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Curcumin solid dispersions were prepared using hydroxypropyl methylcellulose (HPMC) to enhance water solubility of curcumin. The particle size of curcumin solid dispersions was in range from 371 to 528 nm and particles were shaped as spherical with wrinkles. The encapsulation efficiency was over 93% for all samples, and water solubility of curcumin was significantly improved to 238 µg/mL when the ratio of curcumin to HPMC was 20:80. The results of X-ray diffraction, differential scanning calorimeter, and Fourier transform infrared spectroscopy showed that crystalline form of curcumin changed to amorphous form. Curcumin solid dispersions showed improved dissolution behavior compared to pure curcumin and the curcumin release kinetic studies were applied to find best-fitting model. This study showed a great potential of solid dispersion using HPMC as curcumin delivery system with improved water solubility and oral absorption. PRACTICAL APPLICATION: Curcumin has limited applications in the food industry because of low water solubility. Dongoh water-soluble curcumin (DW-CURs) were prepared by solid dispersion method with HPMC. Our results indicated that curcumin solid dispersions improved the water solubility of curcumin and showed a sustained release, demonstrating its possibility of body application. Therefore, DW-CURs are a promising formulation for application as a functional ingredient in the food industry.

To alleviate carbon dioxide (CO2) emission, alternative approaches have been considered, such as employing microorganisms capable of CO2-fixation using their own metabolic pathways. In this study, we introduced a synthetic CO2-fixation pathway into the industrial platform microorganism Escherichia coli to achieve immediate CO2 mitigation with a non-photosynthetic reaction. Specifically, the whole gene clusters (cbbI and cbbII operons) involved in the Calvin–Benson–Bassham (CBB) pathway in Rhodobacter sphaeroides (rCBB) were expressed heterogeneously in E. coli under a restrictive carbon source and dark conditions. The resulting strain with the whole rCBB was able to exhibit a higher level of endogenous CO2 recycling compared to the control strain. In addition, the electron requirements from the cathode and redox cofactors were increased following the activation of the CO2-fixation pathway without light irradiation. Exogenous CO2 from yeast fermentation was also mitigated through a simple gas-phase connection with the E. coli/rCBB culture system. This bacterial CO2 mitigation strategy has great potential to alleviate greenhouse gas emissions through biological processes to produce carbon neutral biofuels and value-added chemicals.

Summary Multiple studies have recently been conducted to develop well-ordered covalent triazine-based frameworks (CTFs). To date, few studies have demonstrated CTFs with high crystallinity using novel synthesis strategies and different building blocks. To construct highly crystalline CTFs with enhanced performance, significant technical advancements in fundamental chemical insights are essential. Here, we report that the phosphorus pentoxide (P2O5)-catalyzed condensation of biphenyl-based amide and nitrile monomers can produce ordered pCTF-2. The pCTF-2A directly synthesized from amide monomers showed unusually higher crystallinity and porosity than the pCTF-2N synthesized from nitrile monomers. Based on experimental results, density functional theory (DFT) calculations revealed that amide groups can be directly trimerized into triazine rings in the presence of P2O5, which is a more thermodynamically favorable reaction than those from nitrile groups. Based on this mechanistic insight, the efficient and better synthesis strategy provides an effective pathway for the formation of crystalline CTFs.

Epigenetic dysregulation is a common characteristic of cancers, including gastric cancer (GC), and contributes to cancer development and progression. Although the efficacy of BET (an epigenetic regulator) inhibition has been demonstrated in various cancer types, predictive genetic markers of its efficacy in GC are currently lacking. Therefore, we aimed to identify markers that predict the response of BET inhibition in GC and, suggest an effective treatment regimen through combined therapy. The effect of BET inhibition was evaluated using iBET-151, a small-molecule inhibitor of BET proteins, in a large panel (n = 49) of GC cell lines and xenograft mouse models. Comprehensive genetic information was used to identify cell lines sensitive to iBET-151. Flow cytometry, Western blotting, and colony-formation and migration assays were used to evaluate the effects of iBET-151 and/or paclitaxel. The synergistic effect of iBET-151 and paclitaxel was evaluated using an organoid model. We found that iBET-151 showed a modest growth-inhibitory effect in GC cells (73%, 36/49). iBET-151 inhibited tumorigenicity in vitro and significantly promoted cell cycle arrest and apoptosis. Based on comprehensive genetic information analysis in relation to BET family expression, we found that BRD4 was highly expressed in the iBET-151-sensitive cell lines. We also identified WNT5B and IRS2 as potential biomarkers that are predictive for sensitivity to iBET-151. In GC xenograft model mice, iBET-151 significantly decreased tumor volumes and Ki-67 and BRD4 expression. Combination treatment showed that iBET-151 increased the sensitivity of GC cells to paclitaxel in approximately 70% of the cell lines (34/49) tested. iBET-151 plus paclitaxel significantly promoted cell cycle arrest and apoptosis and suppressed c-Myc, Bcl-2 and Bcl-xL expression. In GC organoids, iBET-151 and paclitaxel showed a synergistic effect. Collectively, our data suggest that iBET-151 is a potential therapeutic agent for GC, especially in combination with paclitaxel, and that WNT5B and IRS2 may predict iBET-151 sensitivity.

Apart from being experimentally and theoretically interesting, tetraphenylene has potential applications in different fields, including supramolecular chemistry, material science, and asymmetric catalysis. Although a wide range of substituted tetraphenylenes have been reported, octaamine-based tetraphenylene derivatives have not been reported because of their instability. Here, stable octaaminotetraphenylene octahydrochloride is synthesized from the bromination of tetraphenylene to octabromotetraphenylene, which is subsequently aminated into octaiminotetraphenylene. Finally, the imino derivative is deprotected to yield octaaminotetraphenylene octahydrochloride.

Liposomes have been utilized as a drug delivery system to increase the bioavailability of drugs and to control the rate of drug release at the target site of action. However, the occurrence of self-aggregation, coalescence, flocculation and the precipitation of aqueous liposomes during formulation or storage can cause degradation of the vesicle structure, leading to the decomposition of liposomes. To increase the stability of liposomes, post-processing techniques have been applied as an additional process to liposomes after formulation to remove water and generate dry liposome particles with a higher stability and greater accessibility for drug administration in comparison with aqueous liposomes. This review covers the effect of these techniques including freeze drying, spray drying and spray freeze drying on the stability, physicochemical properties and drug encapsulation efficiency of dry liposomes. The parameters affecting the properties of liposomes during the drying process are also highlighted in this review. In addition, the impact of using a protective agent to overcome such limitations of each process is thoroughly discussed through various studies.

To investigate the association between progressive macular ganglion cell/inner plexiform layer (mGCIPL) thinning and change of optical coherence tomography angiography (OCTA)-derived microvascular parameters in early-stage diabetic retinopathy (DR). A retrospective cohort study involved 40 eyes presenting with no DR or mild non-proliferative DR at baseline, and 30 healthy controls were included. All participants underwent spectral-domain OCT and OCTA at baseline and at 6, 12, 18, and 24 months. Change of mGCIPL thickness and OCTA metrics including foveal avascular zone (FAZ) area and FAZ circularity, vessel density (VD), and perfusion index (PI) was measured. Correlations between mGCIPL thickness and OCTA metrics were explored using regression models. Average progressive mGCIPL loss was 0.45 µm per year. Three microvascular parameters were significantly impaired at 24 months compared to baseline (FAZ area: 0.34–0.36 mm2, VD: 18.9–18.5/mm, PI: 0.35–0.34). A strong positive correlation was found between loss of mGCIPL and VD from baseline to 24 months (r = 0.817, p

Telomeres play important roles in genome stability and cell proliferation. High risk neuroblastoma (HRNB), an aggressive childhood cancer, is especially reliant on telomere maintenance. Three recurrent genetic aberrations in HRNB (MYCN amplification, TERT re-arrangements, and ATRX mutations) are mutually exclusive and each capable of promoting telomere maintenance mechanisms (i.e., through telomerase or ALT). We analyzed a panel of 5 representative HRNB cell lines and 30 HRNB surgical samples using assays that assess average telomere lengths, length distribution patterns, single-stranded DNA on the G- and C-strand, as well as extra-chromosomal circular telomeres. Our analysis pointed to substantial and variable degrees of telomere DNA damage in HRNB, including pervasive oxidative lesions. Moreover, unlike other cancers, neuroblastoma consistently harbored high levels of C-strand ssDNA overhangs and t-circles, which are consistent with active “telomere trimming”. This feature is observed in both telomerase- and ALT-positive tumors and irrespective of telomere length distribution. Moreover, evidence for telomere trimming was detected in normal neural tissues, raising the possibility that TMMs in HRNB evolved in the face of a canonical developmental program of telomere shortening. Telomere trimming by itself appears to distinguish neuroectodermal derived tumors from other human cancers, a distinguishing characteristic with both biologic and therapeutic implications.

To investigate the angiographic, tomographic, and clinical characteristics of idiopathic central serous chorioretinopathy (CSC) in elderly patients. The patients were divided into two groups according to a cutoff age of 60 years at baseline. Patients underwent spectral domain optical coherence tomography, fluorescein angiography, and indocyanine green angiography. Angiographic and tomographic features were compared between the two groups (young vs. elderly group). Of 176 patients, 26 patients (15.1%) were 60 years or older. Complete resolution of subretinal fluid after treatment was noted in 72.0% of the elderly group and 90.8% of the young group (P = 0.021). The elderly group showed worse baseline and final vision, more bilateral involvement, and lower male preponderance than the young group (P

Hangover is characterized by a number of unpleasant physical and mental symptoms that occur after heavy alcohol drinking. In addition, consistently excessive alcohol intake is considered as a major reason causes liver disease. The present study investigated the in vivo effects of DA-5513 (Morning careê Kang Hwang) on biological parameters relevant to hangover relief and alcoholic fatty liver. Blood alcohol and acetaldehyde concentrations were determined in rats administered a single dose of alcohol and treated with DA-5513 or commercially available hangover relief beverages (Yeomyungê and Ukonê). The effects of DA-5513 on alcoholic fatty liver were also determined in rats fed alcohol-containing Lieber-DeCarli diets for 4 weeks. Serum liver function markers (aspartate and alanine aminotransferase activities) and serum/liver lipid levels were assessed. Blood alcohol and acetaldehyde concentrations were lower in the groups treated with DA-5513 or Yeomyungê, as compared with control rats. However, Ukonê did not produce any significant effects on these parameters. Treatment with DA-5513 significantly reduced serum aspartate and alanine aminotransferase activities and markedly reduced serum cholesterol and triglyceride levels, as compared with control rats. Histological observations using Oil Red O staining found that DA-5513 delayed the development of alcoholic fatty liver by reversing hepatic fat accumulation. These findings suggest that DA-5513 could have a beneficial effect on alcohol-induced hangovers and has the potential to ameliorate alcoholic fatty liver.

This study evaluated quantitative changes in microvascular parameters after panretinal photocoagulation (PRP) in diabetic retinopathy (DR), using swept-source OCT Angiography (SS-OCTA). A total of 27 treatment-naïve eyes were subjected to PRP and followed-up for > 12 months after the procedure. Foveal avascular zone (FAZ) area, macular perfusion density (PD), and vessel length density (VLD) were calculated on a 3 × 3 mm en face OCTA image and nonperfusion area (NPA) was obtained on a 12 × 12 mm en face OCTA image. One month after PRP, PD and VLD of superficial and deep capillary plexus decreased and subsequently, increased progressively across the next 12 months, with statistically significant differences (P = 0.015 and 0.02). Continuous decreasing trends in total NPA values was observed across 12 months after PRP (P = 0.125). A difference in PD of the superficial capillary plexus between baseline and 6 months post PRP, was significantly associated with the progression of DR, 12 months after PRP (OR 0.528; P = 0.025). We found significant longitudinal retinal microvascular changes after PRP in DR. Overall macular perfusion status was impaired and progressively recovered across the next 12 months, compared to the baseline. Additionally, the early treatment responses in PD can predict the long-term outcomes of PDR after PRP.

Objective: To investigate the pathophysiologic characteristics of diabetic complications, we identified differences in plasma metabolites in subjects with type 2 diabetes (T2DM) with or without diabetic macular edema (DME) and a disease duration > 15 yrs.Subjects and Methods: An elderly cohort of T2DM patients with prolonged disease duration was established, and clinical information and biospecimens were collected following the guidelines of the National Biobank of Korea. DME phenotypes were identified by ophthalmologic specialists. For metabolomics studies, propensity matched case and control samples were selected. To discover multi-biomarkers in plasma, non-targeted metabolite profiling and oxylipin profiling in the discovery cohort were validated in an extended cohort.Results: From metabolomic studies, 5 amino acids (asparagine, aspartic acid, glutamic acid, cysteine, and lysine), 2 organic compounds (citric acid and uric acid) and 4 oxylipins (12-oxoETE, 15-oxoETE, 9-oxoODE, 20-carboxy leukotriene B4) were identified as candidate multi-biomarkers which can guide DME diagnosis among non-DME subjects. Receiver operating characteristic curves revealed high diagnostic value of the combined 5 amino acids and 2 organic compounds (AUC = 0.918), and of the 4 combined oxylipins (AUC = 0.957).Conclusions: Our study suggests that multi-biomarkers may be useful for predicting DME in elderly T2DM patients.

To investigate the diagnostic utility of microvascular parameters for grading the severity of diabetic retinopathy (DR) with a range of views using wide-field swept-source optical coherence tomography angiography (SS-OCTA). This retrospective study grouped 235 eyes with diabetes into the five grades: diabetes without retinopathy (no-DR), mild non-proliferative DR (NPDR), moderate NPDR, severe NPDR, and proliferative DR (PDR). Foveal avascular zone (FAZ) metrics, vessel density (VD), and the capillary nonperfusion area (NPA) were quantified with a customized, semiautomatic software algorithm. Regions of interest were selected from three rectangular fields of different sizes (i.e., 3 × 3 mm2, 6 × 6 mm2, and 10 × 10 mm2), perpendicular to the fovea-optic disc axis. NPA obtained from the 6 × 6mm2 and 10 × 10mm2 areas was the only discriminating parameter for the three NPDR stages. ROC curve analysis revealed that NPA from the 10 × 10mm2 field exhibited the best performance for grading DR into five stages. The NPA cutoff values were 3.7% (area under the curve (AUC): 0.91), 4.7% (AUC: 0.94), 9.3% (AUC: 0.94), and 21.4% (AUC: 0.90) for grading no-DR, mild from moderate NPDR, moderate from severe NPDR, and severe NPDR from PDR, respectively. Increasing DR severity as assessed by conventional grading systems is accompanied with increasing retinal ischemia on SS-OCTA. NPA measured from the larger 10 × 10 mm2 scan area showed the highest sensitivity for determining five-grade DR severity. In the future, the addition of quantitative NPA may provide a more clinically feasible DR grading system.

The design of flexible, highly energetic, and durable bifunctional oxygen electrocatalysts is indispensable for rechargeable metal-air batteries. Herein we present a simple approach for the development of carbon nitride fibers co-doped with phosphorus and sulfur, grown in situ on carbon cloth (PS-CNFs) as a flexible electrode material, and demonstrate its outstanding bifunctional catalytic activities toward ORR and OER compared to those of precious metal-based Pt/C and IrO2 on account of the dual action of P and S, numerous active sites, high surface area, and enhanced charge transfer. Furthermore, we demonstrate the flexibility, suitability, and durability of PS-CNFs as air electrodes for primary and rechargeable Zn-air batteries. Primary Zn-air batteries using this electrode showed high peak power density (231 mW cm-2), specific capacity (698 mA h g-1; analogous energy density of 785 W h kg-1), open circuit potential (1.49 V), and outstanding durability of more than 240 h of operation followed by mechanical recharging. Significantly, three-electrode rechargeable Zn-air batteries revealed a superior charge-discharge voltage polarization of ∼0.82 V at 20 mA cm-2, exceptional reversibility, and continuous charge-discharge cycling stability during 600 cycles. This work provides a pioneering strategy for designing flexible and stretchable metal-free bifunctional catalysts as gas diffusion layers for future portable and wearable renewable energy conversion and storage devices.

Ordered two-dimensional covalent organic frameworks (COFs) have generally been synthesized using reversible reactions. It has been difficult to synthesize a similar degree of ordered COFs using irreversible reactions. Developing COFs with a fused aromatic ring system via an irreversible reaction is highly desirable but has remained a significant challenge. Here we demonstrate a COF that can be synthesized from organic building blocks via irreversible condensation (aromatization). The as-synthesized robust fused aromatic COF (F-COF) exhibits high crystallinity. Its lattice structure is characterized by scanning tunneling microscopy and X-ray diffraction pattern. Because of its fused aromatic ring system, the F-COF structure possesses high physiochemical stability, due to the absence of hydrolysable weak covalent bonds. Two-dimensional covalent organic frameworks (2D COFs) are commonly synthesised through dynamic covalent chemistry, as it allows for thermodynamic ‘error correction' which enhances crystallinity. Here a crystalline 2D COF with amine and hydroxyl functional groups within the pores is synthesised through kinetically-controlled reactions.

Purpose Indocyanine green angiography (ICGA) was compared with swept-source optical coherence tomography angiography (SS-OCTA) for the detection of polypoidal choroidal vasculopathy (PCV). Design Retrospective, cross-sectional. Methods Patients with treatment-naive PCV based on ICGA imaging underwent same-day SS-OCTA imaging at Kyung Hee University Medical Center between April 2017 and November 2018. ICGA and SS-OCTA images were graded independently. SS-OCTA images were graded using both flow and structural information. Images were graded for the number of polypoidal lesions and the total lesion area, which included both the polypoidal lesions and the branching vascular networks (BVNs). Results A total of 31 eyes from 30 patients were enrolled. Polypoidal lesions were identified in all eyes using both modalities, and there was agreement on the number of polypoidal lesions in 17 eyes (55%). In 12 eyes (39%), SS-OCTA graders identified a greater number of polypoidal lesions, and in 2 eyes (6%) ICGA graders identified more lesions. There was no significant difference in the lesion area measurements (standard deviation = 1.09, P = .08). The lesion with the largest difference in area measurements resulted from focal areas of atrophy, misdiagnosed as polypoidal lesions on ICGA, and a low-lying serous retinal pigment epithelial detachment erroneously identified as part of the BVN by ICGA graders. SS-OCTA imaging correctly diagnosed the focal areas of atrophy and the serous retinal pigment epitheial detachment. Conclusions SS-OCTA imaging was comparable to ICGA for the diagnosis of treatment-naive PCV. However, SS-OCTA might be better than ICGA in correctly identifying both polypoidal lesions and BVNs in treatment-naive PCV.

Endothelial progenitor cells (EPCs) play a key role in neovascularization and have been linked to improved cardiovascular outcomes. Although there is a well-established inverse relationship between androgen levels and cardiovascular mortality in men, the role of androgens in EPC function is not fully understood. In this study, we investigated the effects of androgens on 2 subpopulations of EPCs, early EPCs (EEPCs) and late outgrowth EPCs (OECs), and their relationships with coronary collateralization. Early EPCs and OECs were isolated from the peripheral blood of young healthy men and treated with dihydrotestosterone (DHT) with or without androgen receptor (AR) antagonist, hydroxyflutamide, in vitro. Dihydrotestosterone treatment enhanced AR-mediated proliferation, migration, and tubulogenesis of EEPCs and OECs in a dose-dependent manner. Furthermore, DHT augmented EPC sensitivity to extracellular stimulation by vascular endothelial growth factor (VEGF) via increased surface VEGF receptor expression and AKT activation. In vivo, xenotransplantation of DHT pretreated human EPCs augmented blood flow recovery and angiogenesis in BALB/c nude male mice, compared to mice receiving untreated EPCs, following hindlimb ischemia. In particular, DHT pretreated human OECs exhibited higher reparative potential than EEPCs in augmenting postischemic blood flow recovery in mice. Furthermore, whole blood was collected from the coronary sinus of men with single vessel coronary artery disease (CAD) who underwent elective percutaneous intervention (n = 23). Coronary collateralization was assessed using the collateral flow index. Serum testosterone and EPC levels were measured. In men with CAD, circulating testosterone was positively associated with the extent of coronary collateralization and the levels of OECs. In conclusion, androgens enhance EPC function and promote neovascularization after ischemia in mice and are associated with coronary collateralization in men.

There have been extensive efforts to synthesize crystalline covalent triazine-based frameworks (CTFs) for practical applications and to realize their potential. The phosphorus pentoxide (P2 O5 )-catalyzed direct condensation of aromatic amide instead of aromatic nitrile to form triazine rings. P2 O5 -catalyzed condensation was applied on terephthalamide to construct a covalent triazine-based framework (pCTF-1). This approach yielded highly crystalline pCTF-1 with high specific surface area (2034.1 m2 g-1 ). At low pressure, the pCTF-1 showed high CO2 (21.9 wt % at 273 K) and H2 (1.75 wt % at 77 K) uptake capacities. The direct formation of a triazine-based COF was also confirmed by model reactions, with the P2 O5 -catalyzed condensation reaction of both benzamide and benzonitrile to form 1,3,5-triphenyl-2,4,6-triazine in high yield.

Purpose Swept-source optical coherence tomography angiography was used to investigate choroidal changes and their association with pigment epithelial detachments (PEDs) in eyes with polypoidal choroidal vasculopathy (PCV) after treatment with vascular endothelial growth factor (VEGF) inhibitors. Methods Patients with treatment-naïve PCV were included and underwent anti-VEGF therapy. Mean choroidal thickness (MCT), choroidal vascularity index (CVI), and PED volume measurements were obtained before and after treatment. Results Thirty-four treatment-naïve PCV eyes from 33 patients were included. The PED volume decreased after treatment (P < 0.05). The MCT decreased from 223.0 ± 79.6 µm at baseline to 210.9 ± 76.2 µm after treatment (P < 0.001). The CVI at baseline was 0.599 ± 0.024, and the CVI after treatment was 0.602 ± 0.023 (P = 0.16). There was a correlation between the decreased PED volumes and the decreased MCT measurements (r = 0.47; P = 0.006). Also, there was a correlation between the decreased PED volumes and the increased CVI measurements (r = −0.63; P < 0.001). Conclusions In treatment-naïve eyes with PCV, the decreases in PED volumes were correlated with the decrease in MCT and the increase in CVI measurements. We propose that, at baseline, the PCV lesions serve as high-volume arteriovenous shunts between choroidal arterial and venous circulation, causing transudation into the choroidal stroma. We propose that, after treatment, the blood flow through the vascular shunt is reduced, the excess stromal transudation is resorbed, and the exudation from the neovascular lesion is reduced, resulting in thinning of the choroid, resolution of the PEDs, and an increase in the CVI due to the resorption of excess choroidal transudation.

Addition of supplementary materials without loss of dimension in 3D printed products can be carried out by adopting coaxial extrusion. This study aimed to produce starch-xanthan gum gels filled with nanoemulsions for customized food production based on coaxial 3D printing. Nanomemulsion-filled gel (NFG) was prepared by dispersing curcumin nanoemulsion in a mixture of xanthan gum in various concentrations and potato starch. NFGs were inserted as core parts into 3D printed products through the internal nozzle of the coaxial system. Xanthan gum content of 5% or more in NFG inhibited gelation of the starch matrix, resulting in loss of dynamic viscoelasticity and 3D printing performance. The 3% xanthan gum incorporation showed the highest shear modulus value (1792.00 ± 104.50 Pa) and the best shape support ability. The physical properties of the NFG were evaluated using a confocal laser scanning microscope and a DPPH assay; the particle size decreased and antioxidant activity increased as the level of XG increased.

The future of electrochemical energy storage spotlights on the designed formation of highly efficient and robust bifunctional oxygen electrocatalysts that facilitate advanced rechargeable metal-air batteries. We introduce a scalable facile strategy for the construction of a hierarchical three-dimensional sulfur-modulated holey C2N aerogels (S-C2NA) as bifunctional catalysts for Zn-air and Li-O2 batteries. The S-C2NA exhibited ultrahigh surface area (∼1943 m2 g–1) and superb electrocatalytic activities with lowest reversible oxygen electrode index ∼0.65 V, outperforms the highly active bifunctional and commercial (Pt/C and RuO2) catalysts. Density functional theory and experimental results reveal that the favorable electronic structure and atomic coordination of holey C–N skeleton enable the reversible oxygen reactions. The resulting Zn-air batteries with liquid electrolytes and the solid-state batteries with S-C2NA air cathodes exhibit superb energy densities (958 and 862 Wh kg–1), low charge–discharge po...

The purpose of this study was to compare the changes in the aqueous cytokine levels after intravitreal bevacizumab with those after combined intravitreal bevacizumab and subtenon triamcinolone injection in diabetic macular edema (DME). This study examined 24 eyes of 23 patients with DME. Each patient with DME received randomly either an intravitreal injection of bevacizumab (IVBe) or IVBe with a subtenon triamcinolone injection (IVBe + STTA). Best corrected visual acuity and foveal thickness were evaluated and aqueous samples were obtained before and 4 weeks after the injection. The aqueous concentrations of interleukin (IL)-6, IL-8, interferon-induced protein (IP)-10, monocyte chemotactic protein (MCP)-1, platelet-derived growth factor (PDGF)-AA, and vascular endothelial growth factor (VEGF) were measured using a multiplex bead assay. After the injection, the foveal thickness decreased more in the IVBe + STTA group than in the IVBe group (P = 0.042). The MCP-1, PDGF-AA, and VEGF levels decreased significantly in the IVBe + STTA group (p = 0.013, p = 0.004 and p = 0.018 respectively), but only the VEGF level decreased in the IVBe group (p = 0.001). IL-8 was significantly increased in the IVBe + STTA group (p = 0.003) but the changes in the VEGF levels were smaller than in the IVBe group (p = 0.025). Intravitreal bevacizumab and subtenon triamcinolone injection reduces the VEGF, MCP-1 and PDGF-AA levels and increases the IL-8 level in the plural cytokine profiles of patients with DME, which might explain the limited therapeutic effect of combination therapy.

In this study, we have newly developed a flexible adhesive skin patch of electrocardiogram (ECG) device for continuous physiological monitoring of mental disorders. In addition, this flexible patch did not cause any damage to the skin even after 24 hours attachment. We have also suggested the possibility of novel interconnection for copper film on polyimide and polydimethylsiloxane (PDMS) layers of the flexible patch. Self-align and soldering of IC chips such as resistor between metal pads on flexible skin patch have also successfully fabricated for 5 min at 180 °C in vacuum oven. Low temperature interconnection technology based on a Sn42/Bi58 solder was also developed for flexible ECG devices. As a result, we can monitor the mental health status through a comprehensive analysis of biological signals from flexible ECG devices.

Trastuzumab, a humanized anti-HER2 monoclonal antibody, has shown clinically significant benefits for HER2-positive GC patients. Also, all anti-HER2 agents approved by the FDA are used for HER2-positive. However, since HER2-positive is only 10-20% of GC, targeted therapies for non-HER2-positive GC is needed. To overcome these limitations, antibody-drug conjugates (ADCs), which directly deliver cytotoxic drugs to cancer cells, have been developed. T-DXd (Daiichi Sankyo, Japan), an anti-HER2 ADC, can induce the death of neighboring cells because it has a bystander killing effect due to the high membrane permeability of the payload. However, biomarkers for predicting drug response have not yet been studied other than HER2 overexpression/amplification. In this study, we investigated the correlation between HER2 expression level and anti-tumor effect of T-DXd in a 49 GC cell line panel and the HER2-associated molecules related to T-DXd sensitivity. For HER2 status, we analyzed multiple genetic and molecular characteristics using WES, SISH, IHC, flow cytometry, and immunoblotting. GC cell lines (n=49) were divided into 3 groups according to the HER2 expression level through flow cytometry using 4 breast cancer cell lines (SK-BR-3, ZR-75-1, MCF-7, and HCC1937) for quantitative control. Groups with HER2 over- and moderate/low-expression were characterized with higher expression levels compared to ZR-75-1 (HER2 2+) and HCC1937 (HER2-negative), respectively. HER2 non-expression had lower expression levels compared to HCC1937. The sensitivity of T-DXd was evaluated in 49 GC cell lines by cell viability assay. The inhibition rate of T-DXd was calculated at 10 µg/ml. Also, expression levels of RTKs were determined by immunoblotting, and HER2 extracellular domain (ECD) and NRG1 expression were evaluated by ELISA. GC cell lines were divided into 6 HER2 over-, 26 HER2 moderate/low-, and 17 HER2 non-expression cell lines. As expected, HER2 over-expression cell lines were sensitive to T-DXd (5/6, 83.3%). T-DXd also had anti-tumor effects in the HER2 moderate/low-expression cell lines (12/26, 46.2%). There were correlations between HER2 expression level and anti-tumor effect of T-DXd in both HER2 over and moderate/low-expression cell lines. HER2 over and moderate/low-expression cell lines with high HER2 ECD expression were sensitive to T-DXd. NRG1 had relatively low expression in all GC cell lines and was not correlated with T-DXd. Additionally, even HER2 non-expression cell lines were sensitive to T-DXd (10/17, 58.8%). We found that HER2 non-expression cell lines had an RTK amplification (9/17, 52.9%) and among those cell lines, MET amplified cells showed sensitivity to T-DXd. Currently, the evaluation of the underlying mechanisms is ongoing. Our results indicate that T-DXd shows efficacy in HER2-amplified GC cell lines, HER2 moderate/low-expression, and some cell lines with HER2 non-expression. Citation Format: Seo Young Yu, Juin Park, Woo Sun Kwon, Inhye Jeong, Sun Kyoung Kang, Hyun Joo Bae, Tae Soo Kim, Hyun Cheol Chung, Sun Young Rha. Trastuzumab deruxtecan (T-DXd) sensitivity in various levels of HER2 expressing gastric cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 945.

The daily oral administration of acetylcholinesterase (AChE) inhibitors for Alzheimer’s disease features low patient compliance and can lead to low efficacy or high toxicity owing to irregular intake. Herein, we developed a subcutaneously injectable hyaluronic acid hydrogel (MLC/HSA hydrogel) hybridized with microstructured lipid carriers (MLCs) and human serum albumin (HSA) for the sustained release of donepezil (DNP) with reduced initial burst release. The lipid carrier was designed to have a microsized mean diameter (32.6 ± 12.8 µm) to be well-localized in the hydrogel. The hybridization of MLCs and HSA enhanced the structural integrity of the HA hydrogel, as demonstrated by the measurements of storage modulus (G′), loss modulus (G″), and viscosity. In the pharmacokinetic study, subcutaneous administration of MLC/HSA hydrogel in rats prolonged the release of DNP for up to seven days and reduced the initial plasma concentration, where the Cmax value was 0.3-fold lower than that of the control hydrogel without a significant change in the AUClast value. Histological analyses of the hydrogels supported their biocompatibility for subcutaneous injection. These results suggest that a new hybrid MLC/HSA hydrogel could be promising as a subcutaneously injectable controlled drug delivery system for the treatment of Alzheimer’s disease.

Substantial amounts of aluminum (Al), which is one of the most abundant elements and period III post-transition metals, can be incorporated into graphene nanoplatelets (GnPs) by ball-milling graphite in the presence of solid Al beads. After thoroughly etching away any unreacted Al residues, the structure and properties of the resultant aluminated GnPs (AlGnPs) were characterized using various analytical techniques including transmission electron microscopy (TEM) and time-of-flight secondary ion mass spectroscopy (TOF-SIMS). The results indicate that AlGnPs contain a considerable amount of Al (30.9 wt%, by TEM energy dispersive X-ray spectrum) and display good dispersibility in various solvents, including water. Next, composite films from aqueous AlGnP/poly(vinyl alcohol) (1/4, wt/wt) solutions were cast and tested for flame retardation. The results indicate that AlGnPs could serve as an outstanding flame retardant that operates by both chemical (condensation) and physical (cooling and blocking) mechanisms. This suggests that AlGnPs may provide a promising option for a new, cost-effective, eco-friendly, yet efficient flame retardant.

To simplify processes to produce self-assembled nanostructures from polymeric materials, there have been several attempts for in situ self-assembly of block copolymers. As one of these strategies, we developed the in situ nanoparticlization of conjugated polymers (INCP) process to construct various stable nanostructures without postsynthetic treatments. To get spontaneous mesoscopic evolution of the nanostructures obtained by INCP, a new strategy utilizing a unique conformational change of the conjugated polymer is reported herein. The combination of living ring-opening olefin metathesis polymerization (ROMP) and cyclopolymerization produced block and gradient copolymers through one-pot or one-shot polymerization, which initially formed spherical micelles via INCP. Then, the core block of the micelle stiffened through a coil-to-rod conformational change by simple aging in organic solvents because of cis-to-trans isomerization of the conjugated polymer under light. Subsequently, this enhanced the π-π interaction among the cores, and eventually promoted the growth of stable nanostructures from spheres to 1D-nanocaterpillars or 2D-sheet-like architectures. This time-dependent macroscopic evolution provides deeper insight into the production of a variety of kinetically fixed nano- and mesoscale structures through INCP. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017, 55, 3058–3066

Nitrogen-enriched two-dimensional (2D) porous polybenzimidazole (2D-HPBI) network was synthesized from the reaction between 1,2,4,5-tetraaminobenzene (TAB) and benzene-1,3,5-tricarboxylic acid (BTA) in polyphosphoric acid (PPA) medium. Interestingly, the remnant terminal groups such as amine and carboxyl groups at the periphery of 2D-HPBI were selectively stripped off by heat-treatment at 470 °C. The resultant heat-treated 2D-HPBI (HT-HPBI) displayed substantially improved electrical conductivity and thus outstanding performance as the counter electrode (CE) for the cobalt reduction reaction (CRR) in dye-sensitized solar cells (DSSCs). The charge-transfer resistance (Rct=0.51 Ω cm2) at the HT-HPBI-CE/electrolyte interface was even lower than that of Pt-CE (1.09 Ω cm2). More importantly, HT-HPBI-based CE showed near “zero” loss of electrochemical stability (1/Rct) even after 1000 potential cycles, while the 1/Rct of Pt decreased to

The use of a GeO 2 interfacial layer (IL) between a high-k dielectric and a Ge substrate helps to reduce the interface state density in Ge MOS devices. We report that the presence of the GeO 2 IL changes the effective work function (eWF) of the gate stack when annealed after high-k dielectric deposition. The eWF is reduced from 4.31 eV to 3.98 eV for TaN and from 5.00 eV to 4.44 eV for Ni. Consequently, the threshold voltage ( V th ) decreases from 0.69 V to 0.21 V for Ni after post deposition annealing. Our investigation confirms that the generation of oxygen vacancies in the GeO 2 IL near the Ge substrate is the main cause of the eWF modulation. In addition, the reliability of the GeO 2 IL is investigated via the conductance method and a constant-current stress test.

Platinum (Pt) nanoparticles were stably anchored on triazine-functionalized graphene nanoplatelets (TfGnPs), which were prepared by a two-step reaction starting from carboxylic acid- (CGnPs), acyl chloride- (AcGnPs) and amide-functionalized graphene nanoplatelets (AfGnPs). The resulting Pt nanoparticles on TfGnPs (Pt/TfGnPs) exhibited outstanding electrocatalytic activity with significantly enhanced stability compared with commercial Pt-based catalysts for the oxygen reduction reaction (ORR) in fuel cells (FCs) and the iodine reduction reaction (IRR) in dye-sensitized solar cells (DSSCs). For the ORR in FCs, the onset and half-wave potentials of Pt/TfGnPs under acidic conditions displayed greater positive shifts to 0.58 and 0.53 V, respectively, than those of the commercial Pt/C catalyst (0.57 and 0.52 V). For the IRR in DSSCs, Pt/TfGnPs displayed a reduced charge transfer resistance (Rct) of 0.13 Ω cm2 at the CE/electrolyte interface. This value was much lower than the Pt CE of 0.52 Ω cm2. More importantly, Pt/TfGnPs exhibited profoundly improved electrochemical stability in both the ORR and IRR compared to the Pt-based catalysts. The combination of extraordinarily high electrocatalytic activity with stability could be attributed to the high specific surface area (963.0 m2 g−1) and the triazine units of the TfGnPs, respectively, which provided more active sites and stably anchored the Pt nanoparticles.

To evaluate functional and anatomical retinal recovery according to patient age using spectral domain optical coherence tomography in eyes with surgically closed macular holes.We retrospectively studied 83 eyes with anatomically closed idiopathic macular holes after surgery confirmed by spectral domain optical coherence tomography. Patients were divided into four subgroups based on age (Group 1: ≤ 60, Group 2: 61-65, Group 3: 66-70, Group 4:70). Best-corrected visual acuity and reconstruction of the external limiting membrane and ellipsoid zone after surgery were documented for 12 months.Mean patient age was 64.5 ± 9.8 years (range 44-81). Mean visual improvement in logMAR units (ETDRS letter score) at 12 months was worse in older age subgroups (Group 1: 0.4 ± 0.3 [20], Group 2: 0.4 ± 0.3 [20], Group 3: 0.2 ± 0.3 [10], Group 4: 0.1 ± 0.3 [5], P = 0.001). When age was more than 65 years, total number of eyes with restored retinal microstructure after surgery was lower (22 eyes, 53.7%; 32 eyes, 76.2%; P = 0.018) and time (months) to structural recovery was longer (10.2, 7.1, P0.001) than age under 65 years. Visual improvement corresponded to recovery of the outer retinal layers. In multivariate analysis, patients of older age (odds ratio, 0.91; 95% CI, 0.89-0.93) had less visual improvement at month 12.Poor visual outcomes and delayed microstructural recovery occurred in older subjects after anatomically closed macular hole surgery. Older age may be indicative of poor clinical outcome in repaired macular holes.

Neovascular age-related macular degeneration (AMD) is the leading cause of irreversible blindness in elderly population. Several classifications schemes have been developed to provide subtypes of neovascular AMD, which are known to be associated with visual prognosis. However, there is still a large proportion of patient with ambiguous findings according to current classification criteria. In this study, we classified treatment-naïve neovascular AMD patients using novel angiographic classification system and investigated the incidence and clinical characteristics of AMD subtypes. Among 339 eyes, five AMD subtypes were identified: 41 (12.1%) with classic choroidal neovascularization (CNV), 30 (8.8%) with occult CNV, 91 (26.8%) with microaneurysmal choroidal vasculopathy (MCV), 123 (36.3%) with polypoidal choroidal vasculopathy (PCV), and 54 (15.9%) with retinal angiomatous proliferation (RAP). MCV was younger than RAP (P P P = 0.036). Subfoveal choroidal thickness was highest in MCV, and lowest in RAP (P P = 0.046). Our results highlight the importance of angiography for identifying AMD subtypes, particularly the novel MCV group being distinct from other subtypes.

Research efforts towards developing near-infrared (NIR) therapeutics to activate the proliferation of human keratinocytes and collagen synthesis in the skin microenvironment have been minimal, and the subject has not been fully explored. Herein, we describe the novel synthesis Ag2S nanoparticles (NPs) by using a sonochemical method and reveal the effects of NIR irradiation on the enhancement of the production of collagen through NIR-emitting Ag2S NPs. We also synthesized Li-doped Ag2S NPs that exhibited significantly increased emission intensity because of their enhanced absorption ability in the UV–NIR region. Both Ag2S and Li-doped Ag2S NPs activated the proliferation of HaCaT (human keratinocyte) and HDF (human dermal fibroblast) cells with no effect on cell morphology. While Ag2S NPs upregulated TIMP1 by only twofold in HaCaT cells and TGF-β1 by only fourfold in HDF cells, Li-doped Ag2S NPs upregulated TGF-β1 by tenfold, TIMP1 by 26-fold, and COL1A1 by 18-fold in HaCaT cells and upregulated TGF-β1 by fivefold and COL1A1 by fourfold in HDF cells. Furthermore, Ag2S NPs activated TGF-β1 signaling by increasing the phosphorylation of Smad2 and Smad3. The degree of activation was notably higher in cells treated with Li-doped Ag2S NPs, mainly caused by the higher PL intensity from Li-doped Ag2S NPs. Ag2S NPs NIR activates cell proliferation and collagen synthesis in skin keratinocytes and HDF cells, which can be applied to clinical light therapy and the development of anti-wrinkle agents for cosmetics.

Carbonate formations of the Cambro-Ordovician Period occur in the Taebaek and Jeongseon areas, located in the central–eastern part of the Korean Peninsula. This study analyzed the rare earth element (REE) contents and Sr–Nd isotope ratios in these carbonates to elucidate their depositional environment and diagenetic history. The CI chondrite-normalized REE patterns of the carbonates showed negative Eu anomalies (EuN/(SmN × GdN)1/2 = 0.50 to 0.81), but no Ce anomaly (Ce/Ce* = CeN/(LaN2 × NdN)1/3 = 1.01 ± 0.06). The plot of log (Ce/Ce*) against sea water depth indicates that the carbonates were deposited in a shallow-marine environment such as a platform margin. The 87Sr/86Sr ratios in both Taebaek and Jeongseon carbonates were higher than those in the seawater at the corresponding geological time. The 87Sr/86Sr ratios and the values of (La/Yb)N and (La/Sm)N suggest that the carbonates in the areas experienced diagenetic processes several times. Their 143Nd/144Nd ratios varied from 0.511841 to 0.511980. The low εNd values and high 87Sr/86Sr ratios in the carbonates may have resulted from the interaction with the hydrothermal fluid derived from the intrusive granite during the Cretaceous Period.

Ferulic acid (FA) is well known for its variety of biological activities. However, FA has low water solubility, which limits its potential applications in the food and pharmaceutical industries. In this study, FA was encapsulated by spray drying with maltodextrin (MD) and hydroxypropyl methylcellulose (HPMC) under optimal ratios to address this limitation. The FA/MD complex was effectively formed at FA 8%:MD 20% and the FA/HPMC complex at FA 10%:HPMC 25%. Encapsulation efficiency, solubility, and stability were evaluated by high-performance liquid chromatography. The characteristics and morphology of each material and complex were analyzed by an X-ray diffractometry, Fourier transform infrared spectrometry, differential scanning calorimetry and scanning electron microscopy. All these analyses indicated that FA was well encapsulated with MD and HPMC. Moreover, encapsulated FA had enhanced water solubility and stability. Thus, FA may be a promising ingredient for the food and pharmaceutical industries.

The effects of nanotexturing and post-etching on the reflection and quantum efficiency properties of diamond wire sawn (DWS) multicrystalline silicon (mc-Si) solar cell have been investigated. The chemical solutions, which are acidic etching solution (HF-), metal assisted chemical etching (MAC etch) solutions (-HF-DI, HF--DI) and post-etching solution (diluted KOH at ), were used for micro- and nano-texturing at the surface of diamond wire sawn (DWS) mc-Si wafer. Experiments were performed with various post-etching time conditions in order to determine the optimized etching condition for solar cell. The reflectance of mc-Si wafer texturing with acidic etching solution showed a very high reflectance value of about 30% (w/o anti-reflection coating), which indicates the insufficient light absorption for solar cell. The formation of nano-texture on the surface of mc-Si contributed to the enhancement of light absorption. Also, post-etching time condition of 240 s was found adequate to the nano-texturing of mc-Si due to its high external quantum efficiency of about 30% at short wavelengths and high short circuit current density () of .

BACKGROUND AND OBJECTIVE: To evaluate en face spectral-domain optical coherence tomography (SD-OCT) findings of the outer retinal hard exudates in diabetic macular edema (DME). PATIENTS AND METHODS: Exploratory analyses of prospective and consecutive case series. Fifty-five eyes treated with intravitreal ranibizumab (IVR) (Lucentis; Genentech, South San Francisco, CA) for 12 months were classified according to OCT features of DME: diffuse retinal thickening (DRT), cystoid macular edema (CME), and serous retinal detachment (SRD). Area fraction of outer nuclear layer (ONL) hard exudates (HEs) was assessed from en face OCT images. RESULTS: Area fraction of ONL HEs increased from 1.45% ± 1.22% to 2.24% ± 1.31% in DRT and from 2.24% ± 1.85% to 3.25% ± 1.52% in CME. HE gain was greatest during first 3 months (DRT = 0.83%; CME = 1.25%). SRD showed no difference in HEs ( P = .462). CONCLUSIONS: ONL HEs increased in DRT and CME at month 12 following IVR. Rapid gain of HEs was found during the initial loading phase of IVR. [ Ophthalmic Surg Lasers Imaging Retina . 2016;47:313–321.]

To evaluate the in vivo repeatability and reproducibility of spectral-domain optical coherence tomography (SD-OCT) measurements of total retinal thickness (TRT) and retinal nerve fiber layer (RNFL) thickness in rats.Retinal thickness was measured using an RNFL circular scan with AutoRescan and TruTracking modes in 20 eyes of Long-Evans Tokushima Otsuka rats. Three RNFL circular scan images were acquired with a brief rest between measurements to evaluate intra-session repeatability. Three additional RNFL circular scans were acquired 1 day later to evaluate intersession repeatability. Two experienced examiners independently measured TRT using automatic alignment and RNFL thickness using manual alignment according to the same procedure to evaluate inter-examiner reproducibility 1 week later. The correlation of measurements by OCT and histology was determined.For TRT, the intra-session and inter-session intraclass correlation coefficient (ICC) with SD-OCT was between 0.85 and 0.93. The coefficient of variance (CV) ranged from 3.9% to 4.8%. For RNFL thickness, intra-session, and inter-session ICC with SD-OCT were between 0.61 and 0.91. The inter-examiner ICC was 0.74 for TRT and 0.70 for RNFL. The CV was 4.4% for TRT and 6.0% for RNFL. OCT and histologically determined TRT and RNFL thicknesses were significantly positively related based on Pearson's correlation coefficient (TRT, r = 0.781, p0.001; RNFL, r = 0.517, p = 0.019).TRT and RNFL thickness measurements using SD-OCT in rats had high intra-session and inter-session repeatability and inter-examiner reproducibility in vivo. This method will facilitate longitudinal studies to follow disease processes over time and to evaluate therapeutic effects after experimental intervention.

The purpose of this study was to improve the functionality of a healthy drink with examining the possibility of manufacturing different enzymes (alpha-, beta-, glucose-amylase) in barley malts (BM) produced in various malting periods. The study showed that enzyme treatment increased significantly total polyphenol content (TPC), DPPH radical scavenging activity and hydroxly radical scavenging activity in malted liquid samples (MLS) which obtained from various malting periods. The highest of TPC were found in Gluco-24M with 1.981 ㎎TAE/㎖, followed by Beta-24M and Alpha-72M with 1.878 ㎎TAE/㎖ and 1.845 ㎎TAE/㎖, respectively. The DPPH result revealed that percent of inhibition increased by 71-75% compared to the control. No statistical difference was found between MLS obtained by 24 hr of malting (24 M) and 72 hr of malting (72 M) after enzyme treatment. In addition, an increasing of hydroxyl radical was in the same trend to the TPC and DPPH. The hydroxyl radical scavenging activity of enzyme treated samples was 1,5 times higher than the control. These results suggest the possibility of enzyme application to barley malts obtained in various germination periods for improving quality and functionality of barley malts.

Lactate is an important metabolite in cellular metabolism and fluctuates in certain disease conditions including cancer and immune diseases. It was hypothesized that a decrease in lactate would modulate the inflammatory response elicited by lipopolysaccharides (LPS) in macrophages. When RAW 264.7 macrophages were treated with FX11, a specific lactate dehydrogenase (LDHA) inhibitor, the expression of the cytokines, inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX‑2) was downregulated due to reduced cellular lactate levels. Genetic suppression of LDHA by small interfering RNA (siRNA) downregulated the LPS‑activated expression of interleukin (IL)‑6, iNOS, and COX‑2, and reduced the production of IL‑6 and nitrites. Pharmacological and genetic suppression of LDHA inhibited the phosphorylation of p38 mitogen‑activated protein kinase. Microarray gene expression profile demonstrated that the genes involved in cell proliferation and inflammation were mainly altered by siRNA‑mediated LDHA suppression. Collectively, the present observations suggest that lactate may be an important metabolite and implicated in regulation of inflammatory response.

Previously, it was inferred that a high glutamine synthetase (GS) activity in human embryonic kidney (HEK) 293E cells results in elevated resistance to methionine sulfoximine (MSX) and consequently hampers GS-mediated gene amplification and selection by MSX. To overcome this MSX resistance in HEK293E cells, a GS-knockout HEK293E cell line was generated using the CRISPR/Cas9 system to target the endogenous human GS gene. The GS-knockout in the HEK293E cell line (RK8) was confirmed by Western blot analysis of GS and by observation of glutamine-dependent growth. Unlike the wild type HEK293E cells, the RK8 cells were successfully used as host cells to generate a recombinant HEK293E cell line (rHEK293E) producing a monoclonal antibody (mAb). When the RK8 cells were transfected with the GS expression vector containing the mAb gene, rHEK293E cells producing the mAb could be selected in the absence as well as in the presence of MSX. The gene copies and mRNA expression levels of the mAb in rHEK293E cells were also quantified using qRT-PCR. Taken together, the GS-knockout HEK293E cell line can be used as host cells to generate stable rHEK293E cells producing a mAb through GS-mediated gene selection in the absence as well as in the presence of MSX.