Association of sdLDL-C With Incident Carotid Plaques With Stable and Vulnerable Morphology: A Prospective Cohort Study.

BACKGROUND: Small dense low-density lipoprotein cholesterol (sdLDL-C) particles are more atherogenic than large and intermediate low-density lipoprotein cholesterol (LDL-C) subfractions. We sought to investigate the association of sdLDL-C and the sdLDL-C/LDL-C ratio with incident carotid plaques with stable and vulnerable morphology in rural China. METHODS: This community-based cohort study used data from the RICAS study (Rose Asymptomatic Intracranial Artery Stenosis), which enrolled 887 participants (aged ≥40 years) who were living in Kongcun Town, Pingyin County, Shandong, and free of carotid plaques and had no history of clinical stroke or transient ischemic attack at baseline (2017). Incident carotid plaques and their vulnerability were detected by carotid ultrasound at follow-up (2021). Multivariable logistic regression models were used to explore the association of sdLDL-C or sdLDL-C/LDL-C ratio with incident carotid plaques while adjusting for demographic factors, vascular risk factors, and follow-up time. RESULTS: Of the 887 participants (mean age [SD], 53.89 [8.67%] years; 54.34% women), 179 (20.18%) were detected with incident carotid plaques during an average follow-up of 3.94 years (SD=0.14). Higher sdLDL-C or sdLDL-C/LDL-C ratio, but not LDL-C, was significantly associated with an increased risk of incident carotid plaques. The upper tertile of sdLDL-C (versus lower tertile) was associated with the multivariate-adjusted odds ratio of 2.48 (95% CI, 1.00-6.15; P=0.049; P for linear trend=0.046) for carotid plaques with vulnerable morphology (n=41), and the association remained significant in participants with normal LDL-C (<130 mg/dL; n=693; upper versus lower tertile: odds ratio, 3.38 [95% CI, 1.15-9.90]; P=0.027; P for linear trend=0.025). Moreover, the sdLDL-C/LDL-C ratio was associated with a higher odds ratio of incident carotid plaques in participants without diabetes (P for interaction=0.014). CONCLUSIONS: Higher sdLDL-C was associated with an increased risk of incident carotid plaques, especially carotid plaques with vulnerable morphology, even in participants with normal LDL-C. This suggests the potential of sdLDL-C as a therapeutic target for stroke prevention. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR1800017197.

Facile Synthesis of Quinoline-Substituted 3-Hydroxy-2-oxindoles and 3-Amino-2-oxindoles via a Palladium-Catalyzed Cascade Intramolecular Cyclization/Intermolecular Nucleophilic Addition Reaction.

An efficient cascade intramolecular cyclization/intermolecular nucleophilic addition reaction of allenyl benzoxazinone with isatin or isatin-derived ketimine has been established by using Pd0-π-Lewis base catalysis. A series of 3-hydroxy-2-oxindoles and 3-amino-2-oxindoles with quaternary carbon atoms at the C3 position were synthesized in good yields under mild conditions through this protocol.

A continuously efficient O2-supplying strategy for long-term modulation of hypoxic tumor microenvironment to enhance long-acting radionuclides internal therapy.

Radionuclides internal radiotherapy (RIT) is a clinically powerful method for cancer treatment, but still poses unsatisfactory therapeutic outcomes due to the hypoxic characteristic of tumor microenvironment (TME). Catalase (CAT) or CAT-like nanomaterials can be used to enzymatically decompose TME endogenous H2O2 to boost TME oxygenation and thus alleviate the hypoxic level within tumors, but their effectiveness is still hindered by the short-lasting of hypoxia relief owing to their poor stability or degradability, thereby failing to match the long therapeutic duration of RIT. Herein, we proposed an innovative strategy of using facet-dependent CAT-like Pd-based two-dimensional (2D) nanoplatforms to continuously enhance RIT. Specifically, rationally designed 2D Pd@Au nanosheets (NSs) enable consistent enzymatic conversion of endogenous H2O2 into O2 to overcome hypoxia-induced RIT resistance. Furthermore, partially coated Au layer afford NIR-II responsiveness and moderate photothermal treatment that augmenting their enzymatic functionality. This approach with dual-effect paves the way for reshaping TME and consequently facilitating the brachytherapy ablation of cancer. Our work offers a significant advancement in the integration of catalytic nanomedicine and nuclear medicine, with the overarching goal of amplifying the clinical benefits of RIT-treated patients.

Analysis for codon usage bias in membrane anchor of nonstructural protein 5A from BVDV.

The nonstructural protein 5A (NS5A) of the bovine viral diarrhea virus (BVDV) is a monotopic membrane protein. This protein can anchor to the cell membrane by an in-plane amphipathic ⍺-helix, which participates in the viral replication complex. In this study, the effects of synonymous codon usage pattern of NS5A and the overall transfer RNA (tRNA) abundance in cells on the formation of the in-plane membrane anchor of NS5A were analyzed, based on NS5A coding sequences of different BVDV genotypes. BVDV NS5A coding sequences represent the most potential for BVDV genotyping. Moreover, the nucleotide usage of BVDV NS5A dominates the genotype-specific pattern of synonymous codon usage. There is an obvious relationship between synonymous codon usage bias and the spatial conformation of the in-plane membrane anchor. Furthermore, the overall tRNA abundance profiling displays that codon positions with a high level of tRNA abundance are more than ones with a low level of tRNA abundance in the in-plane membrane anchor, implying that high translation speed probably acts on the spatial conformation of in-plane membrane anchor of BVDV NS5A. These results give a new opinion on the effect of codon usage bias in the formation of the in-plane membrane anchor of BVDV NS5A.

Nucleotide and codon usage biases involved in the evolution of African swine fever virus: A comparative genomics analysis.

Since African swine fever virus (ASFV) replication is closely related to its host's machinery, codon usage of viral genome can be subject to selection pressures. A better understanding of codon usage can give new insights into viral evolution. We implemented information entropy and revealed that the nucleotide usage pattern of ASFV is significantly associated with viral isolation factors (region and time), especially the usages of thymine and cytosine. Despite the domination of adenine and thymine in the viral genome, we found that mutation pressure alters the overall codon usage pattern of ASFV, followed by selective forces from natural selection. Moreover, the nucleotide skew index at the gene level indicates that nucleotide usages influencing synonymous codon bias of ASFV are significantly correlated with viral protein hydropathy. Finally, evolutionary plasticity is proved to contribute to the weakness in synonymous codons with A- or T-end serving as optimal codons of ASFV, suggesting that fine-tuning translation selection plays a role in synonymous codon usages of ASFV for adapting host. Taken together, ASFV is subject to evolutionary dynamics on nucleotide selections and synonymous codon usage, and our detailed analysis offers deeper insights into the genetic characteristics of this newly emerging virus around the world.

Hemodialysis Arteriovenous Fistula Dysfunction: Retrospective Comparison of Post-thrombotic Percutaneous Endovascular Interventions with Pre-emptive Angioplasty.

BACKGROUND: We aimed to compare the clinical outcomes of pre-emptive angioplasty versus post-thrombotic percutaneous endovascular restoration of dysfunctional arteriovenous fistula (AVF). METHODS: This retrospective study reviewed the data from 80 patients who underwent 114 endovascular interventions for a malfunctioning AVF from July 2016 to August 2019. Stenotic AVFs were treated with pre-emptive angioplasty. Thrombosed AVFs were treated with percutaneous pharmacomechanical fibrinolysis with urokinase used only during the operation or continuously infused. The differences in patency rates were evaluated using the Kaplan-Meier method. In addition, univariate and multivariate regression Cox models were used to determine influential factors on the postintervention primary patency. RESULTS: Post-thrombotic interventions and pre-emptive angioplasty yielded statistically similar rates in clinical success (100 vs. 100%), anatomic success (94 vs. 89%; P = 0.52), complication (4 vs. 11%; P = 0.29), as well as postintervention primary, assisted primary and secondary patency (P = 0.80; 0.57; 0.57). The use of pre-emptive angioplasty was associated with reduced total cost (¥25,108 vs. ¥30,833, P < 0.001). The patients who used urokinase only during the operation prolonged both the primary and assisted primary patency (P = 0.02; 0.002), while those with continuous infusion of urokinase had worst patency rates and high costs (¥39,275 vs. ¥25,108 vs. ¥27,140, P < 0.001). Compared with the other locations, dysfunction in the anastomotic or juxta-anastomotic segment (HR = 0.41, P = 0.001) was associated with prolonged postintervention primary patency. CONCLUSIONS: No clinical outcome differences were found between the post-thrombotic percutaneous endovascular interventions and pre-emptive angioplasty. However, pre-emptive angioplasty decreased access expenditure.

Five novel RB1 gene mutations and genotype-phenotype correlations in Chinese children with retinoblastoma.

PURPOSE: To identify the spectrum of RB1 gene mutations in 114 Chinese patients with retinoblastoma. METHODS: Genomic DNA was extracted from the peripheral blood of 114 Rb patients. Polymerase chain reactions (PCRs) followed by direct Sanger sequencing were used to screen for mutations in the RB1 gene, which contains 26 exons with flanking intronic sequences, except exon 15. Clinical data, including gender, age at diagnosis, laterality of ocular lesions, and associated symptoms, were recorded and compared. RESULTS: We identified five novel mutations in the RB1 gene. Twenty-five other mutations found in this study have been previously reported. A higher rate of RB1 mutations, with 47.3% of mutations among bilaterally affected patients vs. 6.8% within unilaterally affected patients, was also observed (p < 0.0001). Bilaterally affected patients were diagnosed earlier when compared to unilaterally affected patients (11 ± 7 months versus 20 ± 14 months, p = 0.0002). Furthermore, nonsense mutations were abundant (n = 14), followed by frameshift mutations (n = 8), splicing site mutations (n = 5), while missense mutations were few (n = 3). CONCLUSIONS: We found five novel mutations in RB1 genes, which expands the mutational spectrum of the gene. Children with bilateral Rb exhibited higher mutation rates and were diagnosed earlier than those with unilateral Rb. These findings will inform clinical diagnosis and genetic therapeutic targeting in Rb patients.

Facile and scalable fabrication of self-assembled Cu architecture with superior antioxidative properties and improved sinterability as a conductive ink for flexible electronics.

The inherent susceptibility to oxidation and poor sinterability significantly limit the practical application of Cu-based conductive inks. Most methodologies employed for the inks like organic polymer coatings and inorganic metal deposition are generally ineffective. Herein, we report the design of a novel hierarchical Cu architecture to simultaneously improve the antioxidative and sinterability via a self-passivation mechanism and loose interior structures. The hierarchical Cu architecture was prepared using copper hydroxide, L-ascorbic acid, and polyvinylpyrrolidone in aqueous solution; 40 g Cu were prepared in a scale-up experiment. A possible growth mechanism is proposed, involving the Cu2O-templated and mediated nucleation and growth of Cu nanocrystals, followed by the PVP-directed electrostatic self-assembly of Cu nanocrystals. The synthesized Cu shows high oxidation resistance after stored in ambient environment for 90 d by self-passivation, wherein the dense oxidized external layer prevented further oxidation of Cu, unlike other antioxidative strategies. In addition, the structure became 2D flake after a simple ball-milling for 10 min of 2000r, thus forming a good conductive network at the temperature of 180 °C. Importantly, no obvious decline in the electrical performance after severe surface oxidation. Although the structure cannot offer excellent conductive performance, but it proposes a new solution for the balance of antioxidative capabilities and good sinterability in Cu nanomaterials, thus facilitating greater utilization of Cu-based conductive inks for emerging flexible electronic applications.

ApoA-1 Mimetic Peptide ELK-2A2K2E Decreases Inflammatory Factor Levels Through the ABCA1-JAK2-STAT3-TTP Axis in THP-1-Derived Macrophages.

OBJECTIVE: The aim of this study was to determine whether the apolipoprotein A-1 (apoA-1) mimetic peptide ELK-2A2K2E regulates inflammatory cytokine expression through activating the adenosine triphosphate-binding cassette transporter A1 (ABCA1)-janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3)-tristetraprolin (TTP) signaling pathway in THP-1 macrophage-derived foam cells. METHODS AND RESULTS: The cells were treated with the apoA-1 mimetic peptide ELK-2A2K2E at different concentrations (0, 20, 40, and 80 µg/mL) or incubated with ELK-2A2K2E (40 µg/mL) for different times (0, 6, 12, and 24 hours). Our results showed that the levels of the cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1), were decreased at both concentration- and time-dependent manners. When the cells were exposed to lipopolysaccharides and actinomycin D, ELK-2A2K2E significantly decreased the mRNA stability of inflammatory cytokines at different time points (0, 30, 60, and 120 minutes) by increasing TTP expression as analyzed by real-time quantitative polymerase chain reaction. The effect of ELK-2A2K2E on TTP was obviously blocked by the inhibition of the JAK-STAT3 pathway. Furthermore, we found that ELK-2A2K2E activated the JAK-STAT3-TTP pathway through the upregulation of ABCA1 and then decreased inflammatory cytokine expression. CONCLUSIONS: ApoA-I mimetic peptide ELK-2A2K2E increases the degradation of TNF-α, IL-6, and MCP-1 mRNA and reduces the levels of inflammatory cytokines through activating the JAK2-STAT3-TTP signaling pathway that is dependent on the upregulation of ABCA1.

Photocatalytic Degradation of Oxytetracycline by Ternary Mixed Catalyst and Toxicity Assessment Using Boar Sperm.

Response surface methodology was adopted to obtain ternary mixed catalysts of TiO2-loaded ZSM-5 zeolite and graphene. Oxytetracycline was used as challenged toxicant to evaluate the photocatalytic degradation efficiency of the composites. The optimal weight ratio of graphene, TiO2, and ZSM-5 was 1:8:1. The composites were characterized by ultraviolet-visible spectroscopy, X-ray diffraction, fourier transform infrared, N2 adsorption-desorption isotherms, and transmission electron microscope with an energy-dispersive spectroscopy system, etc. Synthesized samples showed high stability and strong visible-light absorption efficiency. The optimal operating conditions of oxytetracycline photocatalytic degradation were achieved over a wide range of pH and temperature. With 0.1 g/L of optimal ternary mixed composite, the photocatalytic degradation of oxytetracycline was nearly reached completion within 150 min at all treatment temperatures at pH 7. Toxicity of degraded oxytetracycline solution was assayed by a boar sperm quality model using fluorescent staining and flow cytometry. During 180 min of photocatalytic treatment, the degraded oxytetracycline solution showed increasing biotoxicity and changed the morphology and function of boar sperm, despite not killing them.