Codelivery of TRAIL and Mitomycin C via Liposomes Shows Improved Antitumor Effect on TRAIL-Resistant Tumors.

Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) constitutes a promising antitumor drug, tumor resistance to TRAIL has become a major obstacle in its clinical application. Mitomycin C (MMC) is an effective TRAIL-resistant tumor sensitizer, which indicates a potential utility of combination therapy. However, the efficacy of this combination therapy is limited owing to its short half-life and the cumulative toxicity of MMC. To address these issues, we successfully developed a multifunctional liposome (MTLPs) with human TRAIL protein on the surface and MMC encapsulated in the internal aqueous phase to codeliver TRAIL and MMC. MTLPs are uniform spherical particles that exhibit efficient cellular uptake by HT-29 TRAIL-resistant tumor cells, thereby inducing a stronger killing effect compared with control groups. In vivo assays revealed that MTLPs efficiently accumulated in tumors and safely achieved 97.8% tumor suppression via the synergistic effect of TRAIL and MMC in an HT-29 tumor xenograft model while ensuring biosafety. These results suggest that the liposomal codelivery of TRAIL and MMC provides a novel approach to overcome TRAIL-resistant tumors.

Three-Pronged Flower-like Nanoplatforms for the Photothermal/Photodynamic/Quaternary Ammonium Salt Synergistic Antibacterial Method and Bioimaging.

Bacterial infections caused by pathogenic bacteria are extremely threatening to human health. Currently, the treatment of bacterial infections relies heavily on antibiotics, leading to a high incidence of antibiotic abuse. Bacterial resistance appeared along with the misuse of antibiotics that produced growing harm to human beings. Therefore, a cutting-edge strategy for treating bacterial infections is indeed needed. Here we prepared QCuRCDs@BMoS2 nanocomposites (QBs) for an efficient bacterial trapping and triple quaternary ammonium salt/photothermal/photodynamic bactericidal method. Copper-doped carbon quantum dots were first prepared by using a solvothermal method, modified with quaternary ammonium salts, and then combined with grafted MoS2 nanoflowers. The long alkyl chains of QBs and the sharp surface of MoS2 facilitate the destruction of bacterial structures, while the electrostatic adsorption binds closely to bacteria, shortening the bactericidal distance of the reactive oxygen species (ROS). Moreover, the excellent photothermal performance under 808 nm irradiation in the near-infrared (NIR) region and deep penetrating heat can accelerate oxidative stress and achieve a multisynergistic bactericidal purpose. Consequently, QBs with ideal antibacterial properties and inherent brightness hold great promise in the biomedical field.

Liposome-Based Co-Immunotherapy with TLR Agonist and CD47-SIRPα Checkpoint Blockade for Efficient Treatment of Colon Cancer.

Antitumor immunity is an essential component of cancer therapy and is primarily mediated by the innate immune response, which plays a critical role in initiating and shaping the adaptive immune response. Emerging evidence has identified innate immune checkpoints and pattern recognition receptors, such as CD47 and Toll-like receptor 7 (TLR7), as promising therapeutic targets for cancer treatment. Based on the fusion protein Fc-CV1, which comprises a high-affinity SIRPα variant (CV1), and the Fc fragment of the human IgG1 antibody, we exploited a preparation which coupled Fc-CV1 to imiquimod (TLR7 agonist)-loaded liposomes (CILPs) to actively target CT26. WT syngeneic colon tumor models. In vitro studies revealed that CILPs exhibited superior sustained release properties and cell uptake efficiency compared to free imiquimod. In vivo assays proved that CILPs exhibited more efficient accumulation in tumors, and a more significant tumor suppression effect than the control groups. This immunotherapy preparation possessed the advantages of low doses and low toxicity. These results demonstrated that a combination of immune checkpoint blockade (ICB) therapy and innate immunity agonists, such as the Fc-CV1 and imiquimod-loaded liposome preparation utilized in this study, could represent a highly effective strategy for tumor therapy.

An Optimally Designed Engineering Exosome-Reductive COF Integrated Nanoagent for Synergistically Enhanced Diabetic Fester Wound Healing.

Oxidative stress and local overactive inflammation have been considered major obstacles in diabetic wound treatment. Although antiphlogistic tactics have been reported widely, they are also challenged by pathogen contamination and compromised angiogenesis. Herein, a versatile integrated nanoagent based on 2D reductive covalent organic frameworks coated with antibacterial immuno-engineered exosome (PCOF@E-Exo) is reported to achieve efficient and comprehensive combination therapy for diabetic wounds. The E-Exo is collected from TNF-α-treated mesenchymal stem cells (MSCs) under hypoxia and encapsulated cationic antimicrobial carbon dots (CDs). This integrated nanoagent not only significantly scavenges reactive oxygen species and induces anti-inflammatory M2 macrophage polarization, but also stabilizes hypoxia-inducible factor-1α (HIF-1α). More importantly, the PCOF@E-Exo exhibits intriguing bactericide capabilities toward Gram-negative, Gram-positive, and drug-resistant bacteria, showing favorable intracellular bacterial destruction and biofilm permeation. In vivo results demonstrate that the synergetic impact of suppressing oxidative injury and tissue inflammation, promoting angiogenesis and eradicating bacterial infection, could significantly accelerate the infected diabetic fester wound healing with better therapeutic benefits than monotherapy or individual antibiotics. The proposed strategy can inspire further research to design more delicate platforms using the combination of immunotherapy with other therapeutic methods for more efficient ulcerated diabetic wounds treatments.

Hydrophilic Nanocomposite Films with a Fence-Structure-Induced Labyrinth Effect for Greenhouse Cooling and Light Enhancement.

In this paper, we reported a new kind of cooling and light-enhanced hydrophilic nanocomposite film (PE/JW-0.8%) with low-density polyethylene (LDPE) as the substrate. The wetting, photophysical, and mechanical properties of PE/JW-0.8% were tested. The emission band of the fluorescence centers at 420 nm, which is perfectly consistent with the absorption spectrum of plant photosynthesis. In addition, light can be scattered by PE/JW-0.8% to achieve a larger light distribution area. PE/JW-0.8% showed a good durability of hydrophilicity in the water rinsing test. Meanwhile, the elongation at the break of the film was significantly increased. Benefiting from the fence structure induced labyrinth effect, a maximum reduction of 6.7 °C in temperature monitoring for PE/JW-0.8% was observed in the detailed field experiments. Light intensity monitoring showed that light intensity in PE/JW-0.8% increased by a maximum of 57.1% compared to PE/LH. In the biological quality analysis of melon, it was found that the soluble sugar, soluble solid, and vitamin C content of melon increased by 13.34, 22.96, and 50.95%, respectively. In conclusion, these results confirm that PE/JW-0.8% has great application potential in the field of facility agriculture, buildings, and photovoltaic modules.

The clinical effect of WeChat-based MUST education model on patients with chronic heart failure.

OBJECTIVE: To explore the effect of WeChat-based MUST nursing intervention on self-care ability and quality of life in patients with chronic heart failure. METHOD: Convenient sampling was used to select CHF patients who received treatment in XX Hospital from January 1, 2020, to December 30, 2020, as the study subjects and was divided into the experimental group (n = 60) and the control group (n = 60) according to the random number table. The experimental group used the WeChat-based MUST nursing intervention, and the control group used the routine education and follow-up model. Cardiac function parameters, self-care ability, and other indicators were compared between the two groups before and after nursing. The clinical effect of two groups was evaluated. RESULTS: After the nursing intervention, LVEF levels were increased to different extents and NT-proBNP was decreased to different extents in both groups. LVEF level in the experimental group was higher than that in the control group, and the NT-proBNP level in the experimental group was lower than that in the control group. After the nursing intervention, the self-care ability and quality of life of the two groups were increased to varying degrees. Self-care ability was higher in the experimental group than in the control group, and quality of life was higher in the experimental group than in the control group. CONCLUSION: The WeChat-based MUST nursing intervention model in patients with chronic heart failure, compared with the conventional cardiology nursing model, can effectively improve the self-care ability of patients, improve the knowledge level and quality of life of patients with heart failure, and reduce the readmission rate.

An investigation of the role of transition metal ions impurities in CdO: Local structure and electronic properties.

According to the high-order perturbation formulae of 3d5 (Mn2+ ) and 3d9 (Cu2+ ) ions in octahedron, the local structures and electron paramagnetic resonance (EPR) parameters (g factors and hyperfine structure constants A) for Cu2+ and Mn2+ in CdO are theoretically studied in a consistent way. Due to the Jahn-Teller effect, both the substituted sites of Cu2+ and Mn2+ show the tetragonally elongated distortion with different elongation τ. Meanwhile, the crystal field and covalency around doped Cu2+ and Mn2+ are obtained, which can account for the electronic properties in doped CdO. In order to make further investigation of the potential optical and electrical properties, the band structure and density of states (DOS) of pure and transition metal ions (TMs) doped CdO are comparably calculated through density functional theory (DFT). The results show that the band gap of Mn2+ - and Cu2+ -doped CdO can be effectively reduced, due to the improved covalency between the central ions and ligand ions.

Quaternized Chitosan-Coated Montmorillonite Interior Antimicrobial Metal-Antibiotic in Situ Coordination Complexation for Mixed Infections of Wounds.

Conventional drug delivery systems for natural clay materials still face critical challenges in their practical application, including multiple bacterial infections, combined infection of bacteria and fungi, and low sterilization efficiency. In this work, we address these challenges using the multifunctional montmorillonite nanosheet-based (MMT-based) drug nanoplatform, which involves the antibiotic 5-fluorocytosine (5-FC), antibacterial metal copper ions, and quaternized chitosan (QCS). Composite material QCS/MMT/5-FCCu can can strongly inhibit Staphylococcus aureus (a typical Gram-positive bacterium), Escherichia coli (a typical Gram-negative bacterium), and Candida albicans (a fungus) because 5-FC coordinates with copper ions in situ and due to the deposition of QCS. The subsequent drug release behavior of 5-FCCu was studied, and the results show an initial high concentration kills microorganisms and long-acting sustained release inhibition. Moreover, in vivo wound experiments and toxicity experiments show the promotion of wound healing and excellent biocompatibility. As a demonstration of the utility of the latter, we have shown that the MMT-based smart platform can be used for the treatment of mixed infections of wounds.

Hyaluronic Acid-Modified Porous Carbon-Coated Fe3O4 Nanoparticles for Magnetic Resonance Imaging-Guided Photothermal/Chemotherapy of Tumors.

Chemotherapy is an effective method for treating cancer, clinically. However, side effects of drug and multidrug resistance restrict its application. In recent years, the combined treatment of chemotherapy and photothermal therapy (PTT) is becoming a promising method for treating cancer. PTT utilizes nanomaterials absorbing near-infrared light and producing heat to acquire advanced hyperthermia strategy for cancer treatment. Carbon nanomaterials with good biocompatibility, high surface area, and excellent photothermal properties are an excellent nanoplatform for drug delivery and PTT. Herein, porous carbon-coated magnetite nanoparticles (PCCMNs) were successfully synthesized by a one-pot solvothermal method. Magnetite, a contrast agent, can be used for magnetic resonance imaging. Hyaluronic acid was used to modify the PCCMNs to achieve targeted therapy. The obtained nanohybrid with a good photothermal effect can realize combined PTT/chemotherapy and will be a promising nanoplatform for high efficacy theranostics.

Detection of four polymorphisms in 5' upstream region of PNPLA2 gene and their associations with economic traits in pigs.

As an important triglyceride hydrolase in mammalian cells, patatin-like phospholipase domain-containing 2 (PNPLA2) predominantly performs the first step in triglyceride hydrolysis. The objective of this study was to detect and evaluate the effects of mutations in the 5' upstream region of porcine PNPLA2 gene with fat deposition and carcass traits. Four single nuclear polymorphisms were identified, including g.161969 T>C, g.161962 A>G, g.161953 C>G and g.161904 G>T, and subsequently genotyped in five pure breeds. Three haplotypes were constructed, including H1(CGGT), H2(TACG) and H3(CACT), which were the most abundant haplotypes in Duroc (0.75), Landrace (0.78) and Chinese indigenous breeds (>0.73), respectively. Duroc individuals with the H1H1 diplotype always exhibited the lowest feed conversion ratio (FCR) (P < 0.05), while H2H2 had the thickest backfat thickness (P < 0.05). Landrace individuals with H2H3 had lower backfat thickness (P < 0.05), higher muscle thickness (P < 0.05) and estimated lean meat percentage (P < 0.05) than those with diplotype H2H2 and H3H3. Luciferase assay indicated pGL3-basic-H2 had the highest activity and pGL3-basic-H1 had the lowest activity in driving reporter gene transcription in HEK293 cells in vitro. In H1 haplotype, two GR binding sites and an ERα binding site were predicted to be introduced. While in H2 and H3, there were other transcriptional factor binding sites predicted in H2 and H3, such as Sp1, AP-2 and CAC-binding proteins, which were broadly expressed transcription factors and capable of contributing to basal promoter activity. The reduced basal promoter activity of H1 may be due to the lack of inducement for GR and ERα binding sites in HEK293 cells. The identified functional polymorphisms provide new evidence of PNPLA2 as an important candidate gene for fat deposition and carcass traits in pigs.

Multifunctional Integrated Superhydrophobic Coatings with Unique Fluorescence and Micro/Micro/Nano-Hierarchical Structures Enabled by In Situ Self-Assembly.

Conferring versatility to superhydrophobic materials is extremely desirable to advance their utility. Herein, we have developed a superhydrophobic material with montmorillonite as microskeleton supports and in situ grown ZIF-8 nanoparticles and loaded them with newly developed fluorescent carbon dots. In situ growth of the ZIF-8 on OMMT constructs a dense nanoscale rough structure and meanwhile self-assembly generates abundant microporous, thus forming unique hierarchical microporous/microsheet/nanoparticle tri-tier micro and nano structures. Then the multifunctional superhydrophobic coating is fabricated by a facile spraying technique using polydimethylsiloxane (PDMS) as a multifunctional polymer binder. The PDMS/RB-CDs/ZIF-8@OMMT exhibits superhydrophobicity with a water contact angle of 164.7° and a water sliding angle of 1.4°, which also possesses good self-cleaning performance. Moreover, novel carbon dots are developed in this work which can confer unique fluorescent properties and photothermal properties to materials. Fluorescence characterization reveals the multiple emission peaks among 300-800 nm and excitation wavelength dependence and independence. Photothermal experiments unveil an efficient light-to-heat conversion caused by the light traps and absorption wavelengths associated with photothermal heating. Benefiting from the dense microporous/microsheet/nanoparticle structures, the superhydrophobicity is still maintained after 120 cycles of abrasion. Moreover, electrochemical impedance spectroscopy (EIS) reveals a significant increase in impedance, which is associated with excellent corrosion resistance. The superhydrophobic coating also exhibits superior UV resistance and good thermal stability. Multifunctional fluorescent superhydrophobic materials will enable the development of various and potential applications in different fields.

Pangenome obtained by long-read sequencing of 11 genomes reveal hidden functional structural variants in pigs.

Long-read sequencing (LRS) facilitates both the genome assembly and the discovery of structural variants (SVs). Here, we built a graph-based pig pangenome by incorporating 11 LRS genomes with an average of 94.01% BUSCO completeness score, revealing 206-Mb novel sequences. We discovered 183,352 nonredundant SVs (63% novel), representing 12.12% of the reference genome. By genotyping SVs in an additional 196 short-read sequencing samples, we identified thousands of population stratified SVs. Particularly, we detected 7,568 Tibetan specific SVs, some of which demonstrate significant population differentiation between Tibetan and low-altitude pigs, which might be associated with the high-altitude hypoxia adaptation in Tibetan pigs. Further integrating functional genomic data, the most promising candidate genes within the SVs that might contribute to the high-altitude hypoxia adaptation were discovered. Overall, our study generates a benchmark pangenome resource for illustrating the important roles of SVs in adaptive evolution, domestication, and genetic improvement of agronomic traits in pigs.

[Invasive ductal carcinomas of breast showing partial reversed cell polarity are associated with lymphatic tumor spread].

OBJECTIVE: To investigate the relationship between partial reversed cell polarity (PRCP) and lymphatic tumor spread in invasive ductal carcinoma (IDC), not othervise specified (NOS). METHODS: Immunohistochemistry (EnVision method) was used to examine the expression of epithelial membrane antigen (EMA) and the reversed cell polarity in 199 cases of IDC. RESULTS: Of the 199 cases, including five cases with micropapillary differentiation,30 cases with PRCP and 164 cases of IDC-NOS (without micropapillary differentiation and/or PRCP), lymphovascular invasion was seen in four (4/5), 13(43.3%) and 30 cases (18.3%) respectively; nodal metastasis was seen in four (4/5), 19 (63.3%) and 56 cases (34.1%) respectively. The rates of lymphovascular invasion and nodal metastasis were significantly higher in IDC with PRCP or IMPC than IDC-NOS (P = 0.00); there was however no significant difference between IDC with PRCP and IMPC for lymphovascular invasion and nodal metastasis (P = 0.18, P = 0.64). CONCLUSIONS: IDC with PRCP, similar to IMPC, is more likely to show lymphovascular invasion and nodal metastasis. Complete or partial reversal of cell polarity may play a significant role in lymphatic tumor spread.

A multifunctional carbon dot-based nanoplatform for bioimaging and quaternary ammonium salt/photothermal synergistic antibacterial therapy.

The emergence of drug resistance and superbugs poses a devastating threat to public health and can even lead to death. Thus, it is significant to develop a novel antibacterial agent to combat bacterial infections. Herein, we developed quaternary ammonium salt (QAS) modified near-infrared carbon dots (RCDs-C35), which possesses synergistic antibacterial performance under 808 nm irradiation. This nanocomposite exhibits excellent photothermal performance and the photothermal conversion efficiency (PCE) could reach 35%. Generally speaking, the bacterial membrane sensitivity to hyperthermia would be enhanced after QAS caused the initial damage, and thus it can more easily cause bacterial inactivation after irradiation. In vitro and in vivo experiments indicated that the RCDs-C35 exhibit excellent biocompatibility, predominant synergistic antibacterial performance, and the capability of promoting wound healing. The antibacterial ratio against Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus) could reach 99.5% and 99.8%, respectively, after 808 nm irradiation. Additionally, the cellular imaging indicated that the RCDs-C35 could be used as a fluorescent probe in bioimaging. Therefore, RCDs-C35 with synergistic antibacterial performance and inherent luminescence possess great potential for application in the biomedical field.

Silica-supported near-infrared carbon dots and bicarbonate nanoplatform for triple synergistic sterilization and wound healing promotion therapy.

Widespread bacterial infection and the emergence of antibiotic resistance exhibit an increasing threat to public health. Additionally, chronic wounds caused by bacterial infection have become a major challenge and threat in medical. Therefore, it is of great significance to explore effective and safe nanomaterials which possess antibacterial and wound healing promotion performance. Herein, we developed silica-supported near-infrared carbon dots (QPCuRC@MSiO2) and bicarbonate (BC) nanoplatform (BC/QPCuRC@MSiO2@PDA), which possess triple synergistic antibacterial including quaternary ammonium compounds (QACs), photothermal therapy (PTT), and photodynamic therapy (PDT). Meanwhile, the nanoplatform realized the controlled release of CO2 in situ triggered by 808 nm laser irradiation for wound healing. In vitro and in vivo antibacterial assays displayed that the BC/QPCuRC@MSiO2@PDA possess excellent antibacterial property, the antibacterial rate up to 99.6% and 99.99% to Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), respectively. Wound healing evaluation proved that suitable release of CO2 could promote the process of infected wound healing, and the wound healing rate up to 100% after treatment for 14 days. Additionally, the cellular imaging experiment revealed that the BC/QPCuRC@MSiO2@PDA could be considered as fluorescence probe. Together, these results demonstrated that the BC/QPCuRC@MSiO2@PDA have great potential in biomedical field.

Insight into the effect of particle size distribution differences on the antibacterial activity of carbon dots.

Carbon dots (CDs) have a profound effect on elimination of bacteria, fungi, and viruses, but the lack of an exact mechanism to interact with bacterial cells limits their development. Herein, we separated the CDs derived from chlorhexidine gluconate into three groups with uniformly small-scale, middle-scale, and large-scale particle sizes by using different molecular weight cut-off membranes. These positively charged particles exhibit significant antibacterial activity against the Gram-negative bacteria Escherichia coli and the Gram-positive bacteria Staphylococcus aureus; they can cause an increase in bacterial cell permeability, synergistic destabilization, and broken integrity of the plasma membrane. Impressively, we found that antibacterial activity increases as the size of the CDs decreases. This phenomenon may stem from the differences in cellular uptake and distribution of CDs in the plasma membrane or restriction between the polar functional group and DNA molecule. Our study of the size effect as a target may improve the understanding of killing microorganisms by antibacterial CD drugs.

Multiple-Dimensionally Controllable Nucleation Sites of Two-Dimensional WS2/Bi2Se3 Heterojunctions Based on Vapor Growth.

Two-dimensional (2D) heterojunctions have attracted great attention due to their excellent optoelectronic properties. Until now, precisely controlling the nucleation density and stacking area of 2D heterojunctions has been of critical importance but still a huge challenge. It hampers the progress of controlled growth of 2D heterojunctions for optoelectronic devices because the potential relation between numerous growth parameters and nucleation density is always poorly understood. Herein, by cooperatively controlling three parameters (substrate temperature, gas flow rate, and precursor concentration) in modified vapor deposition growth, the nucleation density and stacking area of WS2/Bi2Se3 vertical heterojunctions were successfully modulated. High-quality WS2/Bi2Se3 vertical heterojunctions with various stacking areas were effectively grown from single and multiple nucleation sites. Moreover, the potential nucleation mechanism and efficient charge transfer of WS2/Bi2Se3 vertical heterojunctions were systematically studied by utilizing the density functional theory and photoluminescence spectra. This modified vapor deposition strategy and the proposed mechanism are helpful in controlling the nucleation density and stacking area of other heterojunctions, which plays a key role in the preparation of electronic and optoelectronic nanodevices.

Light-Activated Biodegradable Covalent Organic Framework-Integrated Heterojunction for Photodynamic, Photothermal, and Gaseous Therapy of Chronic Wound Infection.

Chronic wound healing, impeded by bacterial infections and drug resistance, poses a threat to global human health. Antibacterial phototherapy is an effective way to fight microbial infection without causing drug resistance. Covalent organic frameworks (COFs) are a class of highly crystalline functional porous carbon-based materials composed of light atoms (e.g., carbon, nitrogen, oxygen, and borane), showing potential applications in the biomedical field. Herein, we constructed porphyrin-based COF nanosheets (TP-Por CON) for synergizing photodynamic and photothermal therapy under red light irradiation (e.g., 635 nm). Moreover, a nitric oxide (NO) donor molecule, BNN6, was encapsulated into the pore volume of the crystalline porous framework structure to moderately release NO triggered by red light irradiation for realizing gaseous therapy. Therefore, we successfully synthesized a novel TP-Por CON@BNN6-integrated heterojunction for thoroughly killing Gram-negative bacteria Escherichia coli and Gram-positive bacteria Staphylococcus aureus in vitro. Our research identified that TP-Por CON@BNN6 has favorable biocompatibility and biodegradability, low phototoxicity, anti-inflammatory properties, and excellent mice wound healing ability in vivo. This study indicates that the TP-Por CON@BNN6-integrated heterojunction with multifunctional properties provides a potential strategy for COF-based gaseous therapy and microorganism-infected chronic wound healing.

MoO3-x nanosheets-based platform for single NIR laser induced efficient PDT/PTT of cancer.

Traditional combination therapy of photodynamic therapy (PDT) and photothermal therapy (PTT) is limited in the field of clinical cancer therapy due to activation by light with separate wavelengths, insufficient O2 supply, antioxidant ability of glutathione (GSH) in tumor cell, and low penetration depth of light. Here, a multifunctional nanoplatform composed of MoO3-x nanosheets, Ag nanocubes, and MnO2 nanoparticles was developed to overcome these drawbacks. For this nanoplatform, hyperthermia and reactive oxygen species (ROS) were simultaneously generated under single 808 nm near-infrared (NIR) light irradiation. Once this nanoplatform accumulated in the tumor region, GSH was depleted by MnO2 and intracellular H2O2 was catalyzed by MnO2 to produce O2 to relieve hypoxia. Ultrasound (US) imaging confirmed in-situ O2 generation. Magnetic resonance (MR) imaging, photoacoustic (PA) imaging, and fluorescence imaging were used to monitor in vivo biodistribution of nanomaterials. This provides a paradigm to rationally design a single NIR laser induced multimodal imaging-guided efficient PDT/PTT cancer strategy.