (aOR: 4.136, 95% CI: 1.657-10.326). CONCLUSIONS: Prenatal PM10 exposure in the second trimester is associated with an increased risk of a new diagnosis of asthma in school-aged children with AHR at 7 years. This study suggests that PM10 exposure during a specific trimester in utero may affect the onset of childhood asthma via AHR.