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Developing cost-effective and high-performance electrocatalysts for oxygen reduction reaction (ORR) is critical for clean energy generation. Here, we propose an approach to the synthesis of iron phthalocyanine nanotubes (FePc NTs) as a highly active and selective electrocatalyst for ORR. The performance is significantly superior to FePc in randomly aggregated and molecularly dispersed states, as well as the commercial Pt/C catalyst. When FePc NTs are anchored on graphene, the resulting architecture shifts the ORR potentials above the redox potentials of Fe2+/3+ sites. This does not obey the redox-mediated mechanism operative on conventional FePc with a Fe2+-N moiety serving as the active sites. Pourbaix analysis shows that the redox of Fe2+/3+ sites couples with HO- ions transfer, forming a HO-Fe3+-N moiety serving as the ORR active sites under the turnover condition. The chemisorption of ORR intermediates is appropriately weakened on the HO-Fe3+-N moiety compared to the Fe2+-N state and thus is intrinsically more ORR active.
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Recent advances in spatial transcriptomics (ST) have enabled comprehensive profiling of gene expression with spatial information in the context of the tissue microenvironment. However, with the improvements in the resolution and scale of ST data, deciphering spatial domains precisely while ensuring efficiency and scalability is still challenging. Here, we develop SGCAST, an efficient auto-encoder framework to identify spatial domains. SGCAST adopts a symmetric graph convolutional auto-encoder to learn aggregated latent embeddings via integrating the gene expression similarity and the proximity of the spatial spots. This framework in SGCAST enables a mini-batch training strategy, which makes SGCAST memory-efficient and scalable to high-resolution spatial transcriptomic data with a large number of spots. SGCAST improves the overall accuracy of spatial domain identification on benchmarking data. We also validated the performance of SGCAST on ST datasets at various scales across multiple platforms. Our study illustrates the superior capacity of SGCAST on analyzing spatial transcriptomic data.
Subject(s)
Gene Expression Profiling , Transcriptome , Benchmarking , LearningABSTRACT
BACKGROUND & AIMS: The progression of metabolic dysfunction-associated steatotic liver disease (MASLD) has been found to manifest in a series of hepatic and extrahepatic complications. A comprehensive meta-analysis of the longitudinal outcomes associated with MASLD has yet to be conducted. METHODS: To investigate the longitudinal outcomes associated with MASLD, Medline and Embase databases were searched to identify original studies that evaluated the longitudinal risks of incident clinical outcomes among MASLD patients compared with non-MASLD individuals. DerSimonian Laird random-effects meta-analysis was performed. Pooled effect estimates were calculated, and heterogeneity among studies was evaluated. RESULTS: One hundred twenty-nine studies were included in the meta-analysis. Meta-analysis revealed a significant increase in the risk of cardiovascular outcomes (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.27-1.60; P < .01), various metabolic outcomes such as incident hypertension (HR, 1.75; 95% CI, 1.46-2.08; P < .01), diabetes (HR, 2.56; 95% CI, 2.10-3.13; P < .01), pre-diabetes (HR, 1.69; 95% CI, 1.22-2.35; P < .01), metabolic syndrome (HR, 2.57; 95% CI, 1.13-5.85; P = .02), chronic kidney disease (HR, 1.38; 95% CI, 1.27-1.50; P < .01), as well as all cancers (HR, 1.54; 95% CI, 1.35-1.76; P < .01) among MASLD patients compared with non-MASLD individuals. By subgroup analysis, MASLD patients with advanced liver disease (HR, 3.60; 95% CI, 2.10-6.18; P < .01) were also found to be associated with a significantly greater risk (P = .02) of incident diabetes than those with less severe MASLD (HR, 1.63; 95% CI, 1.0-2.45; P = .02) when compared with non-MASLD. CONCLUSIONS: The present study emphasizes the association between MASLD and its clinical outcomes including cardiovascular, metabolic, oncologic, and other outcomes. The multisystemic nature of MASLD found in this analysis requires treatment targets to reduce systemic events and end organ complications.
Subject(s)
Diabetes Mellitus , Fatty Liver , Metabolic Syndrome , Humans , Fatty Liver/complications , Fatty Liver/epidemiology , Metabolic Syndrome/complications , Metabolic Syndrome/epidemiology , Cardio-OncologyABSTRACT
INTRODUCTION: An optimal follow-up schedule for small (≤3-cm) hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) remains unclear in clinical guidelines. We aimed to assess the cost-effectiveness of follow-up strategies in patients with small HCC after RFA. METHODS: In total, 11,243 patients were collected from global institutions to calculate recurrence rates. Subsequently, a Markov model covering a 10-year period was developed to compare 25 surveillance strategies involving different surveillance techniques (computed tomography [CT], magnetic resonance imaging or ultrasonography [US], and α-fetoprotein [AFP]) and intervals (3 or 6 months). The study endpoint was incremental cost-effectiveness ratio (ICER), which represented additional cost per incremental quality-adjusted life year. Sensitivity analysis was conducted by varying the values of input parameters to observe the ICER. RESULTS: In a base case analysis, the dominant strategy was CT every 3 months during an initial 2 years, followed by semiannual CT, and then switch to biannual the combination of US screening and AFP testing after 5 years (m3_CT-m6_CT-m6_USAFP), with an ICER of $68,570.92 compared with the "not followed" strategy. One-way sensitivity analysis showed the ICER consistently remained below the willingness-to-pay threshold of $100,000.00. In a probabilistic sensitivity analysis, m3_CT-m6_CT-m6_USAFP was the most cost-effective approach in 95.6% of simulated scenarios at a willingness-to-pay threshold. DISCUSSION: For small HCC after RFA, the recommended follow-up strategy is CT, with scans scheduled every 3 months for the first 2 years, every 6 months thereafter, and transition to biannual the combination of US screening and AFP testing after 5 years.
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Atherosclerosis is the primary cause of cardiovascular events such as heart attacks and strokes. However, current medical practice lacks non-invasive, reliable approaches for both imaging atherosclerotic plaques and delivering therapeutic agents directly therein. Here, a biocompatible and biodegradable pH-responsive nanoscale coordination polymers (NCPs) based theranostic system is reported for managing atherosclerosis. NCPs are synthesized with a pH-responsive benzoic-imine (BI) linker and Gd3+. Simvastatin (ST), a statin not used for lowering blood cholesterol but known for its anti-inflammatory and antioxidant effects in mice, is chosen as the model drug. By incorporating ST into the hydrophobic domain of a lipid bilayer shell on NCPs surfaces, ST/NCP-PEG nanoparticles are created that are designed for dual purposes: they diagnose and treat atherosclerosis. When administered intravenously, they target atherosclerotic plaques, breaking down in the mild acidic microenvironment of the plaque to release ST, which reduces inflammation and oxidative stress, and Gd-complexes for MR imaging of the plaques. ST/NCP-PEG nanoparticles show efficacy in slowing the progression of atherosclerosis in live models and allow for simultaneous in vivo monitoring without observed toxicity in major organs. This positions ST/NCP-PEG nanoparticles as a promising strategy for the spontaneous diagnosis and treatment of atherosclerosis.
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Inflammatory bowel disease (IBD) is characterized by recurrent inflammatory reactions in the intestinal mucosa, including ulcerative colitis (UC) and Crohn's disease (CD). The expression of Toll-like receptor 2 (TLR2) has been observed to increase during the progression of IBD. Flavokawain B (FKB), a natural chalcone with potent anti-inflammatory activity, exerts its effects through inhibition of the NF-κB pathway. In this study, we aimed to investigate the effects and mechanisms of FKB targeting TLR2 in IBD. C57BL/6 J mice were treated with 2.5% dextran sulfate sodium (DSS) for 7 days, with administration of FKB or TLR2 inhibitor C29 starting on day 2 to establish the model of IBD. In vitro, bone marrow-derived macrophages (BMDMs) were stimulated with the TLR2 agonist Pam3CSK4 to explore the therapeutic effect of FKB and its pharmacological mechanism. Compared with the model group, the FKB-treated group showed significant reductions in colitis-related injuries in the IBD mouse model, including weight gain, increased colon length and reduced inflammation. FKB decreased the formation of TLR2-MyD88 complex by targeting TLR2, leading to suppression of downstream NF-κB signaling pathway. Similar therapeutic effects were observed in the C29-treated group. Additionally, in vitro data suggested that FKB exerted its anti-inflammatory effect by targeting TLR2 and inhibiting Pam3CSK4-induced activation of the NF-κB pathway. The anti-inflammatory effects of FKB were demonstrated through drug affinity responsive target stability assay and cellular thermal shift assay, revealing its binding affinity to TLR2. By inhibiting the activation of the TLR2/NF-κB signaling pathway, FKB effectively prevented DSS-induced IBD and exhibited promising potential as a therapeutic candidate for IBD treatment.
Subject(s)
Mice, Inbred C57BL , NF-kappa B , Signal Transduction , Toll-Like Receptor 2 , Animals , Toll-Like Receptor 2/metabolism , NF-kappa B/metabolism , Signal Transduction/drug effects , Mice , Male , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/chemically induced , Flavonoids/pharmacology , Dextran Sulfate/toxicity , Anti-Inflammatory Agents/pharmacology , Disease Models, Animal , Colon/drug effects , Colon/pathology , Colon/metabolism , Myeloid Differentiation Factor 88/metabolism , Macrophages/drug effects , Macrophages/metabolismABSTRACT
AIM: Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are at increased risk of incident cardiovascular disease. However, the clinical characteristics and prognostic importance of MASLD in patients presenting with acute myocardial infarction (AMI) have yet to be examined. METHODS: This study compared the characteristics and outcomes of patients with and without MASLD presenting with AMI at a tertiary centre in Singapore. MASLD was defined as hepatic steatosis, with at least one of five metabolic criteria. Hepatic steatosis was determined using the Hepatic Steatosis Index. Propensity score matching was performed to adjust for age and sex. The Kaplan-Meier curve was constructed for long-term all-cause mortality. Cox regression analysis was used to investigate independent predictors of long-term all-cause mortality. RESULTS: In this study of 4446 patients with AMI, 2223 patients with MASLD were matched with patients without MASLD using propensity scores. The mean follow-up duration was 3.4 ± 2.4 years. The MASLD group had higher rates of obesity, diabetes and chronic kidney disease than their counterparts. Patients with MASLD had early excess all-cause mortality (6.8% vs. 3.6%, p < .001) at 30 days, with unfavourable mortality rates sustained in the long-term (18.3% vs. 14.5%, p = .001) compared with those without MASLD. After adjustment, MASLD remained independently associated with higher long-term all-cause mortality (hazard ratio 1.330, 95% confidence interval 1.106-1.598, p = .002). CONCLUSION: MASLD embodies a higher burden of metabolic dysfunction and is an independent predictor of long-term mortality in the AMI population. Its early identification may be beneficial for risk stratification and provide therapeutic targets for secondary preventive strategies in AMI.
Subject(s)
Myocardial Infarction , Propensity Score , Humans , Male , Female , Myocardial Infarction/mortality , Myocardial Infarction/complications , Myocardial Infarction/epidemiology , Middle Aged , Prognosis , Aged , Singapore/epidemiology , Fatty Liver/complications , Fatty Liver/mortality , Risk Factors , Retrospective StudiesABSTRACT
AIM: The study was conducted to evaluate the feasibility and safety profile of hepatic arterial infusion chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin (HAIC-FOLFOX) as an alternative therapeutic choice for patients with advanced hepatocellular carcinoma (HCC) that is refractory to systemic treatment including immune checkpoint blockades or molecular targeting agents. METHODS: Two hundred and forty five consecutive patients with advanced HCC who received HAIC-FOLFOX treatment after systemic treatment failure were retrospectively reviewed in six institutions and their survival, tumor response, and tolerance were assessed. RESULTS: The median overall survival (OS) and progression-free survival of the 209 included participants were 10.5 months (95% confidence interval [CI], 8.1-12.9) and 6.0 months (95% CI, 5.1-6.9), respectively. According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, the objective response rate was 21.1%, and the disease control rate was 64.6%. Multivariate analysis of risk factors of OS were albumin-bilirubin grade (2 and 3 vs. 1, hazard ratio [HR] 1.57; 95% CI, 1.05-2.34; p = 0.028), tumor number (>3 vs. 1-3, HR 2.18; 95% CI, 1.10-4.34; p = 0.026), extrahepatic spread (present vs. absent, HR 1.61, 95% CI, 1.06-2.45; p = 0.027), synchronous systemic treatment (present vs. absent, HR 0.55, 95% CI, 0.37-0.83; p = 0.004) and treatment response (responder vs. nonresponder, HR 0.30, 95% CI, 0.17-0.53; p < 0.001). Grade 3-4 adverse events (AEs) occurred in 59 (28.2%) HCC patients. All AEs were manageable, and deaths related to hepatic artery infusion chemotherapy treatment were not observed. CONCLUSIONS: Our findings support the effectiveness and safety of HAIC-FOLFOX treatment for patients with advanced HCC who have failed systemic treatment.
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Non-alcoholic fatty liver disease (NAFLD) is a progressive disease that can further evolve towards liver fibrosis and hepatocellular carcinoma in the end stage. Costunolide (Cos) is a natural sesquiterpene lactone that exhibits both anti-inflammatory and antioxidant properties. However, the therapeutic effect of Cos on NAFLD is not clear. In this study, we explored the potential protective effect and mechanism of Cos on NAFLD. C57BL/6 mice were fed with high-fat diet (HFD) to induce NAFLD. Cos was administered by gavage to observe the effect of Cos on NAFLD. We demonstrated that oral administration of Cos reduced HFD-induced hepatic fibrosis and the release of inflammatory cytokines, limiting the generation of reactive oxygen species. In vitro experiments revealed that pretreatment with Cos significantly decreased PA-induced production of inflammatory cytokines and fibrosis in AML-12 cells. Mechanism study showed that the effect of Cos was correlated to the induction of Nrf-2 and inhibition of NF-κB pathways. Collectively, these findings indicated that Cos exerts hepatoprotective effect against NAFLD through blocking inflammation and oxidative stress. Our study suggested that Cos might be an effective pharmacotherapy for the treatment of NAFLD.
Subject(s)
Liver Neoplasms , Non-alcoholic Fatty Liver Disease , Sesquiterpenes , Mice , Animals , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/drug therapy , Diet, High-Fat/adverse effects , Oxidative Stress , Inflammation/drug therapy , Sesquiterpenes/pharmacology , Sesquiterpenes/therapeutic use , Cytokines , Liver CirrhosisABSTRACT
Hyperglycaemia-induced myocardial injury promotes the induction of heart failure in diabetic patients. Impaired antioxidant capability and sustained chronic inflammation play a vital role in the progression of diabetic cardiomyopathy (DCM). Costunolide (Cos), a natural compound with anti-inflammatory and antioxidant properties, has exhibited therapeutic effects in various inflammatory diseases. However, the role of Cos in diabetes-induced myocardial injury remains poorly understood. In this study, we investigated the effect of Cos on DCM and explored the potential mechanisms. C57BL/6 mice were administered intraperitoneal streptozotocin for DCM induction. Cos-mediated anti-inflammatory and antioxidation activities were examined in heart tissues of diabetic mice and high glucose (HG)-stimulated cardiomyocytes. Cos markedly inhibited HG-induced fibrotic responses in diabetic mice and H9c2 cells, respectively. The cardioprotective effects of Cos could be correlated to the reduced expression of inflammatory cytokines and decreased oxidative stress. Further investigations demonstrated Cos reversed diabetes-induced nuclear factor-κB (NF-κB) activation and alleviated impaired antioxidant defence system, principally via activation of nuclear factor-erythroid 2 p45-related factor-2 (Nrf-2). Cos alleviated cardiac damage and improved cardiac function in diabetic mice by inhibiting NF-κB-mediated inflammatory responses and activating the Nrf-2-mediated antioxidant effects. Therefore, Cos could be a potential candidate for the treatment of DCM.
Subject(s)
Diabetes Mellitus, Experimental , Diabetic Cardiomyopathies , Hyperglycemia , Mice , Animals , Diabetic Cardiomyopathies/metabolism , Antioxidants/pharmacology , Hyperglycemia/metabolism , NF-kappa B/metabolism , Diabetes Mellitus, Experimental/metabolism , Signal Transduction , Mice, Inbred C57BL , Oxidative Stress , Myocytes, Cardiac/metabolism , Anti-Inflammatory Agents/pharmacologyABSTRACT
BACKGROUND: Metabolic associated fatty liver disease (MAFLD) was recently proposed as an alternative name change for better encapsulation of disease. However, there exists a spectrum of MAFLD where both metabolically healthy (MH) and metabolically unhealthy (MU) individuals are included. In view of limited evidence, we sought to examine the prevalence, clinical characteristics, and differences in outcomes of MH-MAFLD at the population level. METHODS: Data were used from the United States National Health and Nutrition Examination Survey 1999 to 2018. Multivariate logistic regression analysis was used to obtain odds ratios for the estimation of events. Survival analysis was conducted with Cox regression and the Fine-Gray subdistribution model. RESULTS: There were 32,683 overweight and obese individuals included in the analysis. In MAFLD patients, the prevalence of MH-MAFLD was 6.92% (95% confidence interval [CI], 6.58%-7.27%), and 93.08% (95% CI, 92.73%-93.42%) were considered as MU-MAFLD. Multivariate analysis found a significantly higher risk of MACE (odds ratio, 1.38; 95% CI, 1.28-1.49; P < .01), all-cause (hazard ratio, 1.24; 95% CI, 1.17-1.32; P < .01), cardiovascular disease (SHR, 1.20; 95% CI, 1.02-1.42; P = .03), and cancer mortality (SHR, 1.24; 95% CI, 1.07-1.44; P < .01) in MU-MAFLD relative to non-MAFLD. However, MH-MAFLD individuals were not associated with a statistically significant increased risk of these adverse outcomes compared with non-MAFLD. MU-MAFLD diabetics were also at a higher risk of adverse events compared with non-diabetics. CONCLUSIONS: This study reports on the heterogeneity and spectrum of metabolic dysfunction that exists in overweight and obese MAFLD. Although MAFLD may potentially be advantageous in improving awareness and patient outcomes, there remains substantial heterogeneity within patients included in MAFLD on the basis of the underlying metabolic burden.
Subject(s)
Cardiovascular Diseases , Non-alcoholic Fatty Liver Disease , Humans , Overweight/complications , Overweight/epidemiology , Nutrition Surveys , Obesity/complications , Obesity/epidemiology , Health StatusABSTRACT
BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is traditionally associated with obesity. However, there is a subtype of NAFLD, namely NAFLD in lean, that occurs without obesity. However, a recent call to redefine NAFLD to metabolic-associated fatty liver disease focuses on obesity and metabolic dysfunction. Criticism has arisen from the perceived over emphasis on systemic comorbidities, which may disadvantage the lean. The current analysis seeks to quantify the degree of metabolic dysfunction in NAFLD in lean and compare with NAFLD in overweight and obese and non-NAFLD. METHODS: Medline and Embase databases were searched from inception to March 3, 2022. The inclusion criteria were articles with NAFLD in lean patients presenting with baseline metabolic parameters. Comparisons were conducted with subgroup analysis. RESULTS: Eighty-five articles were included in the meta-analysis. NAFLD in lean accounted for 13.11% (95% confidence interval [CI], 10.26%-16.62%) of the global population and 14.55% (95% CI, 11.32%-18.51%) in Asia. The degree of metabolic dysfunction was weight dependent with significantly less metabolic dysfunction in NAFLD in lean subjects as compared with NAFLD in overweight counterparts. For NAFLD in lean, only 19.56% (95% CI, 15.28%-24.69%) of the subjects were diabetic, whereas 45.70% (95% CI, 35.01%-56.80%) of obese subjects with NAFLD had diabetes (P < .01). Fasting blood glucose and systolic and diastolic blood pressure values were significantly lower in subjects with NAFLD in lean than in overweight and obese. CONCLUSION: The current analysis highlights the weight-dependent nature of metabolic dysfunction in NAFLD. Lean subjects with NAFLD were significantly less metabolically unhealthy than were obese and overweight persons with NAFLD. An overreliance on metabolic dysfunction in defining fatty liver will be a flaw in potentially excluding previously characterized NAFLD.
Subject(s)
Diabetes Mellitus , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/epidemiology , Overweight/complications , Overweight/epidemiology , Obesity/complications , Obesity/epidemiology , Diabetes Mellitus/epidemiology , ComorbidityABSTRACT
BACKGROUND: Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease which ultimately results in heart failure (HF). Decades of research on DCM have revealed diverse aetiologies. Among them, familial DCM is the major form of DCM, with pathogenic variants in LMNA being the second most common form of autosomal dominant DCM. LMNA DCM is a multifactorial and complex disease with no specific treatment thus far. Many studies have demonstrated that perturbing candidates related to various dysregulated pathways ameliorate LMNA DCM. However, it is unknown whether these candidates could serve as potential therapeutic targets especially in long term efficacy. METHODS: We evaluated 14 potential candidates including Lmna gene products (Lamin A and Lamin C), key signaling pathways (Tgfß/Smad, mTor and Fgf/Mapk), calcium handling, proliferation regulators and modifiers of LINC complex function in a cardiac specific Lmna DCM model. Positive candidates for improved cardiac function were further assessed by survival analysis. Suppressive roles and mechanisms of these candidates in ameliorating Lmna DCM were dissected by comparing marker gene expression, Tgfß signaling pathway activation, fibrosis, inflammation, proliferation and DNA damage. Furthermore, transcriptome profiling compared the differences between Lamin A and Lamin C treatment. RESULTS: Cardiac function was restored by several positive candidates (Smad3, Yy1, Bmp7, Ctgf, aYAP1, Sun1, Lamin A, and Lamin C), which significantly correlated with suppression of HF/fibrosis marker expression and cardiac fibrosis in Lmna DCM. Lamin C or Sun1 shRNA administration achieved consistent, prolonged survival which highly correlated with reduced heart inflammation and DNA damage. Importantly, Lamin A treatment improved but could not reproduce long term survival, and Lamin A administration to healthy hearts itself induced DCM. Mechanistically, we identified this lapse as caused by a dose-dependent toxicity of Lamin A, which was independent from its maturation. CONCLUSIONS: In vivo candidate evaluation revealed that supplementation of Lamin C or knockdown of Sun1 significantly suppressed Lmna DCM and achieve prolonged survival. Conversely, Lamin A supplementation did not rescue long term survival and may impart detrimental cardiotoxicity risk. This study highlights a potential of advancing Lamin C and Sun1 as therapeutic targets for the treatment of LMNA DCM.
Subject(s)
Cardiomyopathies , Cardiomyopathy, Dilated , Humans , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/pathology , Lamin Type A/genetics , Lamin Type A/metabolism , Fibrosis , Inflammation/complications , Transforming Growth Factor beta , MutationABSTRACT
Self-assembled photonic structures have greatly expanded the paradigm of optical materials due to their ease of access, the richness of results offered and the strong interaction with light. Among them, photonic heterostructure shows unprecedent advances in exploring novel optical responses that only can be realized by interfaces or multiple components. In this work, we realize visible and infrared dual-band anti-counterfeiting using metamaterial (MM) - photonic crystal (PhC) heterostructures for the first time. Sedimentation of TiO2 nanoparticles in horizontal mode and polystyrene (PS) microspheres in vertical mode self-assembles a van der Waals interface, connecting TiO2 MM to PS PhC. Difference of characteristic length scales between two components support photonic bandgap engineering in the visible band, and creates a concrete interface at mid-infrared to prevent interference. Consequently, the encoded TiO2 MM is hidden by structurally colored PS PhC and visualized either by adding refractive index matching liquid or by thermal imaging. The well-defined compatibility of optical modes and facility in interface treatments further paves the way for multifunctional photonic heterostructures.
ABSTRACT
Hepatocellular carcinoma (HCC) is one of the most common cancers, with high mortality. Chemotherapy is one of the main treatment options for HCC. However, the high toxicity and poor specificity of chemotherapeutic drugs have limited their clinical application. In this study, dual-ligand liposomes modified with glycyrrhetinic acid (GA) and cyclic arginine-glycine-aspartic acid (cRGD) (GA/cRGD-LP) were designed to target the GA receptor and αvß3 integrin, respectively. The aim was to develop a highly selective targeted drug delivery system and further enhance the antitumor efficiency of drugs by targeting both hepatic tumor cells and vasculature. A novel lipid conjugate (mGA-DOPE) by coupling dioleoylphosphatidyl ethanolamine (DOPE) with methyl glycyrrhetinic acid (mGA) was synthesized, and its structure was confirmed. The targeting efficiency of GA/cRGD-LP by in vitro cellular uptake and ex vivo imaging was assessed. GA- and cRGD-modified doxorubicin-loaded liposomes (GA/cRGD-LP-DOX) were prepared, and their cytotoxicity in HepG2 and antitumor activity were evaluated. The results showed that the average particle size of the GA/cRGD-LP-DOX was 114 ± 4.3 nm, and the zeta potential was -32.9 ± 2.0 mV. The transmission electron microscopy images showed that the shapes of our liposomes were spherical. cGA/cRGD-LP-DOX displayed an excellent cellular uptake in both HepG2 and human umbilical vein endothelial cells. In the in vivo study, pharmacokinetic parameters indicated that cGA/cRGD-LP can prolong the circulation time of DOX in the blood. GA/cRGD-LP-DOX showed greater inhibition of tumor growth for HepG2-bearing mice than either the single-ligand-modified liposomes or nontargeted liposomes. GA/cRGD-LP-DOX displayed higher liver tumor localization than that of single-ligand-modified liposomes or free DOX. GA/cRGD-LP is a promising drug delivery system for liver cancer targeting and therapy and is worthy of further study.
Subject(s)
Carcinoma, Hepatocellular , Glycyrrhetinic Acid , Liver Neoplasms , Humans , Mice , Animals , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Liposomes/chemistry , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Ligands , Glycyrrhetinic Acid/chemistry , Endothelial Cells , Doxorubicin , Cell Line, TumorABSTRACT
The continuous advancements in studying two-dimensional (2D) materials pave the way for groundbreaking innovations across various industries. In this study, by employing density functional theory calculations, we comprehensively elucidate the electronic structures of MZX (M = Ga and In; Z = Si, Ge, and Sn; X = S, Se, and Te) monolayers for their applications in photocatalytic, thermoelectric, and spintronic fields. Interestingly, GaSiS, GaSiSe, InSiS, and InSiSe monolayers are identified to be efficient photocatalysts for overall water splitting with band gaps close to 2.0 eV, suitable band edge positions, and excellent optical harvest ability. In addition, the InSiTe monolayer exhibits a ZT value of 1.87 at 700 K, making it highly appealing for applications in thermoelectric devices. It is further highlighted that GaSnTe, InSnS, and InSnSe monolayers are predicted to be 2D topological insulators (TIs) with bulk band gaps of 115, 54, and 152 meV, respectively. Current research expands the family of 2D GaGeTe materials and establishes a path toward the practical utilization of MZX monolayers in energy conversion and spintronic devices.
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Dietary modifications can help prevent many cardiovascular disease (CVD) events. Endothelial progenitor cells (EPCs) actively contribute to cardiovascular system maintenance and could function as surrogate markers for evaluating improvement in cardiovascular health resulting from nutritional interventions. This review summarizes the latest research progress on the impact of food and nutrients on EPCs, drawing on evidence from human, animal, and in vitro studies. Additionally, current trends and challenges faced in the field are highlighted. Findings from studies examining cells as EPCs are generally consistent, demonstrating that a healthy diet, such as the Mediterranean diet or a supervised diet for overweight people, specific foods like olive oil, fruit, vegetables, red wine, tea, chia, and nutraceuticals, and certain nutrients such as polyphenols, unsaturated fats, inorganic nitrate, and vitamins, generally promote higher EPC numbers and enhanced EPC function. Conversely, an unhealthy diet, such as one high in sugar substitutes, salt, or fructose, impairs EPC function. Research on outgrowth EPCs has revealed that various pathways are involved in the modulation effects of food and nutrients. The potential of EPCs as a biomarker for assessing the effectiveness of nutritional interventions in preventing CVDs is immense, while further clarification on definition and characterization of EPCs is required.
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Oxygen vacancy (VO) defects play an essential role in governing the conductivity of semiconductor materials. The direction-dependency of oxygen vacancy conductive filament (CF) formation and VO migration behaviors in HfO2-based resistive random access memory (RRAM) were systematically investigated through first-principles calculations. The energetic and electronic structural analyses indicate that the continuous distribution of 3-fold oxygen vacancy (VO3) or 4-fold oxygen vacancy (VO4) is more favorable for the CF formation along [010] and [001] directions, and a continuous distribution between VO3 and VO4 in the m-HfO2 system can also combine to promote the formation of CFs along a particular direction. Furthermore, the high annealing temperature and low oxygen partial pressure (PO2) could effectively reduce the VO formation energy and promote the formation of CFs, resulting in a lower applied voltage of the devices. Our results indicate that q = 0 and q = +2 are the most probable charge states for VO3 and VO4 in m-HfO2. Subsequently, it is found that the low activation energy of VO originates from the +2q charged VO3 or VO4 migrating in the CFs along a particular crystallographic [001] direction. The diffusion coefficient (D) of the oxygen atom along the [001] direction is much higher than that of all the other possible pathways considered, due to the lower energy barrier. This demonstrates that the growth of CFs is potentially direction-dependent, and that a lower forming voltage and lower SET voltage are required when the CFs are grown along a particular direction in RRAM devices. The present work would help to provide a fundamental guide and new understanding for the development and application of HfO2-based RRAM.
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Developing transition metal dichalcogenides as electrocatalysts has attracted great interest due to their tunable electronic properties and good thermal stabilities. Herein, we propose a PdTe2 bilayer as a promising electrocatalyst candidate towards the oxygen reduction reaction (ORR), based on extensive investigation of the electronic properties of PdTe2 thin films as well as atomic-level reaction kinetics at explicit electrode potentials. We verify that under electrochemical reducing conditions, the electron emerging on the electrode surface is directly transferred to O2 adsorbed on the PdTe2 bilayer, which greatly reduces the dissociation barrier of O2, and thereby facilitates the ORR to proceed via a dissociative pathway. Moreover, the barriers of the electrochemical steps in this pathway are all found to be less than 0.1 eV at the ORR limiting potential, demonstrating fast ORR kinetics at ambient conditions. This unique mechanism offers excellent energy efficiency and four-electron selectivity for the PdTe2 bilayer, and it is identified as a promising candidate for fuel cell applications.
ABSTRACT
Oxide-based resistive random access memory (RRAM) is standing out in both non-volatile memory and the emerging field of neuromorphic computing, with the consequence of increasing performance demands. Rare-earth doping is often used as an effective means for performance modulation. In this work, the modulation mechanism of the resistive switching (RS) behaviors in trivalent rare-earth Gd-doped HfO2-based RRAM has been carefully investigated using first-principles calculations. The results of electronic structure analysis show that Gd doping would lead to a change in the local geometry of the m-HfO2 defect system and would enhance the Coulomb interaction between the atoms around Gd and oxygen vacancy (VO), which may be one of the reasons for the enhanced conductivity of the HfO2-based RRAM after Gd doping. Thermodynamic and kinetic study results indicate that there is a strong interaction between Gd and its surrounding VO defects, and this strong interaction would not only attract more oxygen vacancies (VOs) to be generated near the dopant Gd, but also increase the migration energy barrier of the +2 charged VOs around the Gd doping site, thus suppressing the random generation of VO filaments, which leads to a better uniformity of the switching parameters during the RS process and improves the performance stability of the devices. The results of this work will provide new insights into modulating the RS behaviors and improving the device performance of HfO2-based RRAM through doping engineering.