Lithiophilic Multichannel Layer to Simultaneously Control the Li-Ion Flux and Li Nucleation for Stable Lithium Metal Batteries.

Although the Li metal has been gaining attention as a promising anode material for the next-generation high-energy-density rechargeable batteries owing to its high theoretical specific capacity (3860 mAh g-1), its practical use remains challenging owing to inherent issues related to Li nucleation and growth. This paper reports the fabrication of a lithiophilic multichannel layer (LML) that enables the simultaneous control of Li nucleation and growth in Li-metal batteries. The LML, composed of lithiophilic ceramic composite nanoparticles (Ag-plated Al2O3 particles), is fabricated using the electroless plating method. This LML provides numerous channels for a uniform Li-ion diffusion on a nonwoven separator. Furthermore, the lithiophilic Ag on the Li metal anode surface facing the LML induces a low overpotential during Li nucleation, resulting in a dense Li deposition. The LML enables the LiNi0.8Co0.1Mn0.1O2|| Li cells to maintain a capacity higher than 75% after 100 cycles, even at high charge/discharge rates of 5.0 C at a cutoff voltage of 4.4 V, and achieve an ultrahigh energy density of 1164 Wh kg-1. These results demonstrate that the LML is a promising solution enabling the application of Li metal as an anode material in the next-generation Li-ion batteries.

A Nationwide Study on HER2-low Breast Cancer in South Korea: Its Incidence of 2022 Real World Data and the Importance of Immunohistochemical Staining Protocols.

Purpose: Notable effectiveness of trastuzumab deruxtecan (T-DXd) in patients with HER2-low advanced breast cancer (BC) has focused pathologists' attention. We studied the incidence and clinicopathologic characteristics of HER2-low BC, and the effects of immunohistochemistry (IHC) associated factors on HER2 IHC results. Materials and Methods: The Breast Pathology Study Group of the Korean Society of Pathologists conducted a nationwide study using real-world data on HER2 status generated between January 2022 and December 2022. Information on HER2 IHC protocols at each participating institution was also collected. Results: Total 11,416 patients from twenty-five institutions included in this study. Of these patients, 40.7% (range: 6.0%-76.3%) were classified as HER2-zero, 41.7% (range: 10.5%-69.1%) as HER2-low, and 17.5% (range: 6.7%-34.0%) as HER2-positive. HER2-low tumors were associated with positive ER and PR statuses (p<0.001 and p<0.001, respectively). Antigen retrieval times (≥ 36 min vs. < 36 min) and antibody incubation times (≥ 12 min vs. < 12 min) affected on the frequency of HER2 IHC 1+ BC at institutions using the PATHWAY HER2 (4B5) IHC assay and BenchMark XT or Ultra staining instruments. Furthermore, discordant results between core needle biopsy (CNB) and subsequent resection specimen HER2 statuses were observed in 24.1% (787/3259) of the patients. Conclusion: The overall incidence of HER2-low BC in South Korea concurs with those reported in previously published studies. Significant inter-institutional differences in HER2 IHC protocols were observed, and it may have impact on HER2-low status. Thus, we recommend standardizing HER2 IHC conditions to ensure precise patient selection for targeted therapy.

Phase Behavior of the Mixtures of 2- and 3-Components for Poly(styrene-co-octafluoropentyl methacrylate) by Dispersion Polymerization under CO2.

The dispersed-phase polymerization of poly(styrene-co-2,2,3,4,4,4-octafluoropentyl methacrylate), also known as p(styrene-co-OFPMA), took place in supercritical carbon dioxide (sc-CO2). The chemical and physical properties of p(styrene-co-OFPMA) were studied by varying the styrene-to-OFPMA ratios (40:1, 30:1, and 20:1) and 2,2'-azobis(isobutyronitrile) (AIBN) initiator amounts (wt %: 1.0, 2.0, 3.0). The cloud-point data were obtained for various systems, including the binary mixtures of p(styrene-co-OFPMA) (30:1 ratio, AIBN wt %: 1.0, 2.0, 3.0) with supercritical solvents such as sc-CO2, sc-CH3OCH3, sc-C3H6, sc-C4H8, and sc-CHClF2. Phase behavior (i.e., mixtures) was studied at temperatures of 324-455 K and pressure below 201 MPa. In the binary system of p(styrene-co-OFPMA) + sc-CH3OCH3, a lower critical solution temperature (LCST)-type curve was observed, characterized by a positive slope. Conversely, the binary systems of p(styrene-co-OFPMA) + (sc-C3H6, sc-C4H8, sc-CHClF2) exhibited an upper critical solution temperature (UCST) behavior with a decreasing slope. The phase equilibrium curves were obtained for p(styrene-co-OFPMA) [30:1; 1.0% (Mw = 42,400), 2.0% (Mw = 33,800), and 4.0% (Mw = 24,100); AIBN: 1.0 wt %] + sc-C3H6, sc-C4H8, and sc-CHClF2 mixtures. These curves exhibited an increasing slope for p(styrene-co-OFPMA) + sc-CH3OCH3 and a negative slope for p(styrene-co-OFPMA) + (sc-C3H6, sc-C4H8, sc-CHClF2) systems, indicating distinct phase behavior. Tetramethyl orthosilicate (TMOS) addition (0.0-68.9 wt %) to P(styrene-co-OFPMA) (30:1; AIBN wt %: 1.0) + solvents altered the phase equilibrium, switching from UCST to LCST, as evidenced by changes in the pressure-temperature slope.

A comprehensive review and perspective research in technology integration for the treatment of gaseous volatile organic compounds.

Volatile organic compounds (VOCs) are harmful pollutants emitted from industrial processes. They pose a risk to human health and ecosystems, even at low concentrations. Controlling VOCs is crucial for good air quality. This review aims to provide a comprehensive understanding of the various methods used for controlling VOC abatement. The advancement of mono-functional treatment techniques, including recovery such as absorption, adsorption, condensation, and membrane separation, and destruction-based methods such as natural degradation methods, advanced oxidation processes, and reduction methods were discussed. Among these methods, advanced oxidation processes are considered the most effective for removing toxic VOCs, despite some drawbacks such as costly chemicals, rigorous reaction conditions, and the formation of secondary chemicals. Standalone technologies are generally not sufficient and do not perform satisfactorily for the removal of hazardous air pollutants due to the generation of innocuous end products. However, every integration technique complements superiority and overcomes the challenges of standalone technologies. For instance, by using catalytic oxidation, catalytic ozonation, non-thermal plasma, and photocatalysis pretreatments, the amount of bioaerosols released from the bioreactor can be significantly reduced, leading to effective conversion rates for non-polar compounds, and opening new perspectives towards promising techniques with countless benefits. Interestingly, the three-stage processes have shown efficient decomposition performance for polar VOCs, excellent recoverability for nonpolar VOCs, and promising potential applications in atmospheric purification. Furthermore, the review also reports on the evolution of mathematical and artificial neural network modeling for VOC removal performance. The article critically analyzes the synergistic effects and advantages of integration. The authors hope that this article will be helpful in deciding on the appropriate strategy for controlling interested VOCs.

Aspirin Challenge-Induced Genome-Wide DNA Methylation Profile of Peripheral Blood Lymphocytes in Aspirin-Exacerbated Respiratory Disease.

Genetic variation and epigenetic factors are thought to contribute to the development of hypersensitivity to aspirin. DNA methylation fluctuates dynamically throughout the day. To discover new CpG methylation in lymphocytes associated with aspirin-exacerbated respiratory disease (AERD), we evaluated changes in global CpG methylation profiles from before to after an oral aspirin challenge in patients with AERD and aspirin-tolerant asthma (ATA). Whole-genome CpG methylation levels of peripheral blood mononuclear cells were quantified with an Illumina 860K Infinium Methylation EPIC BeadChip array and then adjusted for inferred lymphocyte fraction (ILF) with GLINT and Tensor Composition Analysis. Among the 866,091 CpGs in the array, differentially methylated CpGs (DMCs) were found in 6 CpGs in samples from all 12 patients with asthma included in the study (AERD, n = 6; ATA, n = 6). DMCs were found in 3 CpGs in the 6 ATA samples and in 615 CpGs in the 6 AERD samples. A total of 663 DMCs in 415 genes and 214 intergenic regions differed significantly in the AERD compared with the ATA. In promoters, 126 CpG loci were predicted to bind to 38 transcription factors (TFs), many of which were factors already known to be involved in the pathogenesis of asthma and immune responses. In conclusion, we identified 615 new CpGs methylated in peripheral blood lymphocytes by oral aspirin challenge in AERD but not in ATA. These findings indicate that oral aspirin challenge induces epigenetic changes in ILFs, specifically in AERD patients, possibly via changes in TF binding, which may have epigenetic effects on the development of AERD.

S100 Calcium-Binding Protein A9, a Potential Novel Diagnostic Biomarker for Idiopathic Pulmonary Fibrosis.

BACKGROUND: Neutrophilic inflammation is a characteristic feature of idiopathic pulmonary fibrosis (IPF). S100 calcium-binding protein A9 (S100A9) is a neutrophil-derived protein involved in the development of neutrophil-related chronic inflammatory disorders. However, the role of S100A9 in IPF remains unclear. METHODS: We used enzyme-linked immunosorbent assays to measure S100A9 levels in bronchoalveolar lavage fluid (BALF) and serum obtained from healthy controls (HCs) and patients with IPF, non-specific interstitial pneumonia, hypersensitivity pneumonitis, and sarcoidosis. RESULTS: Compared with HCs, BALF S100A9 levels were significantly higher in IPF patients (P < 0.001), patients with hypersensitivity pneumonitis (P = 0.043), and patients with nonspecific interstitial pneumonia (P < 0.001). The S100A9 level in BALF of 0.093 ng/mL could distinguish IPF patients from HCs, with a specificity of 78.8% and a sensitivity of 81.6%. Similarly, the S100A9 level in BALF of 0.239 ng/mL had a specificity of 64.7% and a sensitivity of 66.7% for distinguishing IPF patients from patients with other interstitial lung diseases. Additionally, BALF S100A9 levels were significantly correlated with neutrophil counts (r = 0.356, P < 0.001) in BALF. IPF patients with S100A9 levels in BALF > 0.533 ng/mL had lower survival rates, compared with patients who had levels ≤ 0.553 ng/mL (n = 49; hazard ratio [HR], 3.62; P = 0.021). Combination analysis revealed that IPF patients with S100A9 levels in BALF> 0.553 ng/mL or neutrophil percentages > 49.1% (n = 43) had significantly lower survival rates than patients with S100A9 levels in BALF ≤ 0.553 ng/mL and neutrophil percentages ≤ 49.1% (n = 41) (HR, 3.91; P = 0.014). Additionally, patients with serum S100A9 levels > 0.077 ng/mL (n = 29) had significantly lower survival rates than patients with levels ≤ 0.077 ng/mL (n = 53, HR, 2.52; P = 0.013). S100A9 was expressed on neutrophils and macrophages in BALF from IPF patients as well as α-smooth muscle actin positive cells in the lung tissues. CONCLUSION: S100A9 is involved in the development and progression of IPF. Moreover, S100A9 levels in BALF and serum may be surrogate markers for IPF diagnosis and survival prediction, particularly when analyzed in combination with neutrophil percentages.

Scalp nodules as the first presentation of prostate cancer: A CARE-compliant article.

RATIONALE: Bones are the most common site of prostate cancer metastasis. Other common sites of metastases include the distant lymph nodes, liver, thorax, brain, and digestive system. However, cutaneous metastases from prostate cancer are extremely rare. PATIENT CONCERNS: We present a case of a 61-year-old man with scalp nodules without any cancer history. DIAGNOSIS: The patient was diagnosed with metastatic prostate adenocarcinoma through an incisional biopsy for his scalp nodules. The patient presented with a serum prostate-specific antigen level of 10.2 ng/mL; imaging examinations revealed extraprostatic extension, lymph node involvement, and multiple bone metastases. INTERVENTION: The patient was treated with androgen deprivation therapy with leuprolide acetate (7.5 mg every month) and abiraterone acetate (1000 mg daily). OUTCOMES: The scalp metastases resolved without adverse effects, and the serum prostate-specific antigen level decreased to 0.02 ng/mL. LESSONS: Cutaneous metastasis, especially scalp metastasis from prostate cancer, is extremely rare. If there is a rash or nodule on the skin, it is necessary to evaluate it carefully and to confirm it through a biopsy.

Correction: Suppression of choroidal neovascularization and epithelial-mesenchymal transition in retinal pigmented epithelium by adeno-associated virus-mediated overexpression of CCN5 in mice.

[This corrects the article DOI: 10.1371/journal.pone.0269937.].

Intravitreal Administration of Retinal Organoids-Derived Exosomes Alleviates Photoreceptor Degeneration in Royal College of Surgeons Rats by Targeting the Mitogen-Activated Protein Kinase Pathway.

Increasing evidence suggests that exosomes are involved in retinal cell degeneration, including their insufficient release; hence, they have become important indicators of retinopathies. The exosomal microRNA (miRNA), in particular, play important roles in regulating ocular and retinal cell functions, including photoreceptor maturation, maintenance, and visual function. Here, we generated retinal organoids (ROs) from human induced pluripotent stem cells that differentiated in a conditioned medium for 60 days, after which exosomes were extracted from ROs (Exo-ROs). Subsequently, we intravitreally injected the Exo-RO solution into the eyes of the Royal College of Surgeons (RCS) rats. Intravitreal Exo-RO administration reduced photoreceptor apoptosis, prevented outer nuclear layer thinning, and preserved visual function in RCS rats. RNA sequencing and miRNA profiling showed that exosomal miRNAs are mainly involved in the mitogen-activated protein kinase (MAPK) signaling pathway. In addition, the expression of MAPK-related genes and proteins was significantly decreased in the Exo-RO-treated group. These results suggest that Exo-ROs may be a potentially novel strategy for delaying retinal degeneration by targeting the MAPK signaling pathway.

The Role of Erythrocyte Membrane Protein Band 4.1-like 3 in Idiopathic Pulmonary Fibrosis.

Novel genetic and epigenetic factors involved in the development and prognosis of idiopathic pulmonary fibrosis (IPF) have been identified. We previously observed that erythrocyte membrane protein band 4.1-like 3 (EPB41L3) increased in the lung fibroblasts of IPF patients. Thus, we investigated the role of EPB41L3 in IPF by comparing the EPB41L3 mRNA and protein expression of lung fibroblast between patients with IPF and controls. We also investigated the regulation of epithelial-mesenchymal transition (EMT) in an epithelial cell line (A549) and fibroblast-to-myofibroblast transition (FMT) in a fibroblast cell line (MRC5) by overexpressing and silencing EPB41L3. EPB41L3 mRNA and protein levels, as measured using RT-PCR, real-time PCR, and Western blot, were significantly higher in fibroblasts derived from 14 IPF patients than in those from 10 controls. The mRNA and protein expression of EPB41L3 was upregulated during transforming growth factor-ß-induced EMT and FMT. Overexpression of EPB41L3 in A549 cells using lenti-EPB41L3 transfection suppressed the mRNA and protein expression of N-cadherin and COL1A1. Treatment with EPB41L3 siRNA upregulated the mRNA and protein expression of N-cadherin. Overexpression of EPB41L3 in MRC5 cells using lenti-EPB41L3 transfection suppressed the mRNA and protein expression of fibronectin and α-SMA. Finally, treatment with EPB41L3 siRNA upregulated the mRNA and protein expression of FN1, COL1A1, and VIM. In conclusion, these data strongly support an inhibitory effect of EPB41L3 on the process of fibrosis and suggest the therapeutic potential of EPB41L3 as an anti-fibrotic mediator.

Relationships Between High-Resolution Computed Tomographic Features and Lung Function Trajectory in Patients With Asthma.

PURPOSE: A subset of asthmatics suffers from persistent airflow limitation, known as remodeled asthma, despite optimal treatment. Typical quantitative scoring methods to evaluate structural changes of airway remodeling on high-resolution computed tomography (HRCT) are time-consuming and laborious. Thus, easier and simpler methods are required in clinical practice. We evaluated the clinical usefulness of a simple, semi-quantitative method based on 8 HRCT parameters by comparing asthmatics with a persistent decline of post-bronchodilator (BD)-FEV1 to those with a BD-FEV1 that normalized over time and evaluated the relationships of the parameters with BD-FEV1. METHODS: Asthmatics (n = 59) were grouped into 5 trajectories (Trs) according to the changes of BD-FEV1 over 1 year. After 9-12 months of guideline-based treatment, HRCT parameters including emphysema, bronchiectasis, anthracofibrosis, bronchial wall thickening (BWT), fibrotic bands, mosaic attenuation on inspiration, air-trapping on expiration, and centrilobular nodules were classified as present (1) or absent (0) in 6 zones. RESULTS: The Tr5 group (n = 11) was older and exhibited a persistent decline in BD-FEV1. The Tr5 and Tr4 groups (n = 12), who had a lower baseline BD-FEV1 that normalized over time, had longer durations of asthma, frequent exacerbations, and higher doses of steroid use compared to the Tr1-3 groups (n = 36), who had a normal baseline BD-FEV1. The Tr5 group had higher emphysema and BWT scores than the Tr4 (P = 8.25E-04 and P = 0.044, respectively). Scores for the other 6 parameters were not significantly different among the Tr groups. BD-FEV1 was inversely correlated with the emphysema and BWT scores in multivariate analysis (P = 1.70E-04, P = 0.006, respectively). CONCLUSIONS: Emphysema and BWT are associated with airway remodeling in asthmatics. Our simple, semi-quantitative scoring system based on HRCT may be an easy-to-use method for estimating airflow limitation.

Modulation of Switching Characteristics in a Single VO2 Nanobeam with Interfacial Strain via the Interconnection of Multiple Nanoscale Channels.

We demonstrate the modulation of electrical switching properties through the interconnection of multiple nanoscale channels (∼600 nm) in a single VO2 nanobeam with a coexisting metal-insulator (M-I) domain configuration during phase transition. The Raman scattering characteristics of the synthesized VO2 nanobeams provide evidence that substrate-induced interfacial strain can be inhomogeneously distributed along the length of the nanobeam. Interestingly, the nanoscale VO2 devices with the same channel length and width exhibit distinct differences in hysteric current-voltage characteristics, which are explained by theoretical calculations of resistance change combined with Joule heating simulations of the nanoscale VO2 channels. The observed results can be attributed to the difference in the spatial distribution and fraction ratios of M-I domains due to interfacial strain in the nanoscale VO2 channels during the metal-insulator transition process. Moreover, we demonstrate the electrically activated resistive switching characteristics based on the hysteresis behaviors of the interconnected nanoscale channels, implying the possibility of manipulating multiple resistive states. Our results may offer insights into the nanoscale engineering of correlated phases in VO2 as the key materials of neuromorphic computing for which nonlinear conductance is essential.

Calcium ionophore-activated platelets induce eosinophil extracellular trap formation.

BACKGROUND: Platelets play a modulatory role in inflammatory response by secreting a vast array of granules and disintegrating into membrane-bound microparticles upon activation. The interplay between eosinophils and platelets is postulated to be implicated in the pathology of allergic airway inflammation. In this study, we investigated whether activated platelets can induce eosinophil extracellular trap (EET) formation, a cellular process by which activated eosinophils release net-like DNA fibers. METHODS: Platelets were stimulated with the calcium ionophore, A23187, and the platelet agonists, thrombin and adenosine diphosphate (ADP). Platelet cultures were fractionated into conditioned medium (CM) and pellet, which were then overlaid on eosinophils to examine EET formation. RESULTS: The CM and pellet from A23187-activated platelets stimulated eosinophils to generate EET, whereas those from thrombin- or ADP-activated platelets failed to induce such generation. The EET-inducing activity of the A23187-activated platelet culture was linearly proportional to the number of activated platelets. Interestingly, while EET formation induced by the direct stimulation of eosinophils with A23187 was NADPH oxidase (NOX)-dependent, EET formation induced by A23187-activated platelets was NOX-independent and significantly inhibited by necroptosis pathway inhibitors. CONCLUSIONS: Activated platelets and their products may induce EET formation, thereby potentiating their role in eosinophilic airway inflammation.

Inflammatory Myofibroblastic Tumor of the Prostate Mimicking Prostate Cancer: A Case Report

Inflammatory myofibroblastic tumor (IMT) is an uncommon soft tissue tumor mimicking malignancy, which can be found in any part of the body. However, IMT involving the prostate is extremely rare. Previous reports on prostatic IMTs mainly focused on the pathological and immunohistochemical findings of the tumor and they lacked radiological findings. This report presents a case of prostatic IMT in a 60-year-old man who presented with voiding difficulty and elevated prostate-specific antigen (PSA) level. On magnetic resonance imaging, a hypointense mass was observed on T2-weighted images with broad and extensive extracapsular extension, showing diffusion restriction, early well enhancement and delayed mild washout, which could mimic prostate cancer. On needle biopsy of the prostate mass, cancer cells were not detected; and a benign tumor was suspected with a normalized PSA level. Finally, prostatectomy was performed to rule out prostate cancer; and prostatic IMT was confirmed on histopathologic examination.

Nanoemulsion as an Effective Inhibitor of Biofilm-forming Bacterial Associated Drug Resistance: An Insight into COVID Based Nosocomial Infections.

Antibiotic overuse has resulted in the microevolution of drug-tolerant bacteria. Understandably it has become one of the most significant obstacles of the current century for scientists and researchers to overcome. Bacteria have a tendency to form biofilm as a survival mechanism. Biofilm producing microorganism become far more resistant to antimicrobial agents and their tolerance to drugs also increases. Prevention of biofilm development and curbing the virulency factors of these multi drug resistant or tolerant bacterial pathogens is a newly recognised tactic for overcoming the challenges associated with such bacterial infections and has become a niche to be addressed. In order to inhibit virulence and biofilm from planktonic bacteria such as, Pseudomonas aeruginosa, Acinetobacter baumannii, and others, stable nanoemulsions (NEs) of essential oils (EOs) and their bioactive compounds prove to be an interesting solution. These NEs demonstrated significantly greater anti-biofilm and anti-virulence activity than commercial antibiotics. The EO reduces disease-causing gene expression, which is required for pathogenicity, biofilm formation and attachment to the surfaces. Essential NE and NE-loaded hydrogel surface coatings demonstrates superior antibiofilm activity which can be employed in healthcare-related equipments like glass, plastic, and metal chairs, hospital beds, ventilators, catheters, and tools used in intensive care units. Thus, anti-virulence and anti-biofilm forming strategies based on NEs-loaded hydrogel may be used as coatings to combat biofilm-mediated infection on solid surfaces.

Association of ATP8B3 gene polymorphisms with aspirin-exacerbated respiratory disease in asthmatics.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD), an asthma phenotype, often presents with severe manifestations and it remains widely underdiagnosed because of insufficient awareness of the relationship between the ingestion of nonsteroidal anti-inflammatory drugs, including acetylsalicylic acid (ASA), and asthma exacerbation. Our previous genome-wide association study demonstrated an association between a single nucleotide polymorphism (SNP) of the ATP8B3 gene and the risk of AERD. This study examined AERD-related SNPs of the ATP8B3 gene in a large population. METHODS: Twenty-five SNPs of ATP8B3 were genotyped with the GoldenGate assay using VeraCode microbeads in 141 asthmatics with AERD and 995 Aspirin-tolerant asthma (ATA). The genotype distribution was analyzed using logistic regression models. The declines in forced expiratory volume in 1 second (FEV1)following an ASA challenge were compared among the genotypes and haplotypes using a type III generalized linear model. RESULTS: The minor allele frequencies (MAFs) of rs10421558 A>G in the 5'UTR and rs10403288 G>A in the intron were significantly lower in the AERD than the ATA [34.0% vs. 43.8%, OR = 0.66 (0.62-0.92), Pcorr = 0.03 and 28.4% vs. 35.4%, OR = 0.62 (0.59-0.89), Pcorr = 0.016, respectively]. BL1ht5 was significantly higher in the AERD [7.6% vs. 1.6%, OR = 12.23 (0.2-0.51), P = 4.7 × 10 -4 , Pcorr = 0.001]. Among them, rs10421558 A>G and BL1ht5 were associated with the percent decline in FEV1 on the oral ASA challenge test. CONCLUSION: The minor allele of rs10421558 A>G in the 5'UTR may protect against the development of AERD via the increased production of ATP8B3.

Suppression of choroidal neovascularization and epithelial-mesenchymal transition in retinal pigmented epithelium by adeno-associated virus-mediated overexpression of CCN5 in mice.

Choroidal neovascularization (CNV) is a defining characteristic feature of neovascular age-related macular degeneration (nAMD) that frequently results in irreversible vision loss. The current strategies for the treatment of nAMD are mainly based on neutralizing vascular endothelial growth factor (VEGF). However, anti-VEGF therapies are often associated with subretinal fibrosis that eventually leads to damages in macula. In this study, we tested whether an anti-fibrotic and anti-angiogenic protein CCN5 can potentially be an effective and safe therapeutic modality in a mouse model of CNV. Laser photocoagulation was utilized to induce CNV, which was followed by intravitreal injection of recombinant adeno-associated virus serotype 2 encoding CCN5 (rAAV2-CCN5). Our data demonstrated that rAAV2-CCN5, but not a control viral vector, rAAV2-VLP, prominently attenuated both CNV lesions and angiogenesis. Aflibercept, which was utilized as a positive control, exhibited similar effects on CNV lesions and angiogenesis in our experimental settings. Upon laser photocoagulation, retinal pigmented epithelium (RPE) cells underwent significant morphological changes including cellular enlargement and loss of hexagonality. rAAV2-CCN5 significantly normalized these morphological defects. Laser photocoagulation also led to fibrotic deformation in RPE cells through inducing epithelial-mesenchymal transition (EMT), which was completely blocked by rAAV2-CCN5. In a striking contrast, aflibercept as well as rAAV2-VLP failed to exhibit any effects on EMT. Collectively, this study suggest that CCN5 might provide a potential novel strategy for the treatment of nAMD with a capability to inhibit CNV and fibrosis simaultaneously.

Effect of Modified Yukmijihwang-Tang on Sleep Quality in the Rat.

Many plants have been used in Korean medicine for treating insomnia. However, scientific evidence for their sedative activity has not been fully investigated. Thus, this study was carried out to investigate the sedative effects of the extracts of medicinal plants, including Yukmijihwang-tang and its various modified forms through the 5-HT2c receptor binding assay, and to further confirm its sleep-promoting effects and the underlying neural mechanism in rats utilizing electroencephalography (EEG) analysis. Enzyme-linked immunosorbent assay (ELISA) was used to measure serotonin (5-HT) in the brain. The water extracts of modified Yukmijihwang-tang (YmP) displayed binding affinity to the 5-HT2C receptor (IC50 value of 199.9 µg/mL). YmP (50 mg/kg) administration decreased wake time and increased REM and NREM sleep based on EEG data in rats. Additionally, treatment with YmP significantly increased the 5-HT level in the hypothalamus. In conclusion, the sedative effect of YmP can be attributed to the activation of the central serotonergic systems, as evidenced by the high affinity of binding of the 5-HT2C receptor and increased 5-HT levels in the brain of the rat. This study suggests that YmP can be a new material as a sleep inducer in natural products.

A genome-wide association study on frequent exacerbation of asthma depending on smoking status.

PURPOSE: Exacerbation of asthma is affected by genetic and environmental factors, but little is known about genetic differences according to smoking status. We evaluated genetic factors associated with asthma exacerbations in smokers and non-smokers, and identified the underlying mechanisms via a genome-wide association study (GWAS) and gene-level analyses according to smoking status. METHODS: A GWAS on the annual frequency of asthma exacerbations was performed in 420 non-smoking and 188 smoking patients with asthma. Gene-wise associations were analyzed by Multi-marker Analysis of GenoMic Annotation (MAGMA); Gene Ontology analysis was also performed. RESULTS: In the non-smoker group, 189 genes showed significant associations with the annual frequency of exacerbations (permutated P < 0.001). The top 10 genes were F5, KLRC1, TAFA2, AIRE, IER3IP1, CHMP2A, IL31RA, ZNF497, DNMT3L, and MYT1L (permutated P = 1.0 × 10-4 - 1.7 × 10-4). In smoking asthmatics, 140 genes-including KANK1, ZMYND12, ZNF34, ANXA11, VAV2, CCDC150, CCDC30, CATSPER3, ARMH2, and MPRIP (permutated P = 9.23 × 10-5 - 5.50 × 10-4)-were associated with asthma exacerbations. Genes participating in the innate immune response in non-smokers and the regulation of cell fate (including apoptosis) in smokers were the major causal genes of asthma exacerbation (FDR q < 0.05). CONCLUSIONS: Our findings not only suggest novel genetic candidates for predicting asthma exacerbations, but also that asthma treatment strategies should take into account smoking behavior.