ABSTRACT
The dysregulation of long non-coding RNAs (lncRNAs) are involved in regulating tumor progression in multiple manner. However, little is known about whether lncRNA is involved in the translation regulation of proteins. Here, we identified that the suppressor of inflammatory macrophage apoptosis lncRNA (SIMALR) was highly expressed in nasopharyngeal carcinoma (NPC) tissues by analyzing the lncRNA microarray. Clinically, the high expression of SIMALR served as an independent predictor for inferior prognosis in NPC patients. SIMALR functioned as an oncogenic lncRNA that promoted the proliferation and metastasis of NPC cells in vitro and in vivo. Mechanistically, SIMALR served as a critical accelerator of protein synthesis by binding to eEF1A2 (eukaryotic translation elongation factor 1 alpha 2), one of the most crucial regulators in the translation machinery of the eukaryotic cells, and enhancing its endogenous GTPase activity. Furthermore, SIMALR mediated the activation of eEF1A2 phosphorylation to accelerate the translation of ITGB4/ITGA6, ultimately promoting the malignant phenotype of NPC cells. In addition, N-acetyltransferase 10 (NAT10) enhanced the stability of SIMALR and caused its overexpression in NPC through the N4-acetylcytidine (ac4C) modification. In sum, our results illustrate SIMALR functions as an accelerator for protein translation and highlight the oncogenic role of NAT10-SIMALR-eEF1A2-ITGB4/6 axis in NPC.
ABSTRACT
TP53, a guardian of the genome, suppresses or enhances tumors through various regulatory pathways. However, the role of p53-related long non-coding RNAs (lncRNAs) in immune regulation of tumor microenvironment and prognosis of gastric cancer (GC) is so far unelucidated. We analyzed the role of TP53-associated lncRNAs (obtained from the TP53LNC-DB database) in immune regulation, immune cell infiltration and RNA modification in gastric cancer. Firstly, using multivariate COX regression analysis, we identified eight lncRNAs related to the prognosis of GC. Furthermore, based on the expression of the lncRNA signature and risk score, the GC patients were divided into high-risk and low-risk groups. We found that M2-macrophages have significantly higher infiltration in the high-risk group. Similarly, significant differences in immune function (APC_co_stimulation, CCR, and checkpoint) and m6A modification (FTO, ZC3H13, YTHDC1, and RBM15), and m5C modification (NOP2 and TET1) between both groups were also observed. These signature lncRNAs were also positively associated with oxidative stress-related genes (MPO, MAPK14, HMOX1, and APP). Additionally, we found that high expression of GAS5 and low expression of MALAT1 in Helicobacter pylori (H-pylori) positive GC patients. Finally, GC patients in the low-risk group showed higher resistance to immunotherapy while patients in the high-risk group were more sensitive to various chemotherapy drugs. Based on these findings, we conclude that p53-associated lncRNAs signature could potentially predict the immune status and overall survival, and may also be used for risk management and planning immunotherapy for gastric cancer patients.
ABSTRACT
Early detection plays a critical role in mitigating mortality rates linked to gastric cancer. However, current clinical screening methods exhibit suboptimal efficacy. Methylation alterations identified from cell-free DNA (cfDNA) present a promising biomarker for early cancer detection. Our study focused on identifying gastric cancer-specific markers from cfDNA methylation to facilitate early detection. We enrolled 150 gastric cancer patients and 100 healthy controls in this study, and undertook genome-wide methylation profiling of cfDNA using cell-free methylated DNA immunoprecipitation and high-throughput sequencing. We identified 21 differentially methylated regions (DMRs) between the gastric tumor and nontumor groups using multiple algorithms. Subsequently, using the 21 DMRs, we developed a gastric cancer detection model by random forest algorithm in the discovery set, and validated the model in an independent set. The model was able to accurately discriminate gastric cancer with a sensitivity and specificity of 93.90% and 95.15% in the discovery set, respectively, and 88.38% and 94.23% in the validation set, respectively. These results underscore the efficacy and accuracy of cfDNA-derived methylation markers in distinguishing early stage gastric cancer. This study highlighted the significance of cfDNA methylation alterations in early gastric cancer detection.
ABSTRACT
KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer progression and conferring resistance to treatment. While there have been advancements in the development of small molecules to target specific KRAS mutants, the presence of undruggable mutants and the emergence of secondary mutations continue to pose challenges in the clinical treatment of KRAS-mutant cancers. In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. TKD is composed of a KRAS-binding nanobody, a cell-penetrating peptide selectively targeting cancer cells, and a lysosome-binding motif. Our data revealed that TKD selectively binds to KRAS in cancer cells and effectively induces KRAS degradation via a lysosome-dependent process. Functionally, TKD suppresses tumor growth with no obvious side effects and enhances the antitumor effects of PD-1 antibody and cetuximab. This study not only provides a strategy for developing drugs targeting "undruggable" proteins but also reveals that TKD is a promising therapeutic for treating KRAS-mutant cancers.
ABSTRACT
Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system.
Subject(s)
Docetaxel , Drug Resistance, Neoplasm , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Pyroptosis , Ubiquitin-Protein Ligases , Ubiquitination , Animals , Female , Humans , Male , Mice , Middle Aged , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cisplatin/pharmacology , Cisplatin/therapeutic use , Docetaxel/pharmacology , Docetaxel/therapeutic use , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/drug effects , Dynamins/metabolism , Dynamins/genetics , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Gasdermins , Gene Expression Regulation, Neoplastic/drug effects , Mice, Inbred BALB C , Mice, Nude , Mitochondria/metabolism , Mitochondria/drug effects , Mitochondrial Proteins/metabolism , Mitochondrial Proteins/genetics , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/genetics , Nasopharyngeal Carcinoma/metabolism , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/genetics , Nasopharyngeal Neoplasms/metabolism , Nasopharyngeal Neoplasms/pathology , Phosphoprotein Phosphatases/metabolism , Phosphoprotein Phosphatases/genetics , Phosphorylation/drug effects , Pyroptosis/drug effects , Pyroptosis/genetics , Reactive Oxygen Species/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitination/drug effects , Xenograft Model Antitumor AssaysABSTRACT
To overcome the biological barriers in the journey of systemic gene delivery, a multifaceted genomic synthetic nanomedicine was elaborated and strategically equipped with a multiple of intriguing responsiveness. Particularly, core-shell plasmid DNA condensates were created based on polyionic complexation with block copolymer of polyethylene glycol (PEG)-polylysine (PLys), namely, the nanoscaled PLys&pDNA nanoparticle tethered with the biocompatible PEG surroundings. Furthermore, redox-reversible disulfide crosslinking was introduced into PLys&pDNA nanoparticle to accomplish adequate structural stabilities, and thermal-responsive polypropylacrylamide (PNIPAM) was introduced as the secondary intermediate surroundings onto the pre-formulated PLys&pDNA nanoparticle with the aim of preventing the potential enzymatic degradation from the environmental nucleases. Hence, hundreds of times prolonged survival and retention was determined in pertinent to the blood circulation properties. Additionally, the installation of a guide ligand at the distal end of PEG segments was proposed to encourage selective tumor uptake. A linear peptide of GPLGVRG, which is selectively susceptible to digestion by the tumor-enriched matrix metalloproteinase 2 (MMP-2), was used as the linkage between the shell and core. This peptide has been shown to detach the bio-inert PEGylation, resulting in further facilitated cell endocytosis and intracellular trafficking activities. Hence, the precisely defined synthetic nanomedicine, which exhibits desirable characteristics, efficient expression of the therapeutic gene in the affected cells, and contributed to potent therapeutic efficacy in systemic treatment of intractable tumors by encapsulating the anti-angiogenic gene.
Subject(s)
Nanomedicine , Nanoparticles , Polyethylene Glycols , Polylysine , Polyethylene Glycols/chemistry , Humans , Polylysine/chemistry , Nanoparticles/chemistry , Animals , Plasmids , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Mice , DNA/chemistry , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 2/genetics , Cell Line, Tumor , Particle Size , Acrylic Resins/chemistry , Neoplasms/drug therapy , Surface Properties , Gene Transfer TechniquesABSTRACT
Purpose: The purpose of this study was to investigate the development of optical biometric components in children with hyperopia, and apply a machine-learning model to predict axial length. Methods: Children with hyperopia (+1 diopters [D] to +10 D) in 3 age groups: 3 to 5 years (n = 74), 6 to 8 years (n = 102), and 9 to 11 years (n = 36) were included. Axial length, anterior chamber depth, lens thickness, central corneal thickness, and corneal power were measured; all participants had cycloplegic refraction within 6 months. Spherical equivalent (SEQ) was calculated. A mixed-effects model was used to compare sex and age groups and adjust for interocular correlation. A classification and regression tree (CART) analysis was used to predict axial length and compared with the linear regression. Results: Mean SEQ for all 3 age groups were similar but the 9 to 11 year old group had 0.49 D less hyperopia than the 3 to 5 year old group (P < 0.001). With the exception of corneal thickness, all other ocular components had a significant sex difference (P < 0.05). The 3 to 5 year group had significantly shorter axial length and anterior chamber depth and higher corneal power than older groups (P < 0.001). Using SEQ, age, and sex, axial length can be predicted with a CART model, resulting in lower mean absolute error of 0.60 than the linear regression model (0.76). Conclusions: Despite similar values of refractive errors, ocular biometric parameters changed with age in hyperopic children, whereby axial length growth is offset by reductions in corneal power. Translational Relevance: We provide references for optical components in children with hyperopia, and a machine-learning model for convenient axial length estimation based on SEQ, age, and sex.
Subject(s)
Axial Length, Eye , Biometry , Hyperopia , Machine Learning , Refraction, Ocular , Humans , Hyperopia/physiopathology , Male , Child , Female , Biometry/methods , Child, Preschool , Axial Length, Eye/diagnostic imaging , Refraction, Ocular/physiology , Cornea/pathology , Anterior Chamber/diagnostic imaging , Anterior Chamber/pathologyABSTRACT
In this study, we investigated the effects of various low-frequency ultrasound-assisted extraction processes, including ultrasound-assisted acid-soaked water bath extraction (UAW), ultrasound-assisted water bath extraction after acid soaking (AUW), acid-soaked water bath extraction followed by ultrasonics (AWU), and acid-soaked water bath extraction without ultrasound (CON), on the structural properties, thermal stability, gel properties, and microstructure of sheep's hoof gelatin. The results revealed that the primary components of sheep's hoof gelatin consisted of α1-chain, α2-chain (100-135 kDa), and ß-chain. In addition, it was observed that among the three sonication groups, sheep's hoof gelatin extracted in the AUW group exhibited the highest yield (27.16 ± 0.41 %), the best gel strength (378.55 ± 7.34 g), and higher viscosity at the same shear rate. The gelling temperature (25.38 ± 0.45 °C) and melting temperature (32.28 ± 0.52 °C) of sheep's hoof gelatin in the AUW group were significantly higher than those in the other groups (p > 0.05). Moreover, our experiments revealed that the sequence of low-frequency ultrasonic pretreatment processes was a crucial factor influencing the gel properties and structural characteristics of sheep's hoof gelatin. Specifically, the acid treatment followed by the ultrasound-assisted approach in the AUW group yielded high-quality and high-yield sheep's hoof gelatin.
Subject(s)
Gelatin , Gels , Animals , Gelatin/chemistry , Sheep , Gels/chemistry , Viscosity , Temperature , Ultrasonic Waves , Sonication/methodsABSTRACT
The soil selenium (Se) content and bioavailability are important for human health. In this regard, knowing the factors driving the concentration of total Se and bioavailable Se in soils is essential to map Se, enhance foodstuffs' Se content, and improve the Se nutritional status of humans. In this study, total Se and Se bioavailability (i.e., phosphate extracted Se) in surface soils (0-20 cm) developed on different strata were analyzed in a Se-enriched region of Southwest China. Furthermore, the interaction between the stratum and soil properties was assessed and how did the stratum effect on the concentration and spatial distribution of Se bioavailability in soils was investigated. Results showed that the median concentration of total Se in soils was 0.308 mg/kg, which is higher than China's soil background. The mean proportion of phosphate extracted Se in total Se was 12.2 %. The values of total Se, phosphate extracted Se, and soil organic matter (SOM) in soils increased with the increasing stratum age. In contrast, the coefficient of weathering and eluviation (BA) values decreased. The analysis of statistics and Geodetector revealed that the SOM, stratum, and BA were the dominant controlling factors for the contents and distributions of soil total Se and phosphate extracted Se. This study provided strong evidence that the soil properties that affected the total Se and Se bioavailability were modulated by the local geological background, and had important practical implications for addressing Se malnutrition and developing the Se-rich resource in the study region and similar geological settings in different parts of the globe.
Subject(s)
Selenium , Soil , Selenium/analysis , Soil/chemistry , China , Biological Availability , Soil Pollutants/analysisABSTRACT
The abuse and overuse of antibiotics let drug-resistant bacteria emerges. Antibacterial photodynamic therapy (APDT) has shown outstanding merits to eliminate the drug-resistant bacteria via cytotoxic reactive oxygen species produced by irradiating photosensitizer. However, most of photosensitizers are not effective for Gram-negative bacteria elimination. Herein conjugates of NBS, a photosensitizer, linked with one (NBS-DPA-Zn) or two (NBS-2DPA-Zn) equivalents of zinc-dipicolylamine (Zn-DPA) have been designed to achieve the functional recognition of different bacteria. Due to the cationic character of NBS and metal transfer channel effect of Zn-DPA, NBS-DPA-Zn exhibited the first regent to distinguish P. aeruginosa from other Gram-negative bacteria. Whereas NBS-2DPA-Zn showed broad-spectrum antibacterial effect because the two arm of double Zn-DPA enhanced interactions with anionic membranes of bacteria, led the bacteria aggregation and thus provided the efficacy of APDT to bacteria and corresponding biofilm. In combination with a hydrogel of Pluronic, NBS-2DPA-Zn@gel shows promising clinical application in mixed bacterial diabetic mouse model infection. This might propose a new method that can realize functional identification and elimination of bacteria through intelligent regulation of Zn-DPA, and shows excellent potential for antibacterial application.
Subject(s)
Anti-Bacterial Agents , Gram-Negative Bacteria , Photochemotherapy , Photosensitizing Agents , Picolines , Picolinic Acids , Animals , Photochemotherapy/methods , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Anti-Bacterial Agents/pharmacology , Gram-Negative Bacteria/drug effects , Mice , Picolinic Acids/chemistry , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Biofilms/drug effects , Zinc/chemistry , Pseudomonas aeruginosa/drug effects , Microbial Sensitivity Tests , Gram-Negative Bacterial Infections/drug therapyABSTRACT
BACKGROUND: Our previous study revealed that the COVID-19 pandemic posed mental health challenges to eye care professionals and students. The intent of this study was to identify the longitudinal impact of the COVID-19 pandemic on mental health among ophthalmic personnel and students. Additionally, the potential risk factors for mental health problems were investigated. METHODS: A two-phase survey among eye care professionals and students in the USA and Canada was conducted. Phase 1 was administrated from June 23 to July 8, 2020, and has been published; Phase 2 was conducted from January 21 to February 2, 2021. A total of 824 eye care professionals and students participated in Phase 2, with a response rate of 44.1%. Symptoms of depression, anxiety, and stress were measured and calculated. RESULTS: Compared with Phase 1, stress scores in Phase 2 were significantly reduced (P<0.001) although they were still higher than the pre-COVID level (P < .001). Scores for depression (P = 0.20) and anxiety (P = 0.40) showed no change, comparing Phase 2 to Phase 1. Reduction of stress scores significantly differed among occupations (P = 0.005); students had less reduction of stress than other eye care professionals (all P<0.05). Vaccination status was significantly associated with a reduction in stress scores (P = 0.04). CONCLUSIONS: With the continuing COVID pandemic, although stress level was reduced at 7-month follow-up, the mental health of eye care professionals was still impacted. In this population, COVID-19 vaccination was associated with fewer stress symptoms. These results indicate that the COVID-19 pandemic continues impacting mental health among eye care professionals, especially students. These study results warrant future interventions for eye care personnel and students to prevent or treat mental health disorders.
Subject(s)
COVID-19 , Pandemics , Humans , Mental Health , Longitudinal Studies , COVID-19 Vaccines , COVID-19/epidemiology , Students , Anxiety/epidemiology , Depression/epidemiologyABSTRACT
Background: Noradrenaline (NA) is commonly used intraoperatively to prevent fluid overload and maintain hemodynamic stability. Clinical studies provided inconsistent results concerning the effect of NA on postoperative outcomes. As aging is accompanied with various diseases and has the high possibility of the risk for postoperative complications, we hypothesized that intraoperative NA infusion in older adult patients undergoing major non-cardiac surgeries might potentially exert adverse outcomes. Methods: In this retrospective propensity score-matched cohort study, older adult patients undergoing major non-cardiac surgeries were selected, 1837 receiving NA infusion during surgery, and 1072 not receiving NA. The propensity score matching was conducted with a 1:1 ratio and 1072 patients were included in each group. The primary outcomes were postoperative in-hospital mortality and complications. Results: Intraoperative NA administration reduced postoperative urinary tract infection (OR:0.124, 95% CI:0.016-0.995), and had no effect on other postoperative complications and mortality, it reduced intraoperative crystalloid infusion (OR:0.999, 95% CI:0.999-0.999), blood loss (OR: 0.998, 95% CI: 0.998-0.999), transfusion (OR:0.327, 95% CI: 0.218-0.490), but increased intraoperative lactate production (OR:1.354, 95% CI:1.051-1.744), and hospital stay (OR:1.019, 95% CI:1.008-1.029). Conclusion: Intraoperative noradrenaline administration reduces postoperative urinary tract infection, and does not increase other postoperative complications and mortality, and can be safely used in older adult patients undergoing major non-cardiac surgeries.
Subject(s)
Norepinephrine , Surgical Procedures, Operative , Aged , Humans , Cohort Studies , Norepinephrine/adverse effects , Postoperative Complications/epidemiology , Postoperative Complications/prevention & control , Propensity Score , Retrospective Studies , Urinary Tract Infections/complicationsABSTRACT
OBJECTIVE: This study investigated the effect and mechanism of POU6F1 and lncRNA-CASC2 on ferroptosis of gastric cancer (GC) cells. METHODS: GC cells treated with erastin and RSL3 were detected for ferroptosis, reactive oxygen species (ROS) level, and cell viability. The expression levels of POU6F1, lncRNA-CASC2, SOCS2, and ferroptosis-related molecules (GPX4 and SLC7A11) were also measured. The regulations among POU6F1, lncRNA-CASC2, FMR1, SOCS2, and SLC7A11 were determined. Subcutaneous tumor models were established, in which the expressions of Ki-67, SOCS2, and GPX4 were detected by immunohistochemistry. RESULTS: GC patients with decreased expressions of POU6F1 and lncRNA-CASC2 had lower survival rate. Overexpression of POU6F1 or lncRNA-CASC2 decreased cell proliferation and GSH levels in GC cells, in addition to increasing total iron, Fe2+, MDA, and ROS levels. POU6F1 directly binds to the lncRNA-CASC2 promoter to promote its transcription. LncRNA-CASC2 can target FMR1 and increase SOCS2 mRNA stability to promote SLC7A11 ubiquitination degradation and activate ferroptosis signaling. Knockdown of SOCS2 inhibited the ferroptosis sensitivity of GC cells and reversed the effects of POU6F1 and lncRNA-CASC2 overexpression on ferroptosis in GC cells. CONCLUSION: Transcription factor POU6F1 binds directly to the lncRNA-CASC2 promoter to promote its expression, while upregulated lncRNA-CASC2 increases SOCS2 stability and expression by targeting FMR1, thereby inhibiting SLC7A11 signaling to promote ferroptosis in GC cells and inhibit GC progression.
Subject(s)
Ferroptosis , RNA, Long Noncoding , Stomach Neoplasms , Humans , Amino Acid Transport System y+/genetics , Fragile X Mental Retardation Protein , POU Domain Factors , Reactive Oxygen Species , RNA, Long Noncoding/genetics , Signal Transduction , Stomach Neoplasms/genetics , Suppressor of Cytokine Signaling ProteinsABSTRACT
Monosodium urate (MSU) crystal deposition in joints can lead to the infiltration of neutrophils and macrophages, and their activation plays a critical role in the pathological progress of gout. However, the role of MSU crystal physicochemical properties in inducing cell death in neutrophil and macrophage is still unclear. In this study, MSU crystals of different sizes are synthesized to explore the role of pyroptosis in gout. It is demonstrated that MSU crystals induce size-dependent pyroptotic cell death in bone marrow-derived neutrophils (BMNs) and bone marrow-derived macrophages (BMDMs) by triggering NLRP3 inflammasome-dependent caspase-1 activation and subsequent formation of N-GSDMD. Furthermore, it is demonstrated that the size of MSU crystal also determines the formation of neutrophil extracellular traps (NETs) and aggregated neutrophil extracellular traps (aggNETs), which are promoted by the addition of interleukin-1ß (IL-1ß). Based on these mechanistic understandings, it is shown that N-GSDMD oligomerization inhibitor, dimethyl fumarate (DMF), inhibits MSU crystal-induced pyroptosis in BMNs and J774A.1 cells, and it further alleviates the acute inflammatory response in MSU crystals-induced gout mice model. This study elucidates that MSU crystal-induced pyroptosis in neutrophil and macrophage is critical for the pathological progress of gout, and provides a new therapeutic approach for the treatment of gout.
Subject(s)
Gout , Macrophages , Neutrophils , Pyroptosis , Uric Acid , Gout/pathology , Gout/metabolism , Animals , Neutrophils/metabolism , Neutrophils/drug effects , Macrophages/metabolism , Macrophages/drug effects , Pyroptosis/drug effects , Mice , Extracellular Traps/metabolism , Extracellular Traps/drug effects , Inflammasomes/metabolism , Interleukin-1beta/metabolism , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Caspase 1/metabolismABSTRACT
The concept of molecular design, integrating diagnostic and therapeutic functions, aligns with the general trend of modern medical advancement. Herein, we rationally designed the smart molecule ER-ZS for endoplasmic reticulum (ER)-targeted diagnosis and treatment in cell and animal models by combining hemicyanine dyes with ER-targeted functional groups (p-toluenesulfonamide). Owing to its ability to target the ER with a highly specific response to viscosity, ER-ZS demonstrated substantial fluorescence turn-on only after binding to the ER, independent of other physiological environments. In addition, ER-ZS, being a small molecule, allows for the diagnosis of nonalcoholic fatty liver disease (NAFLD) via liver imaging based on high ER stress. Importantly, ER-ZS is a typeâ I photosensitizer, producing O2 â - and â OH under light irradiation. Thus, after irradiating for a certain period, the photodynamic therapy inflicted severe oxidative damage to the ER of tumor cells in hypoxic (2 % O2 ) conditions and activated the unique pyroptosis pathway, demonstrating excellent antitumor capacity in xenograft tumor models. Hence, the proposed strategy will likely shed new light on integrating molecular optics for NAFLD diagnosis and cancer therapy.
Subject(s)
Carbocyanines , Neoplasms , Non-alcoholic Fatty Liver Disease , Photochemotherapy , Animals , Humans , Non-alcoholic Fatty Liver Disease/diagnostic imaging , Non-alcoholic Fatty Liver Disease/drug therapy , Pyroptosis , Coloring Agents/metabolism , Viscosity , Liver/metabolism , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum Stress , Neoplasms/pathologyABSTRACT
Identifying driving factors is of great significance for understanding the mechanisms of soil pollution. In this study, a data processing method for driving factors was analyzed to explore the genesis of Arsenic (As) pollution in mining areas. The wind field that affects the atmospheric diffusion of pollutants was simulated using the standard k-ε model. Machine learning and GeoDetector methods were used to identify the primary driving factors. The results showed that the prediction performances of the three machine learning models were improved after data processing. The R2 values of random forest (RF), support vector machine, and artificial neural network increased from 0.45, 0.69, and 0.24 to 0.55, 0.76, and 0.52, respectively. The importance of wind increased from 20.85% to 26.22%. The importance of distance to the smelter plant decreased from 43.26% to 33.19% in the RF model. The wind's driving force (q value) increased from 0.057 to 0.235 in GeoDetector. The average value of historical atmospheric dust reached 534.98 mg/kg, indicating that atmospheric deposition was an important pathway for As pollution. The outcome of this study can provide a direction to clarify the mechanisms responsible for soil pollution at the mining area scale.
Subject(s)
Arsenic , Metals, Heavy , Soil Pollutants , Soil , Soil Pollutants/analysis , Environmental Monitoring/methods , Metals, Heavy/analysis , Mining , Arsenic/analysis , China , Risk AssessmentABSTRACT
Brown carbon (BrC) refers to a group of organic compounds in fine atmospheric particles (PM2.5) that are able to absorb light in the ultraviolet and visible range. They have a significant impact on the visibility of air and on the earth's climate. In this study, we used a black carbon analyzer (Model AE33) to conduct field measurements in northern suburban Nanjing from March 2021 to February 2022. We measured the light absorption coefficients of BrC in PM2.5 and quantified the contributions of primary (BrCpri) and secondary brown carbon (BrCsec) in BrC by using the minimum correlation method (MRS), combined with the backward trajectories,potential source contribution function (PSCF) analysis, and diurnal patterns to analyze the seasonal characteristics of BrC. The results showed that the annual average light absorption of BrC was(7.76±7.17)Mm-1 (at 370 nm), and its contribution to the total aerosol light absorption was (22.0±8.8)%. BrC light absorption at different wavelengths all showed a U-shape seasonal variation of high in spring and winter and low in summer and fall. MRS analysis showed that the annual average contributions of BrCpri and BrCsec were (62.9±21.4)% and (37.1±21.4)% (at 370 nm), respectively; however, the contribution of BrCsec increased with the increase in wavelength, and it became dominant in longer wavelengths such as 660 nm. Backward trajectory and PSCF analysis showed that BrC was heavily influenced by air masses from the sea in spring, summer, and fall but was influenced greatly by local and regional continental emissions in winter. Traffic emissions in spring, summer, and fall were more intense to contribute to BrCpri than that in winter, whereas coal and biomass combustion had a greater impact on BrCpri in winter. Detailed analysis revealed that gas-phase photochemistry and aqueous chemistry had different influences on BrCsec formation in different seasons. It was mainly from gas-phase photochemistry in summer but was dominated by aqueous process in winter; both processes, however, were important pathways to BrCsec in spring and fall.
ABSTRACT
Objective: Minority stressors are associated with increased psychological distress, and social support is considered as a significant protective factor to mitigate the psychological distress in LGB individuals. In China, LGB individuals suffer additional pressure from society and family, but only a few studies have explored the effect of social support on the psychological distress of Chinese LGB individuals and the mechanism underlying the association. The current study aimed to examine the mediating role of self-esteem in the relationship between three sources of social support (from family, friends, and others) and psychological distress in Chinese LGB individuals. Methods: 227 LGB individuals (M age = 25.9 years; SD = 5.6) who were voluntarily recruited by a combination of snowballing and targeted sampling strategies. Path analysis was used to test the associations between variables. Results: Results indicated that 31.3% of LGB individuals had a high level of psychological distress. The results showed that social support from family, friends, and others was associated with higher levels of self-esteem and lower levels of psychological distress. Only the mediating effect of self-esteem was found between friend support and psychological distress. Conclusions: This study demonstrated that friend support might be a protective factor against psychological distress in Chinese LGB individuals, and more friend support could potentially relieve psychological distress by building higher self-esteem. These results highlight the importance of fostering friend support in the group of Chinese LGB individuals.