Profiling of Early Immune Responses to Vaccination Using THP-1-Derived Dendritic Cells.

The COVID-19 pandemic has made assessing vaccine efficacy more challenging. Besides neutralizing antibody assays, systems vaccinology studies use omics technology to reveal immune response mechanisms and identify gene signatures in human peripheral blood mononuclear cells (PBMCs). However, due to their low proportion in PBMCs, profiling the immune response signatures of dendritic cells (DCs) is difficult. Here, we develop a predictive model for evaluating early immune responses in dendritic cells. We establish a THP-1-derived dendritic cell (TDDC) model and stimulate their maturation in vitro with an optimal dose of attenuated yellow fever 17D (YF-17D). Transcriptomic analysis reveals that type I interferon (IFN-I)-induced immunity plays a key role in dendritic cells. IFN-I regulatory biomarkers (IRF7, SIGLEC1) and IFN-I-inducible biomarkers (IFI27, IFI44, IFIT1, IFIT3, ISG15, MX1, OAS2, OAS3) are identified and validated in vitro and in vivo. Furthermore, we apply this TDDC approach to various types of vaccines, providing novel insights into their early immune response signatures and their heterogeneity in vaccine recipients. Our findings suggest that a standardizable TDDC model is a promising predictive approach to assessing early immunity in DCs. Further research into vaccine efficacy assessment approaches on various types of immune cells could lead to a systemic regimen for vaccine development in the future.

Detection of Glucose Based on Noble Metal Nanozymes: Mechanism, Activity Regulation, and Enantioselective Recognition.

Glucose monitoring is essential to evaluate the degree of glucose metabolism disorders. The enzymatic determination has been the most widely used method in glucose detection because of its high efficiency, accuracy, and sensitivity. Noble metal nanomaterials (NMs, i.e., Au, Ag, Pt, and Pd), inheriting their excellent electronic, optical, and enzyme-like properties, are classified as noble metal nanozymes (NMNZs). As the NMNZs are often involved in two series of reactions, the oxidation of glucose and the chromogenic reaction of peroxide, here the chemical mechanism by employing NMNZs with glucose oxidase (GOx) and peroxidase (POD) mimicking activities is briefly summarized first. Subsequently, the regulation strategies of the GOx-like, POD-like and tandem enzyme-like activities of NMNZs are presented in detail, including the materials, size, morphology, composition, and the reaction condition of the representative NMs. In addition, in order to further mimic the enantioselectivity of enzyme, the design of NMNZs with enantioselective recognition of d-glucose and l-glucose by using different chiral compounds (DNA, amino acids, and cyclodextrins) and molecular imprinting is further described in this review. Finally, the feasible solutions to the existing challenges and a vision for future development possibilities are discussed.

Transforms of Cell Surface Glycoproteins Charge Influences Tumor Cell Metastasis via Atypically Inhibiting Epithelial-Mesenchymal Transition Including Matrix Metalloproteinases and Cell Junctions.

Cell communication and signal transduction rely heavily on the charge on the cell surface. The cell surface is negatively charged, with glycoproteins on the cell membrane providing a large percentage of the charge. Sialic acid is found on the outermost side of glycan chains and contributes to glycoprotein's negative charge. Sialic acid is highly expressed in tumor cells and plays an important role in tumor metastasis and immune escape by interacting with extracellular ligands. However, the specific effect of negative charge changes on glycoproteins is still poorly understood. In this study, we used 9-azido sialic acid (9Az-Sia) to create artificial epitopes on glycoproteins via metabolic glycan labeling, and we attached charged groups such as amino and carboxyl to 9Az-Sia via a click reaction with dibenzocyclooctyne (DBCO). The charge of glycoproteins was changed by metabolic glycan labeling and click modification. The results showed that the migration and invasion ability of the MDA-MB-231 cell labeled with 9Az-Sia was significantly reduced after the modification with amino groups rather than carboxyl groups. Epithelial-mesenchymal transition (EMT) is the biological process of metastatic tumor cells, with an increasing ability of tumor cells to migrate and invade. In particular, the expression of adhesion molecules increased in the amine-linked group, whereas the expression of matrix metalloproteinases (MMPs) increased significantly, which is not identical to EMT characteristics. In vivo experiments have demonstrated that the loss of negative charge on glycoproteins has an inhibitory effect on tumors. In conclusion, modifying the positive charge on the surface of glycoproteins can inhibit tumor cell metastasis and has great potential for tumor therapy.

The metabolic score for insulin resistance as a predictor of clinical outcome in stroke patients treated by intravenous thrombolysis.

BACKGROUND AND PURPOSE: Insulin resistance is associated with clinical outcomes among patients with ischemic stroke. We aimed to investigate the association between metabolic score for insulin resistance (METS-IR) and clinical outcomes in stroke patients treated by intravenous thrombolysis (IVT). METHODS: We recruited participants treated with IVT from a prospective registry including 3 stroke centers. Poor outcome was defined as a modified Rankin scale score ≥ 3 points at 90 days after the index stroke. We performed logistic regression models to investigate the association between METS-IR and the risk of poor outcome. We used the receiver operative characteristic to assess the discriminative ability and the restricted cubic spline to explore the relationship between METS-IR and the poor outcome. RESULTS: This study enrolled a total of 1074 patients (median age, 68; 63.8% male). Three hundred sixty (33.5%) patients had poor outcome after IVT. METS-IR was associated with the risk of the poor outcome with the increase of confounding factors in models (odds ratio [OR], 1.078; 95% confidence interval [CI], 1.058-1.099; P < 0.001). The area under the curve for METS-IR for predicting the poor outcome was 0.790 (95% CI, 0.761-0.819). The restricted cubic spline revealed an increasing and non-linear association between METS-IR and the poor outcome (P for non-linearity < 0.001). CONCLUSION: Our study found that METS-IR was associated with an increased risk of poor outcome after IVT. Further studies are warranted to investigate the efficacy of anti-diabetic agents regarding IR on clinical outcomes after IVT.

Does local government competition affect the dependence on polluting industries? Evidence from China's land market.

Many countries have formulated strict environmental regulation policies, but unfortunately, environmental pollution is still severe. We believe that this phenomenon may result from institutional factors. We study whether local government competition affects the dependence on polluting industries and test it with the transaction data of China's land market. We find that the decline in the economic ranking of cities increases the scale of land transferred to polluting industries, and the more the ranking decline, the larger the scale of land in polluting industries. Besides, we analyze the impact of the first decline in the urban economic ranking, finding that the land transfer scale of polluting industries exhibits a trend of slowing down after a rapid rise in the short term. Heterogeneity analysis shows that officials with lower education levels and before-retirement age will dependent more on polluting industries to a greater extent when they face local government competition, and cities with economic growth lower than the national average will increase their dependence on polluting industries to a greater extent. This paper provides new insights into the causes of the environmental governance dilemma, which also highlights the need to weaken economic indicators and strengthen environmental indicators in government performance assessment.

Nanoparticle Ligand Exchange and Its Effects at the Nanoparticle-Cell Membrane Interface.

The nanoparticle (nano)-cell membrane interface is one of the most important interactions determining the fate of nanoparticles (NPs), which can stimulate a series of biological events, allowing theranostic and other biomedical applications. So far, there remains a lack of knowledge about the mechanisms governing the nanoparticle-cell membrane interface, especially the impact of ligand exchange, in which molecules on the nanosurface become replaced with components of the cell membrane, resulting in unique interfacial phenomena. Herein, we describe a family of gold nanoparticles (AuNPs) of the same core size (∼13 nm core), modified with 12 different kinds of surface ligands, and the effects of their exchangeable ligands on both nanoparticle-supported lipid bilayers (SLBs) and nanoparticle-natural cell membrane interfaces. The ligands are categorized according to their molecular weight, charge, and bonding modes (physisorption or chemisorption). Importantly, we found that, depending on the adsorption affinity and size of ligand molecules, physisorbed ligands on the surface of NPs can be exchanged with lipid molecules. At a ligand exchange-dominated interface, the AuNPs typically aggregated into an ordered monolayer in the lipid bilayers, subsequently affecting cell membrane integrity, NP uptake efficiency, and the NP endocytosis pathways. These findings advance our understanding of the underlying mechanisms of the biological effects of nanoparticles from a new point of view and will aid in the design of novel, safe, and effective nanomaterials for biomedicine.

Probing Adsorption Behaviors of BSA onto Chiral Surfaces of Nanoparticles.

Chiral properties of nanoscale materials are of importance as they dominate interactions with proteins in physiological environments; however, they have rarely been investigated. In this study, a systematic investigation is conducted for the adsorption behaviors of bovine serum albumin (BSA) onto the chiral surfaces of gold nanoparticles (AuNPs), involving multiple techniques and molecular dynamic (MD) simulation. The adsorption of BSA onto both L- and D-chiral surfaces of AuNPs shows discernible differences involving thermodynamics, adsorption orientation, exposed charges, and affinity. As a powerful supplement, MD simulation provides a molecular-level understanding of protein adsorption onto nanochiral surfaces. Salt bridge interaction is proposed as a major driving force at protein-nanochiral interface interaction. The spatial distribution features of functional groups (COO- , NH3+ , and CH3 ) of chiral molecules on the nanosurface play a key role in the formation and location of salt bridges, which determine the BSA adsorption orientation and binding strength to chiral surfaces. Sequentially, BSA corona coated on nanochiral surfaces affects their uptake by cells. The results enhance the understanding of protein corona, which are important for biological effects of nanochirality in living organisms.

Thermal Unfolding Process of Lysozyme on PEGylated Gold Nanoparticles Reveals Length-Dependent Effects of PEG Layer.

Characterization of bio-nano interface is crucial for developing safer and more efficient nanoparticles in nanomedical application. PEGylation is commonly used in nanocarrier for drug delivery, as it confers nanoparticles good stability, stealth effect and better targeting specificity compared with those without PEGylation. However, the protein binding state on PEGylated AuNP is still limited known. In present work, we prepared 13 nm AuNPs and then PEGylated them with thiol PEG methoxy. Lysozyme is selected as a model protein and to investigate the interactions on protein-PEGylated/AuNP interface. The thermal unfolding processes of lysozyme in absence and presence of PEGylated AuNP were measured by synchrotron radiation based circular dichroism (SRCD), dynamic light scattering (DLS) and infrared spectroscopy (IR). The results suggest that in terms of secondary structural changes, α helix content is decreased, while ß sheet content is increased, and thus the adsorbed lysozyme may be present in PEG layer.

Transferrin Adsorbed on PEGylated Gold Nanoparticles and Its Relevance to Targeting Specificity.

Polyethylene glycol (PEG) has been frequently used for surface modification of nanoparticles (NPs) to reduce non-specific binding of proteins on NPs. The investigation of protein absorption on PEGylated nanoparticles is necessary. In the work, the conjugation of transferrin (Tf) to PEGylated AuNPs via adsorption or bonding was studied. The 13 nm AuNPs were coated with various molecular weight (300, 2000, 5000) carboxyl and methoxy PEG thiol. The presence of Tf on PEGylated AuNP was characterized by dynamic light scattering (DLS) and infrared spectroscopy (IR). The data of IR confirmed the presence of Tf on PEGylated AuNPs. The diameter decrease of PEGylated AuNPs after Tf adsorption was observed by DLS measurement, which is attributed to competitive adsorption between Tf and PEG molecules. These phenomena may be important to the preservation of Tf targeting specificity on PEGylated AuNPs.

Comprehensive Interventional treatment for severe central airway collapse caused by Relapsing Polychondritis: A case report.

Relapsing Polychondritis (RP) is a rare systemic inflammatory disease. One major cause of death for patients with RP is severe tracheobronchial tree collapse. Treatment guidelines for RP are mainly based on case reports. We report a rare and challenging case of RP in a patient who experienced asphyxia due to severe central airway collapse. The patient had previously been misdiagnosed with refractory asthma due to recurrent wheezing. Following interventions including bronchoscopic laser tracheobronchoplasty, stent placement, corticosteroid therapy, and both invasive and non-invasive mechanical ventilation, the patient was successfully stabilized and subsequently discharged from the hospital. Notably, after discharge, the patient did not require rehospitalisation for worsening respiratory symptoms and was managed with only a gradually tapering glucocorticoid regimen. In our case report, stent placement rapidly relieved asphyxia due to severe tracheobronchial stenosis, and laser tracheobronchoplasty may be a potential cure for diffuse airway collapse due to RP.