Disruption of G-quadruplex dynamicity by BRCA2 abrogation instigates phase separation and break-induced replication at telomeres.

Dynamic interaction between BRCA2 and telomeric G-quadruplexes (G4) is crucial for maintaining telomere replication homeostasis. Cells lacking BRCA2 display telomeric damage with a subset of these cells bypassing senescence to initiate break-induced replication (BIR) for telomere synthesis. Here we show that the abnormal stabilization of telomeric G4 following BRCA2 depletion leads to telomeric repeat-containing RNA (TERRA)-R-loop accumulation, triggering liquid-liquid phase separation (LLPS) and the assembly of Alternative Lengthening of Telomeres (ALT)-associated promyelocytic leukemia (PML) bodies (APBs). Disruption of R-loops abolishes LLPS and impairs telomere synthesis. Artificial engineering of telomeric LLPS restores telomere synthesis, underscoring the critical role of LLPS in ALT. TERRA-R-loops also recruit Polycomb Repressive Complex 2 (PRC2), leading to tri-methylation of Lys27 on histone H3 (H3K27me3) at telomeres. Half of paraffin-embedded tissue sections from human breast cancers exhibit APBs and telomere length heterogeneity, suggesting that BRCA2 mutations can predispose individuals to ALT-type tumorigenesis. Overall, BRCA2 abrogation disrupts the dynamicity of telomeric G4, producing TERRA-R-loops, finally leading to the assembly of telomeric liquid condensates crucial for ALT. We propose that modulating the dynamicity of telomeric G4 and targeting TERRA-R-loops in telomeric LLPS maintenance may represent effective therapeutic strategies for treating ALT-like cancers with APBs, including those with BRCA2 disruptions.

UBE4B regulates p27 expression in A549 NSCLC cells through regulating the interaction of HuR and the p27 5' UTR.

Ubiquitination factor E4B (UBE4B) has a tumor-promoting effect, demonstrated by its aberrant expression in various types of cancers, and in vitro studies have shown that the retardation of cancer cell proliferation can be induced by targeting UBE4B. However, the molecular pathways through which UBE4B exerts its oncogenic activities have not yet been clearly identified and existing knowledge is limited to p53 and its subsequent downstream targets. In this study, we demonstrated that UBE4B regulates p27 expression in A549 cells via the cap-independent translation pathway following treatment with rapamycin and cycloheximide (CHX). Subsequently, we identified that UBE4B regulates p27 translation by regulating the interaction between human antigen R (HuR) and the p27 internal ribosomal entry site (IRES). First, UBE4B interacts with HuR, which inhibits p27 translation through the IRES. Secondly, the interaction between HuR and the p27 IRES was diminished by UBE4B depletion and enhanced by UBE4B overexpression. Finally, HuR depletion-induced growth retardation, accompanied by p27 accumulation, was restored by UBE4B overexpression. Collectively, these results suggest that the oncogenic properties of UBE4B in A549 cells are mediated by HuR, suggesting the potential of targeting the UBE4B-HuR-p27 axis as a therapeutic strategy for lung cancer.

Assessment of potential environmental and human risks for Bisphenol AF contaminant.

Bisphenol AF (BPAF) is found in high concentrations in aquatic environments due to the increased use of thermal paper and food packaging. However, there have been relatively few toxicological studies and potential risk assessments of BPAF. In this study, the risk quotient (RQ) and hazard quotient (HQ) of BPAF were derived to present the safety standards for environmental risk management and protection in lakes, rivers, bays, and Italian regions. We applied the species sensitivity distribution (SSD) method based on the previous ecotoxicological data and the results of supplementary toxicity tests on BPAF. From the SSD curves, the hazardous concentration for 5 % of the species (HC5) values for the acute and chronic toxicity data were 464.75 µg/L and 3.59 µg/L, respectively, and the acute- and chronic-based predicted no-effect concentration were derived as 154.92 µg/L and 1.20 µg/L, respectively. The acute-based RQ (RQA)values of BPAF in all regions were negligible (RQ < 0.1). The chronic-based RQ (RQC) in the Xitang River (XR) and the Central Italy (CI) showed a considerably high ecological risk (12.77 and 1.29) and the Hangzhou Bay (0.21), the South and North Italy (0.79 and 0.27), and the Tamagawa River (0.13) had a medium ecological risk (0.1 < RQ < 1.0). However, the HQ values based on the tolerable daily intake for BPAF over all age groups in these regions was < 0.1, indicating the low health risk. Nonetheless, the result of this study indicates that BPAF contamination is serious in XR and CI, and their use and emissions require continuous monitoring.

Assessment of potential ecological risk for polycyclic aromatic hydrocarbons in urban soils with high level of atmospheric particulate matter concentration.

Polycyclic aromatic hydrocarbons (PAHs) are known to be representative carcinogenic environmental pollutants with high toxicity. However, information on the potential ecological and environmental risks of PAH contamination in soil remains scarce. Thus, this study was evaluated the potential ecological risks of PAHs in soils of five Korean areas (Gunsan (GS), Gwangju, Yeongnam, Busan, and Gangwon) using organic carbon (OC)-normalized analysis, mean effect range-median quotient (M-ERM-Q), toxic equivalent quantity (TEQ) analysis, and risk quotient (RQ) derived by the species sensitivity distribution model. In this study, atmospheric particulate matter has a significant effect on soil pollution in GS through the presence of hopanes and the similar pattern of PAHs in soil and atmospheric PAHs. From analysis of source identification, combustion sources in soils of GS were important PAH sources. For PAHs in soils of GS, the OC-normalized analysis, M-ERM-Q, and TEQ analysis have 26.78 × 105 ng/g-OC, 0.218, and 49.72, respectively. Therefore, the potential ecological risk assessment results showed that GS had moderate-high ecological risk and moderate-high carcinogenic risk, whereas the other regions had low ecological risk and low-moderate carcinogenic risk. The risk level (M-ERM-Q) of PAH contamination in GS was similar to that in Changchun and Xiangxi Bay in China. The Port Harcourt City in Nigeria for PAH has the highest risk (M-ERM-Q = 4.02 and TEQ = 7923). Especially, compared to China (RQPhe =0.025 and 0.05), and Nigeria (0.059), phenanthrene showed the highest ecological risk in Korea (0.001-0.18). Korea should focus on controlling the release of PAHs originating from the PM in GS.

Real-Time Acoustic Simulation Framework for tFUS: A Feasibility Study Using Navigation System.

Transcranial focused ultrasound (tFUS), in which acoustic energy is focused on a small region in the brain through the skull, is a non-invasive therapeutic method with high spatial resolution and depth penetration. Image-guided navigation has been widely utilized to visualize the location of acoustic focus in the cranial cavity. However, this system is often inaccurate because of the significant aberrations caused by the skull. Therefore, acoustic simulations using a numerical solver have been widely adopted to compensate for this inaccuracy. Although the simulation can predict the intracranial acoustic pressure field, real-time application during tFUS treatment is almost impossible due to the high computational cost. In this study, we propose a neural network-based real-time acoustic simulation framework and test its feasibility by implementing a simulation-guided navigation (SGN) system. Real-time acoustic simulation is performed using a 3D conditional generative adversarial network (3D-cGAN) model featuring residual blocks and multiple loss functions. This network was trained by the conventional numerical acoustic simulation program (i.e., k-Wave). The SGN system is then implemented by integrating real-time acoustic simulation with a conventional image-guided navigation system. The proposed system can provide simulation results with a frame rate of 5 Hz (i.e., about 0.2 s), including all processing times. In numerical validation (3D-cGAN vs. k-Wave), the average peak intracranial pressure error was 6.8 ± 5.5%, and the average acoustic focus position error was 5.3 ± 7.7 mm. In experimental validation using a skull phantom (3D-cGAN vs. actual measurement), the average peak intracranial pressure error was 4.5%, and the average acoustic focus position error was 6.6 mm. These results demonstrate that the SGN system can predict the intracranial acoustic field according to transducer placement in real-time.

Expression of SARS-CoV-2 receptor angiotensin-converting enzyme 2 by activating protein-1 in human mast cells.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection activates mast cells and induces a cytokine storm, leading to severe Coronavirus disease in 2019 (COVID-19). SARS-CoV-2 employs angiotensin-converting enzyme 2 (ACE2) for cell entry. In the present study, the expression of ACE2 and its mechanism in activated mast cells were studied utilizing the human mast cell line, HMC-1 cells and it was elucidated whether dexamethasone used as a treatment for COVID-19 could regulate ACE2 expression. Here we documented for the first time that levels of ACE2 were increased by stimulation of phorbol 12-myristate 13-acetate and A23187 (PMACI) in HMC-1 cells. Increased levels of ACE2 were significantly diminished by treatment with Wortmannin, SP600125, SB203580, PD98059, or SR11302. The expression of ACE2 was most significantly reduced by the activating protein (AP)-1 inhibitor SR11302. PMACI stimulation enhanced the expression of the transcription factor AP-1 for ACE2. In addition, levels of transmembrane protease/serine subfamily member 2 (TMPRSS2) and tryptase were increased in PMACI-stimulated HMC-1 cells. However, dexamethasone significantly lowered levels of ACE2, TMPRSS2, and tryptase generated by PMACI. Treatment with dexamethasone also reduced activation of signaling molecules linked to ACE2 expression. According to these findings, levels of ACE2 were up-regulated through activation of AP-1 in mast cells, suggesting that suppressing ACE2 levels in mast cells would be a therapeutic approach to lessen the harm caused by COVID-19.

TSLP up-regulates inflammatory responses through induction of autophagy in T cells.

Thymic stromal lymphopoietin (TSLP), a type I cytokine belonging to the IL-2 cytokine family, promotes Th2-mediated inflammatory responses. The aim of this study is to investigate whether TSLP increases inflammatory responses via induction of autophagy using a murine T cell lymphoma cell line, EL4 cells, and lipopolysaccharide (LPS)-injected mice. TSLP increased expression levels of autophagy-related factors, such as Beclin-1, LC3-II, p62, Atg5, and lysosome associated membrane protein 1/2, whereas these factors increased by TSLP disappeared by neutralization of TSLP in EL4 cells. TSLP activated JAK1/JAK2/STAT5/JNK/PI3K, while the blockade of JAK1/JAK2/STAT5/JNK/PI3K signaling pathways reduced the expression levels of Beclin-1, LC3-II, and p62 in TSLP-stimulated EL4 cells. In addition, TSLP simultaneously increased levels of inflammatory cytokines via induction of autophagy by activation of JAK1/JAK2/STAT5/JNK/PI3K signaling pathways. In an LPS-induced acute liver injury (ALI) mouse model, exogenous TSLP increased expression levels of Beclin-1 and LC3-II, whereas functional deficiency of TSLP by TSLP siRNA resulted in lower expression of Beclin-1, LC3-II, and inflammatory cytokines, impairing their ability to form autophagosomes in ALI mice. Thus, our findings show a new role of TSLP between autophagy and inflammatory responses. In conclusion, regulating TSLP-induced autophagy may be a potential therapeutic strategy for inflammatory responses.

Real-world evidence of switching P2Y12 receptor-inhibiting therapies to prasugrel after PCI in patients with ACS: results from EFF-K registry.

BACKGROUND: Potent P2Y12 inhibitors are recommended for up to 12 months after percutaneous coronary intervention (PCI) in patients diagnosed with acute coronary syndrome (ACS). However, the prescription pattern is diverse in real world practice, which includes various switching between antiplatelet regimens. In this study, we analyzed the prescription patterns of prasugrel, and assessed the safety and effectiveness of P2Y12 inhibitors switching patterns in a real world registry of patients subjected to PCI after ACS. METHODS: The EFF-K study included 3077 ACS patients receiving prasugrel-based dual antiplatelet therapy. The cohort was divided into those who were administered with prasugrel as the primary antiplatelet treatment (naïve cohort) or as a substitute agent after clopidogrel or ticagrelor pre-treatment (switch cohort). The primary endpoint was a net adverse clinical event (NACE; a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or TIMI major bleeding unrelated to coronary-artery bypass grafting). RESULTS: A total of 3077 patients diagnosed with ACS were included in the analysis. Among the total population, 726 patients (23.6%) were classed as the naïve cohort and 2351 patients (76.4%) as the switch cohort. Baseline characteristics showed that the switch cohort had more comorbidities, such as hypertension, diabetes mellitus, heart failure and previous PCI. The major cause of switching to prasugrel in the switch cohort was the necessity for a more potent antiplatelet agent (56.3%). During a 12-month follow-up period, 51 patients (1.7%) experienced at least one NACE. The incidence of NACE did not differ between the naïve and switch cohort (1.5% vs. 1.7%, Hazard ratio 1.17, 95% Confidence interval 0.56-2.43, P = 0.677). In subgroup analysis, no significant interaction was observed between the treatment strategy and the incidence of NACE across various subgroups. CONCLUSIONS: Dual antiplatelet therapy with prasugrel seems to be safe and effective both as a primary treatment and as a substitute for other P2Y12 inhibitors in a real world registry of Asian ACS patients receiving PCI. TRIAL REGISTRATION: KCT0002356, registered June 13, 2017.

Euscaphic acid relieves fatigue by enhancing anti-oxidative and anti-inflammatory effects.

BACKGROUND: Oxidative stress and inflammation are involved in chronic fatigue. Euscaphic acid (EA) is an active compound of Eriobotrya japonica (Loquat) and has anti-oxidative effect. METHODS: The goal of present study is to prove whether EA could relieve fatigue through enhancing anti-oxidant and anti-inflammatory effects in in vitro/in vivo models. RESULTS: EA notably improved activity of superoxide dismutase (SOD) and catalase (CAT), while EA reduced levels of malondiadehyde (MDA) and inflammatory cytokines without cytotoxicity in H2O2-stimulated in myoblast cell line, C2C12 cells. EA significantly reduced levels of fatigue-causing factors such as lactate dehydrogenase (LDH) and creatin kinase (CK), while EA significantly incresed levels of anti-fatigue-related factor, glycogen compared to the H2O2-stimulated C2C12 cells. In treadmill stress test (TST), EA significantly enhanced activities of SOD and CAT as well as exhaustive time and decreased levels of MDA and inflammatory cytokines. After TST, levels of free fatty acid, citrate synthase, and muscle glycogen were notably enhanced by oral administration of EA, but EA decreased levels of lactate, LDH, cortisol, aspartate aminotransferase, alanine transaminase, CK, glucose, and blood urea nitrogen compared to the control group. Furthermore, in forced swimming test, EA significantly increased levels of anti-fatigue-related factors and decreased excessive accumulations of fatigue-causing factors. CONCLUSIONS: Therefore, the results indicate that potent anti-fatigue effect of EA can be achieved via the improvement of anti-oxidative and anti-inflammatory properties, and this study will provide scientific data for EA to be developed as a novel and efficient component in anti-fatigue health functional food.

Hepatocyte-specific deletion of Bis causes senescence in the liver without deteriorating hepatic function.

Bcl-2-interacting cell death suppressor (BIS), also called as BAG3, regulates numerous physiological processes, such as apoptosis, protein quality control, and senescence. Whole-body Bis-knockout (KO) mice exhibit early lethality following cardiac and skeletal muscle dysfunction. The first attempt to generate organ-specific knockout mice resulted in constitutive or inducible heart-specific Bis-knockout mice, which exhibited cardiac dilation and underwent premature death. Here, we generated hepatocyte-specific Bis-knockout (Bis-HKO) mice and found no abnormalities in metabolic function and survival. However, depletion of HSPB8 and accumulation of p62 indicated impaired autophagy in Bis-HKO livers. Interestingly, the number of peroxisomes wrapped by phagophore membranes increased as evidenced by transmission electron microscopy analysis, indicating defects in the progression of pexophagy. In addition, increased dihydroethidine intensities and histone H3 K9me3-positive nuclei indicated increased oxidative stress and senescence induction in Bis-HKO livers. Mechanistically, p27 was upregulated in Bis-HKO livers. In SNU368 hepatocellular carcinoma cells, BIS depletion led to p27 upregulation, and increase in histone H3 K9me3 levels and senescence-associated ß-galactosidase staining; therefore, reproducing the in vivo senescence phenotype. Despite the observation of no metabolic abnormalities, BIS depletion led to defective autophagy, increased oxidative stress, and senescence in Bis-HKO livers. Collectively, our results suggest a role for BIS in maintaining liver regeneration potential under pathological conditions.

RANKL down-regulates the mast cell proliferation through inducing senescence.

An increase in the number of mast cells could contribute to inflammatory diseases and pathologic conditions. A receptor activator of NF-κB ligand (RANKL)/RANK system is one of the key signaling pathways accelerating mast cell-mediated allergic inflammatory reactions. However, the biological functions of RANKL in mast cell proliferation remains to be clarified. The aim of the present study is to clarify the role of RANKL in mast cell proliferation. Surprisingly, RANKL remarkably reduced the proliferation of human mast cell line, HMC-1 cells through the inhibition of murine double minute 2 (MDM2) and Ki-67 mRNA expressions in a dose-dependent manner. RANKL significantly reduced cell viability, whereas it increased cellular senescence via increasing levels of p53, phosphorylated(p)-p53, p21, and p16 and decreasing levels of retinoblastoma protein (pRb) and p-pRb in HMC-1 cells. Even in rat peritoneal mast cells, RANKL induced cellular senescence by increasing filamentous-actin polymerization. In addition, RANKL remarkably reduced thymic stromal lymphopoietin (TSLP)-induced mast cell proliferation via the downregulation of MDM2 and Ki-67. RANKL decreased levels of p-signal transducer and activator of transcription 6 in TSLP-stimulated HMC-1 cells. The mast cell growth factor, interleukin-13 was remarkably down-regulated by treatment with RANKL in TSLP-stimulated HMC-1 cells. Furthermore, RANKL increased the number of senescence-associated ß-galactosidase-stained cells and protein levels of p53, p-p53, and p21 in TSLP-stimulated HMC-1 cells. These data suggest that RANKL down-regulates mast cell proliferation by inducing senescence.

Sodium-Glucose Cotransporter-2 Inhibitor-Related Diabetic Ketoacidosis: Accuracy Verification of Operational Definition.

BACKGROUND: The most important aspect of a retrospective cohort study is the operational definition (OP) of the disease. We developed a detailed OP for the detection of sodium-glucose cotransporter-2 inhibitors (SGLT2i) related to diabetic ketoacidosis (DKA). The OP was systemically verified and analyzed. METHODS: All patients prescribed SGLT2i at four university hospitals were enrolled in this experiment. A DKA diagnostic algorithm was created and distributed to each hospital; subsequently, the number of SGLT2i-related DKAs was confirmed. Then, the algorithm functionality was verified through manual chart reviews by an endocrinologist using the same OP. RESULTS: A total of 8,958 patients were initially prescribed SGLT2i. According to the algorithm, 0.18% (16/8,958) were confirmed to have SGLT2i-related DKA. However, based on manual chart reviews of these 16 cases, there was only one case of SGLT2i-related DKA (positive predictive value = 6.3%). Even after repeatedly narrowing the diagnosis range of the algorithm, the effect of a positive predictive value was insignificant (6.3-10.0%, P > 0.999). CONCLUSION: Owing to the nature of electronic medical record data, we could not create an algorithm that clearly differentiates SGLT2i-related DKA despite repeated attempts. In all retrospective studies, a portion of the samples should be randomly selected to confirm the accuracy of the OP through chart review. In retrospective cohort studies in which chart review is not possible, it will be difficult to guarantee the reliability of the results.

Phenolic Profile and Fingerprint Analysis of Akebia quinata Leaves Extract with Endothelial Protective Activity.

In contrast to the stem and fruit of Akebia quinata, A. quinata leaves as a source rich in phenolic compounds with potentially beneficial pharmacological activities have been largely overlooked. To develop and use A. quinata leaves as a resource, we evaluated its potential as a cardiovascular-protective agent. Herein, we investigated the effects and potential mechanisms of A. quinata leaves extract on lipopolysaccharide (LPS)-induced inflammatory responses in human umbilical vein endothelial cells. We found that A. quinata leaves extract pretreatment of 10 µg/mL significantly attenuated LPS-induced protein expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1. Furthermore, this extract also suppressed LPS-induced phosphorylation of nuclear factor-κB p65. In order to elucidate the chemical profiles of the samples, the HPLC fingerprint was established, and prominent peaks were identified via HPLC-electrospray ionization-mass spectrometry. Multivariate statistical analyses, including hierarchical cluster analysis, principal component analysis, and partial least-squares discriminant analysis, were performed to evaluate the clustering of the samples. It was found that isochlorogenic acid C was a key marker for the classification of A. quinata leaves from the Gongju and Muju city in Korea. Collectively, this study not only suggested the potential of A. quinata leaves as a novel therapeutic candidate for inflammatory cardiovascular disease but also developed a quality control method for A. quinata leaves, which could help to expand the application of A. quinata.

Depletion of ST6GALNACIII retards A549 non-small cell lung cancer cell proliferation by downregulating transferrin receptor protein 1 expression.

Alterations in sialylation of terminal residues of glycoproteins have been implicated in forming tumor-associated glycans. ST6GALNAC transfers sialyl moiety to N-acetylgalactosamine residue via α2,6 linkage. Although the oncogenic characteristics of ST6GALNACI or II have been demonstrated in various cancer cells, the impact of ST6GALNACIII on tumor progression remains undefined. In this study, we evaluated the effect of ST6GALNACIII knockdown on the growth of A549 non-small cell lung cancer cells. ST6GALNACIII depletion resulted in significant retardation in growth of A549 cells under various culture conditions, including collagen-supported 3D culture and anchorage-independent soft agar culture conditions. Liquid chromatography with tandem mass spectrometry revealed that two glycopeptides of transferrin receptor protein 1 (TFR1) containing N-acetylhexosamine-sialic acid were not detected in ST6GALNACIII-depleted A549 cells compared with control cells. Subsequent lectin binding assay, western blotting, and real-time RT-PCR indicated that TFR1 sialylation was not significantly changed, but TFR1 protein and mRNA expressions were decreased after ST6GALNACIII knockdown. However, cell growth retardation by ST6GALNACIII knockdown was partially rescued by TFR1 overexpression. Additionally, TFR1 mRNA degradation was accelerated following ST6GALNACIII knockdown with concomitant reduction in mRNA levels of iron regulatory protein 1 and 2, the upstream regulators of TFR1 mRNA stability. Therefore, our results indicated an important role of ST6GALNACIII in promoting A549 cell growth through quantitative regulation of TFR1 expression and provided therapeutic implications for ST6GALNACIII targeting in tumor growth suppression in vivo.

Exposure of ovalbumin during pregnancy prevents the development of allergic rhinitis in offspring through the induction of mast cell autophagy.

Most allergic disease studies have focused on postnatal chemical or microbial exposure. Recent studies have indicated that allergic diseases are associated with the immunological interaction between the mother and her offspring, but the relevant mechanisms are unclear. The aim of this study was to assess whether maternal exposure to allergens during pregnancy could affect allergic rhinitis (AR) in the offspring. Compared with offspring of naïve mothers, offspring of ovalbumin (OVA)-exposed mothers exhibited a significant reduction in AR clinical symptoms and levels of histamine, IgE, T helper type-2(Th2) cytokines, thymic stromal lymphopoietin, cyclooxygenase-2, chemokines, infiltration of inflammatory cell, and activity of caspase-1. Interestingly, we observed that offspring of OVA-exposed mothers regulated OVA-induced Th2 responses by inducing autophagy in mast cells. Our data demonstrated that maternal exposure to OVA during pregnancy decreased allergic sensitivity in offspring, suggesting that the vertical transmission of maternal immune responses may be involved. These findings have important implications in the regulation of AR. Furthermore, we propose that the autophagy of mast cells may be a potential target for AR prevention or treatment.

Estimation of sodium-glucose cotransporter 2 inhibitor-related genital and urinary tract infections via electronic medical record-based common data model.

WHAT IS KNOWN AND OBJECTIVES: In Korea, the side effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) have not been clearly reported, aside from voluntary reporting. We aimed to develop detection algorithms for SGLT2i-related genital tract infections (GTIs) and urinary tract infections (UTIs) via a common data model (CDM), an electronic medical record-based database for supporting multi-hospital clinical research. We estimated the occurrence of GTIs and UTIs and-by assessing the status of each step of the algorithm-we also aimed to determine how clinicians responded to the SGLT2i-related GTIs and UTIs. METHODS: We targeted all patients who were prescribed SGLT2i at Catholic University Seoul St. Mary's Hospital and Hallym University Dongtan Sacred Heart Hospital from January 2014 to August 2018. We developed algorithms for detection of SGLT2i-related GTIs or UTIs that divided patients into "most likely," "possibly" or "less likely" categories of GTIs or UTIs. The numbers of patients at each step were extracted. RESULTS AND DISCUSSION: A total of 4253 patients received their first prescription of SGLT2i. According to the algorithm used in this study, the proportions of "most likely GTI" and "possibly GTI" were 0.9% (37 out of 4253) and 19.4% (826 out of 4253 patients), respectively. Similarly, the proportions of "most likely UTI" and "possibly UTI" were 0.9% (38 out of 4253) and 20.2% (858 out of 4253 patients), respectively. Compared to the various existing prospective studies, both GTIs and UTIs showed lower occurrence among patients who met "most likely" criteria and higher occurrence among those who met "possibly" criteria. When a GTI or UTI occurred or was suspected, the overall rate of discontinuing SGLT2i was 51.8% (1721 out of 3323). Despite a confirmed or suspected GTI and an UTI, 62.8% (1460 out of 2323) and 14.2% (142 out of 1000) of patients continued to take SGLT2i, respectively. The discontinuation rate for suspected GTIs was significantly lower than that for suspected UTIs (37.2% vs. 85.8%, p < 0.001). WHAT IS NEW AND CONCLUSION: In this study, although the GTIs appeared to have a similar occurrence as UTIs, however, the discontinuation rate of SGLT2i for suspected GTIs was relatively lower. Our study is novel in that we identified how the physicians approached SGLT2i-related GTIs or UTIs at each step in a real-world clinical practice setting. Although we could estimate SGLT2i-related GTIs and UTIs via CDM, we were limited in our ability to accurately detect mild drug side effects via CDM, which lacked data for operational definition.

A calcium channel blocker, manoalide exerts an anti-allergic inflammatory effect through attenuating NF-κB activity.

BACKGROUND: Many people are troubled by allergic inflammation including ocular allergic diseases, anaphylaxis, allergic rhinitis, atopic dermatitis, and eczema. Consequently, finding medications for use in allergic inflammation therapy is crucial in human health. Manoalide, a marine natural product isolated as an anti-bacterial metabolite from Luffariella variabilis, is a calcium channel blocker. However, its latent ability as an anti-allergic inflammatory agent has not yet been reported. Our research aimed to elucidate whether manoalide exerts an anti-allergic inflammatory effect in the human mast cell line, HMC-1. METHODS: Herein, we investigated the immunoregulatory effects and molecular mechanisms of manoalide in HMC-1 cells. RESULTS: Manoalide significantly alleviated secretion of the inflammatory cytokines interleukin (IL)-1ß, thymic stromal lymphopoietin, tumor necrosis factor-α, IL-6, and IL-8 via blockage of caspase-1 without cytotoxicity in activated HMC-1 cells. Activation of nuclear factor-κB increased by mast cell stimulation was attenuated by treatment with manoalide. In addition, we demonstrated that manoalide treatment remarkably attenuated the activation of mitogen-activated protein kinases in activated-HMC-1 cells. CONCLUSIONS: Taken together, our findings indicate manoalide has an anti-allergic inflammatory role, and we propose that manoalide might have potential as a novel anti-allergic inflammatory agent.

Multi-Domain Convolutional Neural Networks for Lower-Limb Motor Imagery Using Dry vs. Wet Electrodes.

Motor imagery (MI) brain-computer interfaces (BCIs) have been used for a wide variety of applications due to their intuitive matching between the user's intentions and the performance of tasks. Applying dry electroencephalography (EEG) electrodes to MI BCI applications can resolve many constraints and achieve practicality. In this study, we propose a multi-domain convolutional neural networks (MD-CNN) model that learns subject-specific and electrode-dependent EEG features using a multi-domain structure to improve the classification accuracy of dry electrode MI BCIs. The proposed MD-CNN model is composed of learning layers for three domain representations (time, spatial, and phase). We first evaluated the proposed MD-CNN model using a public dataset to confirm 78.96% classification accuracy for multi-class classification (chance level accuracy: 30%). After that, 10 healthy subjects participated and performed three classes of MI tasks related to lower-limb movement (gait, sitting down, and resting) over two sessions (dry and wet electrodes). Consequently, the proposed MD-CNN model achieved the highest classification accuracy (dry: 58.44%; wet: 58.66%; chance level accuracy: 43.33%) with a three-class classifier and the lowest difference in accuracy between the two electrode types (0.22%, d = 0.0292) compared with the conventional classifiers (FBCSP, EEGNet, ShallowConvNet, and DeepConvNet) that used only a single domain. We expect that the proposed MD-CNN model could be applied for developing robust MI BCI systems with dry electrodes.

A Multimodal Analysis Combining Behavioral Experiments and Survey-Based Methods to Assess the Cognitive Effect of Video Game Playing: Good or Evil?

This study aims to bridge the gap between the discrepant views of existing studies in different modalities on the cognitive effect of video game play. To this end, we conducted a set of tests with different modalities within each participant: (1) Self-Reports Analyses (SRA) consisting of five popular self-report surveys, and (2) a standard Behavioral Experiment (BE) using pro- and antisaccade paradigms, and analyzed how their results vary between Video Game Player (VGP) and Non-Video Game Player (NVGP) participant groups. Our result showed that (1) VGP scored significantly lower in Behavioral Inhibition System (BIS) than NVGP (p = 0.023), and (2) VGP showed significantly higher antisaccade error rate than NVGP (p = 0.005), suggesting that results of both SRA and BE support the existing view that video game play has a maleficent impact on the cognition by increasing impulsivity. However, the following correlation analysis on the results across individual participants found no significant correlation between SRA and BE, indicating a complex nature of the cognitive effect of video game play.

Developing a Motor Imagery-Based Real-Time Asynchronous Hybrid BCI Controller for a Lower-Limb Exoskeleton.

This study aimed to develop an intuitive gait-related motor imagery (MI)-based hybrid brain-computer interface (BCI) controller for a lower-limb exoskeleton and investigate the feasibility of the controller under a practical scenario including stand-up, gait-forward, and sit-down. A filter bank common spatial pattern (FBCSP) and mutual information-based best individual feature (MIBIF) selection were used in the study to decode MI electroencephalogram (EEG) signals and extract a feature matrix as an input to the support vector machine (SVM) classifier. A successive eye-blink switch was sequentially combined with the EEG decoder in operating the lower-limb exoskeleton. Ten subjects demonstrated more than 80% accuracy in both offline (training) and online. All subjects successfully completed a gait task by wearing the lower-limb exoskeleton through the developed real-time BCI controller. The BCI controller achieved a time ratio of 1.45 compared with a manual smartwatch controller. The developed system can potentially be benefit people with neurological disorders who may have difficulties operating manual control.