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In recent years, underinvestment has become common among subsidised enterprises in China. Stakeholder theory asserts that environmental, social and governance (ESG) performance forces enterprises to prioritise stakeholder needs by incorporating ESG principles into business operations, which in turn influences business investment decision-making. This study examines the impact of government subsidies on firm underinvestment and whether ESG performance plays a moderating role in this direct relationship. A dataset of 17,780 firm-year observations of A-share public firms in China for the period 2011-2021 was employed, and the data were analysed using the ordinary least squares regression model, fixed-effects regression model, propensity score matching difference-in-difference model, and instrumental variable approach. These results indicate that government subsidies mitigate firm underinvestment and tend to reduce underinvestment in firms with higher ESG performance. Moreover, the findings indicate that the performance in ESG factors influences the effect of government subsidies on the lack of investment in state-owned enterprises (SOEs), as opposed to non-SOEs. This effect is more noticeable in heavily polluting industries compared to non-heavily polluting industries. These findings imply that the government should promote the ESG performance of subsidised firms to enhance their overall corporate investment efficiency.
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Hepatitis B Virus (HBV) remains a critical global health issue, with substantial morbidity and mortality. Current therapies, including interferons and nucleoside analogs, often fail to achieve complete cure or functional eradication. This review explores recent advances in anti-HBV agents, focusing on their innovative mechanisms of action. HBV entry inhibitors target the sodium taurocholate cotransporting polypeptide (NTCP) receptor, impeding viral entry, while nucleus translocation inhibitors disrupt key viral life cycle steps, preventing replication. Capsid assembly modulators inhibit covalently closed circular DNA (cccDNA) formation, aiming to eradicate the persistent viral reservoir. Transcription inhibitors targeting cccDNA and integrated DNA offer significant potential to suppress HBV replication. Immunomodulatory agents are highlighted for their ability to enhance host immune responses, facil-itating better control and possible eradication of HBV. These novel approaches represent significant advancements in HBV therapy, providing new strategies to overcome current treatment limitations. The development of cccDNA reducers is particularly critical, as they directly target the persistent viral reservoir, offering a promising pathway towards achieving a functional cure or complete viral eradication. Continued research in this area is essential to advance the effectiveness of anti-HBV therapies.
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Photosynthesis in fluctuating light requires coordinated adjustments of diffusion conductance and biochemical capacity, but the role of chloroplast ATP synthase activity (gH+) in dynamic photosynthesis is not well understood. In this study, we measured gas exchange, chlorophyll fluorescence and electrochromic shift signals in fluctuating light for leaves of tomato (Solanum lycopersicum) and maize (Zea mays). During the transition from sun to shade, simultaneous increases in gH+, effective quantum yield of PSII, and net CO2 assimilation rate (AN) occurred in tomato but uncoupled in maize, indicating that gH + limited AN during the sun-to-shade transition in tomato but not in maize. During the shade-to-sun transition, gH + increased simultaneously with stomatal conductance, mesophyll conductance and Rubisco carboxylation capacity in tomato, suggesting that gH+ is an overlooked factor affecting light induction of AN in tomato. By comparison, gH + maintained at high levels in maize and its AN was mainly restricted by stomatal conductance. Our results reveal that the kinetics of gH+ in fluctuating light differs between species, and chloroplast ATP synthase may be a potential target for improving dynamic photosynthesis in crops such as tomato.
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Wheat is one of the most important staple foods in the world. Genetic characterization of wheat agronomically important traits is crucial for yield improvement through molecular breeding. In this study, a recombinant inbred line (RIL) population was developed by crossing a local adapted high yield variety Jimai 22 (JM22) with an external variety Cunmai no.1 (CM1). A high-density genetic map containing 7,359 single nucleotide polymorphism (SNP) markers was constructed. Quantitative trait loci (QTL) mapping identified 61 QTL for eight yield-related traits under six environments (years). Among them, 17 QTL affecting spike number per plant, grain number per spike and thousand grain weight showed high predictability for theoretical yield per plant (TYP), of which, 12 QTL alleles positively contributed to TYP. Nine promising candidate genes for seven of the 12 QTL were identified including three known wheat genes and six rice orthologs. Four elite lines with TYP increased by 5.6%-15.2% were identified through genotype selection which carried 7-9 favorable alleles from JM22 and 2-3 favorable alleles from CM1 of the 12 QTL. Moreover, the linked SNPs of the 12 QTL were converted to high-throughput kompetitive allele-specific PCR (KASP) markers and validated in the population. The mapped QTL, identified promising candidate genes, developed elite lines and KASP markers are highly valuable in future genotype selection to improve wheat yield. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01496-3.
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Background: This study aimed to develop and validate a nomogram model for predicting 28-day mortality in patients with sepsis in the intensive care unit (ICU). Methods: We retrospectively analyzed data from 331 patients with sepsis admitted to the ICU as a training set and collected a validation set of 120 patients. Both groups were followed for 28 days. Logistic regression analyses were performed to identify the potential prognostic factors for sepsis-related 28-day mortality. A nomogram model was generated to predict 28-day mortality in patients with sepsis in the ICU. Receiver operating characteristic (ROC) curve analysis, calibration curves, and decision curve analysis (DCA) were used to evaluate the model's prediction performance and clinical application. In addition, we used ROC curve analysis and DCA to compare this model with the sequential organ failure assessment (SOFA) and Acute Physiology and Chronic Health Evaluation (APACHE II) scores and further assessed the clinical value of our model. Results: Logistic multivariate regression analysis revealed that mechanical ventilation, oxygenation index, and lactate and blood urea nitrogen (BUN) levels were independent predictors of 28-day mortality in patients with sepsis in the ICU. We developed a nomogram model based on these results to further predict 28-day mortality. The model demonstrated satisfactory calibration curves for both training and validation sets. Additionally, in the training set, the area under the ROC curve (AUC) for this model was 0.80. In the validation set, the AUC was 0.82. DCA showed that the high-risk thresholds ranged between 0 and 0.86 in the training set and between 0 and 0.75 in the validation set. We compared the ROC curve and DCA of this model with those of SOFA and APACHE II scores in both the training and validation sets. In the training set, the AUC of this model was significantly higher than those of the SOFA (P = 0.032) and APACHE II (P = 0.004) scores. Although the validation set showed a similar trend, the differences were not statistically significant for the SOFA (P = 0.273) and APACHE II (P = 0.320) scores. Additionally, the DCA showed comparable clinical utility in all three assessments. Conclusion: The present study used four common clinical variables, including mechanical ventilation, oxygenation index and lactate and BUN levels, to develop a nomogram model to predict 28-day mortality in patients with sepsis in the ICU. Our model demonstrated robust prediction performance and clinical application after validation and comparison.
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Studying the stoichiometric characteristics of soil nutrients aids in evaluating soil quality and deciphering the coupling of soil nutrients. The influence of migratory bird activities on the dynamics of wetland soil nutrients and their stoichiometric remains unclear. We classified the central, peripheral and adjacent natural grassy areas as severe, mild, and no bird activity (control), respectively, in Donghu Carex meadow, a representative migratory bird habitat in Poyang Lake, based on flock characteristics and initial surveys. We analyzed the contents and stoichio-metry of soil organic carbon (SOC), total nitrogen (TN), and total phosphorus (TP) across soil depths of 0-100 cm under different intensities of migratory bird activities. The results showed that the activities of migratory birds significantly impacted nutrient levels exclusively within 0-30 cm soil. Mild activities markedly enhanced SOC and TN across 0-30 cm soil, while both mild and severe activities significantly raised TP within the same depth. For the 0-100 cm soil profiles, soil C/N ratios were 10.0, 10.8, and 9.9, C/P ratios were 23.5, 30.0, and 22.7, and N/P ratios were 2.3, 2.7, and 2.3 under no, mild, and severe bird activities, respectively. Further, mild activities of migratory birds significantly increased soil C/N, C/P and N/P ratios only within the 0-30 cm depth, while the stoichiometric ratios of all soil layer had no significant difference under severe bird activity. Soil stoichiometric ratios strongly correlated with physicochemical properties. SOC, TN, and TP primarily mediated the effects of migratory bird activity on soil carbon, nitrogen, and phosphorus stoichiometric ratios in Poyang Lake wetland. In conclusion, the influence of migratory bird activity on the stoichiometric ratios of soil carbon, nitrogen, and phosphorus in Poyang Lake wetland exhibited depth threshold (approximately 30 cm), aligning with the "Intermediate Distur-bance Hypothesis". These findings could provide a new perspective for the protection of wetlands and migratory birds.
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Migración Animal , Aves , Carbono , Lagos , Nitrógeno , Fósforo , Suelo , Humedales , Animales , Fósforo/análisis , Nitrógeno/análisis , Suelo/química , China , Carbono/análisis , Lagos/química , Carex (Planta)/crecimiento & desarrollo , Carex (Planta)/metabolismo , Monitoreo del Ambiente , EcosistemaRESUMEN
Allergen-crosslinked IgE triggers allergy by interacting with its receptor on basophils and mast cells. The anti-IgE monoclonal antibody omalizumab can alleviate allergy by competing with the receptor for IgE binding. However, along with neutralization, omalizumab also inhibits IgE degradation, which is clinically associated with high dose and total IgE accumulation problems. In this study, we have developed an IgE-eliminating antibody on the basis of omalizumab, which has pH-dependent Fabs and an Fc with high affinity for FcγRIIb. In mice, the antibody rapidly eliminated total serum IgE to baseline levels and caused lower free IgE levels than omalizumab. At low dosages, the antibody also exhibited favorable IgE elimination effects. In addition, the antibody can degrade the corresponding allergen with the removal of IgE, addressing the allergy from its source. Introduction of the M252Y/S254T/T256E (YTE) mutation into this antibody prolongs its serum half-life without reducing potency. Thus, this engineered antibody holds a promising therapeutic option for allergy patients. Mechanistic insights are also included in this study.
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Interleukin-10 (IL-10) exerts complex effects on tumor growth, exhibiting both pro- and anti-tumor properties. Recent focus on the anti-inflammatory properties of IL-10 has highlighted its potential anti-tumor properties, particularly through the enhancement of CD8+ T cell activity. However, further research is needed to fully elucidate its other anti-tumor mechanisms. Our study investigates novel anti-tumor mechanisms of IL-10 in a murine mammary carcinoma model (4T1). We found that IL-10 overexpression in mouse 4T1 cells suppressed tumor growth in vivo. This suppression was accompanied by an increase in IFN-γ-secreting CD8+ T cells and a decrease in myeloid-derived suppressor cells (MDSCs) in tumor tissue. In vitro experiments showed that IL-10-rich tumor cell-derived supernatants inhibited myeloid cell differentiation into monocytic and granulocytic MDSCs while reducing MDSCs migration. In addition, IL-10 overexpression downregulated CXCL5 expression in 4T1 cells, resulting in decreased CXCR2+ MDSCs infiltration. Using RAG1-deficient mice and CXCL5 knockdown tumor models, we demonstrated that the anti-tumor effects of IL-10 depend on both CD8+ T cells and reduced MDSC infiltration. IL-10 attenuated the immunosuppressive tumor microenvironment by enhancing CD8+ T cell activity and inhibiting MDSCs infiltration. In human breast cancer, we observed a positive correlation between CXCL5 expression and MDSC infiltration. Our findings reveal a dual mechanism of IL-10-mediated tumor suppression: (1) direct enhancement of CD8+ T cell activity and (2) indirect reduction of immunosuppressive MDSCs through CXCL5 downregulation and inhibition of myeloid cell differentiation. This study provides new insights into the role of IL-10 in anti-tumor immunity and suggests potential strategies for breast cancer immunotherapy by modulating the IL-10-CXCL5-MDSCs axis.
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Alzheimer's disease (AD) is the most common form of dementia among the elderly, accounting for 60 %-70 % of cases. At present, the pathogenesis of this condition remains unclear, but the hydrolysis of acetylcholine (ACh) is thought to play a role. Acetylcholinesterase (AChE) can break down ACh transmission from the presynaptic membrane and stop neurotransmitters' excitatory effect on the postsynaptic membrane, which plays a key role in nerve conduction. Acetylcholinesterase inhibitors (AChEIs) can delay the hydrolysis of acetylcholine (ACh), which represents a key strategy for treating AD. Due to its complex etiology, AD has proven challenging to treat. Various inhibitors and antagonists targeting key enzymes and proteins implicated in the disease's pathogenesis have been explored as potential therapeutic agents. These include Glycogen Synthase Kinase 3ß (GSK-3ß) inhibitors, ß-site APP Cleaving Enzyme (BACE-1) inhibitors, Monoamine Oxidase (MAO) inhibitors, Phosphodiesterase inhibitors (PDEs), N-methyl--aspartic Acid (NMDA) antagonists, Histamine 3 receptor antagonists (H3R), Serotonin receptor subtype 4 (5-HT4R) antagonists, Sigma1 receptor antagonists (S1R) and soluble Epoxide Hydrolase (sEH) inhibitors. The drug development strategy of multi-target-directed ligands (MTDLs) offers unique advantages in the treatment of complex diseases. On the one hand, it can synergistically enhance the therapeutic efficacy of single-target drugs. On the other hand, it can also reduce the side effects. In this review, we discuss the design strategy of dual inhibitors based on acetylcholinesterase and the structure-activity relationship of these drugs.
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Aplastic anemia (AA) is an autoimmune hematopoietic disease mediated by autoreactive T cells leading to bone marrow failure. However, the precise role of autoreactive T cells in the development of AA is not fully understood, hindering the advancement of therapeutic and diagnostic strategies. In this study, we conducted a single-cell transcriptome analysis of CD8+ T cells, conventional CD4+ T (CD4+ Tconv) cells, and Treg cells, to elucidate the potential disruption of T cell homeostasis in patients with AA. We identified changes in CD4+ Tconv cells, including loss of homeostasis in naïve and memory cells and increased differentiation potential in T helper type 1 (TH1), T helper type 2 (TH2), and T helper type 17 (TH17) cells. Additionally, we identified naïve and memory CD8+ T cells that were enforced into an effector state. CD127 is an ideal surface marker for assessing the immune state of CD8+ T cellsï¼as identified by flow cytometry. Abnormal expression of TNFSF8 has been observed in AA and other autoimmune diseases. Flow cytometry analysis revealed that TNFRSF8 (CD30), a receptor for TNFSF8, was predominantly present in human Treg cells. Importantly, patients with AA have a decreased CD30+ Treg subset. RNA-sequencing analysis revealed, that the CD30+ Treg cells are characterized by high proliferation and a remarkable immunosuppressive phenotype. Taken, together, we propose that abnormal TNFSF8/TNFRSF8 signaling is involved in dysfunctional T cell immunity by increasing the destruction of CD30+ Treg cells.
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Acute graft-versus-host disease (aGVHD) is primarily driven by allogeneic donor T cells associated with an altered composition of the host gut microbiome and its metabolites. The severity of aGVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not solely determined by the host and donor characteristics; however, the underlying mechanisms remain unclear. Using single-cell RNA sequencing, we decoded the immune cell atlas of 12 patients who underwent allo-HSCT: six with aGVHD and six with non-aGVHD. We performed a fecal microbiota (16SrRNA sequencing) analysis to investigate the fecal bacterial composition of 82 patients: 30 with aGVHD and 52 with non-aGVHD. Fecal samples from these patients were analyzed for bile acid metabolism. Through multi-omic analysis, we identified a feedback loop involving "immune cell-gut microbes-bile acid metabolites" contributing to heightened immune responses in patients with aGVHD. The dysbiosis of the gut microbiota and disruption of bile acid metabolism contributed to an exaggerated interleukin-1 mediated immune response. Our findings suggest that resistin and defensins are crucial in mitigating against aGVHD. Therefore, a comprehensive multi-omic atlas incorporating immune cells, gut microbes, and bile acid metabolites was developed in this study and used to propose novel, non-immunosuppressive approaches to prevent aGVHD.
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Ácidos y Sales Biliares , Heces , Microbioma Gastrointestinal , Enfermedad Injerto contra Huésped , Ácidos y Sales Biliares/metabolismo , Humanos , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/microbiología , Microbioma Gastrointestinal/inmunología , Femenino , Masculino , Heces/microbiología , Persona de Mediana Edad , Enfermedad Aguda , Adulto , Retroalimentación Fisiológica , Inmunidad , Metabolómica , Trasplante de Células Madre Hematopoyéticas , MultiómicaRESUMEN
AIM: Hypothermia is one of the common complications of cesarean section, which has a serious impact on intraoperative surgical safety and postoperative recovery of pregnant women. Mitigation of the risk factors of hypothermia in pregnant women undergoing cesarean section may reduce the probability of its occurrence and improve the perioperative comfort of pregnant women. Therefore, this study systematically evaluates the influencing factors of hypothermia in patients undergoing cesarean section, aiming to provide references for the prevention of hypothermia in pregnant women undergoing cesarean section. METHODS: A systematic search was conducted across various databases, including PubMed, Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang, and Chinese Biomedical Literature databases to gather observational studies on the factors affecting hypothermia in pregnant women undergoing cesarean section. The search deadline was January 30, 2024. Two researchers independently screened literature, extracted data, evaluated quality, and crosschecked the outcomes. Meta analysis was conducted using RevMan 5.3 and Stata17.0. RESULTS: Twelve studies were included in this review, all of which were case-control studies conducted from 2014 to 2022, encompassing a total of 5561 pregnant women. The quality of the studies included was average or above. The meta-analysis results showed that body mass index (mean difference (MD) = -1.47; 95% confidence interval (CI) [-2.84, -0.11]; p = 0.03), operating room temperature (odds ratio (OR) = 2.08; 95% CI [1.56, 2.76]; p < 0.00001), anesthesia method (OR = 1.84; 95% CI [1.40, 2.42]; p < 0.0001), fluid loss (MD = 160.09; 95% CI [77.31, 242.87]; p = 0.0002), flushing volume (MD = 66.43; 95% CI [8.46, 124.40]; p = 0.02), and hypothyroidism (OR = 2.29; 95% CI [1.61, 3.27]; p < 0.00001) were risk factors for perioperative hypothermia in pregnant women undergoing cesarean section (p < 0.05). CONCLUSIONS: The occurrence of hypothermia in pregnant women during the perioperative period is influenced by factors such as low body mass index, spinal anesthesia, low operating room temperature, intraoperative fluid loss, large flushing volume, and hypothyroidism.
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Cesárea , Hipotermia , Complicaciones Intraoperatorias , Femenino , Humanos , Embarazo , Índice de Masa Corporal , Cesárea/efectos adversos , Cesárea/estadística & datos numéricos , Hipotermia/epidemiología , Hipotermia/etiología , Hipotermia/prevención & control , Complicaciones Intraoperatorias/prevención & control , Complicaciones Intraoperatorias/etiología , Complicaciones Intraoperatorias/epidemiología , Factores de RiesgoRESUMEN
Metal halide perovskites (MHPs) have undergone rapid development in the fields of solar cells, light diodes, lasing, photodetectors, etc. However, the MHPs still face significant challenges, such as poor stability and heterocompositing with other functional materials at the single nanoparticle level. Herein, the successful synthesis of well-dispersed CsPbBr3@TiO2 heterostructure nanocrystals (NCs) is reported, in which each heterostructure NC has only one CsPbBr3 with a precise anatase TiO2 coating ranging from asymmetric to symmetric. Due to the protection of anatase TiO2, CsPbBr3 shows dramatically improved chemical stability and photostability. More significantly, the synthesized CsPbBr3@TiO2 heterostructure NCs form a type II heterojunction, which strongly promoted efficient photogenerated carrier separation between anatase TiO2 and CsPbBr3, hence leading to improved optoelectronic activity. This study provides a robust avenue for synthesizing stable and highly efficient MHPs@metal oxide heterostructure NCs, paving the way for the practical application of all inorganic perovskites.
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LAIR1, a receptor found on immune cells, is capable of binding to collagen and is involved in immune-related diseases. However, the precise contribution of LAIR1 expressed on hepatocellular carcinoma (HCC) cells to tumor microenvironment is still unclear. In our study, bioinformatics analysis and immunofluorescence were employed to study the correlation between LAIR1 levels and clinical indicators. Transwell and scratch tests were used to evaluate how LAIR1 affected the migration and invasion of HCC cells. The chemotactic capacity and alternative activation of macrophages were investigated using RT-qPCR, transwell, and immunofluorescence. To investigate the molecular mechanisms, transcriptome sequencing analysis, Western blot, nucleus/cytoplasm fractionation, ELISA, and cytokine microarray were employed. We revealed a significant correlation between the presence of LAIR1 and an unfavorable outcome in HCC. We indicated that LAIR1 promoted migration and invasion of HCC cells through the AKT-IKKß-p65 axis. Additionally, the alternative activation and infiltration of tumor-associated macrophages induced by LAIR1 were reliant on the upregulation of IL6 and CCL5 within this axis, respectively. In conclusion, blocking LAIR1 was found to be an effective approach in combating the cancerous advancement of HCC.
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Carcinoma Hepatocelular , Movimiento Celular , Neoplasias Hepáticas , Proteínas Proto-Oncogénicas c-akt , Receptores Inmunológicos , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Quinasa I-kappa B/metabolismo , Quinasa I-kappa B/genética , Factor de Transcripción ReIA/metabolismo , Factor de Transcripción ReIA/genética , Línea Celular Tumoral , Microambiente Tumoral , Regulación Neoplásica de la Expresión Génica , Transducción de Señal , Macrófagos/metabolismo , Macrófagos/patología , Proliferación Celular , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/patología , Macrófagos Asociados a Tumores/inmunología , Invasividad NeoplásicaRESUMEN
OBJECTIVE: To investigate the distribution of nine (9) urine biomarkers in people living with type 2 diabetes mellitus (T2DM), with or without microvascular complications. METHODS: In total, 407 people with T2DM were enrolled from 2021 to 2022. According to diabetic retinopathy (DR) and urinary albumin-creatinine ratio (UACR), the 407 people were divided into four (4) groups, DR(-)UACR(-), DR(+)UACR(-), DR(-)UACR(+), and DR( + )UACR(+). In addition, 112 healthy volunteers were enrolled during the same period. The nine (9) urine markers included α1-microglobulin (u-α1MG), immunoglobulin G (u-IgG), neutrophil gelatinase-associated lipid carrier protein (u-NGAL), cystatin C (u-CysC), retinol-binding protein (u-RBP), ß2-microglobulin (u-ß2MG), N-acetyl-ß-D-glucosaminidase (u-NAG), transferrin (u-Trf), and collagen type IV (u-Col). For each marker, the respective level of 97.5 percentile in healthy volunteers was taken as an upper reference limit. RESULTS: Among the 407 people, 248 individuals (61%) were DR(-)UACR(-), 100 (25%) were DR(-)UACR(+), 37 (9%) were DR(+)UACR(-), and 22 (5%) were DR(+)UACR(+). The u-NAG/Cr biomarker level showed a significant difference between healthy participants and people with T2DM. In the DR(-)UACR(-)group, u-Trf/Cr showed the highest positive rate (21.37%), followed by u-IgG/Cr (14.52%); u-NAG/Cr (10.48%); u-ß2MG/Cr (4.44%); u-CysC/Cr (4.03%); u-NGAL/Cr (4.03%); u-RBP/Cr (2.82%); u-α1MG/Cr (2.42%); 17.34% of people with T2DM showed multiple biomarkers positive (≥2 biomarkers). The positive rates of one biomarker (21.33%) and two biomarkers (18.67%) in people who have less than five (5) years of T2DM were almost close to those of the DR(-)UACR(-) group (21.37%, and 12.10%, respectively). CONCLUSION: Renal tubule biomarkers may be used as an indicator in the early detection and monitoring of renal injury in diabetes mellitus. The u-NAG biomarker should be measured for the people with T2DM of the first-time diagnosis.
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Albuminuria , Biomarcadores , Diabetes Mellitus Tipo 2 , Retinopatía Diabética , Humanos , Diabetes Mellitus Tipo 2/orina , Diabetes Mellitus Tipo 2/complicaciones , Biomarcadores/orina , Masculino , Femenino , Persona de Mediana Edad , Retinopatía Diabética/orina , Albuminuria/orina , Anciano , Creatinina/orina , alfa-Globulinas/orina , Microglobulina beta-2/orina , Cistatina C/orina , Cistatina C/sangre , Proteínas de Unión al Retinol/orina , Nefropatías Diabéticas/orina , Adulto , Angiopatías Diabéticas/orina , Lipocalina 2/orinaRESUMEN
We developed a novel method based on self-supervised learning to improve the ghost imaging of occluded objects. In particular, we introduced a W-shaped neural network to preprocess the input image and enhance the overall quality and efficiency of the reconstruction method. We verified the superiority of our W-shaped self-supervised computational ghost imaging (WSCGI) method through numerical simulations and experimental validations. Our results underscore the potential of self-supervised learning in advancing ghost imaging.
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Transarterial chemoembolization (TACE), the mainstay treatment of unresectable primary liver cancer that primarily employs nondegradable drug-loaded embolic agents to achieve synergistic vascular embolization and locoregional chemotherapy effects, suffers from an inferior drug burst behavior lacking long-term drug release controllability that severely limits the TACE efficacy. Here we developed gelatin-based drug-eluting microembolics grafted with nanosized poly(acrylic acid) serving as a biodegradable ion-exchange platform that leverages a counterion condensation effect to achieve high-efficiency electrostatic drug loading with electropositive drugs such as doxorubicin (i.e., drug loading capacity >34 mg/mL, encapsulation efficiency >98%, and loading time <10 min) and an enzymatic surface-erosion degradation pattern (â¼2 months) to offer sustained locoregional pharmacokinetics with long-lasting deep-tumor retention capability for TACE treatment. The microembolics demonstrated facile microcatheter deliverability in a healthy porcine liver embolization model, superior tumor-killing capacity in a rabbit VX2 liver cancer embolization model, and stabilized extravascular drug penetration depth (>3 mm for 3 months) in a rabbit ear embolization model. Importantly, the microembolics finally exhibited vessel remodeling-induced permanent embolization with minimal inflammation responses after complete degradation. Such a biodegradable ion-exchange drug carrier provides an effective and versatile strategy for enhancing long-term therapeutic responses of various local chemotherapy treatments.
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Quimioembolización Terapéutica , Doxorrubicina , Animales , Quimioembolización Terapéutica/métodos , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Conejos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/tratamiento farmacológico , Porcinos , Resinas Acrílicas/química , Polielectrolitos/química , Portadores de Fármacos/química , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/farmacocinética , Gelatina/química , Nanopartículas/química , Humanos , Liberación de Fármacos , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificaciónRESUMEN
In recent years, poly(ADP-ribose)polymerase-1 (PARP-1) and histone deacetylase (HDAC) have emerged as significant targets in tumor therapy, garnering widespread attention. In this study, we designed and synthesized two novel phthalazinone PARP-1 inhibitors and dual PARP-1/HDAC-1 inhibitors, named DLC-1-46 containing dithiocarboxylate fragments and DLC-47-63 containing hydroxamic acid fragments, and evaluated their inhibitory activities on enzymes and cells. Among the PARP-1 inhibitors, most compounds exhibited high inhibitory activity against the PARP-1 enzyme, with DLC-1-6 being particularly notable, showing IC50 values <0.2â¯nM. Notably, DLC-1 demonstrated significant anti-proliferative activity, with IC50 values for inhibiting the proliferation of MDA-MB-436, MDA-MB-231, and MCF-7 cells reaching 0.08, 26.39, and 1.01⯵M, respectively. Further investigation revealed that DLC-1 arrested MDA-MB-231 cells in the G1 phase and induced apoptosis in a dose-dependent manner. Among the designed dual PARP-1/HDAC-1 inhibitors, several compounds exhibited potent dual-target inhibitory activity, with DLC-49 displaying IC50 values of 0.53â¯nM and 17â¯nM for PARP-1 and HDAC-1, respectively. DLC-50 demonstrated the most potent anti-proliferative activity, with IC50 values for inhibiting the proliferation of MDA-MB-436, MDA-MB-231, and MCF-7 cells at 0.30, 2.70, and 2.41⯵M, respectively. Cell cycle arrest and apoptosis assays indicated that DLC-50 arrested the cell cycle in the G2 phase and induced apoptosis in HCT-116 cells. Our findings present a novel avenue for further exploration of PARP-1 inhibitors and dual PARP-1/HDAC-1 inhibitors.
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Antineoplásicos , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Histona Desacetilasa 1 , Inhibidores de Histona Desacetilasas , Ftalazinas , Poli(ADP-Ribosa) Polimerasa-1 , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 1/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Relación Estructura-Actividad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/síntesis química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Ftalazinas/farmacología , Ftalazinas/síntesis química , Ftalazinas/química , Estructura Molecular , Relación Dosis-Respuesta a Droga , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Simulación del Acoplamiento MolecularRESUMEN
Amidst the rapid advancements in the fields of photovoltaics and optoelectronic devices, CsPbBr3 nanosheets (NSs) have emerged as a focal point of research due to their exceptional optical and electronic properties. This work explores the application potential of CsPbBr3 NSs in photonic and catalytic domains. Utilizing an optimized hot-injection method and a ZnBr2-assisted in situ passivation strategy, we successfully synthesized CsPbBr3 NSs with controlled dimensions and optical characteristics. Comprehensive characterization revealed that the nucleation environment and thickness significantly influenced the structure and optical performance of the materials. The results indicate that the optimized synthesis method enables control over the lateral dimensions of the nanoparticles, ranging from 9.1 ± 0.06 nm to 334.5 ± 4.40 nm, facilitating the tuning of the excitation wavelength from 460 nm (blue) to 510 nm (green). Further analyses involving photoresponse and electrochemical impedance spectroscopy demonstrated the substantial potential of these NSs in applications such as photocatalysis and energy conversion.
RESUMEN
The microenvironment of hepatocellular carcinoma (HCC) is characterized by hypoxia, which leads to immune evasion of HCC. Therefore, gaining a comprehensive understanding of the mechanism underlying the impact of hypoxia on HCC cells may provide valuable insights into immune checkpoint therapy. Based on analysis of databases and clinical samples, we observed that expression level of programmed cell death ligand 1 (PD-L1) and long non-coding RNA (lncRNA) MIR155HG in patients in the hypoxia group were higher than those in the non-hypoxia group. Furthermore, there was a positive correlation between the expression of PD-L1 and MIR155HG with that of HIF-1α. In vitro experiments using hypoxic treatment demonstrated an increase in PD-L1 and MIR155HG expression levels in HCC cells. While the hypoxia-induced upregulation of PD-L1 could be reversed by knocking down MIR155HG. Mechanistically, as a transcription factor, HIF-1α binds to the promoter region of MIR155HG to enhance its transcriptional activity under hypoxic conditions. Hypoxia acts as a stressor promoting nuclear output of ILF3 leading to increased binding of ILF3 to MIR155HG, thereby enhancing stability for HIF-1α mRNA. In vivo, knocking down MIR155HG inhibit subcutaneous tumor growth, reduce the expression of HIF-1α and PD-L1 within tumors; additionally, it enhances anti-tumor immunity response. These findings suggested that through inducing MIR155HG to interact with ILF3, hypoxia increases HIF-1α mRNA stability resulting in elevated PD-L1 expression in HCC and thus promoting immune escape. In summary, this study provides new insights into the effects of hypoxia on HCC immunosuppression.