Prognostic Value of Pulmonary Artery Systolic Pressure in Severe Rheumatic Mitral Stenosis.

BACKGROUND: Current guidelines recommend intervention for asymptomatic rheumatic mitral stenosis (MS) with mitral valve area ≤1.5 cm2 based on indicators including pulmonary arterial systolic pressure (PASP) >50 mm Hg and new-onset atrial fibrillation; however, evidence supporting this is lacking. METHODS: This single-center retrospective study included patients with rheumatic MS between 2006 and 2022. Pulmonary hypertension was evaluated by using echocardiography to estimate PASP. Primary outcomes were major adverse cardiovascular events (MACE), including all-cause mortality, hospitalization for heart failure, and arterial thromboembolic events for up to 5 years. RESULTS: Overall, 287 patients with severe rheumatic MS were enrolled (mean age, 62.5±11.3 years; 74.6% women). During a median follow-up of 2.52 years, MACE occurred in 99 patients. There were no differences in echocardiographic parameters, such as the mean mitral valve pressure gradient, mitral valve area, and proportion of mitral valve area <1.0 cm2, between patients who developed primary outcomes and those who did not. Survival analysis showed a worse prognosis in patients with estimated PASP (ePASP) >50 mm Hg than in those with ePASP ≤50 mm Hg (log-rank P<0.001); however, atrial fibrillation was not a significant prognostic indicator. As a continuous variable, ePASP (mm Hg) was a significant predictor of MACE (adjusted hazard ratio, 1.027 [95% CI, 1.011-1.042]; P<0.001). Receiver operating characteristic analysis revealed an optimal ePASP threshold of >45 mm Hg, which was an independent predictor of MACE in patients with severe rheumatic MS (adjusted hazard ratio, 2.127 [95% CI, 1.424-3.177]; P<0.001). Competing risk analysis considering mitral valve intervention as a competing risk showed similar results. CONCLUSIONS: Our study demonstrated the prognostic significance of ePASP, rather than atrial fibrillation, in relation to MACE among patients with severe rheumatic MS. Additionally, we proposed a lower ePASP threshold (>45 mm Hg) as a predictor of an unfavorable prognosis.

The Influence of Solvent Choice on the Extraction of Bioactive Compounds from Asteraceae: A Comparative Review.

While the potential of Asteraceae plants as herbal remedies has been globally recognized, their widespread application in the food, cosmetic, and pharmaceutical industries requires a deeper understanding of how extraction methods influence bioactive compound yields and functionalities. Previous research has primarily focused on the physiological activities or chemical compositions of individual Asteraceae species, often overlooking the critical role of solvent selection in optimizing extraction. Additionally, the remarkable physiological activities observed in these plants have spurred a growing number of clinical trials, aiming to validate their efficacy and safety for potential therapeutic and commercial applications. This work aims to bridge these knowledge gaps by providing an integrated analysis of extraction techniques, the diverse range of bioactive compounds present in Asteraceae, and the influence of solvent choice on isolating these valuable substances. By elucidating the interplay between extraction methods, solvent properties, and bioactivity, we underscore the promising potential of Asteraceae plants and highlight the importance of continued research, including clinical trials, to fully unlock their potential in the food, cosmetic, and pharmaceutical sectors.

Dual-Seed Strategy for High-Performance Anode-Less All-Solid-State Batteries.

Interest in all-solid-state batteries (ASSBs), particularly the anode-less type, has grown alongside the expansion of the electric vehicle (EV) market, because they offer advantages in terms of their energy density and manufacturing cost. However, in most anode-less ASSBs, the anode is covered by a protective layer to ensure stable lithium (Li) deposition, thus requiring high temperatures to ensure adequate Li ion diffusion kinetics through the protective layer. This study proposes a dual-seed protective layer consisting of silver (Ag) and zinc oxide (ZnO) nanoparticles for sulfide-based anode-less ASSBs. This dual-seed-based protective layer not only facilitates Li diffusion via multiple lithiation pathways over a wide range of potentials, but also enhances the mechanical stability of the anode interface through the in situ formation of a Ag-Zn alloy with high ductility. The capacity retention during full-cell evaluation is 80.8% for 100 cycles when cycled at 1 mA cm-2 with 3 mAh cm-2 at room temperature. The dual-seed approach provides useful insights into the design of multi-seed concepts in which, from a mechanochemical perspective, various lithiophilic materials synergistically impact upon the anode-less interface.

Osmotic energy conversion in serpentinite-hosted deep-sea hydrothermal vents.

Cells harvest energy from ionic gradients by selective ion transport across membranes, and the same principle is recently being used for osmotic power generation from salinity gradients at ocean-river interfaces. Common to these ionic gradient conversions is that they require intricate nanoscale structures. Here, we show that natural submarine serpentinite-hosted hydrothermal vent (HV) precipitates are capable of converting ionic gradients into electrochemical energy by selective transport of Na+, K+, H+, and Cl-. Layered hydroxide nanocrystals are aligned radially outwards from the HV fluid channels, constituting confined nanopores that span millimeters in the HV wall. The nanopores change the surface charge depending on adsorbed ions, allowing the mineral to function as a cation- and anion-selective ion transport membrane. Our findings indicate that chemical disequilibria originating from flow and concentration gradients in geologic environments generate confined nanospaces which enable the spontaneous establishment of osmotic energy conversion.

Trapped in Cells: A Selective Accumulation Approach for Type-I Photodynamic Ablation of Cancer Stem-like Cells.

Aldehyde dehydrogenase (ALDH) is an enzyme responsible for converting aldehyde functional groups into carboxylate metabolites. Elevated ALDH activity is a characteristic feature of cancer stem-like cells (CSCs). As a novel approach to target the CSC trait of overexpressing ALDH, we aimed to utilize ALDH activity for the selective accumulation of a photosensitizer in ALDHHigh CSCs. A novel ALDH substrate photosensitizer, SCHO, with thionylated coumarin and N-ethyl-4-(aminomethyl)benzaldehyde was developed to achieve this goal. Our study demonstrated the efficient metabolism of the aldehyde unit of SCHO into carboxylate, leading to its accumulation in ALDHHigh MDA-MB-231 cells. Importantly, we established the selectivity of SCHO as an ALDHHigh cell photosensitizer as it is not a substrate for ABC transporters. SCHO-based photodynamic therapy triggers apoptosis and pyroptosis in MDA-MB-231 cells and further reduces the characteristics of CSCs. Our study presents a novel strategy to target CSCs by exploiting their cellular metabolism to enhance photosensitizer accumulation, highlighting the potential of photodynamic therapy as a powerful tool for eliminating ALDHHigh CSCs.

Evaluation of PD-L1 expression in PBRM1-altered clear cell renal cell carcinoma.

PURPOSE: Clear cell renal cell carcinoma (ccRCC) often harbors Polybromo 1 (PBRM1) alterations. These alterations are associated with immune checkpoint blockade response in ccRCC, particularly antiprogrammed cell death 1 (PD1)/programmed cell death ligand 1 (PD-L1)-targeted therapy. However, the association between PBRM1 alterations and PD-L1 expression in ccRCC remains unclear. MATERIALS AND METHODS: We analyzed alterations in PBRM1 and PD-L1 expression using immunohistochemistry (IHC) targeting PBRM1 and PD-L1 (22C3) in tissues collected from patients with localized ccRCC (Cohort 1) and advanced ccRCC (Cohort 2). Additionally, next-generation sequencing (NGS) was conducted on Cohort 2 patients to analyze PBRM1 alterations. RESULTS: Cohort 1 comprised 526 patients, of whom 139 (26.4%) exhibited PD-L1 positivity and 205 (38.9%) exhibited loss of PBRM1 expression in IHC. PD-L1 expression was positively associated with the loss of PBRM1 expression (P < 0.001) in localized ccRCC. Kaplan-Meier analysis indicated that PBRM1 expression loss and PD-L1 expression positively correlated with tumor recurrence (P < 0.001 and P = 0.003, respectively). Cohort 2 comprised 59 patients with advanced ccRCC, of whom 33 (56.9%) exhibited PBRM1 genetic alterations. PBRM1 IHC exhibited a sensitivity of 84.48% and specificity of 87.5% compared to NGS results. We did not find a significant association between PBRM1 mutation and PD-L1 expression, in contrast to the findings in Cohort 1. However, we frequently observed that PBRM1 mutation and PD-L1 expression occur concurrently, with 60% of PBRM1-altered ccRCC cases being PD-L1 positive. CONCLUSION: Although our study did not establish a correlation between PBRM1 mutations and PD-L1 expression, it demonstrated that the occurrence of PBRM1-altered ccRCC with PD-L1 expression is not uncommon. Therefore, the presence of PBRM1 alterations may challenge the use of PD-L1 IHC as a predictive marker for PD-L1 blockade in ccRCC.

p16 Immunohistochemical Patterns in Triple-Negative Breast Cancer: Clinical and Genomic Similarities of the p16 Diffuse Pattern to pRB Deficiency.

INTRODUCTION: Triple-negative breast cancer (TNBC) is associated with alterations in the retinoblastoma pathway. As a consequence of retinoblastoma protein (pRB) loss, compensatory upregulation of p16 occurs due to the loss of phosphorylated pRB-mediated negative feedback on p16 expression. The aim of this study is to investigate the clinicopathologic and genomic characteristics associated with the diffuse pattern of p16 immunohistochemistry (IHC) in TNBC. METHODS: The study analyzed surgically resected TNBC for whole-exome sequencing in 113 cases and for cDNA microarray in 144 cases. The p16 IHC results were classified into two patterns: diffuse and negative/mosaic. RESULTS: In the entire cohort (n = 257), the diffuse pattern of p16 IHC was observed in 123 (47.9%) patients and the negative/mosaic pattern in 134 (52.1%). Bi-allelic RB1 inactivation was observed in 14.3% of patients with the diffuse pattern. The diffuse pattern of p16 IHC showed more frequent RB1 alterations and cell cycle progression signatures, a higher Ki-67 labeling index, more frequent chromosome segment copy number changes, a higher frequency of homologous recombination deficiency high, and immune-related signatures. PIK3CA mutations were more frequent in the negative/mosaic pattern. CCND1 amplification was identified in five cases, all with the negative/mosaic pattern Conclusion: In TNBC, the diffuse p16 pattern shows clinical and genomic similarities to pRB-deficient tumors, suggesting shared characteristics. This suggests that p16 IHC testing may provide new therapeutic approaches, underscoring its potential clinical importance.

Exploring the anti-obesity effects of kimchi through enhanced thermogenesis in differentiated T37i brown adipocytes.

Background: Previous research has demonstrated the anti-obesity effects of kimchi in 3T3-L1 adipocytes and mice with diet-induced obesity by assessing the expression of obesity-associated genes. Additionally, recent studies have identified mechanisms involving thermogenesis that support these effects. Objective: This study aims to further investigate the anti-obesity properties of kimchi, focusing on its impact on thermogenic activity in differentiated T37i brown adipocytes. Design: The study first evaluated the antioxidant potential of kimchi using total antioxidant capacity (TAC) and ferric reducing antioxidant power (FRAP) assays. Optimal differentiation conditions for T37i adipocytes were established before proceeding with evaluations of cell viability, intracellular triglyceride (TG) content, lipid accumulation, and the expression of genes and proteins related to obesity and thermogenesis. Results: Kimchi maintained over 90% cell viability in T37i adipocytes at concentrations up to 1,000 µg/mL. Efficient differentiation of T37i preadipocytes was achieved using a medium containing 10% calf serum, 2 nM 3,3',5-triiodo-L-thyronin (T3), and 100 nM insulin. Kimchi significantly reduced intracellular TG levels and lipid accumulation, compared to the control group, and enhanced the expression of genes and proteins related to thermogenesis while reducing the expression of obesity-related genes. Discussion: The findings suggest that kimchi exerts its anti-obesity effects by modulating thermogenic and obesity-related pathways in brown adipocytes, which may be partially attributed to its antioxidant properties. Conclusions: Kimchi shows promise as a preventive measure against obesity by influencing metabolic pathways associated with both obesity and thermogenesis in T37i brown adipocytes.

Content Analysis of Online Resources Regarding Needs for Advance Care Planning.

Purpose: This study aimed to investigate advance care planning needs expressed online. Methods: This study collected data from online community posts and healthcare news sites. The search keywords included "death," "euthanasia," "life-sustaining medical care," "life-sustaining treatment," "advance directives," "advance medical directives," and "advance care planning." Data collection spanned from February 2018 to February 14, 2020. Out of 2,288 posts, 1,190 were included in the final analysis. Data analysis was conducted using NVivo 12, a qualitative data analysis software program. Results: Content analysis categorized patients' advance care planning needs into eight themes, 11 theme clusters, and 33 meaningful statements. Similarly, care providers' advance care planning needs were categorized into eight themes, 14 theme clusters, and 42 meaningful statements. The identified themes of care needs included life-sustaining medical care, decision-making related to life-sustaining medical care, physical care, environmental care, supportive and spiritual care, respect, preparing for death, and family. Conclusion: This study identified care needs from the perspectives of patients and their families. The findings may serve as preliminary data for future research and clinical applications.

Role of MYO1F in neutrophil and macrophage recruitment and pro-inflammatory cytokine production in Aspergillus fumigatus keratitis.

PURPOSE: Myosin 1f (Myo1f), an unconventional long-tailed class Ⅰ myosin, plays significant roles in immune cell motility and innate antifungal immunity. This study was aimed to assess the expression and role of Myo1f in Aspergillus fumigatus (AF) keratitis. METHODS: Myo1f expression in the corneas of mice afflicted with AF keratitis and in AF keratitis-related cells was assessed using protein mass spectrometry, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunofluorescence. Myo1f expression following pre-treatment with inhibitors of dendritic cell-associated C-type lectin-1 (Dectin-1), Toll-like receptor 4 (TLR-4), and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) was also examined. In AF keratitis mouse models, Myo1f small interfering RNA (siRNA) was administered via subconjunctival injection to observe disease progression, inflammatory cell recruitment, and protein production using slit lamp examination, immunofluorescence, hematoxylin-eosin (HE) staining, and western blotting. RESULTS: Myo1f expression was upregulated in both AF keratitis mouse models and AF keratitis-related cells. Dectin-1, TLR-4, and LOX-1 were found to be essential for the production of Myo1f in response to the infection with AF. In mice with AF keratitis, knockdown of Myo1f reduced disease severity, decreased the recruitment of neutrophils alongside macrophages to inflammatory areas, suppressed the myeloid differentiation factor 88 (MyD88)/ nuclear factor-kappaB (NF-κB) signaling pathway, and decreased the production of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, along with IL-6. Additionally, Myo1f was associated with apoptosis and pyroptosis in mice with AF keratitis. CONCLUSIONS: These findings demonstrated that Myo1f contributed to the recruitment of neutrophils and macrophages, the production of pro-inflammatory cytokines, and was associated with apoptosis and pyroptosis during AF keratitis.

Nanoscale Graded Nitrogen-Doping of TiO2 via Pulsed Laser Deposition for Enhancing Charge Transfer in Perovskite Solar Cells.

An electron transport layer (ETL) for highly efficient perovskite solar cells (PSCs) should exhibit superior electrical transport properties and have its band levels aligned with interfacing layers to ensure efficient extraction of photo-generated carriers. Nitrogen-doped TiO2 (TiO2:N) is considered a promising ETL because it offers higher electrical conductivity compared to conventional ETLs made from spray-pyrolyzed TiO2. However, the application of highly doped TiO2:N in PSCs is often limited by the misalignment of energy band levels with adjacent layers and reduced optical transparency. In this study, a novel approach is introduced to enhance the charge transport characteristics and accurately align the electronic band alignment of TiO2:N layer through nanoscale doping level grading, achieved through the pulsed laser deposition (PLD) technique. The TiO2:N ETL with a graded doping profile can combine characteristics of both highly doped and lightly doped phases on each side. Furthermore, a nanoscale doping gradation, employing an ultrathin sub-layer structure with graded doping levels, creates a smoothly cascading band-level alignment that bridges the adjacent layers, enhancing the transport of photo-generated carriers. Consequently, this method leads to a substantial increase in the power conversion efficiency (PCE), exceeding 22%, which represents a relative improvement of 11% compared to traditional spray-pyrolyzed TiO2-based PSCs.

Dual-porous ZIF-8 heterogeneous catalysts with increased reaction sites for efficient PET glycolysis.

Poly (ethylene terephthalate) (PET) has been widely used for drink bottles, food packing, films, and fibers, resulting in millions of tons of waste PET. Less than 10% of that waste is recycled, and the rest is discarded or incinerated. Waste PET upcycling employs chemical recycling and particularly glycolysis to create the bis(2-hydroxyethyl) terephthalate (BHET) monomer. Herein, we report a dual-porous zeolitic imidazolate framework-8 nanoparticle (DPZIF-8) heterogeneous catalyst for efficient PET glycolysis. The DPZIF-8 nanoparticles were prepared using a triethylamine modulator, which can control the nucleation and growth mechanisms of the ZIF-8 nanoparticles. The DPZIF-8 nanoparticles include both intrinsic micropores and particle-particle adhesion-induced mesopores that can provide a larger external surface area of the zinc sites in the ZIF-8 architecture. The PET glycolysis catalyzed by DPZIF-8 at 180 °C and 1 atm for 4 h shows a PET conversion of 91.7% and a BHET yield of 76.1%, the latter particularly being much higher than with a traditional heterogeneous ZIF-8 catalyst. This dual-porous structure rational design strategy can be versatile for other metal-organic frameworks (MOFs) to increase the interfacial catalytic reaction sites between the metal-organic framework and the polymer, enhancing the PET depolymerization performance and efficiency.

First Report of Nigrospora oryzae Causing Leaf Spot on Peanut (Arachis hypogaea L.) in the Republic of Korea.

Peanut (Arachis hypogaea L.) is one of the most profitable upland crops, yielding 10,711 tonnes in an area of 4,062 ha in the Republic of Korea (Ministry of Agriculture, Food and Rural Affairs 2023). In September 2023, dark gray spots surrounded by yellow halos were observed on the peanut leaves over an area of 880 m2 at the National Institute of Crop Science (35°50'31.4"N 127°02'41.0"E), with a disease incidence up to 80%. Early symptoms appeared as small, brown, circular or irregular spots that enlarged and were surrounded by chlorotic halos. Leaf cuttings (5 mm x 5 mm) from five symptomatic plants were surface-sterilized with 70% EtOH for 1 min, followed by 1% NaClO for 1 min, and rinsed 3 times with sterile water. The pieces were placed on Potato Dextrose Agar (PDA) and incubated at 25 °C in the dark for 3 days. Three isolates obtained by single-spore isolation were designated as F23025, F23026, and F23027. Two isolates, F23025 and F23026 were deposited in the Korean Agricultural Culture Collection (https://genebank.rda.go.kr) under the accession numbers 410722 and 410723. Fungal colonies were initially white and turned sooty gray after 5 days. Conidia were unicellular, brown to black, and spherical or sub-spherical with 6.8 µm to 14.3 µm (mean = 11.1 µm ± 1.8, n = 50). The morphology of the three isolates was identical and showed the same characteristics as Nigrospora oryzae (Ellis 1971; Hudson 1963). For molecular identification, the Internal Transcribed Spacer (ITS) region (GenBank accession PP388306 and PP574448), beta tubulin (PP397027 and PP580108), and translation elongation factor 1- ɑ (PP397028 and PP580109) of isolates F23025 and F23026 were amplified and sequenced with primers of ITS5/ITS4, Bt2a/Bt2b, EF1-727F/EF2, respectively and showed high identity of 99.62% (530 bp/532 bp), 100% (384/384), and 99.79% (475/476) with N. oryzae strain LC2693 (GenBank accessions KX985994, KY019471, and KY019299, respectively). Multilocus sequence analysis showed isolates F23025 and F23026 were on the same clade with N. oryzae strain LC2693. To determine the pathogenicity to peanut, a conidial suspension (1 x 106 conidia/mL) was sprayed onto leaves of five 3-week-old plants 'Sewon' grown in pots, while sterile distilled water was sprayed onto two plants used as negative control. Sprayed plants were placed in a dew chamber at 25℃ for two days and grown in a growth chamber at 25℃ and 80% of relative humidity with a 16L:8D cycle. Two weeks later, dark spots with chlorotic halos appeared only on leaves sprayed with conidia, and no symptoms on leaves sprayed with sterile distilled water. The pathogenicity test was repeated three times, and each time the pathogen was re-isolated and identified by ITS sequence, thus fulfilling Koch's postulates. Nigrospora species are cosmopolitan, and some species have a wide host range as plant pathogens. Recently, two species of the genus Nigrospora, N. sphaerica and N. aurantiaca, were reported to cause peanut leaf blight in China (Liu et al. 2020; He et al. 2023). To the best of our knowledge, this is the first report of N. oryzae causing leaf spot to A. hypogaea L. in the Republic of Korea. As identifying new pathogens and registering fungicides to control them are important for the continued cultivation of peanut, this report will help in that endeavor.

Investigating Implicit and Explicit Communication of Highly Automated Vehicles in Japan: How do Light-band eHMIs affect Pedestrians' Willingness to Cross, Trust and Perceived Safety?

In the near future, pedestrians will face highly automated vehicles on the roads. Highly automated vehicles (HAVs) should have safety-enhancing communication tools to guarantee traffic safety, e.g., vehicle kinematics and external human-machine interfaces (eHMIs). Pedestrians, as highly vulnerable road users, depend on communication with HAVs. Miscommunication between pedestrians and HAVs could quickly result in accidents, and this, in turn, could cause severe impairments for pedestrians. Light-band eHMIs have the potential to enhance traffic safety. However, eHMIs have been less explored in Japan so far. As a first-time approach, this experimental online study shed light on the effect of a light-band eHMI on Japanese pedestrians (N=99). In short video sequences, the participants interacted with two differently sized HAVs equipped with light-band eHMI. We investigated the effect of vehicle size (small vs. large), eHMI status (no eHMI vs. static eHMI vs. dynamic eHMI), and vehicle kinematics (yielding vs. non-yielding) on pedestrians' willingness to cross, trust, and perceived safety. To investigate possible side effects of eHMIs, we also included experimental conditions in which the eHMI mismatched the vehicle's kinematics. Results revealed that Japanese were more willing to cross the street and indicated higher trust- and safety ratings when they received information about the vehicle's intention and automation status (dynamic eHMI) compared to when they received no information (no eHMI) or only about the vehicle automation status (static eHMI). Surprisingly, Japanese participants tended to rely on the eHMI when there was mismatching information between eHMI and vehicle kinematics. Overall, we concluded that light-band eHMIs could contribute to a safe future interaction between pedestrians and HAVs in Japan under the requirement that the eHMI is in accordance with vehicle kinematics.

Different diabetogenic effect of statins according to intensity and dose in patients with acute myocardial infarction: a nationwide cohort study.

Statin is crucial for acute myocardial infarction (AMI) patients. However, the risk of new-onset diabetes mellitus (NODM) associated with statin is a concern. This study aimed to determine the incremental diabetogenic effects of statins according to their intensity and dose in AMI patients undergoing percutaneous coronary intervention (PCI). Among 13,104 patients enrolled in the Korea AMI Registry between 2011 and 2015, 6152 patients without diabetes mellitus (DM) who underwent PCI and received moderate-to-high-intensity atorvastatin and rosuvastatin were selected for the study. The endpoints were NODM and major adverse cardiovascular events (MACE), composite of all-cause mortality, recurrent MI, and revascularization up to 3 years. Among the participants, 3747 and 2405 received moderate- and high-intensity statins, respectively. The Kaplan-Meier curves demonstrated a higher incidence of NODM in patients with high-intensity statins than those with moderate-intensity. High-intensity statin was a significant predictor of NODM after adjusting for other co-variables (HR = 1.316, 95% CI 1.024-1.692; P < 0.032). Higher dose of rosuvastatin was associated with a higher cumulative incidence of NODM, but this dose-dependency was not apparent with atorvastatin. Cumulative incidence of MACE decreased dose-dependently only with atorvastatin. High-intensity statin was associated with a higher cumulative incidence of NODM in AMI patients, and this association was more evident in rosuvastatin. The different diabetogenic effects of the two statins provide supporting evidence for understanding the nuanced nature of statin treatment in relation to NODM.

Design, synthesis, and anti-melanogenic efficacy of 2-mercaptobenzoxazoles with nanomolar tyrosinase activity inhibition.

Tyrosinase is a metalloenzyme that contains copper(II) ions. We designed and synthesized eight known low-molecular-weight 2-mercaptobenzoxazole (2-MBO) analogs as tyrosinase inhibitors. Our focus was on the mercapto functional group, which interacts with copper ions. Analogs 1-3 exhibited mushroom tyrosinase inhibitory activity at the nanomolar level and demonstrated strong potency with extremely low half-maximal inhibitory concentration (IC50) values of 80-90 nM for l-dopa and 100-240 nM for l-tyrosine. Analogs 2, 4, and 5 showed the most potent anti-melanogenic effects in B16F10 cells, and their mode of action was demonstrated by kinetic analysis. Their anti-melanogenic effects were similar to the tyrosinase inhibition results, suggesting that their anti-melanogenic effects could be attributed to their tyrosinase inhibitory ability. Experiments using copper-chelating activity assays and changes in tyrosinase inhibitory activity with and without CuSO4 demonstrated that 2-MBO analogs inhibit tyrosinase activity by chelating the copper ions of tyrosinase. In conclusion, the 2-MBO analogs show potential as anti-melanogenic agents with potent tyrosinase inhibitory activity.

A single-particle mechanofluorescent sensor.

Monitoring mechanical stresses in microchannels is challenging. Herein, we report the development of a mechanofluorescence sensor system featuring a fluorogenic single polydiacetylene (PDA) particle, fabricated using a co-flow microfluidic method. We construct a stenotic vessel-mimicking capillary channel, in which the hydrodynamically captured PDA particle is subjected to controlled fluid flows. Fluorescence responses of the PDA particle are directly monitored in real time using fluorescent microscopy. The PDA particle displays significant nonlinear fluorescence emissions influenced by fluid viscosity and the presence of nanoparticles and biomolecules in the fluid. This nonlinear response is likely attributed to the torsion energy along the PDA's main chain backbone. Computational fluid dynamic simulations indicate that the complete blue-to-red transition necessitates ~307 µJ, aligning with prior research. We believe this study offers a unique advantage for simulating specific problematic regions of the human body in an in vitro environment, potentially paving the way for future exploration of difficult-to-access areas within the body.

Highly potent anti-melanogenic effect of 2-thiobenzothiazole derivatives through nanomolar tyrosinase activity inhibition.

Compounds with sulfhydryl substituents and azole compounds exhibit potent anti-tyrosinase potency. 2-Thiobenzothiazole (2-TBT), a hybrid structure of sulfhydryl and azole, exists in two tautomeric forms, with the thione form being predominant according to several studies. 2-TBT derivatives were synthesized as potential tyrosinase inhibitors as the thione tautomeric form has the same N-CS moiety as phenylthiourea (PTU), which is suitable for chelation with the copper ions present in the tyrosinase active site. Eight of the ten 2-TBT derivatives inhibited the monophenolase and diphenolase activities of mushroom tyrosinase, with IC50 values of 0.02-0.83 µM. Kinetic studies and molecular dynamics simulations were performed to determine their mode of action and confirm that the 2-TBT derivatives bind to the tyrosinase active site with high stability. Derivatives 3, 4, 8, and 10 strongly inhibited melanogenesis in B16F10 cells in a pattern similar to the results of cellular tyrosinase inhibition, thereby suggesting that their ability to inhibit melanogenesis was due to their tyrosinase inhibitory activity. In a depigmentation experiment using zebrafish embryos, all 2-TBT derivatives showed better potency than kojic acid, even at 400 to 2000 times lower concentration, and 1 and 10 reduced zebrafish larva pigmentation more strongly than PTU even at 20 times lower concentration. Experiments investigating the changes in tyrosinase inhibitory activity of 2-TBT derivatives in the presence and absence of CuSO4 and their copper chelating ability supported that these derivatives exert their anti-melanogenic effect by chelating the copper ions of tyrosinase. These results suggest that 2-TBT derivatives are promising candidates for the treatment of hyperpigmentation-related disorders.

MUC16 as a serum-based prognostic indicator of prometastatic gastric cancer.

Metastatic gastric cancer (GC) presents significant clinical challenges due to its poor prognosis and limited treatment options. To address this, we conducted a targeted protein biomarker discovery study to identify markers predictive of metastasis in advanced GC (AGC). Serum samples from 176 AGC patients (T stage 3 or higher) were analyzed using the Olink Proteomics Target panels. Patients were retrospectively categorized into nonmetastatic, metastatic, and recurrence groups, and differential protein expression was assessed. Machine learning and gene set enrichment analysis (GSEA) methods were applied to discover biomarkers and predict prognosis. Four proteins (MUC16, CAIX, 5'-NT, and CD8A) were significantly elevated in metastatic GC patients compared to the control group. Additionally, GSEA indicated that the response to interleukin-4 and hypoxia-related pathways were enriched in metastatic patients. Random forest classification and decision-tree modeling showed that MUC16 could be a predictive marker for metastasis in GC patients. Additionally, ELISA validation confirmed elevated MUC16 levels in metastatic patients. Notably, high MUC16 levels were independently associated with metastatic progression in T3 or higher GC. These findings suggest the potential of MUC16 as a clinically relevant biomarker for identifying GC patients at high risk of metastasis.

Hole-Carrier-Dominant Transport in 2D Single-Crystal Copper.

In 2D noble metals like copper, the carrier scattering at grain boundaries has obscured the intrinsic nature of electronic transport. However, it is demonstrated that the intrinsic nature of transport by hole carriers in 2D copper can be revealed by growing thin films without grain boundaries. As even a slight deviation from the twin boundary is perceived as grain boundaries by electrons, it is only through the thorough elimination of grain boundaries that the hidden hole-like attribute of 2D single-crystal copper can be unmasked. Two types of Fermi surfaces, a large hexagonal Fermi surface centered at the zone center and the triangular Fermi surface around the zone corner, tightly matching to the calculated Fermi surface topology, confirmed by angle-resolved photoemission spectroscopy (ARPES) measurements and vivid nonlinear Hall effects of the 2D single-crystal copper account for the presence of hole carriers experimentally. This breakthrough suggests the potential to manipulate the majority carrier polarity in metals by means of grain boundary engineering in a 2D geometry.