The Therapeutic Effects of Blueberry-Treated Stem Cell-Derived Extracellular Vesicles in Ischemic Stroke.

An ischemic stroke, one of the leading causes of morbidity and mortality, is caused by ischemia and hemorrhage resulting in impeded blood supply to the brain. According to many studies, blueberries have been shown to have a therapeutic effect in a variety of diseases. Therefore, in this study, we investigated whether blueberry-treated mesenchymal stem cell (MSC)-derived extracellular vesicles (B-EVs) have therapeutic effects in in vitro and in vivo stroke models. We isolated the extracellular vesicles using cryo-TEM and characterized the particles and concentrations using NTA. MSC-derived extracellular vesicles (A-EVs) and B-EVs were round with a lipid bilayer structure and a diameter of ~150 nm. In addition, A-EVs and B-EVs were shown to affect angiogenesis, cell cycle, differentiation, DNA repair, inflammation, and neurogenesis following KEGG pathway and GO analyses. We investigated the protective effects of A-EVs and B-EVs against neuronal cell death in oxygen-glucose deprivation (OGD) cells and a middle cerebral artery occlusion (MCAo) animal model. The results showed that the cell viability was increased with EV treatment in HT22 cells. In the animal, the size of the cerebral infarction was decreased, and the behavioral assessment was improved with EV injections. The levels of NeuN and neurofilament heavy chain (NFH)-positive cells were also increased with EV treatment yet decreased in the MCAo group. In addition, the number of apoptotic cells was decreased with EV treatment compared with ischemic animals following TUNEL and Bax/Bcl-2 staining. These data suggested that EVs, especially B-EVs, had a therapeutic effect and could reduce apoptotic cell death after ischemic injury.

BML-281 promotes neuronal differentiation by modulating Wnt/Ca2+ and Wnt/PCP signaling pathway.

Histone deacetylase (HDAC) inhibitors promote differentiation through post-translational modifications of histones. BML-281, an HDAC6 inhibitor, has been known to prevent tumors, acute dextran sodium sulfate-associated colitis, and lung injury. However, the neurogenic differentiation effect of BML-281 is poorly understood. In this study, we investigated the effect of BML-281 on neuroblastoma SH-SY5Y cell differentiation into mature neurons by immunocytochemistry (ICC), reverse transcriptase PCR (RT-PCR), quantitative PCR (qPCR), and western blotting analysis. We found that the cells treated with BML-281 showed neurite outgrowth and morphological changes into mature neurons under a microscope. It was confirmed that the gene expression of neuronal markers (NEFL, MAP2, Tuj1, NEFH, and NEFM) was increased with certain concentrations of BML-281. Similarly, the protein expression of neuronal markers (NeuN, Synaptophysin, Tuj1, and NFH) was upregulated with BML-281 compared to untreated cells. Following treatment with BML-281, the expression of Wnt5α increased, and downstream pathways were activated. Interestingly, both Wnt/Ca2+ and Wnt/PCP pathways activated and regulated PKC, Cdc42, RhoA, Rac1/2/3, and p-JNK. Therefore, BML-281 induces the differentiation of SH-SY5Y cells into mature neurons by activating the non-canonical Wnt signaling pathway. From these results, we concluded that BML-281 might be a novel drug to differentiation into neuronal cells through the regulation of Wnt signaling pathway to reduce the neuronal cell death.

Effects of HDAC inhibitors on neuroblastoma SH-SY5Y cell differentiation into mature neurons via the Wnt signaling pathway.

Histone deacetylase (HDAC) inhibitors affect cell homeostasis, gene expression, and cell cycle progression and promote cell terminal differentiation or apoptosis. However, the effect of HDAC inhibition on SH-SY5Y cells, which are neuroblastoma cells capable of differentiating into neurons under specific conditions, such as in the presence of retinoic acid (RA), is unknown. In this study, we hypothesized that HDAC inhibitors induced the neuronal differentiation of SH-SY5Y cells. To test this hypothesis, we used phase contrast microscopy, immunocytochemistry (ICC), qPCR, and western blotting analysis. MS-275 and valproic acid (VPA), two HDAC inhibitors, were selected to evaluate neuronal differentiation. It was confirmed that cells treated with MS-275 or VPA differentiated into mature neurons, which were distinguished by bipolar or multipolar morphologies with elongated branches. In addition, the mRNA expression of neuronal markers (Tuj1 and NEFH) and the oligodendrocyte marker (CNP) was significantly increased with MS-275 or VPA treatment compared to that with RA treatment. In addition, the protein expression of the other neuronal markers, Tuj1 and NeuN, was highly increased with HDAC inhibitor treatments compared to that with RA treatment. Furthermore, we confirmed that noncanonical Wnt signaling was upregulated by HDAC inhibitors via MAPK signaling and the Wnt/JNK pathway. Therefore, both MS-275 and VPA promoted the differentiation of SH-SY5Y cells into mature neurons via the Wnt signaling pathway.

Understanding Nasal Valve Compromise in Nasal Airway Obstruction: A New Classification System.

OBJECTIVES: A key aspect of rhinoplasty is integrity of nasal valves area because of its fundamental role in patent nasal airway. furthermore, nasal obstruction is a dominant feature in patient with nasal valves dysfunction (NVD) which can be devastating outcome after rhinoplasty. METHODS: Nonetheless, NVD has been widely investigated regarding their etiologies and management. However, it has been assumed that the anatomical complexity and interplay between its structures causing a confusion for a beginner surgeon to diagnose and treat NVD. This study was approved by the institutional review board of Chosun University Hospital, Gwangju, Korea (2022-11-005). RESULTS: To date, the lack of consensus on nasal valve pathologies and corrective procedures has led to its underestimations during analysis and management. As result, we proposed a classification system based on its affected anatomical part, location, and their management. Thus, implementing a classification system for NVD will help guide the practice of rhinoplasty and introduce a more structured approach. CONCLUSION: This approach will prove useful in expanding our understanding of how important to locate the pathology of NVD and apply the most relevant management options, particularly for a beginner surgeons. LEVEL OF EVIDENCE: V.

Simultaneous Enhancement in Visible Transparency and Electrical Conductivity via the Physicochemical Alterations of Ultrathin-Silver-Film-Based Transparent Electrodes.

A methodology for the simultaneous modulation of the chemical and physical states of an amorphous TiOx layer surface and its impact on the subsequent deposition of a polycrystalline Ag layer are presented. The smoothened TiOx layer surface comprising chemically altered, oxygen-deficient states serves as a nucleating platform for Ag deposition, facilitating a marked increase (∼75%) in the nucleation number density, which strongly enhances the wettability of ultrathin Ag layers. The physically smoothened TiOx/Ag interface further reduces the optical and electrical losses. When the proposed methodology is applied to TiOx/Ag/ZnO transparent conductive electrodes (TCEs), exceptional TCE properties are yielded owing to the simultaneous improvement in visible transparency and electrical conductivity; specifically, a record-high 0.22 Ω-1 Haacke figure of merit is realized. TCEs are prepared on flexible substrates to verify their applicability as stand-alone flexible transparent heaters and as integrated heaters within electrochromic devices to enhance color-switching reactions.

Influenza Screening via Deep Learning Using a Combination of Epidemiological and Patient-Generated Health Data: Development and Validation Study.

BACKGROUND: Screening for influenza in primary care is challenging due to the low sensitivity of rapid antigen tests and the lack of proper screening tests. OBJECTIVE: The aim of this study was to develop a machine learning-based screening tool using patient-generated health data (PGHD) obtained from a mobile health (mHealth) app. METHODS: We trained a deep learning model based on a gated recurrent unit to screen influenza using PGHD, including each patient's fever pattern and drug administration records. We used meteorological data and app-based surveillance of the weekly number of patients with influenza. We defined a single episode as the set of consecutive days, including the day the user was diagnosed with influenza or another disease. Any record a user entered 24 hours after his or her last record was considered to be the start of a new episode. Each episode contained data on the user's age, gender, weight, and at least one body temperature record. The total number of episodes was 6657. Of these, there were 3326 episodes within which influenza was diagnosed. We divided these episodes into 80% training sets (2664/3330) and 20% test sets (666/3330). A 5-fold cross-validation was used on the training set. RESULTS: We achieved reliable performance with an accuracy of 82%, a sensitivity of 84%, and a specificity of 80% in the test set. After the effect of each input variable was evaluated, app-based surveillance was observed to be the most influential variable. The correlation between the duration of input data and performance was not statistically significant (P=.09). CONCLUSIONS: These findings suggest that PGHD from an mHealth app could be a complementary tool for influenza screening. In addition, PGHD, along with traditional clinical data, could be used to improve health conditions.

Publisher Correction: Comparison of Fever-reducing Effects in Self-reported Data from the Mobile App: Antipyretic Drugs in Pediatric Patients.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Comparison of Fever-reducing Effects in Self-reported Data from the Mobile App: Antipyretic Drugs in Pediatric Patients.

We compared the fever-reducing efficacy of acetaminophen (AA), ibuprofen (IBU), and dexibuprofen (DEX) using data collected from the mobile healthcare application FeverCoach, which provides parents with guidelines for determining their child's health condition, according to body temperature. Its dataset includes 4.4 million body temperature measurement records and 1.6 million antipyretics treatment records. Changes in body temperature over time were compared after taking one of three different antipyretics (AA, IBU, and DEX), using a one-way ANOVA followed by a post-hoc analysis. A multivariate linear model was used to further analyze the average body temperature differences, calibrating for the influences of age, weight, and sex. Children administered IBU had average body temperatures that were 0.18 °C (0.17-0.19 °C), 0.25 °C (0.24-0.26 °C), and 0.18 °C (0.17-0.20 °C) lower than those of children administered AA, at time intervals of 1-2 hours, 2-3 hours, and 3-4 hours, respectively. Similarly, children administered DEX had average body temperatures that were 0.24 °C (0.24-0.25 °C), 0.28 °C (0.27-0.29 °C), and 0.12 °C (0.10-0.13 °C) lower than those of children administered AA, at time intervals of 1-2, 2-3, and 3-4 hours, respectively. Although the data were collected from the application by non-professional parents, the analysis showed that IBU and DEX were more effective in reducing body temperature than AA was.

New variable selection strategy for analysis of high-dimensional DNA methylation data.

In genetic association studies, regularization methods are often used due to their computational efficiency for analysis of high-dimensional genomic data. DNA methylation data generated from Infinium HumanMethylation450 BeadChip Kit have a group structure where an individual gene consists of multiple Cytosine-phosphate-Guanine (CpG) sites. Consequently, group-based regularization can precisely detect outcome-related CpG sites. Representative examples are sparse group lasso (SGL) and network-based regularization. The former is powerful when most of the CpG sites within the same gene are associated with a phenotype outcome. In contrast, the latter is preferred when only a few of the CpG sites within the same gene are related to the outcome. In this paper, we propose new variable selection strategy based on a selection probability that measures selection frequency of individual variables selected by both SGL and network-based regularization. In extensive simulation study, we demonstrated that the proposed strategy can show relatively outstanding selection performance under any situation, compared with both SGL and network-based regularization. Also, we applied the proposed strategy to identify differentially methylated CpG sites and their corresponding genes from ovarian cancer data.

Effect of the Online Game Shutdown Policy on Internet Use, Internet Addiction, and Sleeping Hours in Korean Adolescents.

PURPOSE: Internet addiction has emerged as a major public health problem worldwide. In November 2011, the South Korean government implemented an online game shutdown policy, lasting from 12:00 to 6:00 am, as a means of preventing Internet addiction in adolescents aged 15 or below. This study analyzed the effect of this shutdown policy on adolescent Internet use, addiction, and sleeping hours. METHODS: We analyzed data collected from the Korea Youth Risk Behavior Web-based Survey from 2011 to 2015. Respondents were divided into two groups by age: aged 15 or below (male = 76,048, female = 66,281) and aged 16 or above (male = 52,568, female = 49,060). A difference-in-difference analysis was used to evaluate the effect of this shutdown policy. RESULTS: In 2012, which is immediately following policy enforcement, daily amount of Internet use (in minutes) decreased more in adolescents affected by the policy (i.e., the aged 15 or below group). However, it steadily increased in 2013, 2014, 2015, and showed no meaningful long-term improvements 4 years after policy implementation (-3.648 minutes in 2012 [p = .001], -3.204 minutes in 2013 [p = .011], -1.140 minutes in 2014 [p = .384], and 2.190 minutes in 2015 [p = .107]). The shutdown policy did not alter Internet addiction or sleeping hours. Interestingly, female adolescents, adolescents with low academic performance, and adolescents with low exercise levels exhibited comparatively stronger and longer lasting initial declines in Internet usage. CONCLUSIONS: The shutdown policy had practically insignificant effects in reducing Internet use for target adolescents. Thus, policymakers aiming to reduce or prevent Internet addiction should use different strategies.

Anti-cancer effect of novel PAK1 inhibitor via induction of PUMA-mediated cell death and p21-mediated cell cycle arrest.

Hyper-activation of PAK1 (p21-activated kinase 1) is frequently observed in human cancer and speculated as a target of novel anti-tumor drug. In previous, we also showed that PAK1 is highly activated in the Smad4-deficient condition and suppresses PUMA (p53 upregulated modulator of apoptosis) through direct binding and phosphorylation. On the basis of this result, we have tried to find novel PAK1-PUMA binding inhibitors. Through ELISA-based blind chemical library screening, we isolated single compound, IPP-14 (IPP; Inhibitor of PAK1-PUMA), which selectively blocks the PAK1-PUMA binding and also suppresses cell proliferation via PUMA-dependent manner. Indeed, in PUMA-deficient cells, this chemical did not show anti-proliferating effect. This chemical possessed very strong PAK1 inhibition activity that it suppressed BAD (Bcl-2-asoociated death promoter) phosphorylation and meta-phase arrest via Aurora kinase inactivation in lower concentration than that of previous PAK1 kinase, FRAX486 and AG879. Moreover, our chemical obviously induced p21/WAF1/CIP1 (Cyclin-dependent kinase inhibitor 1A) expression by releasing from Bcl-2 (B-cell lymphoma-2) and by inhibition of AKT-mediated p21 suppression. Considering our result, IPP-14 and its derivatives would be possible candidates for PAK1 and p21 induction targeted anti-cancer drug.

Granular cell tumor on larynx.

Granular cell tumors (GCTs) are uncommon neoplasm. They can originate in any part of the body. The most common sites of origin are in the head and neck, while the larynx is a relatively uncommon location. Patients affected with a laryngeal GCT typically present with persistent hoarseness, stridor, hemoptysis, dysphagia, and otalgia but, the tumor may be asymptomatic. Care must be taken to differentiate this lesion from others due to the presence of pseudo-epitheliomatous hyperplasia which overlies the GCT and may occasionally mimic squamous cell carcinoma. Therefore, a confirmative diagnosis should be made histopathologically and should be supported by immunohistochemical staining. These tumors are treated by complete surgical resection. Examining the complete removal of the tumor through securing a negative free margin is considered to be a consequential procedure. We experienced a 64-yr-old man with a laryngeal granular cell tumor involving the right true vocal cord. He was treated by surgical resection under a fine dissection laryngomicroscope. Here we present this case and a review of literature.