Activation mechanism and novel binding sites of the BKCa channel activator CTIBD.

The large-conductance calcium-activated potassium (BKCa) channel, which is crucial for urinary bladder smooth muscle relaxation, is a potential target for overactive bladder treatment. Our prior work unveiled CTIBD as a promising BKCa channel activator, altering V 1/2 and G max This study investigates CTIBD's activation mechanism, revealing its independence from the Ca2+ and membrane voltage sensing of the BKCa channel. Cryo-electron microscopy disclosed that two CTIBD molecules bind to hydrophobic regions on the extracellular side of the lipid bilayer. Key residues (W22, W203, and F266) are important for CTIBD binding, and their replacement with alanine reduces CTIBD-mediated channel activation. The triple-mutant (W22A/W203A/F266A) channel showed the smallest V 1/2 shift with a minimal impact on activation and deactivation kinetics by CTIBD. At the single-channel level, CTIBD treatment was much less effective at increasing P o in the triple mutant, mainly because of a drastically increased dissociation rate compared with the WT. These findings highlight CTIBD's mechanism, offering crucial insights for developing small-molecule treatments for BKCa-related pathophysiological conditions.

Fermented Gold Kiwi for Improved Gastric Health: Evaluation of Efficacy and Safety in a Randomised, Double-Blind, Placebo-Controlled Trial.

This randomised double-blind placebo-controlled trial evaluated the efficacy and safety of fermented gold kiwi (FGK) in improving gastrointestinal health. A total of 100 participants were enrolled and randomly assigned to treatment or placebo groups. Over 8 weeks, the participants consumed an FGK or placebo preparation daily. Primary outcomes included changes in gastrointestinal symptoms assessed using the Gastrointestinal Symptom Rating Scale (GSRS) and the Korean version of the Nepean Dyspepsia Index (NDI-K), as well as quality of life assessed using the Functional Dyspepsia-related Quality of Life questionnaire. The FGK group showed significant improvements in GSRS and NDI-K total and subdomain scores compared with the placebo group. Moreover, the quality of life scores were significantly better in the FGK group than in the placebo group. Safety evaluations revealed no significant adverse events or clinically meaningful changes upon assessing laboratory test results. This study demonstrated that FGK is a safe and effective dietary supplement for improving gastrointestinal health in adults with gastrointestinal symptoms.

Interplay between YAP/TAZ and metabolic dysfunction-associated steatotic liver disease progression.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming an increasingly pressing global health challenge, with increasing mortality rates showing an upward trend. Two million deaths occur annually from cirrhosis and liver cancer together each year. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), key effectors of the Hippo signaling pathway, critically regulate tissue homeostasis and disease progression in the liver. While initial studies have shown that YAP expression is normally restricted to cholangiocytes in healthy livers, the activation of YAP/TAZ is observed in other hepatic cells during chronic liver disease. The disease-driven dysregulation of YAP/TAZ appears to be a critical element in the MASLD progression, contributing to hepatocyte dysfunction, inflammation, and fibrosis. In this study, we focused on the complex roles of YAP/TAZ in MASLD and explored how the YAP/TAZ dysregulation of YAP/TAZ drives steatosis, inflammation, fibrosis, and cirrhosis. Finally, the cell-type-specific functions of YAP/TAZ in different types of hepatic cells, such as hepatocytes, hepatic stellate cells, hepatic macrophages, and biliary epithelial cells are discussed, highlighting the multifaceted impact of YAP/TAZ on liver physiology and pathology.

Parallel Analysis of Exosomes and Cytokines in Aqueous Humor Samples to Evaluate Biomarkers for Glaucoma.

Recent emerging studies have demonstrated numerous critical roles of exosomes in cell-to-cell signaling. We investigated exosomes in the aqueous humor of glaucoma patients and controls and compared their characteristics with other biomarkers such as cytokines. Glaucoma patients exhibited higher exosome particle counts and smaller sizes compared to controls. Higher exosome density was correlated with more severe visual field loss. Conversely, concentrations of aqueous humor cytokines, particularly PD-L1, were primarily associated with intraocular pressure, and none of the cytokines showed a significant association with visual field damage. This may reflect the characteristics of exosomes, which are advantageous for crossing various biological barriers. Exosomes may contain more information about glaucoma functional damage occurring in the retina or optic nerve head. This highlights the potential importance of exosomes as signaling mediators distinct from other existing molecules.

Gonadal efficacy of Thymus quinquecostatus Celakovski: Regulation of testosterone levels in aging mouse models.

Late-onset hypogonadism (LOH) is an age-related disease in men characterized by decreased testosterone levels with symptoms such as decreased libido, erectile dysfunction, and depression. Thymus quinquecostatus Celakovski (TQC) is a plant used as a volatile oil in traditional medicine, and its bioactive compounds have anti-inflammatory potential. Based on this knowledge, the present study aimed to investigate the effects of TQC extract (TE) on LOH in TM3 Leydig cells and in an in vivo aging mouse model. The aqueous extract of T. quinquecostatus Celakovski (12.5, 25, and 50 µg/mL concentrations) was used to measure parameters such as cell viability, testosterone level, body weight, and gene expression, via in vivo studies. Interestingly, TE increased testosterone levels in TM3 cells in a dose-dependent manner without affecting cell viability. Furthermore, TE significantly increased the expression of genes involved in the cytochrome P450 family (Cyp11a1, Cyp17a1, Cyp19a1, and Srd5a2), which regulate testosterone biosynthesis. In aging mouse models, TE increased testosterone levels without affecting body weight and testicular tissue weight tissue of an aging animal group. In addition, the high-dose TE-treated group (50 mg/kg) showed significantly increased expression of the cytochrome p450 enzymes, similar to the in vitro results. Furthermore, HPLC-MS analysis confirmed the presence of caffeic acid and rosmarinic acid as bioactive compounds in TE. Thus, the results obtained in the present study confirmed that TQC and its bioactive compounds can be used for LOH treatment to enhance testosterone production.

Associations of long-term fluctuation in blood pressure and ocular perfusion pressure with visual field progression in normal-tension glaucoma.

BACKGROUD: The aim of this study was to investigate the associations between fluctuation in blood pressure (BP), ocular perfusion pressure (OPP) and visual field (VF) progression in normal-tension glaucoma (NTG). METHODS: This prospective, longitudinal study included 44 patients with NTG. Only newly diagnosed NTG patients who had not been treated with a glaucoma medication were included. Patients were examined every year for 7 years. Intraocular pressure (IOP), heart rate (HR), systolic BP (SBP), diastolic BP (DBP), ocular perfusion pressure (OPP), and diastolic ocular perfusion pressure (DOPP) were measured at the same time. Ophthalmic examinations, including perimetry, were performed also. Initial VF were compared with follow-up data after 7 years. RESULTS: After 7 years of follow-up, 9 of the 44 patients showed VF progression. The standard deviation (SD) of SBP and OPP were significantly associated with VF progression (P = 0.007, < 0.001, respectively). Multiple regression analysis showed that VF progression was significantly associated with SD of OPP (odds ratio, OR = 2.012, 95% CI = 1.016-3.985; P = 0.045). CONCLUSIONS: Fluctuation in OPP was associated with VF progression in patients with NTG.

Characteristic Differences between Normotensive and Hypertensive Pseudoexfoliative Glaucoma.

PURPOSE: To compare the differences between eyes with pseudoexfoliative glaucoma (PXG) when they are divided into two groups (hypertensive PXG and normotensive PXG) according to the intraocular pressure (IOP). METHODS: This is a retrospective study. Data from 86 hypertensive PXG eyes and 80 normotensive PXG eyes were included. Hypertensive PXG was defined as PXG with IOP ≥ 22 mmHg, and normotensive PXG was defined as with IOP ≤ 21 mmHg). Central corneal thickness (CCT) was measured by ultrasound pachymetry. Lamina cribrosa thickness (LT) was evaluated using swept-source optical coherence tomography. RESULTS: No significant differences were observed between hypertensive and normotensive PXG in terms of age, gender, axial length, hypertension, or diabetes. Normotensive PXG eyes had thinner CCT than hypertensive PXG eyes (p = 0.02). To compare LT, a sub-analysis was performed after matching age, VF MD and retinal nerve fiber layer thickness. The normotensive PXG group (n = 32) demonstrated significantly thinner LT compared with the hypertensive PXG group (n = 32) at similar ages and levels of glaucoma severity (p < 0.001). CONCLUSIONS: Eyes with normotensive PXG demonstrated thinner CCT and LT compared with those with hypertensive PXG, suggesting structural vulnerability to glaucoma.

Anti-Wrinkle and Skin Moisture Efficacy of 7-MEGATM: A Randomized, Double-Blind, Placebo Comparative Clinical Trial.

7-MEGATM is a food product made from purified Alaska pollack fish oil containing palmitoleic acid (16:1), commonly referred to as omega-7. We sought to quantitatively evaluate whether this substance inhibits skin aging. A total of 101 middle-aged females were randomly allocated to the intervention (N = 50) or placebo group (N = 51). Each participant was advised to take either 500 mg of 7-MEGATM or a placebo twice daily for 12 weeks. The primary outcomes were the degree of improvement in wrinkles and the degree of moisture filling after consumption for 12 weeks compared to baseline. The secondary outcomes were improvement in skin wrinkles; moisture changes at 4 and 8 weeks from baseline; changes in transdermal water loss, skin elasticity, the melanin index, the erythema index, and the Global Photo Damage Score. We found a significant improvement in skin wrinkles and elasticity at 12 weeks in the 7-MEGATM-consuming group compared to that in the placebo group; skin moisture, elasticity, and the melanin index were also improved. No supplement-related adverse reactions were observed and 7-MEGATM was identified as safe. 7-MEGATM was effective for human skin function in terms of wrinkles, moisture, elasticity, and melanin production and may be useful as a skin nutritional supplement.

Mitochondrial stress activates YAP/TAZ through RhoA oxidation to promote liver injury.

Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1; also known as TAZ) are the main effectors of the Hippo pathway and their dysregulation contributes to diseases in tissues including the liver. Although mitochondria are capable of transmitting signals to change transcriptomic landscape of diseased hepatocytes, such retrograde signaling and the related nuclear machinery are largely unknown. Here, we show that increased YAP activity is associated with mitochondrial stress during liver injury; and this is required for secondary inflammation, promoting hepatocyte death. Mitochondrial stress inducers robustly promoted YAP/TAZ dephosphorylation, nuclear accumulation, and target gene transcription. RNA sequencing revealed that the majority of mitochondrial stress transcripts required YAP/TAZ. Mechanistically, direct oxidation of RhoA by mitochondrial superoxide was responsible for PP2A-mediated YAP/TAZ dephosphorylation providing a novel physiological input for the Hippo pathway. Hepatocyte-specific Yap/Taz ablation suppressed acetaminophen-induced liver injury and blunted transcriptomic changes associated with the pathology. Our observations uncover unappreciated pathway of mitochondrial stress signaling and reveal YAP/TAZ activation as the mechanistic basis for liver injury progression.

Hepatocyte GPCR signaling regulates IRF3 to control hepatic stellate cell transdifferentiation.

BACKGROUND: Interferon Regulatory Factor 3 (IRF3) is a transcription factor that plays a crucial role in the innate immune response by recognizing and responding to foreign antigens. Recently, its roles in sterile conditions are being studied, as in metabolic and fibrotic diseases. However, the search on the upstream regulator for efficient pharmacological targeting is yet to be fully explored. Here, we show that G protein-coupled receptors (GPCRs) can regulate IRF3 phosphorylation through of GPCR-Gα protein interaction. RESULTS: IRF3 and target genes were strongly associated with fibrosis markers in liver fibrosis patients and models. Conditioned media from MIHA hepatocytes overexpressing IRF3 induced fibrogenic activation of LX-2 hepatic stellate cells (HSCs). In an overexpression library screening using active mutant Gα subunits and Phos-tag immunoblotting, Gαs was found out to strongly phosphorylate IRF3. Stimulation of Gαs by glucagon or epinephrine or by Gαs-specific designed GPCR phosphorylated IRF3. Protein kinase A (PKA) signaling was primarily responsible for IRF3 phosphorylation and Interleukin 33 (IL-33) expression downstream of Gαs. PKA phosphorylated IRF3 on a previously unrecognized residue and did not require reported upstream kinases such as TANK-binding kinase 1 (TBK1). Activation of Gαs signaling by glucagon induced IL-33 production in hepatocytes. Conditioned media from the hepatocytes activated HSCs, as indicated by α-SMA and COL1A1 expression, and this was reversed by pre-treatment of the media with IL-33 neutralizing antibody. CONCLUSIONS: Gαs-coupled GPCR signaling increases IRF3 phosphorylation through cAMP-mediated activation of PKA. This leads to an increase of IL-33 expression, which further contributes to HSC activation. Our findings that hepatocyte GPCR signaling regulates IRF3 to control hepatic stellate cell transdifferentiation provides an insight for understanding the complex intercellular communication during liver fibrosis progression and suggests therapeutic opportunities for the disease. Video Abstract.

Industry Culture Matters: Sexual Harassment in the South Korean Film Industry.

This study analyzes factors of sexual harassment in the workplace based on sample survey data on women working in the Korean film industry (n = 449) using logistic regression analysis. It finds higher education, younger age, and union membership increase harassment risk, suggesting backlash against feminism post-#MeToo. A higher proportion of men at shooting locations raises harassment likelihood, reflecting the industry's unique conditions. Longer work hours also increase harassment probability. The findings highlight the importance of considering industrial context in addressing workplace harassment. They emphasize the need for policies improving gender representation in film.

Capillary gingival hemangioma in a cat.

A 12-year-old spayed female American short-haired cat presented with a palatal gingival mass located between the right maxillary third incisor and the canine teeth. The mass was dark red and had a narrow attachment to the gingival margin of the canine tooth. The mass was completely removed by marginal excision and the histopathological diagnosis was a capillary hemangioma. The mass did not relapse until 1 year later; however, the tooth was extracted because of cervical resorption of the right maxillary canine immediately adjacent to the mass resection site. This report presents a rare case of the gingival hemangioma in a cat and the possibility of a causal relationship between the occurrence of external cervical tooth resorption and hemangioma resection.

Development of Reproducible and Scalable Culture Conditions for In Vitro Maintenance of Pig Embryonic Stem Cells Using the Sandoz Inbred Swiss Mouse Thioguanine-Resistant Ouabain-Resistant Cell Line as a Feeder Layer.

Feeder cells play a crucial role in maintaining the pluripotency of embryonic stem cells (ESCs) by secreting various extrinsic regulators, such as extracellular matrix (ECM) proteins and growth factors. Although primary mouse embryonic fibroblasts (MEFs) are the most widely used feeder cell type for the culture of ESCs, they have inevitable disadvantages such as batch-to-batch variation and labor-intensive isolation processes. Here, we revealed that the Sandoz inbred Swiss Mouse (SIM) thioguanine-resistant ouabain-resistant (STO) cell line, an immortalized cell line established from mouse SIM embryonic fibroblasts, can be used as a feeder layer for in vitro culture of authentic pig ESCs instead of primary MEFs. First, the expression of genes encoding ECM proteins and growth factors was analyzed to compare their secretory functions as feeder cells. Quantitative real-time polymerase chain reaction (qPCR) showed that the gene expression of these pluripotency-associated factors was downregulated in STO cells compared to primary MEFs of similar density. Therefore, subsequent optimization of the culture conditions was attempted using higher STO cell densities. Notably, pig ESCs cultured on STO cell density of 3 × (187,500 cells/cm2) exhibited the most similar pluripotent state to pig ESCs cultured on primary MEF density of 1 × (62,500 cells/cm2), as determined by alkaline phosphatase staining, qPCR, and immunocytochemistry. In addition, pig ESCs cultured on STO cell density of 3 × formed complex teratoma containing multiple types of tissues derived from all three germ layers. Our culture conditions using optimal STO cell density can be applied to fields requiring reproducible and scalable production of pig ESCs, such as preclinical research and cellular agriculture.

Primary well differentiated hepatic liposarcoma in a meerkat (Suricata suricatta).

A 9-year-old female meerkat (Suricata suricatta) succumbed to progressive abdominal distension, anorexia, and depression. Necropsy revealed an extensively distended abdomen with ascites and markedly enlarged liver. The liver had multiple yellowish masses and displaced the thoracic cavity and abdominal organs. There was no evidence of metastatic lesions based on the gross and microscopic findings. Histologically, the liver mass was composed of locally invasive well-differentiated neoplastic adipocytes with Oil Red O-positive lipid vacuoles. Immunohistochemistry revealed positive immunoreactivity to vimentin, S-100 and negative to pancytokeratin, desmin, smooth muscle actin (SMA), ionized calcium-binding adapter molecule 1 (IBA-1). Thus, the primary well differentiated hepatic liposarcoma was diagnosed based on gross, histological and immunohistochemistry results.

High-Resolution Tactile-Sensation Diagnostic Imaging System for Thyroid Cancer.

In this study, we propose the direct diagnosis of thyroid cancer using a small probe. The probe can easily check the abnormalities of existing thyroid tissue without relying on experts, which reduces the cost of examining thyroid tissue and enables the initial self-examination of thyroid cancer with high accuracy. A multi-layer silicon-structured probe module is used to photograph light scattered by elastic changes in thyroid tissue under pressure to obtain a tactile image of the thyroid gland. In the thyroid tissue under pressure, light scatters to the outside depending on the presence of malignant and positive properties. A simple and easy-to-use tactile-sensation imaging system is developed by documenting the characteristics of the organization of tissues by using non-invasive technology for analyzing tactile images and judging the properties of abnormal tissues.

Efficacies of Potential Probiotic Candidates Isolated from Traditional Fermented Korean Foods in Stimulating Immunoglobulin A Secretion.

The aim of this study was to evaluate efficacies of selected lactic acid bacteria (LAB) in inducing immunoglobulin A (IgA) secretion. Twenty-five different LAB isolated from traditional fermented Korean foods were characterized for their probiotic properties and screened to identify those that could stimulate lamina propria cells (LPCs) from Peyer's patch to secret IgA in vitro. Among them, four strains (Lactiplantibacillus plantarum CJW55-10, Lactiplantibacillus pentosus CJW18-6, L. pentosus CJW56-11, and Pediococcus acidilactici CJN2696) were found to be strong IgA inducers. The number of IgA positive B cells and soluble IgA level were increased when LPCs were co-cultured with these LAB. Expression levels of toll-like receptor (TLR) such as TLR2 and TLR4 and secretion of interleuckin-6 were augmented in LPCs treated with these LAB. Further, we determined whether oral intake of these LAB enhanced IgA production in vivo. After one-week of daily oral administration, these LAB feed mice increased mucosal IgA and serum IgA. In conclusion, selected strains of LAB could induce systemic IgA secretion by activating lamina propria B cells in Peyer's patch and oral intake of selected strains of LAB can enhance systemic immunity by inducing mucosal IgA secretion.

Gut Lactobacillus and Probiotics Lactobacillus lactis/rhamnosis Ameliorate Liver Fibrosis in Prevention and Treatment.

The progression and exacerbation of liver fibrosis are closely related to the gut microbiome. It is hypothesized that some probiotics may slow the progression of liver fibrosis. In human stool analysis [healthy group (n = 44) and cirrhosis group (n = 18)], difference in Lactobacillus genus between healthy group and cirrhosis group was observed. Based on human data, preventive and therapeutic effect of probiotics Lactobacillus lactis and L. rhamnosus was evaluated by using four mice fibrosis models. L. lactis and L. rhamnosus were supplied to 3,5-diethoxycarbonyl-1,4-dihydrocollidine or carbon tetrachloride-induced liver fibrosis C57BL/6 mouse model. Serum biochemical measurements, tissue staining, and mRNA expression in the liver were evaluated. The microbiome was analyzed in mouse cecal contents. In the mouse model, the effects of Lactobacillus in preventing and treating liver fibrosis were different for each microbe species. In case of L. lactis, all models showed preventive and therapeutic effects against liver fibrosis. In microbiome analysis in mouse models administered Lactobacillus, migration and changes in the ratio and composition of the gut microbial community were confirmed. L. lactis and L. rhamnosus showed preventive and therapeutic effects on the progression of liver fibrosis, suggesting that Lactobacillus intake may be a useful strategy for prevention and treatment.

Normotensive Glaucoma in the Fellow Eye of Patient with Unilateral Pseudoexfoliation.

PURPOSE: To investigate the characteristics of normotensive glaucoma (NTG) in the fellow eye of patients with unilateral pseudoexfoliation syndrome (PXS). METHODS: This study is a retrospective chart review. We included 313 patients with NTG. Using the 1:1 matched propensity score, only 94 well-matched patients were selected. A total of 47 NTG patients who had PXS in their contralateral eye (PXS group) and 47 NTG patients who did not (control group) were compared. The propensity score was matched based on age, mean intraocular pressure (IOP), baseline retinal nerve fiber layer (RNFL) thickness and baseline mean deviation (MD) of visual field (VF) score. The diagnosis of NTG was based on the presence of glaucomatous optic nerve head injury with VF defect, intraocular pressure less than 22 mmHg, open angles and no pseudoexfoliation material. RESULTS: The PXS group had a higher ratio of males (34.0%) than the control group (17.0%). No significant differences were observed between the two groups in terms of CCT, axial length, untreated baseline IOP, baseline PSD of VF, systemic blood pressure and follow-up duration. The rate of RNFL thinning was significantly faster in the PXS group (-1.88 ± 2.83 µm/year) compared with the control group (-0.27 ± 5.29 µm/year) (p = 0.02). The progression rate of VF MD was slightly faster in PXS than in the control group, but there was no statistically significant difference (PXS group, -0.33 ± 0.90 dB/year; control group, -0.11 ± 0.84 dB/year; p = 0.236). CONCLUSIONS: NTG eyes with PXS showed faster RNFL thinning than did control NTG eyes.

[Radiologic Evaluation of Uterine Lesions Using a Pattern Recognition Approach]. / 패턴 인식 ì ‘ê·¼ë²•ì„ 기반으로 한 자궁병변의 ì˜ìƒì˜í•™ì  평가.

It is important to distinguish uterine lesions from other lesions occurring in the pelvic cavity for the proper management. The primary radiological evaluation of uterine lesions is performed using transvaginal ultrasonography, and if the lesion is too large or shows atypical benign imaging findings, magnetic resonance imaging should be performed. Analyzing radiological findings of uterine lesions through a pattern recognition approach can help establish the accurate diagnosis and treatment plan. In this pictorial assay, we describe imaging characteristics of various lesions arising from the uterus and evaluate them based on the pattern recognition approach.

Tall cell carcinoma with reversed polarity of breast: Sonographic and magnetic resonance imaging findings.

Tall cell carcinoma with reversed polarity (TCCRP) of breast is a rare subtype of breast cancer, which show tall and columnar cells with nuclei of reversed polarity, resembles tall cell variant in papillary thyroid cancer. Only 78 cases in 20 published studies had been reported by 2021. TCCRP was recently included as a separate subgroup of rare tumors in the World Health Organization Blue Book Classification of breast tumors (5th edition). We describe a TCCRP case in a 64-year-old woman with detailed radiologic features including quantitative ultrasonography.