Enzyme Core Spherical Nucleic Acid That Enables Enhanced Cuproptosis and Antitumor Immune Response through Alleviating Tumor Hypoxia.

Cuproptosis, a copper-dependent cell death process, has been confirmed to further activate the immune response and mediate the immune resistance. However, hypoxic tumor microenvironment hampers cuproptosis sensitivity and suppresses the body's antitumor immune response. Herein, we have successfully immobilized and functionalized catalase (CAT) with long single-stranded DNA containing polyvalent CpG sequences through rolling circle amplification (RCA) techniques, obtaining an enzyme-cored spherical nucleic acid nanoplatform (CAT-ecSNA-Cu) to deliver copper ions for cuproptosis. The presence of long-stranded DNA-protected CAT enhances mitochondrial respiration by catalyzing the conversion of H2O2 to O2, thereby sensitizing cuproptosis. Meanwhile, increased tumor oxygenation suppresses the expression of the hypoxia-inducible factor-1 (HIF-1) protein, resulting in the alleviation of the immunosuppressive tumor microenvironment. Of note, cuproptosis induces immunogenic cell death (ICD), which facilitates dendritic cell (DC) maturation and enhances antigen presentation through polyCpG-supported Toll-like receptor 9 (TLR9) activation. Furthermore, cuproptosis-induced PD-L1 upregulation in tumor cells complements checkpoint blockers (αPD-L1), enhancing antitumor immunity. The strategy of enhancing cuproptosis-mediated antitumor immune responses by alleviating hypoxia effectively promotes the activation and proliferation of effector T cells, ultimately leading to long-term immunity against cancer.

Dual-trait genomic analysis in highly stratified Arabidopsis thaliana populations using genome-wide association summary statistics.

Genome-wide association study (GWAS) is a powerful tool to identify genomic loci underlying complex traits. However, the application in natural populations comes with challenges, especially power loss due to population stratification. Here, we introduce a bivariate analysis approach to a GWAS dataset of Arabidopsis thaliana. We demonstrate the efficiency of dual-phenotype analysis to uncover hidden genetic loci masked by population structure via a series of simulations. In real data analysis, a common allele, strongly confounded with population structure, is discovered to be associated with late flowering and slow maturation of the plant. The discovered genetic effect on flowering time is further replicated in independent datasets. Using Mendelian randomization analysis based on summary statistics from our GWAS and expression QTL scans, we predicted and replicated a candidate gene AT1G11560 that potentially causes this association. Further analysis indicates that this locus is co-selected with flowering-time-related genes. The discovered pleiotropic genotype-phenotype map provides new insights into understanding the genetic correlation of complex traits.

Investigation on large-scale 3D seepage characteristics of a pumped-storage power station: a case study in Zhejiang Province, China.

Pumped-storage power stations (PSPSs) have higher requirements for anti-seepage compared with regular power stations. As a result, investigating the seepage distributions of PSPSs is particularly important. However, existing researches remain limited in assessing engineering needs such as ensuring the efficiency of a power station. Taking the Qingyuan PSPS as a typical case, this study aims to investigate the large-scale seepage field distribution while exploring the efficiency of the anti-seepage system. Considering the geological characteristics and structural location, a 3D finite element model is established. Based on the continuous medium model while combined with seepage control measures, the change in leakage while the anti-seepage system failed is further assessed. It is concluded that the operation status of anti-seepage measures will have a certain impact on the leakage volumes of each part. Using a comprehensive assessment, anti-seepage measures can effectively prevent seepage. When failure occurs on anti-seepage curtains, the leakage volume at the corresponding position will show an obvious growth. In summary, the findings of this study highlight the significance of avoiding excessive leakage caused by anti-seepage structure failure, the effective operation of anti-seepage measures must be ensured. The abovementioned results can provide scientific support for the seepage optimization design of PSPSs.

Phytotoxicity of VO2 nanoparticles with different sizes to pea seedlings.

Vanadium dioxide nanoparticles (VO2 NPs) have been massively produced due to their excellent metal-insulator transition characteristics for various applications. Pilot studies indicated the toxicity of VO2 NPs to bacteria and mammalian cells, but the environmental hazards of VO2 NPs to plants have been unrevealed to date. In this study, we reported the inhibitive effects of VO2 NPs to the growth and photosynthesis of pea seedlings. Laboratory synthesized monoclinic VO2 NPs (N-VO2), commercial nanosized VO2 NPs (S-VO2), and commercial microsized VO2 particles (M-VO2) were carefully characterized for environmental toxicity evaluations. VO2 particles were supplemented to culture medium for seed germination and seedling growth. All three VO2 samples did not affect the germination rates of pee seeds, while serious growth inhibition of pea seedlings was observed at 10 mg/L for S-VO2 and N-VO2, and 100 mg/L for M-VO2. VO2 particles had no impact on the chlorophyll contents, but the photosynthesis of leaf was significantly decreased following the consequence of N-VO2 > S-VO2 > M-VO2. The inhibition of photosynthesis was attributed to the damage of acceptor side of photosystem II by VO2 particles at high concentrations. Abundant bioaccumulations of vanadium in roots aroused oxidative damage and changed the root structure. Our results collectively indicated that the phytotoxicity of VO2 NPs was related to the concentration, size and crystalline degree.

Exosomes derived from lipopolysaccharide-preconditioned human dental pulp stem cells regulate Schwann cell migration and differentiation.

Purpose: Schwann cells (SCs) are the main source of odontoblasts. They can migrate to the sites of injury and differentiate into odontoblasts during tooth development and regeneration. However, the molecular mechanisms by which SCs repair dental damage remain to be fully elucidated. In addition, exosomes play a crucial role in regulating cell-cell interaction. Hence, we aim to explore the biological function of exosomes secreted by human dental pulp stem cells (hDPSCs) and their effect on SCs.Materials and Methods: Exosomes were extracted from the supernatant of hDPSCs (exo) and LPS- preconditioned hDPSCs (LPS-exo), respectively. Following the evaluation of specific surface proteins and exosomes size and morphology, SCs were treated with exo and LPS-exo, and we examined SCs proliferation, migration, and odontogenic differentiation in vitro.Results: Exosomes had the capacity to regulate SCs proliferation and migration. Furthermore, exosomes from both groups stimulated SCs to produce dentin sialoprotein and undergo mineralization; however, LPS-exo had a better ability to modulate SCs migration and odontogenic differentiation compared with exo.Conclusions: Exosomes from hDPSCs, especially from LPS- preconditioned hDPSCs, can promote the proliferation, migration and odontogenic differentiation of SCs. LPS might change the hDPSCs' intercellular signals, which might mediate the odontogenic differentiation of SCs, transmitting in the manner of "exosomes".

Cytotoxicity of vanadium dioxide nanoparticles to human embryonic kidney cell line: Compared with vanadium(IV/V) ions.

Vanadium dioxide (VO2) is a class of thermochromic material with potential applications in various fields. Massive production and wide application of VO2 raise the concern of its potential toxicity to human, which has not been fully understood. Herein, a commercial VO2 nanomaterial (S-VO2) was studied for its potential toxicity to human embryonic kidney cell line HEK293, and two most common vanadium ions, V(IV) and V(V), were used for comparison to reveal the related mechanism. Our results indicate that S-VO2 induces dose-dependent cellular viability loss mainly through the dissolved V ions of S-VO2 outside the cell rather than S-VO2 particles inside the cell. The dissolved V ions of S-VO2 overproduce reactive oxygen species to trigger apoptosis and proliferation inhibition via several signaling pathways of cell physiology, such as MAPK and PI3K-Akt, among others. All bioassays indicate that the differences in toxicity between S-VO2, V(IV), and V(V) in HEK293 cells are very small, supporting that the toxicity is mainly due to the dissolved V ions, in the form of V(V) and/or V(IV), but the V(V)'s behavior is more similar to S-VO2 according to the gene expression analysis. This study reveals the toxicity mechanism of nanosized VO2 at the molecular level and the role of dissolution of VO2, providing valuable information for safe applications of vanadium oxides.

Arthroscopy-Assisted Closed Reduction and Percutaneous Internal Fixation for Medial Malleolus Fracture.

BACKGROUND: Arthroscopy-assisted closed reduction and percutaneous internal fixation is a minimally invasive technique for medial malleolus fracture treatment. The purpose of the study was to assess the quality and functional outcomes of this technique. METHODS: Seventy-eight patients with combined medial malleolus fractures were treated with arthroscopy-assisted closed reduction and percutaneous screw fixation technique. The surgical procedure was described in detail; the clinical efficacy of this method was evaluated in terms of time of operation, postoperative complications, and fracture healing time; and functional outcomes were analyzed. RESULTS: All of the patients were followed up for a minimum of 12 months without complications of the medial malleolus wound, and all of the medial malleolus fractures healed within 6 to 8 weeks. At the last follow-up, the visual analog scale scores ranged from 0 to 3 and the American Orthopaedic Foot and Ankle Society ankle and hindfoot function scores ranged from 75 to 95. CONCLUSIONS: Arthroscopy-assisted closed reduction and percutaneous internal fixation makes the treatment of medial malleolus fractures less invasive compared with traditional surgical methods and allows simultaneous exploration and management of the articular surface.

Polyvalent Aptamer-Functionalized NIR-II Quantum Dots for Targeted Theranostics in High PD-L1-Expressing Tumors.

Ag2S quantum dots (QDs) show superior optical properties in the NIR-II region and display significant clinical potential with favorable biocompatibility. However, inherent defects of low targeting and poor solubility necessitate practical modification methods to achieve the theranostics of Ag2S QDs. Herein, we used rolling circle amplification (RCA) techniques to obtain long single-stranded DNA containing the PD-L1 aptamer and C-rich DNA palindromic sequence. The C-rich DNA palindromic sequences can specifically chelate Ag2+ and thus serve as a template to result in biomimetic mineralization and formation of pApt-Ag2S QDs. These QDs enable specific targeting and illuminate hot tumors with high PD-L1 expression effectively, serving as excellent molecular targeted probes. In addition, due to the high NIR-II absorption of Ag2S QDs, pApt-Ag2S QDs exhibit remarkable photothermal properties. And besides, polyvalent PD-L1 aptamers can recognize PD-L1 protein and effectively block the inhibitory signal of PD-L1 on T cells, enabling efficient theranostics through the synergistic effect of photothermal therapy and immune checkpoint blocking therapy. Summary, we enhance the biological stability and antibleaching ability of Ag2S QDs using long single-stranded DNA as a template, thereby establishing a theranostic platform that specifically targets PD-L1 high-expressing inflamed tumors and demonstrates excellent performance both in vitro and in vivo.

Decreased plasma apolipoprotein A-IV levels in patients with acute coronary syndrome.

PURPOSE: The purpose of this study was to evaluate the relationship between apolipoprotein A-IV (apoA-IV) plasma concentrations and acute coronary syndrome (ACS). METHODS: Plasma apoA-IV concentrations were measured in 115 patients with different types of ACS and in 68 gender- and age-matched control subjects using Enzyme-Linked Immunosorbent Assay (ELISA) kits. The clinical data were collected by an internist, who was blinded to plasma apoA-IV concentrations. RESULTS: Plasma apoA-IV levels in ACS patients were significantly decreased compared to the levels in control subjects (437.0±157.5 µg/mL vs. 590.2±183.7 µg/mL, P<0.001). An statistically significant decreasing trend of plasma apoA-IV levels from the control subjects, to patients with unstable angina pectoris (UAP) (457.3±152.9 µg/mL), to patients with acute myocardial infarction (AMI) (311.7±127.8 µg/mL), was observed. Moreover, plasma apoA-IV level was negatively associated with New York Heart Association (NYHA) functional class. NYHA class II (467.2±142.1 µg/mL, P<0.001) and class III/IV (368.1±170.8 µg/mL, P<0.001) patients had statistically decreased levels of plasma apoA-IV when compared to the control subjects. A stepwise multivariate regression analysis identified types of ACS, NYHA classes, and plasma fibrinogen levels as the most important determinants of plasma apoA-IV levels in ACS patients. CONCLUSIONS: Low plasma apoA-IV levels are associated with ACS, and plasma apoA-IV levels may be a potential treatment target for ACS patients.

The potencies and neurotoxicity of intrathecal levobupivacaine in a rat spinal model: Effects of concentration.

This study was aimed at examining the anesthetic effects and spinal cord injuries in the rats by intrathecal injection of levobupivacaine at different concentrations. Rats with successful intrathecal cannulation were selected and randomly divided into six groups (n = 72), and administered 0.1 mL of 0.125%, 0.25%, 0.5%, or 0.75% levobupivacaine, saline or 5% lidocaine via intrathecal catheters. The potency of levobupivacaine was evaluated by walking behavior. To identify the motor and sensory function, walking behavior and paw withdrawal thresholds (PWTs) were measured once a day. After 7 days, the L4-5 spinal cord segments were removed for histological examination. The onset time of 0.125% levobupivacaine intrathecal injection was 70.0 ± 8.9 s, and the maintenance time was 9.5 ± 1.8 min. The onset time of 0.75% levobupivacaine intrathecal injection was significantly shortened to 31.0 ± 5.5 s, and the maintenance time was significantly extended to 31.3 ± 5.4 min. The severe injury was observed in the 5% lidocaine group, while milder injury was observed in the 0.75% levobupivacaine group. The damage in the 0.5% levobupivacaine group was mild, and there were no histological abnormalities in the 0.125%, 0.25% levobupivacaine and saline groups. The neurotoxicity of intrathecally administered levobupivacaine was concentration dependent. In addition, higher concentrations of levobupivacaine were associated with shorter onset and longer maintenance times. The clinical concentration of levobupivacaine should not exceed 0.5% to avoid potential damage.

Effects of extracorporeal circulation with different time on platelet count after cardiac surgery: a retrospective study based on medical records.

Our objective was to observe the effects of extracorporeal circulation (ECC) with different time on platelet count in patients undergoing cardiac surgery. A total of 427 patients who underwent elective cardiac surgery under ECC in affiliated hospital of north Sichuan medical college from January 1, 2018 to July 31, 2021 were divided into three groups according to ECC time. We concluded that thrombocytopenia was common after ECC, maximum drop of the platelet counts after ECC was usually seen on the second day after ECC, and platelet counts started to recover on the fifth day after ECC. With the extension of ECC time, the drop in platelet counts is more pronounced, the volume of perioperative blood loss and blood products transfusion are more, and the recovery level and speed of platelet counts is lower.

Effects of organic amendments and ridge-furrow mulching system on soil properties and economic benefits of wolfberry orchards on the Tibetan Plateau.

Water scarcity and low soil fertility severely constrain crop growth and sustainable agricultural productivity on the Tibetan Plateau. Organic amendments and ridge-furrow mulching system (RFMS) are widely used to improve soil moisture, soil structure, and crop production in arid and semi-arid areas. However, their combined effects on soil physicochemical properties and economic benefits of wolfberry (Lycium barbarum L.) on the Tibetan Plateau remain unclear. A two-year field experiment was undertaken to evaluate the combined effects of organic amendments and RFMS on soil water, soil structure, soil saturated hydraulic conductivity, soil organic carbon (SOC), total nitrogen (TN), and economic benefits on wolfberry. Four cultivation practices were established: traditional flat plot with mulching (FP), traditional flat plot with mulching and organic amendment (FPOA), ridge-furrow planting with mulching (RF), and ridge-furrow planting with mulching and organic amendment (RFOA). The organic amendment and RFMS treatments had higher soil water storage (SWS) and soil desiccation index (SDI) than the FP treatment in both growing seasons, especially at 20-60 cm soil depth. In addition, organic amendment significantly decreased soil bulk density by 6.4% and increased soil saturated hydraulic conductivity by 16.8% in the 0-60 cm soil layer, respectively, and improved the proportion of larger soil aggregates (0.02-2 mm) by 10.8% in the 0-40 cm soil layer. Furthermore, the RFOA treatment significantly improved SOC and TN contents at 0-60 cm soil depth by 47.7% and 19.4%, respectively, relative to FP. The measured soil properties were highly correlated with wolfberry yield and water use efficiency over 2 years. In particular, the RFOA treatment had higher crop yield and economic benefit than the other treatments due to the more favorable soil environment. Therefore, the RFOA treatment could be a sustainable and efficient cultivation practice for alleviating drought stress, improving soil properties, and increasing economic benefit on the Tibetan Plateau.

Structures of +1 nucleosome-bound PIC-Mediator complex.

RNA polymerase II-mediated eukaryotic transcription starts with the assembly of the preinitiation complex (PIC) on core promoters. The +1 nucleosome is well positioned about 40 base pairs downstream of the transcription start site (TSS) and is commonly known as a barrier of transcription. The +1 nucleosome-bound PIC-Mediator structures show that PIC-Mediator prefers binding to T40N nucleosome located 40 base pairs downstream of TSS and contacts T50N but not the T70N nucleosome. The nucleosome facilitates the organization of PIC-Mediator on the promoter by binding TFIIH subunit p52 and Mediator subunits MED19 and MED26 and may contribute to transcription initiation. PIC-Mediator exhibits multiple nucleosome-binding patterns, supporting a structural role of the +1 nucleosome in the coordination of PIC-Mediator assembly. Our study reveals the molecular mechanism of PIC-Mediator organization on chromatin and underscores the significance of the +1 nucleosome in regulating transcription initiation.

Effects of etomidate combined with dexmedetomidine on adrenocortical function in elderly patients: a double-blind randomized controlled trial.

Etomidate has been advocated to be used in anesthesia for the elderly and the critically ill patients due to its faint effect on cardiovascular system. But the dose-dependent suppression of etomidate on adrenal cortex function leads to the limitation of its clinical application. Clinical research showed that dexmedetomidine could reduce the dose requirements for intravenous or inhalation anesthetics and opioids, and the hemodynamics was more stable during the operation. The objective was to observe the effect of etomidate combined with dexmedetomidine on adrenocortical function in elderly patients. 180 elderly patients scheduled for elective ureteroscopic holmium laser lithotripsy were randomly allocated to PR group anesthetized with propofol-remifentanil, ER group anesthetized with etomidate-remifentanil, and ERD group anesthetized with dexmedetomidine combined with etomidate-remifentanil. Patients in each group whose operation time was less than or equal to 1 h were incorporated into short time surgery group (PR1 group, ER1 group and ERD1 group), and whose surgical procedure time was more than 1 h were incorporated into long time surgery group (PR2 group, ER2 group and ERD2 group). The primary outcome was the serum cortisol and ACTH concentration. The secondary outcomes were the values of SBP, DBP, HR and SpO2, the time of surgical procedure, the dosage of etomidate and remifentanil administered during surgery, the time to spontaneous respiration, recovery and extubation, and the duration of stay in the PACU. The Serum cortisol concentration was higher at t1~2 in ERD1 group compared to ER1 group (P < 0.05). The Serum cortisol concentration at t1~3 was higher in ERD2 group than in ER2 group (P < 0.05). The Serum ACTH concentration was lower at t1~2 in ERD1 group compared to ER1 group (P < 0.05). The Serum ACTH concentration at t1~3 was lower in ERD2 group compared to ER2 group (P < 0.05). The SBP at T1 and T3 were higher in ER2 and ERD2 group than in PR2 group (P < 0.05). The DBP in ER1 and ERD1 group were higher at T1 compared to PR1 group (P < 0.05). The dosage of etomidate was significantly lower in ERD1 group and ERD2 group than in ER1 group and ER2 group (P < 0.05), respectively. The administration of dexmedetomidine combined with etomidate can attenuate the inhibition of etomidate on adrenocortical function in elderly patients and maintain intraoperative hemodynamic stability.

RPAP2 regulates a transcription initiation checkpoint by inhibiting assembly of pre-initiation complex.

RNA polymerase II (Pol II)-mediated transcription in metazoans requires precise regulation. RNA Pol II-associated protein 2 (RPAP2) was previously identified to transport Pol II from cytoplasm to nucleus and dephosphorylates Pol II C-terminal domain (CTD). Here, we show that RPAP2 binds hypo-/hyper-phosphorylated Pol II with undetectable phosphatase activity. The structure of RPAP2-Pol II shows mutually exclusive assembly of RPAP2-Pol II and pre-initiation complex (PIC) due to three steric clashes. RPAP2 prevents and disrupts Pol II-TFIIF interaction and impairs in vitro transcription initiation, suggesting a function in inhibiting PIC assembly. Loss of RPAP2 in cells leads to global accumulation of TFIIF and Pol II at promoters, indicating a critical role of RPAP2 in inhibiting PIC assembly independent of its putative phosphatase activity. Our study indicates that RPAP2 functions as a gatekeeper to inhibit PIC assembly and transcription initiation and suggests a transcription checkpoint.

Coordinated regulation of RNA polymerase II pausing and elongation progression by PAF1.

Pleiotropic transcription regulator RNA polymerase II (Pol II)-associated factor 1 (PAF1) governs multiple transcriptional steps and the deposition of several epigenetic marks. However, it remains unclear how ultimate transcriptional outcome is determined by PAF1 and whether it relates to PAF1-controlled epigenetic marks. We use rapid degradation systems and reveal direct PAF1 functions in governing pausing partially by recruiting Integrator-PP2A (INTAC), in addition to ensuring elongation. Following acute PAF1 degradation, most destabilized polymerase undergoes effective release, which presumably relies on skewed balance between INTAC and P-TEFb, resulting in hyperphosphorylated substrates including SPT5. Impaired Pol II progression during elongation, along with altered pause release frequency, determines the final transcriptional outputs. Moreover, PAF1 degradation causes a cumulative decline in histone modifications. These epigenetic alterations in chromatin likely further influence the production of transcripts from PAF1 target genes.

A CORM loaded nanoplatform for single NIR light-activated bioimaging, gas therapy, and photothermal therapy in vitro.

Carbon monoxide (CO) can cause mitochondrial dysfunction, inducing apoptosis of cancer cells, which sheds light on a potential alternative for cancer treatment. However, the existing CO-based compounds are inherently limited by their chemical nature, such as high biological toxicity and uncontrolled CO release. Therefore, a nanoplatform - UmPF - that addresses such pain points is urgently in demand. In this study, we have proposed a nanoplatform irradiated by near-infrared (NIR) light to release CO. Iron pentacarbonyl (Fe(CO)5) was loaded in the mesoporous polydopamine layer that was coated on rare-earth upconverting nanoparticles (UCNPs). The absorption wavelength of Fe(CO)5 overlaps with the emission bands of the UCNPs in the UV-visible light range, and therefore the emissions from the UCNPs can be used to incite Fe(CO)5 to control the release of CO. Besides, the catechol groups, which are abundant in the polydopamine structure, serve as an ideal locating spot to chelate with Fe(CO)5; in the meantime, the mesoporous structure of the polydopamine layer improves the loading efficiency of Fe(CO)5 and reduces its biological toxicity. The photothermal effect (PTT) of the polydopamine layer is highly controllable by adjusting the external laser intensity, irradiation time and the thickness of the polydopamine layer. The results illustrate that the combination of CO gas therapy (GT) and polydopamine PTT brought by the final nanoplatform can be synergistic in killing cancer cells in vitro. More importantly, the possible toxic side effects can be effectively prevented from affecting the organism, since CO will not be released in this system without near-infrared light radiation.

Cytotoxicity and genotoxicity of low-dose vanadium dioxide nanoparticles to lung cells following long-term exposure.

Vanadium dioxide nanoparticles (VO2 NPs) have been massively produced and widely applied due to their excellent metal-insulator transition property, making it extremely urgent to evaluate their safety, especially for low-dose long-term respiratory occupational exposure. Here, we report a comprehensive cytotoxicity and genotoxicity study on VO2 NPs to lung cell lines A549 and BEAS-2B following a long-term exposure. A commercial VO2 NP, S-VO2, was used to treat BEAS-2B (0.15-0.6 µg/mL) and A549 (0.3-1.2 µg/mL) cells for four exposure cycles, and each exposure cycle lasted for 4 consecutive days; then various bioassays were performed after each cycle. Significant proliferation inhibition was observed in both cell lines after long-term exposure of S-VO2 at low doses that did not cause apparent acute cytotoxicity; however, the genotoxicity of S-VO2, characterized by DNA damage and micronuclei, was only observed in A549 cells. These adverse effects of S-VO2 were exposure time-, dose- and cell-dependent, and closely related to the solubility of S-VO2. The oxidative stress in cells, i.e., enhanced reactive oxygen species (ROS) generation and suppressed reduced glutathione, was the main toxicity mechanism of S-VO2. The ROS-associated mitochondrial damage and DNA damage led to the genotoxicity, and cell proliferation retard, resulting in the cellular viability loss. Our results highlight the importance and urgent necessity of the investigation on the long-term toxicity of VO2 NPs.

Effects of VO2 nanoparticles on human liver HepG2 cells: Cytotoxicity, genotoxicity, and glucose and lipid metabolism disorders.

The rapid development of smart materials stimulates the production of vanadium dioxide (VO2) nanomaterials. This significantly increases the population exposure to VO2 nanomaterials via different pathways, and thus urges us to pay more attentions to their biosafety. Liver is the primary accumulation organ of nanomaterials in vivo, but the knowledge of effects of VO2 nanomaterials on the liver is extremely lacking. In this work, we comprehensively evaluated the effects of a commercial VO2 nanoparticle, S-VO2, in a liver cell line HepG2 to illuminate the potential hepatic toxicity of VO2 nanomaterials. The results indicated that S-VO2 was cytotoxic and genotoxic to HepG2 cells, mainly by inhibiting the cell proliferation. Apoptosis was observed at higher dose of S-VO2, while DNA damage was detected at all tested concentrations. S-VO2 particles were internalized by HepG2 cells and kept almost intact inside cells. Both the particle and dissolved species of S-VO2 contributed to the observed toxicities. They induced the overproduction of ROS, and then caused the mitochondrial dysfunction, ATP synthesis interruption, and DNA damages, consequently arrested the cell cycle in G2/M phase and inhibited the proliferation of HepG2 cells. The S-VO2 exposure also resulted in the upregulations of glucose uptake and lipid content in HepG2 cells, which were attributed to the ROS production and autophagy flux block, respectively. Our findings offer valuable insights into the liver toxicity of VO2 nanomaterials, benefiting their safely practical applications.

Clinical Outcome between Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndrome and Diabetes.

BACKGROUND: The increased thrombotic risk in patients with acute coronary syndrome (ACS) and diabetes highlights the need for adequate antithrombotic protection. We aimed to compare the 6-month clinical outcomes between ticagrelor and clopidogrel in patients with ACS and diabetes. METHODS AND RESULTS: The study was a single-center, prospective, randomized, open-label, blinded endpoint, and controlled registry trial. A total of 270 ACS patients with diabetes were randomly assigned in a 1 : 1 ratio to either the ticagrelor group or the clopidogrel group. Follow-up was performed for 6 months, and the data on efficacy outcomes and bleeding events were collected. At 6 months, complete follow-up data were available for 266 (98.5%) of 270 patients, and 4 were lost to follow-up. There was no significant difference in the survival rate of the effective endpoints between the ticagrelor group (n = 133) and the clopidogrel group (n = 133) (HR 0.83, 95% CI 0.44-1.56, p = 0.561), but the incidence of bleeding events in the ticagrelor group was higher than that in the clopidogrel group (HR 1.76, 95% CI 1.00-3.10, p = 0.049). CONCLUSION: Ticagrelor did not improve the composite of nonfatal MI, target vessel revascularization, rehospitalization, stroke, and death from any cause; however, it significantly increased the incidence of bleeding events defined by the Bleeding Academic Research Consortium (BARC) criteria in Chinese patients with ACS and diabetes during the 6-month follow-up compared with clopidogrel.