USP8 promotes cancer progression and extracellular vesicle-mediated CD8+ T cell exhaustion by deubiquitinating the TGF-ß receptor TßRII.

TGF-ß signaling is a key player in tumor progression and immune evasion, and is associated with poor response to cancer immunotherapies. Here, we identified ubiquitin-specific peptidase 8 (USP8) as a metastasis enhancer and a highly active deubiquitinase in aggressive breast tumors. USP8 acts both as a cancer stemness-promoting factor and an activator of the TGF-ß/SMAD signaling pathway. USP8 directly deubiquitinates and stabilizes the type II TGF-ß receptor TßRII, leading to its increased expression in the plasma membrane and in tumor-derived extracellular vesicles (TEVs). Increased USP8 activity was observed in patients resistant to neoadjuvant chemotherapies. USP8 promotes TGF-ß/SMAD-induced epithelial-mesenchymal transition (EMT), invasion, and metastasis in tumor cells. USP8 expression also enables TßRII+ circulating extracellular vesicles (crEVs) to induce T cell exhaustion and chemoimmunotherapy resistance. Pharmacological inhibition of USP8 antagonizes TGF-ß/SMAD signaling, and reduces TßRII stability and the number of TßRII+ crEVs to prevent CD8+ T cell exhaustion and to reactivate anti-tumor immunity. Our findings not only reveal a novel mechanism whereby USP8 regulates the cancer microenvironment but also demonstrate the therapeutic advantages of engineering USP8 inhibitors to simultaneously suppress metastasis and improve the efficacy of cancer immunotherapy.

Sensitive and selective polymer condensation at membrane surface driven by positive co-operativity.

Biomolecular phase separation has emerged as an essential mechanism for cellular organization. How cells respond to environmental stimuli in a robust and sensitive manner to build functional condensates at the proper time and location is only starting to be understood. Recently, lipid membranes have been recognized as an important regulatory center for biomolecular condensation. However, how the interplay between the phase behaviors of cellular membranes and surface biopolymers may contribute to the regulation of surface condensation remains to be elucidated. Using simulations and a mean-field theoretical model, we show that two key factors are the membrane's tendency to phase-separate and the surface polymer's ability to reorganize local membrane composition. Surface condensate forms with high sensitivity and selectivity in response to features of biopolymer when positive co-operativity is established between coupled growth of the condensate and local lipid domains. This effect relating the degree of membrane-surface polymer co-operativity and condensate property regulation is shown to be robust by different ways of tuning the co-operativity, such as varying membrane protein obstacle concentration, lipid composition, and the affinity between lipid and polymer. The general physical principle emerged from the current analysis may have implications in other biological processes and beyond.

Rational Design of Biomaterials to Potentiate Cancer Thermal Therapy.

Cancer thermal therapy, also known as hyperthermia therapy, has long been exploited to eradicate mass lesions that are now defined as cancer. With the development of corresponding technologies and equipment, local hyperthermia therapies such as radiofrequency ablation, microwave ablation, and high-intensity focused ultrasound, have has been validated to effectively ablate tumors in modern clinical practice. However, they still face many shortcomings, including nonspecific damages to adjacent normal tissues and incomplete ablation particularly for large tumors, restricting their wide clinical usage. Attributed to their versatile physiochemical properties, biomaterials have been specially designed to potentiate local hyperthermia treatments according to their unique working principles. Meanwhile, biomaterial-based delivery systems are able to bridge hyperthermia therapies with other types of treatment strategies such as chemotherapy, radiotherapy and immunotherapy. Therefore, in this review, we discuss recent progress in the development of functional biomaterials to reinforce local hyperthermia by functioning as thermal sensitizers to endow more efficient tumor-localized thermal ablation and/or as delivery vehicles to synergize with other therapeutic modalities for combined cancer treatments. Thereafter, we provide a critical perspective on the further development of biomaterial-assisted local hyperthermia toward clinical applications.

E3 ubiquitin ligase DTX2 fosters ferroptosis resistance via suppressing NCOA4-mediated ferritinophagy in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) remains the foremost contributor to cancer-related fatalities globally, with limited effective therapeutic modalities. Recent research has shed light on the role of ferroptosis in various types of cancers, offering a potential avenue for improving cancer therapy. Herein, we identified E3 ubiquitin ligase deltex 2 (DTX2) as a potential therapeutic target candidate implicated in promoting NSCLC cell growth by inhibiting ferroptosis. Our investigation revealed a significant upregulation of DTX2 in NSCLC cells and tissues, which was correlated with poor prognosis. Downregulation of DTX2 suppressed NSCLC cell growth both in vitro and in vivo, while its overexpression accelerated cell proliferation. Moreover, knockdown of DTX2 promoted ferroptosis in NSCLC cells, which was mitigated by DTX2 overexpression. Mechanistically, we uncovered that DTX2 binds to nuclear receptor coactivator 4 (NCOA4), facilitating its ubiquitination and degradation via the K48 chain, which subsequently dampens NCOA4-driven ferritinophagy and ferroptosis in NSCLC cells. Notably, DTX2 knockdown promotes cisplatin-induced ferroptosis and overcomes drug resistance of NSCLC cells. These findings underscore the critical role of DTX2 in regulating ferroptosis and NCOA4-mediated ferritinophagy, suggesting its potential as a novel therapeutic target for NSCLC.

Andrographolide sensitizes glioma to temozolomide by inhibiting DKK1 expression.

BACKGROUND: Temozolomide (TMZ) is the first-line chemotherapeutic drug for gliomas treatment. However, the clinical efficacy of TMZ in glioma patients was very limited. Therefore, it is urgently needed to discover a novel approach to increase the sensitivity of glioma cells to TMZ. METHODS: Western blot, immunohistochemical staining, and qRT-PCR assays were used to explore the mechanisms underlying TMZ promoting DKK1 expression and andrographolide (AND) inhibiting DKK1 expression. HPLC was used to detect the ability of andrographolide (AND) to penetrate the blood-brain barrier. MTT assay, bioluminescence images, magnetic resonance imaging (MRI) and H&E staining were employed to measure the proliferative activity of glioma cells and the growth of intracranial tumors. RESULTS: TMZ can promote DKK1 expression in glioma cells and brain tumors of an orthotopic model of glioma. DKK1 could promote glioma cell proliferation and tumor growth in an orthotopic model of glioma. Mechanistically, TMZ increased EGFR expression and subsequently induced the activation of its downstream MEK-ERK and PI3K-Akt pathways, thereby promoting DKK1 expression in glioma cells. Andrographolide inhibited TMZ-induced DKK1 expression through inactivating MEK-ERK and PI3K-Akt pathways. Andrographolide can cross the blood-brain barrier, the combination of TMZ and andrographolide not only improved the anti-tumor effects of TMZ but also showed a survival benefit in an orthotopic model of glioma. CONCLUSION: Andrographolide can enhance anti-tumor activity of TMZ against glioma by inhibiting DKK1 expression.

Hydrogel Grating Sensors with Boron Affinity and Molecular Imprinting Effects for Rapid and Sensitive Detection of Tumor Marker Sialic Acid.

Rapid and sensitive detection of the concentration of sialic acid (SA) in serum is crucial for early tumor screening and prognostic assessment; however, it still remains challenging. Here, we propose a novel kind of hydrogel grating sensor with boron affinity and molecular imprinting effects (B-MIP) for the rapid and sensitive detection of SA concentration in serum. The hydrogel gratings feature uniform surface relief microstructures and incorporate highly specific recognition binding sites into SA molecules provided by boron affinity and molecular imprinting. The periodic nanoridges of hydrogel gratings increase the specific surface area contacting the environmental solution; therefore, fast detection can be achieved within 2 min. Upon recognition of SA molecules, the height of hydrogel gratings changes at the nanoscale, causing a change in the diffraction efficiency of the hydrogel gratings. The B-MIP hydrogel grating sensors have highly specific binding sites to SA molecules distributed throughout the whole hydrogel and can preferentially and selectively recognize and respond to the SA molecules even in the presence of interference substances glucose and fructose with high concentrations. The B-MIP hydrogel grating sensors are effectively applicable for the rapid and sensitive detection of SA concentrations in real serum samples with satisfactory accuracy and precision. Our approach provides an excellent strategy to address the current challenges in SA detection and provides new insights into the detection of tumor markers in serum, thereby opening up new ways to accurately detect complex biological samples in analytical science.

Exploring Metabolic Aberrations after Intracerebral Hemorrhage In Vivo with Deuterium Metabolic Spectroscopy Imaging.

Aberrations in metabolism after intracerebral hemorrhage (ICH), particularly lactate metabolism, play a crucial role in the pathophysiology and patient outcome. To date, the evaluation of metabolism relies heavily on invasive methods such as microdialysis, restricting a comprehensive understanding of the metabolic mechanisms associated with ICH. This study proposes a noninvasive metabolic imaging method based on 2H magnetic resonance spectroscopy and imaging (2H-MRS/MRSI) to detect metabolic changes after ICH in vivo. To overcome the low-sensitivity limitation of 2H, we designed a new 1H-2H double-resonance coil with 2H-channel active detuning and proposed chemical shift imaging based on the balanced steady-state free precession method (CSI-bSSFP). Compared with the volume coil, the signal-to-noise ratio (SNR) of the new coil was increased by 4.5 times. In addition, the SNR of CSI-bSSFP was 1.5 times higher than that of conventional CSI. These two technologies were applied to measure lactate metabolic flux at different phases of ICH. The results show a higher lactate concentration in ICH rats than in control rats, which is in line with the increased expression of lactate dehydrogenase measured via immunohistochemistry staining (AUCLac_area/Glc_area: control, 0.08 ± 0.02 vs ICH-3d, 0.39 ± 0.05 vs ICH-7d, 0.18 ± 0.02, P < 0.01; H-score: control, 126.4 ± 5.03 vs ICH-3d, 168.4 ± 5.71 vs ICH-7d,133.6 ± 7.70, P < 0.05). A higher lactate signal also appeared near the ICH region than in normal brain tissue. In conclusion, 2H-MRS/MRSI shows potential as a useful method for in vivo metabolic imaging and noninvasive assessment of ICH.

ACADL-YAP axis activity in non-small cell lung cancer carcinogenicity.

BACKGROUND: The role of Acyl-CoA dehydrogenase long chain (ACADL) in different tumor types had different inhibiting or promoting effect. However, its role in non-small cell lung cancer (NSCLC) carcinogenicity is not clear. METHOD: In this study, we utilized The Cancer Genome Atlas (TCGA) database to analyze ACADL expression in NSCLC and its correlation with overall survival. Furthermore, we investigated the function of ACADL on cellular proliferation, invasion, colony, apoptosis, cell cycle in vitro with NSCLC cells. Mechanistically, we evaluated the regulatory effect of ACADL expression on its downstream factor yes-associated protein (YAP) by assessing YAP phosphorylation levels and its cellular localization. Finally, we verified the tumorigenic effect of ACADL on NSCLC cells through xenograft experiments in vivo. RESULTS: Compared to adjacent non-cancerous samples, ACADL significantly down-regulated in NSCLC. Overexpression of ACADL, effectively reduced the proliferative, colony, and invasive capabilities of NSCLC cells, while promoting apoptosis and inducing cell cycle arrest. Moreover, ACADL overexpression significantly enhanced YAP phosphorylation and hindered its nuclear translocation. However, the inhibitory effect of the overexpression of ACADL in NSCLC cells mentioned above can be partially counteracted by YAP activator XMU-MP-1 application both in vitro and in vivo. CONCLUSION: The findings suggest that ACADL overexpression could suppress NSCLC development by modulating YAP phosphorylation and limiting its nuclear shift. This role of ACADL-YAP axis provided novel insights into NSCLC carcinogenicity and potential therapeutic strategies.

Circular RNA circASH1L(4,5) protects microRNA-129-5p from target-directed microRNA degradation in human skin wound healing.

BACKGROUND: Skin wound healing involves a complex gene expression program that remains largely undiscovered in humans. Circular RNAs (circRNAs) and microRNAs (miRNAs) are key players in this process. OBJECTIVES: To understand the functions and potential interactions of circRNAs and miRNAs in human skin wound healing. METHODS: CircRNA, linear RNA, and miRNA expression in human acute and chronic wounds were analyzed using RNA sequencing and qRT-PCR. The roles of circASH1L(4,5) and miR-129-5p were studied in human primary keratinocytes (proliferation and migration assays, microarray analysis) and ex vivo wound models (histological analysis). The interaction between circASH1L(4,5) and miR-129-5p was examined using luciferase reporter and RNA pull-down assays. RESULTS: We identified circASH1L(4,5) and its interaction with miR-129-5p, both of which increased during human skin wound healing. Unlike typical miRNA sponging, circASH1L enhanced miR-129 stability and silencing activity by protecting it from target-directed degradation triggered by NR6A1 mRNA. TGF-ß signaling, crucial in wound healing, promoted circASH1L expression while suppressing NR6A1, thereby increasing miR-129 abundance at the post-transcriptional level. CircASH1L and miR-129 enhanced keratinocyte migration and proliferation, crucial for re-epithelialization of human wounds. CONCLUSIONS: Our study uncovers a novel role for circRNAs as protectors of miRNAs and highlights the importance of regulated miRNA degradation in skin wound healing.

rGO/ZIF-8 Aerogel for Effective Removal of Malachite Green from Wastewater.

In this study, dopamine-modified graphene aerogel (DGA) is synthesized through a one-step hydrothermal method using graphene oxide as the precursor and dopamine as the reducing agent. Subsequently, in situ immersion synthesis is conducted to obtain ZIF-8 loaded on a dopamine-modified graphene aerogel skeleton (ZDGA), featuring a regular honeycomb interconnected mesoporosity and a high specific surface area of 532.8 m2/g. The synthesized ZDGA exhibited exceptional adsorption performance for the cationic dye malachite green. At room temperature, ZDGA achieved an impressive equilibrium adsorption capacity of 6578.34 mg/g. The adsorption process followed pseudo-secondary kinetics and adhered to the Langmuir model, indicating chemically dominated adsorption on a monomolecular layer. Intraparticle diffusion was the primary rate determinant, with π-π stacking, electrostatic adsorption, hydrogen bonding, and Lewis acid-base interactions serving as the key driving forces. It has an ideal specific surface area and good cycling performance, which highlights its potential application in dye wastewater treatment.

An unenhanced 3D-FLAIR sequence using long repetition time and constant flip angle to image endolymphatic hydrops.

OBJECTIVES: To evaluate a three-dimensional fluid-attenuated inversion recovery (3D-FLAIR) sequence using a long repetition time (TR) and constant flip angle (CFA) in differentiating between perilymph and endolymph in a phantom study, and unenhanced endolymphatic hydrops (EH) imaging in a patient study. METHODS: Three solutions in similar ion and protein concentrations with endolymph, perilymph, and cerebrospinal fluid were prepared for variable flip angle (VFA) 3D-FLAIR (TR 10,000 ms) and CFA (120°) 3D-FLAIR using different TR (10,000, 16,000, and 20,000 ms). Fifty-two patients with probable or definite Meniere's disease received unenhanced CFA (120°) 3D-FLAIR using a long TR (20,000 ms) and 4-h-delay enhanced CFA (120°) 3D-FLAIR (TR 16,000 ms). Image quality, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) of them were compared. Agreement in the evaluation of the EH degree between them was analyzed. RESULTS: In the phantom study, CNRs between perilymphatic and endolymphatic samples of VFA 3D-FLAIR (TR 10,000 ms) and CFA 3D-FLAIR (TR 10,000, 16,000, and 20,000 ms) were 6.66 ± 1.30, 17.90 ± 2.76, 23.87 ± 3.09, and 28.22 ± 3.15 (p < 0.001). In patient study, average score (3.65 ± 0.48 vs. 4.19 ± 0.40), SNR (34.56 ± 9.80 vs. 51.40 ± 11.27), and CNR (30.66 ± 10.55 vs. 45.08 ± 12.27) of unenhanced 3D-FLAIR were lower than enhanced 3D-FLAIR (p < 0.001). Evaluations of the two sequences showed excellent agreement in the cochlear and vestibule (Kappa value: 0.898 and 0.909). CONCLUSIONS: The CFA 3D-FLAIR sequence using a long TR could be used in unenhanced EH imaging with high accuracy. CLINICAL RELEVANCE STATEMENT: Unenhanced imaging of endolymphatic hydrops is valuable in the diagnosis and follow-up of patients, especially those who cannot receive contrast-enhanced MRI. KEY POINTS: Ion and protein concentration differences can be utilized in differentiating endolymph and perilymph on MRI. Endolymphatic and perilymphatic samples could be differentiated in vitro on this 3D-FLAIR sequence. This unenhanced 3D-FLAIR sequence is in excellent agreement with the enhanced constant flip angle 3D-FLAIR sequence.

Baicalein attenuates oxidative damage in mice haematopoietic cells through regulation of PDGFRß.

Platelet-derived growth factor receptor ß (PDGFRß) plays a crucial role in murine haematopoiesis. Baicalein (BAI), a naturally occurring flavonoid, can alleviate disease damage through anti-oxidative, anti-apoptotic, and anti-inflammatory mechanisms. However, whether BAI attenuates oxidative damage in murine haematopoietic cells by PDGFRß remains unexplored. In this study, we utilized a tert-butyl hydroperoxide (TBHP)-induced BaF3 cell injury model and an ionising radiation (IR)-induced mice injury model to investigate the impact of the presence or absence of PDGFRß on the pharmacological effects of BAI. In addition, the BAI-PDGFRß interaction was characterized by molecular docking and dynamics simulations. The results show that a specific concentration of BAI led to increased cell viability, reduced reactive oxygen species (ROS) content, upregulated nuclear factor erythroid 2-related factor 2 (NRF2) expression, and its downstream target genes heme oxygenase 1 (HO-1) and NAD(P)H Quinone Dehydrogenase 1 (NQO1), and activated protein kinase B (AKT) pathway in cells expressing PDGFRß plasmid and experiencing damage. Similarly, BAI elevated lineage-Sca1+cKIT+ (LSK) cell proportion, promoted haematopoietic restoration, enhanced NRF2-mediated antioxidant response in PDGFRß+/+ mice. However, despite BAI usage, PDGFRß knockout mice (PDGFRß-/-) showed lower LSK proportion and less antioxidant capacity than the total body irradiation (TBI) group. Furthermore, we demonstrated an interaction between BAI and PDGFRß at the molecular level. Collectively, our results indicate that BAI attenuates oxidative stress injury and helps promote haematopoietic cell recovery through regulation of PDGFRß.

Polydopamine nanoplatform with near infrared light and pH dual stimuli-responsive for chemo-photothermal cancer therapy.

Photothermal agent accompanying with thermally responsive materials, displays well controlled drug release property, which is well-received as an outstanding design strategy for simultaneous photothermal/chemotherapy in cancer. Cyanine dye, as the prestigious photothermal agent has shown great potential due to its preeminent near-infrared absorbance and excellent thermal conversion efficiency. However, their inherent defect such as inferior photothermal stability, high leakage risk and poor therapy efficacy limit their further application in cancer therapy. Hence, a facile and universal strategy to make up these deficiencies is developed. Chemotherapeutic drug DOX and cyanine dye were loaded into polydopamine (PDA) nanoparticles. The PDA encapsulation dramatically improved the photothermal stability of cyanine dye. Attributed by the PDA structure feature, the thermo-sensitive small molecule glyamine (Gla) is introduced into the PDA surface to lessen leakage. The Gla can form a dense encapsulation layer on the dopamine surface through hydrogen bond. This newly fabricated Cyanine/DOX@PDA-Gla nanopaltform is characterized with NIR light/pH dual-responsive property, high NIR photothermal conversion performance and fluorescence guided chemo-photothermal therapy.

Characteristics of a heavy metal resistant heterotrophic nitrification-aerobic denitrification bacterium isolated from municipal activated sludge.

The heterotrophic nitrification-aerobic denitrification (HNAD) is a new biological denitrification technology, the present study isolated a new HNAD strain named Cupriavidus metallidurans TX6 with heavy metal resistance. The gene expression, electron transport, enzyme activity and nitrogen removal property of strain TX6 were studied with different influencing factors. Strain TX6 has five nitrogen metabolism pathways (NH4+ → NH2OH → NO → NO2- → NH4+ → GOGAT/GDH; NH4+-N → NH2OH → NO → N2O → N2; NH4+ → NH2OH → NO → NO2- → NO3-; NO3- → NO2- → NH4+ → GOGAT/GDH; NO3-→ NO2- → NH4+ → GOGAT/GDH). Nitrogen balance analysis shows that 29 ± 4 mg/L of N was converted to intracellular nitrogen by assimilation and 50 ± 3 mg/L N loss may be attributed to aerobic denitrification. The results provide a theoretical basis for the HAND bacteria application in nitrogen removal from wastewaters containing heavy metals.

A nomogram for prediction of early mortality in patients undergoing cardiac surgery for infective endocarditis: a retrospective single-center study.

OBJECTIVE: Despite advancements in surgical techniques, operations for infective endocarditis (IE) remain associated with relatively high mortality. The aim of this study was to develop a nomogram model to predict the early postoperative mortality in patients undergoing cardiac surgery for infective endocarditis based on the preoperative clinical features. METHODS: We retrospectively analyzed the clinical data of 357 patients with IE who underwent surgeries at our center between January 2007 and June 2023. Independent risk factors for early postoperative mortality were identified using univariate and multivariate logistic regression models. Based on these factors, a predictive model was developed and presented in a nomogram. The performance of the nomogram was evaluated through the receiver operating characteristic (ROC) curve, calibration plot, and decision curve analysis (DCA). Internal validation was performed utilizing the bootstrapping method. RESULTS: The nomogram included nine predictors: age, stroke, pulmonary embolism, albumin level, cardiac function class IV, antibotic use <4weeks, vegetation size ≥1.5 cm, perivalvular abscess and preoperative dialysis. The area under the ROC curve (AUC) of the model was 0.88 (95%CI:0.80-0.96). The calibration plot indicated strong prediction consistency of the nomogram with satisfactory Hosmer-Lemeshow test results (χ2 = 13.490, p = 0.142). Decision curve analysis indicated that the nomogram model provided greater clinical net benefits compared to "operate-all" or "operate-none" strategies. CONCLUSIONS: The innovative nomogram model offers cardiovascular surgeons a tool to predict the risk of early postoperative mortality in patients undergoing IE operations. This model can serve as a valuable reference for preoperative decision-making and can enhance the clinical outcomes of IE patients.

Greatly isolated heterogeneous circulating tumor cells using hybrid engineered cell membrane-camouflaged magnetic nanoparticles.

BACKGROUND: Circulating tumor cells (CTCs) are considered as a useful biomarker for early cancer diagnosis, which play a crucial role in metastatic process. Unfortunately, the tumor heterogeneity and extremely rare occurrence rate of CTCs among billions of interfering leukocytes seriously hamper the sensitivity and purity of CTCs isolation. METHODS: To address these, we firstly used microfluidic chips to detect the broad-spectrum of triple target combination biomarkers in CTCs of 10 types of cancer patients, including EpCAM, EGFR and Her2. Then, we constructed hybrid engineered cell membrane-camouflaged magnetic nanoparticles (HE-CM-MNs) for efficient capture of heterogeneous CTCs with high-purity, which was enabled by inheriting the recognition ability of HE-CM for various CTCs and reducing homologous cell interaction with leukocytes. Compared with single E-CM-MNs, HE-CM-MNs showed a significant improvement in the capture efficiency for a cell mixture, with an efficiency of 90%. And the capture efficiency of HE-CM-MNs toward 12 subpopulations of tumor cells was ranged from 70 to 85%. Furthermore, by using HE-CM-MNs, we successfully isolated heterogeneous CTCs with high purity from clinical blood samples. Finally, the captured CTCs by HE-CM-MNs could be used for gene mutation analysis. CONCLUSIONS: This study demonstrated the promising potential of HE-CM-MNs for heterogeneous CTCs detection and downstream analysis.

Effect of parenting style on the emotional and behavioral problems among Chinese adolescents: the mediating effect of resilience.

BACKGROUND: Although previous studies have found that parenting style significantly predicts emotional and behavioral problems (EBPs) among Chinese adolescents, the mechanism between different parenting styles and EBPs requires in-depth investigation. In our study, we aimed to investigate the mediating effect of resilience, a positive psychological characteristic, between parenting style and EBPs among Chinese adolescents. METHODS: In this cross-sectional study, we used a multistage stratified cluster random sampling method to collect data in Shenyang, Liaoning Province from November to December 2019. Self-developed questionnaires were distributed to 1028 adolescents aged 10-18. Finally, the study consisted of 895 participants. The bootstrap method was used to investigate the role of resilience as a mediator in the relationship between different parenting styles and EBPs from a positive psychology perspective. RESULTS: The mean score of EBPs was 12.71 (SD = 5.77). After controlling for variables such as gender, age, left-behind children, family type and family income, resilience partially played a mediating role in the associations of paternal rejection (a × b = 0.051 BCa95%CI:0.023,0.080), maternal rejection (a × b = 0.055 BCa95%CI: 0.024, 0.086), paternal emotional warmth (a × b = -0.139 BCa95%CI: -0.182, -0.099) and maternal emotional warmth (a × b = -0.140 BCa95%CI: -0.182, -0.102), with EBPs. The effect sizes were11.28%, 11.51%, 40.76%, and 38.78%, respectively. CONCLUSIONS: Resilience could partially mediate the relationship between parenting style and EBPs, highlighting that parents should adopt a positive parenting style and that resilience improvement could be effective in reducing EBPs among Chinese adolescents.

Inhalable nanocatchers for SARS-CoV-2 inhibition.

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2), presents an urgent health crisis. More recently, an increasing number of mutated strains of SARS-CoV-2 have been identified globally. Such mutations, especially those on the spike glycoprotein to render its higher binding affinity to human angiotensin-converting enzyme II (hACE2) receptors, not only resulted in higher transmission of SARS-CoV-2 but also raised serious concerns regarding the efficacies of vaccines against mutated viruses. Since ACE2 is the virus-binding protein on human cells regardless of viral mutations, we design hACE2-containing nanocatchers (NCs) as the competitor with host cells for virus binding to protect cells from SARS-CoV-2 infection. The hACE2-containing NCs, derived from the cellular membrane of genetically engineered cells stably expressing hACE2, exhibited excellent neutralization ability against pseudoviruses of both wild-type SARS-CoV-2 and the D614G variant. To prevent SARS-CoV-2 infections in the lung, the most vulnerable organ for COVID-19, we develop an inhalable formulation by mixing hACE2-containing NCs with mucoadhesive excipient hyaluronic acid, the latter of which could significantly prolong the retention of NCs in the lung after inhalation. Excitingly, inhalation of our formulation could lead to potent pseudovirus inhibition ability in hACE2-expressing mouse model, without imposing any appreciable side effects. Importantly, our inhalable hACE2-containing NCs in the lyophilized formulation would allow long-term storage, facilitating their future clinical use. Thus, this work may provide an alternative tactic to inhibit SARS-CoV-2 infections even with different mutations, exhibiting great potential for treatment of the ongoing COVID-19 epidemic.

Transmucosal Delivery of Nasal Nanovaccines Enhancing Mucosal and Systemic Immunity.

Intranasal vaccines can induce protective immune responses at the mucosa surface entrance, preventing the invasion of respiratory pathogens. However, the nasal barrier remains a major challenge in the development of intranasal vaccines. Herein, a transmucosal nanovaccine based on cationic fluorocarbon modified chitosan (FCS) is developed to induce mucosal immunity. In our system, FCS can self-assemble with the model antigen ovalbumin and TLR9 agonist CpG, effectively promoting the maturation and cross-presentation of dendritic cells. More importantly, it can enhance the production of secretory immunoglobin A (sIgA) at mucosal surfaces for those intranasally vaccinated mice, which in the meantime showed effective production of immunoglobulin G (IgG) systemically. As a proof-of-concept study, such a mucosal vaccine inhibits ovalbumin-expressing B16-OVA melanoma, especially its lung metastases. Our work presents a unique intranasal delivery system to deliver antigen across mucosal epithelia and promote mucosal and systemic immunity.

DNA Nanostructures: Self-Adjuvant Carriers for Highly Efficient Subunit Vaccines.

Subunit vaccines based on antigen proteins or epitopes of pathogens or tumors show advantages in immunological precision and high safety, but are often limited by their low immunogenicity. Adjuvants can boost immune responses by stimulating immune cells or promoting antigen uptake by antigen presenting cells (APCs), yet existing clinical adjuvants struggle in simultaneously achieving these dual functions. Additionally, the spatial organization of antigens might be crucial to their immunogenicity. Hence, superior adjuvants should potently stimulate the immune system, precisely arrange antigens, and effectively deliver antigens to APCs. Recently, precisely organizing and delivering antigens with the unique editability of DNA nanostructures has been proposed, presenting unique abilities in significantly improving the immunogenicity of antigens. In this minireview, we will discuss the principles behind using DNA nanostructures as self-adjuvant carriers and review the latest advancements in this field. The potential and challenges associated with self-adjuvant DNA nanostructures will also be discussed.