The aim of this study was to conduct an anthropometric analysis of the 5 portraits painted by Botticelli that depict Simonetta Vespucci. Five images in the Simonetta series by Botticelli workshop were measured. The anthropometric measurements of the face included 22 parameters on the lateral view (in 4 portraits; 18 distances and 4 angles) and 17 distances on the frontal view (in one portrait), which were measured using Adobe Photoshop. The absolute distances were calculated relative to the vertical corneal diameter (10.6 mm), which was calculated by multiplying the distance from the pupil's center to the lower margin of the iris. In the lateral faces, the nasofrontal angle (g-n-prn) was 157.6±2.4 degrees, and the nasal tip angle (n-prn-sn) was 99.7±3.4 degrees. The nasolabial angle (prn-sn-ls) was 125.7±4.9 degrees, and the labiomental angle (li-sl-pg) was 131.6±4.4 degrees. The ratio of the upper lip height to the lower lip height (sn-sto/sto-sl) was 85.4±9.0%. The ratio of the upper lip vermillion to the upper lip height (ls-sto/sn-sto) was 27.7±3.9%. The ratio of the lower lip vermillion to the lower lip height (sto-li/sto-sl) was 47.2±6.6%. Comparing the data with 21st-century Italian females, forehead II height (tr-n), physiognomical face height (tr-gn), and morphologic face height (n-gn) of the beauties of the 15th century were significantly greater than those of 21st-century Italian females. However, there were no significant differences in lower face height (sn-gn) and nose height (n-sn). Considering the ongoing cultural relevance of Renaissance art, the esthetic proportions from this study may have reflection to the present day plastic surgery.
Mesenchymal stem cells (MSCs) have garnered attention for their regenerative and immunomodulatory capabilities in clinical trials for various diseases. However, the effectiveness of MSC-based therapies, especially for conditions like graft-versus-host disease (GvHD), remains uncertain. The cytokine interferon (IFN)-γ has been known to enhance the immunosuppressive properties of MSCs through cell-to-cell interactions and soluble factors. In this study, we observed that IFN-γ-treated MSCs upregulated the expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), associated with immune evasion through the inhibition of natural killer (NK) cell cytotoxicity. To co-opt this immunomodulatory function, we generated MSCs overexpressing CEACAM1 and found that CEACAM1-engineered MSCs significantly reduced NK cell activation and cytotoxicity via cell-to-cell interaction, independent of NKG2D ligand regulation. Furthermore, CEACAM1-engineered MSCs effectively inhibited the proliferation and activation of T cells along with the inflammatory responses of monocytes. In a humanized GvHD mouse model, CEACAM1-MSCs, particularly CEACAM1-4S-MSCs, demonstrated therapeutic potential by improving survival and alleviating symptoms. These findings suggest that CEACAM1 expression on MSCs contributes to MSC-mediated regulation of immune responses and that CEACAM1-engineered MSC could have therapeutic potential in conditions involving immune dysregulation.
Distant metastasis, the leading cause of cancer death, is efficiently kept in check by immune surveillance. Studies have uncovered peripheral natural killer (NK) cells as key antimetastatic effectors and their dysregulation during metastasis. However, the molecular mechanism governing NK cell dysfunction links to metastasis remains elusive. Herein, MAP4K1 encoding HPK1 is aberrantly overexpressed in dysfunctional NK cells in the periphery and the metastatic site. Conditional HPK1 overexpression in NK cells suffices to exacerbate melanoma lung metastasis but not primary tumor growth. Conversely, MAP4K1-deficient mice are resistant to metastasis and further protected by combined immune-checkpoint inhibitors. Mechanistically, HPK1 restrains NK cell cytotoxicity and expansion via activating receptors. Likewise, HPK1 limits human NK cell activation and associates with melanoma NK cell dysfunction couples to TGF-ß1 and patient response to immune checkpoint therapy. Thus, HPK1 is an intracellular checkpoint controlling NK-target cell responses, which is dysregulated and hijacked by tumors during metastatic progression.
Plant pathogenic fungi cause serious diseases, which result in the loss of crop yields and reduce the quality of crops worldwide. To counteract the escalating risks of chemical fungicides, interest in biological control agents to manage plant diseases has significantly increased. In this study, we comprehensively screened microbial culture filtrates using a yeast screening system to find microbes exhibiting respiratory inhibition activity. Consequently, we found a soil-borne microbe Brevibacillus brevis HK544 strain exhibiting a respiration inhibitory activity and identified edeine B1 (EB1) from the culture filtrate of HK544 as the active compound of the respiration inhibition activity. Furthermore, against a plant pathogenic fungus Fusarium graminearum, our results showed that EB1 has effects on multiple aspects of respiration with the downregulation of most of the mitochondrial-related genes based on transcriptome analysis, differential EB1-sensitivity from targeted mutagenesis, and the synergistic effects of EB1 with electron transport chain complex inhibitors. With the promising plant disease control efficacy of B. brevis HK544 producing EB1, our results suggest that B. brevis HK544 has potential as a biocontrol agent for Fusarium head blight.IMPORTANCEAs a necrotrophic fungus, Fusarium graminearum is a highly destructive pathogen causing severe diseases in cereal crops and mycotoxin contamination in grains. Although chemical control is considered the primary approach to control plant disease caused by F. graminearum, fungicide-resistant strains have been detected in the field after long-term continuous application of fungicides. Moreover, applying chemical fungicides that trigger mycotoxin biosynthesis is a great concern for many researchers. Biocontrol of Fusarium head blight (FHB) by biological control agents (BCAs) represents an alternative approach and could be used as part of the integrated management of FHB and mycotoxin production. The most extensive studies on bacterial BCAs-fungal communications in agroecosystems have focused on antibiosis. Although many BCAs in agricultural ecology have already been used for fungal disease control, the molecular mechanisms of antibiotics produced by BCAs remain to be elucidated. Here, we found a potential BCA (Brevibacillus brevis HK544) with a strong antifungal activity based on the respiration inhibition activity with its active compound edeine B1 (EB1). Furthermore, our results showed that EB1 secreted by HK544 suppresses the expression of the mitochondria-related genes of F. graminearum, subsequently suppressing fungal development and the virulence of F. graminearum. In addition, EB1 exhibited a synergism with complex I inhibitors such as rotenone and fenazaquin. Our work extends our understanding of how B. brevis HK544 exhibits antifungal activity and suggests that the B. brevis HK544 strain could be a valuable source for developing new crop protectants to control F. graminearum.
Natural killer (NK) cells are key effectors in cancer immunosurveillance, eliminating a broad spectrum of cancer cells without major histocompatibility complex (MHC) specificity and graft-versus-host diseases (GvHD) risk. The use of allogeneic NK cell therapies from healthy donors has demonstrated favorable clinical efficacies in treating diverse cancers, particularly hematologic malignancies, but it requires cytokines such as IL-2 to primarily support NK cell persistence and expansion. However, the role of IL-2 in the regulation of activating receptors and the function of NK cells expanded for clinical trials is poorly understood and needs clarification for the full engagement of NK cells in cancer immunotherapy. Here, we demonstrated that IL-2 deprivation significantly impaired the cytotoxicity of primary expanded NK cells by preferentially downregulating NKp30 but not NKp46 despite their common adaptor requirement for expression and function. Using NK92 and IL-2-producing NK92MI cells, we observed that NKp30-mediated cytotoxicity against myeloid leukemia cells such as K562 and THP-1 cells expressing B7-H6, a ligand for NKp30, was severely impaired by IL-2 deprivation. Furthermore, IL-2 deficiency-mediated NK cell dysfunction was overcome by the ectopic overexpression of an immunostimulatory NKp30 isoform such as NKp30a or NKp30b. In particular, NKp30a overexpression in NK92 cells improved the clearance of THP-1 cells in vivo without IL-2 supplementation. Collectively, our results highlight the distinct role of IL-2 in the regulation of NKp30 compared to that of NKp46 and suggest NKp30 upregulation, as shown here by ectopic overexpression, as a viable modality to harness NK cells in cancer immunotherapy, possibly in combination with IL-2 immunocytokines.
Cytotoxicity, Immunologic , Interleukin-2 , Killer Cells, Natural , Natural Cytotoxicity Triggering Receptor 3 , Humans , Natural Cytotoxicity Triggering Receptor 3/immunology , Natural Cytotoxicity Triggering Receptor 3/metabolism , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Interleukin-2/metabolism , Natural Cytotoxicity Triggering Receptor 1/metabolism , K562 Cells , THP-1 Cells , B7 Antigens/genetics , B7 Antigens/metabolism , B7 Antigens/immunology
In this study, we investigated the hepatoprotective effects of an ethanol extract of Sophora flavescens Aiton (ESF) on an alcohol-induced liver disease mouse model. Alcoholic liver disease (ALD) was caused by the administration of ethanol to male C57/BL6 mice who were given a Lieber-DeCarli liquid diet, including ethanol. The alcoholic fatty liver disease mice were orally administered ESF (100 and 200 mg/kg bw/day) or silymarin (50 mg/kg bw/day), which served as a positive control every day for 16 days. The findings suggest that ESF enhances hepatoprotective benefits by significantly decreasing serum levels of aspartate transaminase (AST) and alanine transaminase (ALT), markers for liver injury. Furthermore, ESF alleviated the accumulation of triglyceride (TG) and total cholesterol (TC), increased serum levels of superoxide dismutase (SOD) and glutathione (GSH), and improved serum alcohol dehydrogenase (ADH) activity in the alcoholic fatty liver disease mice model. Cells and organisms rely on the Kelch-like ECH-associated protein 1- Nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) system as a critical defensive mechanism in response to oxidative stress. Therefore, Nrf2 plays an important role in ALD antioxidant responses, and its level is decreased by increased reactive oxidation stress (ROS) in the liver. ESF increased Nrf2, which was decreased in ethanol-damaged livers. Additionally, four polyphenol compounds were identified through a qualitative analysis of the ESF using LC-MS/MS. This study confirmed ESF's antioxidative and hangover-elimination effects and suggested the possibility of using Sophora flavescens Aiton (SF) to treat ALD.
Inflammatory bowel disease (IBD) is a chronic inflammatory condition caused by the disruption of the intestinal barrier. The intestinal barrier is maintained by tight junctions (TJs), which sustain intestinal homeostasis and prevent pathogens from entering the microbiome and mucosal tissues. Ziziphus jujuba Miller (Z. jujuba) is a natural substance that has been used in traditional medicine as a therapy for a variety of diseases. However, in IBD, the efficacy of Z. jujuba is unknown. Therefore, we evaluated ZJB in Caco2 cells and a dextran sodium sulfate (DSS)-induced mouse model to demonstrate its efficacy in IBD. Z. jujuba extracts were prepared using 70% ethanol and were named ZJB. ZJB was found to be non-cytotoxic and to have excellent antioxidant effects. We confirmed its anti-inflammatory properties via the down-regulation of inflammatory factors, including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). To evaluate the effects of ZJB on intestinal barrier function and TJ improvement, the trans-epithelial electrical resistance (TEER) and fluorescein isothiocyanate-dextran 4 kDa (FITC-Dextran 4) permeability were assessed. The TEER value increased by 61.389% and permeability decreased by 27.348% in the 200 µg/mL ZJB group compared with the 50 ng/mL IL-6 group after 24 h. Additionally, ZJB alleviated body weight loss, reduced the disease activity index (DAI) score, and induced colon shortening in 5% DSS-induced mice; inflammatory cytokines, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were down-regulated in the serum. TJ proteins, such as Zonula occludens (ZO)-1 and occludin, were up-regulated by ZJB in an impaired Caco2 mouse model. Additionally, according to the liquid chromatography results, in tandem with mass spectrometry (LC-MS/MS) analysis, seven active ingredients were detected in ZJB. In conclusion, ZJB down-regulated inflammatory factors, protected intestinal barrier function, and increased TJ proteins. It is thus a safe, natural substance with the potential to be used as a therapeutic agent in IBD treatment.
BACKGROUND: Psoriasis is an inflammatory skin disease characterized by the hyperproliferative epidermal keratinocytes and significant immune cells infiltration, leading to cytokines production such as IL-1ß, TNF-α, IL-23, and IL-17. Recent study highlights the critical role of IL-1ß in the induction and activation of pathogenic Th17 and IL-17-producing γδ T cells, contributing to psoriasis. However, the mechanism underlying IL-1ß dysregulation in psoriasis pathogenesis is unclear. Autophagy regulates IL-1ß production and has a pleiotropic effect on inflammatory disorders. Previous studies showed controversial role of autophagy in psoriasis pathogenesis, either pro-inflammatory in autophagy-deficient keratinocyte or anti-inflammatory in pharmacologically autophagy-promoting macrophages. Thus, the direct role of autophagy and its therapeutic potential in psoriasis remains unclear. METHODS: We used myeloid cell-specific autophagy-related gene 7 (Atg7)-deficient mice and determined the effect of autophagy deficiency in myeloid cells on neutrophilia and disease pathogenesis in an imiquimod-induced psoriasis mouse model. We then assessed the pathogenic mechanism focusing on immune cells producing IL-1ß and IL-17 along with gene expression profiles associated with psoriasis in mouse model and public database on patients. Moreover, therapeutic potential of IL-1ß blocking in such context was assessed. RESULTS: We found that autophagy deficiency in myeloid cells exacerbated neutrophilic inflammation and disease pathogenesis in mice with psoriasis. This autophagy-dependent effect was associated with a significant increase in IL-1ß production from myeloid cells, particularly macrophages, Cxcl2 expression, and IL-17 A producing T cells including γδ T cells. Supporting this, treatment with systemic IL-1 receptor blocking antibody or topical saccharin, a disaccharide suppressing pro-IL-1ß expression, led to the alleviation of neutrophilia and psoriatic skin inflammation linked to autophagy deficiency. The pathophysiological relevance of this finding was supported by dysregulation of autophagy-related genes and their correlation with Th17 cytokines in psoriatic skin lesion from patients with psoriasis. CONCLUSIONS: Our results suggest that autophagy dysfunction in myeloid cells, especially macrophages, along with IL-1ß dysregulation has a causal role in neutrophilic inflammation and psoriasis pathogenesis.
The mycelium of the plant pathogenic fungus Fusarium graminearum exhibits distinct structures for vegetative growth, asexual sporulation, sexual development, virulence, and chlamydospore formation. These structures are vital for the survival and pathogenicity of the fungus, necessitating precise regulation based on environmental cues. Initially identified in Magnaporthe oryzae, the transcription factor Con7p regulates conidiation and infection-related morphogenesis, but not vegetative growth. We characterized the Con7p ortholog FgCon7, and deletion of FgCON7 resulted in severe defects in conidium production, virulence, sexual development, and vegetative growth. The mycelia of the deletion mutant transformed into chlamydospore-like structures with high chitin level accumulation. Notably, boosting FgABAA expression partially alleviated developmental issues in the FgCON7 deletion mutant. Chromatin immunoprecipitation (ChIP)-quantitative PCR (qPCR) analysis confirmed a direct genetic link between FgABAA and FgCON7. Furthermore, the chitin synthase gene Fg6550 (FGSG_06550) showed significant upregulation in the FgCON7 deletion mutant, and altering FgCON7 expression affected cell wall integrity. Further research will focus on understanding the behavior of the chitin synthase gene and its regulation by FgCon7 in F. graminearum. This study contributes significantly to our understanding of the genetic pathways that regulate hyphal differentiation and conidiation in this plant pathogenic fungus. IMPORTANCE: The ascomycete fungus Fusarium graminearum is the primary cause of head blight disease in wheat and barley, as well as ear and stalk rot in maize. Given the importance of conidia and ascospores in the disease cycle of F. graminearum, precise spatiotemporal regulation of these biological processes is crucial. In this study, we characterized the Magnaporthe oryzae Con7p ortholog and discovered that FgCon7 significantly influences various crucial aspects of fungal development and pathogenicity. Notably, overexpression of FgABAA partially restored developmental defects in the FgCON7 deletion mutant. ChIP-qPCR analysis confirmed a direct genetic link between FgABAA and FgCON7. Furthermore, our research revealed a clear correlation between FgCon7 and chitin accumulation and the expression of chitin synthase genes. These findings offer valuable insights into the genetic mechanisms regulating conidiation and the significance of mycelial differentiation in this plant pathogenic fungus.
Fungal Proteins , Fusarium , Gene Expression Regulation, Fungal , Plant Diseases , Spores, Fungal , Transcription Factors , Fusarium/genetics , Fusarium/pathogenicity , Fusarium/growth & development , Spores, Fungal/genetics , Spores, Fungal/growth & development , Plant Diseases/microbiology , Fungal Proteins/genetics , Fungal Proteins/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Virulence , Chitin Synthase/genetics , Chitin Synthase/metabolism , Chitin/metabolism , Gene Deletion
Bacterial soft rot caused by Pectobacterium carotovorum subsp. carotovorum (Pcc) is one of the most severe diseases in radish cultivation. To control this plant disease, the most effective method has been known to cultivate resistant cultivars. Previously, we developed an efficient bioassay method for investigating resistance levels with 21 resistant and moderately resistant cultivars of radish against a strain Pcc KACC 10421. In this study, our research expanded to investigate the resistance of radish cultivars against six Pcc strains, KACC 10225, KACC 10421, ATCC 12312, ATCC 15713, LY34, and ECC 301365. To this end, the virulence of the six Pcc strains was determined based on the development of bacterial soft rot in seedlings of four susceptible radish cultivars. The results showed that the Pcc strains exhibited different virulence in the susceptible cultivars. To explore the race differentiation of Pcc strains corresponding to the resistance in radish cultivars, we investigated the occurrence of bacterial soft rot caused by the six Pcc strains on the 21 resistant and moderate resistant cultivars. Our results showed that the average values of the area under the disease progress curve were positively correlated with the virulence of the strains and the number of resistant cultivars decreased as the virulence of Pcc strains increased. Taken together, our results suggest that the resistance to Pcc of the radish cultivars commercialized in Korea is more likely affected by the virulence of Pcc strains rather than by race differentiation of Pcc.
As electronic devices for aviation, space, and satellite applications become more sophisticated, built-in energy storage devices also require a wider temperature spectrum. Herein, an all-climate operational, energy and power-dense, flexible, in-plane symmetric pseudocapacitor is demonstrated with utmost operational safety and long cycle life. The device is constructed with interdigital-patterned laser-scribed carbon-supported electrodeposited V5O12·6H2O as a binder-free electrode and a novel high-voltage anti-freezing water-in-salt-hybrid electrolyte. The anti-freezing electrolyte can operate over a wide temperature range of -40-60 °C while offering a stable potential window of ≈2.5 V. The device undergoes rigorous testing under diverse environmental conditions, including rapid and regular temperature and mechanical transition over multiple cycles. Additionally, detailed theoretical simulation studies are performed to understand the interfacial interactions with the active material as well as the local behavior of the anti-freeze electrolyte at different temperatures. As a result, the all-weather pseudocapacitor at 1 A g-1 shows a high areal capacitance of 234.7 mF cm-2 at room temperature and maintains a high capacitance of 129.8 mF cm-2 even at -40 °C. Besides, the cell operates very reliably for over 80 950 cycles with a capacitance of 25.7 mF cm-2 at 10 A g-1 and exhibits excellent flexibility and bendability under different stress conditions.
An Eosin Y-catalyzed visible light-promoted 1,4-peroxidation-sulfonylation of enynones was achieved to give tetrasubstituted allenes. The photoredox catalysis of Eosin Y allowed the concomitant formation of peroxy and sulfonyl radicals, where the preferential peroxy radical addition to the alkene moiety of enynones resulted in the subsequent α-keto radical-sulfonyl radical cross couplings. The developed photoredox catalysis of Eosin Y demonstrates a regioselective 1,4-diradical addition strategy, opening up a new possibility of diradical functionalization of conjugate systems.
The facile electron transfer catalysis of diaryl diselenides was utilized for the visible-light [4+2] homodimerization of decomposition-prone styrenes. The reaction required only 0.5 mol % TPT+BF4- photocatalyst and 1.5 mol % electron transfer catalyst (ArSe)2. The spontaneous electron transfer capability of diaryl diselenides was demonstrated for the first time, leading to the sequestration of redox-prone radical cation intermediates via electron transfer processes. A variety of polymerization-prone styrenes smoothly underwent the visible-light-promoted [4+2] homodimerization to tetralin derivatives.
Purpose: Notable effectiveness of trastuzumab deruxtecan (T-DXd) in patients with HER2-low advanced breast cancer (BC) has focused pathologists' attention. We studied the incidence and clinicopathologic characteristics of HER2-low BC, and the effects of immunohistochemistry (IHC) associated factors on HER2 IHC results. Materials and Methods: The Breast Pathology Study Group of the Korean Society of Pathologists conducted a nationwide study using real-world data on HER2 status generated between January 2022 and December 2022. Information on HER2 IHC protocols at each participating institution was also collected. Results: Total 11,416 patients from twenty-five institutions included in this study. Of these patients, 40.7% (range: 6.0%-76.3%) were classified as HER2-zero, 41.7% (range: 10.5%-69.1%) as HER2-low, and 17.5% (range: 6.7%-34.0%) as HER2-positive. HER2-low tumors were associated with positive ER and PR statuses (p<0.001 and p<0.001, respectively). Antigen retrieval times (≥ 36 min vs. < 36 min) and antibody incubation times (≥ 12 min vs. < 12 min) affected on the frequency of HER2 IHC 1+ BC at institutions using the PATHWAY HER2 (4B5) IHC assay and BenchMark XT or Ultra staining instruments. Furthermore, discordant results between core needle biopsy (CNB) and subsequent resection specimen HER2 statuses were observed in 24.1% (787/3259) of the patients. Conclusion: The overall incidence of HER2-low BC in South Korea concurs with those reported in previously published studies. Significant inter-institutional differences in HER2 IHC protocols were observed, and it may have impact on HER2-low status. Thus, we recommend standardizing HER2 IHC conditions to ensure precise patient selection for targeted therapy.
NADP/NADPH plays an indispensable role in cellular metabolism, serving as a pivotal cofactor in numerous enzymatic processes involved in anabolic pathways, antioxidant defense, and the biosynthesis of essential cellular components. NAD/NADH kinases (NADKs) phosphorylate NAD/NADH, constituting the sole de novo synthetic pathway for NADP/NADPH generation. Despite the pivotal role of NADP/NADPH in cellular functions, the physiological role of NADK remains largely unexplored in filamentous fungi. In this study, we identified three putative NADKs in Fusarium graminearum-FgNadk1, FgNadk2, and FgNadk3-responsible for NAD/NADH phosphorylation. NADK-mediated formation of intracellular NADPH proved crucial for vegetative growth, sexual reproduction, and virulence. Specifically, FgNadk2, the mitochondrial NADK, played a role in oxidative stress resistance and the maintenance of mitochondrial reactive oxygen species levels. Moreover, the deletion of FgNADK2 resulted in arginine auxotrophy, contributing to the reduced fungal virulence. These findings underscore the necessity of mitochondrial NADK in fungal virulence in F. graminearum, revealing its involvement in mitochondrial redox homeostasis and the arginine biosynthetic pathway. This study provides critical insights into the interconnectedness of metabolic pathways essential for fungal growth, stress response, and pathogenicity.
Fusarium , NAD , Virulence , NAD/metabolism , NADP/metabolism , Oxidative Stress , Oxidation-Reduction , Fungal Proteins/genetics , Fungal Proteins/metabolism
Randomized controlled trials (RCTs) and real-world evidence (RWE) studies are crucial and complementary in generating clinical evidence. RCTs provide controlled settings to validate the clinical effect of specific drugs or medical devices, while RWE integrates extrinsic factors, encompassing external influences affecting real-world scenarios, thus challenging RCT results in practical applications. In this study, we explore the impact of extrinsic factors on RWE outcomes, focusing on "dark data," which refers to data collected but not used or excluded from the analyses. Dark data can arise in many ways during research process, from selecting study samples to data collection and analysis. However, even unused or unanalyzed dark data hold potential insights, providing a comprehensive view of clinical contexts. Extrinsic factors lead to divergent RWE outcomes that could differ from RCTs beyond statistical correction's scope. Two main types of dark data exist: "known-unknown" and "unknown-unknown." The distinction between these dark data types highlights RWE's complexity. The transformation of unknown into known depends on data literacy-powerful utilization capabilities that can be interpreted based on medical expertise. Shifting the focus to excluded subjects or unused data in real-world contexts reveals unexplored potential. Understanding the significance of dark data is vital in reflecting the complexity of clinical settings. Connecting RCTs and RWEs requires medical data literacy, enabling clinicians to decipher meaningful insights. In the big data and artificial intelligence era, medical staff must navigate data complexities while promoting the core role of medicine. Prepared clinicians will lead this transformative journey, ensuring data value shapes the medical landscape.
Biomedical Research , Literacy , Humans , Data Collection
Hepatocellular carcinoma (HCC) stands as a leading cause of mortality, and despite recent advancements in the overall survival rates, the prognosis remains dismal. Prunetin 4-O-glucoside (Prunetrin or PUR), an active compound derived from Prunus sp., was explored for its impact on HepG2 and Huh7 cells. The cytotoxicity assessment revealed a notable reduction in cell viability in both cell lines, while exhibiting non-toxicity towards HaCaT cells. Colony formation studies underscored PUR's inhibitory effect on cell proliferation, dose-dependently. Mechanistically, PUR downregulated cell cycle proteins (CDC25c, Cdk1/CDC2, and Cyclin B1), inducing G2/M phase arrest, corroborated by flow cytometry. Western blot analyses exhibited dose-dependent cleavages of PARP and caspase 3, indicative of apoptosis. Treatment with the apoptotic inhibitor z-vmd-fmk provided evidence of PUR-induced apoptosis. Annexin V and PI flow cytometry further affirmed apoptotic induction. Enhanced expression of cleaved-caspase 9 and the pro-apoptotic protein Bak, coupled with reduced anti-apoptotic Bcl-xL, and affirmed PUR's induction of intrinsic apoptosis. Additionally, PUR activated the MAPK pathway, evidenced by elevated phospho p38 and phospho ERK expressions in both cell lines. Notably, a concentration-dependent decrease in mTOR and Akt expressions indicated PUR's inhibition of the Akt/mTOR pathway in HepG2 and Huh7 cells. These findings illuminate PUR's multifaceted impact, revealing its potential as a promising therapeutic agent against HepG2 and Huh7 cells through modulation of cell cycle, apoptosis, and key signaling pathways.
Apoptosis , Carcinoma, Hepatocellular , G2 Phase Cell Cycle Checkpoints , Liver Neoplasms , Proto-Oncogene Proteins c-akt , Humans , Apoptosis/drug effects , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , G2 Phase Cell Cycle Checkpoints/drug effects , Hep G2 Cells , Liver Neoplasms/pathology , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , MAP Kinase Signaling System/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/drug effects , TOR Serine-Threonine Kinases/metabolism , Isoflavones/pharmacology , Cell Cycle Checkpoints/drug effects
All-solid-state lithium-sulfur batteries (ASSLSBs) have advantageous features, such as high energy, low costs, enhanced safety, and no polysulfide dissolution. However, the use of sulfur as an active material in all-solid-state batteries is difficult because of its ionic and electrical insulating properties. Herein, we introduce a flower-shaped composite material consisting of MoS2 nanoparticles and sulfur, designed to establish interconnected ionic and electrical conduction pathways at the cathode. As a host material, MoS2 nanoparticles with a large specific surface area can coconduct Li ions and electrons, possessing the potential for effectively utilizing sulfur. However, MoS2 nanoparticles are prone to physical-electrochemical isolation by being surrounded by sulfur due to their crumpling property in the process of mixing and impregnation with sulfur. This problem is addressed by mildly milling the MoS2 nanoparticles and sulfur, after which melt diffusion is applied to generate uniform MoS2/sulfur composite materials to establish an interconnected conducting pathway within the composite. A sulfide solid electrolyte (Li6PS5Cl)-based ASSLSB incorporating the proposed MoS2/sulfur composite demonstrates a stable operation over 1000 cycles with a Coulombic efficiency of nearly 100%. This study emphasizes the significance of the structural design of the sulfur composite material on top of the intrinsic properties of the material for high-performance ASSLSBs.
The directional antenna combined with beamforming is one of the attractive solutions to accommodate high data rate applications in 5G vehicle communications. However, the directional nature of beamforming requires beam alignment between the transmitter and the receiver, which incurs significant signaling overhead. Hence, we need to find the optimal parameters for directional beamforming, i.e., the antenna beamwidth and beam alignment interval, that maximize the throughput, taking the beam alignment overhead into consideration. In this paper, we propose a reinforcement learning (RL)-based beamforming scheme in a vehicle-to-infrastructure system, where we jointly determine the antenna beamwidth and the beam alignment interval, taking into account the past and future rewards. The simulation results show that the proposed RL-based joint beamforming scheme outperforms conventional beamforming schemes in terms of the average throughput and the average link stability ratio.
